Technology situation

Technical situation

Summary

In this page we review the proximate technology situation. 

Technology has been a key driver of consumer interest in health care since the 1940s.  Significant current developments are reviewed.
Health Information Technology policy is discussed. 

Introduction

Heath care markets are deeply affected by technology developments and constraints.  Since the 1940s deployment of penicillin Americans have been convinced that their health issues have technological solutions.  The health care VDS has formed around this view, supporting and leveraging it. 


Expected technological advances, some discussed by NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   director Francis Collins, suggest major transformations & powerful justification of health care:







Technology contents
  • AI & Robotics
  • Application development
  • Biotechnology research
  • Circuits
  • Epidemiology studies patterns, causes and effects of health and disease in populations.  It identifies risk factors for disease and focuses on preventative health care.  Being observational it suffers from a core limitation.  It can only show association, not causation.  It can suggest hypothesis but it can not disprove them.  
  • Epigenetics
  • Financial services
  • Obitiary of emergent force in venture capital (Jun 2016)
  • Distributed ledgers: bitcoin is a set of open-source software, used to provide infrastructure that supports a distributed cryptocurrency and payment system, based on the blockchain.   All transaction inputs are unspent outputs from previous transactions.  All transaction inputs are signed.  Change is provided in an additional output to the transaction. 
    's blockchain is a bitcoin distributed database technology that allows several bitcoin operators to keep a shared, cryptographically verified, ledger and consensus mechanism to allow agreement on what transactions have happened and in what order.  It implements a Merkle tree.  Six times an hour on average, a new group of validated transactions, a block, is created, added to the local block chain and published to all nodes.  Paraphrasing breadwallet's Aaron Voisine, publishing is robust because: Each operator has connected via references from its initial peers to a random subset of all the other operators; and the new block is offered to the connected peers who can both ask for it if they have not seen it previously from some other source and pass it on to their other peers in a cascade (a gossip network).  To build new blocks an operator must have all the prior blocks in the chain.  All unspent bitcoins are represented [only] in the blockchain.  Miners keep the blockchain consistent by verifying that a new block has a proof-of-work.  This requires that miners find a nonce that multiplied by the block hash is smaller than the network's difficulty target. 
    (Oct 2016)
  • Genomics
  • Microbiology
  • Modeling
  • Neuroscience
  • Payments
  • Process engines
    • Business process management
  • Proteomics
  • Quality
  • Robotics
  • Scientific method
  • Screening
  • Search
  • Servers


  • Neuroscience reveals how we develop and operate.  It is highlighting changes in health care practice that can optimize treatments.



    Neuroscience

  • Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    as a behavioral disorder (Jul 2016)
  • Boston University SOM's Matthew Pase finds sugary drinks tied to rapid brain aging and Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    markers (Apr 2017)
  • Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    (May 2014May 2016)
  • Obama brain initiative (Sep 2015)
  • Brain maps (Connectome based Jul 2016)
  • Syngenta's Paraquat is NN-dimethyl-44-bipyridinium dichloride, a systemic weed killer, used on oranges, coffee and suger cane, manufactured and sold by the Swiss pesticide company Syngenta.  It is banned in the EU, but still allowed to be sold and used in the US.  Drinking even a sip can be lethal.  Recent research by the NIH links paraquat to Parkinson's disease.  The 2011 research found Iowa and North Carolina farmers and family members that handled paraquat or rotenone were 2.5 times more likely to develop Parkinson's disease.  A 2012 study found paraquat increased the likelihood 11 fold for people with certain genetic variations.  The link is disputed by Syngenta. 
    linked by N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   to Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop. 
    E.P.A. is the Environmental Protection Agency of the Federal government. 
    considers restrictions in US is the United States of America.   (Dec 2016)
  • Temporal Interference is a technique for targeting electrical stimulation at neurons within a brain by superposing two very high frequency electronic fields which only interfere constructively at the target neuron and at a low enough frequency to have an effect on the neuron. 
    technique developed by MIT is Massachusetts Institute of Technology.   Picower Institute of Learning's Tsai shows promise in mice (Jun 2017)
  • Brigham & Women's finds mothers' sounds needed for babies' brains to grow (Feb 2015)
  • McGurk effect is an illusion, described by Harry McGurk and John MacDonald, where a video shows a person speaking, and saying 'da da da da'.  But on closing your eyes you hear what is being said as 'ba ba ba'.   The illusion is generated by setting up conflicting signals: The mouth is moving to say 'ga'; while the sound is 'ba'.  the brain resolves the conflict into a single intermediate percept 'da'.  The illusion demonstrates how late in the processing chain and reconstructed our conscious experience is.  Imaging indicates the illusion is constructud in the frontal lobes and or superior temporal sulcus and is then sent back to the early sensory regions. 
    (Feb 2017)
  • Memories in the brain includes functionally different types: Declarative (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb noted that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening.  This strengthening is sustained by subsequent LTP.  The non-realtime learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   actively destroyed in fruit flies using Rac is a class of small monomeric GTP-binding proteins including Rac1 and Rac2.  Rac GTPases are implicated in memory removal (Feb 2010) and control of cytoskeleton assembly. 
    (Feb 2010
  • Purpose of sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis. 
    is to forget.  The mechanism includes removing synapses, a neuron structure which provides a junction with other neurons.  It generates signal molecules, either excitatory or inhibitory, which are kept in vesicles until the synapse is stimulated when the signal molecules are released across the synaptic cleft from the neuron.  The provisioning of synapses is under genetic control and is part of long term memory formation as identified by Eric Kandel.  Modulation signals (from slow receptors) initiate the synaptic strengthening which occurs in memory. 
    Wisconsin-Madison's de Vivo supports synaptic homeostasis is Tonini & Cirelli's hypothesis that proposes sleep-wake cycles cause generalized synaptic weakening which leads to down-selection of weak synapses.  Pruning does not strike every synapse.  They argue that well established memories are left intact. 
    Johns Hopkins's Diering shows Homer1A is the product of the Homer1 gene short form splice.  The HomeriA has an EVH1 domain which competes with the long splice forms such as Homer1B and Homer1C, uncoupling mGluR signalling and shrinking dendritic spline structures.  Homer1a is expressed by neuronal activity.   is shipped to synapses where in sleep it pairs back synapses (Feb 2017). 
  • Northeastern & Mass. General hospital psychologist Feldman Barrett's fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG. 
    studies found superagers' is a older person who remains as mentally agile: in terms of memory and attention; as a twenty year old according to neurologist Marsel Mesulam.  In fMRI analyses superagers are found to retain well developed 'emotional' brain regions: midcingulate cortex, anterior insula; which are major hubs for general communication throughout the brain.  In comparison in other older people these regions have thined and their mental responses are relatively poor.  The superagers maintain the communication networks by regularly performing hard tiring and taxing mental or physical work (Jan 2016). 
    hard mental work sustains their major neural communication networks (Jan 2017)
  • Cohen & Andersen's review common reference frames is a coordinate system (set of axis) centered on a particular aspect of the situation that describes the location of an object.  The brain supports many frames of reference including for vision (2009), hearing & movement planning (Jul 2002).  Auditory stimuli are initially coded in a head-centered reference frame.  The motor system codes actions in reference frames that depend on motor effectors.  Eye movements are codes in a reference frame that depends on the difference between current and desired arm position.  It is often necessary to transform the location representation of the sensory stimulus into a representation appropriate for the motor act.  An eye-centered reference frame depends on the location of the eye in the head.  A retinotopic reference frame depends on the retinal location that is activated by a visual stimulus.  Double-saccade tasks show how the location of the second visual target is coded relative to current and desired eye position (eye-centered).  
    for movement plans in the posterior parietal cortex of the cerebral cortex is at the back of the brain divided into two.  It associates sensory signals of various modalities with:
    • Details about the location of the body and
    • Models interpreting touch, visual signals, language and mathematics. 
    (Jul 2002)






  • Jul 2016 NYT A new Harbinger of Alzheimers

    Pam Belluck reports personality differs in at least five key ways:
    • Extroversion-introversion - whether the person gains energy from socializing or retiring
    • Neuroticism-stability - does a person worry or are they calm and self-satisfied
    • Agreeableness-antagonism - is a person courteous & trusting or rude and suspicious
    • Conscientiousness-un-directedness - is a person careful or careless
    • Openness-non-openness - are they daring or conforming
    changes could indicate the earliest stage of dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease and prion infections such as Alzheimer's disease, CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It appears to develop faster in women than men.  

    Alzheimer is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    's experts want to recognize and measure sharp changes in mood and behavior that can precede the memory and thinking problems of dementia.  They are proposing a new diagnosis: MBI is mild behavioral impairment, a proposed early diagnosis for dementia.  It recognizes and measures something that some experts say is often overlooked: Sharp changes in mood and behavior can precede the memory and thinking problems of dementia.  But there is a risk of over diagnosis which could leave many people unnecessarily fearful about their futures and seeking more tests.  And the diagnosis could affect insurance premiums.  To imply MBI the symptoms must last for more than six months and be a fundamental change in behavior.  
    which would precede MCI is mild cognitive impairment, a sense of memory loss despite normal performance on memory tests.  It is often associated with Alzheimer's disease. 


    University of Calgary neuropsychiatrist Dr. Zahinoor Ismail notes that studies and anecdotes suggest emotional are low level agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this emotions clash with group goals and are disparaged by the powerful.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Disgust, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism.   and behavioral changes are symptomatic of dementia, not seperate from it.  People with MCI that also have mood and behavior changes develop full-blown dementia faster and do much worse over time.  Autopsies show they had more brain damage. 




    Sep 2015 NYT Putting Her Mind to How the Brain Works

    Claudia Dreifus reports that Dr. Cori Bargmann's mission to help lead a president's initiative starts with a search for the needed tools. 
    Dr. Bargmann was an M.I.T. graduate student when she discovered a gene HER2 is a gene encoding the protein 'human epidermal growth factor receptor 2', which is similar in structure to the native receptor HER1. 
    in rats that mutated to generate a cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  .  Later other researchers noted that the same gene is altered in humans for a breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    .  Bargmann's work in the rat cancer showed the immune system could attack the product of the gene.  Genentech then developed Herceptin, grow rapidly because they respond via the human EGF receptor (HER), coded for by the gene 'Her2', to cell growth signal epidermal growth factor (EGF).  Herceptin inhibits the growth of the Her-2+ tumors by inhibiting the EGFR.   to deploy the immune system against the cell surface receptor product of Bargmann's gene. 

    She then moved on to working on the nervous system using the simple system C. elegans because its genes had been completely sequenced and it was transparent.  It's brain has 7,000 connections and 300 neurons.  So Bargmann could observe and "know what any cell does.  I know what it's connected to.  I know what genes it expresses."  For a researcher she noted that's a lot. 

    Bargmann notes that her work provides details about human brains because the genes are not very different.  In 1993 Bargmann showed that C. Eligans could smell.  She then moved the gene that is the sensor for an attractant and moved it to a different neuron that senses things the worm finds dangerous. Now the worm ran away from the attractant.  Bargmann said "This said that the odor-sensing nerve cells form an innate map where each one knows whether something is good or bad about the environment.  There's a completely unlearned internal set of preferences, a set of instincts about what's good and bad. 

    Bargmann explained the problem facing the 'brain innitiative'.  We have $100 million for the first year.  They had to prioritize some aspects of brain research that the $100 million would really make a difference.  The team agreed on a basic outline: Use the money for mapping brain activity in circuits and networks. 

    Bargmann says to do this they will do two steps:
    1. Create new and improved technologies to study the brain.  With better tools, all the neuroscience will move forward. 
    2. Apply these technologies to make discoveries about how the brain functions. 
    The theme is understanding brain activity, the flows of information through millions of interconnected nerve cells. 

    The long term goal is to use that knowledge to help prevent and treat brain disorders.  That may be a decade or two away. 





    Jun 2017 NYT New Electrical Brain Stimulation Technique Shows Promise in Mice

    Pam Belluck reports pulses of electricity delivered to the brain can help patients with Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop. 
    , depression is a debilitating state which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels; and an accumulation of traumatic events.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  There is an association between depression and particular brain regions: Hippocampal dendrite and spine number reductions, Dorsal raphe nucleus linked to loneliness, Abnormalities of the ACC.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Treatments include: CBT, UMHS depression management.  As of 2010 drug treatments take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult;, obsessive-compulsive disorder and possibly other conditions.  But the available methods all have shortcomings: They either involve the risks of surgery, from implanting electrodes deep within the brain, or they stimulate from the skull's surface, limiting the ability to target electricity to the right brain areas. 

    Research by the MIT is Massachusetts Institute of Technology.   Pickower institute of learning & memory's Li-Huei Tsui reported in Cell experiments demonstrating temporal interference is a technique for targeting electrical stimulation at neurons within a brain by superposing two very high frequency electronic fields which only interfere constructively at the target neuron and at a low enough frequency to have an effect on the neuron. 
    of target neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    in mice. 

    Some researchers question if the technique can deliver 130 hertz frequencies.  Others wonder if the technique would be able to support treatment for Parkinson's disease where the stimulation would have to be continuous.  It is also questioned if the targeting can be precise and localized enough to be useful. 



    Jul 2016 NYT In Brain Map, Mind's Gears Get Rare Look

    Carl Zimmer reports the brain looks like a featureless expanse of folds and bulges, but it's actually carved up into invisible territories.  Each is specialized: Some groups of neurons become active when we recognize faces, others when we read, others when we raise our hands. 

    Neuroscience researchers at Washington University School of Medicine lead by Dr. Matthew Glasser, associated with the HumanConnectome published a new larger Brodmann type map of brain regions.  It includes: 97 unknown/forgotten regions, 84 familiar Brodmann's areas in additional detail. 

    A computer used the connectome data to recognize discrete regions of the cortex based on myelination is the fatty insulating material deployed by Schwann cells & oligodendrocytes, both types of glial cells, around axons to improve their conduction rate.  In humans it is still occurring 25 years after birth.  It has great impact on long axons, in neurons that project over long distances, where it helps brain inter-region signalling.  The long development time of myelination allows for the later myelinated brain regions to be particularly shaped by the proximate environment. 
    , activity, etc.  The software can map any new brain in about one hour. 

    New area 55b is now viewed as working in tandem with Broca's area is the inferior frontal cortex.  It is involved with spoken language.  Lesions have resulted in an inability to speak or write even though language is understood.   on language processing. 




    Feb 2017 NYT When Mismatched Voices and Lips Make Your Brain Play Tricks

    Joanna Klein reports the good news is, the human brain is flexible and efficient.  This helps us make sense of the world.  But the bad news is, the human brain is flexible and efficient.  This means the brain can sometimes make mistakes. 

    Klein notes that the McGurk effect is an illusion, described by Harry McGurk and John MacDonald, where a video shows a person speaking, and saying 'da da da da'.  But on closing your eyes you hear what is being said as 'ba ba ba'.   The illusion is generated by setting up conflicting signals: The mouth is moving to say 'ga'; while the sound is 'ba'.  the brain resolves the conflict into a single intermediate percept 'da'.  The illusion demonstrates how late in the processing chain and reconstructed our conscious experience is.  Imaging indicates the illusion is constructud in the frontal lobes and or superior temporal sulcus and is then sent back to the early sensory regions. 
    has become more visible day-to-day with the bad sound synchronization delivered with streaming video. 

    Research by Baylor College neuroscientist's John Magnotti, Michael Beuchamp and Lin Zhu published in PLOS computational biology, reports the brain:





    Feb 2010 NYT Forgetting, With a Purpose

    Science times notes just why the brain erases certain memories in the brain includes functionally different types: Declarative (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb noted that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening.  This strengthening is sustained by subsequent LTP.  The non-realtime learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   has long been a topic of interest to scientists. 

    In US is the United States of America.   and China Dr. Yi Zhong of Cold Spring Harbor Laboratory and Tsinghua University reported in Cell, that fruit flies short-term memory is erased by the brain on purpose, so that new, more relevant memories can be recorded.  Rac is a class of small monomeric GTP-binding proteins including Rac1 and Rac2.  Rac GTPases are implicated in memory removal (Feb 2010) and control of cytoskeleton assembly. 
    participates in the erosion of the memories. 

    The researchers varied Rac levels in fruit flies while subjecting the flies to two situations:
    1. Foul smelling odor
    2. A different Foul smelling odor associated with an electric shock.  Under normal Rac levels the flies usually pick situation 1. 
    Researchers then switched which odor was associated with the shock.  The flies soon learned to pick situation 2, unless Rac was blocked when the flies would zigzag back and forth.  The researchers conclude Rac is required for the earlier short-term memory to be erased so it does not interfere with the later memory. 



    Jan 2017 NYT How to Become a 'Superager'

    In professor Lisa Feldman Barrett's NYT opinion she writes -- think about the people in your life who are 65 and over:  Some of them are experiencing the usual mental difficutlies of old age, like forgetfulness or a dwindling attention span.  Yet others somehow manager to remain mentally sharp.  [Barrett notes] her father-in-law, a retired doctor, is 83 and he still edits books and  runs several medical websites. 

    Feldman Barrett compared 17 superagers is a older person who remains as mentally agile: in terms of memory and attention; as a twenty year old according to neurologist Marsel Mesulam.  In fMRI analyses superagers are found to retain well developed 'emotional' brain regions: midcingulate cortex, anterior insula; which are major hubs for general communication throughout the brain.  In comparison in other older people these regions have thined and their mental responses are relatively poor.  The superagers maintain the communication networks by regularly performing hard tiring and taxing mental or physical work (Jan 2016). 
    with other similarly aged regular people using fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG. 
    brain scans.  They found that superagers were using hard work to remain sharp.  They observed the hard work was exercising the major brain communication hubs with vigorous exercise and strenuous mental effort.  They found the work had to be hard enough to make you feel bad. 

    Feldman Barrett makes the point that the major communication hubs are participating in many aspects of executive control, highlighting the failure of Dr. Paul MacLean's 1940s triune brain is Dr. Paul MacLean's popular but discredited 1940s theory of the brain.  He proposed a three layer structure:
    1. Reptilian inner brain containing circuits for basic survival; which is interfaced to layer 2 through the hypothalamus and together with the brain stem, spine and projections into the body make up the autonomic nervous system. 
    2. Limbic middle brain containing emotional circuits which signal layer 1 through the hypothalamus. 
    3. Rational outer brain which is uniquely human.  
    model, which predicts their separation.  Feldman Barrett argues "The human brain didn't evolve like a piece of sedimentary rock, with layers of increasing cognitive sophistication slowly accruing over time.  Rather (in the words of the neuroscientist Georg Striedter), brains evolve like companies do: they reorganize as they expand." 


    Spring 2017 Kent State Magazine Attention, Please

    Adam Piore reports MIT is Massachusetts Institute of Technology.   neuroscientist Earl Miller, Kent State BA 1985, continues to break new ground in the understanding of cognition is the ability to orchestrate thought and action in accordance with internal goals according to Princeton's Jonathan Cohen. 
    -- and his research may help us move beyond the limits of the brain's working memory is a dominant function of the dorsolateral prefrontal cortex and the areas it connects with.  Prefrontal neurons implement an active memory continuing to fire after the signal is gone for potentially dozens of seconds from the inferior temporal cortex (multi-sensory integration area) and lower level sensory neurons characterized by Hubel & Weisel, while the short-term memory task continues.  If the prefrontal cortex gets distracted the memory is lost from consciousness.  Earl Miller argues the prefrontal cortex implements the rules that decide which working memory neurons will fire (Spring 2017). 


    Piore explains that in 1990 Miller worked at the NIMH is the National Institute of Mental Health. 
    for Bob Desimone looking for neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    in the inferior temporal cortex of the cerebral cortex is involved in associating sensory input with comprehending language (TEO), storing new memories, visual memory, emotion and deriving meaning.  The temporal lobe is located bellow the parietal lobe, and between the frontal lobe and occipital lobe. 
    that only fired when an animal spotted an item it was storing in short-term memory.  Aiming to progress the work of Hubel & Wiesel recorded neuronal activity in the primary visual area of the cat in the 1960s.  They noted that these neurons signalled in response to simple bars of light.  This ground breaking insight induced researchers to explore the temporal cortex and eventually led to Tanaka's identification of neuronal alphabets.   into this sensory integration area Miller was interested to understand:
    • What happens in the inferior temporal cortex after a unified picture emerges?
    • How do our brains tell us what it means?
    During experiments using repetition, Desimone & Miller noticed certain parts of the brain were focused on repetition, regardless of what the current cognitive goal was.  They detected two firing patterns:
    1. Neurons firing when animals saw a second matching object
    2. When an animal spotted a picture it was actively holding in working memory different neurons fired and much more intensely. 
    Miller wondered what was applying the switch to change the volume.  Scientists were already implicating the prefrontal cortex (PFC) is
    • The front part of the frontal lobe of the cerebral cortex.  It evolved most recently.  During adolescence when the PFC is still deploying, older brain agents provide equivalent strategies: ventral striatum.  The PFC has been implicated in planning, working memory: dorsolateral; decision making: Orbitofrontal cortex; and social behavior.  Different PFC circuits track internal reward driven strategies and externally signalled advice.  The PFC chooses between conflicting options, letting go or restraint, especially between cognition and emotions.  It imposes an overarching strategy for managing working memory.  It is essential for thinking about multiple items with different labels.  It includes neurons that are interested in particular sub-categories: Dog, Cat.  Once it has made a decision it signals the rest of the frontal lobe just behind it.  Glucocorticoids decrease excitability of the PFC.  
    in high-level executive functions of cognition is the ability to orchestrate thought and action in accordance with internal goals according to Princeton's Jonathan Cohen. 
    including working memory so Miller focused his research there.  He wanted to explain how the executive functions could turn up the volume when a matching high level object was detected. 
    He asked his animals to wait for a second cue before deciding there was a match.  He hypothesized he would detect activity in multiple neurons in the prefrontal cortex every time he changed the rule about what matched.  These neurons, he asserted turned up or down the volume of the neurons he had studied previously.  As predicted a rule change caused twice as many neurons in the prefrontal cortex to fire.  Miller concluded the prefrontal cortex role was not short-term memory but to learn the rules of the situation.  It was controlling which lower level neurons should be actively firing and which should be taken offline. 

    This model suggests that neurons are multi-functional, rather than only performing the specialized functions demonstrated by Hubel & Weisel recorded neuronal activity in the primary visual area of the cat in the 1960s.  They noted that these neurons signalled in response to simple bars of light.  This ground breaking insight induced researchers to explore the temporal cortex and eventually led to Tanaka's identification of neuronal alphabets.  , and explains:

    Miller subsequently characterized the significance of neural oscillations are repetitive firing of sets of neurons.  They are seen throughout the central nervous system. 
    (brain waves).  Miller argues that when an item is held in working memory, neural oscillations allow the prefrontal cortex to act as the switch operator holding several items on the cusp of awareness.  He argues the oscillations aren't enough to make the neurons spike.  But the brain waves bind together all the neurons in a circuit with every crest, pushing the neurons so close to their firing point that they're primed to respond to just the slightest extra stimulus.  This might help answer a question that has long intrigued scientists: How can the human brain store a virtually unlimited number of long-term memories, yet remain severely limited in the information we can hold in our conscious minds at once?  There is a limit to how many oscillations can be supported per second so working memory ends up with a finite capacity nominally "7 +/- 2". 

    Miller hypothesizes that it should be possible to tailor the neural oscillations raising the capacity of working memory. 


    Memory and sleep


    Feb 2017 NYT The purpose of sleep? To Forget, Scientists Say

    Carl Zimmer reports Over the years, scientists have come up with a lot of ideas about why we sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis. 


    Two papers published in Science support University of Wisconsin-Maddison scientists Tononi and Cirelli's synaptic homeostasis is Tonini & Cirelli's hypothesis that proposes sleep-wake cycles cause generalized synaptic weakening which leads to down-selection of weak synapses.  Pruning does not strike every synapse.  They argue that well established memories are left intact. 
    hypothesis:
    Other researchers remain to be convinced.  Some question if this is the main function of sleep.  And some argue it has not been shown if it is sleep or the biological clock that generates the pruning. 






    Jun 2017 NYT You Look Familiar.  Now Scientists Know Why.

    Nicholas Wade reports the brain has an amazing capacity for recognizing faces.  It can identify a face in a few thousandths of a second, from a first impression of its owner and retain the memory in the brain includes functionally different types: Declarative (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb noted that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening.  This strengthening is sustained by subsequent LTP.  The non-realtime learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   for decades. 

    Caltech's Le Chang & Doris Tsao reported in Cell they had deciphered how primate brains recognize specific faces. 

    They used fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG. 
    augmented with electrode monitoring of active face cell are neurons which respond when the features of a face are presented to the retina.  Faces are recognized by dedicated neural networks consisting of face cells grouped into 6 patches of 10,000 cells on each side of the brain in the cortex just behind the ear.  The face cells respond abstractly to the dimensions and features of faces.  Each face cell responds to a combination of facial dimensions, creating a holistic representation.  A single face cell represents a vector of about 6 dimensions.  Two hundred cells can together represent the 50 dimensions which are required to identify a face in a face space where an infinite number of faces can be represented.  Cal tech's Chang & Tsao argue there is an average face at the origin of the face space and each actual face is represented as differences from it in the face space (Jun 2017). 
    neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    of macaque monkey brains, to detect neural activity as they presented the monkeys with a series of pictures of 2,000 human faces with subtly altered feature sets. 

    This allowed Le Chang and Tsao to identify which aspects of the faces triggered the cells and how the features of the faces were encoded. 

    They found:

    Jul 2017 NYT Study of How We Look at Faces May Offer Insight Into Autism

    Pam Belluck reports how we look at other people's faces is strongly influenced by our genes, scientists have found in new research that may be especially important for understanding autism is a major hereditary mental disorder that starts before age three.  Autistics do not attribute minds to other people.  They almost never pretend.  They can't explain the difference between an instance of an object and a memory of it.  Autism occurs in every country and social class.  It lasts a lifetime.  It has genetic and neurological causes.  The genes: SHANK3, CDH10; are involved but account for a very small percentage of the risk.  Facial gaze studies indicate a high genetic influence and an opportunity to identify more genes associated with autism (Jul 2017).  ASD is associated with a reduced fusiform face area response.  Tests [in development] for autism include: SynapDx's blood test. 
    because it suggests that people are born with neurological differences that affect how they develop socially. 

    A study by: Emory School of Medicine's pediatrician is a doctor who specializes in the treatment of infants, children and adolescents.  They are represented by the American Academy of Pediatrics. 
    Dr. Warren Jones, Washington School of Medicine's child psychiatrist Dr. John Constantino, & Children's Healthcare of Atlanta's psychologist Dr. Ami Klin; reported in Nature provides data on how children look at faces:
    The study tracked eye movements of 338 toddlers, 18 to 24 months, who were watching videos of motherly women and children playing at a day care.  There were:
    • 250 toddlers who were developing normally including 41 pairs of identical twins, 42 pairs of non-identical twins and 84 unrelated children. 
    • 88 children with autism. 
    The results showed:
    • Identical twins matched how much the other twin looked at the eyes [or mouths] of people on screen 91%.  The identical twins actually had matching movements of their eyes in terms of time and direction.  
    • Fraternal twins the match dropped to 35%
    • Unrelated children randomly paired had no matching.  
    • Children with autism spent significantly less time looking at faces and more time looking at objects.  Children with autism could be identified from their eye tracking data. 


    Dr. Jones noted: "When we started to get the results back, I thought that I had the wrong data because the match between identical twins was so strong.  I thought I might have mistakenly matched data from the same twin." 

    Researchers see an opportunity to use eye are major sensors in primates, based on opsins deployed in the retina & especially fovea, signalling the visual system: Superior colliculi, Thalamus (LGN), Primary visual cortex; and indirectly the amygdala.  They also signal [social] emotional state to other people.  And they have implicit censorious power with pictures of eyes encouraging people within their view to act more honorably.  Eyes are poor scanners and use a saccade to present detail slowly to the fovea.  The eye's optical structures and retina are supported by RPE.  Eyes do not connect to the brain through the brain stem and so still operate in locked-in syndrome.  Evo-devo shows eyes have deep homology.  High pressure within the eye can result in glaucoma.  Genetic inheritance can result in retinoblastoma.  Age is associated with AMD. 
    movements to identify genes for autism.  Dr. Jones explained: "How much Twin 1 looked at the eyes in a video that Twin 2 didn't get to see predicted how much Twin 2 would look at the eyes in a different video."  He asserts that indicates a genetically driven behavior of "seeking out" social information found in the eyes rather than "merely responding to" facial features.  He hopes to pinpoint "what is disrupted in children with autism as they develop and learn about the world." 







    Jul 2002 Nature Neuroscience Review Yale Cohen & Richard Andersen describe a common movement planning reference frame


    Dartmouth College's Cohen & Cal Tech's Andersen explain orchestrating a movement towards a sensory target requires many computational processes, including a transformation between reference frames is a coordinate system (set of axis) centered on a particular aspect of the situation that describes the location of an object.  The brain supports many frames of reference including for vision (2009), hearing & movement planning (Jul 2002).  Auditory stimuli are initially coded in a head-centered reference frame.  The motor system codes actions in reference frames that depend on motor effectors.  Eye movements are codes in a reference frame that depends on the difference between current and desired arm position.  It is often necessary to transform the location representation of the sensory stimulus into a representation appropriate for the motor act.  An eye-centered reference frame depends on the location of the eye in the head.  A retinotopic reference frame depends on the retinal location that is activated by a visual stimulus.  Double-saccade tasks show how the location of the second visual target is coded relative to current and desired eye position (eye-centered).  
    .  This transformation is important because the reference frames in which sensory stimuli are encoded often differ from those of motor effectors.  The posterior parietal cortex of the cerebral cortex is at the back of the brain divided into two.  It associates sensory signals of various modalities with:
    • Details about the location of the body and
    • Models interpreting touch, visual signals, language and mathematics. 
    (PPC) has an important role in these transformations.  Recent work indicates that a significant proportion of parietal neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    in two cortical areas transforms the sensory signals that are used to guide movements into a common reference frame.  This common reference frame is an eye are major sensors in primates, based on opsins deployed in the retina & especially fovea, signalling the visual system: Superior colliculi, Thalamus (LGN), Primary visual cortex; and indirectly the amygdala.  They also signal [social] emotional state to other people.  And they have implicit censorious power with pictures of eyes encouraging people within their view to act more honorably.  Eyes are poor scanners and use a saccade to present detail slowly to the fovea.  The eye's optical structures and retina are supported by RPE.  Eyes do not connect to the brain through the brain stem and so still operate in locked-in syndrome.  Evo-devo shows eyes have deep homology.  High pressure within the eye can result in glaucoma.  Genetic inheritance can result in retinoblastoma.  Age is associated with AMD. 
    -centered representation that is modulated by eye-, head-, body-, or limb-position signals.  A common reference frame might facilitate communications between different areas that are involved in cooridinating the movements of different effectors.  It might also be an efficient way to represent the locations of different sensor targets in the world. 

    Cohen & Anderson argue goal directed behavior dynamically links sensory stimuli to motor acts.  Several intermediate processes must occur:
    • Change the locus of attention
    • Response selection
    • Coordinate transformations
    • Decision to act on sensory stimuli
    Cohen & Anderson note the neural correlates of these strategies occur in the PPC is posterior parietal cortex.  Its neurons receive visual, auditory and somatosensory inputs and are involved in:
    • Planning
    • Cognitive intermediaries (encoded as firing rates): Attention, Salience, Decision variables; of sensorimotor transformations.   PPC areas LIP and PRR are involved in transforming target locations into a common reference frame. 
    .  They review the coordinate transformations that occur during this movement planning. 

    Movement planning is a focus of the PPC.  Functional subdivisions of PPC cells: AIP is anterior intraparietal area of the intraparietal sulcus.  It is involved in grasp planning. 
    , LIP is either the
    • Medicaid supplemental 'low-income pool' hospital funding program which reimburses hospitals for the cost of care for the uninsured.  LIP is being wound down as the ACA Medicaid expansion occurs.  Or it is the
    • Lateral intraparietal area is involved in saccades of the eyes.  Some neurons in the LIP code the location of visual and auditary targets in an eye-centered reference frame.  Others code the location of a sound in reference frame intermediate between head-centered and eye-centered.  For many cells the magnitude of response is 'gain' modulated by eye, head, body or initial hand position. 
    , PRR is the parietal reach region of the intraparietal sulcus.  It is specialized for reaching.  It includes the MIP and dorsal aspect of the PO.  PRR neurons code visual targets in an eye-centered reference frame.  Some PRR neurons code auditory-target locations in eye-centered reference frames.  Others may code auditory-targets in a head-centered reference frame.  A third set encode auditory-target locations in an intermediate frame between eye- and head-centered.  For many cells the magnitude of response is 'gain' modulated by eye, head, body or initial hand position. 
    ; code for specific types of movement plan.  LIP and PPR both include neurons which use an eye-centered reference frame for auditory, visual, sensory and motor aspects suggesting eye-centered is being used as a common reference frame. 

    They conclude the PPC, and other cortical areas, in primates and humans, can 'read out' a stimulus-target location in different reference frames by using gain fields alters the responsiveness of neurons based on factors including: eye, head, body or initial hand position.  Gain modulation provides a mechanism for coordinate transformations.  While certain neurons code their auditory targets in a head-centered reference frame, their level of responsiveness is modulated by eye position.  The neuron responded robustly when the eye position was to the left but when the eye position was to the right the neuron hardly responded.  The neuron was not affected by changes in hand position.  
    as a selector in conjuction with common eye-centered representations of target locations.  Cohen & Anderson note that this architecture and representation provides great flexibility with simultaneous readout of many reference frames.  And they suggest evidence, neural network simulation including hidden layer analysis & midbrain and cortical auditory centers projecting directly to the PPC, implicates the PPC as the site of many coordinate transformations, such as:
    • Head-centered representations of auditory targets to eye-centered representations. 
    • Modelled body-centered representations of auditory targets had hidden layer neurons with gain effects for both eye and head position. 






    Feb 2015 NYT Mothers' Sounds required for Babies' Brains to Grow

    Douglas Quenqua writes that the sound of a mother's voice plays a critical role in a baby's early development is a phase during the operation of a CAS agent.  It allows for schematic strategies to be iteratively blended with environmental signals to solve the logistical issues of migrating newly built and transformed sub-agents.  That is needed to achieve the adult configuration of the agent and optimize it for the proximate environment.  Smiley includes examples of the developmental phase agents required in an emergent CAS.  In situations where parents invest in the growth and memetic learning of their offspring the schematic grab bag can support optimizations to develop models, structures and actions to construct an adept adult.  In humans, adolescence leverages neural plasticity, elder sibling advice and adult coaching to help prepare the deploying neuronal network and body to successfully compete. 
    .  Researchers recently demonstrated that the brain itself may rely on a mother's voice and heartbeat to grow. 

    Researchers at Brigham and Women's Hospital showed that premature babies without these signals had significantly less developed auditory cortex is part of the temporal lobe that processes auditory information.  It is present in both brain hemispheres.  Auditory sensations only reach consciousness once signalled by the auditory cortex.  Final sound processing is performed by the parietal and frontal lobes in humans. 


    The findings published in the Proceedings of the National Academy of Sciences can help guide doctors and parents caring for premature babies who often suffer from developmental and cognitive disabilities. 


    Aug 2015 NYT For Evolving Brains, a Diet of Carbs

    Carl Zimmer argues that the diet of our Pleistocene ancestors went through two big shifts:
    1. Addition of meat
    2. Addition of cooking released carbohydrates.  Campfires have been dated back to 1.8 million years ago. 
    Some evolutionary geneticists, such as Mark Thomas of University College London, argue that the addition of cooked carbohydrates provided the additional energy supply to enable the enlargement of our brains.  Today our brain consumes as much as a quarter of the calorie intake.  

    The assertion is based on the following logic: 
    • Our bodies convert starch into glucose using amylase.  But the reaction works better on pre-cooked starches.  That was a significant benefit to a hungry hunter gatherer. 
    • Chimpanzees have two copies of the amylase gene.  Humans have as many as 18 copies. 
      • Studies of pre-agricultural hunters from Europe reveal that people had extra copies long before they started farming.  
      • The survival value of the extra gene copies allowed them to spread through the population. 
    • Brain size increases started about 800,000 years ago. 

    Aug 2015 NYT Turn the Page, Spur the Brain

    Dr. Perri Klass reports that the year old AAP policy that all pediatric primary care should include literacy promotion starting at birth is of major significance. 
    Klass developed the policy based on extensive research associating growing up with books and reading aloud with language development is a phase during the operation of a CAS agent.  It allows for schematic strategies to be iteratively blended with environmental signals to solve the logistical issues of migrating newly built and transformed sub-agents.  That is needed to achieve the adult configuration of the agent and optimize it for the proximate environment.  Smiley includes examples of the developmental phase agents required in an emergent CAS.  In situations where parents invest in the growth and memetic learning of their offspring the schematic grab bag can support optimizations to develop models, structures and actions to construct an adept adult.  In humans, adolescence leverages neural plasticity, elder sibling advice and adult coaching to help prepare the deploying neuronal network and body to successfully compete. 
    and school success. 

    pediatricians is a doctor who specializes in the treatment of infants, children and adolescents.  They are represented by the American Academy of Pediatrics. 
    in charge of infants and toddlers should stress the importance of reading to even the youngest children. 

    The mechanisms behind the benefits of early reading are complex.  fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG. 
    studies of children listening to age appropriate stories found differences in brain activation dependent on if children had been read to at home.  More books and reading corresponded to greater activity in the parietal-temporal-occipital association cortex is a multi-sensory integration area of the sensory signals from parietal, temporal and occipital lobes.  .  It is active in older children when they read to themselves and in younger children when they hear stories.  When children who have been read to hear stories they imagine what is being discussed in their mind's eye

    Researchers are questioning if videos and cartoons remove this 'mind's eye are major sensors in primates, based on opsins deployed in the retina & especially fovea, signalling the visual system: Superior colliculi, Thalamus (LGN), Primary visual cortex; and indirectly the amygdala.  They also signal [social] emotional state to other people.  And they have implicit censorious power with pictures of eyes encouraging people within their view to act more honorably.  Eyes are poor scanners and use a saccade to present detail slowly to the fovea.  The eye's optical structures and retina are supported by RPE.  Eyes do not connect to the brain through the brain stem and so still operate in locked-in syndrome.  Evo-devo shows eyes have deep homology.  High pressure within the eye can result in glaucoma.  Genetic inheritance can result in retinoblastoma.  Age is associated with AMD. 
    ' activity.  Already researchers have determined that children need to hear language spoken by people.  Screens do not work. 

    There are vast disparities between the amounts of language that different children hear.  And reading to and with young children appears to amplify the language they hear more than just talking. 
    One property of books is they include more vocabulary than parents typically use in talking with their children. 


    Oct 2015 NYT Anorexia May Be Habit, Not Resolve, Study Finds

    Erica Goode reports a new study in Nature Neuroscience, by Professor B. Timothy Walsh of Columbia and Dr. Joanna Steinglass at New York State Psychiatric Institute at Columbia University Medical Center, suggests anorexia nervosa is an eating disorder.  As of 2015, 50 percent of hospitalized anorexic patients who are discharged at a normal rate relapse within a year.  It has the highest mortality of any mental illness.  It involves brain circuits involved in habitual behavior.  The initial weightloss acts as a reward with compliments relieving anxiety and increasing self-esteem.  Diet gets paired with weight loss (the reward) in the ventral striatum and eventually dieting becomes the reward as the dorsal striatum gets involved in the patient's decision making making it a habit. 
    is a well-entrenched habit.  People with anorexia nervosa can't stop dieting. 

    The researchers used fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG. 
    to look at brain activity in 21 women with anorexia and 21 healthy women while they made decisions about what to eat. 
    The anorexic women were more likely to choose low-fat, low calorie foods, and didn't find high-fat, high-calorie foods as tasty as the controls. 

    All the subjects activated the ventral striatum is a region within the basal ganglia.   It is a target of the tegmentostriatal dopamine pathway.  It has been captured by brain imaging assigning values to subliminal symbols experimentally associated with winning (highly valued) and losing (low valuation) money.  During adolescence, prior to the deployment of the prefrontal cortex, the ventral striatum helps balance/control emotional decision making. 
    .  But the anorexic women showed more activity in the dorsal striatum is a region within the basal ganglia.   It has been associated with habitual behavior.  .  This suggests they were acting habitually based on past learning. 

    One treatment strategy that would be consistent with this study's conclusions would be to get the patient to look at entrees as well as at the salad bar, or to switch to eating with the left hand, to signal this is a new situation. 


    May 2016 NYT Opinion Never Diet Again - The problem isn't willpower.  It's neuroscience.  And you can't fight back. 

    In an opinion Sandra Aamodt writes six years after dropping an average of 129 pounds on the TV program "The Biggest Loser," a new study reports, the participants were burning about 500 fewer calories a day than other people their age and size.  This helps explain why they had regained 70 percent of their lost weight since the show's finale.  The diet industry reacted defensively, arguing that the participants had lost weight too fast or ate the wrong kinds of food -- that diets do work, if you pick the right one. 

    Aamodt argues this research just adds to a collection showing dieting is rarely effective. 
    Aamodt states neuroscience provides the constraint that undermines diet. The brain has a set of tools that aim to maintain its set point is a weight range that the brain of humans, and rats which have a similar diet, are evolved to maintain.  It varies by person, depending on genes and environmental signals.  The brain has various mechanisms to maintain the set point including: Metabolic suppression.  It is possible dieting may raise the set point May 2016. 
    :
    So Aamodt explains, when a person's weight drops below the set point they burn fewer calories, produce hunger inducing hormones are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
    , and find eating more rewarding and their weight rises.  So Aamodt notes a 2002 report that, only 1% of 231 million Europeans dieters achieved permanent weight loss. 

    Why does dieting lead to weight gain?  Aamodt suggests:


    May 2016 NYT Zika's Secret Assault

    Pam Belluck reports a graduate student's offhand remark led to a remarkable finding about how the virus has caused lasting brain damage in so many babies. 

    Researchers developing an organoid is a tiny ball of brain cells grown from stem cells and mimicking early brain development.  The stem cells have differentiated into most types of brain cells.  A 100-day-old organoid resembles a late second trimester foetus. 
    , have used it with Zika is a Flaviviridae family virus.  It came from the Zika Forest of Uganda isolated in 1947.  It is related to dengue, yellow fever, Japanese encephalitis and West Nile.  Zika is transmitted sexually or via a daytime mosquito vector such as the Aedes genus.  It has resulted in a pandemic in South America.  Zika fever has been associated with a number of troubling complications:
    • Guillain-Barre syndrome
    • Microcephaly.  The mechanism may have been identified (May 2016)
    to identify how the brain damage (Mar 2016) is caused. 

    They reported in Cell that Zika attacks and kills neural progenitor cells, much more than neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    or stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms;.  This resulted in fewer neurons leading to less brain volume.  It appears that Zika infection will be dangerous in both the first and second trimester of pregnancy.  Zika uses the neural progenitor cells as its reproductive factory.  It takes about three days to destroy them and it does not damage all of them.  Zika increases activity of the apoptotic, programmed cell death is a signal initiated DNA controlled process which results in eukaryotic cells self-destructing.   signalling enzyme caspase are mediators of apoptosis. 
    -3.  The researchers hope caspase inhibitors may reduce the effects of Zika.  One drug, of a set of 173 prevented the effects of Zika and is now in clinical trials with cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   patients. 

    The model suggests the mechanism of association of Zika with Guillain-Barre syndrome (GBS) is a condition where peripheral neurons are attacked by the immune system.  Zika virus attacks the Glial cells protecting neurons and can be associated with GBS symptoms.  
    .  Zika attacks Glial cells support neurons: Creating the initial structural tracks along which the neurons travel, Insulating them by deploying the myelin sheath - an activity which is influenced by sleep, Storing energy for them and removing debris from damage to neurons.  Robert Sapolsky notes Glial cells outnumber neurons ten to one.  They include various subtypes.  They greatly influence how neurons speak to one another, and also form glial networks that communicate completely differently from neurons. 
    damaging the neural sheath of long living neurons. 





    Genomics highlights evolved changes and chemical mechanisms.  Discovery of historic samples is necessary: Cholera;




    Study of Genome Deltas

    One of the ten emerging technologies from Technology Review 2004. 


    Researchers include:

    Perlegen

    http://www.eurekalert.org/pub_releases/2003-03/nc-psp022703.php
    Perlegen scientists find genetic basis for difference between humans and non-human primates
    Genomic rearrangements discovered using DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    microarrays is a 2D array on a solid substrate that assays large amounts of biological material using high-throughput screening.  It is the central technology of Bio-MEMS, LOC and MTAS.  They are used with tissues, cells, antibodies, DNA, RNA, protein, peptides and carbohydrates.  Once fed magnetic nanoparticles individual cells can be moved independently and simultaneously on a microarray of magnetic cells.  A microarray of NMR microcells is being developed.   are expected to reveal genetic regions important to human health
    Mountain View, CA ¾ March 3, 2003 ¾ Perlegen Sciences, Inc. today announced the publication of a scientific paper in the latest issue of the peer-reviewed journal Genome Research. The paper, “Genomic DNA insertions and deletions occur frequently between humans and nonhuman primates,” describes novel findings suggesting that genomic rearrangements, not single base pair changes in DNA, provide the genetic basis for the differences between humans and non-human primates such as the chimpanzee.
    “This is a very surprising and important discovery of the fundamental basis of structural genomic differences between humans and other primates,” said David Cox, M.D., Ph.D, Perlegen’s Chief Scientific Officer. “It provides a valuable starting point from which to improve our understanding of what makes human beings unique.”

    Analysis of the differences in sequence between human and chimpanzee DNA has previously established that the two species are approximately 98.5% identical. For this reason, it is widely accepted that qualitative and quantitative differences in gene expression are responsible for the major biological differences among humans, chimpanzees and other non-human primates. To date it has been commonly thought that single base pair changes in these genomes, not larger DNA rearrangements, would underlie the majority of these postulated genomic regulatory differences.

    “Comparative genome analysis of human and non-human primates is a useful technique for deciphering the function of specific genomic regions,” commented Kelly Frazer, Ph.D., Senior Director of Genomic Biology at Perlegen and the lead author on the paper. “This study illustrates the power and versatility of Perlegen’s high-density array technology in the detection of DNA rearrangements.”

    Comparison of human chromosome 21 with chimpanzee, orangutan, rhesus macaque, and woolly monkey DNA sequences identified a significant number of random genomic rearrangements between human and nonhuman primate DNA. This evidence shows, contrary to popular belief, that genomic rearrangements have occurred frequently during primate genome evolution and are a significant source of variation between humans and chimpanzees as well as other primates. These DNA rearrangements are commonly found in segments containing genes, suggesting possible functional consequences and therefore provide natural starting points for focused investigations of variations in gene expression between humans and other primates, including variations which may provide important clues in researching human health and disease.

    Perlegen conducts genetics research and develops products that impact and improve people’s lives through a proprietary, cost-effective method for rapidly analyzing and comparing entire genomes. This whole genome association study capability enables Perlegen to identify genes that work in concert to cause common diseases and affect the body’s response to drugs. Perlegen has ongoing research collaborations with partners including Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline, Pfizer and Unilever.

    Jan 2014 NYT Aiming to push genomics forward in new study

    Having noted that gene sequencing's first wave of businesses have largely failed to generate a bonanza of new drugs NYT looks at the new approach being taken by Regeneron Pharmaceuticals. 

    Regeneron is partnering with Geisinger to sequence 100,000 of Geisinger's 3 million patients, seeking genetic variants lined to different diseases that may provide clues to developing new drugs.  Dr Leslie Biesecker of NHGRI is the NIH's national human genome research institute which aims to advance human health through genomics research. 
    argues that the study is significant.  "It's the largest clinical sequencing undertaking in this country.  The move of sequencing into general health care is going to change medicine.  " 

    George Yancopoulis, the chief scientific officer of Regeneron, said the plummeting cost of DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    seqencing and Regeneron's capabilities point towards successful biotech leverage of genomics. 

    Geisinger already has collected 45,000 DNA samples from its population base.  The population's attributes are described in its EHR refers to electronic health records which are a synonym of EMR.  EHRs have strengths and weaknesses:
    • The EHR provides an integrated record of the health systems notes on a patient including: Diagnosis and Treatment plans and protocols followed, Prescribed drugs with doses, Adverse drug reactions;
    • The EHR does not necessarily reflect the patient's situation accurately. 
    • The EHR often acts as a catch-all.  There is often little time for a doctor, newly attending the patient, to review and validate the historic details. 
    • The meaningful use requirements of HITECH and Medicare/Medicaid specify compliance of an EHR system or EHR module for specific environments such as an ambulatory or hospital in-patent setting. 
    • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  
    .  It makes the data provided to Regeneron anonymous.  However, Geisinger will know the identities matched in the samples which it hope to use for clinical care.  David Ledbetter CSO of Geisinger commented "If the sequencing finds that a patient has a mutation indicating a high risk of getting breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    , the person can be informed and steps can be taken to prevent the disease.  Certain mutations could also provide information helpful to choosing the best drug treatment for the patient". 

    Sequencing 100,000 genomes will probably cost $100 million over five years.  Regeneron is covering Geisinger's costs.  Geisinger will share in the proceeds of any drugs developed. 

    Regeneron said they might also collaborate with other academic centers and health systems. 

    Amgen paid $415 million in 2013 to acquire deCODE Genetics which had decoded the genomic sequences of 300,000 people in Iceland. 

    The previous generation of gene-hunting studies sampled the DNA of people at particular spots on the genome.  While this found many common genetic variations they did not correlate with a significant effect. 

    The new projects by sequencing the complete exomes is the 1 ot 2 percent of the genome which codes for the proteins. 
    or genomes of large populations are able to look for rarer variations that might have a bigger influence on disease risk. 


    May 2016 NYT Private Talks Are Conducted About a Synthetic Genome

    Andrew Pollack reports scientists are now contemplating the fabrication of a human genome, meaning they would use chemicals to manufacture the entire DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    contained in human chromosomes.  They meet with George Church at Harvard.  The organizers included: Jef Boeke, Andrew Hessel.  A paper has been submitted to a journal. 

    The project called "HGP is the human genome project an international research project to determine the sequence of DNA base pairs of humans and identify and map physically and functionally all the genes in the human genome.  The HapMap project proved very helpful for discovering the SNPs. 
    2: The Human Genome Synthesis Project" is still being thought through.  The organizers argue there could be a big benefit.  They explain that the goal is to improve the synthesis of DNA encoded cells, not just human DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    or to create whole people. 

    Synthesizing a gene or an entire genome would allow for many changes to be applied to the DNA.  Already chemical production networks developed to deploy in yeast require adding of multiple genes to the yeast DNA. 

    Currently DNA synthesis is difficult and error-prone.  Strands can be built reliably of length 200 base pairs.  And it still costs three cents to add a base pair so 8 million bases would cost $90 million. 


    Dr. J. Craig Venter has synthesized a full bacterial genome and deployed it successfully into a cell.  However, the initial synthesis was a near copy of an actual bacterium's DNA sequence.  Subsequently in 2016 he has developed a synthetic genome. 




    Dr. Boeke is leading an international consortium that is synthesizing the genome of yeast (12 million base pairs).  The scientists are deleting nonfunctional stretches of the DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    !


    The human genome is 200 times larger than that of yeast so the process may not be feasible. 

    Implicit in the development is the possibility, through cloning, of producing human beings without parents.  This and other ethical issues such as making copies of particular people -- Einstein, or developing chromosomes selected to develop good soldiers worry ethicists.


    DNA2.0's Jeremy Minshull, commented "Our ability to understand what to build is so far behind what we can build, I just don't think that being able to make more and more and more and cheaper and cheaper and cheaper is going to get us the understanding we need." 





    Big Data



    Nov 2016 NYT Simons Foundation Looks to Enhance Computation Tools for Science

    Kenneth Chang reports a new private research institute financed by the billionaire James H. Simons in New York will develop software tools and apply cutting edge computing techniques to science often not possible in academia and industry. 


    Simons Foundation hopes the Flatiron Institute will fill an overlooked niche.  Simons concluded most programs developed for science research are written by graduate students.  Hence they suffer from:
    • Poor development techniques
    • Lack of maintenance
    • University departments not being able to hire professional programmers
    Flatiron Institute is the first in-house research program by the Simons Foundation. 




    Flatiron will deploy professional computer programmers, to produce software for the in-house scientists and anyone else that needs it. 

    Simon said the impetus for the institute developed from a brainstorming workshop about "what we might do to help move the needle in science."  A Belgian physicist and mathematician, Ingred Daubechies, suggested an effort to develop better computational tools.  Daubechies said there is a real need for analyzing big data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
    • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    • Analytics tools (BI) for PHM will be hard to develop.  
      • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
      • A key aspect is providing clear signals about the nature of the data using data visualization. 
    • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 


    Flatiron Institutes first area of focus will be computational biology based on input from New York University's Dr. Leslie Greengard who outlined possibilities. 



    Jan 2017 NYT Data Could Be the Next Tech Hot Button

    Steve Lohr reports wealth and influence in the technology business have always been about gaining the upper hand in software or the machines that software ran on. 
    Now data -- gathered in those immense pools of information that are at the heart of everything from artificial intelligence to online shopping recommendations -- is increasingly a focus of technology competition.  And academics and some policy makers, especially in Europe, are considering whether big internet companies like Google and Facebook might use their data resources as a barrier to new entrants and innovation. 

    Lohr notes:
    Lohr argues the increasing importance of data is indicated by:
    • Artificial intelligence in mainstream business software makes certain data sets very valuable. 
    • Microsoft paid 26.2 billion for LinkedIn because of:
      • 467 million users
      • Profiles and maps of connections of its users;  It is betting LinkedIn can be combined with Office 365 online data and Bing search data to obtain insights of unprecidented power.  CEO Nadella argues it allows the company to
        • "Reinvent productivity and business processes."  
        • Define "how people find jobs, build skills, sell, market and get work done." 
    • IBM has bet heavily on private data for its future:
      • $2.6 billion acquisition of Truven Health (Feb 2016) for its data on the cost and treatment of more than 200 million patients.  
      • $2 billion acquisition of the digital assets of the Weather Company; which it aims to integrate with customer data and use the composite to train Watson to persue tasks:
        • Helping medical researchers discover novel disease therapies
        • Flagging suspect financial transactions for independent auditors.   
    • Google has leveraged its search data and investments in image identification, speech recognition and language translation.  It:
      • Has software for supporting job finding and recruiting.  It is based on data with:
        • More than 17 million online job postings and public profiles and
        • Resumes of 200 million people.  
        • Machine-learning algorithms to collapse that detail to 4 million unique ranked job titles with skills. 
        • Career builder, Dice and Fedex are working with the alpha software. 
    • Baidu's chief scientist Andrew Ng notes "Data is the defensible barrier, not algorithms." 




    Email

    Oct 2016 NYT The age of Email is Nearing an End

    Farhad Manjoo reports every four years, pundits race to anoint this or that newfangled tech trend as the next disruptive force to forever alter the mechanics of American democracy.  The 2016 campaign has already been called the Snapchat election, the Periscope election, the Meerkat election, the Twitter election, the Facebook election and the meme election.  (If there were a vomit emoji, I'd insert one here.  And then we'd have the emoji election.) 

    Manjoo aims to make a couple of points about Email:
    1. There is a lot of discussion of Hillary Clinton's private Email server. 
    2. Email as a discussion infrastructure fails
    Manjoo concludes Email is not up to the rigors of business and politics being open to hacking but is:
    • Tempting
    • Inescapable
    • Asynchronous
    • Easily forged
    • Time consuming
      • People feel efficient but often participate in pointless rumination. 
    • Centralizes distributed group activities like planning
      • Conveys news
      • Set out tactics and strategy
      • Broadcasts:
        • Models for framing discussions
        • Legal/Expert advice and warnings
        • Summaries of meetings and proposed plans
      • Theorize
      • Push back
      • Gossip
      • Used in place of phone calls and face-to-face meetings
      • Used as an instant messenger
      • Daily calendar
      • Collaborative whiteboard
    • Email threads get long, and often do not result in resolution.  Real-time phone meetings are then used to clarify the meaning of the discussions, and to gain coherence and agree on the plan.  
    • Flexible - which can be potentially confusing and chaotic
      • Formal letters
      • Joke
    Manjoo argues that being hacked results in sensitive information being discussed over the phone or face-to-face!

    He suggested using Slack or HipChat so that central archiving could remove hacking access to the sensitive information.  Or Signal which encrypts messages. 





    Moore's law


    Oct 2016 NYT Looking Beyond Silicon to Squeeze More Out of Chips

    John Markoff reports Ali Farhadi holds a puny $5 computer, called a Raspberry Pi, comfortably in his palm and exults that his team of researchers has managed to squeeze into it a powerful program that can recognize thousands of objects. 

    Dr. Farhadi, a computer scientist at the Allen Institute for Artificial Intelligence,  calls the artificial neural network are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.   technique 'artificial intelligence at your fingertips'.  He considers it contributes to:
    • AI cost - it uses a 32 of the memory and runs 58 times faster than rival approaches. 
    • Privacy - since the data is not distributed through a network. 
    Markoff argues that alternative computing approaches are being urgently researched to help cope with the impact of the likely failure of Moore's law, Gordon Moore characterized the two yearly doubling of the number of transistors in each new generation of integrated circuit. 
    .  Two years ago the cost of individual transistors stopped falling.  As a consequence of such issues exascale computing keeps being delayed. 

    One area of focus is reducing energy requirements.  Exascale computers would increase energy demand 1000 fold.  One technique to cope is to reduce precision, when it is not needed.  On Intel processors that allows half the silicon to be shut down until the precision is required again. 

    Markoff sees more leverage of human creativity.  He describes an example from Stanford electrical engineer Alan Huang, who showed how with high school math, Internet links could be reconfigured from a two dimensional mesh to a doughnut structure which reduces Internet delays by a half. 




    Nano Sensors

    Tech review Oct 04 Molly Stevens Imperial College London: Material Scientists are aiming to use nanomaterials to create implantable sensing and drug delivery devices.  Such devices would quickly detect physiological changes in the body, such as a rise in cholesterol and respond by releasing the appropriate dose of a stored drug.  Molly Stevens has shown that gold nanoparticles change behavior with pH.  She attached the particles to specially designed peptides that under the right ph conditions interact with each other to pull the particles together into an organized structure.

    Rebekah Drezek Rice University Tech Review Oct 04: Developing photonic technologies that use targeted nanomaterials to detect, monitor, and treat breast is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    , and gynecological cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.  lessly, and at a fraction of the cost of conventional approaches. 


    May 2016 Stanford radiology professor Zhen Cheng describes ONPs in cancer theranostics

    Professor Cheng has been leveraging ONP is organic nano-particle.  These have a high level of clinical application.  s in cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   theranostics is a combination of diagnostics and therapy that are seen as key in personalized medicine.  Theranostic nanoparticles can be designed to have multiple capabilities: both imaging and carrier; to support diagnosis, drug delivery and monitoring of therapeutic response.  .  Precision medicine leverages the genome, proteome, metabolome, algorithms to build colorful materials as therapeutic diagnostics (Jin Xie et al).  Examples include:

    May 2016 San Jose State University scientist Dr. Folarin Erogbogbo outlines nano-medicine in the 21st century

    Dr. Erogbogbo describes the evolution of nano scale sensors.  They are assumed to be of major significance because they produce structures, devices and systems with at least one novel or superior characteristic or property. 

    Initially quantum dots made of cadmium were developed but they were assumed to be highly toxic.  Other early particles were very inefficient.  While they could be coated with other materials there was a shift to other materials are being developed with a less toxic core. 

    Health care can gain from nanoparticle innovations to transform cardiovascular disease refers to:
    • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    , diabetes is the leading cause of blindness, limb amputations and kidney failure.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
    • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    • Diet
    • Exercise
    , tuberculosis, consumption or otherwise TB, is mostly an airborn bacterial lung infection, but it can also infect the brain, kidneys and other parts of the body.  The only vaccine is still the BCG.  The deployment of antibiotics during the 1940s allowed effective treatment: Streptomycin.  Diagnostic tools for TB are insufficient.  And because TB grows slowly in walled off pockets in the lungs it takes many months of treatment for antibiotics to eradicate the infection.  TB benefits from compromised hosts and has benefited from HIV/AIDS.  TB is also leveraging the plasmids that now carry immunity to all current antibiotics.  In 2016 it is estimated to latently infect two billion people.  9.6 million worldwide became infected in 2014.  1.5 million people will die from TB in 2016.  Deaths from the disease have fallen drastically since 2000.  TB has been halted or reversed in 16 of the 22 countries: India (Sep 2016, Infection base estimate increased Oct 2016), Vietnam, Indonesia; that have the majority of cases.  But it is still the infectious disease causing the most deaths world-wide.  Nano scale drug delivery has the potential to push back on TB and is being actively researched (May 2016).   and cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  

    Examples of the innovative use include:


    May 2016 Cal Berkeley electrical engineering and computer science professor Michel M. Maharbiz, and Neural dust. 

    Professor Maharbiz's approach to research is to build things that interest him.  He is currently developing gadgets that interface living with non-living.  Both central and peripheral nervous system device interconnects are of interest and he sees more immediate opportunity to provide medical benefit from peripheral interface solutions. 

    Current approaches to interfacing with peripheral nerves and muscles depend on wires, creating problems with long term use.  For such recordings it would be more desirable to implant very small devices near nerves, fiber bundles or even single fibers that could report back neural activity through a tether-less communication link. 

    Maharbiz is using neural dust to deliver the solution.  These are small motes deployed in a wireless scalable platform that can power and communicate with implanted bioelectronics:
    It is hoped to eventually perform deep brain stimulation to develop treatments for Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop. 
    but the situation presents tricky challenges.  There are peripheral nerve situations where 10 sensors are all that is needed.  Still placing devices into bags of salt water and attacking cellular agents that will work effectively for 20 years is problematic. 

    Maharbiz developed a mathematical model of neural dust:  including the fundamental tradeoffs, ultimate size, power and bandwidth scaling limits of neural recording systems built from low power CMOS circuitry coupled with ultrasonic power delivery and backscatter communications.  The approach uses
    1. Thousands of 10-100 micro scale free-floating independent sensor nodes (dust) to detect and report local extracellular electrophysiological data. 
    2. Sub-cranial interrogator that establishes power and communication links with the dust. 
    Maharbiz explains that ultrasound penetrates water well (little loss and good performance.  The ultrasound interacts simply (KISS) with each piezoelectric crystal (the dust) to power up a front end when the dust is in the electric field of actively firing neurons. 

    Maharbiz experiments with the dust system showed:
    • Motion artifacts can be disambiguated
    • Platform falls within FDA Food and Drug Administration. 
      constraints
    • When put in muscle can get sigmoidal reports
    • Beam steering is in development.  Deploy as a back pack.  Recalibrates to the dust as the mouse/rat moves around ensuring consistent signal tracking from specific dust generator. 

    The fundamental limits of the approach are:
    • The approach does not place an electrode inside a neuron.  So single neuron recording is not possible.  
    • The electrodes in the dust must be kept apart limiting how small the dust can be -- not Nano scale. 

    May 2016 SJSU Phys Chem prof Abraham Wolcott and FND

    Assistant professor Wolcott describes his investigations of potential tools for active sensing of action potentials of neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    .  He notes that President Obama's brain initiative's first exploration was to track activity in the brain.  Eventually this should support the NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   researching key brain diseases: stroke is when brain cells are deprived of oxygen and begin to die.  There are two structural types: Ischemic and hemorrhagic. 
    , polio is a paralysis caused in a small percentage of cases of infection with poliovirus.  It is transmitted by the fecal-oral route and less commonly from droplets from a sneeze or cough.  Epidemics of paralysis may be related to lack of immunity due to reduced infection rates in babies. 
    , Japanese encephalitis, MS is multiple sclerosis. 
    etc..

    For Wolcott this indicates the importance of research on nano-sensors. 

    High-pressure high-temperature (HPHT) nanodiamonds with nitrogen vacency centers (NVC is nitrogen-vacancy center.  These are negatively charged and support fluorescence in FND.  ) are unique fluorophores (FND is fluorescent nano-diamond.  These are nano-scale particles with long-lived electron spin properties and indefinite photo-stability.  With negatively charged NV centers they are superior imaging probes.  They can detect both magnetic and electric fields.  They are non-cytotoxic.  ). 

    Wolcott notes that FND has been used in biolableling but there have been open questions concerning their surface, bulk and electronic properties that constrained use as an active biosensor. 

    Wolcott describes his work based on the observation of the similarity between FND and bulk diamond: 
    Wolcott concluded the NVC makes the FND the most sensitive magnetic sensor.  Green light stimulates the NVC's two ground states.  Room temperature NMR can be performed.  Wolcott predicts there will be cellular NMR with optical microscopes within 5 to 10 years. 

    Wolcott found that HPHT acts like a bulk single crystal with an alcohol rich surface.  Diamonds have lots of facets but you can only put small molecules in the cavities. 
    Wolcott found NEXAFS is near edge x-ray absorption fine structure spectroscopy. 
    was surface sensitive allowing 289 exciton is an electrically neutral quasiparticle formed by the bound state of an electron and an electron hole through electrostatic Coulomb force. 

    Wolcott found FTIR is Fourier transform infrared spectroscopy. 
    indicated no acid. 
    Wolcott found FND was chemically like bulk diamond.  It looked like a ketone, not an acid. 

    Wolcott argues the research provides progress toward the use of FND sensors as a tool for neuroscience and neuronal connectomics. 







    Applied AI

    Sep 2014 NYT Can a Computer Replace Your Doctor
    Elisabeth Rosenthal visited 'Health by the numbers' a health innovation conference in San Francisco.  She noted 'professor, entrepeneur and tech visionary' Dr Vivek Wadhwa of UCSF's comments "I would trust an A.I. over a doctor any day."  He justified this explaining with artificial intelligence provided "perfect knowledge."  A third of the conference attendees agreed. 

    There were new innovative devices on display at the conference:
    • One device attached to the iphone to create an ontoscope to check children for ear infections. 
    • Another allows the iphone to check blood alcohol. 
    • There were home cholesterol kits
    • A wearable device to track the quality of breathing. 
    Dr Rosenthal wondered will the data promote and ensure better health?  So far there seems to be great promise and disappointment with the outcomes.  Even if the devices did provide useful data it is not clear how easy it would be to get health care providers to act on it. 

    There has been a proliferation of fitness trackers.  However, last month Aetna announced the discontinuation of CarePass

    Rosenthal notes that even health is a hard notion to quantify.  And the ability to collect data has often outpaced the understanding.  Sometime the data indicates good health while the patient dies.  Other times the opposite.  Continuous monitoring can result in overtreating is the application of unnecessary health care.  It is a complex problem:
    • Overtreatment needs to be adaptive.  As people age their medicine levels typically need to be changed.  Often, as in the case of blood pressure, and blood sugar reduction, they should be reduced to avoid inducing falls (Nov 2015).  
    • Patients with chronic diseases, such as type 2 diabetes, often require different treatment settings.  And again these vary with age. 
    • Patients who have learned a regime, and been told it was successful, may resist instructions to change it.  Some worry that they will impact their health care provider's treatment performance measures. 
    .  But in other situations it is proving very useful.  Diabetics includes type 1 and type 2.   can be woken if their blood sugar drifts too low while they are sleeping. 

    Some new technologies are allowing collection and diagnosis uses a tiny blood sample used for diagnostic testing.  Often the testing is based on using DNA sequencing to detect DNA in the blood from cancer cells.  By identifying the mutations in a patient's tumor accurate treatments can be selected, and recurrence can be detected.  But aging generates many similar mutations which could lead to false positives in a broad screening test.  Research and development is ongoing (Jun 2016). 
    from just drops of blood (Theranos).  That is perfect for remote areas where sterile needles and full laboratories are not available. 

    Rosenthal concludes technology is just a tool and must be treated with the wisdom to know when to use and when to ignore it. 

    Mar 2016 KQED Forum Tech Companies Race to Bring Artificial Intelligence to Market with Coursera & Baidu's Andrew Ng, Washington University's Pedro Domingos and Wired's Cade Metz
    Michael Krasny reports it's been a busy month in the field of Artificial intelligence (AI).  In the face-off of man versus machine, the world champion of the Go board game lost to Google's AI program - DeepMind's AlphaGo.  And just last week, Microsoft unveiled a program designed to Tweet like a teenage girl -- only to have it devolve into praising Hitler and lambasting feminists.  Both these events offer a glimpse into the machine learning industry, where companies are competing to create the first viable artificial intelligence software.  Forum discusses the latest in AI and machine learning - a field that's estimated to reach $40 billion by 2020. 

    Andrew Ng stressed that a deep neural network are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.   builds an effective but brittle model of its data space.  It is brittle because the data that builds the network models is effective because it is selected with a focus on the details the researcher wants the network to recognize.  His example was of a speech network for American English that would probably struggle with spoken British English.  Broadening the learning data set can result in unpredictable modelling.  It was argued that this was probably the problem with Microsoft's rogue Tweeter.  Attackers had been able to seed it with defamatory data. 

    Andrew Ng responded to a question about AI and human brain architectures stressing that we know little about how the human brain works and that AI is targeted at the same goals but not in the same way. 

    Pedro Domingos noted that Google's AlphaGo system required fiber laid into the hotel for the game that connected the interface machines to the global Google network where large amounts of computation were performed.  The human brain of the Korean Go master uses the power of one light bulb.  Google's application used megawatts of power during the match.  That would power a small city.  He also noted that the technique used by Google was to build a deep neural network that looked at lots of historic Go games.  This was then used to support a second process which used Samuel learning to develop new Go evaluative models and strategies.  Andrew Ng said he had joined Baidu because of their forward investment in supercomputers that are necessary for his work. 

    Andrew Ng responded to a question about programming deep learning systems.  He agreed that they are not modular.  Changing an aspect of one part of such a system will require work on the other parts.  The strategies used in computer programming are not currently applicable. 

    Andrew Ng responded to a question about the dangers of super powerful AI networks and robots with an analogy.  He noted that people are discussing how to cope with over population on Mars, but that we still haven't landed on the planet yet.  He prefers to focus on the still challenging problem of getting there prior to spending energy on the more distant problem. 


    Spring 2017 UOM I.T. Minnesota Professor He develops mind-controlled robotic arm
    University researchers have made a major breakthrough that allows people to control a robotic arm using only their minds.  The research has potential to help millions of people who are paralyzed or have neurodegenerative diseases. 
    Dec 2016 NYT magazine Alphabet going neural
    Gideon Lewis- Kraus reports late one Friday night in early November, Jun Rekimoto, a distinguished professor of human-computer interaction at the University of Tokyo, was preparing for a lecture when he began to notice some peculiar posts rolling in on social media.  Apparently Google Translate, the company's popular machine-translation service, had suddenly and almost immeasurably improved.  Rekimoto visited Translate himself and began to experiment with it.  He was astonished.  He had to go to sleep, but Translate refused to relax its grip on his imagination. 

    Lewis-Kraus was highlighting the release of a deep-learning neural network based version of Google Translate which in nine months had drastically improved the translation capabilities of the product.  Google CEO Sundar Pichai was part of the subsequent announcement of "A.I. first".  The key point is that Alphabet is executing successfully on a broad strategy to leverage deep neural networks are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.   and machine learning in its products and services.  He writes about how this came about in three related essays:
    1. An institutional story about a small group of artificial intelligence workers at Alphabet who persisted for five years with an old, unproven artificial neural network strategy to become "Google Brain".  
      • Bootstrapped as Project Marvin in X lab by Andrew Ng (Mar 2016), it was adopted by Jeff Dean who brought in Greg Corrado along with Ng's graduate student Quoc Le.  The name morphed to Google Brain. 
      • It was attractive because it could adapt by gradually altering its weights without preprogramming and fixed rules.  Starting with basic capabilities like sensory perception and motor control they hoped that advanced skill would emerge. 
      • When Andrew Ng left Alphabet they hired Geoffrey Hinton, a specialist in deep neural networks, from the University of Toronto.  
        • Deep neural networks trial-and-error strategies get very complicated.  Hinton enhanced an old solution to this layered error problem.  Once there was enough compute power this strategy began to pay off. 
      • Google invested in Tensor Processing Units (T. P. U.) mass-produced and deployed within their operational network to ensure the Hinton architecture deep neural networks had the compute power they required. 
    2. A seventy year long story about the evolution of ideas.  This relates the work of cognitive scientists, psychologists and engineers who worked in obscurity until a paradigm shift about the theory of consciousness occurred. 
    3. A technical story where Google Translate was transformed, tested and introduced in nine months -- a quarter of the time anyone predicted. 
      • Quoc Le proposed leveraging word embeddings are distributional vector representations of words allowing the higher layers of a deep neural network to convolve the lower layers' word vectors to support text classification. 
        to allow neural networks to handle the structure of language. 
        • He realized that 1000 dimensional vector of word associations would allow most real world language mappings.  
        • He needed to allow the input data to flow into the network over time.  
        • His model initially worked well only with sentences of less than eight words. 
      • Mike Schuster took Lee's insights and scaled them for real-world text structures.  
        • He transcribed Lee's research code to run on the TensorFlow open source machine-learning platform Google was developing.  
      • Jeff Dean and Greg Corrado requested Translate director Macduff Hughes consider leveraging the deep learning network.  
        • Dean committed to integrating the network by the end of 2016.  
        • Within a month the neural network was integrated with Google Translate allowing the team to compare the two.  They found:
          • BLEU scores for English-French translation were seven points better for the neural network approach. 
          • Human contractors' side-by-side comparisons agreed with the BLEU assessments. 
      • The team was expanded from three to include many translation experts. 
      • They began turning the project into a product
        • They had to be able to process real world data.  People often wanted to translate small parts of sentences.  
        • The ability to build a training data set that reflects all these use cases is a key aspect of the building a product.  And doing so is, Google agrees, an art. 
        • They had to integrate with the T.P.U. chips.  That required two months of debugging.  
        • They aimed to set expectations that Translate would be much improved but not as good as a human translation.  Reporters preferred to claim they were better than human translaters. 
    Lewis-Kraus notes that Google, Facebook: Hinton post doc, Yann LeCun directs their program; Apple, Amazon, Microsoft and Baidu are in an arms-race, sucking talent from university departments.  He notes that Pichai's ultimate goal is artificial general intelligence.  Pichai asserts his company's future depends on this.  He clarifies what he imagines:
    • It will demonstrate a facility with the implicit, the interpretive. 
    • It will be a general tool, designed for general purposes in a general context. 
    His example includes augmenting human intelligence via assistance.  Lewis-Kraus notes similarities with: Apple's Siri, Facebook's M, Amazon's Echo; built to benefit from knowing broad information about the users they assist.  And he adds that the vision goes further with industrial and medical applications.  He notes Alphabet's purchase of DeepMind arguing that it all suggests progress will be swift. 

    He concludes that Silicon Valley has replaced disruption with institution building.  The consolidation of power is happening fast.  Silicon Valley will not be immune from automation of engineering jobs. 




    Antibiotics


    Mar 2014 NYT The Fat Drug

    Antibiotic are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    slurry has been supplied to bulk up animals as a food additive since 1948 when Lederle Laboratories Thomas Jukes experimented with feeding chlortetracycline (Aureomycin) to pigs, sheep and cows.  All the animals gained weight.  Scientists also experimented with the effects of antibiotics on human weight during the 1950s.  They also noted significant weight gains in these seemingly unethical experiments. 

    In 1954 Eli Lilly created an antibiotic feed addative for farm animals, as an aid to digestion.  Farmers understood that it significantly bulked up their animals.  Further it provided protection from filthy conditions allowing farmers to keep animals indoors, enabling factory farming processes. 

    The reason for the weight gain was unknown. 

    In 2002 Americans were an inch taller and 24 pounds heavier than they were in the 1960s.  More than a third are now classified as obese. 

    While diet and life style contribute to Americans getting heavier it is also possible that antibiotics are contributing. 

    NYT asserts that by the time most meat is eaten by humans it contains little or no antibiotic.  Instead they argue that Americans get their exposure from the pills they take.  American children are prescribed one course of antibiotics a year on average, often for ear and chest infections. 

    Martin Blaser, director of the Human Microbiome Program, and a professor of medicine and microbiology at New York University, is researching the area. 

    Raising mice on high calorie food and antibiotics
    Blaser studied the effects of Antibiotics are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    on the growth of baby mice.   He found female mice fed antibiotic supplements in particular gained about twice as much body fat as the control-group mice who ate the same food.  "For female mice, the antibiotic exposure was the switch that converted more of those extra calories in the diet into fact.  The observations are consistant with the idea that the modern high-calorie diet alone is insufficient to explain the obesity is a disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
    epidemic is the rapid spread of infectious disease: AIDS (Oct 2016), Cholera (2010), Clostridium difficile (May 2015), Ebola, Influenza, Polio, SARS, Tuberculosis, Typhoid, Malaria, Yellow fever, Zika; to large numbers of people in a population within a short period of time -- two weeks or less.  Epidemics are studied and monitored by: NIAID, CDC, WHO; but are managed by states in the US.  Infection control escalation is supported by biocontainment units: Emory, Nebraska.  Once memes are included in the set of infectious schematic materials, human addictions can present as epidemics concludes Dr. Nora Volkow of the NIDA.  CEPI aims to ensure public health networks are effectively prepared for epidemics.  PHCPI aims to strengthen PCPs globally to improve responsiveness to epidemics.  GAVI helps catalyze the development and deployment of vaccines.  Sporadic investment in public health enables development of conditions for vector development: Mosquitos.  The increasing demands of the global population are altering the planet: Climate change is shifting mosquito bases, Forests are being invaded bringing wildlife and their diseases in contact with human networks.  Globalized travel acts as an infection amplifier: Ebola to Texas.  Health clinics have also acted as amplifiers: AIDS in Haiti, C. diff & MRSA infections enabled & amplified by hospitals.  Haiti earthquake support from the UN similarly introduced Cholera. 
    and that antibiotics could be contributing,"  Dr Blaser argues. 

    Interactions with the microbiome
    The Blaser lab also investigates if the Antibiotics are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    are changing the animals' microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria from their mothers.  A variety of diseases may be caused by changes in the microbiome:
    • Eczema can be related to changes in the skin microbiome. 
    • Obesity can be induced by changes to the gut microbiome. 
    .  One recent study found that taking the antibiotic ciprofloxacin decimated entire populations of certain bacteria in some patients' digestive tracts.  And children born via cesarean section (stoping effective deployment of the microbiome by the mother) are more likely to be obese in later life.  

    Alan Meyers fructose consumption
    In response in a letter to the editor: Alan Meyers, a Pediatrics professor at Boston University School of Medicine writes - The Fat Drug shines a welcome light on the use of Antibiotics are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    in industrial agriculture.  But the idea that the modern high-calorie diet alone is insufficient to explain the obesity epidemic flies in the face of the evidence. 

    Beginning in the late 1970s, exactly coincident with the obesity is a disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
    epidemic is the rapid spread of infectious disease: AIDS (Oct 2016), Cholera (2010), Clostridium difficile (May 2015), Ebola, Influenza, Polio, SARS, Tuberculosis, Typhoid, Malaria, Yellow fever, Zika; to large numbers of people in a population within a short period of time -- two weeks or less.  Epidemics are studied and monitored by: NIAID, CDC, WHO; but are managed by states in the US.  Infection control escalation is supported by biocontainment units: Emory, Nebraska.  Once memes are included in the set of infectious schematic materials, human addictions can present as epidemics concludes Dr. Nora Volkow of the NIDA.  CEPI aims to ensure public health networks are effectively prepared for epidemics.  PHCPI aims to strengthen PCPs globally to improve responsiveness to epidemics.  GAVI helps catalyze the development and deployment of vaccines.  Sporadic investment in public health enables development of conditions for vector development: Mosquitos.  The increasing demands of the global population are altering the planet: Climate change is shifting mosquito bases, Forests are being invaded bringing wildlife and their diseases in contact with human networks.  Globalized travel acts as an infection amplifier: Ebola to Texas.  Health clinics have also acted as amplifiers: AIDS in Haiti, C. diff & MRSA infections enabled & amplified by hospitals.  Haiti earthquake support from the UN similarly introduced Cholera. 
    , American food industry production increased by 21 percent; billions were poured into marketing high-calorie-density food to sell the surplus calories; fructose consumption rose by nearly a third thanks to high-fructose corn syrup, and as you reported (aug 3, 2008), the average American began eating 1.8 times more pounds of food a week. 

    This is plenty enough to explain the obesity is a disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
    epidemic, and to point out the way to reverse it. 


    Nov 2016 NYT Infections Tied to Obesity

    Nicholas Bakalar reports is the use of Antibiotics are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    in infancy tied to childhood obesity is a disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
    ?  Some studies (Mar 2014) suggest so, but a new analysis suggests the link may be with infections rather than antibiotics. 

    Data from a large HMO is a health maintenance organization.  Originally HMOs were fashioned after Dr. Paul Ellwood's admiration for group practices such as: Kaiser Permanente, Mayo Clinic; which employed salaried physicians and charged fixed fees rather than FFS.  Ellwood argued that this architecture helped keep subscribers healthy which he termed a health maintenance organization.  President Nixon was convinced by Ellwood signing the HMO Act.  But the legislated HMO did not have to conform to Ellwood's group practice architecture.  Instead by 1997 for-profit commercial insurance companies operated two-thirds of the HMO business.  The legislated HMO:
    • Provides or arranges managed care for:
      • Health insurance
      • Self-funded health care benefit plans
      • Individuals
    • Acts as a liaison with health care providers
    • Covers care rendered by those doctors and others who have agreed by contract to treat patients in accordance with the HMO's guidelines and restrictions in return for access to patients.  Treatment choices were often driven by insurance company rules.  Financial incentives often based the contracted physician income on success in reducing expenses rather than health outcomes.  There are a variety of contracts with physicians:
      • Closed panel plan
      • Open panel plan
      • Network model plan
    • Covers emergency care regardless of the providers contracted status. 
    was analyzed by Kaiser Permanente researchers with lead author Dr. De-Kun Li, reported in The Lancet Diabetes includes type 1 and type 2.   and Endocrinology, who tracked 260,556 infants born from Jan 1997 to March 2013.  The database included:
    • Antibiotic use
    • Diagnosis
    • Height and Weight from birth through age 18. 
    Researchers compared children with no infections and no antibiotics use in the first year of life with those who had untreated infections.  Infants with:
    • One untreated infection had a 15% increased risk for childhood obesity. 
    • Three untreated infections resulted in 40% increased risk
    • Antibiotic treated infections and others with similar infections left untreated had no difference in risk. 
    Infections, but not antibiotics use, were associated with obesity.  Dr. Li commented "You shouldn't avoid antibiotics because you are concerned about childhood obesity." 


    Oct 2015 NYT Should We Bank Our Own Stool?

    Moises Velasquez-Manoff opinion notes American children have had 10 courses of Antibiotics are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    by the time they are 10 years old.  Moises own son of one has taken five courses for ear infections.  Moises worries about damage to the microbiome.  He wondered why the doctors weren't providing 'microbial restoration.'  Studies are associating antibiotic treatment with increased risk of asthma is inflammation of the airways resulting in their narrowing, swelling and generating additional mucus which inhibits breathing.  Its prevalence doubled in the US between 1980 and 2000.  Diagnosis: Propeller Health; Treatments include: Xolair;
    , IBD is inflammatory bowel disease, which is a chronic inflammation of part of the digestive tract.  It includes Crohn's disease and Ulcerative colitis.  Symptoms include: Severe diarrhea, Pain, Fatigue & weight loss.  It typically begins in the teens or twenties.  Incidence has increased exponentially since 1945 in developed countries.  160 genes have been associated with IBD.  These genes all relate to: Producing mucus, solidifying the lining of the gut, or regulating the immune system.  The rapid increase in the incidence of IBD can be explained by societal impacts on the gut microbiome which interacts with these genes and their products.  No particular culprit has been found.  It is probably an ecological shift away from symbiosis.  There is a shift from fibre-fermenters: Faecalibaterium prausnitzii, Bacteroides fragilis; to: Fusobacterium nucleatum, Escherichia coli; which are more inflammatory.  The trigger for disease appears complex: Less early infections with tapeworms, bacteria & viruses, Smaller families - which are typically cleaner, More urban environments - resulting in less contact with animals, Less pets, Antibiotics, Endocrine disrupters, Caeserean births, Formula fed babies - rather than breast milk; all potentially contributing to the altered setup and operation of the immune system and microbiome. 
    , obesity is a disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
    and rheumatoid arthritis.  And animal studies indicate more direct issues (Mar 2014).   

    Fecal transplants are now a cutting-edge treatment for Clostridium difficile (May 2015).  Results suggest transplants are 90% effective at curing these infections.  
    But current practice is to use fecal material from other people.  But that presents some risk. 
    It's safer to re-add your own microbiome.  North York General Hospital in Toronto has piloted banking incoming patients' own stools. 

    Memorial Sloan-Kettering Cancer Center has also started a stool-banking study

    Moises notes there is a nonprofit stool-banking organization OpenBiome

    But for Moises son the treatment is not currently possible.  The infant microbiota changes from month to month.  Anything but immediate restoration would not make sense. 



    Sep 2015 NYT Antibiotics and Diabetes



    In 2012, Danish researchers identified 170,504 case of type 2 diabetes is the leading cause of blindness, limb amputations and kidney failure.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
    • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    • Diet
    • Exercise
    and matched them with 1,364,008 controls without diabetes.  They associated Danish government records on Antibiotic are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    use over the previous 13 years. 

    They reported in the Journal of Clinical Endocrinology and Metabolism that those who had filled two to four prescriptions had a 23 percent higher risk of diabetes than those who had not used antibiotics.  Those who filled five or more had a 53% higher risk.  The association could imply that diabetes caused more use of antibiotics but the risk was apparent up to 15 years before a diabetes diagnosis.  The scientists proposed that antibiotics disrupt gut biota, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria from their mothers.  A variety of diseases may be caused by changes in the microbiome:
    • Eczema can be related to changes in the skin microbiome. 
    • Obesity can be induced by changes to the gut microbiome. 
    , causing changes in insulin regulates the metabolism of carbohydrates, fats and protein by signalling the absorption of glucose by fat, liver and skeletal muscle cells.  It is a peptide hormone generated in the islets of Langerhans beta cells of the pancreas.  Peter Medawar explains it was an early drug therapy success.  As manufacturers have shifted from products developed by extraction to biologics: Humulin, Lantus, Levemir; safety has improved.  But the US list price has risen steeply (Feb 2016, Jan 2017)
    sensitivity and glucose tolerance which can lead to diabetes. 




    May 2015 NYT Drug Overuse Begins an Epidemic

    Jane Brody reports Clostridium difficile thrives in the U.S. as once reliable Antibiotics are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    : ampicillin, amoxicillin, cephalosporins, clindamycin and fluorquinolones; fail.  In England a program of more judicious use of antibiotics was put into effect and C. diff. infections have declined. 

    C. diff. is found in soil and water, and is a low level contaminant of food.  It is typically kept under control by the rest of the microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria from their mothers.  A variety of diseases may be caused by changes in the microbiome:
    • Eczema can be related to changes in the skin microbiome. 
    • Obesity can be induced by changes to the gut microbiome. 
    .  But antibiotics undermine this situation, so if they don't kill the C. diff. there can be problems. 

    C. diff. is a spore forming, toxin producing bacteria that can colonize the large intestine.  The spores are resistant to heat, acid and antibiotics; they are washed away by soap and water but not by alcohol-based hand sanitizers used in hospitals.  Poor bathroom hygiene can spread the organism. 

    C. diff. infections are typically associated with medical institutions.  But Acquisition outside of health care has been increasing dramatically over the last decade.  It now accounts for a third of cases.  But 80% of those infected had recent health care exposure. 

    The risk and severity of C. diff. infections increases with age.  The predominant virulent strain is designated NAP1. 

    There are new effective treatments:


    May 2016 NYT An Infection Raises the Specter of Superbugs Resistant to All Antibiotics

    Sabrina Tavernise and Denise Grady report American military researchers [at Walter Reed Medical Center] have identified the first patient in the United States to be infected with bacteria that are resistant results from plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: CRE (May 2016), C. diff. (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
    to an Antibiotic are compounds which kill bacteria, molds, etc.  The first antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
    • Economically problematic to develop and sell. 
      • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
      • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
      • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
      • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
      • BARDA is promoting public-private partnerships to support promising research.
    • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
    • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    • Monitored globally by W.H.O.
    • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
      • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    that was the last resort against drug-resistant germs. 

    With the identification of a women infected with e coli that included a plasmid provide bacteria with a way to transfer parts of their DNA complement with one another.  The effect is to ensure that useful mutations can become rapidly distributed within a population of bacteria.  , that is resistant to colistin is an old antibiotic that is held in reserve in the US to treat especially dangerous infections (CREs) that are resistant to carbapenems.  , the CDC is the HHS's center for disease control and prevention based in Atlanta Georgia.  
    is concerned about the increased likelihood of untreatable CRE is carbapenem-resistant Enterobacteriaceae.  When carbapenem fails to treat an infection the patient is in serious trouble.  The CDC estimated CRE accounts for around 9,300 infections and 610 deaths yearly in the US in 2010-15.  However the CDC also reports:
    • In July 2010 the state of Florida instigated procedures that reduced the number of patients with CRE from 60% to less than 10% at a problem LTCH.  The improvement was based on
    • Detecting and protecting - Screening, isolating, and grouping patients with CRE to prevent spread to other patients. 
    • Reviewing staff operations for 40 hours checking hand hygene, glove and gown use and other practices during care of patients. 
    • Iterative communications between the problem facility and local, state and federal public health workers.  
    and colistin resistant superbugs.  CDC Director Dr. Thomas Frieden commented "We risk being in a post-antibiotic world.  That wouldn't just be urinary tract infections or pneumonia -- that could be for the 600,000 patient a year who need cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   treatment.  The medicine cabinet is empty for some patients." 

    The Chinese use colistin in pig and poultry breading.  The gene for resistance was first identified there in November 2015.  It has also been found the in intestine of one pig in the US is the United States of America.  

    CRE is still rare but is being found increasingly in the US with 44 states health facilities being sites in 2013.   It typically infects people in hospitals and nursing homes.  Especially those being supported with catheters or breathing machines.  It was also transferred to patients by poorly sterilized scopes (Virginia Mason, Ronald Reagan UCLA); 

    About 2 million Americans fall ill from antibiotic-resistant bacteria every year and at least 23,000 die from these infections. 

    The Obama administration has a strategy to combat the problem. 

    Oct 2016 NYT Copper May Stem Infections

    Nicholas Bakalar reports installing copper equipment in hospital rooms may be a good way to reduce infections, a new study reports. 

    The study, by Grinnell College associate professor Shannon Hinsa-Leasure, reported in the American Journal of Infection Control works to prevent healthcare-associated infections.  It monitors & supports associated hospital processes: Anti-microbial surfaces, Barrier clothing, Cleaning, Disinfection, Hand washing: North shore; Patient access during epidemics, Sterilization; to contain cross infection.  The CDC provides support: Ebola process; and works closely with the primary biocontainment unit at Emory University Hospital. 
    , setup 9 rooms with copper faucet handles, toilet flush levers, door handles, light switches and other commonly touched equipment.  Nine control rooms used traditional plastic equipment.  The researchers measured bacterial contamination and found:
    • Highest bacterial concentrations were on the toilet flush handles. 
    • Fixtures in copper-equipped rooms had bacterial infection rates 92% lower than the controls. 


    Personalized Medicines

    Acute Myelogenous Leukemia (AML) inhibitor

    Sep 2014 NewYorker The Transformation (of AML by AG-221)
    Jerome Groopman describes how patients suffering from AML is acute myelogenous leukemia is a set of eleven disorders of the bone marrow.  Parents of platelets, white and red blood cells fail to differentiate properly and instead replicate wildly.  Patients are at risk of massive bleeding and sepsis.  One of the causes is mutation of the genes for IDH-2.   have until recently been impacted by both the leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.   which lowers the number of platelets and red and white blood cells and the treatments.  Treatments with radiation, immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   and chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    typically destroy the bone marrow which has a similar impact on the health of the sufferer. 

    Now for some patients there is a personalized medicine is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics detailed by the NIH director Francis Collins and includes:
    • NCCN intensive cell therapies
    • Direct to consumer genomic testing
    • Direct to consumer diagnostics
    • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.  
    in phase-1 trial that produces complete remission. 

    For AML induced by a mutation in the gene that produces IDH-2 is a mitochondrial isocitrate dehydrogenase involved in cell metabolism.  Certain mutations of the genes encoding IDH-2 result in the production of 2-hydroxyglutarate inhibiting multiple dioxygenases and causing abnormal histone and DNA methylation producing a molecular inhibition of nuclear gene operations that control cell differentiation.  The result can be A.M.L. 
    the effects are due to the creation of a molecule that alters the operation of the nuclear genes.  The effect is to inhibit the maturation of the replicating stem cells.  Instead of becoming platelets and red and white blood cells the cells just continually replicate crowding out the normal cell lines. 

    Agios has developed an inhibitor of the mutated IDH-2.  Without the mutated IDH-2 byproduct 2-hydroxyglutarate altering the genetic operations the mutant cell lines mature and some patients go into full remission.  


    Aug 2017 NYT A Cancer Conundrum: Too Many Drug Trials, Too Few Patients

    Gina Kolata reports with the arrival of two revolutionary treatment strategies, immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   and personalized medicine is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics detailed by the NIH director Francis Collins and includes:
    • NCCN intensive cell therapies
    • Direct to consumer genomic testing
    • Direct to consumer diagnostics
    • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.  
    , cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   researchers have found new hope -- and a problem that is perhaps unprecedented in medical research.  

    Kolata explains:


    Aug 2016 NYT Animals Grow Human Parts? Labs Hope So

    Gina Kolata reports the [NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.  ] announced [] that it was planning to lift its ban on funding some research that injects human stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms; into animal embryos. 

    The goal is to try to grow human tissues or organs in animals to better understand human diseases and develop therapies to treat them. 
    Previously, in Sep 2015 the NIH had placed a moratorium so as to consider concerns about such research and to ensure no chimeras were developed.  But feedback from researchers was that the moratorium was causing problems. 

    Stem cell based strategies would allow human cells to be deployed and then differentiate into any desired organ. 

    The two types of experiment that could obtain NIH funding are:
    1. Addition of human stem cells to the embryos of animals prior to organ formation. 
    2. Addition of human stem cells in differentiated embryos. 
    Non NIH funded research has already shown that:
    • New types of stem cell have been isolated that can turn into any organ, and the placenta. 
    • Rat stem cells put into mice with pancreas genes knocked out, resulted in mice with rat pancreases. 

    The NIH would now fund similar studies where the host could be a pig with genes knocked out and human stem cells would be deployed to see if human organs would develop. 

    But there are still difficult ethical questions that may stop the proposal going forward.  Regarding stem cells implanted in animal brains, UC Davis stem cell researcher Paul Knoepfler noted "There's no clear dividing line because we lack an understanding of at what point humanization of an animal brain could lead to more humanlike thought or consciousness." 


    Johns Hopkins Berman Institute of Bioethics director Jeffrey Kahn notes two issues:
    1. To decide if there is a fundamental difference between adding DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
      from one species to another -- and adding human cells into an animal. 
    2. Where to draw the human boundary is not agreed. 
    Kahn commented "What are we doing when we are mixing the traits of two species? What makes us human?  Is it having 51 percent human cells?"  Kahn argues those questions "are part of what make people react to this issue." 


    There is a 30 day comment period on the NIH plan. 


    Oct 2016 NYT 2 Trials Show New Treatment for Severe Eczema Can Provide Swift Relief

    Gina Kolata reports the disease is characterized by an itching, oozing rash that can cover almost all of the skin.  The constant itch, to say nothing of the disfigurement, can be so unbearable that many patients consider suicide.  There has never been a safe and effective treatment. 

    Two large clinical trials of dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.   run for 16 weeks with 1,400 subjects, reported in the New England Journal of Medicine, offer hope for the 1.6 million adult Americans with uncontrolled atopic dermatitis, is also called eczema is a long lasting inflammation of the skin.  It can be successfully treated with dupilumab.  
    Patients, who received the drug rather than the placebo, reported the itching reduced within two weeks and was gone within a month.  40% of participant's getting the drug had all or most of the rashes disappear. 

    Reported side effects were a slight increase in conjunctivitis and swelling at the injection site. 


    Northwestern University's Feinberg school of Medicine principle investigator Dr. Jonathan Silverberg said "What we are seeing are some really impressive efficacy numbers, but efficacy alone is not enough.  It is the safety profile that is the real key.  Everything we are seeing really looks great." 




    Mount Sinai Icahn School of Medicine principle investigator Dr. Emma Guttman-Yassky discussed the benefit of dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.   to retired Merck scientist Herb Bull.  "He had weeping lesions all over his body."  Mr. Bull explained "I thought I might as well give up and die."  It took months for the drug to work, but eventually the rash and itching went away.  The new drug "saved my life." 




    Regeneron's Dr. George Yancopoulos said he expects the F.D.A. Food and Drug Administration. 
    to rule on dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.   by March 29, 2017.  The agency has given the drug breakthrough status. 
    He declined to speculate on the drugs price, arguing it would be consistent with the value of the drug. 



    Dec 2016 NYT A patient, 7 Tumors, 100 Billion Cells and a Striking Recovery

    Denise Grady reports the remarkable recovery of a woman with advanced colon cancer, after treatment with cells from her own immune system, may lead to new options for thousands of other patients with colon or pancreatic cancer, researchers are reporting. 

    Her treatment was notable because the mutation in KRAS is a gene that encodes the GTPase KRas, which is part of many signal transduction pathways that propagate growth factors.  Mutations in KRAS are essential for the development of many cancers. 
    had been untreatable.  But the NCI is the national cancer institute. 
    's Dr. Steven Rosenberg's, TIL is tumor infiltrating lymphocyte, a class of lymphocyte that is considered to invade tumors and attack them.  TILs are isolated from the patient's tumors and cloned in large numbers.  Once the patient's native lymphocytes have been depleted with chemotherapy the TILs are infused in combination with interleukin-2 to attack the tumor. 
    based therapies, were applied to Celine Ryan's tumors along with Interluken-2 to stimulate killer T-cells.  Ryan's unusual genetic makeup allowed the treatment to work.  The TILs only attack the tumor cells so they are an attractive immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.  .  Mutations in KRAS are common (all Pancreatic cancers is most often an exocrine tumor.  Islet cell tumors are less common.  These are rare cancers: less than 200,000 US cases per year, but the five year survival rates are extremely low 3%.  They all have KRAS mutations.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
    • Avastin
    • Tarceva 
    and over 30% of colon cancers is a major hereditary cancer also called colorectal cancer.  It follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  It is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; ) so the therapy may have broad significance if it is generally applicable.  Dr. Rosenberg has been studying TILs for decades with the intent of enhancing their ability to attack tumors and become effective treatments. 

    Six of Ms. Ryan's tumors were destroyed.  One mutated around the TIL treatment, by no longer expressing the tissue-type marker the T-cells were targeting and had to be surgically removed.  Johns Hopkin's Bloomberg-Kimmel Institute for Cancer Immunotherapy director, Dr. Drew Pardoll noted that treatments focused on a single mutation will be prone to the tumors mutating around the therapy target. 

    To date TILs have worked best against advanced melanomas is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).   where the treatment has produced long remissions in 20 to 25% of treated patients.  But now Rosenberg's team is targeting colon, pancreas, ovarian is a relatively uncommon disease but is often fatal.  It has been associated with use of talcum powder (May 2016).   and breast cancers is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 


    The researchers:
    • Analyze tumors for mutations that are not present in normal cells. The tumors must be large enough to yield TILs. 
    • Study TILs for cells that recognize cells with the mutations but leave normal cells alone. 
    Celine Ryan's tumors generated killer T-cells that target an important KRAS mutation shared by many other patients with colon and pancreatic cancer.  And her tissue type is unusual carrying a cell surface protein that helps display the KRAS mutation for the T-cells to sense. 

    The researchers hope to take the receptors from Ms. Ryan's T-cells and reengineer them so that they can be deployed in other patients TILs. 


    Jul 2016 NYT Juno Halts Cancer Treatment Trial Using Gene-Altered Cells After 3 Deaths

    Andrew Pollack reports three patients in a study testing the use of genetically engineered cells as a treatment for cancer have died from swelling in the brain, dealing a setback to one of the most exciting pursuits in oncology. 

    Juno Therapeutics, announced the F.D.A. Food and Drug Administration. 
    had temporarily halted the immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    drug trial for ALL is acute lymphocytic/lymphoblastic leukemia.  The cancer starts in the lymphocytes of the bone marrow.  Too many lymphocytes are produced instead of mature white blood cells.  In 2010 combination chemotherapy, including 6-mercaptopurine, cures 85 to 90% of children suffering from ALL. 


    Juno CEO Hans Bishop said the deaths were "difficult and humbling for everyone involved."  Bishop argued that the problems resulted from a combination of the particular CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T cells being used and a chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    drug.  The company proposed that the trial continue without the drug.  Chemotherapy is used to weaken the patient's immune system.  Juno initially used cyclophospamide alone but recently added fludarabine.  The three deaths occurred in patients on the dual chemotherapy, of which there are six or seven.  The company noted there have been no deaths among the 13 or 14 patients receiving cyclophospamide as the chemotherapy component. 

    Early CAR studies have shown major effects of treating leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.   and lymphomas is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    .  But there have been severe side effects: Immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    overreactions, Neurological toxicity including cerebral edema is swelling of the brain. 



    Aug 2016 NYT Immunotherapy Drug Fails Lung Cancer Trial

    Andrew Pollack reports the entire hot new field of immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   got a shock on Friday when a best-selling new drug failed as an initial treatment for lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    in a clinical trial. 

    Bristol-Myers Squibb (BMS) announced that relative to conventional chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    its checkpoint inhibitor release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  Opdivo had not slowed the progression of advanced non-small-cell lung cancer in a 541 patient clinical trial.  It is possible BMS set the PD-L1 levels generated by patient's cancers too low to target a broad market. 

    Shares of BMS plunged 16% as it now has less likelihood of F.D.A. Food and Drug Administration. 
    approval for Opdivo for first-line treatment.  Merck gained 7.5% since Keytruda has succeeded in slowing progression of lung cancer and allowing patients to live longer in an initial trial. 

    The likely implication is that checkpoint inhibitors must be targeted for certain patients whose tumors generate PD-L1.  This is in line with Merck's design strategy while BMS had tried to make Opdivo more generally applicable.  Opdivo is already approved as a second-line lung cancer treatment for all patients while Keytruda is only approved for patient's with high PD-L1.  That was one reason that Opdivo had been out selling Keytruda. 



    Nov 2016 NYT Lifesaving Cancer Drugs May in Rare Cases Cause Heart Damage, Doctors Report

    Denise Grady reports powerful drugs that enlist the Immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    to fight cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   can, in rare cases, cause heart damage, doctors are reporting. 


    A study by Vanderbilt School of Medicine's Dr. Javid Moslehi and Brigham & Women's Dr. Ben Olenchock reported in the New England Journal of Medicine, indicated that 1% of patients taking checkpoint inhibitors release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  : Yervoy and Opdivo for advanced Melanoma is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).  , have developed heart trouble.  But the damage can be severe leading to death.  The study included tests for possible genetic and viral causes for the heart damage which were negative.  Autopsies concluded the immune systems had attacked the heart cells as if they were transplants.  Bristol-Myers Squibb data on 20,594 patients who had taken Yervoy or Opdivo indicated 18 drug related cases of myocarditis is an inflammation of the myocardium, the middle layer of the heart wall. 
    , 6 were fatal. 


    Hospitals responded to the problems by adding extra cardiac tests: echocardiograms, blood tests for troponin; for patients taking multiple checkpoint inhibitors.  When the tests indicate problems steroids and other drugs are used to reduce the immune response. 
    There is a dilemma.  The treatments for heart damage will undermine the treatment strategy for the melanoma. 


    Sloan-Kettering's Dr. Jedd Wolchock noted that one of their patients had developed heart problems but they had cleared up without additional treatment. 




    Brigham & Women's Dr. Olenchock wrote that one patient had been affected at the hospital.  He noted "As the number of patients treated with checkpoint inhibitors release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  has markedly increased, rare cases of cardiac toxicity associated with the use of these cancer therapeutics, sometimes resulting in death, have been seen at multiple institutions including our own." 





    Jul 2016 NYT A sickened Body as Cancer Weapon

    Denise Grady reports Steve Cara expected to sail through the routine medical tests required to increase his life insurance in October 2014.  But the results were devastating.  He had lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    , at age 53.  It had begun to spread, and doctors told him it was inoperable. 


    Steve Cara's oncologist, Memorial Sloan-kettering's Dr. Hellmann recommended immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   using two checkpoint inhibitors release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  : Yervoy and Opdivo.  Cara has non-small-cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.


    About two months into the treatment Cara developed auto-immune responses to the therapies: A rash all over his arms, back and chest, which became so severe he had to stop the treatments while he managed the rash with steroid creams.  Then he resumed using only opdivo.  But a second reaction -- breathing trouble caused by pneumonitis and the therapy was halted again.  Treatment switched to surgery which the immunotherapy had enabled by removing the inoperable secondaries.  And in this case the biopsy showed no sign of cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  

    Dr. Wolchok commented "Time has slowed down to the point where you can pay attention to individual tumors, since you're not running to put out the fire of wholesale systemic progression." 

    Mr. Cara did suffer from Immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    damage to his thyroid is an endocrine gland in the neck, which secretes hormones: Thyroxine; controlling body wide metabolic and protein synthesis rates and calcium homeostatis.  The thyroid is under the direct control of the anterior pituitary (TSH signals) and indirectly the hypothalamus (TRH).   and now takes thyroid medication. 




    M.D. Anderson's Dr. John Heymach commented "We can say in all honesty to patients, that while we can't tell them we can cure metastatic lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    right now, we can tell them there's real hope that they can live for years, and for a lot of patients many years, which really is a complete game-changer." 


    Twenty to 40% of patients have good responses.  The others don't find the drugs work at all.  This could be because of:
    • Other checkpoints that are not being blocked. 

    Checkpoint inhibitor trials are being extended to other cancers. 


    M.D. Anderson used Opdivo to successfully treat metastasized anal cancer is very rare.  The cancer typically develops in the squamous cells of the anus.  It has been associated with HPV.  It is distinct from colon cancer. 
    .  And they argue it will be used in earlier stages of many cancers soon.   

    Anal cancer is often stigmatized because it is associated with the sexually transmitted HPV is human papillomavirus which causes cancer of the cervix in women and is also associated with anal cancer. 


    Lee had anal cancer that had spread to her liver.  "I was told I'd be dead in 12 to 18 months with treatment, six months with no treatment," Lee explained.  Traditional chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    and radiation produced a remediation that lasted only a few months.  The cancer spread to her lungs. 
    Lee became bedridden and in severe pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.  .  She was enrolled in the Opdivo trial in May 2015.  Her liver and lung tumors shrunk 70% and she went back to work. 


    Mr. David Wright, a retired oil engineer from Anchorage, Alaska, developed bladder cancer affects 77,000 new people each year in the US.  And there are 16,000 deaths.  It is typically fast growing, and is often associated with mutated Ras, which may indicate it can be treated by reducing the methylation of the DNA (Dec 2015).   A rare form is plasmacytoid.  Bladder cancer is traditionally treated with surgery, chemotherapy and radiation but these have not been effective with the advanced disease.  New treatments are being deployed:
    • Immuno-oncology immune checkpoint inhibitor Tecentriq (May 2016) is approved for locally advanced or metastatic urothelial carcenoma which accounts for 90% of bladder cancers, where the disease is not controlled by platinum chemotherapy.  Bladder cancer tends to result in many mutations which typically present to the immune system making it a good candidate for immuno-oncology. 
    .  During treatment it was discovered that Mr. Wright had the very aggressive plasmacytoid bladder cancer is a rare and aggressive bladder cancer. 
    chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    and experimental gene therapy cleared his lungs and shrank the plasmacytoid but did not get rid of it.  In June 2014, Mr. Wright was the first M.D. Anderson bladder cancer patient to receive Yervoy and Opdivo.  He flies from Anchorage every two weeks for the treatments.  The tumor shrank and then disappeared.  Mr. Wright is still treated with Opdivo every two weeks although he shows no signs of cancer.  And a side effect of the immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   is that he itches all the time for which he uses antihistamines. 





    Dr. Hellmann notes immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   does not replace chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 


    The brain of one of his lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    patients became invaded by secondary tumors.  But after radiation, treatment with two checkpoint inhibitors did not work.  A switch to chemotherapy resulted in an improved response. 

    There are now trials to see if the checkpoint inhibitors would work synergistically with chemotherapy. 

    Another of his patients used immunotherapy for two years and then had to stop because it had induced sever colitis.  But by that time the tumors had shrunk significantly. 


    The price of checkpoint inhibitors are hidden for clinical trial patients but they will complicate the therapy in the general case of treatment. 


    Aug 2016 NYT As Death Lurked, Tumors Melted

    Matt Richtel reports immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   offers cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   patient hope, not certainty. 

    Richtel describes the struggle of Jason Greenstein, a long time smoker from Bolder Colorado, by 2010 living in Las Vegas.  Jason had fought metastatic HL is Hodgkin lymphoma which is characterized by an orderly spread of the cancerous lymphocytes from one lymph group to the next.  It has a 95% survival rate.  Treatments can include:
    • PD-1 inhibitors such as nivolumab, because HL protects itself by signalling PD-1 to T-lymphocytes. 
    • Hematopoietic stem cell transplantation
    • Radiation therapy
    • Chemotherapy 
    with surgery, traditional chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    , stem-cell transplants which enabled remission during 2013 and eventually, in 2015, an immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    therapy, nivolumab is a PD-1 inhibitor monoclonal antibody.  It is sold branded as Opdivo.  Its mode of action means it is likely to be toxic to a developing fetus.  It is used to treat:
    • Inoperable or metastatic melanoma (with no BRAF mutation) in combination with ipilimumab.  
      • As a second-line treatment when the cancer has a BRAF mutation - with an added BRAF inhibitor.  
    • Certain Hodgkin lymphomas. 
    • As a second-line treatment for squamous non-small cell lung cancer. 
    • As a second-line treatment for renal cell carcinoma. 
    prescribed for HL via compassionate use.  He was one of the 5% who relapsed after the traditional treatments.  The immuno-oncology treatment caused Jason far less discomfort than his prior treatments.  And the MAB as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    visibly "dissolved" Jason's tumor masses.  

    Unfortunately patients who respond also relapse explains UCLA Health oncologist Dr. John Timmerman.  We cross our fingers for Jason. 


    Dec 2016 NYT Taxpayers Finance Cancer Drug, but the Profits Will Be Private

    Matt Richtel and Andrew Pollack report enthusiasm for cancer immunotherapy uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    is soaring, and so is Arie Belldegrun's fortune.  His company Kite Pharma's share price is soaring. 

    Critics of Kite's close relationship with the NCI is the national cancer institute. 
    's CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.   researchers argue that American taxpayers are paying twice for the Kite CAR-T drug: once for the research and then to buy it. 
    The partnership structure was defined by Congress decades ago. 

    Analysts expect Kite to charge at least $200,000 for the new treatment, which will be a one-time therapy for patients. 

    Partnerships between the federal government and technology companies were encouraged by Congressional legislation:

    The number of partnerships have risen since these 1980s acts. 

    Federal researchers argue that forcing partners like Kite to lower prices would drive away innovation in speeding product deployment.  The N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   struck from its negotiating tactics a goal that prices should be reasonable.  Mark Rohrbaugh ran the technology transfer office from 2001 to 2003.  He is still an advisor to the N.I.H. and commented "Companies will not take technologies from us if we say the government will decide in the future what the price will be."  After the reasonable price clause was removed partnership deals increased threefold.  But with so much knowledge and know-how coming from government and academic labs it seems likely the partnerships would still be maintained. 

    The N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   already has an existing price control mechanism available: March-in rights lets the N.I.H. take back control of a patent on an invention made from federal funding if the drug is not being made available to the public on reasonable terms. 
    ; but it remains unused. 

    Dr. Steven Rosenberg argues the Kite partnership "is exactly with way things should work."  When they started to partner other companies were not interested in the technology because of the processing of patient's cells.  The partnership is "absolutely essential or many discoveries will not see the light of day."  He argues that pricing of the drug "is for the market place." 

    The N.C.I. has invested $10 million over the years in Kite's KTE-C19 including 6 years of initial research and development.  The N.C.I. has shown Kite how to treat patients in preparation for the treatment and how to manufacture the therapy. 

    Kite was once considered the underdog to Novartis and Juno, but possibly will be first to market.  Its partnership with the N.C.I. is expanding to develop treatments for other cancers. 

    The N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   publishes technologies it wants to license commercially on its website, and when the government grants a license to a company it is published in the Federal Register.  A process used with Kite. 


    Academic centers and companies often negotiate for stronger terms than the N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.    Sloan-Kettering and Hutchinson cancer center gained payments and stock in Juno for their contributions.  The N.I.H. does not want any appearance of conflict of interest. 

    So critics argue that since the N.I.H. is arguing that its goal is wide distribution of the important drugs it invests in, then the price must be low enough that the drugs are truly available.  That seems particularly true when patients obtain the drugs using Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare includes:
    • Benefits
      • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hosptial. 
      • Part B: Medical insurance
      • Part C: Medicare Advantage 
      • Part D: Prescription drug coverage 
    • Eligibility
      • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived. 
      • Persons under 65 with disabilities who receive SSDI. 
      • Persons with specific medical conditions:
        • Have end stage renal disease or need a kidney transplant. 
        • They have ALS. 
      • Some beneficiaries are dual eligible. 
      • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    • Premiums
      • Part A premium
      • Part B insurance premium
      • Part C & D premiums are set by the commercial insurer. 
    or Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program made state optional by the SCOTUS decision was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
    Washington University's Rachel Sachs sees this as the public paying for the research and then paying again for the public insurance. 




    Aug 2016 NYT Setting Body's 'Serial Killers' Loose on Cancer

    Andrew Pollack reports the young surgeon was mystified.  A fist-sized tumor had been removed from the stomach of his patient 12 years earlier, but doctors had not been able to cut out many smaller growths in his liver.  The cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   should have killed him, yet here he lay on the table for a routine gall-bladder operation. 
    Dr. Steven Rosenberg, performing this surgery in 1968, realized the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    had impeded the cancer.  He is one of a clique who focused on the dream of immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    including: Rosenberg, Dr. Dario Campana, Dr. Zelig Eschar, Dr. Carl June, and Dr. Michel Sadelain

    While there is now contention over who developed the key property Dr. Rosenberg says the NCI is the national cancer institute. 
    's CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.   owes a lot to Dr. Sadelain's work.  Dr. June obtained samples of Dr. Campana's CAR. 

    The latest CAR therapy R&D focus is to:



    Initially the CAR research funding was scarce.  Most pharmaceutical companies prefered volume drug treatments.  Funding eventually came from the Alliance for Cancer Gene Therapy (ACGT) and the Leukemia and Lymphoma Society

    After Dr. Rosenberg's team published a successful result in Blood with a single patient with Lymphoma in 2010 and Dr. June's team published success with complete remission of two out of three sufferers of CLL is chronic lymphocytic leukemia, a blood cancer which begins from an acquired mutation of the DNA of stem cells that generate lymphocytes in the bone marrow.  Some CLL grow fast, others grow slowly and may be responded to with watchful waiting.   
    in 2011 drug companies became interested:

    But then problems occured with the CAR research

    Dr. June's success with treating Emily Whitehead, a young girl suffering from leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.   attracted sponsorship from Internet billionaire Shaun Parker.  But Dr. June's paper did not acknowledge that his CAR was based on Dr. Campanas.  Saint Jude's sued the University of Pennsylvania.  When the suit was settled in 2015 Novartis agreed to pay $12.5 million plus potential future payments and royalties to Saint Jude's and Juno Therapeutics.  Dr. June sent a letter acknowledging the initial CAR was from St. Jude's. 

    CAR therapy is personal raising its costs.  It is complicated to produce the tailored cells. 
    And the therapy can be impacting.  The patients must be treated with chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    to destroy their current T-cells to allow for acceptance of the CAR-T cells. 
    The CAR-T treatment causes problematic responses in the body. 

    Remissions based on CAR-T therapy do not always last.  Some times the tumor evolves so that it no longer displays the target antigens.  In other cases the CAR-T cells do not last long enough to kill all the cancer cells. 

    CAR's have only been effective with some B-cell lymphomas and leukemias which is only some 80,000 of the 1.7 million cases of cancer diagnosed in the US each year.  Solid tumors do not respond and they cause 90% of the cancer deaths. 


    JUl 2017 NYT F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment

    Denise Grady reports a [F.D.A. Food and Drug Administration. 
    ] panel opened a new era in medicine [] unanimously recommending that the agency approve the first-ever treatment that genetically alters a patient's own cells to fight cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  , transforming them into what scientists call a "living drug" that powerfully bolsters the Immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    to shut down the disease. 

    Grady notes the F.D.A. is likely to accept the recommendation giving Novartis the right to market Tisagenlecleucel, the CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T treatment developed at the University of Pennsylvania for unresponsive B-cell lymphoblastic leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  .  That should open the way for the approval of more of these developments:
    The treatment involves:
    The treatment is risky - Emily Whitehead was six in 2012 at the Children's Hospital of Philadelphia and had raging fever, crashing blood pressure, lung congestion, which nearly killed her.  She lived and is still in remission.  She proposed acceptance to the F.D.A. panel. 

    The panel:
    • Agrees on the lifesaving potential of the treatment
    • Raised concerns about the life-threatening side effects:
      • Short term like Emily's which oncologists have been able to treat. 
      • Long-term potential for the infused cells to cause secondary cancers and other problems.  These patients will be tracked for 15 years. 
    • Concerns about ability to produce consistent treatments and maintain quality control as the operations are scaled up.   

    The product is targeted at a very small market - 15% of the 5,000 people a year, many children and young adults, who are affected by B-cell lymphoblastic leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  .  Analysts suggest the treatments could cost more than $300,000 per person.  If the treatment is successful it may reduce current long-term treatment and hospital stay costs. 

    While the treatment has extended lives 11 of the 52 patients, as of Nov 2016, have relapsed.  Three of the relapsed patients have died. 

    LLS has part funded the research.  LLS's Dr. Gwen Nichols argued "It's a new world, an exciting therapy."  She proposed they now determine "what we can combine it with and ist there a way to use it in the future to treat patient with less disease, so that the immune system is in better shape and really able to fight." 



    Jul 2017 NYT Companies Rush to Develop 'Utterly Tranformative' Gene Therapies

    Denise Grady reports the approval of gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
    • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
      • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
      • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
      • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
      • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
    • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
    for leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  , expected in the next few months, will open the door to a radically new class of cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   treatments. 

    Grady notes that the initial F.D.A. Food and Drug Administration. 
    CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T approvals for University of Pennsylvania researched Novartis marketed therapy (Jul 2017) will be focused on blood cancers and will be expensive since they are totally personalized.  So they will target only 80,000 of the 1.7 million cancer cases diagnosed yearly in the US is the United States of America.  


    Novartis plans to expand the approved market of Tisagenlecleucel, which targets CD19 signals on leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.   and lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    cell surfaces, from a few hundred a year, to add adults with diffuse large B-cell lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    in relapse. 

    Novartis is aiming to market other types of T-cell therapies targeted at: chronic lymphocytic leukemia, multiple myeloma is a cancer of B lymphocytes.  The cause is unknown, but alcohol and obesity are risk factors.  Abnormal antibodies are generated which cause kidney problems and overly thick blood.  If the abnormal lymphocytes form a single mass the diagnosis is plasmacytoma.  If there are multiple masses the diagnosis is multple myeloma.  Treatments include: Revlimid, Velcade;
    and glioblastoma are a fast growing form of glioma which usually strike older people and have an average survival time of 18 months in 2015.  The reason for the aggressive growth of glioblastomas is due to collapse of the barriers between two DNA islands which integrates a highly active loop with a low activation loop containing a growth promotor (Dec 2015). Researched by the TCGA project. 



    Kite Pharma is also applying for CAR-T approval for lymphoma. 

    Research is ongoing to be able to use CAR-T to treat solid tumors: mesothelioma, ovarian is a relatively uncommon disease but is often fatal.  It has been associated with use of talcum powder (May 2016).  , breast is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    , prostate is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    , pancreas is most often an exocrine tumor.  Islet cell tumors are less common.  These are rare cancers: less than 200,000 US cases per year, but the five year survival rates are extremely low 3%.  They all have KRAS mutations.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
    • Avastin
    • Tarceva 
    , & lung affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.


    The Children's Hospital of Philadelphia does not have enough research spots for all the patients who want CAR-T treatment.  F.D.A. Food and Drug Administration. 
    approvals should reduce the waiting times.  Dr. Stephan Grubb is keen to be able to give the treatments earlier in the disease process.  That could help some patients to avoid bone marrow transplants.  He sees promise in developments that target two cell surface signals in the same CAR-T which will be needed for tough diseases like acute myeloid leukemia.  He also sees benefit in combining CAR-T treatment with checkpoint inhibition release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI. 



    University of Texas MD Anderson Cancer Center researchers: Dr. Katy Rezvani, Dr. Elizabeth Shpall; are using a different immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   strategy, genetically engineered NK Cells are natural killer cells:
    • Are cell killing lymphocytes that participate in the innate and adaptive immune system responses.  
    • Are unusual in recognising stressed cells without signalling from antibodies or MHC.  They consequently respond relatively rapidly.  And they kill cells that T-lymphocytes will not. 
    • Attack viral-infected cells and tumor cells.  
    • Express cell surface proteins CD16 & CD56. 
    to:

    The strategy is attractive since it may lead to an off-the-shelf immunotherapy rather than the personalized CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T approach.  Dr. Rezvani explained "We plan to make the product and infuse it fresh to the patient, but we are also working on optimizing the freezing process so we can make the product, freeze it and keep it, so that when patients need it, we can give it." 




    Aug 2017 NYT Drug Aimed at Inflammation May Lower Risk of Heart Disease and Cancer

    Denise Grady reports a drug that fights inflammation can reduce the risk of heart attacks is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
    • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    and strokes is when brain cells are deprived of oxygen and begin to die.  There are two structural types: Ischemic and hemorrhagic. 
    , and possibly lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    , in people who have already had one heart attack and are at high risk for another, a new study finds. 

    The study of: 10,061 patients from 39 countries of average age 61, 40% with Diabetes includes type 1 and type 2.  , 25% women; treated for 3.7 years with Novartis's Ilaris, reported on by Dr. Ridker of Brigham & Women's indicated:
    Medical professionals see the cost of Ilaris as prohibitive for high volume problems like CHD is coronary heart disease, also called heart disease or CAD.  It reflects atherosclerosis of the coronary arteries. 
    .  They advocate targeting Ilaris at patients who have already suffered heart attacks and have high levels of inflammation associating them with high risk of more heart attacks and strokes.  Methotrexate, a much cheaper anti-inflammatory is being trialed to see if it will reduce cardiovascular refers to:
    • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    risk. 


    Nov 2016 NYT Bringing Home Hope

    Sally Jacobs reports patients with lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    are traveling to Cuba to obtain a novel Vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
    • The business model for vaccine development has been failing (Aug 2015): 
      • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
      • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
      • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
      • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
      • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
    • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
    • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
      • Coding : CVX, MVX;
    • Research on vaccines includes: 
      • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
        • NCI:
          • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
      • Geisinger: effective process leverage in treatment. 
      • Stanford Edge immuno-oncology for cancer vaccines.  
      • P53-driven-cancer focused, gene therapy (Jun 2015). 
    that is not approved in the United States. 


    The sufferers, who have often tried advanced US treatments for non-small cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    , are going to La Pradera to obtain the immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   cimavax is a non-small cell lung cancer immuno-oncology vaccine.  It is an active vaccine, containing the ligand EGF and P64k and Montanide ISA 51 which together stimulate the immune system to generate antibodies targeted at EGF.  This results in the EGF concentration in the blood dropping.  Many cancers: Lung, Colon, Kidney, Head, Neck; leverage EGFR to stimulate cell growth. 
    which is currently also available in Peru, Paraguay, Columbia, Bosnia and Herzegovina.  The initial four injections are given at La Pradera, and the rest are carried back home.  They return each year to restock the therapy. 

    With a high rate of lung cancer in Cuba, Cuban researchers began working on cimavax in the 1990s. 


    The W.H.O. is World Health Organization a United Nations organization.   reported in 2015 that "In Cuba, products were developed to solve pressing health problems, unlike in other countries, where commercial interests prevailed." 

    The F.D.A. Food and Drug Administration. 
    has now authorized a trial of cimavax at Roswell Park Cancer Center



    Roswell Park's Dr. Lee has collaborated with scientists from Cuba's Center of Molecular Immunology since 2011.  He hopes cimavax is a non-small cell lung cancer immuno-oncology vaccine.  It is an active vaccine, containing the ligand EGF and P64k and Montanide ISA 51 which together stimulate the immune system to generate antibodies targeted at EGF.  This results in the EGF concentration in the blood dropping.  Many cancers: Lung, Colon, Kidney, Head, Neck; leverage EGFR to stimulate cell growth. 
    can be used on other head and neck cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  .  Eventually he wants to use the Vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
    • The business model for vaccine development has been failing (Aug 2015): 
      • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
      • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
      • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
      • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
      • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
    • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
    • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
      • Coding : CVX, MVX;
    • Research on vaccines includes: 
      • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
        • NCI:
          • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
      • Geisinger: effective process leverage in treatment. 
      • Stanford Edge immuno-oncology for cancer vaccines.  
      • P53-driven-cancer focused, gene therapy (Jun 2015). 
    to prevent cancer. 

    Roswell Park propose to combine cimavax with a checkpoint inhibitor release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  , Opdivo, which will stop the cancer from turning off the Immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 


    Roswell Park notes that cimavax has been used free in Cuba since 2011 and have been administered to more than 4,000 patients worldwide.  In Cuba, four shots of cimivax costs $100 to manufacture.  The visiting patients are paying up to $1,500 a dose. 



    So far trials in Cuba have shown a modest benefit over all.  The most recent trials have increased the life expectancy by three to five months relative to controls.  The most success correlated with patients with high EGF is epidermal growth factor which signals, via the Ras/Raf/MAP pathway, cell proliferation, differentiation and growth.  It stimulates DNA synthesis in target cells and cell proliferation. 
    levels in their blood. 

    The F.D.A. "Personal importation policy" allows unapproved medications to be brought into the US when:
    • No adequate alternative is available in the US. 
    • If treatment began in another country and the amount imported is less than three months' supply. 
    The policy has not been tested with border control agents for cimavax. 



    Aug 2016 NYT Study Finds Misdiagnosis For Blacks in a Gene Test

    Denise Grady reports genetic tests uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations.  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
    for an inherited heart disorder are more likely to have incorrect results in black Americans than in whites, according to a new study that is likely to have implications for other minorities and other diseases, including cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  

    A new study of HCM is hypertrophic cardiomyopathy, a condition where the heart muscle (myocardium) becomes abnormally thick.  HCM can result in abnormal heart rhythms and sudden death.  It is a common disease at all ages.  It can be caused by over a 1000 mutations that can occur in one of 10 to 20 genes. 
    , published by Harvard's biomedical informatics develops techniques for storing, retrieving, organizing and analyzing biological data. 
    researchers Dr. Arjun Manrai & Dr. Isaac Kohane, in the New England Journal of Medicine, found diagnostic mistakes (Oct 2015) are being caused by reference to earlier faulty research which linked genetic traits to illness in trials without a statistically significant sample of minority groups.  Genetic testing is offered to family members of HCM sufferers.  But the new report shows that black people are more likely to be told mistakenly they are at risk of HCM.  The misdiagnosis can lead to:
    Earlier studies of HCM mistakenly associated certain mutations which are more often found in blacks.  And some testing labs have not kept track of the latest research.  It is likely that labs some labs that are aware of the issues have not contacted patients to warn them of the change in status of their test results. 

    Sloane-Kettering Cancer Center's Dr. Kenneth Offit said this issue of genetic testing applies more broadly than just to HCM. 


    He has seen outside genetic testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations.  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
    labs give invalid cancer results to Ashkenazi Jews for example. 

    Offit argued in an email to the NYT "We had to generate our own data using close to a thousand stored DNA samples to finally conclude that this variant was not associated with cancer risk in the population in which it was most prevalent.  But until these findings are published, some may continue to receive false alarms." 




    Jun 2015 NYT Pursuit of Cash Taints Promise of Gene Tests

    Genetic testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations.  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
    aims to better identify who is at risk of developing a disease, to guide existing treatments and develop new ones. 

    Reed Abelson and Julie Creswell report that Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare includes:
    • Benefits
      • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hosptial. 
      • Part B: Medical insurance
      • Part C: Medicare Advantage 
      • Part D: Prescription drug coverage 
    • Eligibility
      • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived. 
      • Persons under 65 with disabilities who receive SSDI. 
      • Persons with specific medical conditions:
        • Have end stage renal disease or need a kidney transplant. 
        • They have ALS. 
      • Some beneficiaries are dual eligible. 
      • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    • Premiums
      • Part A premium
      • Part B insurance premium
      • Part C & D premiums are set by the commercial insurer. 
    and private insurers are struggling to keep up with the proliferation of tests being offered. 

    After receiving $130 million in Medicare funds and $55 million from a unit of TPG, Renaissance RX halted its study in 2014 when Medicare suspended payments and began reviewing the companies billing practices.  The company's internal documents suggest it was aware of the high dollar awards doctors could amass.  Three of its executives came from a similar company Natural Molecular Testing that was criminally investigated by the DOJ - U.S. Department of Justice. 


    The entire lab industry is undergoing heightened federal scrutiny over its relationships with doctors. 

    Tens of millions have been invested in clinical laboratories that are developing genetic tests.  The industry is worth $6 billion.  But many of the genetic tests, which can cost $1,000 each, have not proved valuable. 
    And federal regulators have become worried about fraud in the area. 


    Dec 2015 NYT Degrees of Danger

    Roni Caryn Rabin reports progress is made in finding whether a case of prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    requires surgery. 

    Genomic Health's Oncotype DX offers patient's with a prostate cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   diagnosis the potential to actively monitor the cancer and only resort to surgery and radiotherapy when the probability is high that the cancer will spread, or is identified as aggressive. 

    But Vanderbilt University Medical Center urologic surgery chair Dr. David Penson warns that the rules governing lab tests are less rigorous than those for new drugs and so these new tests have not typically been fully studied and understood. 

    The F.D.A. Food and Drug Administration. 
    does not currently have authority to monitor tests developed and used within one laboratory, but it is seeking to cover this area. 

    The P.S.A. is prostate specific antigen.  It is assessed from a blood sample and high counts are indicators of prostate cancer.  PSA increases with age any way.  Typical levels for: 50 - 59 year old are 3 nanograms (ng) per millilitre (ml), 60 - 69 year old are 4 ng/ml and 70 - 79 year old are 5 ng/ml.  The USPSTF recommended against routine PSA based screening in 2012. 
    test can be misleading, often suggesting cancer when there is none. And biopsies is taken with a rectal probe.  It finds cancer in only 30 - 40% of men with abnormal PSAs.  They can result in infections and can miss more aggressive cancers because they examine only tiny snippets of the prostate.  Research and development of liquid biopsys aims to replace and enhance the traditional biopsy. 
    can also mislead and may cause pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.  , bleeding and infection. 

    MDxHealth plans to deploy a urine sampled test SelectMDx in the U.S. in 2016. 

    Swedish researchers have developed a new liquid biopsy uses a tiny blood sample used for diagnostic testing.  Often the testing is based on using DNA sequencing to detect DNA in the blood from cancer cells.  By identifying the mutations in a patient's tumor accurate treatments can be selected, and recurrence can be detected.  But aging generates many similar mutations which could lead to false positives in a broad screening test.  Research and development is ongoing (Jun 2016). 
    STHLM3 is an active surveillance prostate cancer test developed by the Karolisa Institutet that combines P.S.A., single nucleotide polymorphisms, plasma protein biomarkers and clinical variables.   which they have clinically tested in comparison to P.S.A. 



    Sep 2016 NYT Prostate Study Details Validity of Treatments

    Denise Grady reports a new study offers important information to men who are facing difficult decisions about how to treat prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    in its early stages, or whether to treat it at all. 

    After a 10 year longitudinal study of 1,643 British patients aged 50 - 69, who had localized early prostate cancers found with PSA is prostate specific antigen.  It is assessed from a blood sample and high counts are indicators of prostate cancer.  PSA increases with age any way.  Typical levels for: 50 - 59 year old are 3 nanograms (ng) per millilitre (ml), 60 - 69 year old are 4 ng/ml and 70 - 79 year old are 5 ng/ml.  The USPSTF recommended against routine PSA based screening in 2012. 
    and a biopsy is taken with a rectal probe.  It finds cancer in only 30 - 40% of men with abnormal PSAs.  They can result in infections and can miss more aggressive cancers because they examine only tiny snippets of the prostate.  Research and development of liquid biopsys aims to replace and enhance the traditional biopsy. 
    , lead by Oxford's Dr. Freddie Hamby, published in the New England Journal of Medicine, which continues on, with patients allocated randomly to surgery, radiation or active monitoring is an approach to early-stage prostate cancer which replaces treatment, such as surgery or radiation, with monitoring to ensure the cancers aren't growing rapidly.  It started to be used in about 2000 and so will take time to build a predictive history of the success of the regimen (10 year longitudinal study results Sep 2016).  Active surveillance treatements include: Oncotype DX, PSA, STHLM3;
    it was found that:
    Dr Hamby commented "I can counsel patients better now.  I can tell them very precisely, 'look, your risk of dying from cancer is very, very small.  If you receive treatment you will get some benefit.  It will reduce the disease from growing outside your prostate, but htese are exactly the side effects you might expect." 



    Dr. Peter Scardino said the research was important in adding to the previously limited comparative data on prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    treatments.  He argued the results confirm that active monitoring is an approach to early-stage prostate cancer which replaces treatment, such as surgery or radiation, with monitoring to ensure the cancers aren't growing rapidly.  It started to be used in about 2000 and so will take time to build a predictive history of the success of the regimen (10 year longitudinal study results Sep 2016).  Active surveillance treatements include: Oncotype DX, PSA, STHLM3;
    is a valuable tool.  Early prostate cancer is not an emergency.  It was appropriate in one third to a half of men with early prostate cancer as long as the monitoring was done regularly and with great care over the rest of the patient's life.  Only a third of them would need treatment within 10 years. 




    Nov 2016 NYT Dried Blood Can Be Tested for Type of Leukemia

    Donald G. McNeil Jr. reports a rare but treatable form of cancer can now be diagnosed cheaply and easily with dried blood spots instead of whole blood, scientists in Seattle announced []. 



    CML is chronic myelogenous leukemia.  It is a leukemia characterized by the unregulated growth of myeloid cells in the bone marrow.  The growth is encouraged by the cellular signalling system (gene change that generates a faulty tyrosine kinase) being locked on.  Visual methods allowed Dr. Janet Rowley's team to recognize that most CML includes the Philadelphia chromosome.  It encodes the chimeric always on tyrosine kinase protein seen only in CML.  Targeted treatments such as Gleevec block the pathway for the tyrosine kinase. 
    is often diagnosed late in developing counties by which time the victims have distended spleens and massive white blood cell counts.  They can be treated with drugs such as Gleevec is the Novartis trade name for Imatinib.  It is a tyrosine-kinase inhibitor that was designed to treat CML through a partnership between Dr. Brian Druker and Novartis who selected and productized it from a long list of potential small molecule inhibitors.  Due to the binding site that Gleevec targets being present in a variety of related cancer inducing proteins Gleevec is being used to successfully treat other types of cancers. 
    .  Such advanced and costly drugs are being donated by the manufacturers to Max Foundation which deploys them to 80 poor and middle-income countries. 

    But first the patients must be diagnosed at a central lab from a blood sample.  This was far to costly for the typical patient to pay for ($600). 

    Fred Hutchinson Cancer Research Center's leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.   specialist Dr. Jerald Radich developed a solution for the problem  He explained the new test for CML is chronic myelogenous leukemia.  It is a leukemia characterized by the unregulated growth of myeloid cells in the bone marrow.  The growth is encouraged by the cellular signalling system (gene change that generates a faulty tyrosine kinase) being locked on.  Visual methods allowed Dr. Janet Rowley's team to recognize that most CML includes the Philadelphia chromosome.  It encodes the chimeric always on tyrosine kinase protein seen only in CML.  Targeted treatments such as Gleevec block the pathway for the tyrosine kinase. 
    can be run with dried blood, collected with a test card, mailed to the central lab for diagnosis. 


    Max Foundation's Pat Garcia-Gonzalez asked Dr. Radich for the cheaper alternative.  Dr. Radich explained the paper based test "began as a summer project for high school and college students in my lab."  An important aspect was finding a paper that wasn't so acidic or starchy that it destroyed the RNA (RNA), a polymer composed of a chain of ribose sugars.  It does not naturally form into a paired double helix and so is far less stable than DNA.  Chains of DNA are converted by transcription into equivalently sequenced messenger m-RNA.  RNA also provides the associations that encode the genetic code.  Transfer t-RNAs have a site that maps to the codon and match the associated amino-acid.  Stuart Kauffman argues that RNA polymers may be the precursor to our current DNA based genome and protein based enzymes.  In the adaptive web framework's (AWF) Smiley we use a similar paradigm with no proteins. 
    markers in the dried blood sample. 


    Jun 2016 NYT 'Liquid' Test Offers Hope for Alternative to Biopsies

    Andrew Pollack reports a blood test to detect cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   mutations produced results that generally agree with those of an invasive tumor biopsy, researchers reported, heralding a time when diagnosing cancer and monitoring its progression may become less painful amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.   and risky. 

    Liquid biopsies uses a tiny blood sample used for diagnostic testing.  Often the testing is based on using DNA sequencing to detect DNA in the blood from cancer cells.  By identifying the mutations in a patient's tumor accurate treatments can be selected, and recurrence can be detected.  But aging generates many similar mutations which could lead to false positives in a broad screening test.  Research and development is ongoing (Jun 2016). 
    use the property of some tumors to shed DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    fragments in tiny amounts in to the cancer patient's blood.  It is hoped they can replace surgical biopsies which are invasive and may have problematic side effects including lymphedema is a permanent pooling of lymphatic fluid.  This is a serious condition that can result in massive swelling.  It can be induced surgically when lymph nodes are removed for biopsy.   Prophylactic switching to nano-sensors to detect cancer metastasis in the nodes and sensing of high risk situations is developing.  Until 2016 there were no recognized treatments.  Collagen structures deployed by surgeons may encourage cells to rebuild the lymphatic network. 


    The largest study of liquid biopsies looked at the results of more than 150,000 of Guardant Health's liquid biopsies.  Most of the researchers worked for Guardant.  For nearly 400 patients, tumor biopsies were available for comparison.  If a mutation was found in the blood it was also found in the tumor biopsy 94 - 100% of the time. 

    A short coming of the liquid biopsy is the 15% of patients where no tumor DNA was detected in the blood.  Guardant Health's Dr. Mack commented "There are simply tumors that do not shed DNA into circulation at detectable levels, so we are bound to miss them."  And tissue biopsies allow for more thorough analysis, including assessing more mutations.  But there are times when a tissue biopsy can't be taken.  Liquid biopsies offer an option in that scenario. 

    Another developer of liquid biopsies, Foundation Medicine, is suing Guardant for patent infringement. 

    The F.D.A. Food and Drug Administration. 
    recently gave its approval for a liquid biopsy developed by Roche to detect mutations in a particular gene.  lung cancers affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    with mutations in that gene are treated with Tarceva and equivalents. 

    Illumina has launched Grail to develop liquid biopsies which can detect many cancers at an early stage. 


    Jun 2016 NYT Direct-to-You Lab Tests

    Anahad O'Connor reports two years ago, Kristi Wood was tired and achy and could not think clearly, and she had no idea why.  "I was in a fog and feeling awful."  She had her blood tested by a consumer service called InsideTracker which analyzes 30 hormones are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
    and biomarkers.  They told Ms. Wood she had excessive levels of vitamin D.  She cut back on a supplement and almost immediately felt better.  So she has her blood drawn and tested every four months 'to be proactive about her health'. 

    The market for direct-to-consumer diagnostics has grown from $15 million in 2010 to $131 million in 2015. 

    The services have been criticised as lacking proper medical supervision and convincing health people they are sick leading to overtesting and treatment is the application of unnecessary health care.  It is a complex problem:
    • Overtreatment needs to be adaptive.  As people age their medicine levels typically need to be changed.  Often, as in the case of blood pressure, and blood sugar reduction, they should be reduced to avoid inducing falls (Nov 2015).  
    • Patients with chronic diseases, such as type 2 diabetes, often require different treatment settings.  And again these vary with age. 
    • Patients who have learned a regime, and been told it was successful, may resist instructions to change it.  Some worry that they will impact their health care provider's treatment performance measures. 


    New York State attorney general, Eric Schneiderman, accused DirectLabs and LabCorp of violating a state law that requires laboratory tests to be carried out at the request of a licensed medical practitioner.  DirectLabs paid fines and stopped operating in New York state.  LabCorp paid fines. 

    Some doctors argue there is no evidence that this monitoring improves health.  There is also a concern that different people have different baselines of these biomarkers.  The companies appear to be screening for lots of markers and setting arbitrary ranges for what is normal.  By giving the customers advice they already know they should be following there is no added value. 

    Advocates of direct-to-consumer tests say industry practice, illustrated by InsideTracker and WellnessFX, was to work with doctors who reviewed all test results. 


    Aug 2016 NYT Gene Tests Identify Breast Cancer Patients Who Can Skip Chemo, Study Says

    Denise Grady reports when is it safe for a woman with breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    to skip chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    ?
    A new study helps answer that question, based on a test of gene activity in tumors.  It found that nearly half of women with early stage breast cancer who would traditionally receive chemo can avoid it, with little extra risk of the cancer coming back or spreading in the next five years. 

    The genomic test uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations.  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
    used in the study MammaPrint, was estimated to apply to 35,000 to 40,000 women a year in the US and 60, to 70,000 in Europe.  These are patients with early stage cancer but who have: Large tumor size, Cancer in lymph nodes; are typically prescribed chemotherapy.  MammaPrint competes with Oncotype DX is a trademark of Genomic Health.  It is a diagnostic test based on RNA biopsy assays and gene sequencing, of disease recurrence in sufferers of various types of cancer including:
    • Estrogen receptor positive breast cancer.  The tests may help predict the benefit of tamoxifen or aromatase inhibitor treatments in lymph node-negative patients. 
    • Colon cancer. 
    • Prostate cancer. 


    The research by Champalimaud Clinical Center's Dr. Fatima Cardoso, published in the New England Journal of Medicine, is one of the largest and most rigorous trials of genomic testing.  An editorial, written by Sloan-Kettering's Dr. Hudis, and Dr. Dickler, noted that the study was not large enough to validate the 1.5% difference.  Additional research was designed to provide even more clarity.  The study found that women who skipped chemotherapy had low recurrence rates, but they were found to be slightly higher than for the women who took chemotherapy. 

    The 6,693 patients at 112 European hospitals across nine countries were early cases of the most common type of breast cancer: hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
    sensitive stage 1 or 2 tumors that test negative for her2 is a gene encoding the protein 'human epidermal growth factor receptor 2', which is similar in structure to the native receptor HER1. 
    Agendia performed the testing.  1550 of the women were at high clinical risk and low genomic risk.  They were assigned randomly to be treated according to their clinical risk or genomic risk.  There was monitoring to see if the cancer metastasized.  After 5 years 94.4% without chemotherapy had no distant spread.  With chemotherapy 95.9% had no distant spread.  There will be continued monitoring to see what has happened after 10 years. 


    Pregnancy

    Sep 2015 NYT The Cords That Aren't Cut

    Carl Zimmer reports fetal cells often remain in a mother's body, perhaps exerting their own influence.  Pathologists at the university of Leiden Medical Center reported in the journal Molecular Human Reproduction that they had collected tissue from 26 women who had died during or just after pregnancy.  All of them had been carrying sons.  The pathologists stained the samples for 'Y' chromosomes.  They found microchimerism is the escape of cells from a baby in the uterus and their spreading around the mother's body.  The fetal cells then differentiate into cells of the organ type in which they end up.  This process occurs when ever women become pregnant.  This means that sons will leave cells with 'y' chromosomes in the mother.  There are some risks attached:
    • There is the opportunity for the fetus to take advantage of the situation to obtain more resources than the mother desires. 
    • Tumors can be loaded with fetal cells suggesting that they may help drive cancer.  But other studies suggest microchimerism helps protect against cancer.  
    • Mother's immune systems increase activity after giving birth which may help clear fetal cells.  
    - there were 'y' chromosomes in every tissue sampled at a ratio of 1 in 1000 cells. 





    Molecular diagnostics (research)


    Oct 2004 GenoME Sciences Technology Review startup 

    Develops Molecular diagnostics using electrochemical detection of DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    and RNA (RNA), a polymer composed of a chain of ribose sugars.  It does not naturally form into a paired double helix and so is far less stable than DNA.  Chains of DNA are converted by transcription into equivalently sequenced messenger m-RNA.  RNA also provides the associations that encode the genetic code.  Transfer t-RNAs have a site that maps to the codon and match the associated amino-acid.  Stuart Kauffman argues that RNA polymers may be the precursor to our current DNA based genome and protein based enzymes.  In the adaptive web framework's (AWF) Smiley we use a similar paradigm with no proteins. 
    ; Shana Kelley of Boston College builds nanoscale electrocemical and electrical sensors to detect medically relevant gene sequences and proteins. 

    Oct 2004 Oxamer Technology Review startup

    Develops super cheap DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    chips for research and diagnostics;  Ryan Egeland is Director and cofounder.  Slashed the cost of producing a DNA chip from hundreds of dollars to a few dollars by combining microfluidics, computer control, and novel electrochemistry.  He and Edwin Southern (Genetic-analysis pioneer) cofounded Oxamer in Oxford UK. 



    May 2016 NYT No More Room to Shrink

    John Markoff reports for decades the computer industry has been guided by a faith that engineers would always find a way to make the components on computer chips smaller, faster and cheaper.  But he notes there are signals that this is changing:
    Markoff notes other barriers are looming:
    • Per transistor cost of computer chips has stopped falling. 







    Mar 2016 Science Friday Mauro Ferrari talks about success in killing metastatic cancers in mice

    Houston Methodist's Mauro Ferrari was interviewed about his paper in Nature Biotech describing a decade long program to use nanoparticles is the application of nanotechnology to medicine (May 2016).  Commercial applications are focused on research and clinical tools for drug delivery, therapies, in vivo imaging, neuro-electronic interfaces, other nanosensors, and eventually cell repair machines!!  There are issues with determining toxicology etc. 
    as the deployment vector to attack metastatic cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  

    Dr. Ferrari is a former researcher at the NCI is the national cancer institute. 
    and is president of Houston Methodist Research Institute and the Alliance for NanoHealth

    He described working on a program at the NCI to develop silicon nanoparticles as a delivery vehicle to attack and kill metastatic cancers.  Decades later he has succeeded in mice. 

    There were a number of problems that made this difficult:
    • Metastatic cells build multiple barriers to attack
    • It is thus necessary to design agents to attack the walls one after another in the right order. 
    • Series of vectors and drugs must be built. 
    • Nano particles can't penetrate the walls. 

    So assemble the particles in pieces that can penetrate barriers and then have them self-reassemble. 

    A reassembled nanoparticle looks like an exosome which the cancer uses for nutrition.  It thus integrates with the nanoparticles.  Then the drug is absorbed. 




    Sep 2017 NYT Silicon Valley Courts Brand-Name Teachers, Raising Ethics Issues

    Natasha Singer reports one of the tech-savviest teachers in the [US is the United States of America.  ] teaches third grade here[ in North Dakota] at Mapleton Elementary, a public school with about 100 students in the sparsely populated plains west of Fargo.  

    Kayla Delzer has redesigned the classroom to allow her pupils to relax or concentrate as they need.  It is referred to as Starbucks for kids.  Her EdSurge article about it was widely read in education circles.  Soon in 2015 a TEDxFargo talk followed about using technology and other approaches to give pupils more autonomy.  Now many teachers request to visit and see the classroom in action.  Delzer treats her pupils as adults and they like it. 
    Kayla Delzer, leverages apps: Seesaw; to integrate teachers and parents with the children's schoolwork; she is an Amazon Education "Teacher Innovator", a GoEnnounce Digital Image champion, A brand ambassador for GoNoodle, A lead Digital Innovator for PBS LearningMedia.  Delzer notes that she only advocates for products she believes in.  Teachers like her are becoming sponsored advocates of: TenMarks - Amazon's math teaching site.  Public schools are increasingly deploying technologies: Laptops, tablets, math teaching sites, quiz apps and parent-teacher messaging apps. 

    The difficulty of assessing the benefit of these new technologies leaves the process open to influence of technology companies with deep pockets who are in a race with each other to become the market leader in educational tools and infrastructure. 

    Singer notes examples:
    • TenMarks offered teachers who acted as company advisers Amazon gift cards and an additional $80 gift card for writing a post on TenMarks blog. 
    • Established start-ups provide travel expenses for teacher advocates to attend industry-sponsored conferences attended by teachers.  
    • School administrators are keen to leverage free technology and product training.  
    • Typically underappreciated teachers are pleased to get some attention from product & service companies that are interested in their needs. 
    • Sophisticated yearlong teacher development programs select teachers to attend conferences and work with Apple, Google or Microsoft to help develop education innovations is the economic realization of invention and combinatorial exaptation. 
      :
      • Apple's Apple Distinguished educators program.  Microsoft and Apple work with school districts to ensure compliance of any travel expenses they reimburse. 
      • Google for Education's Certified Innovator Program.  Google provides meals but not travel expenses. 
      • Microsoft's Microsoft Innovative Educator Expert
    • Non-tech companies leverage the power of the star advocates; donating equipment in the hope of an endorsement. 

    The advocate teachers can benefit in a number of ways:
    • The corporate relationships can result in schools hiring the advocates to train their teachers.  Training engagements are typically paid. 
    • Influential teachers are selected to be speakers at conferences
    • Ms. Delzer gets outfits from designers she endorses to wear to speaking engagements.  They select the items for her. 
    The strategy has risks for the sponsoring companies as there are regulatory constraints on providing benefits to public employees.  The F.T.C. - is either:
    • Federal Trade Commission.  Setup during the Wilson administration.  Its powers include blocking mergers due to antitrust concerns using the powers of the Clayton act. 
    • Follicular thyroid cancer. 
    considers sponsored posts to be a form of advertising which must be clearly stated.  And the perks to evangelists have been escalating as companies try to entice the key brand advocates to their programs. 

    Singer notes the similarities to the incentives pharmaceutical companies use to encourage doctors to prescribe their drugs.  These include: meals, speaking fees, & conference junkets.  But the pharmaceutical company's relationship with doctors is highly regulated while there is little regulation on the inducements provided to teachers. 

    Researchers who study medical marketing recognize the similarity in the techniques:





    Dec 2015 NYT Changing Up What's Passed Down

    Carl Zimmer reports scientists mull the possibility that environment can alter a man's genetic legacy. 

    Animal experiments show epigenetic leverage of the environment onto the germ-line:
    The sperm in these types of experiment have been examined.  There are epigenetic represent state surfaces within cells and eggs which can be operationally modified so as to provide a heritable structure.  DNA, histones and other stable structures provide surfaces where these states may be setup.  Egg carriers are in a particularly powerful position to induce epi-genetic changes.  Sapolsky notes [childhood] events which persistently alter brain structure and behavior via epi-genetic mechanisms including: pair-bonding in prairie voles, as they first mate, is supported by changes in oxytocin & vasopressin receptor gene regulation in the nucleus accumbens. 
    differences identified:
    Human epigenetic experiments are still too small scale to be statistically significant. 


    Dec 2015 NYT Scientists Discover Reason Brain Tumors Grow Fast

    Gina Kolata reports scientists who scoured the DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
    of brain tumors, searching gene by gene for bad actors, were puzzled.  The cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   had none of the mutations in growth-causing genes that are typical of other tumors, yet they grew quickly, with no brakes.  The question was why -- what had altered their genetic instructions to lead to runaway cell division?

    Researchers at the Broad Institute lead by Dr. Bradley Bernstein, reporting in Nature, realized the three-dimensional structure and organization of the DNA was disrupted in aggressive gliomas are the most common type of malignant brain tumors of adults.  The most aggressive form are glioblastomas.  , resulting in two genetic islands becoming connected.  This resulted in waking up a near-dormant growth gene and the cells became cancerous. 

    The researchers noticed that in 80% of the low- and moderate -grade gliomas a common gene was mutated.  The gene IDH codes for isocitrate dehydrogenase, part of the cell's metabolic pathways.  The mutation is one of the first changes in the cancer cells.  The researchers noted that the mutated cell's DNA became unusually highly methylated.  The researchers realized the methylation was disrupting the loop structure of the DNA inhibiting the formation of CTCF is a transcription factor that acts as a transcriptional repressor.  It is an 11-zinc finger protein.  It regulates the 3D structure of chromatin.  It binds together strands of DNA to form chromatin loops and anchors DNA to cellular structures including nuclear lamina.  
    based barriers between the loops. 

    With the two loops integrated a gene PGDFRA that makes cells grow and is rarely turned on merges with a seperate gene's promotor that turns on PGDFRA a lot. 

    The methylation issue was tested by treating cells with 5-Azacytidine which dissolves methyl groups.  The loops reformed in the chromatin and the rapid cell proliferation stopped.  Dr. Bernstein suggested treating gliomas as soon as they are detected with a drug like 5-Azacytidine can restore the DNA loops.  The method should apply to the growing list of other cancers with excessive methylation on the DNA: liver cancers is the sixth most frequent cancer globally, and the second leading cause of cancer based death.  It is mainly associated with cirrhosis from hepatitis B, C,  or alcohol, but there is also a correlation with obesity (Aug 2016).  The most common liver cancer is HCC.  Immature hepatocytes can produce hepatoblastomas.  Some types of the fungus Aspergillus produce aflatoxins, which