Sunday, February 19, 2017

The FUTURE...?

A sunny day or a cloudy day, both stem from the same nature. Success and failure are fugue states in a quantum foam that collapse into perceived outcomes. But beneath it all is the daunting spirit of humanity to forge ahead.

Whether by words or by deeds, humans continue to imagine the future. Through science that retracts sometime from editing or art that gets plagiarized, the incremental advance of what endures, continues in the pursuit of the future.



Immunity was masqueraded in scientific circles to help in the fight against cancer many years ago alas without the tools of molecular technology. What were considered miraculous cures in cancer (no less miracles today) seem to have walked the less traveled path through the eye of the immune surveillance needle. 

Today inhibiting the Immune cellular dysfunction and enhancing the killer cell function by coopting the over-expression of the cancer cells’ exposed vulnerability, we can control and collapse the structure of this infirmity.


Many years ago, the movie Minority Report image manipulation on virtual screens has turned into a reality as two-year-old toddlers know how to do that effortlessly. 


Indeed, the convergence of technology and knowledge of molecular biology of the state of the cell and its future is determinable. For instance, today, disrupting certain cell-surface signals within the wayward cancer cell, one can propel these life-threatening mischief mongers into self-destruction (apoptosis) or targeted for cannibalism (autophagy).



Medicine continues to press against current self-imposed limits. Today’s evidentiary basis of care continues to morph into tomorrow’s therapy.

We can peer with a hand-held ultrasound into the body with amazingly accurate diagnoses. What was the realm of listening with a stethoscope can now be fairly accurately determined by sound-waves. 


Wearables are proliferating as engineering scientists and biology experts merge their respective disciplines into creating gizmos, which record vital signs that transmit to a machine and the machine via algorithms deciphers change and demands a human intervention (for now). 


Some foretell about days ahead when the human eye and touch will be a thing of the past in healthcare, but that is ways away. Humans need humans. Trust and empathy are not borne of an algorithm, yet the latter can be faked by a machine defying the Turing test almost akin to a sociopath’s maneuverings. Perhaps when we have silicon embedded in our brains to enhance our intellect and function and we can tweak function as we do today with heart defibrillators then maybe we will have arrived at the Start Trek Hologram-doctor who can cure illness with a magic gizmo wand. 


Presently however, we remain consigned to testing our technological limits of embedding gold nanowires and nano-discs to warn us of our health threats that might be inhabiting the human body. are restricted to research science. The trend to recognizing cell free DNA in a patient's blood to determine a cancer's state in the body is however in use today,



Meanwhile outside of the human body and its blood vessel highways, the streets and roads are getting ready to accommodate driverless vehicles, and air-transport drone machines to ease the burden of human travel. meanwhile, technology and Moore’s Law is constantly fanning the flames of better processing power to allow us to speed across the ends of the earth and see a holographic fellow human being in an instant with a simple act of pressing the Return button on the computer, hand held device or virtual reality device.



From the world of IFTTT we are slowly marching towards a machine driven Artificial Intelligence that will one day upend the way we live and function. Asimov’s dream just might come true and Robot Laws might yet have to be enacted to protect humanity itself from this self-recognizing robotic entity. When armies of robots designed to help the aging human race and arm themselves for self-preservation, humanity will face a test. Perhaps the soft tentacles of the gooey brain cells merged with the silicon or ceramic or biological wafer charmed by a quantum computer CPU in each cybernaut might organize the next coming of a new race? Or perhaps the endeavor might devolve this utopian future into a dystopian dust bowl. Time will tell, if there is a robot to record such history.



For its own survival, humanity will hurtle in deep sleep through deep space to reach and populate distant planets. Colonies on the Moon and Mars and perhaps on Kepler 22b might herald us into populating new planets. 


Perhaps the art of imagination will tailor the future, determined by the reality of worm-holes and tesseracts (currently in our art and inspired via mathematics), which might give us an eye into these distant lands.

With every turn of the screw…and time…

The universe awaits.



Monday, February 13, 2017

CANCER of UNKNOWN PRIMARY

Ever wonder why 5 percent (5%) of metastatic cancer the primary site is never found! There is some enlightenment on the subject and is the purpose of this discourse.

Here are some well-known fact:

Experimental data from Ductal Carcinoma In Situ (DCIS) suggest that after “curative” treatment shows 2 -3% of cases will develop metastasis in spite of no residual primary. This is indeed the launch-pad for the inquiry.



We know that cancer cells have single or multiple constraints, which prevent them from progressing. The most important of these constraints is the Tumor suppressor genes. An example of that is the BRCA1. A mutation in that gene (disabling the function of the gene) leads to a higher risk of developing breast cancer. Consider the tumor suppressor gene as brakes in a car. Juxtaposed to the brake is the accelerator; the oncogene. An oncogene when overexpressed (driver with a lead foot) within the cell leads to cancer formation and promotion. An example of the oncogene would be HER 2-neu (erbB-2) in breast and stomach cancer. And MYC gene in lymphomagenesis.

Now researchers have tied the two processes together to come up with a composite concept in breast cancer-genesis.



The proposal based on experimental data suggests both the brake and acceleration process sequentially can go awry leading to the formation of the breast cancer cell. The tumor suppressor gene proposed in this experimental data is p38 gene (P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as ultraviolet and irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. -Wikipedia), while HER 2-neu is the promoter oncogene. The latter leads to the initiation of the Epithelial Mesenchymal Transition (EMT). It is here that the transformed cell “by melting down of the barriers and cross talk between the EP tissues” causes the transition of the breast cancer cell into distant organs. Additionally, the Progesterone Receptors play a big role in allowing mammary cells to move through the mammary gland, hollow out a tubular and the branching network of milk ducts, where the cancer cell develops. These cancer cells, migrate through tissues and via blood vessels to distant organs (liver, bones, lungs etc.) still in their G0/G1 phase and can sit around until further stimuli (stressors: hormones, smoking, drinking, diet etc.) appear, which cause them to go forth and multiply (metastasis) (2).

If the p38 is turned off and the HER 2-neu is constantly turned on (no brake, only accelerator) one can conceptualize a progressive proliferation of the mammary cell turned cancerous forming a nidus to spread via the EMT into other tissues, lymphatic spaces and blood vessels.  The Klein group showed in mice that 80% of metastasis originated from the early spread cells and not from the large tumors and the mechanism of spread was more efficient in early lesions than in large tumors (1).



Inherent in this experimental data is the suggestion that not only size of the primary tumor (where a growing primary tumor is known to cause spread to the adjacent lymphatics and lymph-nodes in a somewhat linear fashion – as most text books equate size equals the potential of stage of the disease) but also the molecular changes within the cancer cell have a part to play both in growth and spread. Hence the cases where metastases are noted first and then through elaborate histological/immunological/molecular diagnostics the primary source of the cancer is determined, are the very seeds of oncogeny.

The benefit of this understanding is both a study in ontogeny and oncogeny of the breast cell. The tautological basis of the experimental data is self-evident. From these basic science experiments, will come the genesis of better management of cancer. Determining the presence via impregnated none discs and nanowires to launch an investigation into potential sites where these wayward cells hide and molecularly targeting them to end them.



Notwithstanding the lead time bias issues, the logic here also explains the fallacy in the “time to spread” argument. It is suggested that 2/3rd of the life history of the cancer is already lived when the diagnosis is made in most cases. It is suggested in these experiments, the growth from 1 million cells (barely visible or causing signs and symptoms) to 1 billion cells (obvious tumors visible on radiological diagnostic tests), where most analyses are undertaken, time in the growth question does not appear to be a linear process and may also be dependent on molecular/hormonal/other stressor issues than believed.


Understanding reality is All.

“It was the lark, the herald of the morn,
No nightingale. Look, love, what envious streaks
Do lace the severing clouds in yonder east.
Night’s candles are burnt out, and jocund day
Stands tiptoe on the misty mountain tops.” - Shakespeare




References:
Christoph A. Klein. Early dissemination seeds metastasis in breast cancer. Nature, 2016.
Julio A. Aguirre-Ghiso. Mechanism of early dissemination and metastasis in Her2 mammary cancer. Nature, 2016.

Friday, January 27, 2017

SPURIOUS CORRELATIONS -Oh My!


“Statistics teach absolutely nothing about the mode of action of medicine nor the mechanics of cure.” – Claude Bernard

Spurious Correlations, a term coined by Karl Pearson to describe the relationship between ratios and absolute measurements, is defined in Wikipedia: In statistics, a spurious relationship or spurious correlation is a mathematical relationship in which two or more events or variables are not causally related to each other (i.e. they are independent), yet it may be wrongly inferred that they are, due to either coincidence or the presence of a certain third, unseen factor (referred to as a "common response variable", "confounding factor", or "lurking variable").
Harvard Business Review cautions…https://hbr.org/2015/06/beware-spurious-correlations



Little insight is gained from the accruing enormous research. To resolve ambiguity by using mathematical probability without a tincture of skepticism sterilizes the intellect and obfuscates the truth. While mathematical probability is a human invention to ease our understanding of the world of science. “Willful ignorance entails simplifying our understanding in order to quantify our uncertainty as mathematical probability.” -Herbert Weisberg

Tylervigen.com


The scientific journals fill pages of mathematically derived studies to prove an intent, but do little to advance the cause of the physicians faced with the dilemma of treating disease.
Today quantification is the game in town. If you cannot quantify then it does not matter. Essentially the modern halls of medicine have relegated qualification of a disease process to the charred bin of history. A clinician once and still in some cases treats disease with the qualification of his or her earned and educated wisdom from experiential hindsight. The deluge of quantified guidelines inundating the landscape of medical IFTTT (If This Then That), which determines payment by the third-party insurers is circumventing the very essence of medical care of patients.

The illusion of certainty is compounded by the statistical geniuses who have little to do with medical facts or care and more to do with number manipulation to find the statistical significance. After having found the golden p-value of less than 0.05 deem the experiment, correlation, or a randomized control trial a landmark success. The quest to succeed supersedes intuition and judgment of the researcher. Today the desire for publication overrides all other questioning beasts of the mind. Studies are done for the sake of publishing and not for the sake of science of discovery itself.

No wonder the biotech giant Amgen reviewed 53 “Landmark studies” and found only 6 verifiable!

Validation data of drug target studies could only prove 14 of 67 projects.

If you look at the financial picture, the US government spends nearly $31 billion every year in science funding through NIH , which is given as research grants to academic scientists. Given the reproducibility rate of 11% (6 of 53) suggests that 89% or $28.74 Billion is being wasted. The obvious implications of such frivolous spending in healthcare costs are staggering when scaled to the entire medical industry.

Today scientific investigation considers human intuition and judgment as flawed and outmoded. Poisson once determined medical care through the lens of mathematical probability, is alive, well and wildly flourishing in the halls of scientific search. And few scientists straighten their spine to ask the question, “Can probability and statistics arbitrate the truth?”


Probability a subjective and ambiguous prospect, once an adjunct to reality has redefined itself as the objectified norm. The frequency of observable events as a hypothesis generating concept has now by the magic of quantification become “real” evidence as in medicine. The term “Risk” as one  might realize, in medicine is associated with causation, yet no precise term of the relationship between correlation and risk has a unified support, meanwhile, statistical fiat controls the issue of risk and harm. The anticipated “Harm” is exposed in this article from the Harvard Professors: https://www.washingtonpost.com/posteverything/wp/2017/01/23/repealing-the-affordable-care-act-will-kill-more-than-43000-people-annually/ The logic here relies on estimates based solely on assumptions. There are no hard facts except disparate data to prove their ideological point. So is that harm?

Calling into question the human subjectivity as a failing, quantified methods reign supreme today. Judgement, intuition, experiential reference subjugated to the quantified, computerized IFTTT norms. And the developed algorithms of best treatment are based on probability of response and the cost of the treatment. The hard truth willingly being ignored is the spark of intuition gained from the potential response of a single patient and the molecular truths that might lie beneath, rather than the quantified “logical” guideline based patient’s care. Even more dumbfounding is this concept at play in "scientific journals:"
Brenda J. Klement, Douglas F. Paulsen and Lawrence E. Wineski are authors of: Clinical Correlations as a Tool in Basic Science Medical Education Journal of Clinical correlation as a Tool in basic Science Medical Education. The article published in Journal of Medical Education and Curricular Development. In this article the authors propose the following; “Clinical correlations are tools to assist students in associating basic science concepts with a medical application or disease.”  One only needs to imagine the impact on the spongy brains that absorb these concepts and use them as the foundation for all future patient management in medicine.

tylervigen.com


While doubt and ambiguity grow uncertainty, quantified statistical inference deems to reduce doubt by applying certainty where certainty does not exist. Whereas real experimentation means a chance meeting error in the face, quantified inference on the other hand, suggests a sterilized, clean and objectified certainty. We are awash with "incremental advancements" that ebb and flow but real breakthroughs in medicine are few and far between. This exalted form of science of statistical "purity" has caused a slew of retractions in its wake. The retractions come in bigger and bigger waves, some by authors, others by peer complaints, and still others by the journals themselves. Most of these “high impact” articles have been cited in other literature and by other scientists as well. The scale of damage to the real advancement of science and medicine continues at unprecedented pace. Copied below are a few recent retractions;
5.     http://www.jbc.org/content/291/53/27434


The human mind has the uncanny ability to use logic, experience, outcomes, experimental design, minority opinion and other perspectives to grow their intuition map. From there the seeds of truth grow. The mechanized, automated, statistically quantified world of today leads to the unnatural and uncomfortable way of a flawed linear thinking. Today’s “Evidence,” as proclaimed by the statistical manipulators, remains a soft flowing sea of sand, moved by the vagaries of the winds of numerical information and/or misinformation. Panaceas abound in the form of “Coffee,” “Antioxidants,” “Vitamins” to name a few that were dismissed after being regaled in laity publications, the NEWS print and digital media. Coffee was correlated to cause cancer and then it was not.


Here are a few booms and busts related to faulty science.

Coffee causes cancer…
1.     Stocks P. (1970) Cancer mortality in relation to national consumption of cigarettes, solid fuel, tea, and coffee. Br J Cancer, 24:215–225
2.     IARC, (1991) ‘Monographs on the Evaluation of Carcinogenic Risks to Humans: Coffee, Tea, Mate, Methylxanthines and Methylglyoxal. Volume 51

Coffee does not cause cancer…
"After thoroughly reviewing more than 1,000 studies in humans and animals, the Working Group found that there was inadequate evidence for the carcinogenicity of coffee drinking overall."

Antioxidants and Cancer…
Initially Antioxidants were supposed to prevent cancer, later it was suggested that it might promote it!
Cochrane Review of the benefits of Antioxidants finds there is 1.03 higher risk of cancer with it’s use: http://www.cochrane.org/CD007176/LIVER_antioxidant-supplements-for-prevention-of-mortality-in-healthy-participants-and-patients-with-various-diseases
And studies in mice show; Antioxidants accelerate tumors in mice
Meanwhile Vitamin D still remains the science writer’s current favorite who present both sides of the benefit and risk arguments with zeal of their intent.
Current Conclusions: We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.


It is wise to remember Galton’s “Correlation Coefficient;” a numerical measure of the degree of relationship between two quantities, once heralded and later quantified by Karl Pearson as a measure of “partial causality,” since 1890 and through time, has been transformed by the manipulation of “quantified metrics” into “absolute causality.” This arbitrary measure of conjecture has now become fact du jour. The evidence in medical science is supposed to be based on “causation” and not using statistical generalizations via mathematical probability. At best this new "science" gives us partial causality and lends to harm for all.