Tuesday, May 14, 2013

ALCHEMY and EPIDEMIOLOGY


"Alchemy is the art of manipulating life, and consciousness in matter, to help it evolve, or to solve problems of inner disharmonies" ~Jean Dubuis

  
The other, hot and humid, day as I sat wishing the sun would quickly drown itself in the Pacific Ocean and cool the air off a bit, A thought came to me…

Why do apples fall from the tree?

Indeed why do they?

It could be that they get so ripe and heavy and unsupportable that the Newton’s defined gravitational pull brings them down. Or the birds alight on the branches and shake them off. Or the breezes swoop in and shake the branches to dislodge their burden. Or the farmers harvest them. Or maybe the worms eat at them and their larvae pupate inside making them heavier. Or maybe there is a botanical mechanism that pinches off the nutrient supply to the stalk that holds a ripe fruit.


Now if one were to be present at any of these events and records them, he or she would consider that as a cause and effect. Simple. You see, record and determine! Whichever was the observed event becomes the cause. But there is more to it when you start seeing other possible mechanisms and then the simplicity is no longer there. It becomes a complex argument. Which of these is the likely cause or are there many other mechanisms that are the cause of the apple falling from the tree? For instance the breeze only shook off the ripe apples but not the green ones, The farmer harvested only the ripe apples too, the animal lunged for the ripe ones too and the birds that sit atop an apple tree branch is unable to dislodge some of the ripe ones, yet the green ones fell to the ground. The conundrum is quite unnerving. Isn’t it?

Heady, wily, thought-provoking but at its very essence, the argument is worth a look.

That phase transition of thought into reality without supporting information becomes the alchemist’s Philosopher’s Stone. It suddenly turns from white to yellow and instead of silver it yields gold by the conjurations of the alchemist. There is where we are in our processes at present. In the rush to decision, in a rush to claiming the fame, in the rush to reaping the rewards, in the rush to immortality, the alchemist uses, that sprinkle of magic dust and what was once steel is now the much lusted over, gold.

The projections of the physicians, physicists, chemist glitterati are being discounted in glorious fashion because they have all fallen victim to the alchemy trap. Some have conjured, cajoled, manipulated and forced a squared peg into a round hole through the art of this magic. Some have done so unknowingly while others deliberately. This art form hurts us all. Unfortunately the peer-review that peers at these out of the box events seem to be taken in by the alchemy too and they, the peers, sign their names on the dotted lines. No one really thinks, except maybe to determine how they, themselves would use this new scientific information or its methodology to advance their own field of inquiry.

Read not to contradict and confute; nor to believe and take for granted; nor to find talk and discourse; but to weigh and consider. ~ Francis Bacon

The burgeoning science of Epidemiology has taken a front seat in medicine and we hear of “this causes that.” The other day, one “study” determined that Vitamin D was good for health and the very next day another stated, it wasn’t. One study stated that the length of the index finger was a risk factor for prostate cancer (all on the basis of a subjective survey), while another professed that earlobe crease was a risk factor for heart disease (from the days of yore). The newspaper and the media love to publish nonsense because they have now become a part of the problem. They are illiterate in judging the benefits of a study and parrot anything that is considered a “Study.”  Any one with good writing skills can now do the devil’s work.
Deciding the fate of many through limited observation

Epidemiology has a place in science. It is at best a correlative discipline, at its worst a terrible stitched together rag of lies. A good epidemiology study is one that would be a prospective, one, which would then be confirmed by basic science. If the correlation is determined then the cause has to be proofed out before subjecting the populace to the nonsense that currently pervades.

How this current form of “science” hurts us is by enabling behaviors that serve a purpose other than for the benefit of the individual. It provokes a fear of things, a sense of loss, a sense of meaninglessness in life. When confrontation and retractions become a daily discourse, belief itself is violated. “Throw some mud and something will stick.,” is the current mantra. A society so narcissistically tuned with subjugated belief in the provocative untruth, is ripe for inaction, lethargy and annihilation. No belief to guide, leads to no morals to comply with. And no morals, leads to a state of subjugated indifference.

In the name of Good Science, let us all think and do better to serve each other. We should learn from the past to advance the future with real progress.

Histories make men wise; poets witty; the mathematics subtile; natural philosophy deep; moral grave; logic and rhetoric able to contend. ~ Francis Bacon

Thursday, May 9, 2013

HACKED


 "One good thing about music, when it hits you, you feel no pain." ~ Bob Marley

Listening to music, the only thought that comes to mind is the raw emotions of peace and tranquility. Of course it depends on the kind of music that is playing. But hear me out on this one for a moment.

Why does music change our being as it enters through the portals of our brain? How does it assimilate and recruit the neuronal cell mass within our brains to collectively enter into this lowered key of existence? But syncing billions of neurons into a coordinated step as in a dance to evoke emotional and physical behavior is a mystery that many neuroscientists have been working to solve. Some say it is hard-wired and others say that the individual cells are programmed to the cadence of a certain key. While others express the mathematical formula based on the octave and its 3rd, 5th and 7th sine wave. The key of "A" vibrates at 110Hz and any frequency other than a multiple would be disharmonious. From Beethoven's Moonlight Sonata to the Arpeggios of J.S. Bach in Prelude to C Major the sea of sounds recruit our sense of wonder and capture our imagination. This recruitment phenomenon is not limited to the neurons alone, since the limb muscle cells also get secondarily recruited by the evoked potential from the brain cells to do their bidding, the whole human element eventually in gear. It is a cascade effect, touching, invoking, evoking and expressing the base pattern of a willingness to belong. A religion, if you will, of emotions expressed in the coordinated motion; Life!

"If music be the food of love, play on." ~ William Shakespeare

Now imagine that an old vinyl record is playing the beautiful symphony and someone drags the needle across the vinyl record. Imagine the grating sound that suddenly shuts down the blissful harmony and drags you back to reality.

Ah yes, that is where we live today, in that grating, caustic world of dissonance.

We are constantly being challenged by the grating noise. The news feed of the 24/7 outlets that must express news and then by virtue of their value proposition, create news just to keep our interest and the constant barrage of bad news emanating from all sources that surround us.

“The boyfriend killer!” the girlfriend killer!” “the abductor!” and the “child molester!” All are sensational stories of illicit human behavior. All such sensational stories gather and collate our desires, wrap them up in a crinkled bag of emotions and throw them out in the garbage everyday for us to, in a warped sort of a way, to yearn for more!

This has become our music!

This, then has become our reality!

We have been hacked and we don’t know it. The societal persona has changed from the house with an open door welcoming neighbors to one jammed with four bolts for security. Today the society rests on the prime of a primal thought; what next?

The real question then is how can we get “un-jacked” from this matrix? How can we resist the illusion of this horrible reality and redefine it the way it used to be, or better yet a way that could be better then the yesterdays and the yesteryear?

It would take a simple act…

Recognition.

Once we recognize that, that is where we are, the next step is to figure out what can be done about it.

Hack back into our brain with that, which creates a positive emotion in life like music, laughter, family and love. Things that some consider “corny.”

Remembering that it takes a hacker to hack into your personal liberty and steal from you what is yours. Hack back into yourself and change the domain password. Create a firewall with passwords encrypted with simplicity and beauty that the corrupted minds will not be able to decipher.

And live your life in peace and tranquility.

I am going to leave you with this beautiful rendering from Daniel Sierra to ponder upon.


Thursday, May 2, 2013

Degrees of Freedom




Why are Docs afraid of the technological innovations?” he asked. There was some degree of defiance in the verbiage.

    That set me thinking. Are we as physicians afraid of innovation? Are we afraid that the smart-phones now have apps that help individuals take self responsibility? My immediate answer was “No, of course not! No doctor worth his salt would be afraid. From time immemorial, doctors have embraced innovative tools to help against maladies. Why should we be afraid?”

But then, it got me thinking.

“Prediction is very difficult, especially if it is about the future.” ~ Niels Bohr



     Using a portion to describe the whole is a monumental task. It is based on many assumptions. The largest one of these assumptions is the belief that every portion is identical to the whole. But nature is not like that. Is it? Even worms exposed to similar circumstances have different genomic structural activity. So to buy into a concept that has its main pillar of support made of fudge is not too firm a foundation to bank on. Is it?

     We are progressively evolving into the linear algorithms of Boolean Logic. If this, then that mind set. We are taking a sampling of the population and deriving methodologies to render therapies. Is that an advance in medicine? After all it is as all men and women inspired by mastering public health seem to determine that what’s good for the public interest is good for the individual. And now we are relegating those human inspired tools to the linear logic of machines. Yes, yes, they claim to have the fuzzy logic and the Artificial Intelligence of a rat or a mouse, or a monkey. But do these machines have the antero-lateral prefrontal cortex? If they don't, can we invoke a verisimilitude of the same in their machine - structured software driven un-empathic hard drives? 

Can we?

     Yet the larger argument diffuses the one above easily. Even the statisticians who develop these wonderful equations to satisfy societal issues consider the possibility of outliers in the field. Due deference is accorded to these few percentages of men and women that don’t fit the mold of the many. And even looking at the classic Bell curve, one finds that 95% of the “majority” nicely fits between the two bookends of 2 standard deviations. And each deviation amounts to roughly 34% on either side of the mean. So the populace in between the first and second deviation is roughly 14% on wither side and they obviously would have variances in their makeup with some discord to the mean populace, now wouldn’t they?



(Here x is the individual data, u (mu) is the population mean and n is the total number, all this results in (sigma) the standard deviation).

      Now given this degree of error even sampling formulas have allowed for some degree of freedom in the form of (N-1) rather than (N). Which basically means that even the statisticians realize there is some error associated with the formula and they further acknowledge that the sampling error albeit small still remains even when allowing for the (N-1) in the equation.

So when someone says that we as doctors are afraid of the algorithms defined by guidelines and mandates that define the best form of therapy for a patient, aren’t they missing something? When One of One becomes One of Many, is the treatment rendered appropriate?

Let me ask a question…

     A patient aged 44 comes for a physical examination. The ensuing examination is normal. The patient asks for a PSA test, because he has heard that it detects prostate cancer and since he has never had it before, he wants to stay on top of the “game.” The results of the PSA fall in the normal range at 2.0ng/L. But then he states that some difficulty with ejaculation after sex but it has resolved. What would you tell him? “Everything is okay?” “Your PSA is normal?” “Come back in a year?”
If you did bat it off based on the guidelines and the algorithms on the computer, what would be the consequences to the patient when a year later he was discovered to have advanced prostate cancer? Was the population-based scenario treatment was none better then quackery?

     Is there then some room in the robotic devices, the computer hard drives loaded with 1 and 0s that give the doctors the degrees of freedom to practice the art of medicine on a One on One basis? Or is that passé? 

From, "e Pluribus Unum" we are morphing into "Ex Uno Plures!" 

Just some food for thought!

Sunday, April 21, 2013

(In Search of...) VARIABLES


In Search of Understanding Variables



What are variables” Are they some form of molecules, differing thoughts, concepts, ideas, behaviors, emotions, feelings, personalities or people? I guess the answer would be yes to all. Now wouldn’t it? Each one of us aspires to be different. We want to achieve, plan, create, modify, build, manufacture, harness or sometime merely express our inner most feelings. The variability in our expression and desires changes with the nuance of the day, the shades of reflections, the brightness of the sun or the silvery calm of the moonlight. Each moment bestows it’s own separate and distinct milieu that drenches thoughts and changes passion.



There are many variables, for instance; heat, volume, filters, position etc. each has a lasting value and impact on the ultimate result. And don't forget Lorentz "strange Attractor" in this wild and funky world. Yes, Indeed we are surrounded by variables. So when, some list one or two and forget the others without reason, I say bolder dash!



So how in the world can we as individuals, groups or organizations cater to the needs of the individual? How so?

In the days past, it was easy, there was little to go around and what was created was utilized. Today the world is awash with variability. There is literally something for everyone’s desire. You don’t portrait, we have a landscape for you. You don’t like desktops, we have a laptop for you and if you are a curmudgeon about laptops, why then we have a tablet for you. Every color of the rainbow and those other colors conspired by humans in between, is represented in clothes and objects. And yet with all this mass of commerce there is still a need for selective difference. That tiny wisp of individuality.



Big Data is here to fill in some of the salesman shoes that used to walk up to every door. Ah the computers are busy accumulating this information in large swaths of binary codes and storing them in large servers that hum cooled with the needed refrigeration to keep them from liquefying under enormous generated heat or worse through that heat, transmuting into a different frequency of the signal. Thus far it is the human that sits and uses his or her analytical smarts to decipher messages from these non-linear swarms. It is the analytical skills filled with Boolean Logic that determines the IFs that lead to the THENs. But soon we in our ever logical mind will be abrogating that decision-making process to the whir and whiz of spinning or solid state hard drives.

But lately Artificial Intelligence also a product of, you guessed it; human intellect is making its overtures. AI as it is called is slowly transforming our life.

It is!

You want some real life example? How about the driver-less cars zooming around the Google complex and soon to a neighborhood near you? Or, and this is near to the human Achilles Heal, the ubiquitously well known 16-terabyte phenom housed in New York, affectionately called “Watson?”  This machine is a giant repository of resource. But relegating the soft, yielding, compliant, argumentative, rebellious mind of the human to the even, linear, programmed, multiprocessing, cold, calculating 1 and 0s, residing within the set parameter machine, bodes a difference in the fortunes of the future is the difference between one that is naturally created through trial and error or the other crafted by the mechanized “soul” of a cold hard entity of yes and no and only calculated probabilistic in-between(s). One can only be reminded of the echoes from the past, “Dave, I am afraid, I can’t do that.”



You see, transformation in a society is a slow ooze of intellect, baked in the kiln of understanding, hardened to the cold biting air of the real world and then utilized. This is not meant to be pejorative by any means. There is a delightful repository of data that resides in Watson’s terabytes, indeed there is! But there is also the self-wielding algorithm couched by the human mind, the bromide, which would confuse Confucius himself by its selective bias. In all it is the number and kind of variables one uses to create such self-replicating chains of evidentiary information. It is in the intersection of the variables that real truth exists. Can we then know all the variables? Yes, If you can know the mind and body of the 7 billion people! Other than that we are playing with the play-dough of uncertainty and probability.



So what is a variable? It is a logical set of attributes. It may be dependent and thereby change as a result of other values within the system or strictly independent, messianic, authoritative and deliberate. But these nuances change the meaning of the meaning.



You might have heard the term “Multivariate” analysis! This implies that in doing the analysis many variables were considered so that the results were robust and not likely to be confounded by artifact. But just naming “multivariate” analysis does not release the chain of burden on the author nor the reader. For in that term the variables so chosen have to be specified and it is up to the reader to determine if from the reader’s perspective the utilized variables are enough to warrant the validity of the results. However no matter the result they will always be bounded by the confines of the "Confidence Intervals" called "CI." This CI has limits to about 95% in most scientific and medical literature because a probability is never the absolute reality and therefore suggests in a polite manner that outliers outside the confines of this 95% boundary do exist! For instance, I came across a well-referenced scientific paper that suggested that the benefits of a drug were superior to the standard treatment in a particular cancer. Okay, that is good. But reading further through the jungle of the graphs and the Tables and Boxed algorithms, I realized that the variables did not include ethnicity breakdown within the trial methodology. Now that would seem nit-picking wouldn’t it? But dare I say that there was a relevant piece of information about the disease suggesting that the ethnicity had a major impact on the survival of patients. So if one were to artificially bunch the ethnic details on one “Arm” of the study, the results would pleasingly benefit the "other" treatment arm, now wouldn’t it?



Another “brilliant” study suggested a human anatomical difference suggests the risk of a certain “disease/illness.” But here the variable used was a questionnaire handed over to the subject to see if he thought there was an apparent discrepancy between the anatomical regions. These subjects were everyday lay people and some with known medical illnesses and others without any. Given the filled in forms by the two cohorts of with and without the specified medical illness were cross tabulated with the subjectively-filled forms of anatomical differences. And voila there was a correlation determined and then using the probability function, a risk was derived at and the paper was published in a “peer-reviewed-high-impact” journal. An utter travesty, don’t you think?

So you say, “Variable, What Variable?” Slow down Watson, there is more than meets the eye. Be careful in your variable evaluation, in your analysis and thus in your thoughts for future actions. And you know what the “experts” dearly love to avoid? The “confounding variables!” These confounding variables create substantial aberration in results and thus can negate the premise being expounded, exploited, expressed or otherwise being shoved down the throats. Oops! Too strong eh? I am reminded of the Challenger disaster where the cold rings were never cross-tabulated and it took a Feynman to figure it out (watch below).

http://youtu.be/6Rwcbsn19c0

You see from a mathematical perspective, the additive values of the variables change the downstream results. They do. The formula is 
Here “i” is the summation variable that calls upon each of the integers and “n” is a non-varying parameter.

In Physical phenomenon, the Institute of Physics defines investigations under this light, “When investigating physical phenomena, there are two strands to thinking about variables: the difference between independent, dependent and control variables; 
the intrinsic nature of the variables, i.e. continuous, discrete, or categorical variables.”

Countering physical phenomena, Algebra however defines Variables as, “A Variable is a symbol for a number we don't know yet.”

However in medicine variables loom large (from California State University, Fresno),

Demographics – Examples: Age, sex, race, religion, income, etc.
Physical Characteristics – Examples: Height, weight, etc.
Physical and Mental Health – These concern the presence (vs. absence) of physical and mental disorders, along with their symptoms.  Examples: medical diagnosis, psychiatric diagnosis, number of headaches per week, number of panic attacks per week, etc.
Personal History – These concern experiences that people have had.  Examples: number of lifetime sexual partners,
Individual Differences – These include standard personality traits (e.g., the Big Five), along with other relatively stable psychological characteristics.  Examples: Extroversion, intelligence, financial responsibility, self-esteem, etc.
Beliefs and Attitudes – This category also includes knowledge, opinions, and judgments.  Examples: attitude toward divorce, opinion of the President’s job performance, beliefs about the seriousness of the AIDS epidemic, etc.
Affective Variables – These include emotions, moods, and feelings about the goodness or badness of a stimulus.  Examples: depression, subjective well being (i.e., happiness), anger, how much one “likes” a photograph.
Performance Variables – This refers to people’s performance on all sorts of physical and cognitive tasks.  Examples: number of points on a final exam, number of errors on a memory test, time taken to recognize a stimulus, etc.
Naturally Occurring Behaviors – These include essentially all other behaviors that people might engage in and that might be of interest to psychologists.  Examples: whether or not one person helps another, number of hours of television watched per week, whether or not use public recycling containers, etc.
Treatments – These are actions that are taken (vs. not taken), which are intended to have a positive (i.e., beneficial) effect on another variable.  Although the term treatment comes from medicine, neither the action nor the effect needs to be medical or biological.  Examples: taking a drug (vs. not taking it) to reduce anxiety, using cognitive therapy (vs. psychotherapy) to treat depression, using a new method of studying (vs. the standard method) to improve exam performance, etc.
Other Situation / Task Variables – This is an enormous catch-all category that includes anything about a person’s situation or the task he or she is performing.  Number of people in the room, difficulty of a test, noise level, time allowed to complete a task,  
And others dependent on the stated premise being evaluated.



So before you take the next step of doing a trial, evaluating a premise, exploiting an idea, understanding the world around you, contemplate your methodology, before critics start running you out of town after your 15 minute of fame.

Wednesday, April 10, 2013

miRNA and CANCER


So there we were, heralding the onset of a new dawn, drunk into a stupor with the insight of two men, Watson and Crick, who had just seen the X-ray diffraction images, projected by a woman named Rosalind Franklin. The fabled cloaked life of what made humans tick had been revealed. The DNA that carried the codes that made us, us, had been discovered. Now there was no end to the treatments that this knowledge would spawn. All those inimical diseases would be eradicated. Ah but that was such a long time ago, back at the dawn of genetic time in 1953.

And then again, our senses took leave, spread across the vast vistas of exotic thoughts of human life extensions into two or even three centuries. Oh yes, there were expert scientists who paid no heed to the term exaggeration. And on and on they boasted till there was no place on the front pages of the newspapers. Ah yes, a consortium of intellectuals had finally mapped the entire genome of a human being. A big and grand achievement worth celebrating indeed! They had found between 25,000 and 30,000 active genes on the DNA helix, not the 100,000+ that had been predicted. Well now! There would be little in the way of barriers in achieving the cures of cancer and other lamentable chronic diseases. Yes, truly the era of modern medicine was here. The Human Genome Project after 10 years and $3 billion had succeeded and every thing would be wonderful soon. That was 50 years after Watson and Crick, in 2003. A lot has transpired since then.

Every new discovery details a new path towards winning the war against disease, but every new discovery also brings with it questions. When I was 10, I thought there was nothing left to discover. When I was 20 that was really true. In my 30s it was really, really true, but then as time elapsed, none of it was true. Discoveries will keep coming as we try to figure out the mechanisms that keep us alive and eventually put us to a permanent sleep, "where dreams may come." Somewhere in there is the holy grail of a real understanding and if one would just stand a little far back, one can see that the intricacies are infinite.

The intricacies are infinite, because humans are constantly at war and peace simultaneously with their environment and life is in a flux of the ravages of storms and the glistening smooth calm of a silent sea.

And that brings me to the little pixies that create ruckus in our lives and simultaneously protect us. Sound familiar from a few paragraphs ago?


We’ve all heard the term Epigenetic, here “epi” the prefix means “upon” and quite literally that is true. The epi on the genetics is the rule of the meek over the mighty. Victor Ambros and colleagues Rosalind Lee and Rhonda Feinbaum discovered the first miRNA in 1993. The microRNA with only 18-24 nucleotides in their arsenal can wreak havoc on the function of a gene. In other words, put a miRNA on top of a gene and it can accelerate its function, decelerate it or completely silence it. Yup, the tiny maestros within, stand and shake their arms with aplomb!

Now that is called oomph! 

They do that by base pairing with the target messenger RNA or mRNA and inhibit heir expression through translation, or destruction. Humans have around 400 or so miRNA genes encoding their behavior ~ the guards, guarding. And if that wasn’t enough each miRNA sequence can mess with dozens if not hundreds of genes at one time, or the power of one! To boot, about 30% of the genes or more seem to be driving under this influence. These supervisory “little beings” if we can call them that, have taken on the responsibility of life and death decisions in the affairs of humans. They act as specific regulators of gene expression. In humans 3% of human genes encode for miRNAs, and up to 30% of human protein coding genes may be regulated by miRNAs. 



(The biogenesis and function of miRNAs. a Primary miRNAs (pri-miRNA) are transcribed from longer encoding DNA sequences (miRNA genes). The pri-miRNA contains one or more stem-loop structures of about 70 bases. In the nucleus, the ribonuclease enzyme Drosha excises the stem-loop structure to form the precursor miRNA (pre-miRNA). b After export into the cytoplasm, the pre-miRNA is cleaved by the ribonuclease Dicer to generate a short RNA duplex (miRNA:miRNA*). The mature single-stranded miRNA is incorporated into the RNA-induced silencing complex (RISC), while the complementary strand (miRNA*) is usually rapidly degraded. The miRNA incorporated into the silencing complex can bind to the target messenger RNA by base pairing, causing inhibition of protein translation and/or degradation of the target messenger RNA) Stephanie Sasson et al. Virchows Arch. 2008 January; 452(1): 1–10


Naturally, we as humans can’t sit around and party all day in oblivion. So we have created a set of double-stranded synthetic miRNA called siRNA or small interfering RNA that have the ability to degrade the mRNA. And they can target specific ones to achieve the purpose of silencing or activating to cool down an active oncogene or heat up the tumor suppressor gene. Human ingenuity is always nearby to exploit and defend its turf.

Some specifics for those who love specifics:

Colorectal Cancer: In Cancer Epidemiol Biomarkers Prev; 20(7); 1272–86. Hermann Brenner states, “A total of 160 miRNAs were found to be dysregulated in CRC. MiR-20a and miR-31 were found to be significantly upregulated in more than one study, and miR-143 and miR-145 were found to be significantly downregulated in CRC tissue in six or more studies. MiR-92a was significantly upregulated in CRC patients in two of the plasma-based studies and in CRC tissue in one of the tissue-based studies.”

Breast cancer: In Genome Biol. 2007;8(10): R214, Blenkiron  et al. state, Of 309 human miRNAs assayed, we identify 133 miRNAs expressed in human breast and breast tumors. We used mRNA expression profiling to classify the breast tumors as luminal A, luminal B, basal-like, HER2+ and normal-like. A number of miRNAs are differentially expressed between these molecular tumor subtypes and individual miRNAs are associated with clinicopathological factors.” (Supervised hierarchical clustering over selected miRNAs 

(Pearson correlation, average linkage). Heatmap colors represent relative miRNA expression as indicated in the color key for each panel. Brackets in the right margin indicate members of the same miRNA family. (a) Clustering of 51 tumor samples that could be classified as basal-like (red), HER2+ (pink), luminal A (dark blue), luminal B (light blue) or normal-like (green) over 38 miRNAs with Benjamini-Hochberg adjusted Kruskal-Wallis p < 0.05. (b) Clustering of 24 tumor samples classified as luminal A (dark blue) or luminal B (light blue) over 9 miRNAs with Benjamini-Hochberg adjusted Wilcoxon p < 0.05.)

Lung cancer: In Journal of Experimental & Clinical Cancer Research 2012, 31:54 Peng Guan states, “A total of 184 differentially expressed microRNAs were reported in the fourteen microRNA expression profiling studies that compared lung cancer tissues with normal tissues, with 61 microRNAs were reported in at least two studies. In the panel of consistently reported up-regulated microRNAs, miR-210 was reported in nine studies and miR-21 was reported in seven studies. In the consistently reported down-regulated microRNAs, miR-126 was reported in ten studies and miR-30a was reported in eight studies. Four up-regulated microRNAs (miR-210, miR-21, miR-31 and miR-182) and two down-regulated mcroiRNAs (miR-126 and miR-145) were consistently reported both in squamous carcinoma and adenocarcinoma-based subgroup analysis, with the other 14 microRNAs solely reported in one or the other subset… In conclusion, the top two most consistently reported up-regulated microRNAs were miR-210 and miR-21.”

Prostate Cancer: In Methods Mol Biol. 2011; 732:69-88, Tang et. al state, “As an example, profiling of miRNAs in four prostate cancer cell lines has revealed that a set of miRNAs were differentially expressed between androgen-dependent and androgen-independent metastatic prostate cancer cells. Among them, the differential expression of miR-205 and miR-200c were further validated by Northern blot analysis in these two types of prostate cancer cells.”

Epethelial-Mesenchymal Transition: In Journal of Hematology & Oncology 2012, 5:9, Oudai Hassan  et al. state, “Generally, the importance of miRNAs in cancer is emphasized by the fact that around 50% of all miRNA genes are positioned in the so called 'fragile sites', the cancer associated genomic regions which are repeatedly changed in cancer. The miRNA 143 and miRNA 145 are other two miRNAs that are assumed to play a role in EMT. In Prostate Cancer, miR-143 and miR-145 are deregulated in primary cancer compared with normal prostate tissue. The up-regulation of miR-143 in prostate cancer cells represses mesenchymal markers (vimentin and fibronectin) and increases the epithelial marker E-cadherin, while the up-regulation of miR-145 leads to the same effects except for vimentin."

Chronic Lymphocytic leukemia: In Proc Natl Acad Sci USA 99:15524–15529, Calin et al, “found that two miRNA genes, mir-15 and mir-16, were located within this 30-kb deletion. They subsequently analyzed the expression of miR-15 and miR-16 in blood samples from patients with CLL. Both miRNAs were absent or downregulated in the majority (68%) of cases when compared to normal tissue or lymphocytes. This finding suggested that these two miRNAs were causally involved in the pathogenesis of chronic lymphocytic leukemia.”

As equally as the miRNA are implicated as causal factors, their absence presages similar calamity, “A global decrease in miRNA levels has been observed in human cancers, indicating that small RNAs may have an intrinsic function in tumor suppression.”



Untangling the web of this deceitful malady called cancer, we learn a little and find out that we need a lot more to learn. For every one answer, more questions pop up, needing further investigation.


The human body is amazing evolving machinery. The beauty in it is the leaps of faith towards perfection and with each leap the unintended consequences leave us slightly more imperfect, more fallible, more in need of more information. Thus the cycle of profligate proliferation of the human race, like the viruses and their counterparts; bacteria, the race, is always on to survive the vicissitudes of out environment one piece of information at a time!


Tuesday, April 2, 2013

MORTALITY PARADOX



To-morrow, and to-morrow, and to-morrow,

Creeps in this petty pace from day to day,

To the last syllable of recorded time;

And all our yesterdays have lighted fools

The way to dusty death. Out, out, brief candle!

Life's but a walking shadow, a poor player,

That struts and frets his hour upon the stage,

And then is heard no more. It is a tale

Told by an idiot, full of sound and fury,

Signifying nothing. _Shakespeare

In the finite existence of humans, man is destined to inquire into the infinity of life. Yet in this very endeavor, he cannot escape being mortal. After all what is life? Except for existence amidst survival in the best of times and the worst of times. It is the slow tick of the clock edging ever close to the limits of its mechanism, the minute hand slowly and inexorably moving towards that fateful hour. And what of this life, except within short term memories of a few generations, extinguished as the hour hand sweeps to the next day.



The tale hangs by a tenuous thread.

There was a man in his forties, who was fastened to the horrors of a disease, always contemplating his survival. His dream was that he would build a magnificent house, buy a boat and speed across the ocean on a summer’s sunny day and barbecue at the edge of land with all those he loved and cherished. That was his dream. He would not listen to reason, for reason had treasonous intent and had betrayed him. He would not listen to limits, for they were self-imposed, in his mind. He would not listen because he did not want to listen. His, was a mind that defied rules of existence. He wanted to, nay, he believed that life limits were self-imposed and that death came when you let it enter the front door.

He accomplished some of his dreams. The summer of pain was mollified by the warmth of the sun and as surely as the sun rises each morning, the hope and dreams of one were drowned by the setting sun in the fall. The house he had desired, remained as nothing but an architects rendering. yet the door in those drawings had been left open.

Life is predictable! It always ends!

As humans we know that there is a predictable end to living, yet we cannot, do not and will not comprehend it and there lies the paradox. Death only comes to others. Loss is ours but we cannot comprehend our own exit. We can imagine it but always as a hovering presence of the third person. Can you imagine what death would be like? Is it a black void? Or is it an endless sea of light? Or is it just blank? What is it? What happens when the brain fails and the mind stops and one enters the “undiscovered country from whose borne no traveler returns?” Are there trumpets announcing arrival? Or as the Mortality Paradox forces us humans to say, “This is getting dense, let me change the channel.”

The Dying Gaul


This mortality paradox has drawn a more vibrant color in present day society. It appears to have become an imperative, that death can somehow be circumvented forever for me, even though it marches on consuming others. That disease is a function of the past and ridding it must be the exclamation of the present. As humans, we think that our capabilities transcend the vagaries of disease and the exclamation of death. In this metaphor ordained, quasi-scientific culture of a self-interest society, the denial of reality is the new norm, steeped in false hope and unfounded in reality.

Confronted with mortality, an 80-year-old will now evoke a sense of missed opportunity, missed expertise or just wrongful curtailment of his or her rights. Because we have cultured our culture with the false residue of life-extended perfect survival even in the face of the grim reality, denial is an easy retort.

British philosopher, Stephen Cave writes in his book, Immortality: The Quest to Live Forever and How It Drives Civilization (Crown 2012), “Death therefore presents itself as both inevitable and impossible,” and defines this as the Mortality Paradox.

While Woody Allen wants to achieve immortality “by not dying,” Christopher Hitchens on a more realistic tone, said at a lecture once, “I’m dying, but so are all of you.”



What about Shakespeare’s idiot? Are we him? Since he is telling the tale and ultimately whether an idiot or an intellectual be, we all share the same fate that eventually life, “signifies nothing?”


Friday, March 29, 2013

I THINK





I think,
In abstract,
In ways I cannot explain.
Mountains,
Valleys, Rocks and
Refrain.


I 

think,
About things
And how they come into being.
Paper,
Plastic, Lights and
Their meaning.


I 

think,
In substance
When form fails to train.
Will, wants
Desire, and snow into
Rain.


I 

think,
About days
And why are they all so different?
Mornings, Noon,
Sunshine, Poverty and
Reign!


I
 think,

About nights
And why they wash away time?
Dark, Moon
Blackness, Emotions and
Decline.


I 

think,
About people
Why they behave as they do.
Cry, Smile
Pretend, Laugh and
Renew.


I 

think,
Of creatures
And what are they to do.
Fight, Kill,
Eat, Hunt and
Zoo.


I 

think,
Of the sky
And why it is so blue.
Orange, Yellow
White, Grey and
Maroon.


I 

think,
Of the oceans
And how they reflect the hue.
Deep, Dark
Fluid, Angry differing
Milieu.


I 

think,
Of thoughts
And how they emerge from naught.
Sadness, Anger,
Serene, Laughter and
Forethought.


I 

think,
About thoughts
And how thinking merges them too.
Happiness, Love,
Sunshine, Warmth,
Anew.


I
 think,

Of reason
And how it changes thought.
No! But!
Listen! Understand or
Not.


I 

think,
Of Life
And why our time is short?
Moments, Memories
Laughter, Joy all in
Thought.


I 

think,
Of a thought
And how it plays in reason.
Hot, Cold,
Maybe, Sense or
Season.


I 

think,
Of Death
And think its nature’s treason?
Short, Quick,
Dark, Emptiness and
Milton.


I
 think,

Every moment
‘cause there is so much to life.
Smile, Wonder,
Laughter, Humor and some
Strife.


I 

think,
Of life
And that moment passes too.
Fleeting, Wispy,
Nebulous, Ether and
Something askew!


I 

think,
Of you
And me and you.
For in my thinking
There’s only anon
And me, and you
Till we are gone.