Wednesday, September 17, 2014


 The Cancer Prevention Study II (CPS II) examined the risk of cancer mortality in obese men and women in the U.S. They reported that obesity is associated with a significant increase in mortality from multiple cancers, including esophageal, colorectal, liver, gallbladder, pancreatic, breast, endometrial, cervical, ovarian, renal, brain, kidney, and prostate cancer; non-Hodgkin lymphoma; and multiple myeloma.

 It has been estimated that overall overweight and obesity cause approximately 20% of all cancer cases.  International Agency for Research on Cancer has reported that obesity causes 39% of endometrial cancer cases.

Asia-Pacific Cohort Collaboration set out to to specifically examine the association of cancer mortality with BMI. They reported a significant increase in the risk of mortality from colon, rectal, postmenopausal breast, ovarian, cervical, and prostate cancer and leukemia in overweight and obese individuals from this population.

The CPS II study examined the association between diabetes and cancer mortality in 467,922 men and 588,321 women in the U.S. After 16 years of follow-up, they found a significantly increased risk of mortality from bladder, colon, pancreatic, and liver cancer in men and from pancreatic, colon, and breast cancer in women with diabetes. In the CPS II study, an inverse association was found between diabetes and prostate cancer mortality.

After 26 years of follow-up, in addition to finding an increased risk of mortality from bladder, pancreatic, breast, liver, and colon cancers, they reported that diabetes was associated with an increased risk of oral and pharyngeal cancer, breast cancer in men, and endometrial cancer in women.
The Metabolic Syndrome and Cancer Project (Me-Can) cohort in Austria, Sweden, and Norway is examining the association between the metabolic syndrome as a whole and its individual components on the risk of cancer. From this cohort, the investigators have reported that higher glucose levels were associated with an increased risk of liver, gallbladder, respiratory, and thyroid cancer and multiple myeloma in men, and pancreas, bladder, endometrial, cervical, and stomach cancer in women.

Syllogisms aside, if infections cause inflammations, by Giuseppe Peano’s logic, cancer must to some degree come from an infection.

A more apt question would be; does inflammation promote cancer? The answer to this statement is more apt to be a yes.

The most well-known is the disease Ulcerative Colitis. In this disease there is generalized inflammation of the colon.  This constant inflammation leads to intestinal crypt deformation and a 43% chance of colon cancer within 25-35 years.

PMNs produce enzymes/cytokines to evoke the inflammatory and immune response. The immune cells are provoked via a protein product liberated by the (TAM1) or T cell activated Macrophages. This product is called TNFa. TNFa promotes another agent called NFkB that sends signals to the immune system via IL6 (a cytokine). This signal essentially motivates the immune system with an “intruder alert” warning.

In the immune system, the NFkB is designed to eradicate the potential for injury but in the tissues the mischief it creates is a whole different ballgame.

This leads to the continuous inflammatory response and further production of the TNFa and by shared cross-talk the production of NFkB in the infected tissue cells. 

The overabundance of the NFkB leads to signaling via the STAT3 and IL6. The latter agent induces COX2, which stimulates the Prostaglandin E or PGE. This final agent then provokes the inflammatory response. The continued inflammation leads to a constant provocation of the tissue cells and a self-sustained vicious cycle of cytokine production that induces the cells to grow or proliferate. Somewhere in that confluence of this potpourri of enzymes, a genetic mutation lives or occurs and a cancer is born.

It appears that the NFkB causes about 500 different reversible and irreversible actions within the cellular DNA through epigenetics (Modulating the gene function by virtue of minor or major pressures from micro RNA, Histones etc. imposed on the genome) So not only is this cascade in flow, but other mechanisms are also being cumulated and promoted.

Specific COX-2 inhibitors (Celexecob) including aspirin and other NSAIDs (Advil. Aleve etc.) the increased incidence of polyp formation and cancer is reduced many-fold in patients with ulcerative colitis, in Familial Polyposis Coli and Inflammatory Bowel Disease.

Interestingly, the mitochondria undergo stresses via infection and inflammation by releasing Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). 80% of all ROS is produced by the mitochondria. These reactive or nascent radical elements (when released within the mitochondria) lead to damage to the mitochondrial DNA (mtDNA), which leads to loss of energy needed for cell growth and function, cell senescence and finally cell death. In the aging process, mtDNA damage occurs over decades. While in infection-inflammation scenario the time is shorter. These ROS and RNS liberations are directly related to the TNFa and NFkB production.

Breast Implants: Recent studies have shown a higher risk of Malignant Lymphoma arising in the breasts of patients with breast implants. Questions remain as to the inflammatory link as the probable causality.

Mutation of the c-Myc and the K-Ras genes lead to the production of TNFa and NFkB, both within the tissue cells and the mitochondria spontaneously thus liberating the ROS and RNS (Oxidative Stressors)

Aspirin. A large meta-analysis of eight studies done by Rothwell et al revealed that those individuals talking daily aspirin had a 60% lower risk of colo-rectal cancer and a 30% lowered risk of other solid malignancies.

Natural agents: Fruits, vegetables, legumes and spices are notable in their ability to reduce inflammatory response.

Curcumin used in curry has been shown to decrease the levels of Y+TNFa and NFkB in the blood of individuals consuming curcumin when exposed to inflammatory provocations. In addition there was a reduction by 40% of abnormal crypt formation in the intestines of patients with inflammatory bowel disease (IBD), which also is proof positive.

Green Tea, Red wine, grape juice and other bioflavonoid also reduce the ROS liberation and the inflammatory response.

Hippocrates: Let food be thy medicine and medicine be thy food.”

Potential mechanisms:
Increased insulin secretion from the pancreas into the portal circulation may lead to increased hepatic growth hormone–mediated synthesis of IGF-1. High-normal levels of insulin, C-peptide, and IGF-1 have been associated with an increased risk of certain cancers in epidemiological studies.

An analysis of 12 prospective studies reported that men with serum IGF-1 levels in the highest quintile of the population range had an odds ratio of 1.38 for developing prostate cancer, compared with men with the lowest IGF-1 levels not all studies have reported positive findings.

In vitro, both IGF-1 and insulin stimulate the proliferation of tumor cells lines. In vivo animal studies have demonstrated that endogenous hyperinsulinemia increases the growth and metastasis of mammary tumors, while increased circulating IGF-1 levels increased the growth and metastases of colon cancers in mice.

Many tumors are known to overexpress the IR, and some studies have reported that higher expression of the IR is associated with a worse prognosis.

Therefore, in obesity, diabetes, and the metabolic syndrome, glucose may be playing a role in concert with hyperinsulinemia, inflammation, adipokines, and altered estrogen levels.

Similarly, increased endogenous estrogen levels have been reported to increase the risk of postmenopausal breast cancer twofold. Obesity has long been known to be associated with increased circulating estrogen levels, due to increased aromatase activity in adipose tissue. In addition, insulin-resistant women have suppressed hepatic production of sex hormone–binding globulin, leading to increased levels of free estrogen. More recent studies have also demonstrated that obese women express increased levels of aromatase in breast stromal tissues, the expression of which is increased by inflammatory mediators including TNF-α, IL-1β, prostaglandin E2, and cyclooxygenase-2 (COX-2)
The estrogen receptor (ER) and IGF-1R are known to have significant cross-talk in the normal mammary gland and breast cancer.

Obesity is considered a state of chronic inflammation. In obesity, adipocytes increase in size and have a greater number of macrophages. Adipose tissue macrophages secrete a number of inflammatory molecules including IL-6 and TNF-α.

Increased IL-6 levels have been implicated in the pathogenesis of hepatocellular carcinoma and ovarian, prostate, and breast cancer.

IL-6 has also been implicated in the development of breast cancer metastases by inducing changes in cells that lead them to have greater invasive and migration properties: a phenomenon known as epithelial-mesenchymal transition. TNF-α has also been seen to play a role in tumor promotion. TNF-α is associated with increased colon tumor growth in animal models and with more aggressive prostate cancer and in breast adipose tissue has been shown to increase the expression of aromatase. 
Studies have demonstrated cross-talk between IL-6 and epidermal growth factor receptor signaling in epidermal growth factor receptor–driven breast cancer.

Knocking down IL-6 was also associated with a decrease in the number of tumor-associated macrophages. Tumor-associated macrophages are a source for cytokines and TNF-α and may contribute to tumor growth and metastases.

Low adiponectin levels and high leptin have been associated with an increased risk of colorectal cancers in a cohort study nested within the Women’s Health Initiative cohort. Leptin is also a proangiogenic factor and increases the expression of matrix metalloproteases (MMP-2 and MMP-9) that are important for cell invasion.

The bottom line is simple: Obesity is linked with chronic Inflammation and the latter drives the wheel of misfortune (cancer).

"Live Long and Prosper: Eat less (consider fasting a few days a month a prelude to healthy living), Exercise more (Walking daily for an hour) and De-stress a bit (don't take everything seriously)."


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Friday, September 12, 2014

TIME to say "HELLO"

Can we quantify and qualify everything we do?

Is that a good thing?

Think about the latest craze about wearables. Our heart rates, respirations, movements are being monitored and stored in some digital universe for retrieval later by us or someone else all the time. There are methods measuring the measures that measure our progress or lack thereof. There is a constant cacophony of “talking heads” on television that it is a must for the 21st Century being to make certain that each step is quantified, each wink immortalized, each view in the mirror, mirrored to the world and each thought expressed. The makers of the wearables are eager to have you buy the latest greatest gizmo and attach it to your limb, body, ear or eye in the hopes of gathering data about the “pathetic’ populace that is so out of touch with itself in staying healthy. In so doing they are tethering us into this virtual world of electronic emptiness.

I wonder…

What did the older generations do?

Really what did they do?

Asking a 90 year old and his response is simple. “We played stick ball in the streets and our elders watched from the sidelines keeping a watchful eye on traffic.” He added, “”We played football with a stuffed toy, or jumped in a brook nearby to cool down.”


“Yes and we were as thin as rails.” I could throw a stick like a javelin, hurl a ball as a hammer throw and swim like a fish in a lake. Yes we did all that and more!” He closes his eyes to the present in search of a distant but a pleasing past.

Now we have a constant flow of gadgets and gizmos galore that a 3 year-old can expertly navigate to the latest You-Tube video of Disney character in under ten seconds and there sit with eyes staring at the flicker of the screen, mesmerized by the limits of time during which the adult seeks refuge in their virtual world transgressions.

Is the progress we seek that is around us today, the progress we sought in days past? Apparently it is, after all we are here. The verse has changed. Maybe it needs a revision?

Asking a 20 year old and her response is simpler. “Umm…” as her eyes are glazed over by the flicker of her computer screen.

We want connections, we want to be liked for all the selfish reasons, we want to have a constant wave of onlookers that give “thumbs up” and a one word response of “Great, Brilliant, Excellent,” or the implied sentiment thru, “LOL, LMAO or some other contrived messaging that appeals to the vacuous nature of such connections.” We fear direct contact for fear of appearing stupid, or quiet or humble. We fear our real life persona might not hold up the candle to the digital persona we have crafted. And we are constantly in the narcissistic jungle of “how much and how many” virtual beings we have. Whereas taking a "selfie" is an immediacy for gratification, drawing a sketch is losing oneself on the road less traveled, which brings with it unimaginable happiness and satisfaction.

Maybe it is time to recognize that measuring, messaging and living in the digitally archived virtual world is not the real reality. It limits activity, which limits the fecundity of the brain and makes us all lethargic. This virtual existence damages our real connections, isolates us into compartments and groups and cabals that function to self-glorify. It makes for an under-nourished mind, a weaker thought and a “followers” instinct-a drone, rather than a leader’s virtue.  

Maybe we should learn to “feel” the touch, “hear” the angst of another being and “see” the wonder in someone’s eyes. And from there gather what is and what needs to be.

Maybe it is time to power down the wearables. Shut the flicker on the screen. Stop looking at the digital world for a response and move into existential reality.

Maybe it is time to say, “FUGGADABOUTIT!”

And maybe it is time to say, “HELLO!”

.....Rather than just write it an be governed by "Morons," Peter Drucker's term for computers.

Sunday, September 7, 2014

SOLITUDE, the Power of SILENCE and the neon gods!

Several years ago upon walking into the room of an elderly patient in the hospital, the noise of my heels on the floor startled her out of a sleep state or so I thought. I apologized and she shrugged it off. She was 91 years old with a long history of chronic leukemia. Two days later, I happen to walk into the room when her husband who was 90 years sat by her bedside. He was holding her hand and as I approached she was again startled out of her reverie. Again with deep apologies I examined her and noted her progress and left the room. She continued to improve and was discharged a few days later. I realized as I reflect back on that time; the power of silence.

There is something to be said about the power of silence. We are constantly inundated with powerful messaging, the clink and clang of technology, the seduction of verbal contact, the force to communicate to everyone, to no one in particular or just reclaim the beast of “being alive.” Where has all that solitude gone?

A person seeking solitude was at first considered a hermit, now he or she is considered an antisocial and in some circles labeled as an anomaly of human behavior. Yet we are forever trying to hide in our rooms, bury our ears beneath pillows to drown out the noise, wear noise-cancelling headsets, turn up the volume of the music that feels good to drown out the cacophony of daily life. Why?

There must be an edge to silence over noise!

What is it?

In Finland the power of branding to increase tourism has taken on a whole new meaning. The country has espoused and advertises the “Silence” to attract tourists as the quiet getaways from the humdrum of daily chaos. And they are winning over the hearts and minds of their segmented population. Wealthy citizens of this world buy islands to escape the ticker-tape of life. Why?

Children growing up, sleep for 12-14 hours a day during their first year of life, this sparks neural growth and their brains increase three times in neural density and synaptic connections. Mice brains relegated to silence also grow more neuronal density. In humans, with neuronal density and a plethora of new synaptic connections, new ideas take shape from old memories and experiences that are stored within. From new ideas come new actions and the world changes! We make better decisions away from the constant noise that robs us of our peace and inner strengths.

Professional skiers, swimmers, runners, and other athletes before any performance will close their eyes and imagine their moves. Why? Because in the quiet of their brain they are able to evoke the countless hours of positive imagery developed and stored during practice and training. Some wear headsets tuned to their favorite music, others just the noise-cancelling headsets for silence.

As the daily grind and the cacophony to join this that and the other, to be known, to be heralded, to be retweeted, to be liked or to be commented about takes over our being, but through it all, the quiet seems also to have a quiet resurgence. In the 1980s 9% of the adult population was single now that number has steadily climbed to 16%. Solitude is not an illness or a disease of the mind. It is a conscious voluntary act of living in harmony. Just like silence is not measurable in ounces or pounds, in dollars and cents or in good and bad, solitude too is without metrics, except maybe in happiness!

Solitude and silence does not mean the absence of love and friendship. It means the opposite: tethered to the wings of silence, the two achieving greater heights in thought, in friendship, in love, in affection and in living.

The 90 year old lived for a few more years in the firm and ever present loving hand of her husband. When they passed away it was within a month of each other. The transference of the sole energy of each other’s silent love ceased and life became meaningless for the survivor. Their love was in the silence and their touch.

Tuesday, September 2, 2014


Some things are patently wrong and require the conscious to speak out...

I read about the King family that is awaiting extradition to the United Kingdom after taking their child out of the UK hospital where the child was denied the benefit of Proton beam Therapy for a diagnosis of Medulloblastoma (a brain tumor). It does not matter whether Proton Beam Therapy will cure or even extend survival of the child for that matter. What is important is that the King family’s desired to seek help on their own dime and not on the public dole, outside the reaches of the NHS and this want should not be the purview of any authority, state or liege.

What is beguiling is the long heavy arm of the law going after the parents whose only intent is to save their child. The father sold a home to have the money so he could seek Proton Beam therapy in one of the close neighboring European Countries. The parents decided to take the child out of the UK hospital in search for the medical help they sought. What could be wrong with that? The Public Healthcare of the National Health Services of the United Kingdom comes to mind? A denied need by the Central Planners cannot be overturned even if one wants to spend one’s own money? It is a system of Cost Control on the treatment of malignant illness! “No, that is not in the rule book, Sir!”

It brings the bile wave crashing at one’s conscience’s shores to allow something like this to happen. It is a travesty to prevent someone to seek a different modality of care. To exercise the long arm of the law and the heavy hand of the enforcers in order to quell such a desire is beneath a country that has always dedicated itself to Liberty and Freedom.

These might be the times the future will look upon with tinted shades. The darkness itself appears deadly and the only way to visit the present in the future will be to avoid it.

The King family now awaits extradition orders while the Spanish judge has enforced that the King family is barred from visiting the child and the child is now a ward of the court. A travesty upon travesty! What on earth is going on in these so-called “civilized societies” is nothing less than a value proposition that borders on barbaric.

Maybe sense will prevail. Just maybe?

Sunday, August 24, 2014


When one comes up on two diametrically opposing views, it turns into a learning experience of how both sides cannot proverbially see the forest of the trees? When one side claims and tugs and pushes its viewpoint to the point of abstraction and the other emulates with equal passion somewhere in that monologue from either side lies the seed for a dialog, a seed, that neither one sees. Don’t you think?

Two households both alike in dignity, are drawn to ancient grudge to bring proof of their supreme excellence. The Epidemiological house derides the Randomized Controlled Trial house as too focused and limited in scope due to its optimized conditions, which does not meet the requirements of the large populations. And that is true to a large extent, even Thomas Bayes, he of the English statistician, philosopher and Presbyterian minister fame would agree that using random samples can only have so much strength and integrity to export validity of a meager sampled experiment to an entire population.

Meanwhile the reductionist household of empiricists are also employing the same war chest. Both sides want to win the argument: Population statistics and results equate at the individual level and small samples of the population equate to the whole population is the new creed of this crude thought. Both sides employing similar tools are being drawn to a similar conclusion: The “missionary” work of the empiricists however would look at it the other way and say, “we, of the reductionist point of view, from deciphering the needs of a few can determine what ails the whole society. Our carefully crafted experiments see the forest as it represents itself !” They however momentarily forget those new saplings and an occasional oak on either side of their 95% curved landscape.

So who is right? Maybe neither!

The Epidemiologists now have a new war chest. The Biggish Data that they are fond of using for proof of their methodology seems to satisfy their needs. They no longer find the need to get their hands dirty. They merely need to ascertain the weight of the compiled digits that someone has keyed into the servers.  Data defines reality for all! Or does it? Is it the data, its selection or its manipulation that defines the concocted reality? One must also remember the Bird Flu A(H1N1) rallied by the World Health Organization as an pandemic in 2009, wasn't! It is a stark reminder of the strong carry-trade of emotional currency, when projections based on math overwhelm logic and reason! Not only was the logic denuded of reliable data but the fear-mongering projections thus mathematically reasoned were accentuated only by the comparisons between the Bird Flu of 2009 to the Influenza of 1918.

From the ePluribus Unum we have arrived at ex multis! John Snow, he of Cholera as a waterborne disease rather than air-borne fame, would be resigned to depression today. After all, epidemiology certainly has a part to play in protecting the population from potential risk, but utilizing the large umbrella of public safety could these experts venture into the habitat of the empiricists without so much as a nod to the causality, except by dint of thought or bias? In other words can the protective umbrella of the epidemiologist wrongfully detract from reality by force-seeking the causality without hurtling through the rigors of the empiricist’s evidence, which are similar in scope and therefore be blinded to project false causality to the whole or a select portion of the citizenry? Ah therein lie the seeds of discord!

Epidemiology studies are a boon for societies as a whole, if they are done correctly to find causal factors of potential vectors of the flame that incite wide-spread epidemics. But using limited data arrived at through statistical torture and casting it as a wide net of causality can prove a detriment to science itself. Today the rigors go so far as to admit and deny the causal factors of an affliction in the same breath. There are a lot of “mays” and “mights” thrown around for full disclosure and future immunity.

The purity of science is in the rigor and not in the shortcuts that one seeks today to publish, gain recognition, make a name for oneself, get a promotion and seek further advancement among one’s peers. That desire of self-aggrandizement, based on the mishmash of the scientific conversations in print seems diametrically at odds with good science. John Iannodis, MD in his article, “Why Most Published Research Findings Are False,” found that more than 50% of the experimental studies were unverifiable! With the 15-minute fame over, the focus of the scientist-statistician moves on towards new mining.

In the world of data-mining from large data-warehouses where any selected digit is a means to an end and reliance upon the statistical methodology so employed a means to a better future, science suffers from such inaccuracies. Both sides are embroiled in the latest rendition of such thought that would compile the argument into a tightly bound Confidence Interval and then determine the 95% probability making all other nuances of differing thoughts, mere distractions.

There is an epidemic of false starts and forced understanding in medical science today. It is time to unwind the clocks and rethink our future otherwise this pleiotropic nature of “one size fits all” will indeed one day end individualism, creativity and innovation. It is time for each side to think its own set of tools and merge the information for a unified theory of existence where real world problems are handled through real world thinking, not some sham-based probabilities!

Monday, August 18, 2014


The crispness of the morning breeze brings with it a shudder to the blanketed-warm skin, its freshness evokes desires and wants for more. Such is with truth, undiluted by the perpetual sea of falsehood, it forces within the mind, a revolution. Away from the interlocking strains of glorified lies, this monastery of reality stands firm against these manipulating truth defying savages.

It is the mark of an educated mind to be able to entertain a thought without accepting it. - Aristotle

The mind, the organ of intuit and reason, the wisp of nothingness that holds within its nebulous architecture, a version of reality, seems oddly the place where reality or for that matter anything should exist. Yet it does and no one has yet been able to decipher, what “mind” is or for that matter where it is?

Is mind a concoction of the human brain, deflecting responsibility of its own action or inaction? Is it the personage of the being? An oddly relevant companion that lurks in the shadows of existence, who no one can see, measure or understand, yet is probed for all things seemingly justified.

The new PET/reporter gene-PET/reporter probes might give this invisible existence, structure one day or may rob us humans of a perfectly legitimate scapegoat for our own misdoings. How then will we ascribe our socially wayward behaviors to the aegis of mind-control? And speaking of mind-control what about the realm of psychic warriors where exactly will their battalion of “seers” end up? If we can see the “mind” in action then the psychic domain becomes a visual for all to see.

This mind probing thing could bring with it an upheaval in human rational thought, couldn’t it? How would one translate, “In my mind there exists…” Yeah, okay, now where would that existence next find habitat?
Conjuring up the next artificial intelligent robot then could we sprinkle a little dust of the “mind” in it so that one day Asimov’s dream would come alive but at what human peril? I shudder to think about the HALs; their next generation! Imagine HAL 10000. “No you may not drink the 16oz big gulp…if you disobey my laser is set on stun.”

Yes but, some might like that idea. Why not empower robots to modify human behavior on the streets, after all those that envision such a life seem to want control and safety against all liberties. It would be well, until the laser is pointed at them.

Indeed life is about to change with 20 petabytes of data emerging every day and being harnessed in “warehouses,” “lakes,” and soon “cities” and “states” appear not too far behind. Analyzing them through the wonders of predictive models will bring the era of machine ordered security of the Jetsons or was it the Flintstones? And might not we humans end up in the “planet of the robots?” Something for Hollywood to consider!

So I ask you dear reader after that first chill of the morning air, a loaded cup of hot coffee and a desire, what would you do differently?

Tuesday, August 12, 2014


Targeting Therapy: Kinase Inhibitors

The human body functions on the backs of proteins called enzymes that modulate cellular behavior. These enzymes act as catalysts for a biochemical reaction within the human body milieu. One such class of enzymes called Kinases has a profound effect on the internal machinery of the cell. The human genome of 25,000 genes has a total of 500 kinase genes that have the ability to modify 30% of the genome.

With the advent of tumor genomics and high throughput machines the gene expression signatures has brought forth an array of medicines to counter malignancies.
Our understanding of the normal function of the kinases has enabled us to realize the pathology within. The governing gene of the kinases and their mutations, rearrangements and copy number variations can thus enhance, inhibit or modify the normal physiological function of the cell by interfering in the cellular signals and create chaos. It is this understanding and our ability to recognize that will help transform cancer care in the very near future.

A Kinase
acts as a mediator to transfer a phosphate moiety from the ATP molecule to a target substrate. A receptor recruited kinase most commonly such as EGFR is activated when the receptor plus ligand dimerizes the receptors and initiates the downstream cascade. The kinase phosphorylate other protein substrates to transduce the signal downstream via pathways directly or indirectly to the nucleus for enhancing proliferation or arresting growth. This act of phosphate transfer is called “phosphorylation.” Kinases have the ability to orient the substrate and the phosphate in such a manner so as to stabilize a high level energy reaction.
Courtesy McGraw Hill Companies

It is this activity that signals the interior of the cells to modify, grow, and self-destruct or cease-function. The kinases govern such initiation, inhibition or disruption of cellular activities, all through the charged phosphoryl-group. This regulatory function of the kinases comes from their ability to have reversible covalent modification of the substrates.
Courtesy McGraw Hill Companies

Such external modifying measures also create allosteric activity (feedback loops) within the interior of the cells that can potentiate and maximize the initial reaction.

Biotechnology companies are creating various Kinase Inhibitors. These inhibitors are used to suppress the kinase turned rouge -due to modification of its function as a forerunner of gene mutation. To prevent the mutated kinase from over-function and excessive uncontrolled cellular proliferation as happens in cancer, the inhibitors shut the signals emanating from the kinase and thus arrest any untoward cellular behavior.

There are a total of 60 Receptor Tyrosine Kinases (RTK) and an additional 30 intracellular Tyrosine Kinases that have been identified. Amongst the RTKs include the well-known families of: EGFR, PDGFR, VEGF, MET and ALK and amongst the non-RTKs included are: ABL, FES, FAK, SRC, IGFR and SCFR(c-kit) and JAK families. The various TKIs thus far developed include: Crizotinib (Xalkori), Dasatinib (Sprycel), Erlotinib (Tarceva), Imatinib (Gleevec), Lapatinib (Tykerb), Nilotinib (Tasigna), Sorafenib (Nexavar), Sunitinib (Sutent). Most are familiar with Imatinib against the BCR-ABL mutation in CML, Crizotinib against the ALK mutated lung cancer and Sunitnib against renal cell carcinoma. The list of TKIs in development currently exceeds 38 at this time and future studies will highlight the benefits of these developments.

Aside from the RTKs there are three other kinases worth mentioning: Cycle Dependent kinases (CDKs), Phosphoinositol kinase (PIKs) and Mitogen Activated Protein Kinases (MAPKs).The CDK enzymes regulate the cell cycle in mitosis. CDKs control transcription, metabolism and because of their role in cell division they are vested heavily via mutation in creating malignancies within lymphatic tissue, pancreas and breast tissues. The PIKs phosphorylate the Inositol, which regulates the Insulin signaling pathways and is involved in both cancer and Insulin resistance. The MAPKs are activated by mitogens such as Epidermal growth factor (EGF), platelet derived growth factor (PDGF) and Insulin growth factor (IGF) to initiate a downstream signal transduction into the nucleus via the RAF-MEK-ERK pathway for cellular proliferation. Again kinase mutations cause dysregulation of the cell growth in most cases leading to cancer.

A word of caution
as we explore and enhance our understanding of the new TKIs is that the benefits from TKIs appear to be temporary in most cases.
The reasons are many-fold; the feedback loop mechanism within the cellular interior may abrogate the inhibitor function, cellular cross-talk between different pathways may take over the function of the kinase and cancer controlled degradation of the inhibitor might undermine the kinase inhibitor activity.
A case in point recently featured in the New England Journal of Medicine showed that a mutation of the Bruton Kinase in patients with Chronic Lymphocytic Leukemia (CLL) resulted in resistance to Ibrutinib a BTK inhibitor that is very effective in this disease!

The changing face of Cancer Care...Sustainability, Durability and the hope of longer term survival!

(Hey, I didn't say Science was easy, but it sure the heck beats contemplating the navel!)


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