Wednesday, January 30, 2013

HER2neu and the PI3K/AKT pathway


Simplifying the Comprehension Chasm

“We are glorious accidents of an unpredictable process with no drive to complexity, not the expected results of evolutionary principles that yearn to produce a creature capable of understanding the mode of its own necessary construction.” ~ Stephen Jay Gould

There is a lot of discussion about cellular pathways. Almost every month it seems that there is a new drug marketed that inhibits a specific pathway within the cell and shuts down an errant behavior of that cell within the human body.

Pathways, pathway, pathways...

After all what on earth are they all talking about?

Pathways? What are these, like roads? Well not exactly, they are more like chutes and ladders, I think! The chutes take the information down to the interior of the cell, the nucleus while the ladders climb up the scaffolding to reach the inside part of the cells limit, the cell membrane. A built in feedback loop.

Okay, here is the deal. If you don’t click off now, I’ll tell you a little story:



One day a little mouse happens to run by large piece of Munster cheese. You know the kind that is better in taste than Gouda, has the sprinkle of red on its side and is just heavenly? Yeah, that one! Anyway as you might expect his whiskers erected at the site but he couldn’t smell it, because it was in a wooden container with a glass front.

He ran around with joy for a moment until the hurdle ahead became clear. He sniffed and sniffed and ran some more in encircling joy, but the cheese would not yield its scent, it was behind the “glass curtain.”

What to do?

His name was not Colombo for nothing, so he snooped and saw a tiny hole in the side of the wooden side piece. “There is a start,” he exhaled. He called out to his friend, Ralph who climbed the short table in a hurry at the news. And both of them started chewing away at the hole from the sides. The hole got bigger and bigger as the gnawing and chewing got effusive. Finally they could see inside the container.

Looking in, there was a surprise waiting for them; they found their little friend, Mark. He had already somehow gotten inside, the little trickster! He was inside the container but curled into a ball in the corner, apparently asleep. They called his name quietly and he awakened.



“Hey Mark, how’s it going?” Columbo asked.
“Who, What…?” Mark shook the dream away.
“How’d you get in there?”
“By accident, been here for ages, seems to me.” Is all Mark would say.
“Okay, buddy, we have a plan to get to that cheese. You with us?”
“Of course. I have been waiting for this moment, or the other when the owner lifts the wooden case and swats at me."


Mark described the inside that the container apparently had another chamber within where the cheese was placed. The cheese container was composed of a double chamber of glass. Realizing the difficulty, the two outside devised a method to push a small fork lying by the side in through the hole for the mouse inside to use as leverage to lift the inside glass enclosure.



After hours of work in the dark with all kinds of contraptions at their disposal, including flashlights, and spoons and knives, they were able to use the small fork as a fulcrum and lift the glass container, just enough for the inside mouse to enter the hallowed chamber where the cheese sat in perfect uneaten, rectangular state.

Soon the cheese was gone and the container empty and the three mice lay with their underbellies exposed, unable to move.

That is the P13K/AKT pathway - in the mousy world! For the human world, here is a more deliberate but tedious exercise...

The messy receptors and the signaling pathways that litter the inside of a cell! (from Cell Signaling)


The cell surface has receptors that attract growth molecules. When these molecules attach to the receptor site, they trigger an over expression or dimerization (merging with another of its kind) to help propagate the signal. So having gained the growth molecule...

The dimerization of the Receptor Tyrosine Kinases leads to the activation of the PI3Kinase. The active PI3Kinase migrates to and docks with PIP-2 a serine-threonine kinase with its lipid-layer docking-site on the inner side of the cell membrane. The phosphorylation of the PIP-2, leads to an activated PIP-3 which in turn activates AKT and that circulates around the cell cytoplasm, invoking different mechanisms of action:

PI3K / AKT Pathway


a) AKT binds with BAX, which shuts down apoptosis, (the chute mode) Akt is a major mediator of cell survival through direct inhibition of pro-apoptotic signals”

b) AKT enhances the protein synthesis through RheB impact the mTOR pathway, which activates S6K that binds to the ribosome and produces messenger RNA to produce the protein for cellular proliferation (the ladder mode). (Inhibitors of mTOR include: Rapamycin, Metformin and Starvation)

c) AKT can merge with FOXO a human tumor suppressor protein and restrict it’s function by enabling cytoplasmic sequestration and thereby allow the tumor or cancer to grow at full speed(The chute mode).

Realize the conundrum?




The mentioned modes of operation are limited to only three, but there are many other mechanisms equally as effective in promoting cellular division and proliferation of the cancer progeny. The Akt cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, G protein coupled receptors and other stimuli that induce the production of phosphatidylinositol 3,4,5 triphosphates (PtdIns(3,4,5)P3) by phosphoinositide 3-kinase (PI3K).”



So the dimerization (Two pieces coming together) of the RTK is the combined effort of Columbo and Ralph, while AKT is Mark, who is given and uses various different mechanisms to lift the interior glass chamber to get to the cheese. The cheese here is the excess luxury food that the mice eat that fattens them and drives them into an obese food coma and ultimately kills them (maybe via excess Insulin Receptor Site-1 (IRS-1 that is an important mediator in the promotion of the PI3K/AKT pathway, but that is another story). No, no, maybe not! Okay, bringing that out in the open and away from the brackets, let me discuss the importance of the IRS-1 both in the Diabetes pathway and cancer promotion. The risk of high Insulin levels (as in Insulin Resistance) trigger the Insulin Receptor Factors  (IRS1 and IGF) that activate a downstream signal transduction through the various other -not mentioned -pathways into the nucleus of the cell to initiate/promote a potential or actual malignant process.  “There is a link, then, Isn’t there?” you cry. “Yes indeed! Observational studies seem to imply a higher incidence of cancer in diabetics for a reason after all.”

This vile behavior of AKT (Mark) creates mechanisms to shut down the suppressor proteins (FOXO, that acts as a kill-switch for abnormal growth) and/or excite the "promoters"(activating S6K) to perpetuate the cellular growth via the messenger RNA, into the bloated cancer that eventually kills.

But what of the HER-2-neu you ask?

HER2neu protein molecule


The Receptor Tyrosine Kinases are the Epidermal Growth Factor Receptors or EGFR/erb and the HER-2-neu is one of the four EGFRs. "HER-2/neu (erbB-2) encodes an 185-kDa orphan receptor tyrosine kinase that is constitutively active as a dimer and displays potent oncogenic activity when overexpressed." The “HER” stands for Human Epidermal Receptor and the “neu” stands for neural factor (It was discovered in a rodent glioblastoma initially). So the PI3K/AKT pathway is subservient to the HER-2-neu Receptors as one of the many triggers. (Besides HER-2-neu there are also several other receptor sites that exist on the cell surface that can provoke the PI3K/AKT pathway).

Considering Her-2-neu is Colombo and Ralph is HER-4 and these are two brothers in a four children family that got together to go after the cheese.

MAP Kinase pathway


The Her-2-neu protein is managed by the ERBB2 proto-oncogene that resides on Chromosome 17 ~ which is the switch! And we have a few antibodies directed mechanisms against the HER2neu: including Herceptin and Pertuzamab others...

Herceptin: that Blue "Y" thingy on top!


And just in case you think there is only a single version of a PI3Kinase, you’d be off target. There are many isoforms of the PI3Kinases and they are expressed in various degrees. “For example, the expression of p110! which is generally thought to be ubiquitous and uniform in various tissues, appears to be markedly enriched in the non-proliferating tumour regions of ovarian cancer in vivo.” ~ Interesting!



Other mechanisms also modulate the PI3K expression especially the p53 gene/protein. Active over expression of p53 suppresses PI3K activity ~ a good thing!

RAF / MEK pathway


“Indeed, p53 overexpression reduces p110" protein levels, whereas suppression of p53 expression increased p110" mRNA and protein levels. These data are in line with earlier reports of negative regulation of PIK3CA expression by p53.”



Just like p53 can act as an inhibitor there are promoters of the signal excitation and transmission: “Recently, three studies have begun to characterize the PIK3CA promoter, indicating that p110" expression can be positively controlled by FOXO3a (forkhead box O3a) and NF-!B (nuclear factor-kappa B) ( NFkB is one of the inflammasones, molecules that is triggered and is intimately involved with the process of inflammation ~ as all chronic disease, including diabetes and cancer have a large underpinnings of the inflammatory component embedded within).



Additionally Estrodiol has an impact on PI3K expression too, “In several cell types, stimulation with estradiol leads to an induction of PI3K activity, ranging from minutes to hours The immediate increase in PI3K activity upon estradiol stimulation is likely due to a direct interaction between ER! and p85! leading to increased PI3K recruitment to the plasma membrane. Yet, in MCF-7 breast cancer
cells, Akt phosphorylation was increased up to 72 h after estradiol stimulation and is accompanied by an increase in p85 protein expression, suggesting that enhanced p85! expression might result in increased PI3K activity.” This brings us the Estrogen Receptor triggers seen in various cancers, especially breast cancer and others like ovarian cancer, colon cancer, uterine cancer and prostate cancer. All Receptors by the way have a controlling genetic switch behind them. For example the ER receptors are controlled by ESR1 and ESR2 genes found on 6th and 14th Chromosomes.

The entire process is an elegant dance between need and desire. Need, after the cell has achieved its growth phase it sends back a feedback via loops to shut down further transmission of any proliferative signals. In the desire version, it is the desire of the growth ligand (attachment) that triggers the receptor to over express itself or dimerize (join with its counterpart) into keep signaling, to the nucleus, unchecked. 

By the way most of these receptors are needed during the early formative years to shape our human destiny. It is the over stimulation that leads to trouble in most cases. For example take p53 (aka The Guardian of the Genome) without this the cellular division if left unchecked leads to untold human misery. (Li Fraumeni Syndrome). The p53 monitors any mismatch occurrences within the swapped codes between mother and daughter cells. Any abnormalities in that DNA code is picked up by p53 and the cell is thrown in the trash heap for recycling.

Under un-stimulated conditions the PI3K expression is under a tight transcriptional control via miRNA. Over stimulation leads to the dysfunctional signal propagation and that leads to a deregulated cellular behavior. (I repeat myself sometime)

Okay! Okay! I didn’t say that the metaphor was that foolproof! But hopefully you got the gist. And here is another disclaimer, there are many other crossroads that link AKT to the nuclear proliferating machinery with many other negative and positive feedback loops to accelerate or decelerate the cellular division ~ that we know not of -yet!

Oh and while I am at it, if one considers the PI3K activator as the leveraging fork, then the treatment paradigm might just nicely fit into our little tale of the tails. Stop making the tiny forks and make more chopsticks (PI3K inhibitors) instead. The thought can be quite moving if you swim in it for a while.

(cartoons employed from articles below, Genentech website, the web and Cell Signalling).

REFERENCES:

Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF (2008) The PTEN/PI3K/AKT signaling pathway in cancer, therapeutic implications.  Curr Cancer Drug Targets 8(3), 187–98.

Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8(8), 627–44.

Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7), 1261–74.

Yang, N. et al. (2008). Transcriptional regulation of PIK3CA oncogene by NF-kappaB in ovarian cancer microenvironment. PLoS ONE 3, e1758.

Geering, B., Cutillas, P.R., Nock, G., Gharbi, S.I. and Vanhaesebroeck, B. (2007). Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci U S A 104, 7809-14.

Okkenhaug, K. and Vanhaesebroeck, B. (2001). New responsibilities for the PI3K regulatory subunit p85 alpha. Sci STKE 2001, PE1.

Lee, Y.R., Park, J., Yu, H.N., Kim, J.S., Youn, H.J. and Jung, S.H. (2005). Up-regulation of PI3K/Akt signaling by 17beta-estradiol through activation of estrogen receptor-alpha, but not estrogen receptor-beta, and stimulates cell growth in breast cancer cells. Biochem Biophys Res Commun 336, 1221-6.

Hui, R.C. et al. (2008). The forkhead transcription factor FOXO3a increases PI3K/Akt activity in drug-resistant leukaemic cells through induction of PIK3CA expression. Mol Cell Biol, epub

Astanehe, A., Arenillas, D., Wasserman, W.W., Leung, P.C., Dunn, S.E., Davies, B.R., Mills, G.B. and Auersperg, N. (2008). Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer. J Cell Sci 121, 664-74.

Bandyopadhyay, G.K., Yu, J.G., Ofrecio, J. and Olefsky, J.M. (2005). Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54, 2351-9.

Castoria, G. et al. (2001). PI3-kinase in concert with Src promotes the S-phase entry of oestradiol- stimulated MCF-7 cells. Embo J 20, 6050-9.

Simoncini, T., Hafezi-Moghadam, A., Brazil, D.P., Ley, K., Chin, W.W. and Liao, J.K. (2000). Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538-541.

Guo, C., Sah, J.F., Beard, L., Willson, J.K., Markowitz, S.D. and Guda, K. (2008). The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3- kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer




Sunday, January 27, 2013

The PATIENT (and the Swarm)

 

A society as fragmented as ours that takes the daily push and pull of the verbal and digital swarm, lives on the edge of its sanity. There is a shyness mixed with fear. A fractured thought that regales the mind and keeps it teetering between this and that. Never a cohesive thought, our minds are the arbitrariness of jumbled thinking. We are addicted to the addiction for bits and pieces of fragmented information, trying to unearth explanations and reasons for this fracture.

The daily digital swarm litters the landscape, like the sea washing cracked sea-shells on the shore; pieces with little meaning or beauty. We spend hours piecing them together under the waning light of the day, trying to find some meaning, after all once the fragments belonged to a whole.

Every day breaks the code of the previous one. No it is this and not that! Yesterday’s edicts are meaningless echoes, swept away by today’s bright and shiny new.

"Too much information running through my brain, too much information driving me insane." The Police

Caught in this terrible cacophony is the lone and pleading voice of the patient. The competing voices that barge against his eardrum get louder and louder to win support from his senses. And he listens, for support, for comfort, for any and all help.

The voices are many.

The PATIENT and the swarm (by: PDara, MD)


The emotional cascade runs afoul.

Jason, a stockbroker who lived a good lifestyle, lies on the white sheets, impaled with the word cancer. His ashen face and wide red-rimmed eyes are a testimony to his fears. He looks for meaning, for answers and he finds many.


Doctor:

“Jason, things will be okay.”

“Jason, don’t worry we will do everything to get rid of this.”

“Jason, we will try this new treatment plan for you.”

“Jason, there is one more thing we can try, if you want.”

“I am sorry Jason, but there is little we can do.”

Family:

“Don’t worry honey, we called the “superlative” institution and they have a new trial program that has a lot of promise.”

"Thats right! I saw it on TV."

"Yeah, thats true, I read that in the recent journal."

“Oh dear, I don’t know if I can take this.”

“What am I going to do?”

“We must be strong for his sake.”

“Oh the poor thing is suffering. Oh how I wish, I could make it go away.”

“Oh is there a heaven? He was always so good.”

Friends:

“Jason buddy, we are here for you.”

“Jason, Emily sends her love.”

“We are gonna miss him.”

“We have to put a cheerful face for him.”

“I don’t know if I can bear to see him.”

Family:

“What are we going to do now? There is no other income. We don’t have savings!”

“Who is going to take care of us?”

“I have to get a job. But there are no jobs around?”

“Don’t worry sweetie, we are here for you.”

The evening sun filters through the window shades and paints the inside of the small hospital room golden. Little by little the voices recede and the overhead speakers call for the visitors to leave. The nurse walks in smiling with empathic but worn out eyes and asks Jason, “How are you feeling?” He nods.

He has seen this play out before. He remembers the attribution bias. The stock falls and the fear of loss is covered over by the desire of retribution and recovery. The stockholder against all advice continues to pine for its recovery as his wealth dwindles steadily in the daily ebb and flow. Buoyed by the minor up-ticks and terrified by the constant surrender of wealth. The drama plays out to its bitter end.

In the quiet of the twilight, he turns his head towards the window and a solitary tear rolls down his eye, leaving behind a trace of salt.

His mind is clear. His thoughts are crisp. His reasoning is strong. He knows his life is at an end. And no human can help him. The cacophony must die. It is time for peace.

Rest in Peace dear Jason.


Tuesday, January 22, 2013

YORICK'S SKULL


"Alas poor Yorick, I knew him…"



There are days of reflection, where the past looks crystal clear and the future dull and pasty. Is it my bias that reigns in these events? Is it the longing for the days gone by, when things were simpler? Is it?

Perhaps!

But perhaps it is more than that. Maybe there is a locked door to the past that opens up when the door that you see in front seems barricaded. Maybe the longing for the past is a simultaneous event, when faced with adversity that forges a benign memory of the days gone by.

Yet people say that when adversity aligns in the stars there are opportunities. My question is for whom?

And there is where we lay our scene…

I met a former fellow physician the other day. We talked about life. You know the kind of things physicians talk about. “I had this horrendous aortic aneurysm, the other day…” And so the stories went. One after another the cautionary tale of the human frailty laid itself bare.

Somewhere in that conversation his demeanor changed. “In the good old days, we worked hard and we had something to show for it; patient’s gratitude, a reasonable compensation for the surgery performed and a few winks of sleep and an hour or two with the family,” He shrugged his head, “but now it is expected without any gratitude, minimal compensation after weeks of haggling with the insurers, and fewer winks and almost total isolation from the family due to lack of hours in a day.”

There was a pregnant pause, pregnant with thought and frustration. I looked at him and unable to contain the urge, he went on to reveal his inner fear, “I don’t know that I can do it much longer.”

“You are a good surgeon,” I looked at him in all sincerity, “your work is needed in the community.”

“No there is no loyalty anymore. If I leave tomorrow others are there to fill in, in my shoes.” He looked at his hands clutched tight on the table between us. “We put everything into a patient, our thoughts, our fears, our desires, our years of knowledge and experience before and during our management of their disease and all we get is, ‘how bad doctors are.’ We are maligned for doing too many tests, we are castigated for earning too much, which by the way is a fantasy created by the media. I barely made $150,000 last year after working 70-hour weeks. Besides the medical malpractice risks, the onerous regulatory compliance and the daily drumbeat of new demands placed on me, what’s the point?”

Ah the slings and arrows...

What is the point I thought? He was right in his thinking. How had we come to this?

“And to think I paid $35,000 for the new EMR system in the office and Medicare denied me the promised reimbursements because of lack of “meaningful use.” I spoke with other docs and they told me they had to hire a Medicare certified company, another middle man earning big bucks, to send in their papers. All the dots had to be in the right boxes, otherwise the computer spits them out.”

There was nothing more to say. I looked at my hands and hey too were clutched with the knuckles all white. A thought came to me…

“Why don’t you join or create an ACO?”

“I looked into that. That is another clever way to cut into physician reimbursement. The ACOs contract for a capitated fee and over time the insurers will pit one ACO against another to reduce payments.” He thought for a moment and then said, “Wouldn’t that make it so convenient for the insurers? One swipe and an x-amount of doctors, or providers as they call us, will be knocked down in reimbursement. More profits for their shareholders.” The revulsion in his face was obvious. “What a concept?”

“But in the meantime, you will have saved yourself a lot of headaches.” I replied.

“Not sure, that I will.” It will be another hamster wheel!”

“I don’t…don’t know what to say.” I stammered.

He looked up and a spark came into his eyes. “Maybe I can go back to fee for service, like in the old days.”

Yes Maybe…

As Hamlet looks at Yorick’s skull and contemplates those glory days spent, with his father’s court jester, when life was full of promise and compares it to now, where he sees the same world through a different lens, colored by the whips and scorns of experience. The world has lost its enchantment. As in all wonderful notions of implied easement of human sufferings, eventually the creators of such phantoms of false mirth reach the same wanton act of chivalry, as when their skulls that had a tongue in them once, are nothing more than a means to block a gaping hole to steel against the raw winds of time.

There is a blank anonymity in death!

Remember the skull, it will be yours, one day! Great powers and fortunes in all hands will leave. Emptiness will reign. So think well of those whose labors you wish to demean.

Should one fight or lay down against a sea of troubles?

"To be or not to be, that is the question."







Wednesday, January 16, 2013

OPEN ACCESS


O
P
E
N
Access

Medicine as Science lives in the shadows of vulnerability. The granite conformity that exists if peeled would reveal the distortions and countless contrary opinions. Each layer has been imbued with the color of discord. The problem that discord does not reach the lighted hallways.


The medical venue is rich in its diversity in spite of the outward image of uniformity. For so long the shroud that has covered - protected that image, is finally being swept away. The hidden knowledge up until now available to a select few is falling in the hands of more. No longer does one have to find and comb through the journals stored away on shelves of a hard to access medical library. The written word once ensconced in the hallowed halls is at the fingertip of anyone with access to a computer, jacked into the Net. This medium not only allows the ability of fast access but also allows those hitherto with dissenting voices to express their rants to merge with the raves.


The tedium of the glacial paced written word on a journal’s page is now available instantly and open to question in some venues. The richness of differing opinions prevents a well-articulated -but minimally reviewed article, to become the hard currency of thought, Open Access will change it. Previously this currency, could lay its foundation into the minds of many scientists and physicians and become semi-permanently inked. It would become the style of thought and the mode of action, taken down only after a considered rebuttal after an agonizingly long time. But that is a-changing.



Or at least I hope it is!

The past, although rejoiced for its many advances has also been the historical review of too long entrenched in a thought that went unquestioned for too long. The promoters of such thought for whatever reason, either drenched in egotism or delusional perceptions, failed to call their own data into question. Now change is afoot; the thousands of pairs of eyes that review such information are armed with easily available broad spectrum of knowledge that can critique any potential error before it gains semi-permanence.



Through the strict principles of science, rigor, experience, experimentation and review at the most basic of levels, a plethora of faulty papers are being discussed. The authors that have committed such heinous travesty against science (and humanity through science at times) are being taken to task one by one.



Open access is ready to revolutionize the science and soon in the near future, the art of medicine. But there are flies in the ointment; if the finder of the research pays for the online publication for open access then one might consider a conflict of interest, or if the peer evaluation process is based on "single blind" analytical review then bias can creep in. Here lies the broadened knowledge base of the reader, who, given this open access can now make a critical and qualified evaluation of the study for all to consider. More eyeballs equals more scrutiny! The process does and will on a rapid basis weed out the charlatans and bad or junk science. The written publication which, moves at a glacial pace from completion of the study to information dissemination for consumption, equally hampers the flow of knowledge and criticisms through letters to the editors taking even larger parcels of time to get through to the authors. This infernal tedium, makes the old printed publication process archaic, yet relevant. So time helps keep the author's ego in check and his or her cling to power.



And yet there is this firewall of secrecy that enshrouds some of the research data, hidden in vaults and away from the eyes of the very people who could with access to that knowledge change the thought. Protectionism at the cost of a potential scientific revolution! Such triviality in thought and action conspire between the hoarders and the posse that support such a malignant attitude towards science. What are they hiding? Facts, or fiction labeled as facts?



History has taught us that a published journal article without the applied criticism can become ingrained into the minds of the scientists especially the physicians and thereby can alter patient care and management. Equally this sluggish pace leads others to using the "published article" as a reference in future studies thus contaminating and obfuscating the truth. A recent case of a Duke University scientist, Dr. Anil Potti grabbed headlines when his study could not be reproduced by others but at time of discovery, Dr. Potti's article had been cited 100 times in the scientific literature- the contamination had gone "viral." The drama has ended with his resignation from the university. Other notables of ill-repute in the recent past include; Maria Carmen Palazzo, a psychiatrist on the payroll of GlaxoSmithKline has been sentenced to 13 months in prison after pleading guilty to committing research fraud in trials of the company’s antidepressant Paxil on children. Dr. Scott Reuben, a Massachusetts anesthesiologist with several hundred papers to his name, 21 of which were found to be pure fiction pleaded guilty to charges of research fraud in 2010.
The dilemma of fraudulent research is significant; Dr. R. Grant Steen in the Journal of Medical Ethics reported that 788 retracted papers from 2000 to 2010. Steen's research found that U.S. scientists were lead authors on 169 of the papers retracted for serious errors, as well as 84 retracted for outright fraud. This practice, although rare in overall terms (1 in 6109 published paper is retracted or 0-0164 retraction rate) is also prevalent in other countries: China with 89 retractions, Japan with 60 followed by India and the United Kingdom.


Additionally there is monetary cost associated with this fraudulence. Researchers from the Roswell Park Cancer Institute in New York have developed a model that estimates the monetary costs of scientific misconduct cases placing a direct cost of investigation for each case at $525,000.00 or $110 million for 217 cases of alleged misconduct in 2009..


Today's headlines are tomorrow's footnotes and in some cases, day after tomorrow's retractions. The open access process would, given a wide net of critical thought, clear the cobwebs of improper technique, observer, selection and a whole host of biases with quick dispatch. Although hoped but improbable, it certainly will not weed out all bias or errors and in fact it might add unneeded and questionable comments, but on the whole it will purge the unnecessary, the delusional, the slipshod- intentional or otherwise, the dogmatic and the unexamined axioms of scientific arguments. The discordant clamor and exposed inattention from diverse viewpoints will eventual loosen the grip of firm misconceptions revealing a truer reality.



What Open Access will do, is water the fertile minds and allow them to grow even bigger and better ideas. 

Medicine is at the threshold of a transformative change. Open access will enable a larger number of researchers and would-be researchers to have access to information that might lead to new ideas. Each new idea can generate a new hypothesis and thus a new scientific breakthrough. This arborized arterial knowledge base will herald a new era in understanding. A minority opinion based on legitimate scientific research can call to question the stranglehold of the conforming thought. The partitioned cells of knowledge will coalesce into an amalgam of richly diverse easy harvest, for use.

Suppose you want information about a specific gene function and related research, it will be a click away. The isolation between scientists will end and even though the desire to compete for the top prize will always linger, as it should- since we are humans, the shared information will give others in the field help with their own research. It might force competitors to exceed any self-imposed limits. More importantly it will bring the breakthroughs closer and faster to the practicing clinician who can formulate the best plan for his or her patient. And in science itself a new thought into a concrete reality.

Scientific rigor will increase, it will help the competition and bring products to fruition faster to market. Eventually as now the winner will always be the one with the ideas, the desire and the one who burns the midnight oil. It will not be the one who contemplates, worries, closets and hoards the data, which  sits fruitless and awaits a key to unlock.



Where does one go today in search of this scientific grail?

There are easy search engines that provide free information backed by peer-reviewed scholarly information. The list by no means is complete but serves as a starting point.
There is a vast growing library that can be freely accessed today:

Directory of Open Access Journals: http://www.doaj.org/doaj?func=findJournals In Health Sciences alone there are 422 journals dedicated to General medicine, of which 252 are  internal medicine related, 78 are surgery specific publications and 70 related solely to oncology.

Among the many other free access areas, included below are a few that can be accessed via computer or through iPad apps:

PubMed. This excellent resource gives abstracts of all available information in its database. There are free full text articles also available. Those that are in abstract form can be purchased through a separate online source. But the diversity of the information available makes the search more productive for a specified query. An app for the iPad is also available.

Medscape: This resource is an excellent collation of recent scientific data well referenced by peer-reviewed scholarly articles. An app for the iPad is also available.

Google Scholar: The references mentioned here are similar with an as yet smaller database than that which is available in Pub Med. But it is growing rapidly.

PLoS Tree


PLoS (Public Library of Science): This online service has scholarly peer-reviewed new articles unpublished elsewhere open access for all. The references are excellent and an app for the iPad is also available.

PNAS or Proceedings of the National Academy of Sciences is considering online publishing (PNAS Plus) as a major format starting in 2011. Other major leading widely read scientific journals including Science, Nature, JAMA and Cell amongst others are also online bringing abstracts and an occasional full text article to the public for free. Times-are-a-changing when 20% of all peer-reviewed scientific articles are available through open access!


These examples are heralding a future of intellectual properties freely available to all. Some are free and some tease with abstracts only, hoping to sell entire articles for a price, I believe time will dispel such pecuniary limits.

Like the HIGGS express, share and enrich lives with understanding


And although open access is the wave of the future, just like any other new paradigm its control has to remain with the users. A worrisome historical record encountered in the book “The Master Switch” by Tim Wu suggests that when a technological breakthrough paradigm sprouts its wings, there is a desire by some elite to control and manipulate it. Vigilance, in a dialogue for openness will always be a prerequisite for open access survival.

 Open Access CHAMPION; Aaron Swartz, 26. RIP

Saturday, January 12, 2013

OWNERS into OWNED~>The Physicians



It is the comfort away from the difficulty. It is the ease away from the decisions. It is the many-imagined virtues over the many-imagined vices. The doctors are moving away in droves from being owners into being owned. The new owners cite an endless litany of the benefits; no more paperwork, no more meeting payroll, no more regulatory issues, no more complaints related to the business of things. “Its all about you’re being able to practice the art and science of medicine in peace without the headaches.” They say.

That sounds great, doesn’t it? Or does it?

I asked this of a private practice physicians looking into becoming a hospitalist.
“Yeah, but imagine, if there was a lull in the patients, I would still be guaranteed a salary.” He wrung his hands in anticipation. “I would be practicing medicine and at the end of the day, just like the nurses and the transporters and the house-keeping people, I would go home without the aide of a beeper. Just me, my world and I! No tethers!”

That did sound like a good sale of goods.

“But what about the demands of the hospitals?”

“What demands?” he raised an eyebrow.

“Well, like issues of cutting costs by reducing the diagnostic procedures and in some cases advocating against certain therapies related to age, infirmity etc.?”

“Oh, I don’t think that will affect me. Besides, I told them, I’ll practice my kind of medicine. And they have agreed to it.”

“Really?”

“Yes.”

“But don’t you like being the owner. Calling your shots of when to go on vacation, how many patients to see, what type of patients to see, how much time to spend with them and their follow-up care?” I inquired.

“At this point, with all the government interference and the pressures to perform the regulatory dance, I am tired of this nonsense. Let me practice medicine and let someone else handle the headaches.”

Sounded good, the way he put it.

Anyway one year later, I met him again, this time his face was a little downcast.

“Hey how goes it?”

“It’s o.okay.” There was a hesitation in the okay.

“Enjoying it better than your own practice?”

“Yeah a little.” He hesitated.

“You seem unsure.”

“I, I am not making as many decisions as before. Something is amiss.” He said with downcast eyes.

“But you have time off, right?”

“Yes, but, I go home thinking about the procedures I did and never get any feedback from my… or… our patients, or from my colleagues in the outside world or for that matter within the group.” He said. “It appears that the 9 to 5 job environment creates a 9-5 job mentality.”

“I don’t know what you mean?”

“You know what I mean.” He chided.

I met him again two years later at a national conference and he looked unhappy.

“Hey there! Is everything okay?”

“Not so good. My contract was terminated by the hospital because of ‘productivity’.” He said, “Imagine! They cited the cuts from insurers and the cost of my care delivery to the patients. It was more like what was asked of me that I could not deliver.” He looked up with a hint of red rims around his eyes. “Now at my age, I have to look for a job or restart a private practice, which is next to impossible. DAMN them!” His arms were limp by his side and his eyes told the tale of woe, much more then the words that he uttered..

Sadness is the state of affairs when we allow ourselves to hand over our liberty and freedom to another. Where the imposed mini-hassles on a private practice makes us modulate our decisions and become stronger in our governance, these magnified hassles are forcing us to abdicate our responsibility. We are  falling into the trap of a pink slip and loss of control. 


Morlock (The Time Machine, 2002)
Eloi (The Time Machine, 2002)

A costly reminder lurks in this encounter. It reminds me about H.G.Wells mythic residents; the Morlocks and the Eloi living 800,000 years in the future. The elite "cared-for" and the "worker-class" complex was the premise behind The Time Machine. But adroitly H.G. Wells realized that the working Morlocks would end up attacking the elegant Eloi for their own sustenance.  (again you might have a different opinion of the book)

Morlock massacre (from Comicvine)


And that reminded me of the French Revolution and the inept King Louis XVI!

Storming of the Bastille

The catch-words of today for the hospitalists are:

  • Attain rapid improvement of patient satisfaction.
  • Assess individual hospitalists according to patient satisfaction scores. ƒ
  • Benchmark hospitalists according to patient satisfaction scores.
  • Align bonuses to individual patient satisfaction performance.
  • Track hospitalists’ patient satisfaction performance over time and assess performance coaching effectiveness.
  •  

This is the bureaucratic format that fills the forms, applies the binary code, assesses and then calculates the "statistical significance". All the words are carefully chosen to appeal to the sense of duty, a sense of comfort, a sense of responsibility. They are carefully weighted in the formulae to reach the ultimate answer selected prior.  But that is all they are, just empty WORDS used for forcing a mindset of "cost-efficiency" and nothing else. This mindless prattle that is pervasive in the society today is a nightmare that will startle us into a bleak awareness one day soon. Today's "intellectuals" that have never practiced medicine a day in their lives, sit in their ivory tower appointed seats and perpetuate their axiomatic concepts into reality. Failing which they are eager to deploy another one.

The hurtfulness of little hassles created by the insurers and government, are constantly eroding our sense of comfort and forcing us into decisions away from the difficulties of personal responsibility in medicine, to a more corporate approved and funded program of basic utility and a bureaucratic unemotional dispatch. This is the progressive emotional runaway with nary an impediment ahead. The roads all lead to homogeneity of thought and loss of individual excellence. Where will be the Jenners, the Watsons, the Cricks, the Salks and Sabins? Will they rise above the fray of this mush that we are creating? We need the tinkerers. We need the entrepreneurs. We need the Risk-Takers. We need the fertile minds, unbiased by the mandates of imposed guidelines. We need the freedom to think and experiment and operate! We need to create. We need to build. We need to understand. And above all we need to REASON.

There are no floating islands of Shangrilas out there (maybe in our minds)...



There are no pies in the sky either (maybe in our minds)...



But there are the cold hard facts!

Maybe it will be okay under a new master?

But then again, maybe it won’t!

Time will tell…

But who will ultimately suffer is the patient, like Oliver Twist, who wanted just a little more and the doctor who wanted to give that little extra bit of time, attention and comfort…

References:
http://www.jaoa.org/content/104/9/364.full

http://www.pressganey.com/ourSolutions/hospitalSettings/satisfactionPerformanceSuite/hospitalistinsights.aspx


Tuesday, January 8, 2013

A Fragile Society


Stochastics... the end of reality and maybe the beginning of the end.

Read on...

The human element as some evolved intellectuals refer to themselves is composed of a fair number of basic elements, with Oxygen (65%) being the most common of all. Carbon, the basic unit of all organic molecules comes in at distant second place. Since the cells are composed of 65-90% of water weight, it is no wonder that Oxygen is the most prodigious element within the human element. Aside from Oxygen, Carbon (18%), Hydrogen (10%), Nitrogen (3%), Calcium (1.5%) and Phosphorus (1.0%) round out 99% of the total element base. Most of the remaining 1% is composed of, Potassium (0.35%), Sulfur (0.25%), Sodium (0.15%), Magnesium (0.05%) and other traces of Copper, Zinc, Selenium, Molybdenum, Fluorine, Chlorine, Iodine, Manganese, Cobalt, Iron (0.70%)Lithium, Strontium, Aluminum, Silicon, Lead, Vanadium, Arsenic, Bromine (trace amounts) – The elements of “Star-Dust.”



Why would I spend regurgitating such a litany of chemical names to bore you? Well consider the domain of the human element itself. It is this, a rather fluid and almost ripe medium for an external invasion, wouldn’t you think? I mean, seriously grasp the basic tenet of this argument by the neck and you can see that the ebb and flow of other microbial life can easily find “the rivers of plenty” in the human body to float in, proliferate, cohabitate and prosper, even to the detriment of the host.



The eco-system that some espouse, via agencies such as EPA to prevent and preserve the environment, fail to conceive of the environment within their own human element! But finding fault in others is the incomprehensible, but state of the art, schoolyard gambit of the elite. It maybe time for them to contemplate on their own navels. You see just like "tampering with nature" by exterminating one species ends up with unintended consequences. Reducing or eliminating minor stressors in daily life will lead to future tumult. 



We are a society, given to the excess of thought (sometime useless) like everything around us, we wish everything to be in a smooth and orderly fashion. There should be no rip-roaring ragged cliffs or deeply gashed valleys, just the smoothened road like Route 80 from Coast to Coast. But therein in the stochastic of our existence, we have also invoked and unveiled the most terrible of all curses. We have brought to bear the concept of sterility in all things, big and small. We have turned ourselves into the “bubble-populace!”

The human element is an evolving piece of ingenious machinery, conceived and crafted by the Great Tinkerer. By Creating the largesse of an “eco-system” of life from where to gather and learn from each other, becomes the single opportunistic directive for this human species that has managed to forge an intellectual bent some 2.5 million years ago (The dent in the left temporal region and the frontal region of the skull: where language, speech and decision-making lie).



Anyway, here we are floundering at the ragged self-replicating Mandelbrot’s .......



......coastline of disorder creating more chaos. We fail to see the ordered intelligence within the fractal coastline. We are busy bringing mounds of sand to smooth the coastline, knowing full well in the back of our minds that eventually there will be price to pay, through the ravages of a tsunami or an earthquake. We fail to heed that nature makes its own tracks.


A Mandelbrot Fractal


Think, how the species has evolved? Somewhere a long time ago, a unicellular organism (archaea) ingested a plant life (mitochondrium) and together they forged the self-organized, energy-independent cellular system that was to become the basis of all life form.



Now let us think some more about this incorporation of another life for a second.

The presence of Junk DNA in different species


Dwelling just a little on the DNA itself. There are Introns and Exons present in the helix of our life. Majority of the DNA used to be called “Junk DNA” because of our limits of understanding. 




Now comes the world-view that indeed here lie the species transforming gateways delivered onto us humans via the microbial life itself. Resplendent in their invisible but very able selves are the very essence of making life the fittest for survival.

Rut Roh!

Junk DNA may also be the very reason that life evolved as it did. Humans have the largest component of Junk DNA compared to all other forms of life


Translating Invasion through Invasion


What?

Oh yes! Indeed. Our exposure to microbial life is conducive for survival for both species. The microbes, be it viruses, bacteria, fungi, all serve a purpose in propagating and strengthening the future of life and by extension humanity.

I show this to show that exposure to constant radiation to certain form of bacterium resulted in the Radioduran Duran bacteria that is Resistant to high doses of radiation!


How?

Well, think about this little paradigm quietly. How many “bubble babies” can survive this harsh climate where microbes make our population look puny in numbers and abilities? The constant tug of invasion by the microbes, cohabitation within the human body, purge of the weak and Immune tolerance by the adaptive is the hallmark of survival. Isn’t that true?



Now, proceed with me into out modern current-day culture, where the definition of survival is based on how many “Purell Containers” line the hallways. What have we here? The modern day version of the “Bubble babies.”

True washing hands is a way to avoid getting infected, but to the point of fanaticism is beyond common intelligence. Some would snark and bark right about now. If washing hands is good, using Purell is better! Ah but something is lost on these souls. Washing hands is a prerequisite before attempting to eat a meal or where exposure to unsavory environment has been undertaken, but using Purell at every bend in the hallway is tantamount to eliminating the very elements that makes us resilient humans and gives us the wherewithal to survive. We are in essence trying to make our bodies so clean that they will not possess the ability to fight an errant germ.



Why?

There is a process called Hormesis. In this process is the small amounts of “bad” or “harmful” substances, both organic and inorganic constitute a certain strengthening of our  “exposed” flesh immunity. 

The purpose behind Hormesis is the small harmful elements exposure over time lead to Desensitization

A simile would be the desensitization to an allergen in a person who has allergies to a particular food or environmental product. The process of desensitization is the small but periodic irreverence of this exposure, which ultimately leads to acceptance and tolerance by the immune system for one’s survival.



Does the Flu virus mutate? Why of course it does, every season or even intrseason. We humans have the crafty science of mathematical modeling that determines which strain is most likely to strike and through that we predict the make of the Infuenza Vaccine (we are proven wrong more often then not). Even with the correct recipe, only 60% of the healthy and 48% of the sick are protected by the vaccination (CDC/NIH). It so happens that the crafty viruses are more adept at mutation due to their proliferating abilities. You see, a human generation changes every 15 years or so, while the viral generations grow at the speed of light; doubling of a virus takes minutes and thus is more adaptable to the environment via mutation, then the slow plod of human destiny. Here lies the wrath from the Influenza of 1918 where 500 million people were infected and 20-50 million died, the “Black Death” in 1848-1850 circa Europe that killed between 75-100 million people. Both had the commonness of an unprepared (immunity-wise) population to the ravages of a new pathogen, a lack of understanding, a virus in the former and Yersinia Pesitis in the latter.




Even in slow plodders amongst bacterial agents, mutation is the likely transformation that has created the pharmaceutical industry. Every generation of antibiotics is limited in functional time, because the bacteria mutate and acquire abilities to conform and survive the antibiotic attacks. There are a plethora of bacteria that have shown those capability; MRSA, TB, VRE, C-Diff etc. We are constantly trying to “kill” the “un-killable.” In so doing, we are creating bigger monsters. Equally, viruses have the same capabilities; Hepatitis B virus which has transformed from HBV-A to HBV-I with multiple layers within each subdivision is a product of selection bias of the HBV exposed to various vaccines, Hepatitis C virus with its four subdivisions and of course who can forget HIV.



But aren’t the viruses bad all the time?



Not really. You see our DNA as I mentioned is made up of many viral particles that reside within our DNA as inclusions (junk). These viral DNAs portions can come to reside next to genes that are in the business of proliferation. The viral inclusions can thus act either as “Inhibitors” or “Promoters” of that gene function. If that gene is triggered in a cancer the adjacent viral DNA if it exists, can enhance either of those duties, which can either shut down the gene and prevent cancer or enhance the gene and make the cancer become more aggressive. The c-myc, n-myc, ras and scores of other genes all conform to these ideologies. Read further here~> http://phys.org/news114266805.html

Economics 101

Our thinking of mitigating risks has reached a new climax, which is also inherent to our precepts of “sterility.” The use of Purell in every hallway is like “bailing out a company in distress.” Using an orderly bankruptcy due to the limited exposure to self if not allowed in a rational and systematic manner of enhancing the immune surveillance and survival, will lead to a large “Failure” of the entire body later.



Giving everyone a house with a picket fence with “cheap and easy” money that the top-down politicians deemed a winning strategy for re-elections, lead to the financial debacle of 2008. The sense of bundling mortgages into traunches (CDS, CDO, CLO,MBS) was an attempt by the mortgagors to limit their own exposure by spreading the risks to the many. And that “Risk” became the calamity that is today. But the intellectuals at the seat of government remain ignorant based on their ongoing behaviors and foster a newer version of the failed mandate. Oh but for the profligate idiocy in humanity!



Will the human species survive? Maybe to a yes. (As long as we don't destroy ourselves)



It is the miracle of the "Jumping Genes" or the Transposons that have helped in finding the answers for the evolving human race (See http://jedismedicine.blogspot.com/2011/02/human-diversity-in-genes.html?spref=tw )

I would be classified as a nihilist by many waiting to pounce on the above words. For if anyone dares to express an opinion differing from the "experts," then he or she must be reclassified through the artistry of demonizing.

So what have we wrought?

A panacea against disease?

A plague for the future?

Or just “kick the can down the road” towards a colossal calamity?

You decide.

I'll pay that doctrine, or else die in debt. ~ Romeo and Juliet, Shakespeare