Friday, August 30, 2013

Metformin and PCa

There was an interesting paper on the use of metformin and the reduction of prostate cancer. The article by Margel et al concludes:

Adjusted HR for PC-specific mortality was 0.76 (95% CI, 0.64 to 0.89) for each additional 6 months of metformin use. The association with all-cause mortality was also significant but declined over time from an HR of 0.76 in the first 6 months to 0.93 between 24 and 30 months. There was no relationship between cumulative use of other antidiabetic drugs and either outcome... Increased cumulative duration of metformin exposure after PC diagnosis was associated with decreases in both all-cause and PC-specific mortality among diabetic men. 

 Generally we know that metformin is used in Type 2 Diabetes and that in addition Type 2 Diabetics are obese. We also know that they generally consume high carbs and often have high oxidants resulting therefrom. Metformin increases insulin secretion somewhat and thus may drive down this process. This of course is speculation, logically somewhat correct, but of interest.

Curiouser and Curiouser

As Alice said:

'Curiouser and curiouser!' cried Alice (she was so much surprised, that for the moment she quite forgot how to speak good English); 'now I'm opening out like the largest telescope that ever was! Good-bye, feet!'

I have examined the negative votes on one star ratings on Crawford and it gets curiouser and curiouser.

As of this AM there are 3 reviews with exactly 4 positive and 415 negative for a total of 419.  There is one with 4 of 420. There are 3 with 3 of 418. Close enough. Coincidence? Remember my writing on Groups vs Crowds. This is Group attack. It is too organized and exact.

This type of attack tells you two things. One is that the buyer should beware and always look at the bad reviews. The left wing technocrats only looked at what they saw as the "bad" parts of the negative reviews. There is no similar attack on the five star reviews.

The more I think of this the more I am convinced that the Internet Group think is potentially one of the most dangerous capabilities ever invented. The cost of starting a Group is small and the power it wields is great.

Wednesday, August 28, 2013

It is Just a Little Cancer. Don't Worry.

In a recent JAMA article there is a discussion of the alleged problem of over-diagnosis of cancer. The authors are trying to make the point that we now discover malignancies quite early and that for the most part they will not kill the patient so we should not be treating them.

They start by saying:

Screening for breast cancer and prostate cancer appears to detect more cancers that are potentially clinically insignificant.

 The operative word is potentially. The problem is that in PCa we still cannot differentiate between the 90% indolent and 10% deadly types of PCa. Ductal CIS of the breast has a similar situation. Thus one errs on the side of caution and advises the patient accordingly. They ultimately make the decision, often based upon their mindset rather than medical evidence.

They continue:

Optimal screening frequency depends on the cancer’s growth rate. If a cancer is fast growing, screening is rarely effective. If a cancer is slow growing but progressive, with a long latency and a precancerous lesion (eg, colonic polyps or cervical intraepithelial neoplasia), screening is ideal and less frequent screening (eg, 10 years for colonoscopy) may be effective. In the case of an indolent tumor, detection is potentially harmful because it can result in overtreatment. These observations provide an opportunity to refocus screening on reducing disease morbidity and mortality and lower the burden of cancer screening and treatments.

Again the issue of what is indolent.  That is the operative phrase and that unfortunately is the problem. Now here is the operative position:

National Cancer Institute convened a meeting to evaluate the problem of “overdiagnosis,” which occurs when tumors are detected that, if left unattended, would not become clinically apparent or cause death. Overdiagnosis, if not recognized, generally leads to overtreatment. 

Do we have the tools at this point to determine what is capable of being left unattended and what is not. If we diagnose a melanoma, just a little melanoma, just a few clusters about the rete, some small spreading down to the dermis, should we just wait? But even to get there we had to excise. What of those few hundreds of thousands of cells in the prostate that have a Gleason 7 grade at biopsy. Do we say, "see you in a couple of years".

They conclude:  

Physicians and patients should engage in open discussion about these complex issues. The media should better understand and communicate the message so that as a community the approach to screening can be improved.

Now the first part is often difficult.  You tell a patient they have cancer and you can predict the result. Get rid of it. Worse the family finds out and you have the whole clan on your back, and then their lawyers. So you suggest, cajole, guide, and hope for the best. The Press on the other hand is often placing gasoline on the flames. Then add the glory docs who take to TV and have to tell a tale a day and you have a massive stew just boiling.

Now let us review some of their data:
First, the incidence. The argument is that incidence has increased because we are diagnosing earlier. This is true in prostate, breast and melanoma. That means that in all cases we are finding early stage cancers that would not change the ultimate end state. Namely the patient would never die from this cancer.
Now mortality as above. In breast and prostate we see a drop of mortality. That is due to better treatments. But melanoma is up, and up a lot percentage wise. But I thought we were diagnosing earlier, but more people are dying. Why? No answer given.
Finally I did a survival analysis. They did not do this. Survival of prostate and breast is up. But is that because of better treatment or because the numerator is enlarged due to the over diagnosis? In which case we may actually have worse survival despite all the improved treatments. There is a problem of logic here. The argument is far from compelling.

Finally look at melanoma. Survival is up but I thought we had over diagnosed here as well. Makes no sense.

The story is more complex that the authors seem to state it. We are still left with telling what we see and doing the best we can.

How Much is 2+2?

I am really starting to hate these MOOCs. They requested the answer be in "prose". Prose is not poetry, that is all. So if one is asked:

"What is 2+2?"

The answer is 4. No, according to the other students one needs a paragraph to explain. But the directions said prose, not poetry. But the Peer, what an abuse of the word, Graders said it must be a "paragraph". So you lose all credit. No recourse.

I suspect that the desired answer should be:

"The questions asked what, and by what it means providing a numerical value to the terms which follow. Then the question poses the specifics. Namely the terms 2, +, and 2. The repetitive use of the symbol 2 may also imply a multiplicative  operator as well as the given addition operator. Now we assume that the 2 chose is a numeral in the standard number system, and applying a Cantor set analysis one can determine by upward counting that the use of the addition operator one attains a total of 2 plus 1 or three then plus one that is 4 which is the equivalent of 2+2. Thus using this process one can obtained the desired answer of 4."

Are you out of you ever loving mind! The answer is 4. No paragraph, no subject, predicate, verb! Just 4! This appears to be an episode of Faulty Towers but in Australia!

This is why the MOOCs will never work as an academic performance system. Having thousands of untrained random folks deciding what the right answer is when they most likely never had the material or anything close is insane!

I suspect that the academics and politicians who push this nonsense have never tasted the medicine.

And yes, 4 is prose. It is not poetry. Poetry is:

I once had the answer as 4
But the grader lowered my score
So I write this long blog
To simmer and slog
And then go back no more

I have also recently heard that some new teachers are using this peer assessment approach. They do the following:

1. Assign the material to be read by the student

2. Have peer assessment in homework and exams

3. The instructor then sits in class and oversees the students arguing amongst each other who has the correct answer.

4. And this is at a $40,000 a year Prep School.

No wonder we are falling behind Uganda and Mongolia. Who allows such stuff. At least Socrates asked questions and had a method to his madness. I wonder what ever happened to teaching. At MIT I knew each of my students personally. I knew their performance, and when they were off top levels and when I was not performing.  In this new world of teaching it appears we pay a fortune for at best being the school monitor.

Thus Peer Assessment is the worst idea I have ever heard of. Some of the peers are in my opinion just a bit short of being evil doers. There is no positive feedback and the basic premise of education has been removed. It appears as who can destroy more peers than anyone else. I guess Coursera is not alone, it include the real expensive schools as well. Too bad America!

Tuesday, August 27, 2013

Thou Doth Protest Too Much

The NY Times has a rebuttal of sorts by the gnome from the south alleging that economics is indeed a science despite all that we see in its performance related thereto.

The piece states:

Yet obviously something is deeply wrong with economics. While economists using textbook macro models got things mostly and impressively right, many famous economists refused to use those models, in fact, they made it clear in discussion that they didn’t understand points that had been worked out generations ago. Moreover, it’s hard to find any economists who changed their minds when their predictions, say of sharply higher inflation, turned out wrong.

Nor is this a new thing. My take on the history of macro is that the notion of equilibrium business cycles had, by the standards of any normal science, definitively failed by any normal scientific standard by 1990 at the latest. The original idea that money had real effects because people were surprised by monetary shocks fell apart in the face of evidence of business cycle persistence; the real business cycle view that nominal shocks didn’t actually matter after all was refuted by decisive evidence that, in fact, it did. 

 Notwithstanding the cri de couer above, the fundamentals still remain. The models are speculations, they are gross assumptions of individual behavior and are based not upon fundamental physical facts but oftentimes based upon what the author believes are, or worse, should be facts. Those parts of economics which are accounting tautologies generally yield reliable results, as well they should by definition. Those parts which get involved into human interaction, demand curves and the like, often are the source of our troubles. Individuals really exist, not just crowds, or groups, and as a result oftentimes things just get in another direction.

One need look no farther that the above statement. One the one hand the gnome states that the truth is in the books but on the other hand the purveyors of the trade refuse to apply the very truths they espouse. In Medicine that would be per se malpractice and they would get sued. For an economist it is their opinion and non-actionable. Engineers get sued if the bridge collapses, Architects if the building does not function properly, and even lawyers themselves can get in trouble. For all there are professional ethical standards. Again I ask, what economist has ever been sued? Never will it happen, it is NOT a science.

Monday, August 26, 2013

Crowds are Not Always The Answer

There is an article in the Science News site commenting on the putative "crowd" behavior of ratings. They state:

The “wisdom of crowds” has become a mantra of the Internet age. Need to choose a new vacuum cleaner? Check out the reviews on Amazon. Is that restaurant any good? See what Yelp has to say. But a new study suggests that such online scores don’t always reveal the best choice. A massive controlled experiment of Web users finds that such ratings are highly susceptible to irrational “herd behavior”—and that the herd can be manipulated.

 As to Amazon and many other sites it is often not the crow that manipulates but the real manipulators manipulate. Shills are often used to praise a topic so it gets high points or to drive out a bad review if it detracts from the story to be pushed. I have argued and demonstrated that again and again. They are active "politically" driven sites.

The piece concludes:

The “wisdom of crowds” has become a mantra of the Internet age. Need to choose a new vacuum cleaner? Check out the reviews on Amazon. Is that restaurant any good? See what Yelp has to say. But a new study suggests that such online scores don’t always reveal the best choice. A massive controlled experiment of Web users finds that such ratings are highly susceptible to irrational “herd behavior”—and that the herd can be manipulated.

 I argue that all too often it is not this random crowd but deliberate groups pushing an agenda. I have seen several late. The first was the pro-Government controlled Internet crew who pushed a book by some contender for a FCC position. The group wrote dozens of positive reviews while voting down any negative reviews. The second is a review of a book about the HeLa cancer cells. This set of reviews slammed any negative comments as well.

The solution is simple. Always go for the most negative review and work upwards. The solution is that there should be no anonymous reviews at all and the identity of the reviewer and their bona fides should be available. Otherwise any character can praise of slam anything. Is there a crowd effect? Possibly, but many times it is a "group" rather than "crowd" effect.

Now for the purpose of this discussion let's define the two terms:

Crowd: A crowd is a collection of independent but manipulable individuals who have a propensity for commenting on some topic.

Group: A group is a collection of individuals who are bound in some manner by a common world view which they have a need to reaffirm or express to others.

Crowds just like to belong whereas Groups desire to influence and self affirm an a priori world view. 

Crowds as contrast to Groups are malleable and tend to reaffirm an a posteriori consensus.

Now to the MIT researchers. How does one differentiate between a Crowd and a Group. Hint, timing and intensity. Groups have a semblance or organization. They tend to jump on an issue and they tend to be more clustered in intensity and position. In contrast the Crowd is more diffusion like, slowly building and following. 

Given these general characteristics the interesting question is to apply some form of pattern recognition to the responses to ascertain whether the responses are Crowd or Group driven.This has been done in the intelligence world and one would suspect that the Amazons of the world would find this useful, Google certainly would.

Economics and Reality

There is a piece today in the NY Times asking the existential question about Economics, What good it is? At the same time DeLong has a post with a quote which is the answer:

Larry Summers (1983): "The first way to find a topic is to open Keynes's General Theory at random, read what's on that page, and math it up…"

Now I do not have the reference to the quote but what I believe it says is to write something of merit to the economics community just go to Keynes and take a paragraph and set it to a massive set of incomprehensible equations.

 Which oftentimes is what they do, and even more often without any thought to the reality of the situation.

Imagine, if you will, doing that to say the Bible. Take a paragraph, any paragraph, and then reduce it to equations. Take John Chapter 1:

He came unto his own, and his own received him not. But as many as received him, he gave them power to be made the sons of God, to them that believe in his name. Who are born, not of blood, nor of the will of the flesh, nor of the will of man, but of God.  And the Word was made flesh, and dwelt among us, (and we saw his glory, the glory as it were of the only begotten of the Father,) full of grace and truth.  John beareth witness of him, and crieth out, saying: This was he of whom I spoke: He that shall come after me, is preferred before me: because he was before me. 

Well I tried but no luck. But then I am not an economist. But Summers had a point.

The Times article states:

The fact that the discipline of economics hasn’t helped us improve our predictive abilities suggests it is still far from being a science, and may never be. Still, the misperceptions persist. A student who graduates with a degree in economics leaves college with a bachelor of science, but possesses nothing so firm as the student of the real world processes of chemistry or even agriculture. Before the 1970s, the discussion of how to make economics a science was left mostly to economists. But like war, which is too important to be left to the generals, economics was too important to be left to the Nobel-winning members of the University of Chicago faculty. Over time, the question of why economics has not (yet) qualified as a science has become an obsession among theorists, including philosophers of science like us.

As we have noted before so many times Economics is not only NOT a science, it is akin to a religion, a religion with many waring sects. Instead of just putting equations to Keynes, they have like the early Church various numbers of their Bishops meeting at various Synods trying to reach a consensus on say John 1: 11]-[16]. 

Saturday, August 24, 2013

College and Some More Poor Ideas

I read a piece in the WSJ regarding the costs of colleges. Now the dumbest statement I have ever read, in my opinion, is in this article, by of all people, an academic. It states:

A better idea, Mr. Vedder suggests, would be to implement a national exam like the GRE (Graduate Record Examination) to measure how much students learn in college. This is not on Mr. Obama's list. 

Now imagine MIT EECS students being judged by a GRE exam! They learn hardware, software, mathematics, AI, networks, neuro-nets, and none of that would be on any GRE fit for all. Would we have to make certain the bio majors did the same as EECS, as History. It is clear that this individual has no clue as to the breath of the undergraduate curricula. Once one hears that statement one rejects all else coming from that neurocortex.

The reasons for escalating college costs are simple:

1. Government pays whatever is asked. Thus there is no real supply and demand. It is like public education and health care. But with a slight twist. In this case the student is stuck with the bill, sooner or later. And that bill becomes a drag on the total economy.

2. Buildings. This is the bane of higher Ed. They build again and again and for every dollar of capital spent there is $0.10 per year spent on maintenance, or even more. Thus if you have spent $1B in new buildings you face $100 million or more on just plain feeding the dragon you created. No one seems to figure that in.

3. More Government demands means more Deans and VPs. This has exploded over the past three decades. Behind each new Dean is an army of staff and they get paid, get benefits, get pensions. Worse they get more buildings, and the death spiral continues.

4. Salaries for Administrative folks is obscene. Take MIT. The new President I gather is paid almost $1.25 million. Now I can see someone getting a good salary but parity may have to be considered. Is this position, not person, worth that amount, and what are the conditions for getting rid of them? No one seems to consider that factor.

It is a systemic problem. It is not a GRE issue or an issue of graduates getting good jobs. It is that we have allowed and even supported expansive and expensive growth. The Government has been at the core of this.

Now the article continues:

Nor is the president addressing what Mr. Vedder believes is a fundamental problem: too many kids going to college. "Thirty-percent of the adult population has college degrees," he notes. "The Department of Labor tells us that only 20% or so of jobs require college degrees. We have 115,520 janitors in the United States with bachelor's degrees or more. Why are we encouraging more kids to go to college?" 

Mr. Vedder sees similarities between the government's higher education and housing policies, which created a bubble and precipitated the last financial crisis. "In housing, we had artificially low interest rates. The government encouraged people with low qualifications to buy a house. Today, we have low interest rates on student loans. The government is encouraging kids to go to school who are unqualified just as it encouraged people to buy a home who are unqualified."

Yes indeed we have too many people going to colleges for degrees they will never use. We need plumbers, carpenters, electricians, but we have few places to train them and we have unions that make certain that they are NOT employed. And the Government supports that as well.

Yes there is a bubble, but unlike the housing bubble that broke and spewed forth its debris, this one unfortunately will become a chronic festering burden on our economy for decades. The Government funds degrees in Fine Arts and Classic music and there frankly are few jobs. Even Oceanography has just so many openings.

MDS and Methylation


Introduction

Epigenetic factors are appearing to be more prevalent in our understanding of the causes of many cancers. These factors include such elements as methylation, long non-coding RNAs (lncRNA), micro RNAs and acetylation. None of these reflect a fundamental change in the DNA of the underlying genes, but they do reflect a complex process whereby the way the DNA is processed and presented functions. Unlike translocations and gene changes which are difficult to unravel, many of these epigenetic changes may be found to be reversible in part or in whole. We focus on methylation and methylation related disorders herein. The details are in a report we have just completed[1].

The MDS Therapeutic Paradigm

MDS, the myelodysplastic syndrome, is a multifaceted disease of the bone marrow cells which leads to the over-production of immature blood cells; erythrocytes, lymphocytes, platelets and others. It is often indolent in its early stages but then turns quite virulent and is often fatal, frequently due to the development of AML, acute myelogenous leukemia. However, recent understanding of a key driver of MDS, namely hypermethylation, has resulted in complex therapies which may have proven not only efficacious but curative.

We use this disorder as an example of how methylation causes potential cancers and further how it can be targeted and treated.

The therapeutic responses to MDS are representative to the multi-prong attack on various cancers. The fact that MDS is not per se a cancer but an artifact of a hypermethylation state, and that hypermethylation can be reversed, as compared to a genetic change such as found in CML, the Philadelphia chromosome translocation, and that we know how to deal with hypermethylation, lends MDS to some form of initial treatment. However demethylation does not always work.

Thus the second attack is more aggressive which is a modified hematologic stem cell transplant.

That further reduces the aberrant cell load to an almost miniscule amount. The final hit is using modified T cells called cytokine induced killer cells specifically targeted for the remaining hypermethylated cells.

This paradigm has been applied to other malignancies with substantial success. The classic cases are the childhood leukemias and Hodgkin’s lymphoma. One would suspect that MDS being substantially of the same class would fit this paradigm. Our intent here is to examine the literature across the above spectrum and attempt to make an assessment of progress in this disease.


Methylation has been know of for decades but it has only been in the last fifteen years or so that the connection between methylation and cancers has been somewhat understood. In a 1997 paper by Jones and Gonzalgo the authors state[2]:

DNA methylation is a mechanism for changing the base sequence of DNA without altering its coding function. As a heritable, yet reversible, epigenetic change, it has the potential of altering gene expression and has profound developmental and genetic consequences. The methylation reaction itself is mechanistically complex and involves the flipping of the target cytosine out of the intact double helix, so that the transfer of the methyl group from S-adenosylmethionine can occur in a cleft in the enzyme.

Cytosine methylation is inherently mutagenic, which presumably has led to the 80% suppression of the CpG methyl acceptor site in eukaryotic organisms, which methylate their genomes. It contributes strongly to the generation of polymorphisms and germ-line mutations, and to transition mutations that inactivate tumor-suppressor genes. Despite a 10- to 40-fold increases in the rate of transitions.

This was somewhat of an opening salvo regarding methylation and cancers. One should remember that this was almost five years before the complete reading of human DNA and also at a time when actually reading the methylated states was complex at best.

The authors hypothesized a mechanism for uncontrolled growth using the methylation construct. They posited three ways in which methylation functioned.

First, it caused a gene change. This was the C to T mutation change. 

Second they posited the promoter suppression via methylation of the promoter.  This method is seen quite frequently in the process.

Third, there may be a chromosome instability resulting from methylation.


At the same time Robertson and Jones wrote a paper on DNA methylation and its affects and they also suggested a strong link between that and cancer[3]. They stated:

As with the demethylation and de novo methylation observed during development, changes in methylation patterns during neoplasia have been recognized for some time. Initially it was shown that malignant cells have lower levels of methylation than do normal cells. This global hypomethylation accompanies a hypermethylation of CpG islands, DNA regions often associated with promoters of human genes that are normally protected from methylation.

The above statement is a clear description of what we now know to be correct; namely hypomethylation globally but hypermethylation of the CpG islands. The hypomethylation allows expression of a wide variety of proliferation genes while the CpG Island silencing via hypermethylation deactivates control genes. They continue:

 The mechanism by which these regions remain unmethylated in the normal cell is not known, but it may be mediated by the binding of certain transcription factors. In malignant cells, these CpG-island regions become methylated and expression of the associated gene is silenced. In the case of a tumor-suppressor gene, this may result in a growth advantage for the cell.

DNA methylation– mediated transcriptional inhibition has thus been proposed as a mechanism that is alternative to mutation and deletion, in the removal of tumor suppressor– gene function. Examples of such genes include the two cell-cycle regulators p16 Ink4a and p15 Ink4b, the von Hippel–Lindau gene VHL in some renal carcinomas, the retinoblastoma gene product Rb, BRCA1, the angiogenesis inhibitor thrombospondin, and the metastasis-suppressor gene E-cadherin.

… Chuang et al. have shed new light on how methylation patterns are maintained and how they may of the associated gene is silenced. In the case of a tumor-suppressor gene, this may result in a growth advantage for the cell. DNA methylation– mediated transcriptional inhibition has thus been proposed as a mechanism that is alternative to mutation and deletion, in the removal of tumor suppressor– gene function.

Examples of such genes include the two cell-cycle regulators p16 Ink4a and p15 Ink4b, the von Hippel–Lindau gene VHL in some renal carcinomas, the retinoblastoma gene product Rb, BRCA1, the angiogenesis inhibitor thrombospondin, and the metastasis-suppressor gene E-cadherin (Graff et al. 1995). In a recent issue of Science …has shed new light on how methylation patterns are maintained and how they may become altered in cancer. It was shown that the DNA methyltransferase is targeted to newly replicated DNA by the replication associated protein PCNA (proliferating cell nuclear antigen).

PCNA is the polymerase-processivity factor for the d and e DNA polymerases, is homologous to the E. coli b subunit, and is required for DNA replication becomes altered in cancer. It was shown that the DNA methyltransferase is targeted to newly replicated DNA by the replication associated protein PCNA (proliferating cell nuclear antigen). PCNA is the polymerase-processivity factor for the d and e DNA polymerases, is homologous to the E. coli b subunit, and is required for DNA replication  


There are slightly more than 10,000 new cases of MDS each year. There may be a little difficulty in determine them because they can often go un-noticed until they convert to AML at which point the diagnosis would be clear. There may be a slight anemic, thrombocytopenia, and the presence of blasts, immature hematopoietic cells. A true diagnosis requires a bone marrow biopsy. The MDS patient may have one of many variants which we shall discuss latter.

However what seems common is the presence of hypermethylation resulting in the suppression of cell growth and proliferation control genes on the lineage of hematopoietic cells first affected. Thus the thrombocytes may be the initial ones affected and we see a drop in platelets and a presence of blasts. But in all cases it is the hypermethylation. There is as of yet in the process no genetic change, the excess immature growth is due solely to hypermethylation. Thus the control is simply control of hypermethylation via drugs which block the process. It is a somewhat simple model for developing a therapeutic.

Thus why study MDS? The answers are:

1. MDS is not a full blown cancer. It lacks the genetic breakdown.

2. MDS is a hypermethylation disease. Hypermethylation can be reversed. Thus there is an opportunity to seek a “cure”.

3. MDS does lead to cancer, most likely AML. The process that results in that change is worth of study as a means to seek both prevention and cure.

4. MDS can be monitored both genetically as well as via hypermethylation measurements.


In this report we examine several factors in depth. Specifically:

MDS: We present an overview of MDS and its various forms. This is a complex disease and it is almost as if no one patient is identical to any other patient. We consider the cause of methylation at the DNA level but we can at best speculate on the ultimate initiator. We know that many MDS patient had pre-existing malignancies for which the received both chemotherapy and radiation therapy. The nexus there seems to somewhat clear. However, many, if not most, MDS patients have no clearly defined initiating event.

Methylation: We explore methylation and examine how it occurs, and what it does to the functioning of the DNA expression. In many of our cancer models we often just look at gene, RNA and protein flow. As we have indicated before we often look at the epigenetic factors as noise. However it has become clear that the epigenetic elements are integral parts of a cells expression of its genetic capabilities and thus should be included in any model.

Demethylating Therapies: We examine the various demethylating therapies. The specifics are discussed in some detail as well as the efficacy of the therapeutics.

Acetylation: The histones around which the DNA is wound also exhibit acetylation. We examine this phenomenon and relate it to methylation.

Immunotherapy: We discuss immunotherapy focusing on the use of CIKs, cytokine induced killer cells, primed T cells directed at the remaining methylated hematopoietic cells.

We conclude with observations relevant to combined therapies.

Now the histones may also be acetylated and drawn together. When histones are drawn closer the genes in between cannot be read and thus they are not expressed. Now we can summarize this as follows:


The third general step is the use of CIK, or cytokine induced killer cells. These are somewhat akin to NK cells and have been developed specifically for cancers of these type. We briefly discuss how they are prepared. The efficacy is yet to be fully determined but there is a large base of Phase I and II Trials demonstrating efficacy

Lin and Hui provide a definition for CIK cells[4]:

Cytokine-induced killer (CIK) cells are polyclonal T effector cells generated when cultured under cytokine stimulation. CIK cells exhibit potent, non-MHC-restricted cytolytic activities against susceptible tumor cells of both autologous and allogeneic origins. Over the past 20 years, CIK cells have evolved from experimental observations into early clinical studies with encouraging preliminary efficacy towards susceptible autologous and allogeneic tumor cells in both therapeutic and adjuvant settings. …

we anticipate that the continuous therapeutic application of CIK cells will likely be developed along two major directions: overcoming the challenge to organize large prospective randomized clinical trials to define the roles of CIK cells in cancer immunotherapy and expanding its spectrum of cytotoxicity towards resistant tumor cells through experimental manipulations.

Jiang et al add to this description as follows[5]:

The number of immune cells, especially dendritic cells and cytotoxic tumor infiltrating lymphocytes (TIL), particularly Th1 cells, CD8 T cells, and NK cells is associated with increased survival of cancer patients. Such antitumor cellular immune responses can be greatly enhanced by adoptive transfer of activated type 1 lymphocytes.

Recently, adoptive cell therapy based on infusion of ex vivo expanded TILs has achieved substantial clinical success. Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD8 T cells with diverse TCR specificities, possessing non-MHC-restricted cytolytic activities against tumor cells. Preclinical studies of CIK cells in murine tumor models demonstrate significant antitumor effects against a number of hematopoietic and solid tumors. Clinical studies have confirmed benefit and safety of CIK cell-based therapy for patients with comparable malignancies.

Enhancing the potency and specificity of CIK therapy via immunological and genetic engineering approaches and identifying robust biomarkers of response will significantly improve this therapy.

The preparation and creation of CIK cells is done as described by Jakel et al[6]:

CIK cells are generated by culturing peripheral blood lymphocytes (PBL) with

1.     interferon-γ (INF-γ) monoclonal
2.     antibody against CD3 (anti-CD3) and
3.     IL-2 in a particular time schedule.

The cytokines INF-γ and IL-2 are crucial for the cytotoxicity of the cells and anti-CD3 provides mitogenic signals to T cells for proliferation. Most of these CIK cells (87%) are positive for CD3 and for one of the T-cell coreceptor molecules CD4 (37.4%) or CD8 (64.2%), respectively.

IFN-γ, added at day 0, activates monocytes providing crucial signals to T cells via interleukin-12 (IL-12) and CD58 (LFA-3) to expand CD56+ cells.

After 14 days of culture, 37.7% of cells are CD3+CD8+CD56+. These cells are referred to as natural killer T (NK-T) cells and represent the cell type with the greatest cytotoxicity in the CIK cell population.

Interestingly, these CD3+CD56+ double positive CD8+ T cells do not derive from the rare CD3+CD56+ cells in the starting culture but from proliferating CD3+CD8+CD56− T cells.

Their cytotoxicity is nonmajor histocompatibility complex (MHC)-restricted and they are able to lyse a variety of solid and hematologic tumors. Cell lysis is not mediated through FasL but through perforin release. CIK cell cytotoxicity depends on NKG2D recognition and signaling.


Jiang et al propose the following:

 Jiang et al prepare their cells as follows:

CIK cells have been evaluated as an adoptive cell immunotherapy for cancer patients in a number of clinical trials.

Peripheral blood mononuclear cells (PBMC) were isolated by apheresis.

T cells were then activated, expanded, and differentiated by

1.     anti-CD3 in the presence of cytokines including
2.     IFN-γ,
3.     IL-1α, and
4.     IL-2

for 14 to 21 days to generate CIK, which were subsequently infused into patients.

There are no significant clinical results for this in MDS but there are many Trials underway. One could suppose that this is a substantial third step after a BMT procedure. Logically it could be curative.

Observations

We now want to make some general and specific observations. WE shall discuss each as a separate topic.


Epigenetics has become as significant a factor in cancer as the pathway and immunological approaches. The impact of miRNA, lncRNA, methylation, acetylation, and other epigenetic elements are now understood as causative. However the drivers initiating many of these are not clearly understood. The methylation in MDS for example is understood as a cause but what leads to the methylation is still speculative. For example in melanoma one could speculate that backscatter X-rays in full body airport scans provide just the driver for methylation if it is applied at the right time. However that is also speculative and no studies have been done. It is speculated that excess radiation, excess CAT scans or radiation for cancers can cause the methylation seen in MDS. Clinical proof is lacking however.


Methylation treatment with DNMT suppressors is known to drive down the blast percentage. However it is a broad based therapeutic and demethylates many other cell. This may also give rise to secondary neoplasia, by activating proliferation genes in other cells in the body. It is not known how significant this is. It might result in sequelae as is found in Hodgkin’s lymphoma but the sequelae there are often found 20-30 years later. Thus since MDS occurs at 70 years of age that well exceeds any life expectancy.


The problem with MDS is known to be hypermethylation. But there are many cases of hypomethylation as well. One then wonders if the approach taken herein applies to those cases as well.


Limited survival data is clinically available using the CIK approach. Koreth et al present data based upon a Markov model but we have considerable concerns about the approach[7]. The results are shown below.

It should be noted that the top graph is for low to low intermediate and the bottom graph is high intermediate to high, using IPSS scoring. These Kaplan Meir curves show that for the high case we have a rapid drop and then a slow decline with about 20% at 10 years. Since the average age is about 70, the average life expectancy is 14 years and so 20% seem to have reached average life expectancy. In contrast the opposite is the case for the more indolent forms.

The problem that we see is the initial conditions. Perhaps one would expect most patients have initial health conditions which would bias them against a BMT survival. Perhaps other health conditions are also a concern. The problem is that MDS is so complex and given the patients initial health status conditions it is expected that any case is different and thus any generalized result is problematic.


[2]  Jones, P., M. Gonzalgo, Altered DNA methylation and genome instability: A new pathway to cancer?, Proc. Natl. Acad. Sci. USA Vol. 94, pp. 2103–2105, March 1997

[3] Robertson, Jones, Dynamic Interrelationships between DNA Replication, Methylation, and
Repair, Am. J. Hum. Genet. 61:1220–1224, 1997.

[4] Linn, Y., K. Hui, Cytokine-Induced NK-Like T Cells: From Bench to Bedside, Journal of Biomedicine and Biotechnology, Volume 2010.

[5]  Jiang, J., et al, Cytokine-induced killer cells promote antitumor immunity, Journal of Translational Medicine 2013, 11:83.

[6] Jakel, C., et al, Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma, Clinical and Developmental Immunology, Volume 2012.

[7] Koreth J., et al, Role of Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem-Cell Transplantation in Older Patients With De Novo Myelodysplastic Syndromes: An International Collaborative Decision Analysis, JOURNAL OF CLINICAL ONCOLOGY, June 2013.

Friday, August 23, 2013

More on the MOOC Problem

Again I have been reading the Discussions on the MOOC I have finished. The Peer Graded final was in my opinion a total disaster. There was, in my opinion, one arrogant student who decided not just to grade 4 exams but some 17 if memory serves me correctly. His grades were atrocious. He posted them all, I guess to boost his ego, which of course backfired.

Then another student, this one I would hire, looked at the students bios and did a calculation and found that more than a third had PhDs or MDs or both. Oops I guess I was found out. Then he checked their bios and publications and found that many had written extensively in the area. He then concluded that perhaps this one third might know something, something more than the other student who had given his rather arrogant grade. Then he took it one step further and calculated the probability that of the 17 or so grades given what number were true experts, even better that the teacher in Australia! Brilliant. Then he concluded that the arrogant guy most likely made a blunder.

Then what happened. The foolish  student, in my opinion, went and regraded all 17 or so! Upwards of course without any basis. So what were the first grades and even more so what good were the second! So Coursera had, in my opinion, this moronic way to get peer grades with a system which is fatally flawed. Namely cultural troglodytes who push their egos but with a modicum of intellect. I could have told them that. In running my companies across some 20 plus countries my greatest concern was cultural mollification, keeping everyone happy while minding local cultural norms. Had I tried something like this, well you understand.

Whoever came up with this approach just missed the mark. It sets a bad taste in people mouths especially as to the integrity of the process. They just ought drop this approach and return to multiple choice questions. Otherwise you have the Facebook generation mindset that whatever I think is as good if not better than whatever you think because I thought it.

Fools all too often get in trouble whenever they try to use the thought process.

Open Access

Science has a piece this week stating that now more than 50% of "published" papers are open access and in the biotech world it exceeds 60%. The lowest number is in engineering. They state:

Efforts to give the public free access to peer-reviewed papers have reached a milestone: One-half of all papers are now freely available within a year or two of publication, concludes a new study sponsored by the European Commission. That means so called open-access publishing has reached a “tipping point” and will now accelerate, suggests Éric Archambault, the lead author of the study and president of Science-Metrix Inc. in Montreal, Canada. “Things are likely to move much faster now.” But some open access observers have been quick to criticize the study, which yielded a number twice as high as other analyses.

This is a most interesting indication of several things. First the biotech world is fast moving and having the ability to get results from a broad base of sources makes it move quicker. Engineering is a slow plodding field. Just look at IEEE publications most of which are recast papers written by a mass of faculty and students rehashing what a single person did decades ago. So who cares. In contrast having access to the latest papers can result in the conversation and ideas spreading at the speed of light, literally.

The next issue is the whole question of peer reviewed papers. Peer review is time consuming and does not always do what was intended, for at heart it is all too often a political process. Open non-anonymous commentaries would be more effective, not the type that one finds after some blog post, but well though out "letter" replying to the papers. I suspect we may very well see a change in that direction, and as PLOS and others move forward perhaps a web site can combine rapid publications with credible named reviews written to be informative not just snarky bits which we all too often see.

Thursday, August 22, 2013

Now Let's Destroy Higher Ed


In a brief piece in today's NY Times the article previews the proposal of the current Administration to get its hands into the higher education system, even further that it has.

The article states:

A draft of the proposal, obtained by The New York Times and likely to cause some consternation among colleges, shows a plan to rate colleges before the 2015 school year based on measures like tuition, graduation rates, debt and earnings of graduates, and the percentage of lower-income students who attend. The ratings would compare colleges against their peer institutions. 

 This means that the schools will most likely add a new Dean or even VP to oversee the collection, analysis, comparison, of this information, just adding to the already overburdened overhead at American Universities.

Now I did not need the Federal Government to have accomplish this task for me some fifty plus years ago. I gathered the information myself, no Internet, no iPhone, no Facebook. Just a set of paper catalogs, which I really liked, and some hard work. I went through a process of beginning life on my own and never once assumed to rely on the Government.

The piece continues:

... proposal urges colleges to experiment with approaches that reduce costs. The plan mentions so-called competency-based degrees, in which college credits are based not on the hours students spend in classrooms, but on how much they can show they know. 

Another approach mentioned in the plan is online education through what have become known as “massive open online courses,” or MOOCs, which are mostly free.

 Competency? No grade? What is the difference. When I taught electronics some 40 plus years ago the circuit worked or it did not. Try med school, dead or alive. Then we also see them grabbing onto the MOOCs. They are not ready for prime time, and I would guess that not a one in the current Administration has actually take a few to understand their deficiencies. And back to competence, are we having the Administration define what a student must learn? It sounds a lot like that one. Does that means that MIT and Country College of Morris will be measured pari passu, they must teach at the same competency level?

If so then we will create just an extension of our existing Public School system and we know where that got us.

The solution is simple, but now near impossible. Get Government out of higher education, and that means even taking the student money away. Why, because that was the driver for allowing schools to ramp up tuition. The article clearly states:

Almost all of the federal government’s $150 billion in annual student aid is distributed based on the number of students a college enrolls, regardless of how many graduate or how much debt they incur. 

We know we have more than a trillion in Government backed student debt and we are adding to it at the rate of $150 billion a year. That in my opinion is a major driver for escalating student costs. Adding the Government in the mix even more will just send that higher and the quality lower.

Wednesday, August 21, 2013

More Observations on MOOCS

I just finished a MOOC course and it included a peer grading exercise. What chaos! Imagine several thousands of people of varying degrees of competence in hundreds of countries grading other people whom they have no knowledge of. It is interesting but it becomes uncontrolled chaos.

For example:

There were N questions and of course one looks for N answers. Without exception not one sample I saw linked an answer to a question. You had to read a complex paragraph to try to intuit where the question was answered. If I were teaching the course they all would have failed. But that was not to be.

What is an answer? If you ask a question then one or two words may suffice. Why write the great American novel for an answer. But alas they just rambles on.

Plagiarism, some students who wrote on the Discussion Group went looking for it anywhere. Frankly the "rules" are so loose and it was open book that if you found the answer somewhere, anywhere, let it be, this is not for real folks, it is a free course and you will not be judged by anyone except yourself.

Rambling Discussions. Not being a Twitter or Facebook user perhaps I am deficient in understanding run of the thumbs discussions. But they go on all over the place. I wonder if any of these people have a life.

Culture does come through. I should not have been surprised but one can see cultural factors coming through in judgmental statements.

You have the Twitter generation, the Facebook crowd, people just mouthing off as if each person is equal, no matter what they know or what they achieved. Every person has their opinion and they throw this into the mix. This is intellectual chaos. Frankly the system is rigged for chaos. 

I had never seen this type of  back stage discussions in my years of teaching but I guess it must have existed. But I suspect that it presents a treasure trove for sociologists and anthropologists.Peer grading in my opinion is a disaster. It brings forth the total cultural confusion of our world. Black and white multiple choice keeps those forces under control. But the cat is now out of the bag!

One wonders what all the hype is about. Some Mongolian teenager gets 100% on MIT electronics? Praiseworthy indeed, akin to some backwater American doing the same, if we knew the ancestry. Details do count. Again the reason people go to MIT is not to ace an online test. They most likely did that in Secondary School. The reason they go is to understand how to understand. How to pose the question, how to use a plethora of tools to come up with the right answer, or at least a good one, and recognizing good from bad. If the goal is just doing well on a test, then we become India and China, masses of test takers, all prepping to score high. Frankly we already have that in the SATs, and we see masses of prepping. True education is thinking differently, questioning the common and extending the mind to new areas. Manipulating on line courses is at best a means to an end, never the end in itself.

Saturday, August 17, 2013

Economics Versus Medicine

There is a piece in the WSJ, a paper which now appears as some pop publications with all sorts of things other than the financial news, which was written by an economist bemoaning medicine. The article was written by a female economist. She bemoans all the advice that is given women as to how to care for themselves during pregnancy. Her main gripe appear to be that there is little if an evidence behind any of this advice.

Now she complains about coffee as follows:

A far bigger issue for me was coffee. I love coffee. The thought of giving it up during pregnancy struck fear into my heart. Of course, for the baby, I'd do anything. But I didn't want to do it for no reason.

The big concern with consuming caffeine during pregnancy is that it might lead to higher rates of miscarriage. Caffeine can cross the placenta, entering the fetus's bloodstream, and it isn't clear how the fetus processes it. In addition, researchers have speculated that caffeine can inhibit fetal development by limiting blood flow to the placenta.

Still, these effects have not been proven. In the end, randomized experiments are difficult or impossible, and women who drink coffee tend to be different from those who don't. One big issue is that older women tend to drink more coffee, and age and miscarriage are closely linked.

Now I know little about obstetrics, I did deliver a baby or two, but that was decades ago. It may be like riding a bike but I dare not try that. However, mothers are given tons of advice which may or may not be scientifically based. She further bemoans that:

I'm hardly alone. Pregnant women are clamoring for better information about everything from exercise to hair dye to bed rest and delivery. They don't want categorical limits based on fuzzy science and half-baked research. They want to assess risks for themselves and make their own best decisions. 

 Now let me deal with a few facts:

Physicians have a ton of data regarding smoking, drug use, excess alcohol, preexisting conditions, age related birth issues, genetic complications and the like. I have a few old obstetrics books on my shelves that relate those warning and even way back then there were clinical studies and true science backing up the claims. But a cup or two of coffee or a glass of wine may be  a bit too over-bearing, except that in today's legal mess of malpractice what is a physician to do.

On the other hand did an economist ever get sued for malpractice? Hardly! Did an economist ever do a double blind study? Never. They can even do a study in macroeconomics with their eyes fully open. Thus I see this bemoaning the failures of medicine as a complete admission of the real total failure of economics. There is no body of science akin to physiology, genetics, and the like in economics. No economist can do an experiment. They only play with numbers after the fact and when they try to predict, diagnose, prognosticate, the seem to end up in screaming matches where no one even comes close to the right answer.

So we have a female economist bemoaning the issue of whether two or four cups of coffee will do fetal damage. I do not know, I have read the literature. I can do some good guesses on clinically based results in several fields of cancer, but telling a person whether a glass or two of red wine at dinner is bad for the fetus may be difficult unless some study has been done, but I suspect that there are hundreds.

Perhaps Economists who live in glass castles should not throw stones.

Oh yes, I just checked my NEJM looking for caffeine and pregnancy and got a few dozen hits. The latest is worth a look. The NEJM article states:

Obesity, cigarette smoking, alcohol use, and moderate-to-heavy caffeine use may be associated with sporadic miscarriage, but relationships between these conditions and recurrent miscarriage have not been extensively studied and are uncertain. There is no good evidence that physical activity, including sexual activity and exercise, causes miscarriage.

References:

  1. The ESHRE Capri Workshop Group. Nutrition and reproduction in women. Hum Reprod Update 2006;12:193-207
  2. Mishra GD, Dobson AJ, Schofield MJ. Cigarette smoking, menstrual symptoms and miscarriage among young women. Aust N Z J Public Health 2000;24:413-420
  3. Henriksen TB, Hjollund NH, Jensen TK, et al. Alcohol consumption at the time of conception and spontaneous abortion. Am J Epidemiol 2004;160:661-667
  4. Weng X, Odouli R, Li DK. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J Obstet Gynecol 2008;198(3):279.e1-279.e8.
 Hope the facts help out here!