Tuesday, December 30, 2014

Brilliant Book on the Individual

The concept of the Individual has evolved over the past two millennia and the discussion by Siedentop is a superb overview of that process. (See Siedentop, Inventing the Individual) It has been a complex process, moving from family and tribal identity to the ability to have an identity as a self, an individual. Along with that ability to identify with self, a single person and an individual comes many attributes as well as the basis for many of our current theories of political science.

Siedentop has presented a brilliant addition to the body of materials on the development of the individual as a vital political and social entity. This book is an excellent presentation of his ideas. It is well written, encompasses all the key issues, and his arguments are concise, compelling, and highly informative.

Siedentop starts with the Ancient world as a world of families and towns. Athens was a typical example of the Ancient World and the Platonic tales of Socrates were key to their understanding. Loyalty and identity were to the city of Athens, or later, to the Empire of Rome, via ones family. In Plato’s Gorgias, Protagoras and Meno we see the loyalty to Athens and in turn to the gods as being the means to relate, the family being the linkage binding all to the city state. In Chapters 1 through 3 the authors lays out how he sees such relationships.

Then in Chapter 4 we see the author introduce Paul of Tarsus. On p 60 the authors presents the opening salvo of the individualism of Paul. The “one” in Christ is a double edged sword. One is “one” as a group in Christ but one is also “one” morally, having an individual path to salvation? The concept of individual salvation or perdition is developed to its fullest in Paul.  On p 61 the author asserts that it is with Paul that the “fusion marks the birth of a “truly” individual will”.

On pp 74-75 the author discusses Marcion and his heresy of extreme Paul individualism. The soul is individual in each person and salvation is an individual act and the communal nature of the Old Testament must be rejected with the individual responsibility of the New Testament. In fact Marcinon said all one needs is Paul’s Epistles and Luke, and reject the rest. For that he was rejected as a heretic.

The author then examines monasticism and the martyrs in the process to building up to Augustine. Chapter 8 is an analysis of Augustine in the context of the individual. Augustine was on the one hand a strong adherent to Paul while also being imbued in the classic culture of the Roman Empire. In a sense the author sees a strong flow of individual identity in the writing of the Confessions. The author also included the Pelagian conflict, which in a sense if a conflict of the individual qua person and the individual qua grace. Without grace man is doomed. Yet man’s actions alone cannot provide redemption, each individual must, according to Augustine; have grace given if he is ever to gain eternal redemption. One can see a stand for individuality in Augustine but the demand of grace as given and not earned has always sent a penumbra of concern.

On pp 132-133 the author discusses Gregory I and Columbanus. This could have represented an interesting point for contrast. Gregory was from a classic old Roman family and had even been the martyr of Rome before becoming its Bishop. Columbanus was an Irish monk who established dozens of monastic institutions of study, and was in conflict with Gregory, albeit with respect. Columbanus as an Irish monk had never had his country subject to Rome, and thus in this interaction we could see the move from old Rome to the new non-Roman church.

The author progresses by moving on to the development of natural law and natural rights in Chapter 16. This is a wonderful exposition of these topics. Natural Law was a vehicle to explain the basis for law extra the Church and Natural Rights became the cornerstone for what became individual rights.

Chapter 21 is a discussion of the Friars. In a sense this is a battle between Aquinas and Ockham, between Dominican and Franciscan, between group and individual, between Aristotle and the opening of new philosophical insights. In Chapter 21 the author nicely uses the Franciscan issue of property and the New Testament to discuss property and individual ownership. To follow Christ one must abjure one’s property. To do such, one must have some nexus with the property as an individual in the first place. This may very well be the basis for Locke’s subsequent arguments. Chapter 22 then is a focus on Ockham. And it follows in detail in Chapter 23. I felt that these were the best chapters in the book, but perhaps it is my bias towards Ockham.

William of Ockham is extolled throughout the book. It is a worthy discussion. Ockham was a nominalist; namely he believed that universals were a fiction and that subjects were in essence individuals, not humans, but individual things. Thus, when we say; “The daylily is blue.” we mean a specific daylily, the subject. Yet Ockham would allow for the predicate “blue” to have some nexus to a universal called blue. Daylilies as a universal do not exist. A specific daylily like the one I may hold does exist, as an individual. But to extend this and say that the specific daylily is blue, do we mean as a predicate some universal concept of blue or blue like a coneflower? As we progress to a more scientific venue we may use a predicate like the spectrum of the blue we want, and then say blue like “this”. Thus ultimately we do not use the construct of a universal but an individual for the subject and likewise for the predicate.

Locke clearly must have had a clear understanding and acceptance of the individual when he developed his concept of property. For Locke property was the result of an individual providing some form of work and the conversion of that labor into a one to one relationship with the property; namely the individual owned the property and from that he had certain rights.

To expand on Siedentop we must then look towards the political philosophers who integrate Individuals into society. As de Tocqueville noticed about mid-19th century America, there was a preponderance of Individualism, an Individualism not of the type that abhors collective associations, quite the contrary, but an Individualism of the type that demands individual equality of rights and opportunity. I would argue that to understand this strain in de Tocqueville that one must read his American analysis in conjunction with his analysis of the French Revolution and of Ireland under English suppression and subjugation.

On the end the author tries to connect the individualism of Christianity with the secular goals of modern society. Also the author does see the threat to modern political theory from the ascendancy of more rigid past religions which eschew the individual and build on the tribe.

Overall the book is a powerful and superbly presented argument for the individual, and their rights. The argument that the concept of the individual did not suddenly arise from the Enlightenment is powerful and compelling. This book is a valuable contribution to understanding the individual, individualism, and the conflict with alternative societal political constructs which demean the individual and their rights.

Thursday, December 25, 2014

Exaggeration of Medical Experiments

In a recent paper in BMJ the authors present an analysis of exaggeration in the Medical Literature of the results obtained. They state:

For our analysis of advice we found that 40% of the press releases contained more direct or explicit advice than did the journal article (bootstrapped 95% confidence interval 33% to 46%). For our analysis of statements based on correlational results (cross sectional or longitudinal) we found that  33% of primary claims in press releases were more strongly deterministic than those present in the  associated journal article (bootstrapped 95% confidence interval 26% to 40%). For studies on animals, cells, or simulations, 36% of press releases exhibited inflated inference to humans compared with the journal article (bootstrapped 95% confidence interval 28% to 46%). Given the likelihood that some statements in journal articles themselves would be considered exaggerated by other scientists in the specialty, our levels of measured exaggeration are likely to be underestimates.

We have commented on this frequently. Typical of the exaggerations are claims to therapeutic implementations using just a mouse model, claims to targets of specific genes, miRNAs and the like.

The problem has become pandemic and claims are made which truly extend the limits of credibility. The result of this may be significant if not managed better.

Merry Christmas

1 And it came to pass in those days that a decree went out from Caesar Augustus that all the world should be registered.

2 This census first took place while Quirinius was governing Syria.

3 So all went to be registered, everyone to his own city.

4 Joseph also went up from Galilee, out of the city of Nazareth, into Judea, to the city of David, which is called Bethlehem, because he was of the house and lineage of David,

5 to be registered with Mary, his betrothed wife, who was with child.

6 So it was, that while they were there, the days were completed for her to be delivered.

7 And she brought forth her firstborn Son, and wrapped Him in swaddling cloths, and laid Him in a manger, because there was no room for them in the inn.

8 Now there were in the same country shepherds living out in the fields, keeping watch over their flock by night.

9 And behold, an angel of the Lord stood before them, and the glory of the Lord shone around them, and they were greatly afraid.

10 Then the angel said to them, “Do not be afraid, for behold, I bring you good tidings of great joy which will be to all people.

11 For there is born to you this day in the city of David a Savior, who is Christ the Lord.

12 And this will be the sign to you: You will find a Babe wrapped in swaddling cloths, lying in a manger.”

13 And suddenly there was with the angel a multitude of the heavenly host praising God and saying:

14 “ Glory to God in the highest, And on earth peace, goodwill toward men!

15 So it was, when the angels had gone away from them into heaven, that the shepherds said to one another, “Let us now go to Bethlehem and see this thing that has come to pass, which the Lord has made known to us.”

16 And they came with haste and found Mary and Joseph, and the Babe lying in a manger.

17 Now when they had seen Him, they made widely[d] known the saying which was told them concerning this Child.

18 And all those who heard it marveled at those things which were told them by the shepherds.

19 But Mary kept all these things and pondered them in her heart.

20 Then the shepherds returned, glorifying and praising God for all the things that they had heard and seen, as it was told them.

Wednesday, December 24, 2014

Exosomes, miRNAs and Cancer

In a recent Science article there is a discussion of exosomes and miRNAs in the context of cancer metastasis.
The discussion presents the exosome as a vehicle to transport miRNAs across intercellular borders and create effects at distant cells which are malignant in nature. We have seen this concept in another venue, that of the stem cell. Thus is we have a cancer that has a stem cell basis, then perhaps they way it functions is as an exosome creator transmitting miRNAs, such as miR-34, to other cells, creating malignant cell growth.

The article states:

Melo et al. reveal a role of exosomes in cell-independent miRNA biogenesis that affects cancer progression. The authors show that only exosomes derived from cancer cells, but not those derived from normal cells, contain key enzymes involved in miRNA biogenesis such as Dicer, TAR (trans-activation response) RNA-binding protein (TRBP), and AGO2 (see the first figure). The exosomes also contain the membrane protein CD43, which plays a role in accumulating Dicer in cancer exosomes. The study also shows that Dicer-containing cancer exosomes process precursor miRNAs into mature miRNAs (including oncomiRs) over time, and upon encounter with normal human mammary epithelial, cells induces them to become cancerous. Healthy mammary human epithelial cells formed tumors when they were injected into mice that were treated with cancer exosomes. Moreover, miRNAs in the cancer exosomes inhibited the expression of their respective mRNA targets—phosphatase and tensin homolog [(PTEN), a tumor suppressor protein] and the transcription factor homeobox D10 (HOXD10)—in the recipient epithelial cells. The authors suggest a possible temporal oncogenic “field effect” induced by cancer exosomes that recruits surrounding normal cells to become tumorigenic. The tantalizing results of Fabbri et al. and Melo et al. merit further investigation in immunocompetent mouse models. 

This should be an interesting alternative to many other models.

Also it should be seen that this model must be incorporated into what some have done to develop systems models for cancer. The exosome then becomes an additional metastatic transport mechanism that has characteristics differing from those of cells, and especially for transport in the blood.

What Property Right?

Let me see if I get this straight. Comcast makes their customer pay an exorbitant monthly fee for a cable model which then then use to sell services to anyone passing by the customer's home and thus allowing third parties access to their local address so that if someone does something illegal on this address, say a criminal act, then the police are led back to the customer's home who had no knowledge but their house can now be confiscated by the police who can argue that the house was party to this illegal act!

Yes, that is what it appears to be. In Ars Technica they state:

A pair of Comcast customers has sued the company for turning Xfinity Internet routers into public Wi-Fi hotspots, saying Comcast’s actions pose risks to subscribers and are taken without seeking their authorization.

 So, hypothetically, if some drug dealer sits out side the person's home, uses this address to do a drug deal, then the police could find the location, see its someone's house and under the Federal seizure provisions, seize the house and possessions, and let the person hang out to dry!

Thanks Comcast, I guess its great to have MSNBC on your side.

Saturday, December 20, 2014

More On the Government Grading Universities

As I had commented earlier the intent of the Government is to control everything, including all education. In reviewing some comments I saw one by the President of Harvard who said:

“I think we need to argue with any notion of college that says it’s simply about putting people in jobs,” Faust said. “Certainly that’s a significant part of what we intend with the way we educate you.… We also want a sense of creativity and adaptability that will ready people for a job that we don’t even know about yet.”

I strongly beg to differ. Most students should be considering how their education can be immediately monetized. That means getting a job. Harvard students have that thought well within their grasp despite this rather false statement.

Creativity is part of any professional education. We want creative Chemical and Mechanical Engineers, but they also want a job! We want creative entrepreneurs, and at MIT almost 100 undergrads "dropped out" to start their own companies. They "burned their boats" and of that MIT should be proud. 

Frankly we do not need a great many fine arts majors, English majors, History majors, or even lawyers. Harvard may very well have sent too many of these folks to Washington and it is these people who are causing the problems we now face.

The Medical School produces people who create, create cures. MIT has a great many who create but one concern is that even at MIT we see more and more politically correct overhead. The overhead is a direct result of relying on the Government trough. The result of that is the explosion of tuition and costs for the students. It is a deadly spiral that can only be changed by separating themselves from the Government, like an alcoholic who must walk away from that last drink....never to return.

More Genes and Prostate Cancer

There seems to be a never ending set of claims regarding genes and gene expression as related to various cancers. In this writeup we present our opinions regarding this matter when we examine a recent paper relating loss of expression of SIRT1 and the resulting expansion of high grade PIN, HGPIN. This is gene suppression examined in mouse models. Now this examination is of interest for a multiplicity of reasons.

First, HGPIN is often problematic. We have examined HGPIN some five years ago and demonstrated that in many cases it leads to PCa but in some anecdotally observed cases the HGPIN may actually disappear. The disappearance of HGPIN in a 24 core biopsy after a similar one none months prior is not readily explainable under the current murine models. Specifically most murine models as well as clinical studies tend to indicate that HGPIN is irreversible. However there are cases demonstrating the reverse.

Second, Sirt1 is not, in my opinion, an apparently generally accepted gene related to malignant or metastatic behavior. It does have multiple control points but in general it is more related to neurological controls rather than controls over adenocarcinomas. In addition it connects to certain histone acetylation mechanism and thus presents a possible epigenetic linkage via histone control of expression.

In this analysis we use the recent paper by Di Sante et al as a touchstone to examine Sirt1 and its behavior and again to use the Press around the paper as a way to examine how the researchers either directly or indirectly present their work and its implications. We all know that a great deal has been derived from murine models. However, they are not human. Humans live longer and face many more assaults on their cells than mice do. PCa for the most part is a cancer of old age. It is a cancer which putatively is driven by a multiplicity of cell assaults, resulting in genetic changes and changes in gene expression. Also we may be facing strong epigenetic alterations via methylations and acetylations. Which are these is the driving factor we really do not know.

Thus this presentation serves two purposes:

First, in my opinion, it is just another gene thrown on the table to be examined. The question that should and must be asked is; what is causal? Ultimately we must also understand the temporal sequences that give rise to these processes and the causal elements of those temporal sequences.

Second, in my opinion, it is another demonstration of how one should cautiously approach reporting results, both to the Press as well as in the literature itself. Again, as it seems with the publishing of any and all such “discoveries” we find the Press become an outlet for what may truly be exaggerated statements regarding the immediacy of use for such an observation. Thus there is the key question as to what the responsibility is to the researchers regarding balanced presentation of the results.

The recent paper Di Sante et al states[1]: 

Prostatic intraepithelial neoplasia is a precursor to prostate cancer. Herein, deletion of the NAD+-dependent histone deacetylase Sirt1 induced histological features of prostatic intraepithelial neoplasia at 7 months of age; these features were associated with increased cell proliferation and enhanced mitophagy.

In reality the statement is not definitive. We have observed HGPIN actually disappearing and doing so for prolonged periods. The question is; what makes HGPIN disappear. Also there is still a lack of total clarity as to the genetic progression of PCa. One may still consider inflammation as a major cause and possible mitigation of inflammation being a reason for the reversal of HGPIN. However that also is conjecture. The problem here is the definitive statement regarding HGPIN. 

In human prostate cancer, lower Sirt1 expression in the luminal epithelium was associated with poor prognosis. Genetic deletion of Sirt1 increased mitochondrial superoxide dismutase 2 (Sod2) acetylation of lysine residue 68, thereby enhancing reactive oxygen species (ROS) production and reducing SOD2 activity.

The question on the expression of Sirt1 is; is this a cause or an effect, or is it a concomitant from some related but no causal element? 

The PARK2 gene, which has several features of a tumor suppressor, encodes an E3 ubiquitin ligase that participates in removal of damaged mitochondria via mitophagy. Increased ROS in Sirt1−/− cells enhanced the recruitment of Park2 to the mitochondria, inducing mitophagy. Sirt1 restoration inhibited PARK2 translocation and ROS production requiring the Sirt1 catalytic domain. Thus, the NAD+-dependent inhibition of SOD2 activity and ROS by SIRT1 provides a gatekeeper function to reduce PARK2-mediated mitophagy and aberrant cell survival.

Sirt1 seems to be a gene whose function, if expression is reduced, could lead to malignant behavior. Now articles like this often get significant Press coverage. In Medical express we have[2]: 

Prostate cancer affects more than 23,000 men this year in the USA however the individual genes that initiate prostate cancer formation are poorly understood. Finding an enzyme that regulates this process could provide excellent new prevention approaches for this common malignancy. Sirtuin enzymes have been implicated in neurodegeneration, obesity, heart disease, and cancer. Research published ... show the loss of one of sirtuin (SIRT1) drives the formation of early prostate cancer (prostatic intraepithelial neoplasia) in mouse models of the disease. "Using genetic deletion we found that SIRT1 normally restrains prostatic intraepithelial neoplasia in animals. Therefore too little SIRT1 may be involved in the cellular processes that starts human prostate cancer," ... "As we had shown that gene therapy based re expression of SIRT1 can block human prostate cancer tumor growth, and SIRT1 is an enzyme which can be targeted, this may be an important new target for prostate cancer prevention."

Upregulation of SIRT1 is one path and developing a therapeutic for initiating that upregulation is also critical. However there may be a multiplicity of other factors that would or could be required. The mouse studies are clearly not definitive for humans. They are suggestive at best. 

The researchers ...created a mouse model that lacked SIRT1 and noticed that these mice were more likely to develop an early form of prostate cancer called prostatic intraepithelial neoplasia (PIN).

One of our ongoing concerns is the use of mouse models. We know that they are useful for certain studies but problematic for others. In addition a knockout mouse may have more complex genetic interactions that a random human. 

Other researchers had shown that SIRT1 can defend the cell against damage from free radicals. ... took the work further by showing that in this prostate cancer model, free radicals built up in cells lacking SIRT1. They showed that normally, SIRT1 proteins help activate a mitochondrial protein called SOD2, in turn activating those proteins to keep free-radical levels in check. When SIRT1 level are diminished, SOD2 is no longer effective at removing free radicals, allowing a dangerous build up in the cells, and leading to PIN.

Now Pestell and his group are highly respected and they have reported on Sirt1 effects before[3]. 

"The next step," says first author ... "is to determine if this is also important in the development of human prostate cancer."

Overall it is known that Sirt1 does works against inflammatory tendencies. The last statement however is critical. It is clear that the determination for human cells is still problematic. This seems to be one of the major problems in murine models. The mouse prostate growth is not always the same as human. Goldstein et al some five years ago did studies in mice regarding the cell leading to HGPIN and thus PCa. Was it a basal cell or a luminal cell? Carrying this over the humans was and is not definitive in any manner.

Let us briefly examine HGPIN. HGPIN is an excessive growth of cells in the glandular regions composed of an amalgam of basal and luminal cells. It is an excess of growth within the confines of existing cells. It often appears as a hyperplasia, but since the cells do not appear exactly as they were in a normal region, they are considered as neoplasia. The luminal space surrounded by the luminal cells tends to get crowded by these new cells which tend to be confined to existing glandular locations. The growth we would see in a Gleason 1 or 2 is generally not seen, namely the cells do not start to proliferate outside of existing glands, or creating new glandular areas.

HGPIN is often observed in cases where there is a sudden increase in PSA, generally above 6.0. However HGPIN can also be present in low PSA cases, below 1.9 and it is often in these cases where it may regress.In a paper by Lefkowitz et al the authors note: 

In a high proportion of men with high grade prostatic intraepithelial neoplasia prostate cancer will develop in a 3-year interval. Our findings support the concept that high grade prostatic intraepithelial neoplasia is a precursor to prostate cancer and that repeat biopsy at a delayed interval is recommended regardless of changes in PSA….

The question is; what caused the biopsy in the first place? Generally it was due to a material increase in PSA. In the study the average PSA was about 6.5, which is low and the average age was 65. We also know that the prevalence of PCa in say the seventh decade of life if one were to biopsy the entire prostate could be well above 50%. 

It is difficult to determine precisely the natural history of a single high grade prostatic intraepithelial neoplasia lesion since it is not feasible to follow-up with precision the exact areas of abnormality on repeat biopsy. Since the natural history of prostatic intraepithelial neoplasia has not been elucidated, current recommendations for serial repeat biopsy have not been validated by evidence based medicine, and several investigators have reported results of follow-up biopsies. To our knowledge there have been no reports of follow-up interval biopsy in a cohort of men with high grade prostatic intraepithelial neoplasia independent of changes in PSA or digital rectal examination findings. We provide insight into the natural history of high grade prostatic intraepithelial neoplasia by performing an empiric follow-up interval biopsy 3 years after the initial diagnosis regardless of change in PSA or digital rectal examination.

The paucity of studies regarding HGPIN follow up appears to be the same as it was a decade ago when this paper was written. 

A high proportion of men with high grade prostatic intraepithelial neoplasia will have prostate cancer, independent of changes in PSA, 3 years following initial diagnosis. Our study reaffirms the approach that men with high grade prostatic intraepithelial neoplasia and no evidence of coexisting cancer should be followed and re-biopsied to exclude prostate cancer. Our longitudinal data in men with high grade prostatic intraepithelial neoplasia strongly support the concept that it is a risk factor for the development of prostate cancer, thereby further validating the lesion as a target for chemopreventive and therapeutic agents. We recommend a 3-year follow-up interval biopsy in men with high grade prostatic intraepithelial neoplasia, regardless of change in serum PSA.

The conclusion is critical. Namely they recommend that a 3 year biopsy be done after a positive HGPIN determination. However what if after a HGPIN determination a 9 month biopsy comes back normal, no HGPIN at all, then should one go back again, independent of PSA? That is problematic. We have argued that PSA has a normal growth pattern and like some many medical observations if things continue on the same course, slow progression, then perhaps that is a better alternative. However, it may also be prudent to perform these biopsies, albeit being quite expensive and having some modicum of morbidity. The question seems to be still unanswered.

We now will examine Sirt1 and the family of genes from which it derives the Sirtuins. These genes have generally been examined in other venues and not PCa. However they are well examined and we shall consider them in some detail.

We begin with the work of Guatente has recently written an extensive review paper on Sirtuins and especially Sirt1 in NEJM. It concludes as follows: 

Sir2 is one of a complex of proteins that mediate transcriptional silencing at selected regions of the yeast genome. Mutations that extend the replicative life span of yeast mother cells have been shown to increase the silencing activity of Sir2 at the ribosomal DNA repeats. Although the silencing of ribosomal DNA has turned out to be an idiosyncratic feature of aging in yeast, the role of Sir2-related gene products (sirtuins) in aging appears to be universal. Sir2 orthologues slow aging in the nematode Caenorhabditis elegans, in the fruit fly Drosophila melanogaster, and in mice. The sirtuins have been shown to have NAD-dependent protein deacetylase activity, which is associated with the splitting of NAD during each deacetylation cycle…

The studies to date have been on yeasts and fruit flies and there have been some studies on humans. However the main focus on sirtuins is their beneficial effects on the aging process, and one suspects as an antioxidant and anti-inflammatory type of behavior. 

Of the mammalian sirtuins, SIRT1, 2, 3, 4, 5, and 6 have been shown to have this activity. Some SIRT family members (e.g., SIRT4 and SIRT6) also have ADP-ribosyltransferase activity. In mammals, the Sir2 orthologue SIRT1 is primarily a nuclear protein in most cell types and has evolved to deacetylate transcription factors and cofactors that govern many central metabolic pathways. Targets of SIRT1 include transcriptional proteins that are important in energy metabolism, such as nuclear receptors, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), and forkhead box subgroup O (FOXO). SIRT1 also regulates components of the circadian clock, such as BMAL1 and PER2, which underscores the interconnectedness of protein acetylation, metabolism, circadian rhythm, and aging. SIRT1 is also closely coupled to AMP-kinase activity in a mutually enforcing mechanism that adjusts cellular physiology for conditions of energy limitation.

Sirt1 is the gene of focus yet Sirt2-6 also play roles, none of which seem to have a role in PCa. The FOXO target is of considerable interest[4]. 

The earliest connection between SIRT1 and endothelial cells was the finding that SIRT1 deacetylates and activates endothelial nitric oxide synthase (eNOS). The activation of eNOS and repression of AT1 suggest that SIRT1 activity ought to curb high blood pressure. SIRT1 also inhibits the senescence of endothelial cells, and its salutary effect on these cells may mitigate atherosclerosis. Interestingly, calorie restriction is known to protect against atherosclerosis,46 and many of the physiological effects of calorie restriction are blunted in eNOS−/−mice.21 These findings all indicate that SIRT1 helps facilitate the favorable effect of calorie restriction on cardiovascular function by its effects on eNOS, AT1, and perhaps other targets.

From Powell et al we have as more detailed discussion of the functions of Sirt1: 

The Sirtuin family of proteins (SIRT) encode a group of evolutionarily conserved, NAD-dependent histone deacetylases, involved in many biological pathways. SIRT1, the human homologue of the yeast Silent Information Regulator 2 (Sir2) gene, de-acetylates  histones, p300, p53, and the androgen receptor. Autophagy is required for the degradation of damaged organelles and long-lived proteins, as well as for the development of glands such as the breast and prostate. Herein, homozygous deletion of the Sirt1 gene in mice resulted in prostatic intraepithelial neoplasia (PIN) associated with reduced autophagy. Genome-wide gene expression analysis of Sirt1/ prostates demonstrated that endogenous Sirt1 repressed androgen responsive gene expression and induced autophagy in the prostate. Sirt1 induction of autophagy occurred at the level of autophagosome maturation and completion in cultured prostate cancer cells. These studies provide novel evidence for a checkpoint function of Sirt1 in the development of PIN and further highlight a role for SIRT1 as a tumor suppressor in the prostate.

The autophagy cleans up the cells and brings them back to a normal stasis. The recognition of Powell et al regarding the role of Sirt1 is key. They continue: 

The role of SIRT1 in regulating prostate gland formation and androgen signaling in vivo was previously unknown. SIRT1is expressed in several cell types in the prostate gland including basal cells, luminal cells, and stromal cells. Given the evidence that SIRT1 functions as a tissue-specific regulator of cellular growth and that SIRT1 inhibits tumor cell line growth in nude mice, we sought to determine the role of endogenousSirt1 in regulating prostate gland development. Genome-wide expression profiling of Sirt1/ mice prostates and their littermate controls identified a molecular, genetic signature regulated by endogenous Sirt1.

The above clearly shows the understanding of the function of Sirt1. Note that the Powell work was in 2010 so that this understanding has been available for a while.

This signature highlights the ability of Sirt1 to inhibit androgen signaling and apoptosis in the prostate, while promoting autophagy. The Sirt1/ prostates demonstrated epithelial hyperplasia and PIN suggesting that Sirt1 promotes autophagy and inhibits prostate epithelial cell proliferation in vivo.

The above demonstrates the ability of Sirt1 to control androgen signalling. This also is a key factor in controlling prostate health.

Gene expression analysis further demonstrated that loss of endogenous Sirt1 inhibited autophagy. At a higher level of resolution, our studies demonstrated that SIRT1 antagonized DHT-mediated inhibition of autophagy in the prostate. Autophagy allows for degradation of proteins and organelles  and is induced by nutrient withdrawal, rapamycin (inhibition of mTOR signaling), and hormone signaling . Our findings are consistent with prior studies demonstrating that SIRT1 induces autophagy by deacetylating ATG5, ATG7, and ATG8 and inhibits AR signaling via deacetylation of the AR . Comparisons with previously published studies identified an overlap of 12.45% between genes regulated by endogenous Sirt1 and those targeted by androgens in the prostate gland and in prostate cancer cells. These results are consistent with prior findings that Sirt1 inhibits ligand-dependent AR signaling and gene expression in vitro   

Again we come back to the role of autophagy. Perhaps the buildup of protein segments may act as normal cell blockage, inhibiting normal expression and control. The autophagy allows for a return to such normality. The emphasize this issue as follows:

The role of autophagy in cancer was proposed over 20 years ago. Autophagy appears to be essential for tumor suppression as well as for cell survival. Autophagy plays a prosurvival function for cancer cells during nutrient deprivation or when apoptotic pathways are compromised, a phenotype often accompanied by inflammation.

Again we see the putative role of inflammation. This appears to be a significant factor in PCa and the suppression of genes which deal with the remnants of inflammation seem to be a key benchmark in PCa progression. They continue: 

In contrast, upon disruption of tumor suppressors, autophagy adopts a pro-death role with apoptotic pathways. In prostate, breast, ovarian, and lung cancer, loss of Beclin1 or inhibition of Beclin1 by the BCL-2 family of proteins causes defective autophagy, increased DNA damage, metabolic stress, and  genomic instability. These cancers also display neoplastic changes and increased cell proliferation, unlike cells overexpressing Beclin1, which undergo apoptosis. Loss of PTEN, p53, ATG4, ATG5, and MAP1LC31 (ATG8) are linked to tumorigenesis, whereas upregulation of PI3K, AKT, BCL-2, and mTOR are associated with inhibition of autophagy and the promotion of tumorigenesis. Prostate cancer onset and progression are correlated strongly with aging and SIRT1 function governs aging in multiple species. Further studies will be required to determine whether this checkpoint function of Sirt1 in regard to prostate growth is linked to its role in organismal aging.

From Shackelford et al we have additional insights including pathway control issues as follows: 

AMPK has recently been shown to increase sirtuin 1 (SIRT1) activity by increasing cellular NAD+ levels, resulting in the regulation of many downstream SIRT1 targets, including FOXO3 and peroxisome proliferator activated receptor-γ co-activator 1 (PgC1; also known as PPARgC1A), both of which have also been proposed to be direct substrates of AMPK46,76. As SIRT1 is also implicated in tumorigenesis, this connection between AMPK and SIRT1 might further explain how nutrients control cell growth. AMPK also suppresses mTOR-dependent transcriptional regulators to inhibit cell growth and tumorigenesis. Two mTORC1-regulated transcription factors involved in cell growth are the sterol-regulatory element-binding protein 1 (SReBP1) and hypoxiainducible factor 1a (HIF1α). SReBP1 is a sterolsensing transcription factor that drives lipogenesis in many mammalian cell types. mTORC1 signalling is required for nuclear accumulation of SReBP1 and the induction of SReBP1 target genes78, and this can be inhibited by rapamycin or AMPK agonists

From Hines et al we have an expression of Sirt1 in terms of overall cell control: 

The NAD + -dependent deacetylase SIRT1 is an evolutionarily conserved metabolic sensor of the Sirtuin family that mediates homeostatic responses to certain physiological stresses such as nutrient restriction. Previous reports have implicated fluctuations in intracellular NAD + concentrations as the principal regulator of SIRT1 activity. However, here we have identified a cAMP-induced phosphorylation of a highly conserved serine (S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic deacetylase activity independently of changes in NAD + levels. Attenuation of SIRT1 expression or the use of a nonphosphorylatable SIRT1 mutant pre- vented cAMP-mediated stimulation of fatty acid oxidation and gene expression linked to this path- way. Overexpression of SIRT1 in mice significantly potentiated the increases in fatty acid oxidation and energy expenditure caused by either pharmacological b -adrenergic agonism or cold exposure. These studies support a mechanism of Sirtuin enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis

From Dominy et al we have: 

From an evolutionary perspective, the nutrient-dependent control of protein acetylation through acetyltransferases and deacetylases is highly conserved and is a major mechanism for coupling metabolic activity with carbon/energy availability. The regulated acetylation of PGC-1a by GCN5 and Sirt1 is an excellent example: PGC-1a acetylation by GCN5 is favored under conditions of nutrient/energy abundance, whereas deacetylation by Sirt1 is favored under conditions of nutrient dearth and high energy demand

Finally Brooks and Gu state: 

SIRT1 is a multifaceted, NAD+-dependent protein deacetylase that is involved in a wide variety of cellular processes from cancer to ageing. The function of SIRT1 in cancer is complex: SIRT1 has been shown to have oncogenic properties by down regulating p53 activity, but recent studies indicate that SIRT1 acts as a tumour suppressor in a mutated p53 background, raising intriguing questions regarding its mechanism of action. Here we discuss the current understanding of how SIRT1 functions in light of recent discoveries and propose that the net outcome of the seemingly opposite oncogenic and tumour-suppressive effects of SIRT1 depends on the status of p53.

They clearly indicate the tumor suppressor role of Sirt1. p53 status is important but the observation above is truly intriguing if it is sustained.We have examined miRNAs in previous papers and they may play a key role here as well. The control of Sirt1 may be done via miRNAs. As Pekarik et al note: 

Importance of miRNAs is underscored by the fact that nearly half of the genes coding miRNAs are located at fragile sites or at regions with lost homozygozity. For example, a loss of p-arm of chromosome 1 is a common finding in sporadic colon carcinomas. Among many genes associated with DNA repair, checkpoint functions, tumour suppressors, etc. are also multiple miRNAs. The most critical is miR-34a, directly regulated by tumour suppressor gene p53  and classified now as tumour suppressor itself. Ectopic miR-34a expression induces apoptosis and a cell cycle arrest in G1 phase. Downstream targets of miR-34 are Bcl2, MYCN, NOTCH1, Delta1, CDK4 and 6, Cyclin D1, Cyclin E2, c-Met, SIRT1, and E2F3, all the genes involved in apoptosis or proliferation and cell growth control…

We have discussed miRNAs and especially mrR-34 as part of PCa process. The control Sirt1 by miR-34 is a key observation It links back to a cause. Thus one may surmise that this is a potential initiator and the miR-34 expression generated in some feedback manner with the inflammation which would have been controlled by Sirt1.

We now first make several observations and then we conclude with some possible recommendations.

1. What are the roles of miRNAs?

We have examined miRNAs extensively before. Yet they seem to have an enduring role in reducing the activity of certain genes. The questions here are; what activates the miRNAs, what are the targets for suppression, and why?

2. What causes the suppression of Sirt1?

We have seen an argument for miRNA suppression of Sirt1. However there may be multiple other arguments. Is it a consequence of an already malignant process or is it a path towards such a development? Frankly we do not seem to have clear answers. This becomes a significant factor when we try to model PCa and its metastatic processes.

3. Is HGPIN the first step in loss of Sirt1 expression?

As Goldstein et al had noted regarding the cell of origin of PCa and especially HGPIN, there is a well-defined genomic alterations leading to this result but yet the details seem to be unknown.

4. Why does HGPIN at times seem reversible? Is it a temporal anomaly?

The reversion seen at times in HGPIN is a significant factor that leads one to ask; why and what is the process. Many conjecture can be made ranging from elimination of a stem cell to reduction of inflammatory states. The problem is that adequate clinical data seems to be missing from analyses.

5. What Genes are key and what Genes are there as a Consequence? And why?

We have examined many dozens of purported genes related to PCa. They continue to arise each time some researchers examine new cells. For example in a study done contemporaneously to the one in this discussion we have one by Thomsen et al regarding JUNB, a transcription factor[5]. They conclude[6]: 

Prostate cancer is a frequent cause of male death in the Western world. Relatively few genetic alterations have been identified, likely owing to disease heterogeneity. Here, we show that the transcription factor JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in low-grade prostate cancer compared with normal human prostate, but downregulated in high-grade samples and further decreased in all metastatic samples. To model the hypothesis that this downregulation is functionally significant, we genetically inactivated Junb in the prostate epithelium of mice. When combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb and Pten were inactivated in a small cell population of the adult anterior prostate by topical Cre recombinase delivery. The resulting tumours displayed strong histological similarity with human prostate cancer. Loss of JunB expression led to increased proliferation and decreased senescence, likely owing to decreased p16Ink4a and p21CIP1 in epithelial cells. Furthermore, the tumour stroma was altered with increased osteopontin and S100 calcium-binding protein A8/9 expression, which correlated with poor prognoses in patients. These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as barriers to invasive prostate cancer, whose concomitant genetic or epigenetic suppression induce malignant progression. 

But is this gene, a transcription factor causal or consequential? The same can be said about the gene Sirt1 as discussed herein. The list of putative PCa related genes seems to grow by the day.

6. Why do researchers all too often make claims which are at best a stretch?

To best understand this point, which we have made several times, let us examine another Press release. As noted in Eureka[7]: 

Prostate cancer affects more than 23,000 men this year in the USA however the individual genes that initiate prostate cancer formation are poorly understood. Finding an enzyme that regulates this process could provide excellent new prevention approaches for this common malignancy. Sirtuin enzymes have been implicated in neurodegeneration, obesity, heart disease, and cancer. Research ... show the loss of one of sirtuin (SIRT1) drives the formation of early prostate cancer (prostatic intraepithelial neoplasia) in mouse models of the disease.

Let us examine the clarity of this statement in light of what we have presented.
They are:

i) The individual genes driving prostate cancer. Do we understand them? We do some, but we also have a plethora of dozens of others whose increase or decrease is somewhat correlated with PCa.

ii) Developing prevention. One develops prevention if and only if one understand the cause or causes and one can then mitigate the processes which lead to those aberrant actions. Frankly at best we can say that inflammation may be a problem but then what part of the complex inflammatory process do we address?

iii) Yes we know Sirt1 and its system genes (proteins) act in certain ways in a wide variety of ailments. But recognizing is presence to cause to prevention is still a long and uncertain process.

Thus the opening statement is possibly in my opinion an exaggeration. 

"Using genetic deletion we found that SIRT1 normally restrains prostatic intraepithelial neoplasia in animals. Therefore too little SIRT1 may be involved in the cellular processes that starts human prostate cancer," .... "As we had shown that gene therapy based re expression of SIRT1 can block human prostate cancer tumor growth, and SIRT1 is an enzyme which can be targeted, this may be an important new target for prostate cancer prevention."

It was not clear that they had shown a therapeutic that allowed for the re-expression of Sirt1 in mice not less than in humans. The process of Sirt1 suppression was not identified and thus suppressing the suppression is uncertain. At least that is what one understands reading the available literature. 

The researchers ....created a mouse model that lacked SIRT1 and noticed that these mice were more likely to develop an early form of prostate cancer called prostatic intraepithelial neoplasia (PIN). Other researchers had shown that SIRT1 can defend the cell against damage from free radicals. ... took the work further by showing that in this prostate cancer model, free radicals built up in cells lacking SIRT1. They showed that normally, SIRT1 proteins help activate a mitochondrial protein called SOD2, in turn activating those proteins to keep free-radical levels in check. When SIRT1 level are diminished, SOD2 is no longer effective at removing free radicals, allowing a dangerous build up in the cells, and leading to PIN.

SOD2 is supported by Sirt1 and thus we see the HGPIN build up. One suggestion is to examine those patients who have HGPIN regression, to see if it has been sustained and moreover what expressions were reactivated or suppressed.

Based upon the above we would make the following recommendations.

1. HGPIN Regression study: We would recommend a detailed HGPIN Regression Study. Simply records of multiple biopsies of HGPIN patients should be considered and examination of those with regression within the next biopsy period should be examined. Then retrospective examination of the patient and their behavior should also be examined. This is a simple first step. It can be accomplished by simple data gathering and no Trial structure is required.

2. HGPIN Regressed Genes Presence

One of the challenges in prostate biopsies is the ability to return to the same location from which the original cells were obtained. Thus even with a high density biopsy of say 24 cores we cannot be certain that we have resampled the original dysplasia. his is even the case with ultrasound guidance, yet it would seem possible to have recorded the location and to have a sophisticated ultrasound system replace the new sample to close proximity to the old. That way there could be a resampling of the same cells.

1.               Berghe W., Epigenetic impact of dietary polyphenols in cancer chemoprevention: Lifelong remodeling of our epigenomes, Pharmacological Research 65 (2012) 565– 576
2.               Brooks, C., W. Gu, How does SIRT1 affect metabolism, senescence and cancer?, Nature Reviews Cancer 9, 123-128 (February 2009)
3.               da Silva, H., et al, Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer, Hindawi Publishing Corporation Prostate Cancer Volume 2013, Article ID 920612, 23 pages
4.               Di Sante, G., et al, Loss of Sirt1 Promotes Prostatic Intraepithelial Neoplasia, Reduces Mitophagy, and Delays Park2 Translocation to Mitochondria
5.               Dominy, J., et al, The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis, Molecular Cell 48, 900–913, December 28, 2012
6.               Goldstein, A., et al, Identification of a Cell of Origin for Human Prostate Cancer, Science, Vol 329, July 2010, p 568.
7.               Guatente, L., Sirtuins, Aging, and Medicine, NEJM, Vol 364 June 2011
8.               Hines, Z., et al, The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD+, Molecular Cell 44, 851–863, December 23, 2011
9.               Lam, E., et al, FOXO Transcription Factors, Biochem Soc Trans 2006, pp 722-726.
10.            Lefkowitz, G., et al, Follow Up Interval Prostate Biopsy of High Grade Prostatic Intraepithelial Neoplasia is Associated with High Likelihood of Prostate Cancer Independent of Change in Prostate Specific Antigen Levels, Journal of Urology, Vol 168, Oct 2002.
11.            McGarty, T., Prostate Cancer Genomics, DRAFT 2013. www.telmarc.com
12.            Ott, R., et al, JunB is a gatekeeper for B-lymphoid leukemia, Oncogene (2007) 26, 4863–4871
13.            Pastell, R., M. Nevalainen, Prostate Cancer, Humana (Totowa) 2008.
14.            Pekarik, V., et al, Prostate Cancer, miRNAs, Metallothioneins and  Resistance to Cytostatic Drugs, Current Medicinal Chemistry, 2013, 20, 534-544
15.            Powell, M., et al, Disruption of a Sirt1 -Dependent Autophagy Checkpoint in the Prostate Results in Prostatic Intraepithelial Neoplasia Lesion Formation, Cancer Res Published OnlineFirst December 28, 2010.
16.            Pulla, V., et al, IRT1 Pathway in T2DM, https://www.researchgate.net/publication/259223485_SIRT1_Pathway_in_T2DM
17.            Roy, S., et al, Inhibition of PI3K/AKT and MAPK/ERK pathways causes Activation of FOXO Transcription Factor, Jrl Mol Sig 2010, pp 1-13.
18.            Shackelford, D., R. Shaw, The LKB1–AMPK pathway: metabolism and growth control in tumour suppression, Nature Reviews, Cancer Volume 9, August 2009, 563
19.            Slaby, O., et al, MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009 Nov 14;8:102. doi: 10.1186/1476-4598-8-102.
20.            Thomsen, M., et al, Loss of JUNB/AP-1 promotes invasive prostate cancer, Cell Death & Differentiation , (19 December 2014) | doi:10.1038/cdd.2014.213.
21.            van der Heide, L., et al, The Ins and Outs of FOXO Shuttling, Biochem Jrl 2004, pp 297-309.
Related White Papers

The following are related White Papers we have written in the recent past which may facilitate the material contained herein. http://www.telmarc.com/White%20Papers/default.html
 No. 120 CNVs and Prostate Cancer
No. 119 SNPs and Prostate Cancer
No. 118 Vitamin D and Prostate Cancer
No. 117 SPDEF, ETS Transcription Factors and PCa
No. 116 Methylation, Prostate Cancer, Prognostics
No. 112 Prostate Cancer: miR-34, p53, MET and Methylation
No. 111 CRISPR and Cancer
No. 110 ERG and Prostate Cancer
No. 108 Cancer Cell Dynamics
No. 107 Prostate Cancer Genetic Metrics
No. 106 Divergent Transcription
No. 104 Prostate Cancer and Blood Borne Markers
No. 103 Prostate Cancer Indolence
No. 101 Exosomes and Cancer
No. 100 lncRNA and Prostate Cancer
No. 99 SNPs and Cancer Prognostics
No. 98 CCP and Prostate Cancer
No. 95  MER Tyrosine Kinase Receptors and Inhibition
No. 93 Cancer Cell Dynamics Methylation and Cancer
No. 91 Methylation and Cancer
No. 88 Extracellular Matrix vs. Intracellular Pathways
No. 87 Prostate Cancer Prognostic Markers
No. 86 Cancer Models for Understanding, Prediction, and Control
No. 85 Prostate Cancer Stem Cells
No. 84 Epistemology of Cancer Genomics
No. 83 Prostatic Intraepithelial Neoplasia
No 82 Prostate Cancer: Metastatic Pathway Identification
No 80 PSA Evaluation Methodologies
No 79 The PSA Controversy

[3] See the book by Pestell and Nevalainen pp 157-158

[4] As Brunet et al state: SIRT1’s effects on FOXO3 are reminiscent of SIRT1’s effects on the tumor suppressor p53. Under conditions of cellular stress, SIRT1 deacetylation of p53 leads to an inhibition of apoptosis. Given that SIRT1 also reduces FOXO3-induced apoptosis in the presence of stress stimuli, it is possible that FOXO3 and p53 somehow function together to mediate the effects of SIRT1.We know p53 is an oncogene and its suppression can result in metastatic behavior and thus SIRT1 has a pivotal role in many areas of cancer development and spread.

[6] JUNB, also known as AP-1, is a proto oncogene seen in many cancers. http://www.ncbi.nlm.nih.gov/gene/3726  Also see Ott et al who state: Activator protein-1 (AP-1) is a dimeric transcription factor composed of members of the Jun family (c-Jun, JunB and JunD), which form homodimers or heterodimers with members of the Fos family (c-Fos, Fra-1, Fra-2 and FosB) and activating transcription factor (ATF) proteins. AP-1 modulates transcription by binding to TPA-response element (TRE) or cAMP-response element (CRE) consensus elements and is involved in proliferation, differentiation and apoptosis. AP-1 members may elicit divergent and even antagonistic effects via a cell-type-specific regulation of target genes…

How to Destroy The US Advantage

The brains in DC have now proposed a way in which they will judge what colleges are worthwhile. Imagine, the brains that have brought us the current mess in Primary and Secondary education are now taking this to the halls of Academe. I guess that is what happens when you take money from the devil.

From the Oracle of DC we have the following proposal:

In today's world, college is not a luxury that only some Americans can afford to enjoy; it is an economic, civic and personal necessity for all Americans. Expanding opportunity for more students to enroll and succeed in college, especially low-income and underrepresented students, is vital to building a strong economy with a thriving middle class and critical to ensuring a strong democracy. That is why .... has set the course for the United States to once again lead the world in college attainment, as we did a generation ago.

College is NOT a necessity for all. Many are not suited for such a process. We need good electricians, plumbers, carpenters. I worked as an electrician while I attended college and it has stuck with me all my life, PhD in EE notwithstanding.  I honor good tradespeople, people who work hard and have skills. College should be a place for those suited to its rigor, assuming that they follow something with rigor, and then work their craft as adults. College is not a necessity.

However excellent and highly competitive educational institutions are essential. They must be selective and produce talent that can contribute to the country's wealth. We currently have many such institutions. We do lead the world in attainment, we do not have to worry about the "once again". Just look at the collection of biotech entities around MIT in Kendall Square. But beware, the Washington hordes desire to control that and make it "better" in their eyes.

They then state:

As a key part of this plan, the President directed the U.S. Department of Education to develop and publish a new college ratings system by the 2015-16 school year that would expand college opportunity by recognizing institutions that: excel at enrolling students from all backgrounds, focus on maintaining affordability, and succeed at helping all students graduate.

 How can we expect DC to rate MIT? The market rates MIT, that is why Kendall Square is build up. Not because DC delivered a rating system. We most likely will have the same morbidly obese GS 9 prepare the RFP for the rating system with help from some lobbyist whose interests are to increase their sponsors revenue. Oh, and it may be the same GS9 who worked on the ACA.

And what metrics do they propose:
  • Percentage of students receiving Pell.
  • Expected family contribution (EFC) Gap.
  • Family Income Quintiles.
  • First-Generation College Status.
  • Average Net Price.
  • Net Price by Quintile.
  • Completion Rates.
  • Transfer Rates.
  • Labor Market Success, such as Short-term "Substantial Employment" Rates and Long-term Median Earnings.
  • Graduate School Attendance.
  • Loan Performance Outcomes.
 These are for the most part social engineering goals. There is NOT a single metric relating to production of value for the country. We can have a lot of completions for students in "Communications" but the last things we need is another Newsreader.

The problem is that many Academic Institutions have been feeding at the trough of the Government and now rely upon it. Then they must comply with these rules. If not they will get their funding cut off. But then what of the many Alumni/Alumnae who truly fund many quality institutions. What of their views. If this system is employed there may be a death spiral down to total mediocrity.

As they say, don't fix it if is ain't broke!

Fundamentally any student, yes the student themselves, should approach college as a means to get a job. There are very few students who are so brilliant that they can approach college for pure knowledge. This approach to college is ones first test of reality. If the student wants to study classic Greek, and the family is now well off, then this is most likely a laudable academic goal but a clueless life directed goal. Someone must tell the student. If a student wants to become a hairdresser, then that is not college. College for almost all is a means to an end. Examine the job postings, then examine those institutions which facilitate entry to those postings and seek out such a path. English majors just do not have a great future. Chemical Engineers are in demand and yes it requires a great deal of work. That should be the lesson.