Monday, January 22, 2018

Scientific Snowflakes?

The Government is back in session. However The Scientist notes, or shall we say bemoans:

Nature spoke with crop researcher Chad Hayes at the US Department of Agriculture whose travel to Mexico today—timed to coincide with a brief window of sorghum pollination—could be disrupted, along with a year’s worth of work. According to Vox, half of the Department of Health and Human Services staff will not work during the shutdown. That means that, while the Centers for Disease Control and Prevention (CDC) will continue to monitor this year’s high flu activity, reports might take on a sluggish pace. “Under a shutdown, CDC’s capacity to track and respond to disease outbreaks will be impacted,” a CDC spokesperson tells Buzzfeed News. “Flu surveillance, for example, will continue to collect data being reported by states, hospitals, etc. However, our staff resources are limited, which means it will take longer to review, analyze, and report out information needed for public health action.”

You can't make this up! CDC closing? Hardly. It was at most a day off! Sorghum pollination? You miss a day of pollination and the world comes to an end! Guys, I spent all June, July, and August crossing plants. Have done it for three decades! Don't get paid! Is there some personal satisfaction in participating in sorghum pollination?

This is why we need some careful attention to our tax dollars and what they are spent for!
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AI, the Industrial Revolution and What Else?

A Professor wrote a piece in Project Syndicate. First I find the name a bit humorous since from New York we always assume a Syndicate is some Mafia like organization. So much for names.

The Professor tries to relate the AI revolution, whatever that is, to the Industrial Revolution. He states:

The elimination of countless cognitive tasks has alarming implications for the future. Just as the Industrial Revolution made most humans physically weaker, the AI revolution will make us collectively duller. In addition to flabby waistlines, we will have flabby minds. It’s not the economy, stupid; it’s the stupid economy. Already, central banks are urgently exploring new ways to dumb down their statements for an increasingly unsophisticated public. Mass stupidity will be driven by technology. But, as with the cult of physical fitness that took hold during the Industrial Revolution, a new industry of intelligence training will likely emerge to counter mental deterioration. Listening to someone constructing a logically articulated argument will become an exclusive source of aesthetic pleasure and distinction. “Difficult” works of literature or visual arts will become an ever more attractive form of conspicuous consumption. And yet something about this seems deeply unpleasant. It is bad enough to listen to people boast about their physical fitness. But braggadocio about superior intellect will be far worse. The need to prove oneself as a lasting relic of the old human supremacy will threaten not just the common good, but also our common humanity.

He basically relates that the Industrial Revolution led to Obesity and that the AI revolution will result in stupidity. 

First, just what is this AI revolution. The Industrial Revolution was the replacement of machines for human work. Thus a engine driven plow replaced the horse drawn implement. Men could do more, eat more, and get fat. In contrast he argues I believe that the AI revolution is that men, women too, will have to think less and get stupid. Now I find that difficult logic to follow. Obesity is a class issue more than a labor issue. Before the Industrial Revolution the wealth were often obese as a showing of their wealth. Then after the Industrial Revolution the wealth class was thin showing their self control. Thus will the same happen here? But the working class is not that smart to begin with and one wonders how more stupid they will become. The wealthy are not that smart as well, thus what will be the change. Again it comes back to the issue of; what is AI?

AI is simply a way to replace some machine function, possibly facilitated by human intervention, to an algorithm that when combined with a machine completes the same function. Thus AI in a simple manner replaced the telephone operator. Not very well I may add. The speech recognition is awful, the logic behind it is infantile, and the replacement is globally despised! I hazard to guess that an Industrial Revolution Replacement was less despised.

Take AI as espoused by IBM, the Watson thing. First as best I can understand no one really understands this. Is it just a marketing hype by a dying company? Is is real, does it work? I dread it ever going into the medical field. There may be a great many corpses before it can act as a First Year Med student.

So again, what is AI? It is simply a set of computer code that may have the possibility to adapt and "learn" Learn how? By mistakes. That is the way these systems work.

So will the AI Revolution lead to stupidity, more stupidity than there already is? Ride the Broadway Local, no one is reading a book or newspaper anymore. The train has no trash. That is good, but people are staring and clicking away telling their life story to the world. But such voices will be lost in the ether. They are no longer conversations at the Agora, interactions in the market, but just snarls and come backs that lead no where. Is this more stupidity? Not likely.

So is this Professor correct. Hardly. The Industrial Revolution was not a singular event. It has been happening throughout history. Rome lost its slaves, the Medieval Kingdoms lost their serfs, England gained its machines, so are we losing our brains? Again hardly.
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Mothers - The Other Kind



I was reading a NY Times piece, as usual, criticizing Trump[1]. It does get a bit long in the tooth but alas one must be patient with those of such limited resources. Then, add to this, the BBC has a discussion on le Carre's descriptives of MI6, the equivalent, if one stretches it, of the CIA[2]. The BBC notes the terms for Americans as:

Mothers – the typists and secretaries for senior MI6 officials.

Now Mothers in MI6 were a bit more than just that. You see, the Brits knew very well that operatives were often childlike, demanding, and ego driven, yet wanting for care and attention, and even more so control. Thus, one did not need an "office wife", as the NY Times so aptly asserts, but Mothers. The "hand that rocks the cradle" and all that stuff you know. One must have spent a bit of time in the land of the Queen to best understand just how this works. One does not need or want an "office wife", yet many of these folks need a "mother". A "mother" in this context has power, authority, respect, and can effect things that otherwise would just run amok. Mothers can over-rule, mothers can direct and govern, mothers are the Type A controls for a Type A personality. Furthermore, "mothers" are those points at which remediation of mess-ups can be attained. If there is a problem at a higher level, the lower level folks can go to "mother" to get things back aright again. You see, "mothers" are essential to the balancing act of complex organizations.

A few Presidents had "mothers". Just a few. Mothers are powerful figures, especially in an MI6 environment, dotted with Oxbridge boys, a very class based society, smart but with a bit of arrogance. Unlike our CIA which has become at times more akin the Department of Agriculture than a want to be MI6 as it was in the le Carre times.

Did the CIA ever have its mothers? Not really, too un-American as the old boys would say. I also fear that too many American Presidents had let us say relationships that were anything but "motherly". Let us then leave the Kennedy, Clinton and others not to be mentioned. Yet, I do recall how my Russian partners would spark up when we had a problem and I told them to speak with "mother". They not only understood, but smiled because they clearly knew that "mother" would solve it for them. I thus often wondered if in Le Carre's world the KGB had its own version of "mothers", for it appeared as if they did.

Thus, perhaps instead of a "House Wife", as the Times suggests, what is really needed is a "House Mother", that stable hand to rock the unstable cradle.
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Sunday, January 21, 2018

1709 Failed

I have an older laptop that was upgraded to Windows 10 from W7. The last upgrade, 1709, failed. I paid not attention since it is a spare system and updates to the new releases usually mess up a few dozen things anyhow. That is Microsoft. But have a few spare moments I went to see if I could remedy the problem. Solution, just go to Google, NEVER and I mean NEVER go to Microsoft. There on Google I found thousands of people with the same problem.

Then, Microsoft has some "Engineer" telling folks how to remedy this. The best part of the response was:

Method 4:
  1. Open registry editor by running regedit.exe
  2. Back up the registry first before making changes to it
  3. Navigate to HKLM\System\CurrentControlSet\Control\Session Manager
  4. Check if PendingFileRenameOperations exists under the Session Manager key
  5. If it exists, please remove it
  6. Restart computer and check if issue persists
If the issue persists,  please follow the steps below and send the CBS log to the e-mail address in private message.
  1. Rename the CBS.log(%systemroot%\Logs\CBS\CBS.log) to CBS.old
  2. Manually update the computer again and restart computer if needed
  3. Send the new generated CBS.log.
If anything is unclear, please feel free to let me know.

 Now for those of you who would dare to change a Registry, let me tell you, it is the holy of holies in Windows OS. It is where Microsoft places millions of landmines. Make one small change and not all others required and CRASH! Yep, down goes the machine and unrecoverable.

 So my question is: where is the Class Action suit lawyers in this case. It has likely taken more productivity from our economy than anything Congress could screw up! 

 If Microsoft were a real company in a competitive market they would not last a femto second. They would have to remedy this. But alas, we all know where this is going. No where. Pity!
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Thursday, January 18, 2018

Video on Demand, Home Shopping


The above was a brief clip of the Warner Cable TIES system of two way video on demand in 1982! Compare to Amazon.
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Corporate Culture

The Wall Street Journal had a piece called Of Furies and Fascism at Google[1] In this piece they discuss a pending suit regarding termination of an employee who allegedly used the internal company communications system to express his opinion regarding certain employment practices. For that he was allegedly terminated. The article then notes:

Some predict Google will quickly settle to avoid discovery of more emails and postings, including from top management. What seems worse, from a public-relations perspective, is a culture inveterately hostile to the liberal principle “I may disagree with what you say but defend your right to say it.” This can’t be good in a business whose mission is to organize the world’s information. Messrs. Brin, Page and Pichai likely feel a tad helpless. The U.S. legal system imposes a need to be race-aware, gender-aware, etc.—to require quotas in all but name, since quotas are illegal. Google simultaneously faces lawsuits and regulatory investigations directed at its alleged shortchanging of women on pay and promotions. Its internal mood may also partly be a victim of self-esteem run amok. It’s a wonder many Googlers don’t worship Donald Trump —he also can’t tolerate to be disagreed with. A good, old-fashioned Presbyterian horror of self-righteousness, once a feature of American life, is nowhere to be seen. Part of growing up is learning to live with your emotions; today’s shortcut is to believe whatever your feelings are, they’re justified. Humanity never met a dictator or demagogue who said, “I’m a bad person. I want to do bad things.” The worst among us always feel justified.

Google apparently suffers from a common ailment; Corporate Culture. Companies get personalities and cultures as they mature. IBM had the IBM salesman, the man in the single color suit with white shirt, simple tie and a hat. You "trusted" this person to deliver your computer solution for which you paid an enormous price. The Watsons had THINK signs everywhere yet that oftentimes was the last thing an IBMer was expected to do. You were in my experience and in my opinion expected to sell the company line and the company products and services. Google started with "Don't be evil"[2]. They tried to position themselves as the good guys. Perhaps a result similar to IBM. In fact the Code as referred by the Washington Post states:

“Employees of Alphabet and its subsidiaries and controlled affiliates (‘Alphabet’) should do the right thing — follow the law, act honorably, and treat each other with respect,” Alphabet’s code of conduct reads. And: “We expect all of our employees and Board members to know and follow this Code of Conduct. Failure to do so can result in disciplinary action, including termination of employment. Any waivers of this Code for directors or executive officers must be approved by our Board.”

Corporate culture evolves but it builds on the DNA of the company from which it started. In the Google case they hired what they saw as the "best" of the "best". The hired from a pool of millennials who were already predispositioned to see themselves as "special" and going to Google then made them the "most special". They were paid handsomely but given where they lived the cost of existence made the compensation modest at best. The best was some big win in a startup, perhaps. Thus one gets a collection of company DNA from this select group of "specials" along with the group think of a political mindset that as "specials" everyone else was not just mundane but effectively illiterate.

Moreover there were no role models. It was not like a Lockheed Skunk Works where a new employee could look towards "Kelly" Johnson as a role model. There was no hierarchy. The employees saw themselves generating what they did as if they were the first and only people to have conceived of and implemented what they produced. They were Googlers, like any group of synchronized thinkers, they could see the world through their own prism. Lacking "adult leadership", adults who themselves had demonstrated creative competence as well as leadership, a culture evolved, a culture more reflective of millennial values than any other.

Corporate culture is a critical element in the long term success or failure of a company. That culture must support and nurture a corporate identity to the outside, it must enable a trust in the company and its offerings, it must embody the processes for a successful evolution of the company. Corporate culture also evolves to meet the challenges of a changing world and customer base. Failures of corporate cultures not so responding litter the landscape. Take GE, a company bred in the industrial 19th century, peaking in the mid to let 20th century and today appearing as a corporate dinosaur with no identity. Its culture mired in the past. IBM is a similar example, a company selling massively expensive almost one of a kind systems with obscenely expensive "support" then moving into a business based on consultancy and now attempting to market an erstwhile AI talking box.

For Google, Facebook and the Silicon Valley crowd of fast buck players, the time scales they may face are not a century long but more likely decades or even less. In a high tech environment change can occur suddenly. In the case of Google, their search engine is a valuable but fungible asset, supported by the advertising linked to the searches. In addition, the search engine provides massive marketing data which enhances the advertising revenue source. Thus a simple feedback. As long as the user trusts Google, then they, Google, will continue to have the "eyeballs" that can be monetized, unless the advertisers find that there is some form of disintermediation from a competing third party. Let me give an example. Half of what I use Google for, or even substantially more, is searching for technical papers. Semantic Scholar, one of Allen's entities, does a wonderful job. It is a tool, a focused and valuable tool, currently devoid of advertising. Thus in that past year my Google time has dropped dramatically. Take Facebook, I may have been a early adopter but I was also an early leaver. Why? Simple, too many people just saying stuff and linking me to it. I really did not want some friend's friend bemoaning their love life or lost cat. In contrast Research Gate is a vehicle to get my draft ideas out there, well more effective than just a web site. Thus there is highly focused disintermediation already in place.

How does corporate culture react to disintermediation? Let not use the in term, "disrupter", a termed most likely coined in the Valley. One does not disrupt, one gets in between, one can create and efficient "appliance". Instead of having an all in one kitchen appliance, one gets an attractive and highly effective "toaster" or "coffee maker".

Corporate cultures evolve as we noted. But the process whereby they are formed and then evolve is critical. The Google corporate culture is interesting in that the company went from a small entity in the late 1990s to a massive institution in the current time. But it did so in an environment for which there was no model to build on. Google type business did not exist, it was being invented on the fly. Compare this to Amazon. Amazon built a business where the difference was the introduction of an electronic marketing and distribution channel. But a channel that was displacing a physical one such as shopping malls. Thus it was well know what had to be done, albeit now electronically. Thus the corporate culture of an Amazon was delivering quality goods to the customer. Here we use quality as the amalgam of value, that is competitive prices, and trust, which means if you don't like it you can return it. That Amazon quality metric was what allowed it to work. It was aided also by the degradation of physical shopping. In even the best shopping malls the staff was rude, incompetent, low paid, and at best they were there to catch a shoplifter not service the customer. Amazon was helped by the degradation of customer service in what should have been their competition.

There are several questions worth examining:

1. How does one identify corporate culture? What are its characteristics? What types of corporate culture are there?

All of these are characterization questions. It is almost Aristotelian in nature to characterize or categorize culture in this manner[3]. The identification of a corporate culture is one thing and its categorization is another. One may ask if a culture of Type A is of that type because of a set of characteristics. What then are these characteristics.

2. What exogeneous factors form a corporate culture? Is it the time, the place, the people, the business, the competition? Perhaps all of these elements. Is there a west coast culture, versus say an east coast culture?

It seems clear that Silicon Valley has its own culture. However fifty years ago when it was all defense related the culture was dramatically different. It was the same place but different work, workers, and of course time. Is time the dominant factor or the change from Defense to software. Even twenty five years ago it was more hard core technology. With both hard core technology one had to have different corporate characteristics. Technical people needed experience, competence, and coordination. RF engineering for example was not easily learned and even less easily transformed to embodiments. Customers were few, many Government entities so building relationships was key. In a Google one could say they have no real nexus with their customers, there are so many and each contributes a miniscule amount.

3. Who is the formative agent for a corporate culture? Is the founder(s) the prime mover for culture? If not then is it from within or from without?

In a company like Tesla one can see Musk as an influencer on culture. In Apple it was Jobs, and unlikely Cook took his place. In Google? Good question. It may briefly have been the founders, but they were very technical and the investors brought in the "resident" adult as Chairman but he was less a manager than a "front" for the marketing of the company to investors. Currently Google has a CEO whose background reflects a rather interesting mix, just what would require a detailed study. But in Google as the WSJ article notes, the culture may be formed in a different way, namely like that in Golding's book, Lord of the Flies. Let us examine that for a moment.

In Lord of the Flies a group of young English school boys are being evacuated during the war, not specified, and their escape aircraft crashes and they end up on a island, with no other inhabitants. They are all young, all somewhat privileged, and all lacking in any skills in terms of dealing with groups. They are after all English school boys, public school boys. Two f them, Ralph and Piggy find a conch, and then the tale takes off. It details how groups and culture are formed, in this case a culture built on the Lord of the Flies, a pseudonym for the Devil. Several of the young students are murdered at the hands of the others, they do not fit within the "culture". The end of the tale is the arrival of the adults, a Naval vessel to rescue the children. The savages, as their culture has turned them into, somehow under an adult revert to the school boys again. The Captain of the ship, now in control, looks at his battered ship in a recognition that the adult culture has similar savage behavior. New culture subsumed into old culture.

Now let us look at Golding and Lord of the Flies as a possible paradigm for the Silicon Valley cultures. In a sense it is a paradigm worth examining regarding corporate culture where the group is homogeneous, lacking maturity, somewhat isolated, and totally unhinged from any underlying ethical framework. Like Silicon Valley with tons of VC cash, lots of millennial youngsters all told how smart they are. Success is not curing cancer, solving poverty, or the like, success is achieving the most return in the shortest period of time with the minimal amount of know how. Coders are the typists of the 21st century. They do what they are told by the system architects, albeit cleverly and efficiently, hopefully.

Where the true problem will arise, however, is in the development of AI, where opinions which define the culture are made as part of the IF, THEN, ELSE statements in the new AI culture. If one sees Lord of the Flies in the Valley human culture, what then does one expect to see in this AI culture. It must be remembered that humans both age and die off. Thus the millennials are not here forever. Yet the AI bots and their off-spring may readily carry forth this culture in those elements of the AI choices that are made. We have people placing their judgements and values into AI statements. Do we stop for the little puppy, or just run it over and crush it like Piggy! Those value statements can become an integral part of the AI world. If we have any concern about the people and their human culture and its values perhaps then we should feel terrified about the AI culture they may leave behind!

Thus the question on the table is simple: is there a role for Government in regards to these dominant players? Is Antitrust law applicable? Some thirty years ago I studied in details the implications of antitrust on the information industry at the time. I argued that information, defined broadly, had the value in the food chain and little value was relegated to actual transport no matter how it evolved. Earlier I had developed an electronic marketing and distribution channel over CATV. Our model was more Ali Baba than Amazon, or at least as Amazon was. Yet we integrated information with transactions. It was a Google plus Amazon, thus its name; TIES or Transaction, Information, Entertainment Services. Great idea just twenty to thirty years too early! This teaches one that nothing is really new, just better timed.

[3] Aristotle's Categories are: Substance, Quality, Quantity, Relation, Time, Place, Position, Having, Action, And Passion. We could however take an Ockhamist view and minimize these to two.
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Economics: Old and Older

In a piece in Project Syndicate, that left wing blog which seems to be a watering hole for economists and others espousing their political versions of reality, springs forth a defense of the economics, both old and older.

Skidelsky, a defender of Keynes and other left leaning purveyors of the art of economics states:

A decade ago, two schools of macroeconomists contended for primacy: the New Classical – or the “freshwater” – School, descended from Milton Friedman and Robert Lucas and headquartered at the University of Chicago, and the New Keynesian, or “saltwater,” School, descended from John Maynard Keynes, and based at MIT and Harvard. Freshwater-types believed that budgets deficits were always bad, whereas the saltwater camp believed that deficits were beneficial in a slump. Krugman is a New Keynesian, and his essay was intended to show that the Great Recession vindicated standard New Keynesian models.But there are serious problems with Krugman’s narrative. For starters, there is his answer to Queen Elizabeth II’s now-famous question: “Why did no one see it coming?” Krugman’s cheerful response is that the New Keynesians were looking the other way. Theirs was a failure not of theory, but of “data collection.” They had “overlooked” crucial institutional changes in the financial system. While this was regrettable, it raised no “deep conceptual issue” – that is, it didn’t demand that they reconsider their theory.

 I believe there was and is a fundamental problem. Economics works best when looking backward. It fails almost continuously looking forwards. It can collect and analyze existing facts, yet it cannot use the facts in any predictive manner. Take the classic example of unemployment as predicted by Romer. She said we would drop to 5% in just a short while. It took nine years. Did unemployment eventually get there? Yes, but time is as important as the end point. 

The Government under the last Administration threw ten trillion dollars at the problem, doubling the debt, and far exceeding anything that FDR ever contemplated. But when did the stock market respond, after a new Administration came. Was it in response to any new policy, perhaps.

Skidelsky continues:

Krugman comes close to acknowledging this: New Keynesians, he writes, “start with rational behavior and market equilibrium as a baseline, and try to get economic dysfunction by tweaking that baseline at the edges.” Such tweaks enable New Keynesian models to generate temporary real effects from nominal shocks, and thus justify quite radical intervention in times of emergency. But no tweaks can create a strong enough case to justify sustained interventionist policy. The problem for New Keynesian macroeconomists is that they fail to acknowledge radical uncertainty in their models, leaving them without any theory of what to do in good times in order to avoid the bad times. Their focus on nominal wage and price rigidities implies that if these factors were absent, equilibrium would readily be achieved. They regard the financial sector as neutral, not as fundamental (capitalism’s “ephor,” as Joseph Schumpeter put it).

Tweaking is what you do when the theory and data do now comport. Macro-economists should admit that their  theories are pure speculation. Inherent in the macro world are the effects of externalities that all too often dominate the result. Radical uncertainties are pandemic in the current world environment. That demands leadership not economics.
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Lipids and PCa, Again

There is a continuing proliferation of targets for the treatment of various cancers especially in prostate cancer, PCa. In a recent paper by Chen et al the authors note that targeting SREBP appears to have some significant efficacy. We briefly examine this approach and attempt to see if it has some value. This gene product has a multiplicity of functions from metabolic to immunologic. Thus as with any of these targets one must be cautious to not have severe unintended consequences.

Now from the recent article by Chen et al we have the following:

Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP).

We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP pro-metastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP.

Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a non-metastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP.

Thus, our findings uncover a pro-metastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.

Now what is the function of SREBP?

SREBP[1]: In mammals, the transcription of several crucial genes required for lipid synthesis is activated by a small family of transcription factors called SREBPs (sterol response element binding proteins). A remarkable feature of SREBPs is that their entry into the nucleus depends on their release from the membrane by proteolysis (see the figure). During their synthesis, SREBPs are inserted into the membrane of the endoplasmic reticulum, a membranous network in the cytoplasm of the cell. In the endoplasmic reticulum, SREBPs form a complex with a membrane-embedded protein called SCAP, which escorts the SREBPs to another cellular compartment called the Golgi apparatus. Here, the SREBPs are sequentially cleaved by two Golgi-specific proteases, releasing a soluble fragment from the amino terminus. This fragment is a transcription factor, which, as a result of cleavage, is free to migrate to the nucleus, where it activates the expression of genes involved in the synthesis of cholesterol and fatty acids. Homeostasis is achieved by a negative feedback loop in which cholesterol and fatty acids block the proteolytic release of SREBPs from Golgi membranes. Interestingly, one of the SREBPs (SREBP-1c) is subject to an additional regulatory step that takes place at the promoter for SREBP-1c itself. Fatty acids, the end products of the SREBP-1c pathway, inhibit the action of a transcription factor called LXR, which is required for optimal expression of the SREBP-1c gene.[2]

As Brown and Goldstein note:

As an end-product repressor, cholesterol presents a special problem because it is an insoluble lipid that resides almost exclusively in cell membranes. How does the cell sense the level of a membrane-embedded lipid, and how is that information transmitted to the nucleus to regulate transcription? Answers are emerging from studies of a novel family of membrane-bound transcription factors called sterol regulatory element binding proteins (SREBPs) that regulate multiple genes involved in cholesterol biosynthesis and uptake.

Here we review the SREBPs, focusing on the novel way in which sterols regulate their proteolytic release from membranes. Remarkably, insight into this processing may teach us about Alzheimer's disease, the most common degenerative disease of the brain, as well as coronary artery disease, the most common degenerative disease of the heart. Other aspects of SREBP physiology, such as the DNA binding activities and interactions with other transcription factors…

As Lewis et al note:

In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers.

We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth.

In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.

From Sengupta et al we have the following Figure:


 From Porstmann et al we have the following Figure which demonstrates a more complete metabolic set of interactions:


Now one also notes that there is a significant relationship also to the actions of the immune system. As Weichhart et al note:

Accumulating evidence suggests that innate immune cells also actively control metabolic processes to adapt and optimize their effector functions. These various effector functions are supported by an adaptation of energy metabolism to accommodate their metabolic needs and link their metabolism to the availability of nutrients. The mTOR network is a central regulator of many core metabolic processes. Activation of mTORC1 usually drives an anabolic response through hypoxia-inducible factor 1α (HIF1α), peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding proteins (SREBPs) and MYC that induces the synthesis of nucleic acids, proteins and lipids. In addition, it drives processes such as glycolysis and mitochondrial respiration to provide the cellular energy and building blocks for these responses. mTORC2 also enhances glycolytic metabolism by activating AKT and promoting an inactivating phosphorylation of class IIa histone deacetylases. This leads to the acetylation and inactivation of forkhead box protein O1 (FOXO1) and FOXO3, which in turn activates MYC transcription.

From Weichhart et al we have the following Figure demonstrating the impact on the immune system:

The above immune interaction is a critical element in understanding the cross reaction of the control of metabolic genes perhaps for malignancy control and the operation of the immune system. It raises the question perhaps of unintended consequences.

Now we also have the overall control element of p53. As Parrales and Iwakuma  note:

Mechanistically, mutant p53 binds to and activates SREBP, crucial transcription factors that regulate transcription of several enzymes involved in the mevalonate pathway, leading to enhanced prenylation of proteins associated with cancer progression and activation of prenylated proteins in breast cancer cells; hence, inhibition of protein prenylation by statins leads to reduced malignancy of human breast cancer cells.

Importantly, the presence of p53 mutation correlates with high expression of sterol biosynthesis genes in human breast tumors. Additionally, since nuclear localization and activation of the YAP and TAZ proto-oncogenes are regulated by prenylation and activation of Rho GTPases, statins could also suppress progression of mutant p53-expressing tumors by inhibiting YAP/TAZ activation by reducing protein prenylation of Rho GTPases, which is promoted by SREBP and its cofactor mutant p53.

Now the second element in the Chen et al system is PML. PML is characterized by NCBI as follows:

PML[3]: The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This phosphoprotein localizes to nuclear bodies where it functions as a transcription factor and tumor suppressor. Its expression is cell-cycle related and it regulates the p53 response to oncogenic signals. The gene is often involved in the translocation with the retinoic acid receptor alpha gene associated with acute promyelocytic leukemia (APL). Extensive alternative splicing of this gene results in several variations of the protein's central and C-terminal regions; all variants encode the same N-terminus. Alternatively spliced transcript variants encoding different isoforms have been identified.

Also from Genecards[4]:

Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation).

From a recent paper by Guan and Kao the authors provide a detailed overview of PML. They state:

The tumor suppressor protein, promyelocytic leukemia protein (PML), was originally identified in acute promyelocytic leukemia due to a chromosomal translocation between chromosomes 15 and 17. PML is the core component of subnuclear structures called PML nuclear bodies (PML-NBs), which are disrupted in acute promyelocytic leukemia cells. PML plays important roles in cell cycle regulation, survival and apoptosis, and inactivation or down-regulation of PML is frequently found in cancer cells. More than 120 proteins have been experimentally identified to physically associate with PML, and most of them either transiently or constitutively co-localize with PML-NBs. These interactions are associated with many cellular processes, including cell cycle arrest, apoptosis, senescence, transcriptional regulation, DNA repair and intermediary metabolism. Importantly, PML inactivation in cancer cells can occur at the transcriptional-, translational- or post-translational- levels. However, only a few somatic mutations have been found in cancer cells. A better understanding of its regulation and its role in tumor suppression will provide potential therapeutic opportunities. In this review, we discuss the role of PML in multiple tumor suppression pathways and summarize the players and stimuli that control PML protein expression or subcellular distribution.
   
The authors demonstrate the many pathway control and interaction functions that PML is involved in. Specifically:

1. DNA Damage Repair: This is accomplished via a complex set of interactions.
2. Transcriptional repression: This is done via a sequestration of the RB and E2Fs blockage.
3. Transcriptional Activation: This is via STAT1 and NF-kB activation amongst others.
4. AKT Pathway: This is via activation of PP2a, PTEN and eIF4e
5. p53 pathway: via SIRTq, MAPK1, HAUSP, and MDM2
6. Epigenetic Regulation: The various HDAC, SIRT, and EZH2.

are just a few the authors present in their Figure 4.

PML appears to Chen et al as a key element in the development of metastasis. It putatively also represents a therapeutic target.

Overall p53 and metabolism are intertwined and PML has that role in the regulation of p53. From Flotter et al we have the detailed dynamics. Flotter et al note:

Tumour development is accompanied by changes in cellular metabolic activity, which allows cancer cells to grow and proliferate under adverse conditions. The influence of p53 on cellular metabolism is complex and involves multiples nodes of regulation. p53 changes the activity of multiple metabolic pathways, including glycolysis, mitochondrial oxidative phosphorylation and fatty acid synthesis via transcriptional and non-transcriptional regulation. In addition, p53 governs the adaptation of cancer cells to nutrient and oxygen deprivation, which is crucial for the survival under the metabolically compromised conditions shaped by the tumour microenvironment. Importantly, it has been shown that the regulation of metabolic activity is essential to the tumour suppressive function of p53

Finally Chen at al conclude:

Our data provide a strong genetic foundation elucidating the mechanisms underlying metastatic progression, and they demonstrate how environmental dietary factors can boost progression from primary to metastatic cancer, intertwining with the genetic makeup of cancer.

We demonstrated that SREBP- dependent lipogenesis, which can be hyperactivated by concomitant activation of the PI3K-AKT and MAPK pathways, or a HFD regimen, functions as an underlying rheostat toward metastatic cancer progression.

Furthermore, we identified PML as a critical mediator of feedback inhibition of MAPK signaling and lipogenesis, and its inactivation propels metastatic progression in cancers driven by PTEN loss and PI3K- AKT activation.

…Numerous mechanisms have been proposed to explain a possible association between dietary lipids and CaP67, including paracrine mechanisms through secreted cytokines from adipose tissues, endocrine mechanisms through alteration of androgen levels and an induction of basal-to-luminal cell differentiation caused by immune-cell infiltration. However, we showed here that specific genetic perturbations or a HFD are probably able to exert a direct effect on metastasis through increased lipid accumulation.

We also characterized the intracellular lipid changes in GEMMs of CaP and detected qualitative changes in four different lipid classes as well as in the saturation of fatty acyl chains. Together, these results established a strong mechanistic and causal link among aberrant lipogenesis, excess lipid accumulation and metastasis, thus providing a compelling rationale for integrating lifestyle data (for example, diet) and tumor genetics into clinical practice to identify patients at high risk of metastasis.

Additionally, lipid metabolism itself is an attractive therapeutic target through inhibition of lipogenic enzymes. Notably, such inhibition decreases CaP cell viability only in the absence of an exogenous lipid source such as lipoprotein, thereby highlighting the importance of integrating pharmacologic approaches with stringent dietary regimens to prevent metastasis. Future studies are warranted to evaluate whether specific lipid subsets/signatures may serve as prognostic biomarkers to distinguish CaP with metastatic potential from indolent disease.

Finally, given that PML is lost in human cancer of multiple histological origins, our study suggests that PML loss may underlie MAPK activation in cancers lacking genetic alterations in MAPK-signaling components. …

This finding has equally important implications for tumorigenesis, because PML loss in the hypoxic core or tumoral lesions not only would activate mTOR, thus resulting in sustained HIF-1 activation, but also would relieve the feedback inhibition of MAPK signaling triggered by mTOR activation, thereby leading to simultaneous activation of both mTOR and MAPK signaling.

Together, our results provide a potential roadmap for targeted therapies tailored to individual patients for the prevention and treatment of metastatic cancer.

Thus is this proposal based upon the experimental identification of PML warranting of a therapeutic targeting? Everything is worth examining, yet the complexity of the interactions, especially with the immune system raises some concern. Chen et al note in their paper:

…PML loss might represent cooperative predictors of overall survival after prostatectomy. Tissue microarray (TMA) analysis was performed in prostatectomy specimens from 144 men with primary CaP. Loss of PTEN and/or PML was significantly correlated with disease progression. Complete loss of PTEN and PML at the protein level occurred in 15% of the high-grade CaP samples, but not in the low-grade CaP samples.

It is well known as to the effect of PTEN. Chen et al argue for a pari passu positioning of PML.

This is an interesting result but it is a long way from any therapeutic targeting. The complexity of the PNL signalling does imply a complex set of unintended consequences that must be explored.

References

1.     Brown and Goldstein, The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor, Cell, Vol. 89, 331–340, May 2, 1997
2.     Chen et al, An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer, Nature Genetics (2018)
3.     Flotter et al, Regulation of Metabolic Activity by p53, Metabolites 2017, 7, 21
4.     Guan and Kao, The function, regulation and therapeutic implications of the tumor suppressor protein, PML, Cell Biosci (2015) 5:60
5.     Lewis et al, Regulation of the SREBP transcription factors by mTORC1, Biochem. Soc. Trans. (2011) 39, 495–499;
6.     Nohturfft and Losick, Fats, Flies, and Palmitate, Science Vol 296 3 May 2002 857
7.     Parrales and Iwakuma, Targeting Oncogenic Mutant p53 for Cancer Therapy, Frontiers in Oncology December 2015 | Volume 5 | Article 288 Review published: 21 December 2015 doi: 10.3389/fonc.2015.00288
8.     Porstmann et al, A new player in the orchestra of cell growth: SREBP activity is regulated by mTORC1 and contributes to the regulation of cell and organ size, Biochemical Society Transactions (2009) Volume 37, part 1
9.     Sengupta et al, Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress, Molecular Cell 40, October 22, 2010
10.  Weichhart et al, Regulation of innate immune cell function by mTOR, Nature Reviews Immunology 15, 599–614 (2015)
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