Calories and the Government

The USDA and the HHS have issued a revised food guide. One of their key statements is:

The food supply has changed dramatically over the past 40 years. Foods available for consumption increased in all major food categories from 1970 to 2008. Average daily calories available per person in the marketplace increased approximately 600 calories, with the greatest increases in the availability of added fats and oils, grains, milk and milk products, and caloric sweeteners. Many portion sizes offered for sale also have increased. Research has shown that when larger portion sizes are served, people tend to consume more calories. In addition, strong evidence shows that portion size is associated with body weight, such that being served and consuming smaller portions is associated with weight loss.

If the increase was 600 cal per day then every 6 days you would gain a pound assuming that in 1971 you were balanced. The portion size is truly a significant factor. When I first had my Czech partners over here I took them out to a restaurant, some chain type, in Framingham, and the wife and daughter looked at me in almost terror as they saw the size of the plate and portion. It was colossal. That was ten years ago. In Prague at lunch we had a small plate of food, smaller than a US pie plate and the beer was 6 oz of beer. I never really drink beer so I passed on that. The issue is portion size, and people eating it all. Supersize is the real problem. From 8 oz cokes in glass bottles to 32 oz cokes in big gulp jugs the calories just add up.

The report is interesting but the problem is really what is being served. One should remember that in WW II the average male weight was 135 pounds. Try and find a normal 18 year old even close.

The Myth Makers

I am continually amazed about economists. The latest is an economist and his statement that people have not "earned" their Social Security and Medicare.

He states:

Myth: The elderly have "earned" their Social Security and Medicare by their lifelong payroll taxes, which were put aside for their retirement. Not so. Both programs are pay-as-you-go. Today's taxes pay today's benefits; little is "saved." Even if all were saved, most retirees receive benefits that far exceed their payroll taxes. Consider a man who turned 65 in 2010 and earned an average wage ($43,100). Over his expected lifetime, he will receive an inflation-adjusted $417,000 in Social Security and Medicare benefits, compared with taxes paid of $345,000, estimates an Urban Institute study.

As we have demonstrated in excruciating detail, this is FALSE, the Myth is TRUE! Now if a family earns $43,100 pa now then going back some 40 years means that they were making about $4.200 pa in 1970! That was minimum wage almost. If you take the lowest paid person and assume that their salary applies to all you are going to come up with the nonsense that the economist comes up with. Remember that Medicare takes its 3% of your GROSS, no limit like SS.

If one makes an assumption that leads to an erroneous conclusion, than garbage in and garbage out! The economist has apparently put garbage in, and of course there is garbage out. Indeed if one makes $43,100 at age 65 then that person will be subsidized. That to a degree was part of Social Security and Medicare. That is why they call it an insurance and not a defined contribution plan, although it is also somewhat of that types as well.

One could suggest that the economist above do some simple calculations which I believe even an economist may have the simplest of tools to do, with the help of Excel perhaps, and reach a more reasonable conclusion.

What I find worse is that all too many economists will reach the same conclusion without examining the detail. The problem is that anyone who has effectively run a business understanding that details and facts are important, that theories and political views are less useful. It is a true shame that these economists seem to avoid the facts, the details, the results. This example of the $43,100 pa 65 year old is at the end of the financial spectrum, the bottom end.

The conclusion is simple. You cannot use the minimum contribution payer, ie lowest salary, and relate it to the highest distribution receivers, namely greatest benefit recipient, and call that an example for all. That is not only sloppy analysis it is, I believe, an outright misrepresentation.

However, having said this, I have also stated that both systems need significant reform. For example:

Social Security needs:

1. A change in eligibility ages to a moving number dependent upon average lifetime of its participants. Namely if expected life is 77 years then it should not start until 67 or ten years prior to end of life.

2. SS should be just that, not a catch all for every other type of program.

3. SS Funds should not be allowed to be confiscated as was started by the Democrats during the Johnson Administration.

Medicare:

1. Raise the 3% to 4%. Make the 4% apply to all types of income including capital gains. They have already done that to individual home sales so why not apply to investment bankers.

2. Move its eligibility as with SS.

3. Increase Part A and B deductibles, making them means tested.

4. Increase the monthly payment and make it means tested also.

5. Make Medicare payment acceptance mandatory otherwise there will be negative disintermediation. However allow over-rides if possible.

6. As with SS make the fund untouchable!

Just some thoughts.

And the Brits Went After the Grays, Perhaps They Thought They Were Irish!

In the WSJ they now state that the demise of the red squirrel in England is not due to the gray squirrel, some of whom are my best friends, but some virus to which the red are most sensitive but the grays are less.

The WSJ states:

The role of parasites in causing species to decline is often overlooked. Native European red squirrels, for example, have long been retreating in Britain at the hands of the American gray squirrel, which menagerie-owning aristocrats introduced in the 19th century. For years it was thought to be the competition for food that prevented the squirrels' co-existence, but now scientists place most of the blame on a parapox virus that causes a mild illness to the grays but kills the reds.

As this case shows, blaming a pathogen does not exculpate people. A new disease usually runs rampant because human beings have introduced it inadvertently—or, in the case of the rabbit disease myxomatosis, deliberately. A virus of native South American rabbits, "myxy" (as it is called) killed 90% of European rabbits when deliberately released in Australia and Europe in the 1950s. Resistance has since grown, but slowly.

 It was just a couple of years ago that the Brits thought they should have an all out massacre of the gray squirrel assuming the American invader was the cause not a co-sufferer of the disease. A classic British response, kill them off.

An Oxymoron: Government Investment

Many of the left wing economists are praising the idea of Government Investment. One is in today's Washington Post, surprise, surprise.

First, let us examine the term investment. It means simply taking assets today in a reasonable and well thought out anticipation of the return of those assets plus more, the return on the investment.

Thus one may invest in the stock market, and unfortunately may not see either the principal or the return. But let us take a simple example, say venture investment. Here is how it goes:

1. Some entrepreneur comes up with an idea.

2. They prepare a plan, develop a prototype or proof of principle, they get letters of intent from customers, they assemble a team, and

3. Then they go to an investor to show the investor what type of return they may get if the investor puts in money. Up to this point the entrepreneur has spent all their own funds. The investor does due diligence on the investment and the entrepreneur and only after significant investigation doe the VC invest the money.

4. Then the VC sits on the Board and like a hawk watches the entrepreneur perform to the plan that he gave the VC. If the entrepreneur does not meet the plan he is toast! If he does then hopefully there is a liquidity event.

5. At the liquidity event, a sale or IPO, the investors are first to get their money back plus a return and then the entrepreneur shares.

Second, now is this what the Government does? No way. Let me give a few examples.

1. The Electric Car: DOE has been "investing" on the electric car since 1970! That is 40+ years. Billions and billions. Now would any rational investor do this! No.

2. Internet. DoD, namely ARPA invested in the initial net. It almost died in the 1980s, and it was saved almost single-handedly by Bob Kahn and Vint Cerf who managed to keep the non-DoD side afloat.

3. NIH, now this a research, not "investment" and it has been productive as a means to fund research. Research is not investment in the classic manner. It uses money for no particular financial return, that is NOT investment.

Third, the problems with Government investment are simply:

1. The investment decision makers are Government employees who have nothing at risk. If they had to bet their life, their incomes, perhaps we could start to call it an investment, yet they have no risk.

2. The Government never kills a dumb idea, the electric car! Thus unlike real investments which often go wrong, a Government investment just lives forever! Special interests are born and the "investment" becomes another drag on the taxpayers.


As the left wing writer in the Post states:

There is a similar emphasis on the private sector in the president's proposal for a National Infrastructure Bank, which will not only help to insulate the government's investment decisions from the political process but will focus on projects with demonstrable financial returns. Toll roads, smart grids, wind farms, freight lines and air-traffic control systems would compete for funding on the basis of their ability to generate user fees to repay the bank's bondholders. 

In the energy sector, (the current President) expects to untap tens of billions of dollars in private investment with modest amounts of seed money and the right regulatory incentive - in this case a requirement that 80 percent of electricity comes from environmentally clean sources by 2035. 

 This is total nonsense. Let us briefly look at Air Traffic Control systems. The FAA has been spending billions on a 1940s vintage system and upgrades have been near impossible to deploy. The FAA is the problem and not the solution.

Private investment is ruthless, not like the Government. The worst disaster will be the Broadband program of NTIA and RUS which gives away billions to entities which for the most part have no demonstrable experience in doing what they were committed to. So the money is equal to that dropped by helicopters!

Did we not have almost a trillion in Stimulus, signs all over our highways with massive interstate traffic jams burning excess fuel while states paid government employees to sip coffee on the road sides! That is Government Investment, a total waste.

Employment of the "Old Folks"

I was reading a set of comments in the Washington Post to an article and was interested in what one, apparently, Democrat said:

There is lots that can be done. Most obvious: bring back the WPA. There is plenty of public work(s) to be done if private employers don't want to hire...Of course there's not much that will be done politically speaking....But you gotta say, the unemployed, under-employed and otherwise disadvantaged don't do themselves any good when they don't vote, or vote for those (i.e., Republicans) who are least likely do anything. Of course when (the current President) can't muster the gumption to even talk about the problem, I guess there's not at present a whole lot to choose.

The article was bemoaning the high unemployment amongst the over 65 job seekers. So this Democrats suggest we re-institute the WPA and send Grandma to the Appalachian Trail to cut through some new paths along the Blue Ridge.

Here is the logical and obvious problems with this comment:

1. The problem discussed was the 65+ and older worker. So the WPA is to solve this? Does this person have any knowledge of history?

2. The WPA costs money and does not create value. Do any of these people who comment have any idea of money, others, not theirs. The problem is that we need new jobs created by private industry which is stalled as a result of Government actions.

3. So voting for a Democrat solves the problem, look how we got here in the last two years!

The advantage of the Internet is to see how many people have half baked factless ideas. Pity because we may eventually go back to the mess again.

Songs and Their Meanings

The White House Dinner had one of those moments, as seems to happen so often in the current Administration, when the Chinese musician one Lang Lang played a tune which was part of an anti-American collection from the days of the Korean War.

The words are from China Daily:

My Motherland (Lyrics by Qiao Yu, Music by Liu Chi)

A big river has broad billows 
Winds sweep the paddy fields on the banks
 My family lives on the shore 
Accustomed to the whistles of the longshoremen 
And to the white sails of the boats
Girls are beautiful like flowers
 Lads have broad chests 
To create a new world 
We waken up sleeping mountains 
And change the courses of rivers 
This is my beautiful country 


Where I was born and grew up 
On this vast land 
Everywhere has great scenery
Great mountains and great rivers 
Every road is wide 
When friends come we give wine 
But if jackals come
They’ll be greeted with hunting guns 
This is my heroic country 
Where I was born and grew up 
On this ancient land
Everywhere has the power of youth 
This is my strong country 
Where I was born and grew up 
On this warm land 
Everywhere has bright sunshine

Yet as China Daily states:

The movie Shangganling, released in 1956, experienced a surge in popularity during the post-"cultural revolution" (1966-76) years. People of my generation are familiar with the plot, a typical war picture, but the song comes at a telling moment, a hiatus in the battle when the soldiers are reminded of the beauty of the motherland, while a few lines refer to "greeting jackals with hunting rifles". 

By Chinese standards the song is quite apolitical and lacks the propaganda vibe of the time. Rendered by the most popular folk singer of the day, the beautiful Guo Lanying, it was an instant hit and has since become a classic. 

The writer in China Daily does state that the Chinese use subtlety in their dealings, and one experienced in the ways understands that quite well.There is never a direct confrontation, they are not Russians or if you will a New Yorker. Yet for one unskilled in the worldly ways, one would neglect to understand that, moreover, neglect is too subtle a word, one would be ignorant. If one is ignorant of this cultural manner than how is one to negotiate with China. This shows a great shortcoming in the staff who organized this. 

One should always remember, prior planning prevents poor performance. Also, nothing is necessarily what it appears to be.

Recession Statistics: January 2011

We continue some detail on the Recession Stats as of the current release of the GDP data as of today and we rely upon the St Louis FED data as before.

GDP

First the GDP and its components. The GDP itself is as below:

The above is the GDP scaled to the minimum point of the Recessions as recorded by the St Louis FED. The Recessions used by the St Louis FED are:

Peak	Trough
November 1948	October 1949
July 1953	May 1954
August 1957	April 1958
April 1960	February 1961
December 1969	November 1970
November 1973	March 1975
January 1980	July 1980
July 1981	November 1982
July 1990	March 1991
March 2001	November 2001
December 2007	June 2009

The  GDP in periods before and after the nadir are shown as follows, in Quarters:

Note that we are near the bottom of upturns. One can make all sorts of arguments but the facts seem to still indicate that it has been the cumbersomeness of the current Administration that caused this.

Personal consumption as above now seems to becoming healthy. It was exceptionally weak after the drop and has lagged.

Private investment had been running along at an average rate but the drop in last quarter is a concern to GDP growth going forward.

Government consumption had been average but with the change in Congress we anticipate a drop here. Frankly that is a good sign since it was exploding and taking money from private interests.

Exports are above average and below we show the same for imports.

The above are the GDP and its elements. There are no truly exceptional signs here so we do not anticipate a rapid move from the Recession.

Other Data

Now we have a few other stats. First is Industrial Production which seems healthy:

 

Then we have personal income which is quite a serious problem. This will be the major factor. While Wall Street is walking away with billions funded by TARP we have Main Street doing worse than ever. Wall Street should really worry about this, but as usual they are ignorant of it in toto.

The above is the personal income data we spoke of. It is well below the worst recession data available!

Now we can look at employment data, and we see the weak recovery.

Finally retail sales has shown some signs of life as we see it climb to above average levels.

The real concern is the income number and this will most likely hold back the economy.

GDP, Inflation, M2 and the Economy

The Government issued the recent Q4 GDP estimates. First GDP grew about 3.6% on an annualized basis. We show the GDP and Chained GDP above. From this one may assume that GDP is now consistently growing at a more normal rate.

As is usual, Krugman notes that the GDP chained to 2005 has returned to what it was just when the economy tanked. That is obvious from the above.

The concern is of course inflation. Above we show M2 and the Monetary Stock. The MS has stabilized and M@ is growing but not at any rapid rate which would be of concern. Clearly the banks have absorbed all the money and it is merely circulating to pay for non-productive Government programs. As they say, if not for that it would have been worse.

The M2 annualized growth is quite small and thus should not as of now be a concern

We calculate inflation from the standard equation and it appears to be slowing. M2 growth is easily balanced by GDP growth so that what we see is a low velocity of money and thus a low inflation.

Finally we depict the components of inflation above and this give a quantitative view of the elements and our argument above.

Conclusion: GDP is growing slowly but growing and inflation seems still at a distance. So far so good.

Happy Birthday Mozart

Mozart was born some 255 years ago. He is worth listening to on a snowy day with breaks of sunlight. This is a public domain photo reproduction.

CBO and Current Policies

The CBO report shows the debt, public held only, as percent of the GDP. Note that this is really worse than WWII since the debt then was just the public debt since Congress has been purloining the SSI and Medicare funds in addition, so we will be well over WWII numbers.

I often think what would happen if this was a start up company and we were on the Board. Would we ever allow the management to continue in this clueless fashion. No! They would be replaced. We will soon exceed, if not already, all previous debt levels. And they keep driving over the cliff!

Global Warming: Climate vs Weather

 

Now there is the debate that there is a difference between weather and climate. What you see is the weather and what the folks from East Anglia and Penn State say ex cathedra is climate. Well just what do you believe, your lying eyes or the charts!

Another two feet plus of snow, and it is occurring almost every five days! We may have a day respite and then back again. 

As the squirrels sit warming themselves at the fire and as they drop the peanut shells in the bowl, they just turn and giggle, weather, climate, it is just snow!

Internet Neutrality and Congress

There is a new bill running around Congress concerning Internet Neutrality. It was issued by Senator Cantwell and it is interesting in many ways. First it is a bit naive in its wording when describing the Internet. In many ways it appears to be written, from the techncal side, by someone who just took one of those executive courses on telecommunications. They got the jist of some of the words and enough just to be dangerous.

The key words seem to be:

A broadband Internet access service provider may not unjustly or unreasonably—

‘‘(1) block, interfere with, or degrade an end user’s ability to access, use, send, post, receive, or  offer lawful content (including fair use), applications, or services of the user’s choice;  

‘‘(2) block, interfere with, or degrade an end  user’s ability to connect and use the end user’s  choice of legal devices that do not harm the network;

‘‘(3) prevent or interfere with competition among network, applications, service or content providers;  

‘‘(4) engage in discrimination against any lawful Internet content, application, service, or service  provider with respect to network management practices, network performance characteristics, or commercial terms and conditions;  

‘‘(5) give preference to affiliated content, applications, or services with respect to network management practices, network performance characteristics,  or commercial terms and conditions;  

‘‘(6) charge a content, application, or service  provider for access to the broadband Internet access  service providers’ end users based on differing levels  of quality of service or prioritized delivery of Internet protocol packets;  

‘‘(7) prioritize among or between content, applications, and services, or among or between different  types of content, applications, and services unless  the end user requests to have such prioritization;  

‘‘(8) install or utilize network features, functions, or capabilities that prevent or interfere with  compliance with the requirements of this section; or

‘‘(9) refuse to interconnect on just and reasonable terms and conditions.  

‘‘(d) REASONABLE NETWORK MANAGEMENT.—  

‘‘(1) IN GENERAL.—Nothing in this section  shall prohibit a broadband Internet access service  provider from engaging in reasonable network management.  

‘‘(2) REASONABLENESS PRESUMPTION.—For  purposes of this section, a network management  practice is presumed to be reasonable for a  broadband Internet access service provider only if it  is—  

‘‘(A) essential for a legitimate network  management purpose assuring the operation of  the network;  

‘‘(B) appropriate for achieving the stated  purpose;  

‘‘(C) narrowly tailored; and  

‘‘(D) among the least restrictive, least discriminatory, and least constricting of consumer  choice available.

There are so many holes in this set of statements that one could drive all the trucks that GM makes through it. What do the words mean? Litigation would ensue for decades while costing the consumer billions to pay for it while delaying any progress to the development of service.

The market will play this one out. There are tons of competitors and with wireless just peaking its head up with 4G, LTE et al, then just let the market work!

HHS and Home Heating

Now HHS Secretary has announced that the Department is "releasing" also known as spending some $200 million for home heating.

The Press Release states:

U.S. Department of Health and Human Services ... announced today the release of $200 million in emergency contingency funding to help eligible low-income homeowners and renters meet home energy costs. These Low-Income Home Energy Assistance Program (LIHEAP) contingency funds will provide states, territories, tribes and the District of Columbia with additional assistance to pay heating and other home energy costs.

It is interesting to see that HHS is spending our money for fuel oil, since I never imagined how far the new health care plan really stretched!

Strategic Investment and NASA

When I was back in corporate America there was a phrase tossed about frequently, "Strategic Investment" which was a euphemism for, "we really want to spend this money but have no idea if it will ever make a return". I spent time at NYNEX cleaning up quite a few prior "Strategic Investments". They are investments because one spends money and "Strategic" because no one had the faintest idea as to how it will ever make a return. "Strategic Investments" are corporate waste. In the case of the current Administration their "Strategic Investments" are just outright squandering of taxpayer funds.

Now where does NASA fit in? Simply, in my early years I spent a few on NASA programs at MIT. They took valuable assets, intellectual talent, and wasted it sending a man to the moon. We could have allowed the economy to work its way and have entrepreneurs, instead we had moon landings. NASA has been a colossal waste of taxpayer money for decades. It continues to be such. DOD launches its own spacecraft, why use NASA. So is what is being proposed nothing more than an extension of that waste? Most likely so.

miRNAs and Cancer: Some Thoughts

Micro RNAs are an interesting recent discovery which have been found to control cancers by making them stop or making them grow faster.

We first look at micro RNA and its process and its impact on prostate cancer (PCa). Micro RNAs, miRNA, are small single stranded RNAs which when in the cytoplasm may often bind to other RNA on complement binding sites and thus change or incapacitate the mRNA to which it binds from being translated into a protein. Craig Mello was awarded the Nobel Prize in 2006 for the discovery and his Nobel Lecture provides an excellent overview of the early stages of miRNA investigation.

We now briefly examine the miRNA production and action. This is graphically demonstrated below. From segments of the DNA, segments not containing genes, a long segment called a pri-miRNA is generated and it is then cut to a shorter segment called a pre-miRNA and transported to the cytoplasm outside of the nucleus. Then another protein called Dicer cuts up the pre miRNA into about 22 base single-stranded pair segments which are the miRNA,

Then as we show below the small miRNA can bind to mRNA at complement sites, and in fact the binding may allow for a loop which extends out from the binding sites composed of non-complement base pairs. This binding then inactivates the mRNA and prevents its translation to a protein.

The process continues as follows (See Garcia and Miska in Appasani):

 The process is described in some detail below. Here we describe the steps one at a time as is currently understood ( an alternative view of this is in the paper by He and Hannon, 2004).

It is also possible for the miRNA to target more than one mRNA since the miRNA may bind in its complement binding with many other such sites on other mRNAs. It is currently not clear what the affinity of binding is for an miRNA and any possible mRNA.

Also miRNA may be obtained from introns as well as exons. The former is called intronic and the latter called exonic. Now the exonic miRNA goes through the pri and preprocess whereas the intronic miRNA is cut directly to a pre miRNA segment (see Ying et al in Appasani).

miRNAs have been identified and currently there are well over 1,000. They are named in a simple numerical order such as miRNA 34.

 

miRNA is a single stranded product of the process above. An alternative double stranded product is called small-interfering RNA or siRNA. siRNA usually trigger mRNA degradation whereas miRNA may cause degradation or suppression of translation to proteins. For this section we shall not focus a great deal on the siRNA functions.

Now there may be some dynamics associated with this miRNA process as well. The model above assumes a simple one to one matching of miRNA and mRNA. However the generation of the two RNAs can be continuous and we should be looking at the concentrations. Thus is we define:

[miRNA] to be the concentration of the miRNA

and

[mRNA] the concentration of the targeted mRNA

then we have a dynamic process. Namely we can see a process such as follows:

If [miRNA] < [mRNA] then there will be excess mRNA and its product protein P will have a [P] >0. Otherwise the miRNA will bind to all mRNA and there will be no resultant protein.

One may view miRNA as a buffer agent which controls the [P] of its associated [mRNA]. One can see in dynamic form of a dynamical model. Now since the binding is not necessarily 1:1, namely the miRNA may bind to several mRNA, then we may want to expand the above as follows:

  

There has been a great amount of research regarding the impact of miRNA on cancer and especially on PCa. miRNAs may downregulate tumor suppressor genes such as PTEN. This has been seen in miRNA 21. Colin and Croce have provided several review article regarding miRNA and their influence on cancers. They argue that miRNA alterations are heavily involved in the initiation of many cancers. Their focus had been on CLL, chronic lymphocytic leukemia, and its initiating miRNAs, miR 15 and miR 16. Coppola et al (2010) provide a detailed summary of miRNAs and PCa.

The graphic from Coppola et al is shown below where it depicts a collection of miRNAs which impact various parts of the PCa process.

For example miR34 can cause the activation and recapitulate p53 which in turn induces cell cycle arrest and apoptosis. Loss of the miR34 can result in the impairment of the p53 control of apoptosis and permit the cells to proliferate. Coppola et al perform a detailed analysis of all of the above related miRNAs and their resultant impact on PCa. miR-21 up-regulation leads to PTEN loss and thus is an oncogene.

Recent work by Poliseno et al have shown that PTENmiR-106b. It had already been known that PTEN could be down-regulated by miR-22, miR-25 and miR-302. Their work demonstrated that miR-22 and miR-106b are overexpressed  in PCa miR-106b is an intronic miRNA. The work of Poliseno thus has demonstrated a proto-oncogenic miRNA dependent network that regulates PTEN and thus can have a significant role in initiating PCa.

Micro RNAs are regulators of mRNA, the post transcriptional result which is then used to generate via translation the operative protein. Currently there are nearly 1,000 identified miRNAs. They are generally 22 nucleotides long, short segments, and they usually target specific mRNA and silence it. Each one of the miRNA may act upon many mRNAs.

As He and Hannon state:

Non-coding RNAs participate in a surprisingly diverse collection of regulatory events, ranging from copynumber control in bacteria1 to X-chromosome inactivation in mammals2.MicroRNAs (miRNAs) are a family of 21–25-nucleotide small RNAs that, at least for those few that have characterized targets, negatively regulate gene expression at the post-transcriptional leve.

Members of the miRNA family were initially discovered as small temporal RNAs (stRNAs) that regulate developmental transitions in Caenorhabditis elegans6. Over the past few years, it has become clear that stRNAs were the prototypes of a large family of small RNAs, miRNAs, that now claim hundreds of members in worms, flies, plants and mammals.

The functions of miRNAs are not limited to the regulation of developmentally timed events. Instead, they have diverse expression patterns and probably regulate many aspects of development and physiology. Although the mechanisms through which miRNAs regulate their target genes are largely unknown, the finding that at least some miRNAs feed into the RNA INTERFERENCE (RNAi) pathway has provided a starting point in our journey to understand the biological roles of miRNAs.

miRNAs are simple yet complex entities and key players in the epigenetics which control gene expression.

It is clear from the above that miRNAs can positively and negatively impact many elements in the pathways we have considered in HGPIN and PCa. Coppola et al review several of the key ones. For example:

·       miR-146: Down regulates the AR.

·       miR-34: Can recapitulate p53 resulting in apoptosis and arrest.

·       miR-23: can result in c-myc overexpression and cell proliferation.

In a recent paper by Poliseno et al they have identified several others:

·       miR-106b: Down-regulates PTEN and triggers PIN in murine models.

·       miR-22, miR-25, miR-302: Down-regulating of PTEN.

Similarly the papers by Petrocca et al and that by Calin and Croce detail many of the miRNAs and their impacts on many cancers. As seen in the above graphic these are but a few in the overall targeting of PCa control genes. As Coppola et al state:

The hypothesis that miRs can be regarded as new broad-spectrum oncogenes or tumor suppressor genes has opened a revolutionary field of research with exciting diagnostic and therapeutic perspectives.

The compelling hint of a widespread miR deregulation in cancer pathogenesis came from the analysis of the genomic distribution of 186 miR. In this study, it was demonstrated that more than half of them mapped in cancer-associated genomic regions, namely in chromosomal sites prone to deletions, amplifications or recombinations. These aberrations can result in miR down- or up-regulation, conferring selective advantages to mutated cells.

Additional mechanisms of miR deregulation include altered expression of miRs as a consequence of excessive or deficient processing; aberrant transcription of the precursors by epigenetic silencing of miR promoters or as a result of the activity of oncogenic transcription factors; and more rarely, point mutations in mature miRs or in target sequences that can interfere with normal target recruitment

The problem that we will have in any modeling of HGPIN and PCa is not only do we have issues regarding the somewhat well-known genes but the impact of the epigenetic factors is unknown, complex, and possibly random.

Furthermore miRNAs can act in a positive or negative manner depending upon the cell and the activated networks in the cell. From Croce (2009) we have:

Importantly, miRNAs should not be described as oncogenes or tumor suppressor genes, unless the tissue or cell type involved in their action is specified. For example, miR-221 and miR-222 target an oncogene, KIT, and inhibit the growth of erythroblastic leukaemia30, and therefore function as tumor suppressors in erythroblastic cells. but they also target at least four important tumor suppressors — phosphatase and tensin homologue (PTEN), p27, p57 and tissue inhibitor of metalloproteinases 3 (TIMP3) — and function as oncogenic miRNAs by suppressing these tumor suppressors in various human solid tumours31 (TABLE 1). Therefore, before describing an miRNA as a tumor suppressor or an oncogene, it is necessary to specify in which cell or tissue, as cellular context is crucial for the function of miRNAs….

Recent work on miR-34 has demonstrated its impact on p53 (Rokhlin et al) and the fact that miR-34 significantly mediates the role of p53 in apoptosis in AR dependent PCa.

As we have indicated elsewhere, the concept of the cancer stem cell has received significant attention. There has also been a great deal of work on the area of linking miRNAs and the stem cell model for PCa. In a recent work by Liu et al (2011) the authors demonstrate the nexus between miR-34a and its ability to inhibit PCa stem cells by directly repressing CD44. They observe that cancer stem cells have been observed in many solid cancers by using the fact that CD44 adheres to the cell surface. PCa stem cells with enhance clonogenic and tumor initiating and metastatic capacities are often enriched with CD44+ cell population. The work of Liu et al demonstrated that the administration of miR-34a to PCa cells inhibited PCa metastasis and inhibited PCa regeneration. This is one of the first uses of miRNA as a tumor suppressor.

In a recent paper by Xia (2008) the author states:

The key characteristics of stem cells are that they are capable of self-renewal and differentiation. The mechanisms by which stem cells maintain self-renewal and differentiation are complicated. In the past years, protein-coding genes had been broadly investigated in stem cell self-renewal and differentiation. Recent studies indicate miRNAs as one of the most abundant classes of post-transcriptional regulators proved to be crucial in a wide range of biological processes, which suggest that miRNAs may also play essential roles in stem cell self-renewal and differentiation. Disruption of Dicer function in murine ESs influences miRNA processing and greatly impairs their ability to differentiate …

Cancer stem cells (CSCs) are the cells within a tumor that possess the capacity to self-renew and to produce the heterogeneous lineages of cancer cells that comprise the tumor. CSCs can thus only be defined experimentally by their ability of self-renewal and tumor propagation.

The implementation of this approach explains the use of alternative terms in the literature, such as “tumor-initiating cells” to describe putative CSCs. …

The identification of growth and differentiation pathways responsible for CSC proliferation and survival will help in the discovery of novel therapeutic targets. Previous studies have shown that many signal pathways may participate in regulating CSC functions, including Wnt/β-catenin, Notch, and Sonic hedgehog homolog (SHH). The canonical Wnt cascade has emerged as a critical regulator of stem cells and activation of Wnt signalling has also been associated with various cancers …

CSC maintenance is dependent on β catenin signaling. Moreover, because Wnt/β-catenin signalling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate CSCs and consequently eradicate squamous cell carcinomas. It is therefore hypothesized that inhibition of Wnt signaling may provide an effective way to reduce the unwanted stem cell renewal which results in cancers.

Inhibition of Wnt signalling may prove to be an effective road to inhibit the uncontrolled cell renewal that drives cancer. Acting as novel and pivotal regulators of protein-encoding genes, miRNAs will have great potential in regulating CSCs’ biological functions by targeting CSCs-related signal pathway molecules.

 

References:

1. Araud, T., Overview of the miRNA Pathways, Thesis, U Geneva, 2008.2.     
2. Bartel, D., MicroRNAs: Genomics, Biogenesis, Mechanism, and Function, Cell 2004 pp 281-297.
3. Calin, G., C. Croce, MicroRNA Signatures in Human Cancers, Nat Rev 2006 pp 857-866.
4. Calin, G., C. Croce, Chrmosomal Rearrangements and microRNAs, Jrl Clin Inves 2007 pp 2059-2066.
5. Coppola, V., et al, MicroRNAs and Prostate Cancer, Endo Rel Canc 2010 pp F1-F17.
6. Croce, C., Causes and Consequences of microRNA Dysregulation in Cancer, Nature 2009 pp 704-714.
7. Gottwein, E., B. Cullen, Viral and Cellular MicroRNAs as Determinants of Viral Pathogenesis and Immunity, Cell Host 2008, pp 375-387.
8. 7.      He, L., G. Hannon, MicroRNAs: Small RNAs with a Big Role in Gene Regulation, Nature, 2004 pp 522-532.
9. Huang, C., et al, A Study of Cancer Related MicroRNAs through Expression Data and Literature Search, World Acad Sci & Engr, 2009 254-256.
10. Jones, P., S. Baylin, The Epigenomics of Cancer, Cell, 2007 pp 683-692.
11. Mello, C., Return of the RNAi World: Rethinking Gene Expression and Evolution, Nobel Laureate Lecture 2006.
12. Petrocca, F., et al, Emerging Role of miR-106b-25/miR-17-92 Clusters in the Control of Transforming Growth Factor β Signalling, Can Res 2008, pp 8191-8194.
13. Poliseno, L., et al, Identification of the miR-106b-25 MicroRNA Cluster as a Proto-oncogenic PTEN-targeting Intron That Cooperates with Host Gene MCM7 in Transformation, Sci Sig 2010.
14. Rakhlin, O. et al, MicroRNA-34 Mediates AR-dependent p53-indiced Apoptosis in Prostate Cancer, Can Bio & Therapy 2008 pp 1288-1296.
15.  Sevigani, C., et al, Mammalian microRNAs: A Small World for Fine-tuning Gene Expression, Mam Gene V 17 2006, pp 189-201.
16. Xia, H., Great Potential of MicroRNA in Cancer Stem Cell, Jrl Can Mol 2008 pp 79-89.

Economics From Rome

The Catholic News Agency reports that the Vatican apparently opposes Keynes and Government control. It states:

Current fiscal and monetary policies in the United States and Europe risk increasing government control over national economies, resulting in weakened political strength throughout “the whole of the western world,” the Vatican’s top banking expert said.

 

Ettore Gotti Tedeschi has been head of the Vatican's bank, known as the Institute for Religious Works, since 2009. He has a long career in finance, having served as the head of Banco Santander, the largest private bank in Europe, as well as on the boards of some of the continent’s leading financial institutions.

He is known as a staunch capitalist with a deep concern for the Church’s social teaching. He is also a former professor of financial ethics at the Catholic University of Milan. 

Writing in the Jan. 14 edition of the Vatican newspaper, L’Osservatore Romano, Tedeschi warned of the growing influence of “Keynesian” economic theory on both sides of the Atlantic.

John Maynard Keynes was a prominent 20th-century economist whose theories were widely embraced by world powers to jump-start their economies after World War II.

Tedeschi cited a 2009 book, "Where Keynes Went Wrong: And Why World Governments keep creating Inflation, Bubbles and Busts," by the American economist and philosopher Hunter Lewis.

He said Lewis had spelled out the "doctrinal errors and practical disasters" of Keynes' theories.

In simple terms, Keynes taught that in times of economic crisis, consumer demand must be stimulated by government investment and an "attitude of saving" must be discouraged, Tedeschi wrote. 

He said Keynes' crisis-averting tactics can be seen in the U.S., where government economic policy has focused on increasing public expenditures – and public debt – in order to stimulate private economic activity, including consumer demand and employment.

In addition, also following Keynesian wisdom, the U.S. is printing more money and has looked at increasing taxes in an effort to generate more public revenues. 

 And I thought I had problems. This may send many back to Church. All kidding aside, it seems well thought out. I look forward to what the Left thinks of this one. One for the Vatican!

Government as the Entrepreneur?

The entrepreneur is one who takes chances, albeit educated and calculated, to try and deploy a novel and potentially profitable new product or service. The entrepreneur will work for nothing, spend their own resources, go 24 by 7 and do this with total risk, no insurance, no safety net. I know since I have been there a few times.

Now the new proposals from the current Administration to have Government sponsored and managed and institutionalized innovation, not only having the Government fund it but also have it in the Government itself is fruitless. It will be a total waste of funds.

However NIH has over the years managed to do some good research. Not entrepreneurial but good research. The Vietnam War in a strange sort of a way was a great stimulus. Any MD avoided the draft or at least going to Vietnam by going to NIH is they could not find a VA Hospital to hide in. Today some of the best minds can find a good post doc slot there, pay is good, and some great minds still left over from the late 60s and early 70s.

The new proposal to have NIH create a pharmaceutical development company may be a stretch. If industry is falling behind as viewed by the Administration perhaps the reason is Government and NOT the industry and the solution is less Government and not more.

The challenges going forward say in cancer is understanding how to deal with all the new knowledge rather than just pumping out standard drugs. For example if miRNAs are a major issue then how do we deal with them. That is a university and industry issue and should not be subsumed under a new power grab by the Government.