Trying Wordie

I have tried Wordie on my Melanoma papers and this is what it looks like. Cute:

A Technical Education

Premier Wen spoke at Eotvos Lorand University in Budapest. His speech as summarized by China Daily stated:

"To solve the troubles facing us now, such as the financial crisis, I think the fundamental way to get rid of the crisis is ... new discoveries, new inventions and a new industrial revolution," Wen said ... I'm not only interested in science, I hold it in awe and veneration," said the premier. The 69-year-old leader worked for 14 years in the mountains and Gobi desert areas of Northwest China's Gansu province after his eight years on-campus, during which he focused on geological structure.

The premier, nicknamed Grandpa Wen by admirers at home because of his common touch, shared a moment with a girl from a local bilingual primary school who is learning both Hungarian and  Chinese. 

The girl asked the premier how she can gain admission to Peking University when she grows up.

"As long as you work hard your dream will be realized. I can tell you there is an empty place at Peking University waiting for you," he said, smiling.

Interesting set of remarks.

1. China is truly pushing technical education.

2. Yet having a technical education does not make one an entrepreneur.

3. If there is an empty place in Beijing for someone from Budapest then why are there so many coming to the United States? Just a thought.

4. Science is a means to an end. New inventions and discoveries must find markets for their value to be delivered. Having just a new technology without a market is like having the world's best factory with no customers. The factory may work well but it soon closes.

Thus markets are essential. Taking the technology from proven idea to value added product is the task of the entrepreneur. Perhaps Wen knows that well, and perhaps this was just a tailored speech. Or perhaps not.

Being Influential

Being influential, via the Internet, is discussed today in the NY Times. They state:

If you have a Facebook, Twitter or LinkedIn account, you are already being judged — or will be soon. Companies with names like Klout, PeerIndex and Twitter Grader are in the process of scoring millions, eventually billions, of people on their level of influence — or in the lingo, rating “influencers.” Yet the companies are not simply looking at the number of followers or friends you’ve amassed. Rather, they are beginning to measure influence in more nuanced ways, and posting their judgments — in the form of a score — online. 

Now I had a Facebook page, nothing on it really, but after seeing some of the comments by those with whom I had become connected I decided that discretion was the better part of being public.  I also have a twitter account, I needed it for something I thought was useful although I never used it. Frankly it all takes up too much time and in addition one really should think a bit before saying something, or frankly anything.

Yes I have seen the tables where some couple is sitting waiting for dinner while each engrossed in their twitter or Facebook pages. Perhaps they know all they need to about each other, perhaps they really do not care.

I even have a Linked In page, my students said I should have one. Never really used it, and I have 100+ links. Again I see no need. Generational, perhaps, style perhaps, but why spend so much time "online".

But the "influence" measure by the likes of Klout allegedly rank you by the following:

1. True Reach is the size of your engaged audience. Something about your tweets.
2. Amplification Probability is the likelihood that your content will be acted upon. Something on how your message is amplified by others.
3. Network Influence is the influence level of your engaged audience. Something about how your message influence others.

Just what this means is in my opinion questionable. First, if you are spending time tweeting then you are probably not working. Influencing others for what purpose. More fun, more food, more entertainment. How about creativity.

Creativity means developing new ideas, new businesses which themselves create or transform value. Not often senseless communications, also known as noise.  Perhaps a measure of how new value is created in out economy would be a better measure. Instead we seem to be fixated on the bread and circus mentality. Thus one wonders why we are in such a poor economic state.

Cookies, Fries, and Soda

There is an article in NEJM discussing diet and weight gain. They conclude:

Within each 4-year period, participants gained an average of 3.35 lb (5th to 95th percentile, −4.1 to 12.4). On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unpro- cessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (−0.22 lb), whole grains (−0.37 lb), fruits (−0.49 lb), nuts (−0.57 lb), and yogurt (−0.82 lb) (P≤0.005 for each comparison). Aggregate dietary changes were associated with substantial differences in weight change (3.93 lb across quintiles of dietary change)....

A habitual energy  imbalance of about 50 to 100 kcal per day may be suff icient to cause the gradual weight gain seen in most  persons.57,58 This means that unintended weight gain occurs easily but also that modest, sustained changes in  lifestyle could mitigate or reverse such an energy imbalance. Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are tareted for decreased (or increased) consumption. Aggregate dietary changes accounted for substantial differences in weight gain, with additional contributions from changes in physical activity and television watching, thus highlighting specific life- style changes that might be prioritized in obesity prevention strategies.

The problem is really much simpler. Remember:

1. One pound on weight gain is due to 3500 excess Kcal

2. The normal burn rate per person is 2000 Kcal.

3. Eat more and after step one you gain a pound.

Simple, no study needed.

Now the BBC speaks of a study which states:

Researchers from Imperial College London and Harvard University analysed data from 2.7m people across every continent, using statistical techniques to project a worldwide figure.

They claim the total number of people with diabetes - which can be fatal - has risen from 153m to 347m. ... Its authors said 70% of the rise was down to people living longer.

The rise has been most pronounced in the Pacific Islands. In the Marshall Islands a third of all women have the condition.

Majid Ezzati, of Imperial College London, said: "Diabetes is becoming more common almost everywhere in the world.

"Unless we develop better programs for detecting people with elevated blood sugar and helping them to control their weight, diabetes will continue to impose a major burden on health systems around the world." 

Diabetes leads to inadequate blood sugar control, which can damage the kidneys and cause blindness. It can also cause heart disease and strokes.

The condition is closely linked with obesity. Patients have to inject themselves with insulin.

Now we have written extensively on this issue:

1. Weight control is simple, keep the consumption down.

2. Obesity is the dominant cause of Type 2 Diabetes.

3. The input is driven by processed food and excess consumption. For example I have seen offices where the junk food is excessive. People are eating all the time. Then they go out and they get American portions which exceed normal portions by a factor of three.

Thus the NEJM study is interesting because it states what some of the specifics are, but that was a well known fact. Nurses are especially at risk as one would suspect since they are in a high stress environment and have food often readily available, just look behind many a nurse station.

The Lancet study in the BBC article just clearly articulates the result.

That I believe will be the major driver for future health care costs!

Double Chest Scans and Costs

Kaiser reports on the use of double CT scans on Medicare patients. They report:

In a double CT scan, patients get two imaging tests consecutively: one without dye and the other with dye injected into their veins. Providence Hospital in Northeast Washington and nearly one of every six hospitals in Virginia were among those performing double scans particularly frequently, according to the most recently published government data, from 2008....Experts say almost all chest problems can be properly diagnosed with a single scan. But some physicians, who order the tests, still value double scans for gathering the most information possible. Hospitals and radiologists are paid more for the double scans, so they have a disincentive to crack down on them. ... The scans’ benefits are great. They allow physicians checking for cancer, heart disease, damage to arteries and blood clots to see inside the body with detailed, multi-dimensional pictures. But chest CT scans also expose patients to about 70 times more radiation than conventional X-rays. Having the combination CT scan can double that exposure, though some physicians say the latest generation of scanners operate with much lower radiation levels.

There are several points worth noting here:

1. Double scans are not scans done twice but two scans done with and without contrast to get better resolution. The process has merit in a very small number of complex cases.

2. The billing is such that there is effectively a double bill. This can be corrected since frankly it does not cost twice the amount.

3. The radiation issue is overwhelming. That should be the driver.

4. Scan this much and I guarantee you will find a batch of new issues to be concerned about.

5. In a hospital like the Brigham in Boston there is 0% whereas in suburban NJ hospitals it is 5-7%. Why? The Brigham has some of the best diagnosticians and radiologists in the world, and perhaps they know better. Or perhaps the Brigham has installed controls in the radiology department to prevent this type of putative patient abuse. I suggest it is a combination of both.

So how should Medicare handle this? Good question, is it better radiology EHR systems or via financial penalties. We will see.

The Conundrum of Health Care Costs

Mankiw has written an interesting piece regarding health care policy and the last point he raises is worth a discussion.

He argues:

Democrats and Republicans generally have different approaches to controlling the growth of health care spending. Democrats often favor a top-down approach: a panel of experts set up by the recent health care law will decide which medical procedures are cost-effective and which are wasteful. Republicans tend to prefer a bottom-up approach: empower consumers to make their own choices, they say, and the power of competition among private providers will keep costs down. 

One thing that the two parties share, however, is the belief that controlling health care costs is possible. Yet many economists believe that the rise in health spending is largely the result of medical advances, which prolong and enhance life at a high cost. Perhaps health spending will inevitably, and even should, keep rising as a share of national income. 

This possibility raises a question: If health care becomes an increasing share of the economy, how will we allocate it, and how will we pay for it? That is, if controlling the cost of health care fails, what is Plan B? 

What he seems to be saying if I read it correctly is that the future is most likely just more of the past but just more of more. Namely health care is inevitably an ever increasing burden on the economy.

Now I would like to argue a different future, and I do so by also looking at the past, the distant past, and also looking at the future, especially the genetic medicine future we have been writing about herein. I have been accused by some in a lighthearted manner as being idiosyncratic, covering a disparate set of issues but in this one statement by Mankiw I believe I can try and tie some of them together.

Fifty years ago if one had congestive heart failure we just took care of you until you died. It was relatively cheap. The average weight of a recruit into the Army in 1943 was about 135 pounds and obesity then was not an issue. If a patient presented with a breast tumor or melanoma we gave then six to nine months of care which was relatively cheap.

We are in a stage in medicine where the tools for diagnosing and treating are massive and costly. But we are seeing tremendous changes and developments in genetic medicine. The imatinib in CML and the recent approaches to melanoma which we have written about, as well as the advances in prostate cancer, and of course our understanding of the costs of obesity and its sequellae.

Thus we will most likely see this growth of genetic tools explode and putatively reduce costs by catching disease early and treating it medicinally. Life style disease is still a conundrum which I see no way other than "taxing" the one making the choice and placing the tax in a future fund to treat them. We kind of do that with smokers. We must do that with the obese.

So what is the counter to Mankiw:

1. Medicine is not a stable field of science. Massive sea state change can occur and we are seeing them now. Looking at the future we see based upon the facts we have discussed herein clearly shows that change and we see a medicine dramatically different and in reality potentially less costly, except for life style choices, which we have discussed in detail.

2. Plan B may very well be this effort. More genetic developments, better understanding disease at the pathway level as we have described it and taxing the life style costs.

There is a second issue Makniw considers, the payment for Medicare, I believe that is what he meant. He states:

Democrats want to increase taxes on the rich to fund the looming fiscal gap, which is driven largely by soaring health costs. Republicans object, saying higher taxes create economic distortions, discourage work and impede growth. Last month, John A. Boehner, the House speaker, said that we should instead consider means-testing Medicare. But what does that mean? 

 But as we have shown this week in our analysis in response to the Washington Post discussions, we have a Medicare system which taxes the rich to pay for the poor. In fact the super rich are already super taxed. The Democrats want to further increase the tax and we proposed a level adjusting along with an age adjustment. The Medicare problem is really solvable by those to means and also can be further improved if we deal with the excessive use, namely people playing the system to maximize income but to no benefit to the patient. Medicare should really focus on catastrophic coverage; cancer, end of life, accidents, debilitating disease, and we should raise the bar on the rest. The new law through the ACO play I believe will do just the opposite.  We have discussed that in detail as well.

Discussing health care and its future must be done in a holistic manner, not just as an economist would do by simply looking at the past and projecting the future, but as a scientist, engineer and physician would, looking at the changes and integrating them in the path forward. It is only by understanding what the future as we see it currently unfolding is going to bring and how to assist its movement forward that we will best understand health care.

It is a pity that no one in Washington seems to either understand or articulate that issue.

Blue Water Navies, Are We Going Thru the 1930s Again?

The CNO has been quoted in the Hill giving a view of the future of the Navy. They state as follows:

During the early 2000s, the Navy had a much smaller role in the Iraq and Afghanistan wars, leading military experts — and some service officials — to wonder how the service would fit into future U.S. combat operations....Several years later, the Navy’s slate of missions is becoming clear. The sea service has spent years building up its tactical aviation fleet, enhancing its information operations abilities and moving toward unmanned craft that operate beneath the ocean’s surface, Adm. Gary Roughead, chief of naval operations (CNO), said Thursday....

In an era when defense budgets are expected to remain flat or shrink, some lawmakers and defense analysts say it is unlikely the Navy will ever have the 313 ships it says are needed. The fleet is now at 285 ships, Roughead said Thursday.... Employing more crewless underwater drones is one way to help offset a smaller fleet, Roughead noted.

Yes they are at now 285 ships, of which roughly 1/3 to 1/2 are at sea at any one time and there may be three to five carrier groups. Imagine Okinawa where a ship was lost per hour for weeks! We would be out of ships real quickly. One need look only at WW II destroyer production of say Fletcher Class. Very complex at its time technically. Theye were made in months. Also they could be destroyed in minutes.

Now look at China Daily which states:

By 2020, a total of 15,000 personnel, compared with 9,000 now, will serve in the China Maritime Surveillance (CMS) force under the State Oceanic Administration, a senior official with the CMS, who declined to be identified, told China Daily.The CMS air arm will be increased to 16 planes and the patrol fleet will have 350 vessels during the period of the 12th Five-Year Plan (2011-2015), the official said, adding that the fleet will have more than 520 vessels by 2020. Currently, nine aircraft, more than 260 surveillance vessels and 280 law enforcement vehicles are in operation. The CMS launched the construction of 36 patrol ships and 54 speedboats last year, the official said.The expansion plan was unveiled as China's biggest civilian maritime patrol ship was sent into the South China Sea to protect national "rights and sovereignty".China's offshore surveillance force will be beefed up to ensure that the country's maritime interests are fully protected amid increasing disputes with its neighbors.

We in the US seem to going in the opposite direction. The South China Sea will become a hot-bed of activity. Ports in China on the South China Sea are expanding and China is exercising its hegemony there to the detriment of countries like Vietnam.

Now one should look at an article in the Naval Institute Naval History in June 2001 by Frank entitled Picking Winners. It recounts the secret list kept by FDR on the then top ranking Navy Admirals, the Navy Departments list of leaders. Nimitz was not there nor was Spruance! Many who were there were soon jettisoned. Political planners often work to preserve their position. As Frank states:

It is vital in assessing the omission of Admiral Chester W. Nimitz and Rear Admiral Raymond A. Spruance from the “most competent” list not to “read back” from the battles of the Coral Sea and Midway or even later events to their stature in the eyes of the members of the selection board in early March 1942.... In a late-March 1942 letter to his wife, Catherine, Nimitz confided: “Ever so many people were enthusiastic for me at the start but when things do not move fast enough they sour on me. I will be lucky to last six months. The public may demand action and results faster than I can produce.” This missive raises the tantalizing possibility that Nimitz had somehow learned of the secret flag selection board results.... Spruance was a very junior cruiser division commander who had enjoyed no opportunity for significant independent command. He carried the reputation in the small world of the Navy’s flag ranks as a quiet-spoken theorist from his tours at the Naval War College. A few weeks later, before Midway, King would press Spruance on Nimitz as a chief of staff with that reputation in mind. Those credentials scarcely warranted anointment as one of the elite flag officers in the Navy.

 
War, if and when it comes, with a good President, finds the true leaders. Having researched this for one of my books, DD 649,  I found that Harry Hopkins played a significant role in feeding FDR the right people and FDR somehow had the genius to find and promote them.

Hopefully if push comes to shove we can do the same again. In many ways it looks as if we are entering the 1930s again. Watch out for the 1940s.

A Little More on Medicare

I thought it would be useful to provide some more details on how the curve I presented may be useful to policy makers. I consider a few cases.

First the above chart shows the details of what we had plotted. Not the contribution increasing and the benefits as horizontal but increasing as health care inflation increases. Now let us look at three cases.

Case 1: This is the case of increasing the contribution from 3% to say 4%. Note the horizontal remains fixed but the contribution increases. Thus the salary at which a benefit occurs decreases meaning that fewer people get a free rid if you will.

 

Case 2: Here we increase the age of eligibility and the contributions increase and the benefits decrease.

Case 3: We look at income brackets by quintile. We show that in this case, say the balanced example, the lower two benefit and the upper two pay and the middle quintile averages out even.

Now from a policy perspective this gives a simple tool to see what the impact would be across large income groups. If we were to use this with our numerical analysis we could readily see the impact of increasing eligibility to 67 and increasing contribution to 4%. We believe that such a change over say the next few years would solve the Medicare issue. Just a thought.

More on Medicare

We have issued a  document which is a revision of a white paper written in mid-2009 as a draft working paper on the issue of Medicare costs. Recently there has been a great deal of interest in the costs of Medicare and the assumptions herein have been revisited. Specifically Lois Matelan has indicated that an assumption that was made regarding expected lifetimes was in error and we have subsequently addressed that issue in the revision.

The issue which this paper addresses is the assertion that most if not all Medicare beneficiaries receive more than what they contributed. This seems to be predicated upon a report by the Urban Institute and reiterated by journalists of the kind like David Brooks of the NY Times and also republican contenders like Ron Paul. We look at this issue in more detail herein. However we propose a methodology commonly accepted in such circumstances called the net present value, NPV, model. Namely we look at cash flows, discount them, and then compare contributions and disbursements or benefits at a single point in time, in our case at retirement at 65.

The model we use is somewhat simple:

1. We assume a starting salary in 1970 and then we escalate that by a percentage, generally well below inflation. That then yields an ending salary in 2009 when we assume retirement.

2. We assume a Medicare contribution percent of 3% of gross salary. We have not reached any limits with the proposed salaries.

3. We then look at the current annual Medicare costs and we grow them first with inflation and then we add a health care inflation in excess of the core inflation. Thus if we see 2% inflation and we add 3% health care above it the total is 5%.

4. We assume a lifetime of 18 years for someone at 65. We then calculate the NPV for the benefits or distributions from Medicare at age 65.

5. We then compare NPV of contributions and NPV of benefits versus salaries and health care inflation.

We show this summary below in the graph. Note that as the salary increases there are point at which the contributions exceed the benefits. At no excess health care inflation it is at about $83,000 and at 5% excess health care inflation it is at about $112,000. Thus unlike the general statement that Medicare is an excess benefit, it is that only for those of lower incomes.

 The above shows two curves, one a set based on excess health care inflation. One curve is the net present value of Medicare contributions at age 65 based on salary at reaching 65 and the second the benefits received in NPV at 65 based upon a specified health care inflation in excess of core inflation. Whenever the contribution exceeds the benefit they individual is funding Medicare in excess and whenever the contribution is less the individual benefits. The Urban report focuses on the lower earning portion of the curve and we consider that less than complete.

Now when one looks at salary distributions we see that over 40% of people are paying in excess of their disbursements. That means that less than 60% are receiving benefits. In fact the people whose contributions have exceeded their disbursements are in many ways covering those who are not. Thus, the bold claim that Medicare beneficiaries are having a free ride must and should be clarified. Some do have a benefit and many provide a benefit to that group.

It should also be noted that this analysis considers the analysis at a high level but it does go, I believe, much deeper than the Urban Institute. Much finer and detailed analyses may reveal even more critical observations.

Medicare Update

I apparently was seen somewhere in an article yesterday regarding my Medicare paper in early 2009. I received an email regarding an apparent flaw in the analysis and had responded personally but thought a discussion on the record may help. There were many assumptions but I think this is worth addressing. Let me re-articulate what I said or should have said.

1. I assumed that the average lifetime of a Medicare beneficiary was 12 more years. This is from the CDC data base. Actually it is 18 years if one reaches 65. I was told the added 6 years was a flaw and indeed it is an error in fact.

2. However, here it gets complicated, there were many Medicare contributors who paid into the system but who died before getting benefits. Should we recognize those contributions? The answer is yes, it is like an insurance plan. But they never benefit. Yet the money must be recognized. So even tough the duration is longer the total imputable contributions are greater.

3. Does the added 6 years make a difference. Again it depends. We discounted future payments by some cost of capital. But they must also be inflated by medical costs inflation. Here it gets sticky. If say the discount factor is 5% from year 13 thru year 18, then this neglected period is an additional 20% to the total NPV at 65. Following me folks? Now if at 65 we had obtained $140,000 and now we have $168,000 but we contributed $174,000 then we still hold water. But wait... If medical care inflation exceed the return on invested capital, then it explodes! However .... one could invest in a portfolio of health care companies and hedge the bet ...

4. My analysis was different from the one critiqued since they assumed a single income family who made $45,000 by age 65 which is just above poverty. My argument was that one should still look at the average not the lowest. Still feel that is correct. Yet the real method should be to consider a real distribution of incomes and weight them. Also one must add in the contributions of those who did not survive to 65 but who contributed. This is somewhat difficult as are all allocation algorithms. This is why I used the average lifetime and not the average lifetime given one had reached 65. This was a plug for the lost revenue from those who did not survive.

5. Then there is the issue of race and sex. Blacks have lower survival and women live longer than men. I did not look into this detail. For example white women have been paid less then men but live longer and benefit more. So ... I really cannot comment but it is a fact ... that is why it is insurance.


So bottom line, was 12 years wrong, yes in a specific manner, no in a general sense. Was the conclusion in error; yes in an exact science manner given the way the problem may have been defined but no when one considers the orders of magnitude of difference when including the data.

However, the main time bomb in all of this is the issue of the inflation in health care. If that exceeds economic growth the system is doomed. Yet that assumes the past is prologue to the future and unchangeable. If we look at the changes in health care we can see clear signs that it is possible to reduce costs thru genetic approaches. However. the costs of life style diseases such as type 2 diabetes, most often driven by obesity, will soon smother the system. That is the challenge, it is a challenge of the present, and has yet to be voiced except by the current President's spouse who went bravely to the front. Should we tell people what to eat, yes if we are forced to collectively pay for the consequences, no if they agree never to charge us for their costs. It is just a matter of dollars and sense!

I have updated the analysis for 18 year lifetime post 65 and attach it below.

As expected it is really not that different. Let me explain:

1. I assumed a typical lower middle class worker with a reasonable job. Starting work in 1970 1ith $16,000 pa but never really going anywhere so I gave him a 6% pa raise. Remember that is thru Carters 18% inflation period.

2. I assumed 3% Medicare tax as was the law.

3. I assumed the payment was invested at 6% during this period. Not too bad.

4. I assumed that the person retires at 65 and lives 18 years. Simple but still skews the real actuarial result. So they live to 83.

5. Assume inflation and Medical care costs rise. I have parameterized the data accordingly.

6. Then I plotted at age 65 the difference between the NPV of Medicare Benefits and Medicare Contributions. The net is the "excess Medicare benefit". Worst case it is $100,000 only if health costs exceed inflation by a factor of 2! Not the several hundreds of thousands that others complain about making no assumptions about such costs.

My argument stands. The Brooks et al argument assumes a two family household where the age 65 income is near poverty. I assume lower middle class individual. Can we adjust this across all of the society, yes, just lots of work but I believe the conclusion will not change much.

Now I have also parameterized this versus starting salary to give an idea as to the benefit.

Note that for the very poor, starting at $4,000 pa in 1970 and receiving marginal raises and with medical inflation 7% in excess of core inflation we can generate an individual benefit of almost $160,000! That is possible but it is for an extreme segment of the population not on average!

Reality and Belief: A Conundrum for Economists

Observation

Economists build models using assumptions that all too often fail to reflect the reality that there is a lack of convergence between belief and reality. The classic efficient market hypothesis assumes that people have equal and timely information and that markets are efficient and always clear, namely markets reflect true value of the assets being traded. This premise is wrong most of the time. There is a frequent failure of reality and belief to align. Economics also fails to both understand this fact and its models all too often fly in the face of reality. The appropriate aphorism for this is: Do you believe me or your lying eyes? The problem is that people often act on belief, facts be damned. In addition there is a herd mentality associated with belief. Yet there is an objective reality, house prices are too high, and the belief being that they will continue to go that way. The challenge is how does one incorporate a belief set, and in reality a stochastic belief set, into economics. People have trust in their belief. Yet trust also can go from total trust to total lack thereof.

Discussion

This assumption is also called the efficient market hypothesis, or a few other names, and is at the heart of many if not all of the models economists use in modeling the economy.

In reality the markets fluctuate from being efficient and to being highly inefficient. Namely there are times when people have equal information, they act rationally, and the price reached in the market reflects the value of what is being transacted. On the other hand there are times when there are bubbles, people have little information and they act irrationally and the price fails to reflect any reality. Real estate bubbles are common. I would also argue that there are bubble being created in university level education, namely the price being paid is a gross distortion of the value being produced.  One could also make a similar argument with respect to health care.

Now there is also the dichotomy between when the EMH is valid, namely when the market is fair, and when people believe it is valid, namely what people think. Bubbles typically result when people believe it is working, namely when EMH is valid, but when it is actually not functioning. This is the dichotomy between belief and reality. There are times when they align but all too often they do not and that lack of alignment leads to bubbles and market collapse.

This has been called the Rowe conjecture, the fluctuations between reality and belief. Economists have assumed a consistent alignment of reality and belief. Rowe has conjectured that reality and belief may not always align, and in fact may have some cyclic behavior. We can show that the balancing of reality and belief is a fundamental element of the instabilities in the markets.

Basis

There is a herd mentality and the time scale of the herding may be affected by the media available but it exists and demonstrates a stickiness factor which means it does not adapt or reflect reality in an instantaneous manner.

Examples

Bubbles are the most common of the examples here and the housing bubble is the most recent of them. Bubbles occur when reality and perception have a tendency to flip.

Implications

All economic models assume alignment of reality and belief. In reality that is not the case and people often act on belief and not reality. An example is inflation, peoples actions are often driven by expectations of say an inflationary trend.

Model

The above is an analytical model of belief versus reality in want was assumed an efficient market. Note that it cycles, namely this is the phase plane plot and the (belief, reality) points moves along this curve. Thus there are times when reality says there is no efficient market, namely a Bernie Madoff type market exists, and for a while everyone believe it cannot happen and then after a while they believe in the reality.

Conclusions

Economics must factor belief as well as reality. Belief is difficult to measure but it is a powerful force in markets, whether efficient or otherwise.

China and Its Inflation

China Daily reports the hike in bank reserves as CPI increases. They state:

China's central bank raised bank reserve ratios on Tuesday for the ninth time since last October after data showed inflation rising in May to 5.5 percent, its highest level in almost three years.

The central bank increased the ratio for China's biggest banks to 21.5 percent, a record high, locking up funds that could otherwise be loaned out and add to inflationary pressures...

At 5.5 percent, China's consumer inflation in May was the highest in 34 months. It compared with expectations for 5.4 percent and showed a pick up from 5.3 percent in April.  

One suspects that with a 21.5% reserve that they are pulling back strongly and that inflation expectations are quite large.Revaluing the Chinese currency will be reflected in increased US prices. That in itself will not be inflationary since there is such excess slack in employment. It will just put further downward pressure on those employed and otherwise.

Medals, Medals, Medals

The Government is asking for nominations for the Citizens Medal. Again I recall my former partners in Central and Eastern Europe and their boxes of medals from the old Soviet regimes. Medals were the substitute for economic success. Every one had some medal.

I am reminded of Admiral King who was head of the Navy in WW II, he hated medals, he saw it as some British affectation. The British Navy wore medals and the US Navy did not. King stressed that. This was the US and you were rewarded by a job well done not by having ribbons all over your body. But alas things have changed. Just look at any general who appears in public, they have more medals that anyone could count. A bit too much, they occupy the entire left side of their body, perhaps bod armor.

I am also reminded of one of my late Czech partners, who was a good Communist until the fall, educated in Moscow, and all the rest. One day in his attic study I came across a box filled with medals. It looked like hundreds. I asked what they were. His answer was that they were what a good Communist got instead of money. The UK has such rewards, the Queen's Honors List, a knighthood, a Lordship, an OBE, a KBE, whatever. It works in Boy Scouts but not in life, except for Hollywood and performers, there they have an award ceremony a week.

The US had a tradition of few if any medals. But now it seems if we cannot allow and foster American ingenuity and creativity then we hand out medals.

10,000 Engineering Teachers

The current President made a speech today stating that the Government must create 10,000 new engineering and science teachers per year going forward. The USA today reports:

President Obama set a goal today of recruiting 10,000 teachers in science, technology, engineering and math, calling these subjects essential to competing in the 21st-century global economy.

As Market Watch reported he also said:

Speaking in the key battleground state of North Carolina, Obama said the program would involve companies like Intel Corp. doubling their summer internship hiring; helping universities pay for engineering programs; and offering students incentives to finish their degrees.

 Now just where are these coming from. You see Engineering Professors, well we never called them teachers, take a bit of time to create and find. I think MIT hires at most a dozen per year in a really great year and then gets 2 or 3 tenured from that batch. You see engineering is kind of really hard, as is physics, biology, chemistry.. Well, Math, that is just impossible. You do not train Math profs, God creates them, and they are rare as hen's teeth.

In fact you do not even train engineers. They are educated, you see, they take really hard courses like strength of materials, solid state electronics, computer architecture, heat moment and mass transfer, organic chemistry, fluid mechanics. You have to choose the best qualified and motivate students. They are educated to make things, not like economists, who just throw equations around and have never been able to predict anything. Not even like lawyers, who talk a lot and well we all know lawyers, my daughter married one. Nice guy but a lawyer.

The stated goal is unachievable. It is based on a fallacy, a set of fallacies! How in heaven's name can one hope to build an economy back with such statements. The Chinese do not do that, their Government is filled with engineers, they at least know of what they speak. They have been working for two generations to get there. Doubtful if any Government program in several lifetimes will get us there.

You see you have to have been educated to get into a good engineering school. Otherwise we train people who do not know engineering. This stated goal is akin to training 10,000 neurosurgeons. Chuckle, chuckle, chuckle!

B-RAF and another Hit

In NEJM today an Italian team did a splendid piece of genetic investigative work finding B-RAF changes identical to that in the melanoma work in Hairy Cell Leukemia patients. Cancer Research in the UK has a good summary as well.

The article states:

In 30 of the 48 patients with the V600E variant (including the index patient), the high purity of leukemic cells (>90%) allowed for the analysis of the zygosity of the mutation without substantial interference of wild-type alleles contributed by contaminating nonleukemic cells. In 26 of these 30 patients, the mutation appeared as a double peak...

 The V600E mutation results in the constitutive activation of BRAF kinase activity. Therefore, we assessed the phosphorylation status of MEK (the immediate downstream kinase target of BRAF) and ERK (the kinase phosphorylated by active MEK), using antibodies that specifically recognize phosphorylated MEK and ERK.

The similarity to the melanoma case is quite interesting. They conclude:

BRAF V600E was present in all 48 patients with HCL in our study. However, given the relatively small number of patients who were evaluated, we cannot rule out the possibility that some patients with HCL may not carry the BRAF V600E mutation. It must also be stressed that all samples that were analyzed in this study contained at least 30% neoplastic cells, which was the threshold for detecting a heterozygous clonal mutation by direct Sanger sequencing in our study. The detection of BRAF V600E in HCL samples containing lower proportions of leukemic cells will require more sensitive molecular techniques. If antibodies against the BRAF V600E variant protein become available, immunohistochemical analysis may be an alternative approach.

Easy Money and the Future

Prof Rajan has penned a short piece regarding the evils of easy money. He makes the point that with the extra low and artificial interest rates people should be spending and not saving, but he argues why the contrary is true and why the burden has been placed square on the shoulders of the savers.

Now one should remember that the good old 401Ks have continued but at an ever increasing pace. Yes they were reduced in number as people were let go but as companies eliminated defined benefit plans for retirement they have grown more than what was lost by unemployment. Much of that 401K money does go to assist the growth of the market since people have this forced form of savings and there is no alternative. Housing is now dead.

However the true burden as Rajan recounts is on the saver, especially those older retired savers who may have moved to Government securities now yielding an infinitesimal rate, say 2% when a few years ago it was 6%. That means for the same cash output they must have three times in savings of what they had just a few years ago. Unlikely. Thus it means they have much less buying power or that this low interest rate is really another form of hyperinflation!

Yes, the FED is feeding the banks and their money loving employees off the backs of the old. Instead of eating your young they are eating their old. Now with Washington killing Medicare, well just wait.

One is reminded of the old dictum. Why did God invent Washington? Because Hell was over-crowded! That may have a point in current times.

European Downgrade of US Debt

Feri Eurorating has downgraded US Debt from AAA to AA. From the release they state:

The Bad Homburg Feri EuroRating & Research AG downgraded the first credit rating agency’s credit rating for the United States from AAA to AA. Feri analysts justify the downgrade by the continuing deterioration of the creditworthiness of the country due to high public debt, inadequate fiscal measures, and weaker growth prospects.

“The U.S. government has fought the effects of the financial market crisis primarily by an increase in government debt. We do not see that there is sufficient attention being paid to other measures, “said Dr. Tobias Schmidt, CEO of Feri Rating & Research AG. “Our rating system shows a deterioration in economic health, so the downgrading of the credit ratings of U.S. is warranted.”

For the third consecutive year the deficit of the United States is in double digit percentages relative to gross domestic product (GDP). “Deficits of such magnitude are not a sustainable fiscal policy. We would reconsider the rating when the U.S. government creates a long-term sustainable budget,” said Schmidt.

Feri Rating is listed on the Federal Financial Supervisory Authority (BaFin) as an EU credit rating agency approved and created with more than 20 years experience in sovereign ratings. Every month, the Feri analysts evaluate sovereign credit ratings from the perspective of a foreign investor based on the ability and willingness of countries to repay their debts. The credit ratings have eleven possible gradations between “AAA” (best credit) and “Default”.

 Something about the chickens and their return to home?

Cancer in the UK

The UK has just released a study on cancer mortality and the reasons why the NHS, the state run health system which is the goal of many in the US, is at fault. The report summarizes the reasons as:

Cancer survival rates in England are improving, but they still lag behind those in the best-performing countries in the world. The current government has identified cancer survival rates as an area for improvement and the cancer strategy commits to saving an additional 5,000 lives by 2015, but how can these improvements be achieved?

How to improve cancer outcomes, published in partnership with Cancer Research UK, considers the existing differences in cancer survival rates between countries and discusses the reasons for these variations including: stage at diagnosis and diagnostic delay; treatment factors; patient factors; and tumour biology and physiological/biological factors.

The authors suggest that the most plausible drivers for improved survival rates are:

1. diagnosis at an early stage, including through effective screening programmes

2. access to optimal treatment

3. improvements in the management of older people with cancer.

This has been rephrased by Cancer UK as:

It highlights the fact that compared with other countries:

• English patients are often diagnosed at a later stage
• In England there are delays in accessing treatment
• In this country evidence suggests that some older patients are being under-treated

The message for us in the US is simple. With the new systems going into place emulating the NHS we too will see a rise in mortality. The Report is worth the read but it needs interpreting. Euphemisms abound.

Employment, Economics, Science: Romer Redux

It is worth a return to the Romer curve, the data that the former head of the CEA presented in January 2009 regarding the effects of the trillion dollar stimulus. Now remember this is economics, not medicine or engineering and especially not science.

First we show the projections that Romer made:

This shows what she predicted to date. Note the tremendous gap between what she said would happen and what did. There is also a great gap between reality and what would have happened if they did nothing. Frankly we would have better off with nothing.

Now for the variance. We do this in two charts.

and

Now what faith should one have in economists if they are that far off? Or was the stimulus just the opposite, namely a drag on the real economy? Lot's of PhD theses will come out of this data. However no employment will.

Also worth a look at a Washington Post note regarding  Romer which states:

The economic team went round and round. Geithner would hold his views close, but occasionally he would get frustrated. Once, as Romer pressed for more stimulus spending, Geithner snapped. Stimulus, he told Romer, was “sugar,” and its effect was fleeting. The administration, he urged, needed to focus on long-term economic growth, and the first step was reining in the debt.

Wrong, Romer snapped back. Stimulus is an “antibiotic” for a sick economy, she told Geithner. “It’s not giving a child a lollipop.”

 Perhaps Romer should kick the sugar habit.

Factions, Madison and Wicked Projects

There is a continuing complaint that the leaders in Washington are always at war with one another and that this is bad. That they should agree, come to a resolution. Take the debt as an example, is it good or bad, do we need to spend more or less.

Now one need go no further than Federalist Paper 10 by Madison which recounts the usefulness of factions, namely the usefulness of there being many fragmented ideas and that from time to time the majority of other factions can block any one from implementing something.

As Madison states:

The latent causes of faction are thus sown in the nature of man; and we see them everywhere brought into different degrees of activity, according to the different circumstances of civil society. A zeal for different opinions concerning religion, concerning government, and many other points, as well of speculation as of practice; an attachment to different leaders ambitiously contending for pre-eminence and power; or to persons of other descriptions whose fortunes have been interesting to the human passions, have, in turn, divided mankind into parties, inflamed them with mutual animosity, and rendered them much more disposed to vex and oppress each other than to co-operate for their common good. So strong is this propensity of mankind to fall into mutual animosities, that where no substantial occasion presents itself, the most frivolous and fanciful distinctions have been sufficient to kindle their unfriendly passions and excite their most violent conflicts.

Thus Progressive or Libertarian, Liberal or Conservative, factions are a natural part of humanity. Silencing any one voice is doing harm to the body politic. Thus for example the Progressives intent to destroy FOX is most likely as abhorrent to Madison as the intent of the Presbyterians to silence the Catholics.

Madison continues:

The inference to which we are brought is, that the causes of faction cannot be removed, and that relief is only to be sought in the means of controlling its effects.

If a faction consists of less than a majority, relief is supplied by the republican principle, which enables the majority to defeat its sinister views by regular vote. It may clog the administration, it may convulse the society; but it will be unable to execute and mask its violence under the forms of the Constitution. When a majority is included in a faction, the form of popular government, on the other hand, enables it to sacrifice to its ruling passion or interest both the public good and the rights of other citizens. To secure the public good and private rights against the danger of such a faction, and at the same time to preserve the spirit and the form of popular government, is then the great object to which our inquiries are directed. Let me add that it is the great desideratum by which this form of government can be rescued from the opprobrium under which it has so long labored, and be recommended to the esteem and adoption of mankind.

Yes, clogging the administration is an effect of a well-structured Government because it blocks the attempts of a faction.

Madison ends with:

The influence of factious leaders may kindle a flame within their particular States, but will be unable to spread a general conflagration through the other States. A religious sect may degenerate into a political faction in a part of the Confederacy; but the variety of sects dispersed over the entire face of it must secure the national councils against any danger from that source.

A rage for paper money, for an abolition of debts, for an equal division of property, or for any other improper or wicked project, will be less apt to pervade the whole body of the Union than a particular member of it; in the same proportion as such a malady is more likely to taint a particular county or district, than an entire State. In the extent and proper structure of the Union, therefore, we behold a republican remedy for the diseases most incident to republican government. And according to the degree of pleasure and pride we feel in being republicans, ought to be our zeal in cherishing the spirit and supporting the character of Federalists.

One need just read his parting remarks. The need for paper money, namely the ability to create dollars out of free air, the equal division of property, what we now call redistribution of wealth. the abolition of debts, what we now see as adjusting mortgages for those stupid enough to get in over their heads, is as Madison clearly states a wicked project! Factions have their evils but they also help block certain other evils, evils of the majority, a Government run by one party which has taken up the wicked projects detested by Madison.

Just a thought for the day.

Two New Elements

IUPAC has announced the acceptance of experimental work to introduce two new elements. The BBC announced the following:

The working party concluded that elements 114 and 116 fulfilled criteria for official inclusion in the table. The others, as yet, do not.

Names have not as of yet been defined. IUPAC includes the above in their discussion.

Melanoma: Pathways, Immune Response, and Progress

There has recently been several pathway control mechanisms developed and tested and also an immunological approach deemed to be somewhat effective. We examine them here and also use them as suggestive of what else may be accomplished.

The current methods focus on two areas: (i) controlling aberrant pathways and (ii) using the immune response to control aberrant cells. It should be noted that in both cases we are dealing with the paradigm of a single but multiplying yet identical cancer cell. There is no hypothesis as regards to a stem cell or to the fact that the cancer may be multi-clonal.

 

1.1.1       Aberrant Pathway Control

We now examine the aberrant pathway approach. First let us consider the pathways that control a single cell. We show them below:

 

The above shows two results; cell proliferation and cell survival. They are two characteristics of a cancer. Namely the cell replicates and it does so in an almost immortal manner. The changed cell then starts to take over where other functional cells have been and the result is an unstable and ultimately deadly takeover of the human. Thus the two pathways are but a few of the many we will discuss at length. Yet the key point is that in examining melanoma it has been discovered that there is a specific mutation in the B-RAF gene that activate the MEK pathway. Activating that pathway creates a situation where we have an uncontrolled growth.

The growth factors activate the RTK kinase which activates the RAS which activates a B-RAF which overexpresses its product and this over-expression is what drives the proliferation pathway. It is this single gene and its protein expression which causes the problem in 60% of the cases.

The cell survival is often controlled by PTEN and it is the loss of PTEN which results in the cancer cell immortality. The PTEN loss is comparable to the same issue we have seen in prostate cancer.

Key to aberrant pathway control is a simple principle. Namely, we base the approach on the observed fact that certain pathway control elements have been changed as a result of a change in the underlying gene. We will show that in the current well known example of B-RAF that the underlying gene of B-RAF has been mutated and it the resulting B-RAF protein which has allowed the pathway to be turned on permanently. Thus the putative solution is to turn off the protein by targeting it with a drug which will pass the cell membrane and bind to the protein and inactivate it. A simple approach based upon an established fact. As we shall see there are two immediate issues: (i) only about 50% of the melanoma patients have the mutation, and (ii) the drug lasts for a relatively short time. It is similar to the effect that imatinib has on CML, a temporary regression and then a return.

As we shall see the possible solution may be multiple drug therapies targeting other pathway elements.

Now another way to view the pathways is shown below with the prominent role of c-Myc displayed at a common point. Note here we have the common surface kinases and the impact of B-RAF as well as PTEN. PTEN can modulate the limited up-regulation of B-RAF but only to a degree. As we have seen in PCa the loss of PTEN functionality leads to very aggressive forms.

 The above also presents alternative control elements for possibly melanoma or frankly many other cancers. Specifically Smalley and Flaherty (2009) had suggested these pathway elements focusing on B-RAF, AKT and PI3K. One could also focus directly on the genes through a suppression mechanism but the technology for doing so is not yet available. Also there must be some specific targeting since we do not desire to target normal types of these products.

The control of aberrant pathways is conceptually simple.

1. Using a methodology such as microarrays, attempt to identify genes, or their expressions, which are present in the malignant cell. These are not unique and sometimes they are transient as well. The B-RAF identification is an example.

2. Develop a target molecule which can attach to and inactivate the aberrant gene or protein. In the current case of B-RAF they have deactivated the protein.

3. Test and use.

It may sound simple but the first step is potentially searching for a needle in a haystack and the second step can be as demanding. One may ask why not just block MEK or AKT just to stop everything. Assuming targets are possible the problem is it would do so for all cells and it would play havoc on the rest of the body. No blood cells, no hair, skin, and the like. 

1.1.2       B-RAF control

The most recent one is the control of a mutated B-RAF, a variant of the RAF pathway. It was observed that there was a mutation in the B-RAF gene so that what was produced was a different B-RAF called V600E which had excessive up-regulation in almost 50-60% of all metastatic melanomas. The identification of this product then allowed for its targeting and suppression as a means to reduce cell proliferation. The results have been reported recently by the work of Chapman et al (2011) and Flaherty et al (2010). A review by Smalley and Flaherty (2009) had made suggestions on controlling both the BRAF as well as the AKT pathway. We will discuss that later. Recent work by Poulikakos and Solit (2011) has also presented both BRAF and MEK control, trying to avoid the loss of efficacy we discuss here.

Specifically, a drug now called Vemurafenib, or PLX4032, binds to the ATP activation site on the B-RAF mutation V600E and as such it blocks the overexpression of this protein and reduces the flow downward which we have shown causes ultimately an up-regulation of proliferation.

 Now we can also see that Vemurafenib can lose its effectiveness and there are several proposals for why this happens. We discuss a few here. From Solit and Rosen (2011) we show one of the possible ways in which resistance can occur. We discuss several of their conjectures in detail.

Below we depict the supposition from Solit and Rosen. Arguably this is what accounts for the mortality in the Kaplan Meir data they have from their trials.

 The paper by Solit and Rosen propose three reasons for loss of action of PLX4032:

(i) In melanomas with the BRAF V600E mutation, levels of activated RAS are too low to promote adequate formation of RAF dimers, and PLX4032 inhibits RAF activity and ERK signaling … This model is consistent with our observation that the introduction of mutant (activated) RAS into cells with mutant BRAF causes insensitivity of the ERK pathway to the drug. This model suggests that increases in RAF dimerization (because of RAS activation or increased RAF expression) will cause ERK signaling to become insensitive to PLX4032 …

(ii) The findings of Johannessen et al. suggest another mechanism for the resistance of ERK signaling to RAF inhibition in cells driven by the BRAF V600E mutations. These investigators used a new technique — the introduction of a library of DNA constructs, each of which encodes a different kinase — into tumor cells with the BRAF V600E mutation to screen for kinases that confer resistance to RAF inhibition. Using this screen, they confirmed a previous finding: that overexpression of RAF1 confers resistance to RAF inhibition. 8 They further showed that the overexpression of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, or COT), which phosphorylates MEK in a RAF-independent manner, can also mediate resistance to RAF inhibitors…

(iii) a third basis for acquired resistance, one in which the activation of other pathways causes the tumor cell to become less dependent on ERK signaling. In these tumors, ERK activation remains sensitive to the RAF inhibitor. Specifically, they report that platelet derived growth factor receptor β (PDGFRβ), a receptor tyrosine kinase, is overexpressed in cellular models selected for RAF-inhibitor resistance in cell culture and in a subgroup of biopsy samples obtained from patients with progressing tumors. In the cell lines, PDGFRβ overexpression was associated with resistance to the anti-proliferative effects of the RAF inhibitor, despite continued inhibition of ERK signaling in the presence of the drug. 

1.1.3       Immunological Techniques

Rosenberg has for decades been examining the use of the immune system to attack cancer cells and he has done a great deal of work specifically on melanoma. The second thrust of the recent advances has been along these lines and Rosenberg has also been a contributor.

The first recent report is by Schwartzentruber et al (2011, NEJM) wherein, along with Rosenberg, they have used a vaccination of a peptide which can recognize melanoma cells and then by increasing the T cells via an interleukin infusion they found that the result was improvement in survival of metastatic melanoma patients. We show the results below from the paper.

 It should be noted that there is some improvement but still there is a very poor survival prognosis.

The second paper by Robert et al (2011 NEJM) uses another approach. They use a combination of a monoclonal antibody and a standard chemotherapeutic element. They state:

Ipilimumab, a fully human, IgG1 monoclonal antibody, blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negative regulator of T cells, and thereby augments T-cell activation and proliferation.

The second agent is dacarbazine. Decarbazine is a classic alkylating agent and has been used before with very limited results.

The data on survival is shown below:

 Survival with the first approach after 36 months is about 38% and with the second approach it is about 45%. The interesting factor however with the second approach is the total remission in patients exhibiting total remission at the end of the study being almost 50%. Thus if total remission was exhibited it was sustained.

As the authors of the second study state:

Prolonged survival was noted among some patients who were followed for up to 4 years. In the ipilimumab–dacarbazine group, an estimated 28.5% of the patients were alive at 2 years, and an estimated 20.8% at 3 years, as compared with an estimated 17.9% and 12.2%, respectively, in the dacarbazine group.

One can seem to state that the second approach was more effective than the first.

Possibly combining the approaches will be more effective and the current understanding is that they intend to examine those paths. 

1.1.4       Considerations

The current efforts clearly show some significant advancement. However there are several key issues which must be clarified:

1. Is melanoma like colon cancer as described by Vogelstein or do we have a somewhat random set of mutations depending on the location of the lesion. Namely is melanoma really a disparate set of different sub-cancers. Is there a clear genetic pathway, is there a gene that predisposes and if so how. The how is all to often the key question.

2. Where does the melanoma stem cell fit in this paradigm? Stem cells have a problem because if they exist and are of the  primary concern then perhaps we are just eliminating the TIC cells and not the CSC.

3. What of the Harahan and Weinberg model of an interacting environment? Namely what about the influence of the other parts of the body including the immune system? This has been a Rosenberg issue for decades and Harahan and Weinberg make a strong case for its consideration.

4. Is it necessary to develop a data base of aberrant expressions of proteins?

5. What about dealing with the gene itself? Why just the protein.

6. How can we identify these cells from say cell surface markers. That would enhance the ability to expand our understanding of the histology down to the expression level.

7. What genes have been changed and how? What was the change agent. We have argued elsewhere that it is radiation, ultraviolet and x-ray. But what of other factors. Where do the miRNAs fit, other epigenetic factors, methylation, and the like.

8. As with other cancers, there may be a sequence of changes, and is MIS, melanoma in situ, one of the steps. Is MIS akin to say HGPIN in prostate cancer or an adenoma in colon cancer?

There are many other issues which will evolve from this study. It represents a step in the forward direction but as has been seen each time we do this we see other new paths as unknown. 

1.2        References

1.               Batchelor, J., MEK and BRAF Therapy Combo Promise for Advanced Melanoma, http://www.onclive.com/conference-coverage/asco-2011/MEK-and-BRAF-Therapy-Combo-Promising-for-Advanced-Melanoma , 2011

2.               Chapman, P., et al, Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation, NEJM, 2011, pp 1-9.

3.               Curtin, J., et al, Distinct Sets of Genetic Alterations in Melanoma, NEJM, 2005 pp 2135-2147.

4.               Eisenmann, K., et al, Mitogen Activated Protein Kinase Pathway Dependent Tumor Specific Survival Signalling in Melanoma Cells, J Can Res 2003 pp 8330-8337.

5.               Ernstoff, M., Been There Not Done That – Melanoma in the Age of Molecular Therapy, NEJM, 2011 pp 1-3.

6.               Flaherty, K., et al, Inhibition of Mutated Activated BRAF in Metastatic Melanoma, NEJM, 2010, pp 809-819.

7.               Hanahan, D., R. Weinberg, Hallmarks of Cancer: The Next Generation, Cell, 2011, pp 646-674.

8.               Hearing V., S. Leong, From Melanocytes to Melanoma, Humana (Totowa, NJ) 2006.

9.               Poulikakos, P., D. Solit, Resistance to MEK Inhibitors, Science Signalling, 2011 pp 1-2.

10.            Robert, C., et al, Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma, NEJM, 2011, pp 1-20.

11.            Schwartzentruber, D., et al, gp100 Peptide Vaccine and Interleukin 2 in Patients with Advanced Melanoma, NEJM, 2011, pp 2119-2122.

12.            Smalley, K., K. Flaherty, Integrating BRAF/MEK Inhibitors into Combination Therapy for Melanoma, Brit Jrl Cancer, 2009 pp 431-435.

13.            Solit, D., et al, BRAF Mutation Predicts Sensitivity to MEK Inhibition, Nature 2006, pp 358-362.

14.            Solit, D., N. Rosen, Resistance to BRAF Inhibition in Melanomas, NEJM, 2011 pp 772-774.

15.            Sumitomo, H., et al, The BRAF-MAPK Signalling Pathway is essential for cancer immune evasion in human melanoma, Jrl Exp Med 2008 pp 1651-1658.