Having spent the last couple of years amongst academic high tech folks, I have seen and heard about a lot of good ideas. However, what has surprised me, and it should not have, is that the "good idea" is believed to be all you need. Sales and operations, implementation and customer care are unheard of.
I think the cause of this is the rash of entrepreneurial help groups, on campus and off. The "shark tank" actors come up like carnival pitch men and have not a clue as to how the will build a full company.
In addition they also do not know that only 1% of the start ups are alive five years later and only 1% of them are a true financial success.
The best one I have seen is fathers taking "maternity leave" at the beginning of a start up! Two months leave and then restarting the process. Really, and that is just one of several of the antics we have seen.
The best thing I try to tell them is that a good idea is not a business. No matter how smart you are you have to have someone willing and able to buy it and more importantly you have to deliver it.
One would have thought with all the talk about the entrepreneur and creativity that the basic principles of the local candy store would apply. Sell the Dinky Twinkies to the kids, along with the grape soda....but make sure they have the money to pay for it. Having a store filled with stuff is not a business, unless you move the stuff...for money.
Sunday, November 30, 2014
The Internet and the Right
I am amazed how the right seems to totally miss the debate in Net Neutrality. Totally amazed. Take the Heritage Foundation, allegedly some form of conservative think tank. In a recent piece the author bemoans common carriage by saying:
He showed that earlier this month when — in an unusually deep wade into the decision-making process at the supposedly independent Federal Communications Commission — the president came out four-square in favor of imposing “common carrier,” or public utility, regulation on America’s Internet service providers. ... n spite of its style points, the president’s policy fails on substance. Simply put, regulating the 21st century Internet under common carrier rules designed for railroads in the 19th century simply makes no sense.
First, common carriage goes back some 600 years, not 200 or less. Second common carriage does not demand regulation, just the opposite. It says the carrier must not discriminate. The carrier sets a price for a capacity and that's that!
As it stands now Comcast sets the conditions and funds its political mouthpiece MSNBC! Are these guys at Heritage out of their minds! They want Comcast to decide what I see. The FCC would not do that under common carriage, just the opposite.
How dumb are some of these people....I forgot it is Washington...dumbness seems to be the condition of entry into the Beltway.
Please folks, try at the very least to understand what you propose!
He showed that earlier this month when — in an unusually deep wade into the decision-making process at the supposedly independent Federal Communications Commission — the president came out four-square in favor of imposing “common carrier,” or public utility, regulation on America’s Internet service providers. ... n spite of its style points, the president’s policy fails on substance. Simply put, regulating the 21st century Internet under common carrier rules designed for railroads in the 19th century simply makes no sense.
First, common carriage goes back some 600 years, not 200 or less. Second common carriage does not demand regulation, just the opposite. It says the carrier must not discriminate. The carrier sets a price for a capacity and that's that!
As it stands now Comcast sets the conditions and funds its political mouthpiece MSNBC! Are these guys at Heritage out of their minds! They want Comcast to decide what I see. The FCC would not do that under common carriage, just the opposite.
How dumb are some of these people....I forgot it is Washington...dumbness seems to be the condition of entry into the Beltway.
Please folks, try at the very least to understand what you propose!
Thursday, November 20, 2014
Use of the English Language, and Cancer
I am always amazed at how a small bit of insight, perhaps well interpreted, may get presented by the Press as the be all and end all. It is especially true with cancer. The most recent case in point is a study by physicians at a Toronto Hospital as well as at MSKCC and other places that the existence of some CNV, copy number variants, can give some modest prognostic data on prostate cancer. Simply, using some 300 patients in toto, theu compared tumor cells to non tumor cells and determined what CNVs across the genome could possibly be prognostic. With the 300 patient sample they got an ROC with about a 70& AUC. Nice but no cigar frankly.
But now to the Press. A Canadian paper states:
Canadian researchers have developed a genetic test to identify which men are at highest risk for recurrence of prostate cancer following localized treatment with surgery or radiation therapy. The genetic test provides a quick and highly accurate tool to determine which men with prostate cancer would do well with only surgery or radiation, and those who would need additional treatment — chemotherapy and hormone therapy, say the researchers, whose findings are described in Wednesday’s online edition of the journal Lancet Oncology. “Our findings set the stage to tackle the ongoing clinical problem of under-treating men with aggressive disease that will recur in 30 per cent to 50 per cent of patients due to hidden, microscopic disease that is already outside the prostate gland during initial treatment,” said ...a clinician-scientist ... in Toronto. "This genetic test could increase cure rates in intermediate- to high-risk men by preventing progression to this metastatic spread of prostate cancer,” said ... a scientist at the Ontario Institute for Cancer Research.
Now if one reads the opening sentence one could be led to believe that there is some massive discovery here. In my opinion, I will be delivering a more detailed analysis later, the following most likely are the results:
1. CNV are found everywhere in DNA. The fact that CNVs are more extensive in cancer cells may or may not be informative.
2. 300 patients is not a lot, especially not enough to in my opinion justify the first opening sentence. However in fairness the researcher did say "could".
3. There is the causative issue here. Why did these CNVs arise and why where they did. That seems to be the compelling issue.
4. Prognosis means that we can tell who after surgery or radiation will fare better or more poorly. But frankly so what if we have no way to mollify the negative results. We get to tell the patient that they are going to die at a greater odds ratio that someone else. We are not really certain but the odds are higher and yes we cannot do anything. Why even have that conversation?
5. There are already dozens of similar tests, genes, mRNAs, CNV, SNPs proteins, exosomes, endosomes, and the list goes on. What does one get by this test?
Yet the real issue is why does the Press make it appear that there is truly something here, here?
But now to the Press. A Canadian paper states:
Canadian researchers have developed a genetic test to identify which men are at highest risk for recurrence of prostate cancer following localized treatment with surgery or radiation therapy. The genetic test provides a quick and highly accurate tool to determine which men with prostate cancer would do well with only surgery or radiation, and those who would need additional treatment — chemotherapy and hormone therapy, say the researchers, whose findings are described in Wednesday’s online edition of the journal Lancet Oncology. “Our findings set the stage to tackle the ongoing clinical problem of under-treating men with aggressive disease that will recur in 30 per cent to 50 per cent of patients due to hidden, microscopic disease that is already outside the prostate gland during initial treatment,” said ...a clinician-scientist ... in Toronto. "This genetic test could increase cure rates in intermediate- to high-risk men by preventing progression to this metastatic spread of prostate cancer,” said ... a scientist at the Ontario Institute for Cancer Research.
Now if one reads the opening sentence one could be led to believe that there is some massive discovery here. In my opinion, I will be delivering a more detailed analysis later, the following most likely are the results:
1. CNV are found everywhere in DNA. The fact that CNVs are more extensive in cancer cells may or may not be informative.
2. 300 patients is not a lot, especially not enough to in my opinion justify the first opening sentence. However in fairness the researcher did say "could".
3. There is the causative issue here. Why did these CNVs arise and why where they did. That seems to be the compelling issue.
4. Prognosis means that we can tell who after surgery or radiation will fare better or more poorly. But frankly so what if we have no way to mollify the negative results. We get to tell the patient that they are going to die at a greater odds ratio that someone else. We are not really certain but the odds are higher and yes we cannot do anything. Why even have that conversation?
5. There are already dozens of similar tests, genes, mRNAs, CNV, SNPs proteins, exosomes, endosomes, and the list goes on. What does one get by this test?
Yet the real issue is why does the Press make it appear that there is truly something here, here?
Monday, November 17, 2014
Why I Do Not Like Football
From an MIT Press release today they list the history of Football on Campus:
- 1881: The MIT football team, nicknamed the Techmen, defeats Exeter College, 2-0.
- 1885: MIT trounces Amherst, 80-0, to tie Williams College for the Northeastern Intercollegiate Football Association (NIFA) league title. In perhaps the first playoff game in college football history, MIT loses to Williams, 18-10.
- 1886: MIT loses to Yale, 96-0.
- 1887-1888: MIT wins back-to-back NIFA league titles.
- 1890: With two games left, the football season is cancelled due to injuries.
- 1901: MIT President Henry S. Pritchett holds a controversial student vote that eliminates the football program by a two-vote margin (119-117).
- 1940: A non-varsity Junior-Senior team forms, plays four games, and Virginia Jewell is crowned “MIT Football Queen” before a football dance.
- 1941: The non-varsity team disbands after two seasons.
- 1966: A student survey indicates a desire for intercollegiate football, but the MIT Athletic Board votes unanimously against adding an MIT team.
- 1978: The MIT football club forms and joins the National Club Football Conference (NCFC), thanks to the efforts of players including Walt Crosby ’81, Bruce Wrobel ’79, and Gary Spletter ’79.
- 1978, cont.: The Rochester Institute of Technology drops their football program, and the MIT club purchases their football equipment and uniforms for $2,000. The team wears orange and white jerseys during the 1978 season.
- 1978, cont.: A crowd of 2,000 attends the club’s only home game. The Engineers loses to Siena College, 30-14, and an Ugliest Man on Campus contest is held at halftime. The team finishes the season 0-6.
- 1987: The NCFC disbands. The club becomes a varsity program and joins the NCAA Division III.
- 1988: The Engineers win their first varsity game of the modern era, beating Stonehill, 29-7.
- 2013: The team wins a then-record six games and post back-to-back winning seasons (5-4 in 2012) for the first time in 124 years.
- 2014: The Engineers finish the regular season 9-0 and win their first NEFC title. The team will play in the NCAA Division III Football Championship tournament on November 22.
Saturday, November 15, 2014
If Elephants Had Wings...
Economists imagine universes to which they can apply their tools, namely, and quite often, mathematics taken from engineers who have to deal with reality. As engineers we use mathematical tools to do things, we model reality and then test it out to be certain our models work. Economists have no such checks and balances. And as we have recently seen they also seem to have the tendency to promote their ideas via prevarication, namely saying one thing to push their belief while holding onto to a reality starkly different. There is no other occupation that allows no less encourage this other than magicians and circus acts. Oh, yes and of course politicians.
Now I read an article in Vox which focuses on the 1% and inequality. They conclude, regarding their proposed extortionary tax plan of some 90%+ marginal rate:
Overall we find that increasing tax rates at the very top of the income distribution and thereby reducing tax burdens for the rest of the population is a suitable measure to increase social welfare. As a side effect, it reduces both income and wealth inequality within the US population. Admittedly, our results apply with certain qualifications. First, taxing the top 1% more heavily will most certainly not work if these people can engage in heavy tax avoidance, make use of extensive tax loopholes, or just leave the country in response to a tax increase at the top. Second, and probably as importantly, our results rely on a certain notion of how the top 1% became such high earners. In our model, earnings ‘superstars’ are made from luck coupled with labour effort. However, if high income tax rates at the top would lead individuals not to pursue high-earning careers at all, then our results might change. Last but not least, our analysis focuses solely on the taxation of large labour earnings rather than capital income at the top 1%. Despite these limitations, which might affect the exact number for the optimal marginal tax rate on the top 1%, many sensitivity analyses in our research suggest one very robust result – current top marginal tax rates in the US are lower than would be optimal, and pursuing a policy aimed at increasing them is likely to be beneficial for society as a whole.
You see they assume that the rich just got rich by luck. There seems to be little hard work involved. But they do seem to admit that perhaps they could avoid taxes by moving, that they may possibly not work as hard.
This is a classic example of some thought based upon no knowledge. But unfortunately our current Government policies are all too often based upon academic advice from these people.
Now I read an article in Vox which focuses on the 1% and inequality. They conclude, regarding their proposed extortionary tax plan of some 90%+ marginal rate:
Overall we find that increasing tax rates at the very top of the income distribution and thereby reducing tax burdens for the rest of the population is a suitable measure to increase social welfare. As a side effect, it reduces both income and wealth inequality within the US population. Admittedly, our results apply with certain qualifications. First, taxing the top 1% more heavily will most certainly not work if these people can engage in heavy tax avoidance, make use of extensive tax loopholes, or just leave the country in response to a tax increase at the top. Second, and probably as importantly, our results rely on a certain notion of how the top 1% became such high earners. In our model, earnings ‘superstars’ are made from luck coupled with labour effort. However, if high income tax rates at the top would lead individuals not to pursue high-earning careers at all, then our results might change. Last but not least, our analysis focuses solely on the taxation of large labour earnings rather than capital income at the top 1%. Despite these limitations, which might affect the exact number for the optimal marginal tax rate on the top 1%, many sensitivity analyses in our research suggest one very robust result – current top marginal tax rates in the US are lower than would be optimal, and pursuing a policy aimed at increasing them is likely to be beneficial for society as a whole.
You see they assume that the rich just got rich by luck. There seems to be little hard work involved. But they do seem to admit that perhaps they could avoid taxes by moving, that they may possibly not work as hard.
This is a classic example of some thought based upon no knowledge. But unfortunately our current Government policies are all too often based upon academic advice from these people.
Tuesday, November 11, 2014
More Thoughts on Internet Neutrality
It seems that the Progressives are taking the fore in the argument of Internet Neutrality. They have managed to rephrase it as a means to have the Government protect people who use the Internet. In reality it should be a scheme whereby a user pays for local transport, and all users are the same for the same service. Namely if I choose not to have Netflix downloaded then I should not have to pay for that capacity. It is akin to my arguments against paying for football and funding the debauched lives of its players.
If however I want Netflix and whatever else that requires broadband then I should pay, not everyone else. That is Net Neutrality.
However, the prices are another issue. You see the Internet is really cheap at least per household. The real problem is why do the carriers charge so much? That is where the argument should be.
I fear that the Progressives have turned the argument around so that it now allows Government regulation. What a mess. The should reread Coll's book, The Deal of the Century.
As noted in the New Republic:
Under Title II, Internet service—and in the president’s plan, that means through computer, mobile or tablet—would become a “common carrier,” much like your phone line. And just as phone providers like AT&T or Verizon cannot deliberately slow down particular phone calls or charge certain businesses more money to connect faster, those standards would apply to the Internet under Title II. That means no “fast lanes,” where companies pay for quicker load times for their Web sites. It means no deliberate throttling of any content. It effectively means no special treatment for anyone, from Netflix and Google to photos of your cat.Broadband providers have argued that Title II authority would subject their businesses to all sorts of cumbersome and costly regulations, and potentially even price-setting. But Obama made clear in his statement that the FCC should exclude the industry from those kinds of rules, focusing on only those “relevant to broadband services.”
Being a Common Carrier means two things: everyone is treated equally, and the carrier has de minimis liability. Queen Elizabeth I created this in 1602. It allowed British ships to sail and created a world shipping power. The same can be done with the Internet, common carriage in a de minimis manner, meaning all are treated equally.
If however I want Netflix and whatever else that requires broadband then I should pay, not everyone else. That is Net Neutrality.
However, the prices are another issue. You see the Internet is really cheap at least per household. The real problem is why do the carriers charge so much? That is where the argument should be.
I fear that the Progressives have turned the argument around so that it now allows Government regulation. What a mess. The should reread Coll's book, The Deal of the Century.
As noted in the New Republic:
Under Title II, Internet service—and in the president’s plan, that means through computer, mobile or tablet—would become a “common carrier,” much like your phone line. And just as phone providers like AT&T or Verizon cannot deliberately slow down particular phone calls or charge certain businesses more money to connect faster, those standards would apply to the Internet under Title II. That means no “fast lanes,” where companies pay for quicker load times for their Web sites. It means no deliberate throttling of any content. It effectively means no special treatment for anyone, from Netflix and Google to photos of your cat.Broadband providers have argued that Title II authority would subject their businesses to all sorts of cumbersome and costly regulations, and potentially even price-setting. But Obama made clear in his statement that the FCC should exclude the industry from those kinds of rules, focusing on only those “relevant to broadband services.”
Being a Common Carrier means two things: everyone is treated equally, and the carrier has de minimis liability. Queen Elizabeth I created this in 1602. It allowed British ships to sail and created a world shipping power. The same can be done with the Internet, common carriage in a de minimis manner, meaning all are treated equally.
Veterans Day; Now and Then
Have They No Shame?
While the ACA was being debated I was deeply concerned by the statements of an MIT Economics Professor who was saying things that were just not correct. I wrote extensively about this and lo and behold I was right. As this Professor has acknowledged (from Reason):
"This bill was written in a tortured way to make sure CBO did not score the mandate as taxes. If CBO [Congressional Budget Office] scored the mandate as taxes, the bill dies. Okay, so it’s written to do that. In terms of risk rated subsidies, if you had a law which said that healthy people are going to pay in – you made explicit healthy people pay in and sick people get money, it would not have passed… Lack of transparency is a huge political advantage. And basically, call it the stupidity of the American voter or whatever, but basically that was really really critical for the thing to pass....Look, I wish Mark was right that we could make it all transparent, but I’d rather have this law than not."
Well some of us were not that stupid. First he is he is an economist, and that knocks off a few IQ points anyhow. However the obfuscation, sadly seemingly supported by the publication in the New England Journal of Medicine (NEJM), is, in my opinion, on the verge of being conspiratorial. We are now all suffering from this massive mess.
One wonders if any of this is ever taken into account in the Academic world. From time to time I am reminded of Heidegger, and his academic foibles.
The tale gets even better when reading Forbes which states:
The new ..... comments come from a panel discussion that he joined on October 17, 2013 at the University of Pennsylvania’s Leonard Davis Institute of Health Economics. He was joined on the panel by Penn health economist ..... was the first to flag .... remarks. In fairness to.......American voters are not the only people whose intelligence he questions; elsewhere in the discussion, he describes New York Sen. ....... as someone who “as far as I can tell, doesn’t understand economics” and calls a staffer for .....—presumably .....—an “idiot.”
This an amazing statement. Here we have the alleged self-proclaimed architect saying that it was an attempt to deceive the American voters. Well frankly many were not fooled, as I had indicated many times. But institutions were used. In my opinion, MIT was used, NEJM was used, and the consequence is what? If this were a physician who did this, most likely he or she would be banned. But as a Professor of Economics, well what does one expect?
Yes, they have no shame. Nor, quite frankly, it seems to appear in my opinion, do the institutions who have seemingly supported them.
Now consider if this were a biologist who had devised a putative cure for say Ebola, but was just posing as such and then admitted publicly that what was done was just a way to deceive the public to sell the drug. What would that persons Institution do? Most likely send them packing. The same would apply to any scientist, physician, or engineer. But apparently not to an Economics Department instructor, and that says something about business. Would Harvard allow this? Possibly not. In fact most likely not.
Consider the classic case of David Baltimore, the brilliant and revered Biologist, who was attacked by Congress with Congressman Dingell at the fore. He had a student make a sloppy entry in a lab notebook and after the bemoaning of another post-doc it started a Federal case. Where is the Federal case here. One assumes the good Professor was compensated by the Government so why not the same level of outrage. Baltimore actually did great deeds for mankind. Rarely if ever does one see this in an Economist.
Academic freedom permits the investigation of ideas not the promoting of error. In my view, it does not permit the propagation of known falsehoods. Back to Heidegger.
"This bill was written in a tortured way to make sure CBO did not score the mandate as taxes. If CBO [Congressional Budget Office] scored the mandate as taxes, the bill dies. Okay, so it’s written to do that. In terms of risk rated subsidies, if you had a law which said that healthy people are going to pay in – you made explicit healthy people pay in and sick people get money, it would not have passed… Lack of transparency is a huge political advantage. And basically, call it the stupidity of the American voter or whatever, but basically that was really really critical for the thing to pass....Look, I wish Mark was right that we could make it all transparent, but I’d rather have this law than not."
Well some of us were not that stupid. First he is he is an economist, and that knocks off a few IQ points anyhow. However the obfuscation, sadly seemingly supported by the publication in the New England Journal of Medicine (NEJM), is, in my opinion, on the verge of being conspiratorial. We are now all suffering from this massive mess.
One wonders if any of this is ever taken into account in the Academic world. From time to time I am reminded of Heidegger, and his academic foibles.
The tale gets even better when reading Forbes which states:
The new ..... comments come from a panel discussion that he joined on October 17, 2013 at the University of Pennsylvania’s Leonard Davis Institute of Health Economics. He was joined on the panel by Penn health economist ..... was the first to flag .... remarks. In fairness to.......American voters are not the only people whose intelligence he questions; elsewhere in the discussion, he describes New York Sen. ....... as someone who “as far as I can tell, doesn’t understand economics” and calls a staffer for .....—presumably .....—an “idiot.”
This an amazing statement. Here we have the alleged self-proclaimed architect saying that it was an attempt to deceive the American voters. Well frankly many were not fooled, as I had indicated many times. But institutions were used. In my opinion, MIT was used, NEJM was used, and the consequence is what? If this were a physician who did this, most likely he or she would be banned. But as a Professor of Economics, well what does one expect?
Yes, they have no shame. Nor, quite frankly, it seems to appear in my opinion, do the institutions who have seemingly supported them.
Now consider if this were a biologist who had devised a putative cure for say Ebola, but was just posing as such and then admitted publicly that what was done was just a way to deceive the public to sell the drug. What would that persons Institution do? Most likely send them packing. The same would apply to any scientist, physician, or engineer. But apparently not to an Economics Department instructor, and that says something about business. Would Harvard allow this? Possibly not. In fact most likely not.
Consider the classic case of David Baltimore, the brilliant and revered Biologist, who was attacked by Congress with Congressman Dingell at the fore. He had a student make a sloppy entry in a lab notebook and after the bemoaning of another post-doc it started a Federal case. Where is the Federal case here. One assumes the good Professor was compensated by the Government so why not the same level of outrage. Baltimore actually did great deeds for mankind. Rarely if ever does one see this in an Economist.
Academic freedom permits the investigation of ideas not the promoting of error. In my view, it does not permit the propagation of known falsehoods. Back to Heidegger.
Monday, November 10, 2014
The Internet, Priority and Neutrality
I heard a presentation by some Law Prof at U Penn this weekend where I believe he claimed that the IP protocol has a priority code so this justifies Comcast discriminating against providers and deciding what customers can see. Now here I have a problem. In the 70s when I was heading part of the Internet implementation in DC, I had the satellite side of the ARPA Net, I had an MIT student do a thesis that looked at priority queuing. Why? Simple the Internet was a DoD network and when a General needed to communicate the General needed priority. It had nothing to do with Comcast. Lawyers know less of technology and even less of history than any others I have ever seen!
Now to today's announcement by the current President. He is apparently supporting the FCC taking the position of supporting Common Carriage. He stated:
.....said that new rules under consideration by the F.C.C. should adhere to several key principles: No website or service should be blocked by an Internet service provider; no content should be purposefully slowed down or sped up; there should be more transparency about where traffic is routed; and no paid deals should be made to provide a speed advantage to some providers over others in delivering content.
Of course the monopolistic cable and telco companies replied:
“Imposing antiquated common carrier regulation, or Title II, on the vibrant mobile wireless ecosystem would be a gross overreaction,” said Meredith Attwell Baker, president and chief executive of the trade association and a former Republican commissioner for the F.C.C.
As we had written a few years back regarding Internet Neutrality :
Internet Neutrality is a term which means many things to many people. In this paper we look at the Internet from a technical, legal, and economic perspective. We look at the ways the various players are trying to position their view and we attempt to apply the factual elements of what actually exists as a set of tests and tools to analyze the options. We as a result of this detailed analysis have come up with a set of conclusion and principles which re -interpret the concepts of Internet neutrality and present a set of principles which are based on the technological facts, the market realities, and legal precedents which go back more than a thousand years. Our concern is that some of the proposal are so self-serving that if accepted of if implemented will do irreparable harm to what has been created in the Internet.
Hopefully the FCC has some modicum of backbone to ensure that individual rights are preserved.
Now to today's announcement by the current President. He is apparently supporting the FCC taking the position of supporting Common Carriage. He stated:
.....said that new rules under consideration by the F.C.C. should adhere to several key principles: No website or service should be blocked by an Internet service provider; no content should be purposefully slowed down or sped up; there should be more transparency about where traffic is routed; and no paid deals should be made to provide a speed advantage to some providers over others in delivering content.
Of course the monopolistic cable and telco companies replied:
“Imposing antiquated common carrier regulation, or Title II, on the vibrant mobile wireless ecosystem would be a gross overreaction,” said Meredith Attwell Baker, president and chief executive of the trade association and a former Republican commissioner for the F.C.C.
As we had written a few years back regarding Internet Neutrality :
Internet Neutrality is a term which means many things to many people. In this paper we look at the Internet from a technical, legal, and economic perspective. We look at the ways the various players are trying to position their view and we attempt to apply the factual elements of what actually exists as a set of tests and tools to analyze the options. We as a result of this detailed analysis have come up with a set of conclusion and principles which re -interpret the concepts of Internet neutrality and present a set of principles which are based on the technological facts, the market realities, and legal precedents which go back more than a thousand years. Our concern is that some of the proposal are so self-serving that if accepted of if implemented will do irreparable harm to what has been created in the Internet.
Sunday, November 9, 2014
MOOCs Again
There is a piece in the New Yorker on MOOCs. The author states:
The other major problem is that MOOCs tend to be set up in a way that minimizes frustration for students (who might drop out at any moment). There often aren’t pop quizzes or the kinds of challenges that can alienate students in traditional settings. The problem here is that easy learning does not make good learning. In fact, the very tools that we believe make for better education may also make students more likely to quit. More frequent testing, for instance, can improve memory, learning, and retention. And, sometimes, the best test of all is the test that you fail: recent work from the cognitive psychologist Elizabeth Ligon Bjork has shown that pre-testing on never-before-seen materials helps students perform better in a subsequent course covering that material. In general, Bjork has found, speed bumps in learning are good—desirable difficulties, she calls them. MOOCs would likely be more effective if they didn’t shy away from challenging students, rather than presenting a fluid experience which gives the false impression of the learning and retention.
Frankly the problem with MOOCs is that those who do so in English do not know English. For example in a recent MIT exam for a materials course they asked a question which required height and width. Except they stated:
a width, b, of 20μm and a depth, h, of 1μm
Now what is depth? One was given the length and allegedly the width but one needed height. Is depth a new word for height? Words mean something. Now I am facile in six languages, so I tried translating into each but came to the same conclusion, there must be some language wherein depth equals height. I think.
This is the problem of MOOCs, students and teachers who don't read what the wrote, at least in the language it is taught!
As to the above suggestion, my response is clap trap! The MOOCs maximize frustrations. Again in the same course one must enter equations in a format that is hidden in the bowels of the course. One spends hours finding out how to do the computer side of the course, NOT the material taught.
In addition the approach to grading is an all or none approach. One must go through all the equations, convert them to a program, run the numbers and then make certain the the units are consistent. To complicate things the units in the problems are disparate to say the least.
Finally the New Yorker shows Lander at MIT, strangely the only existing MOOC instructor who has a course that works. One wonders if the New Yorker writer had the slightest clue!I suspect as a psychology major she does not!
Then there is the Harvard Medical School course on Anatomy. Apparently the TAs has disappeared. The answers are wrong and the students in the discussion group are running wild. The overhead on a good MOOC is significant, and costly. Lander has figured it out, as he has with everything he touches. Almost all the others have not. Some seem clueless.
UPDATE: Well I just found out that depth=height. Amazing what people will come up with.
The other major problem is that MOOCs tend to be set up in a way that minimizes frustration for students (who might drop out at any moment). There often aren’t pop quizzes or the kinds of challenges that can alienate students in traditional settings. The problem here is that easy learning does not make good learning. In fact, the very tools that we believe make for better education may also make students more likely to quit. More frequent testing, for instance, can improve memory, learning, and retention. And, sometimes, the best test of all is the test that you fail: recent work from the cognitive psychologist Elizabeth Ligon Bjork has shown that pre-testing on never-before-seen materials helps students perform better in a subsequent course covering that material. In general, Bjork has found, speed bumps in learning are good—desirable difficulties, she calls them. MOOCs would likely be more effective if they didn’t shy away from challenging students, rather than presenting a fluid experience which gives the false impression of the learning and retention.
Frankly the problem with MOOCs is that those who do so in English do not know English. For example in a recent MIT exam for a materials course they asked a question which required height and width. Except they stated:
a width, b, of 20μm and a depth, h, of 1μm
Now what is depth? One was given the length and allegedly the width but one needed height. Is depth a new word for height? Words mean something. Now I am facile in six languages, so I tried translating into each but came to the same conclusion, there must be some language wherein depth equals height. I think.
This is the problem of MOOCs, students and teachers who don't read what the wrote, at least in the language it is taught!
As to the above suggestion, my response is clap trap! The MOOCs maximize frustrations. Again in the same course one must enter equations in a format that is hidden in the bowels of the course. One spends hours finding out how to do the computer side of the course, NOT the material taught.
In addition the approach to grading is an all or none approach. One must go through all the equations, convert them to a program, run the numbers and then make certain the the units are consistent. To complicate things the units in the problems are disparate to say the least.
Finally the New Yorker shows Lander at MIT, strangely the only existing MOOC instructor who has a course that works. One wonders if the New Yorker writer had the slightest clue!I suspect as a psychology major she does not!
Then there is the Harvard Medical School course on Anatomy. Apparently the TAs has disappeared. The answers are wrong and the students in the discussion group are running wild. The overhead on a good MOOC is significant, and costly. Lander has figured it out, as he has with everything he touches. Almost all the others have not. Some seem clueless.
UPDATE: Well I just found out that depth=height. Amazing what people will come up with.
Tuesday, November 4, 2014
Insight into Ebola as a Public Health Issue
Amid all the turmoil of Ebola the interview in Science with the Nigerian President of their Academy of Sciences is the most telling. It should be mandatory reading for all politicians.
For example he states:
People say African countries are poor. But it’s not poverty. It’s misuse of what we have. As we are talking, with all the crises that are going on, the presidents of our countries are still traveling in the best of conditions. Some will come to New York in their private jets, although their national airlines collapsed years ago; in addition, they will bring along a long retinue of private, personal, and public assistants, all lodged in the best hotels. I am not saying the president should not be treated well, but these are issues we need to look at. Take my country: We do not have a national airline, but the number of private jets we have is more than all the airlines in Africa have together.
Almost sounds like a Secret Service trip.
But the point is that the solution must be enacted by the country. The west alone cannot always take the burden and responsibility. Nigeria acted, almost as an afterthought. The others, if one reads this correctly, failed at the beginning and are continuing to do so.
For example he states:
People say African countries are poor. But it’s not poverty. It’s misuse of what we have. As we are talking, with all the crises that are going on, the presidents of our countries are still traveling in the best of conditions. Some will come to New York in their private jets, although their national airlines collapsed years ago; in addition, they will bring along a long retinue of private, personal, and public assistants, all lodged in the best hotels. I am not saying the president should not be treated well, but these are issues we need to look at. Take my country: We do not have a national airline, but the number of private jets we have is more than all the airlines in Africa have together.
Almost sounds like a Secret Service trip.
But the point is that the solution must be enacted by the country. The west alone cannot always take the burden and responsibility. Nigeria acted, almost as an afterthought. The others, if one reads this correctly, failed at the beginning and are continuing to do so.
Poland
Poland is now some 25 years free of Soviet domination. I entered Poland to work in 1995, and my partner, Peter Mroczyk, a former Solidarity leader had come back and we created a pan Central European business, from the Baltic to the Balkans. I saw the potential of Poland through the eyes of Peter and of those other Poles who saw that they could recreate Poland to its former glory.
It was hard work, some politics, but it lacked the cronyism of Russia and the rigid controls of France. In a sense Poland was allowed to expand because they did what was necessary, and have pulled together splendidly.
In Project Syndicate there is a laudatory article on Poland well worth reading. He states:
It was hard work, some politics, but it lacked the cronyism of Russia and the rigid controls of France. In a sense Poland was allowed to expand because they did what was necessary, and have pulled together splendidly.
In Project Syndicate there is a laudatory article on Poland well worth reading. He states:
Last
month, Donald Tusk, Poland’s former prime minister, was appointed
President of the European Council, thus becoming one of Europe’s three
top leaders. This decision not only reflected Tusk’s successful
leadership in Poland, where he ensured political stability and oversaw
impressive economic progress; it was also a clear signal that EU leaders
fully acknowledge Poland’s political and economic importance. It also
signaled to the other new member states that they are true equals in
European decision-making. Again,
it was Poland that paved the way, reminding the old member states from
the outset of the accession process that it was not an outsider or a
poor relative in need of charity, but rather a source of inspiration in
the European integration process, its impact delayed only by World War
II and its aftermath. Now, after ten years of EU membership, a new
Golden Age for Poland may be on the horizon. Poland
has the potential to become a European leader again. Firmly anchored in
the community of Western democracies, its role transcends the technical
aspects of the European integration process, for it bears the
responsibility of ensuring that no new barrier excludes our Eastern
neighbors from taking part in this process.
Poland is what Russia could have become. The irony is that the tower in downtown Warsaw built as a "gift" of Stalin to the Polish people still stands in all is Soviet "beauty" while across the street is the Marriott, a western hotel built by Russian investors. In between springs forth a new Poland, looking westward and growing economically as an example to the rest of the Free World.
A Fantastic Book
There is a draft of a book, Cell Biology by the Numbers, also see dropbox, by Milo and Phillips, that is just amazing! It is a set of questions with answers briefly given, such as how fast is translation and transcription. Also how big is a cell. It is really a fantastic amalgam of questions, answers, and technique. It is not yet published but I would argue that it should be on the desk of anyone trying to do real work in the life sciences. The questions and answers alone are a gold mine but the way they arrive at them and explain them are sine qua non.
Keep a watch out for this one, it is a true gem!
Keep a watch out for this one, it is a true gem!
Sunday, November 2, 2014
SPDEF and Prostate Cancer
In a recent White Paper we examine some recent results regarding a class of transcription factors and Prostate Cancer. SPDEF is one of the 30-40 transcription factors found in the
ETS family. Recall that transcription factors can be promoters (activators) or
repressors of gene expression and that depending where they act than can
dramatically change the expression of genes in the cell. The general paradigm
is shown below:
The ETS family is a powerful family of transcription factors
and they are often found altered in prostate cancer. In this section we examine
a specific subset of these transcription factors.
The chart below displays the specific factors we discuss
herein. The driver for this discussion is a recent paper by Cheng et al which
discusses SPDEF and the regulation of FOXM1 oncogene. The paper is interesting
in that if examines a transcription factor and the specific influence on an
oncogene expression. SPDEF is in the ETS family and thus the interest in ETS. SPDEF
is the SAM pointed domain containing ETS transcription factor. Thus, the
acronym was formed. It is distinct from another ETS gene the PDEF which the
prostate derived epithelial factor. As they indicate it is not clear what the
role of SPDEF is in PCa and it is not clear whether its expression suppresses
or enhances PCa development. Yet the analysis of this process does present an
alternative view of a complex PCa development mechanism.
As Cheng et al have postulated the increase in SPDEF results
in a suppression of FOXM1 which is a known oncogene, especially for PCa. As in
Gellmann et al (pp 328-333) FOXM1 is a known oncogene. It drives the cell cycle
and thus leads to uncontrolled cell proliferation. We show this below:
The ETS (“E26 transformation specific”) family has some
30-40 genes and many relate to prostate cancer. For example the ERG (the “ETS
related gene”) gene is often found translocated with TPRSS in a fused state and
this translocation is a clear indication of an aggressive form of PCa. From Watson et al we have the following breath
of structure for the ETS family:
Let us begin with a brief overview of ETS family and
specifically the inclusion of SPDEF. As Wasylyk et al state:
The Ets family of transcription factors includes nuclear
phosphoproteins that are involved in cell proliferation, differentiation and
oncogenic transformation. The family is defined by a conserved DNA-binding
domain (the ETS-DBD), which forms a highly conserved, winged, helix-turn-helix
structural motif. As targets of the Ras-MAPK signaling pathway, Ets proteins
function as critical nuclear integrators of ubiquitous signaling cascades. To
direct signals to specific target genes, Ets proteins interact with (other)
transcription factors that promote the binding of Ets proteins to composite
Ras-responsive elements.
We demonstrate the winged or “butterfly” operation of ETS
transcription factors as shown below[1]:
In a 2012 report in Science Daily they state[2]:
Prostate cancer doesn't kill in the prostate -- it's the
disease's metastasis to other tissues that can be fatal. A University of
Colorado Cancer Center study published this week in the Journal of Biological
Chemistry shows that prostate cancer cells containing the protein SPDEF
continue to grow at the same pace as their SPDEF- cousins, but that these
SPDEF+ cells are unable to survive at possible sites of metastasis.
"It's as if these cancer cells with SPDEF can't chew
into distant tissue and so are unable to make new homes," says Hari Koul,
PhD, investigator at the CU Cancer Center and director of urology research at
the University of Colorado School of Medicine, the study's senior author.
Koul and his group discovered the homesteading power of
cancer cells that have lost SPDEF by introducing a gene into cells that makes
them glow in the presence of a dye, and then introducing them into the
bloodstream of animal models. Cells without SPDEF traveled through the blood
and successfully attached to tissue, surviving and so fluorescing many weeks
later when dye was introduced. However, cells with SPDEF flowed through the
blood but were unable to successfully establish new colonies and so soon died
out.
In fact, the protein SPDEF doesn't act directly to
allow cells to attach at possible metastasis sites, but is a transcription
factor that controls the production (or lack thereof) of two other proteins
MMP9 and MMP13. These two downstream proteins work to break down
tissue, like a dissolving agent -- they are the cleaning crew that clears space
for new and different growth, and in the case of prostate cancer metastasis
they chip the tissue footholds that cancer cells need to create
micrometastases.
There has been a great deal of work on MMPs especially MMP9[3]. We will expand this
discussion later.
"Given that MMP9 and perhaps MMP13 are also involved
in metastasis of several other cancers including lung, ovarian, breast and
colon to name a few, our findings could potentially have far-reaching
consequences outside prostate cancer," adds Koul
The group's continuing work points in two directions.
"First, we hope that the presence of SPDEF could
help doctors recognize prostate cancers that don't require treatment." If
future studies confirm the group's initial findings, the presence of SPDEF
could predict prostate cancers that are unable to metastasize and so unable to
kill. These cancers could be left to run their course without the use of
treatments that sometimes carry difficult side effects.
"And second," Koul says, "we hope to
regulate expression of this protein to remove prostate cancers' ability to
metastasize."
Koul points to small molecules, gene therapy or
nanodelivery as possible mechanisms for introducing SPDEF into cells that lack
the protein.
"With this discovery we have opened a hopeful door
into a future in which prostate and potentially other cancers are unable to
metastasize," Koul says.
However it appears that this work has been withdrawn in
several venues. It is not clear where the problem was that caused the
withdrawal.
We will now consider a recent
paper by Cheng et al which we referred to in the Introduction. The interest
here is the collecting together of multiple elements in this SPDEF chain and the
effects of ETS transcription factors.
In the recent paper by Cheng et al the authors state[4]:
SAM-pointed
domain-containing ETS transcription factor (SPDEF) is expressed in normal
prostate epithelium. While its expression changes during prostate
carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial
due to the lack of genetic mouse models. In present study, we generated
transgenic mice with the loss- or gain-of-function of SPDEF in prostate
epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate
cancer. Loss of SPDEF increased cancer progression and tumor cell
proliferation, whereas over-expression of SPDEF in prostate epithelium
inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in
vitro.
Transgenic
over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a
transcription factor critical for tumor cell proliferation, and reduced
expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2,
Plk-1, AuroraB, CKS1 and Topo2alpha.
Deletion of SPDEF in
transgenic mice and cultures prostate tumor cells increased expression of Foxm1
and its target genes. Furthermore, an inverse correlation between SPDEF and
Foxm1 levels was found in human prostate cancers. The two-gene signature of low
SPDEF and high FoxM1 predicted poor survival in prostate cancer patients.
Mechanistically, SPDEF bound to, and inhibited transcriptional activity of
Foxm1 promoter by interfering with the ability of Foxm1 to activate its own
promoter through auto-regulatory site located in the 2745/2660 bp Foxm1
promoter region. Re-expression of Foxm1 restored cellular proliferation in the
SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in
mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by
preventing Foxm1-regulated proliferation of prostate tumor cells.
The present study
identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene
and demonstrated that this crosstalk is required for tumor cell proliferation
during progression of prostate cancer in vivo.
The relationship between SPDEF and Foxm1 are significant and
could become a possible therapeutic target. They continue:
Development of
prostate cancer is a multistep process that involves the loss of tumor
suppressor functions and activation of oncogenes. SPDEF transcription factor is
expressed in normal prostate epithelium and its expression changes during
prostate carcinogenesis (PCa). Since the role of SPDEF in PCa remains
controversial, we generated transgenic mice with loss- and gain-of-function of
SPDEF to demonstrate that SPDEF functions as a tumor suppressor in PCa. In
animal models, the loss of SPDEF promoted PCa and increased the levels of
Foxm1, a well-known oncogenic protein.
Overexpression of
SPDEF in prostate epithelium decreased PCa and reduced Foxm1 levels.
Proliferation defects in SPDEF-containing tumor cells were corrected by
re-expression of Foxm1, providing direct evidence that SPDEF inhibits tumor
cell proliferation through Foxm1. We further showed that SPDEF directly bound
to Foxm1 promoter and prevented its autoregulatory activation. In prostate
cancer patients, the low SPDEF and high Foxm1 were found in most aggressive
prostate tumors that were associated with poor prognosis. The combined two-gene
signature of low SPDEF and high Foxm1 was a strong predictor of survival in
prostate cancer patients. The present study identified novel molecular
mechanism of prostate cancer progression, providing a crosstalk between SPDEF
tumor suppressor and Foxm1 oncogene.
Furthermore, Pal et
al in a paper, that has been subsequently withdrawn, had stated:
Loss of
E-cadherin is one of the key steps in tumor progression. Our previous studies
demonstrate that SAM pointed domain-containing ETS transcription factor (SPDEF)
inhibited prostate cancer metastasis in vitro and in vivo. In the present
study, we evaluated the relationship between SPDEF and E-cadherin expression in
an effort to better understand the mechanism of action of SPDEF in prostate
tumor cell invasion and metastasis.
The results
presented here demonstrate a direct correlation between expression of
E-cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that
modulation of E-cadherin and SPDEF had similar effects on cell
migration/invasion. In addition, siRNA-mediated knockdown of E-cadherin was
sufficient to block the effects of SPDEF on cell migration and invasion. We
also show that stable forced expression of SPDEF results in increased
expression of E-cadherin, whereas down-regulation of SPDEF decreased E-cadherin
expression.
In addition, we
demonstrate that SPDEF expression is not regulated by E-cadherin. Moreover, our
chromatin immunoprecipitation and luciferase reporter assay revealed that SPDEF
occupies E-cadherin promoter site and acts as a direct transcriptional inducer
of E-cadherin in prostate cancer cells. Taken together, to the best of our
knowledge, these studies are the first demonstrating requirement of SPDEF for
expression of E-cadherin, an essential epithelial cell junction protein. Given
that loss of E-cadherin is a central tenant in tumor metastasis, the results of
our studies, by providing a new mechanism for regulation of E-cadherin expression,
could have far reaching impact.
The SPDEF capability to deal with adhesion via the paths
shown is a significant factor in its overall importance in metastasis.
Foxm1 is a transcription activator and can be silenced by
SPDEF. However when SPDEF is deficient then Foxom1 can act as an aggressive
oncogene and can press metastatic growth.
From NCBI we have[7]:
The protein encoded by this gene is a transcriptional
activator involved in cell proliferation. The encoded protein is phosphorylated
in M phase and regulates the expression of several cell cycle genes, such as
cyclin B1 and cyclin D1. Several transcript variants encoding different
isoforms have been found for this gene.
The Foxm1 gene may be a therapeutic target. It pushes the
cell through the cell cycle and can kick off aggressive metastatic growth. This
simple connection between the regulatory role of SPDEF and the aggressive cell
cycle capabilities of Foxm1 is an important observation.
MMP genes have been found to assist metastatic growth by
degrading the ECM structures. As Chiang et al state:
Various members of the matrix metalloproteinase (MMP)
family (e.g., MMP-2 and MMP-9) are also implicated in cancer cell invasion.
Independent screens for genes that mediate bone or lung metastasis in breast
cancer have identified MMP-1 as being necessary for spread to the bone and
lungs.
As noted in NCBI:
Proteins of the matrix metalloproteinase (MMP) family are
involved in the breakdown of extracellular matrix in normal physiological
processes, such as embryonic development, reproduction, and tissue remodeling,
as well as in disease processes, such as arthritis and metastasis. Most MMP's
are secreted as inactive proproteins which are activated when cleaved by extracellular
proteinases. The enzyme encoded by this gene degrades type IV and V collagens.
Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced
mobilization of hematopoietic progenitor cells from bone marrow, and murine
studies suggest a role in tumor-associated tissue remodeling.
MMP actions are shown below in general terms depicting the
activation via the ERB pathway:
MMPs initiate their actions via ECM degradation first and
then enable cell migration and sustainability via angiogenesis. Thus the
evidence of MMP-9 and MMP-14 are significant. As Marks et al note (p 242) there
is no known ligan for ErbB2 but it does form an active heterodimer with either
ErbB1 or ErbB4. We examine that pathway shortly. Also Marks et al note (p 243)
that the organization of the ErbB network is quite complex and demands a
systems based approach. This “systems based approach” is essential as we
consider the interaction of all of these elements.
The details of the ErbB2 pathway are shown below:
Although the paper in question regarding SPDEF does read
onto the MMPs directly the discussing surrounding it does.
In a 2012 paper by Stefan et al[8]:
The role of SPDEF in tumor biology
remains hotly debated. SPDEF suppressed tumor metastasis
in-part by modulating MMP9 and MMP13. SPDEF is a modifiable therapeutic target
in prostate tumors. This is the first study directly implicating SPDEF as a
tumor metastasis suppressor in any system in vivo. Emerging evidence suggests
that SAM Pointed Domain Containing ETS Transcription Factor (SPD
EF), plays a significant role in
tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there
are no in vivo studies with respect to the role of SPDEF in tumor metastasis.
The present study examined the effects of SPDEF on tumor cell metastasis using
prostate tumor cells as a model. Utilizing two experimental metastasis models,
we demonstrate that SPDEF inhibits cell migration and invasion in vitro and
acts a tumor metastasis suppressor in vivo.
Using stable expression of SPDEF in
PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we
demonstrate for the first time that SPDEF diminished the ability of
disseminated tumors cells to survive at secondary sites and establish
micrometastases. These effects on tumor metastasis were not a result of the
effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth
in vitro, or subcutaneous tumor xenograft-growth in vivo. Transcriptional
analysis of several genes associated with tumor metastasis, invasion, and the
epithelial-mesenchymal transition demonstrated that SPDEF overexpression
selectively down-regulated MMP9 and MMP13 in prostate cancer cells.
Further analysis indicated that forced
MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3
cells in vitro, suggesting that the effects of SPDEF on tumor invasion are
mediated, in part, through the suppression of MMP9 and MMP13 expression. These
results demonstrate for the first time, in any system, that SPDEF functions as
a tumor metastasis suppressor in vivo.
From Science Daily they state[9]:
Prostate cancer
doesn't kill in the prostate -- it's the disease's metastasis to other tissues
that can be fatal. A University of Colorado Cancer Center study published this
week in the Journal of Biological Chemistry shows that prostate
cancer cells containing the protein SPDEF continue to grow at the same pace as
their SPDEF- cousins, but that these SPDEF+ cells are unable to survive at
possible sites of metastasis.
"It's as if these cancer cells
with SPDEF can't chew into distant tissue and so are unable to make new
homes," says Hari Koul, PhD, investigator at the CU Cancer Center and
director of urology research at the University of Colorado School of Medicine,
the study's senior author.
Koul and his group discovered the
homesteading power of cancer cells that have lost SPDEF by introducing a gene
into cells that makes them glow in the presence of a dye, and then introducing
them into the bloodstream of animal models. Cells without SPDEF traveled
through the blood and successfully attached to tissue, surviving and so
fluorescing many weeks later when dye was introduced. However, cells with SPDEF
flowed through the blood but were unable to successfully establish new colonies
and so soon died out.
In fact, the protein SPDEF doesn't act
directly to allow cells to attach at possible metastasis sites, but is a
transcription factor that controls the production (or lack thereof) of two
other proteins MMP9 and MMP13.
These two downstream proteins work to
break down tissue, like a dissolving agent -- they are the cleaning crew that
clears space for new and different growth, and in the case of prostate cancer
metastasis they chip the tissue footholds that cancer cells need to create
micrometastases. "Given that MMP9 and perhaps MMP13 are also involved in
metastasis of several other cancers including lung, ovarian, breast and colon
to name a few, our findings could potentially have far-reaching consequences
outside prostate cancer," adds Koul
The group's continuing work points in
two directions. "First, we hope that the presence of SPDEF could help
doctors recognize prostate cancers that don't require treatment." If
future studies confirm the group's initial findings, the presence of SPDEF
could predict prostate cancers that are unable to metastasize and so unable to
kill.
These cancers could be left to run
their course without the use of treatments that sometimes carry difficult side
effects.
"And second," Koul says,
"we hope to regulate expression of this protein to remove prostate cancers' ability to metastasize." Koul
points to small molecules, gene therapy or nanodelivery as possible mechanisms
for introducing SPDEF into cells that lack the protein.
"With this discovery we have
opened a hopeful door into a future in which prostate and potentially other
cancers are unable to metastasize," Koul says.
From Stefan et al (2011)
the authors had stated the following about another ETS transcription factor,
PDEF, not to be confused with SPDEF. :
The prostate-derived ETS factor (PDEF) is the
latest family member of the ETS transcription factor family, although it is
unique in many aspects. PDEF was first described as an mRNA transcript highly
expressed in prostate tumor cells where it regulates prostate-specific antigen
gene expression and is an androgen receptor co-regulator.
PDEF expression is highly restricted to
epithelial cells and has only been found in prostate, breast, colon, ovary,
gastric, and airway epithelium. Strong preclinical evidence is emerging that
PDEF is a negative regulator of tumor progression and metastasis. PDEF
expression is often lost in late-stage, advanced tumors.
The induction of tumor aggressiveness in
response to the loss of PDEF is thought to be due to the plethora of
PDEF-regulated gene targets, many of which are known players in tumor
progression including tumor cell invasion and metastasis. These data have led
to the hypothesis that PDEF may function as a tumor metastasis suppressor.
In this review, we summarize what is known
about PDEF since its discovery over a decade ago and give a detailed overview
of PDEF-regulated gene products and the expression profiles of PDEF in clinical
tumor samples.
Thus many other ETS
transcription factors have similar roles. The therapeutic targeting of these
factors may be of significant merit.
The analysis of
SPDEF is interesting especially because it raises so many other issues.
1. SPDEF deals with
multiple other pathway elements from receptors to promoter factors and the
resulting complex pathway interactions demonstrate the need for having a
complete systems model.
2. No clear
therapeutic targets seem to be evident. Although the results are compelling the
complexity of the pathways and their interactions lead one to examine more
specific control points, since SPDEF by itself seems to be a multiple set of
paths leading to metastasis.
3. There is the
question of whether SPDEF can be prognostic and/or therapeutic. Many of the
prognostic tests use large banks of gene expressions to develop a single
metric. Oftentimes this metric can be useful but it also does not per se
reflect what process is defective and what cells are the most of concern. The
problem is that all too often when one samples a section of tumor that the
cells may have substantially different gene expression profiles. We have examined
technologies that allows the sampling of individual cells and creating a
profile of the tumor in broad profile terms, namely how many cells express what
genes (mRNA or proteins) and from that ascertaining prognostic measures.
4. The complexity of
the relationships between the ETS transcription factor SPDEF, the oncogene
Foxm1 and the MMD metastatic facilitators is of interest. It demonstrates a
“system” view of the cancer. The key questions are; when does this occur, in
what percent of the cells does this occur, and what is its prognostic value?
1.
Aronson, B., et al, Spdef
deletion rescues the crypt cell proliferation defect in conditional Gata6 null
mouse small intestine, BMC Molecular Biology 2014, 15:3
2.
Carver et al, ETS
rearrangements and prostate cancer initiation, NATURE| Vol 457| 12 February
2009, http://www.nature.com/nature/journal/v457/n7231/abs/nature07738.html
3.
Cheng, X, et al, SPDEF Inhibits Prostate Carcinogenesis by Disrupting a
Positive Feedback Loop in Regulation of the Foxm1 Oncogene, PLOS Genetics,
September 2014 | Volume 10 | Issue 9 , J. Biol. Chem. http://www.jbc.org/content/289/32/22020.full.pdf+html
(Withdrawn)
4.
Chiang, A., J. Massagué, Molecular
Basis of Metastasis, NEJM, V 359 2814-2823 2008.
5.
Davuluri, G., et al,
WAVE3-NFkB Interplay Is Essential for the Survival and Invasion of Cancer
Cells, PLOS ONE, www.plosone.org, 1
October 2014, Volume 9, Issue 10, e110627.
6.
Gelmann, E., Molecular
Oncology, Cambridge (New York) 2014.
7.
Deutsch, E., et al,
Environmental, genetic, and molecular features of prostate cancer, THE LANCET
Oncology Vol 5 May 2004.
8.
Jamaspishvili, T., et al, Urine
markers in monitoring for prostate cancer, Prostate Cancer and Prostatic
Diseases (2010) 13, 12–19
9.
Kalin, T., et al, Increased
Levels of the FoxM1 Transcription Factor Accelerate Development and Progression
of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice, Cancer Res. 2006
February 1; 66(3): 1712–1720.
10. Marks, F., et al, Cellular Signal Processing, Garland (New York)
2009.
11. Mintu Pal, Sweaty Koul and Hari K. Koul, (SAM) pointed
domain-containing ETS transcription factor (SPDEF) is required for E-cadherin
expression in prostate cancer cells, 2014, 289:22020.
12. Pal, M., et al, The Transcription Factor Sterile Alpha Motif
(SAM) Pointed Domain-containing ETS Transcription Factor (SPDEF) Is Required
for E-cadherin Expression in Prostate Cancer Cells, http://www.jbc.org/content/288/17/12222.long
April 26, 2013 The Journal of Biological Chemistry, 288, 12222-12231.
(Withdrawn)
13. Pestel, R., M. Nevalainen, Prostate Cancer, Humana, 2008.
14. Penny, K., et al, Association of KLK3 (PSA) genetic variants
with prostate cancer risk and PSA levels, Carcinogenesis vol.32 no.6
pp.853–859, 2011.
15. Riley, T., et al, Transcriptional control of human p53-regulated
genes, Nature Reviews Molecular Cell Biology, Volume 9, May 2008.
16. Schrecengost, R., K, Knudsen, Molecular Pathogenesis and Progression
of Prostate, Seminars in Oncology, Vol 40,No3, June2 013, pp244-258.
17. Stefan, J., et al,
Prostate derived ETS factor (PDEF): a putative tumor metastasis suppressor,
Cancer Lett. 2011 Nov 1; 310(1):109-17. Epub 2011 Jun 29.
18. Stefan, J., et al, The
transcription factor SPDEF suppresses prostate tumor metastasis, First
Published on July 2, 2012, doi: 10.1074/jbc.M112.379396 jbc.M112.379396. JBC.
19. Tomlins, S., et al, ETS
Gene Fusions in Prostate Cancer: From Discovery to Daily Clinical Practice,
European Urology, 2009. doi:10.1016/j.eururo.2009.04.036
20. Turner, D., The Role of ETS Transcriptional Regulation in
Hormone Sensitive and Refractory Prostate Cancer, The Open Cancer Journal,
2010, 3, 40-48.
21. Turner, D., et al, Mechanisms and functional consequences of
PDEF protein expression loss during prostate cancer progression, Prostate. 2011
December; 71(16): 1723–1735. doi:10.1002/pros.21389.
22. Watson, D., et al, ETS Transcription Factor Expression and
Conversion During Prostate and Breast Cancer Progression, The Open Cancer
Journal, 2010, 3, 24-39
23. Wasylyk B1, Hagman J, Gutierrez-Hartmann A., Ets transcription
factors: nuclear effectors of the Ras-MAP-kinase signaling pathway. Trends
Biochem Sci. 1998 Jun; 23(6):213-6.
24. Yordy, J. and Robin C Muise-Helmericks, Signal transduction and
the Ets family of transcription factors, Oncogene (2000) 19, 6503 http://www.nature.com/onc/journal/v19/n55/pdf/1204036a.pdf
[1]
See Marks et al p 405. As adapted.
[3]
See Jamaspishvili et al, Matrix metalloproteinases (MMPs) have been
implicated in invasion and metastasis of human malignancies. Moses et al. used
substrate gel electrophoresis (zymography) to determine MMPs in the urine of
patients with a variety of cancers. MMP9 yielded better sensitivity (64%) than
MMP2 (39%) for CaP whereas specificities (84 and 98%, respectively) were
calculated from controls of both sexes. The same group also detected several
unidentified urinary gelatinase activities with molecular weights 4125 kDa and
recently used chromatography, zymography and mass spectrometry for their
identification. The approximately 140, 4220 and approximately 190 kDa
gelatinase species were identified as MMP9/TIMP1 complex, MMP9 dimer and
ADAMTS7, respectively. MMP9 dimer and MMP9 were independent predictors for
distinguishing between patients with prostate and bladder cancer.
[5] From NCBI: The
androgen receptor gene is more than 90 kb long and codes for a protein that has
3 major functional domains: the N-terminal domain, DNA-binding domain, and
androgen-binding domain. The protein functions as a steroid-hormone activated
transcription factor. Upon binding the hormone ligand, the receptor dissociates
from accessory proteins, translocates into the nucleus, dimerizes, and then
stimulates transcription of androgen responsive genes. This gene contains 2
polymorphic trinucleotide repeat segments that encode polyglutamine and
polyglycine tracts in the N-terminal transactivation domain of its protein.
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