Daniel Evans says the focus on foreign investment is undermining the Welsh economy.
The Welsh economy is once again performing badly. The Welsh news has a distinct groundhog day quality, such is the steady stream of horror stories about Wales' desperate economic situation.
This is not a new problem. Wales has been one of the most impoverished regions of the UK (and indeed Western Europe) for much of the twentieth century. Sadly, this is unlikely to change any time soon.
The Welsh Labour government has increasingly focused on foreign direct investment (FDI) as its main solution to Wales' problems). FDI is widely celebrated in Wales and generally seems to be viewed as a panacea to all our woes. This way of thinking seems to be accepted by all parties.
And why not? After all, the term investment conjures up images of raising people up, of improving things.
But this way of thinking fundamentally misunderstands capitalism. Wales' persistent poverty is not an unfortunate accident, but is an inevitable and indeed a necessary feature of the capitalist system. As Calvin Jones brilliantly noted previously on clickonwales. In order to change, we first need a grasp of history and the nature of capitalist development. In particular, we need to understand Wales' function within global capitalism.
Capital's inherent mobility means that firms are never tied to one particular region. Once they have squeezed as much profit as possible out of a region, they have the ability to move to new regions at a moment's notice. Moving around rather than settling in a particular place may seem counter-productive, but it is vital to realise that the current model of capitalism is based on a short termist version of carpet bagging. This mobility means that FDI can be thought of as a wave breaking on the beach: investment washes over an area, bringing jobs and development (exemplified by 'boom towns'). Yet this development is necessarily temporary: once the region is no longer profitable (perhaps labour may be cheaper in a different area, or perhaps workers are attempting to organise themselves and to demand better working conditions and therefore eating into profit), capital will flee, leaving behind devastated communities, the detritus and sediment left behind by the retreating wave.
Capitalism ultimately creates for itself a 'reserve' of places, in a fashion analogous to the aforementioned industrial reserve army of workers. So just as more workers than necessary are required (so that the reserve workers may be thrown into the breach when required, and so that existing workers' wages can be suppressed), so there are more regions (i.e. concentrated pools of labour) than necessary available to capitalism. There will never be enough work to go around, and this is particularly the case in our post-industrial epoch.
These places which are left behind constitute what Richard Walker calls the lumpen geography of capitalism. The term 'lumpen' comes from Marx's concept of the lumpen-proletariat, and refers to a condition of perpetual marginality and precariousness. In other words, the 'precariat' tend to be concentrated in certain regions.
Just as different workers perform different functions on the production line, different regions perform different functions within the larger mosaic of capitalist production. So capitalism in fact needs these depressed, undeveloped regions- they are not an accident, just like unemployment is not an accident.
Firms 'investing' in Wales can enforce the employment relation they choose: whereas in other regions they may potentially have had to deal with higher worker expectations and a less desperate workforce which demands better working conditions, in Wales everything is entirely on their terms. So 'investor' firms can pay workers less, they can hire and fire workers at will, and so on. The permanently low labour costs in Wales means firms can make more of a profit.
Logically, the jobs which are created in lumpen regions will almost always be unskilled or semi-skilled, on top of being necessarily temporary. Again, this is the case in Wales. What's more, firms can keep coming back to Wales- they know that if they need to establish a branch plant there will always be cheap, compliant labour here. Wales' 'product', its 'unique selling point' is precisely its desperation.
Lumpen regions compete against each other for FDI, for the 'privilege of being struck by lightning'.
Where desperation is all pervasive, whoever secures these 'jobs' through 'investment' will necessarily win over the populace. This is why attracting FDI very much suits the Welsh Assembly. It does not matter that such investments are unwise. Mark Lang poses the question 'why grow your local economy in a sustainable manner when you could just attract multinationals and create 2726 new jobs instead?' The answer is simple: the desire to attract headlines and to maintain political control of Wales.
Whilst Wales' stagnation is not good for the folk who live there, it is extremely virtuous for capitalism and for local political elites. As long as there is a vested interest in it remaining poor, Wales' poverty will continue.
FDI is a false idol. The decision to invest in Wales is not benevolent, as portrayed in the press, but driven solely by profit. It is parasitic: firms come in, make a profit, then leave. They only stay if the Welsh government, desperate to avoid bad press, provides them with ridiculous subsidies from the public purse. It is imperative that we ask radical questions and interrogate the neo-liberal orthodoxy which has caused misery for much of the world's population.
In this feature-length interview, Katy Huckle talks to Dr Ludivine Petetin from Cardiff University about the impact of Brexit on supply chains and trade.
Quite so, '…. there is a vested interest in remaining poor, Wales' poverty will continue'.
Ill-bred, under-educated, talentless youth roaming the streets while the parents relax at home drinking and smoking away the proceeds of their weekly welfare cheques.
Whilst capital is mobile so is labour, you don't mention the counter impact of this. If people don't choose to 'get on their bikes' then local supply quickly exceeds demand suppressing wage levels. Remember all those electricians and fitters who worked down the mines ? Well the smarter ones went out to work in Australia and are doing very nicely thankyou working in Australian heavy industry and running vineyards in the Barossa valley as a sideline.
I do agree that public subsidy to industry is counter productive. Too often, particularly here in Wales, economic development funding goes into basket case initiatives/enterprises that are flawed from the outset and wouldn't get off the ground in a pure market. Let's face it if you are of the calibre of one of our captains of industry or of a leading private equity executive you are unlikely to be found kicking your heels in somewhere like Pembrokeshire County Council's Economic Development Unit ! Public bodies are inevitably going to have second rate players in this area so will always lose the game. Best thing in those circumstances is not to be in the game.
Government involvement in this field should stop at building communications infrastructure (including telecoms) that facilitates movement of people to work.
Genuine question: How would you spend the FDI budget instead to achieve long term sustainable economic growth?
I congratulate Dr Evans on his contribution. I'm not going to comment at length, my views on the failings of FDI in Wales are well known and have been widely published. Indeed as long ago as 1996 the Western Mail published an article written by me entitled "How Inward Investment is Failing our Economy.." Not surprisingly it received considerable negative response, not least in a radio interview with Vincent Kane who attempted to rubbish my argument.
The thinking percolates down to a council level. Tesco and M &S are seen as the primary engines of growth for Aberystwyth I suggest to the detriment of more sustainable long term jobs underpinned by a excellent (not withstanding ….) University and a body of dynamic of people in the area who if they had the infrastructure would start to create some quality jobs, rather 6.50 an hour for 12 hours a week at Screwfix.
Karen's observations may raise a grimace of recognition and resonate with discussions around under-achievement and lack of ambition. Daniel's Marxist critique of FDI is no more than just that. Wales lacks the funds to dig itself out of the current hole. For the foreseeable future it will rely on FDI so we better get better at it. Bring back the WDA and require Welsh Labour to issue a self-denying ordinance on interfering with business, with which they have no affinity. They have enough to do addressing Karen's "talentless youth".
Never having heard of WISERD, two conclusions about it are possible on the basis of this article: (1) someone really wanted a title to fit the acronym; (2) it must be an organisation dedicated to the revival of 19th century Marxian economics – a bit like a less benevolent version of CAMRA.
Yet, if one ignores its dated underlying assumptions, the article does make some good points. Above all, in an overpopulated world, a nation or region that relies solely on the provision of cheap labour to foreign investors is not going to prosper.
However it fails to go on to the complete conclusion, which is that the foreign investment should therefore be considered not as an end in itself but as a stepping stone in the development of an indigenous enterprise culture, which need not rely on cheap labour.
Foreign investment should therefore not be despised, because it is a useful first step – but only a first step. Without foreign investors, building an enterprise culture would be much harder – indeed, the Welsh economy would collapse further.
Wales wasted a century whinging about global 'capitalism' – a better strategy would be to emulate those nations which learned to use it.
I guess this is a problem in Scotland, and in Cornwall, as well as in Wales, and that lots of people here think that Wales should develop its own businesses, small, medium, and large. I tend to think so too. It's difficult to avoid thinking that we are seen as a go-to place for pliant political administration, and appreciative cheap labour. Sadly, we are probably not alone; aren't there a number of fdi firms in England too? Isn't cheap labour just one of the criteria for fdi? I would ask what the other criteria are.
There are plenty of excellent teachers in Wales doing their best to educate young people. Post-sixteen training and education, and in-work skills development seem more patchy and fragile though. A willingness to exploit the young, and to devalue their potential doesn't help restore the economy.
It is not every day I agree entirely with JWR but his final sentence summarises everything that needs to be said on this topic. After all, comrades, what are the alternatives: get our local capitalists to do everything the rest of the world is doing, unaided? Or lead a global proletarian revolution? Time to stop shadow-boxing and face reality.
Or if you have a really refined sense of humour, try the Bath House Road scheme in Cardigan. Ceredigion did everything they could to force the scheme through even though at every step it was evident that the site had all sort of problems. Well, the super-duper market was meant to open in 2011 and as of 2015, they have even given up saying when they will stop waiting for the site to settle down. There is something distinctly odd about wanting to build a supermarket on a steep, unstable slope above a flood zone.
I trust the local sense of exasperation about this absurd approach does not settle down.
For me, the key paragraphs in JWR's intervention are 3 and 4. FDI has often been portrayed as being the endgame which leaves Wales in a somewhat passive position vis-a-vis economic activity. The practical question is how does that investment get retained here and who would have custody of it? One option is that of the Welsh Treasury which will come online in 2018. Also Wales does not have a National Bank though there are a few commercial ones and the recommendation of a regional investment bank in the pipeline. That said, there is a great deal more thought that needs to be given to this idea, but it is, in essence, the right strategy.
JWR is also right to say that FDI should not be despised. It is easy to slip into a victim mindset when we are a poor nation and badly in need of investment. The difficulty with resenting FDI is that it easily slips into a resentment of our need for it. Unfortunately that is a form of self-hatred that can only be corrosive.
FDI worked well for Wales on paper between the mid 1980s and the mid 1990s. Presumably English companies come under foreign as well – they are certainly made to feel foreign in some parts of Wales.
It wasn't FDI that failed Wales it was Wales that failed foreign investors because Wales could not give them the competitive environment in which to work they had been promised when they were lured here by the WDA.
It nearly worked but the plain fact is that Wales is not a competitive place to run a business and it never will be under current mismanagement and current mismanagement includes an alarming amount of the so-called specialist advice coming out of academia.
Hi all. Thanks for the comments: I'll try to address some of the issues which have been raised.
Firstly, to Karen and Robin Lynne: I feel you have drawn the wrong conclusions from my article. The problem with lumpen regions such as Wales is not the lack of ambition/talent within the region. That is an argument about fecklessness which is usually applied to the 'undeserving poor' (i.e. those demonized for being on benefits) and extrapolated to a whole country. My point is exactly the opposite- people in Wales, just like Wales as a whole, is not poor because of any inherent 'attitude problem' but because our continuing poverty is beneficial to capitalism and to local political elites. When your function within the world is precisely to remain poor, so that you may be exploited again and again, this is an accident of historical uneven development which has been perpetuated by politics, rather than a character defect.
Brian: I get your point, but I would argue precisely the opposite. Lumpen regions remain poor and people remain there precisely because they are not mobile. Individual people may emigrate, sure, but most of the communities are stuck and dependent. In theory perhaps it may be possible for large swathes of whole regions to uproot and move- this has happened in Ireland and in the South of Italy in the past- but this will never be enough to change the character of the region. If anything, the people who move are the young, something which will depress the region even further. So my point is that you can't extrapolate from a few individuals. Walker in fact argues that labour in these regions is held hostage by global capitalism- people stay precisely because they are desperate and they think (correctly) that low paid employment (but employment nonetheless) will be just around the corner. Little do they know that any jobs that move in will be low skilled and temporary. But of course people who need to put food on the table cannot really afford to think long term, they do not have that luxury.
JWR: Thanks for your comments. Far from being outdated, my article is a very condensed and simplified version of the work of very contemporary human geographers such as David Harvey, Richard Walker etc That is, capitalists and socialists alike agree about the nature of capitalism and uneven regional development- they disagree about what is to be done.
On one level I agree with your point about an 'enterprise culture'. I obviously disagree that Wales' poverty is caused by a lack of ambition or entrepreneurial spirit: it is caused by structural weaknesses in its infrastructure and its position within the global market. Where I agree is that Wales has to begin to stand on its own two feet, but this first requires recognizing the barriers that stand in the way of this. First and foremost we must realise that Wales is, as Calvin Jones has pointed out, a dependent region. This is of course a legacy of colonialism and our uneven relationship with England. This is a fact that Labour historians and politicians will not accept. This dependency is exemplified by our horrendous transport links- George Monbiot has pointed out that only in former colonies do all the railways run like rivers to the metropole. This is the case in Wales where the rail network was (largely) created to serve the movement of raw materials from Wales to England. So now we have a situation whereby it is easy for people to travel West to East from Wales to England, but impossible for people in West Wales to get to North Wales without having to go to England. It is a ludicrous hangover and one which has to be corrected.
You can have the best enterprise culture in the world but without a proper rail, road or communications infrastructure you will get nowhere. The only way to (eventually- it will take decades) to reverse dependency is to invest in infrastructure and education.
The main thrust of my original article, but which was cut out of the final draft, was that the Labour party lack the political will to invest in these long term, unglamorous investments. Since they are obsessed with retaining their political hegemony in Wales at all costs, they instead will always seek short termist vote winning, headline friendly investments (low quality work or white elephants such as the moto track in Gwent or Wylfa). This short termism is desperately damaging to Wales' economy and natural environment but it allows the Labour party and their allies in the Welsh media to perpetuate the narrative that they are creating jobs (true, but the small print is these jobs are awful and temporary) and that anyone who contests their plans (i.e., Plaid), therefore hates working class people, doesn't want to bring prosperity to local people etc etc (witness their behaviour over Wylfa).


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New York Times Touts New Study to Resolve Mental Health Conflict with the Second Amendment
The front page of Sunday's New York Times led with "When the Right to Bear Arms Includes the Mentally Ill", a nearly 5,000-word essay by two journalists amping up the volume in the latest attack on the Second Amendment. The motive was clear from the beginning: there's a mental illness "loophole" in the law that allows crazies to walk the streets and something must be done about it.
The article opens with the story of a psychiatric patient, Mark Russo, who threatened to shoot his mother if police tried to take his arsenal of weapons he had cached at her home. He was off his meds for paranoid schizophrenia, said the authors, and that caused him to go crazy. But now that he's back on his meds, wrote the horrified investigators, he'll be able to get his guns back shortly. They added:
The Russo case highlights a central, unresolved issue in the debate over balancing public safety with the Second Amendment right to bear arms: just how powerless law enforcement can be when it comes to keeping firearms out of the hands of people who are mentally ill.
The Gun Control Act of 1968 restricts "prohibited persons" from purchasing firearms, including those addicted to "controlled substances", those involuntarily committed to a mental institution or who have been judged to be incompetent or dangerous, and those who have received a verdict of not guilty by reason of insanity. The "problem", according to the authors, is that the states have differing and constantly changing definitions of mental illness, and many of them don't report those who suffer from such illness to the national gun registration database, the NICS.
This "loophole" puts the public in danger, according to the authors who invested hundreds of hours poring over more than 1,000 court and police records "in which guns were seized in mental-health-related episodes." What they found were cases where individuals deemed mentally ill were allowed to have their weapons returned to them even though they might possibly be dangerous.
There was the story of Ryan Piatt, a veteran of the war in Afghanistan, who suffered from depression, anxiety and paranoia upon his return to the states. He had done simply awful things, according to the reporters, such as making "intimations of violence to his psychiatrist" – the authors failing to note exactly what they were – and trying to renounce his citizenship. Despite these extreme examples of mental instability, according to the writers, Piatt was able to have his guns returned to him.
There was one Curtis Zetterman, a resident of Caribou, Maine, who, according to the article, "was sent to a hospital after talking about shooting people" and "later accused of threatening a neighbor with a gun." The charge that Zetterman illegally possessed the firearm was dismissed and he never went to jail. This conflicts with the story reported by the Bangor (Maine) Daily News (BDN) which the reporters apparently overlooked while doing their research. According to BDN, the judge in the case, U.S. District Court Judge John Woodcock, sentenced Zetterman to five years of probation after he pleaded guilty to the charge, adding that if the defendant ever possessed a gun again, "nobody will prevent me from sending you to jail."
Apparently that didn't fit the narrative and so the Times' story was modified to make it fit.
Reference was made in the article to a study conveniently released earlier in December from a consortium of college professors, mental health "experts" and gun control advocates, innocuously titled "Guns, Public Health, and Mental Illness: An Evidence-based Approach for State Policy." That study was released following a conference at the University of Virginia more accurately entitled "From Virginia Tech to the Navy Yard: New Approaches to Keeping Guns from Dangerous People." Said UVA law professor Richard Bonnie, head of the conference and leader of the consortium:
We want to make a contribution to this debate by finding common ground on policy proposals that would really have a prospect of reducing the risk of gun violence – not only among people with mental illness, but also among other people who are at an elevated risk of gun violence. (emphasis added)
The time is right. These are sensible recommendations. And there's nothing [in the report] that's too big a stretch…
There's going to be a set of policies that relate to the federal background check system and we want to make that more effective.
Just to clarify the report's intent to address mental illness, restrictions on gun ownership and enhanced background checks, another professor who contributed to the consortium's study, Johns Hopkins professor Shannon Frattaroli, said:
[Despite the fact that] people with mental illness are responsible for only about 4 percent of the violence in society … we want to do a better job of keeping guns out of the hands of people with mental illness … but we think the focus should not be exclusively on people with mental illness.(emphasis added)
That the consortium's study was going to be polemic rather than balanced was clear in its introduction:
These rare events [the Navy Yard shooting, Sandy Hook, etc.] need to be seen in the context of the broader problem of firearms-related injury and mortality in the population: an estimated 31,000 people die and 74,000 suffer non-fatal gunshot injuries each year.
On the day of the massacre at Sandy Hook Elementary School in December, 2012, an estimated 85 other people died of gunshot injuries throughout the US, including gang shootings, intimate partner attacks, and suicides, another 85 died the day before, and the day after.
Mental illness is only the excuse for this gathering of left-wing professors: it's much more about using it as an opening wedge to get at the real problem: citizens owning guns. From the report:
Although major mental illnesses are associated with increased risk of violent acts, policies targeted at this group alone will be ineffective at reducing the vast majority of violence towards others… (emphasis added)
Current federal policies do not adequately reduce access to firearms by individuals … future gun violence prevention policy efforts should use evidence-based criteria shown to increase the risk of violence … to disqualify individuals meeting those criteria from purchasing or possessing firearms.
In addition, new mechanisms to remove firearms from individuals at immediate risk of harming themselves or others should be created. (emphasis added)
In the report's summary full evidence of the target – innocents currently legally owning guns – is in view:
Successful implementation of any firearm prohibition or expansion of state law depends upon a) states entering all relevant records into the NCIS firearm background check system, and b) all firearm sales requiring a background check.
With the Times' full-throated attack on the Second Amendment now on display, and its link to a report issued by a gaggle of liberal professors comes a lesson from history. When President George H. W. Bush was running for reelection in 1992, rumors surfaced about a movement to remove Vice President Dan Quayle from the ticket. Insiders manufactured a poll that allegedly showed Quayle as a liability, despite there being no such poll in existence. As John McManus, President of the John Birch Society, wrote in 2003:
Lying is not out of the question. In his 1995 memoir, Call the Briefing, former presidential Press Secretary Marlin Fitzwater told of a plan to concoct a poll to create a supposed need to dump Vice President Dan Quayle for the 1992 Bush reelection effort.
Secretary of State James Baker and campaign manager Robert Teeter actually created a fictitious poll to demonstrate that Quayle was a drag on the ticket. Fitzwater wrote that the president's son, George W. Bush, was in on the plot.
The fact that Quayle stayed on the ticket misses the point, according to McManus. It illustrates instead the willingness of insiders to create such a poll, counting on a gullible public to buy it:
Though this planned fraud wasn't employed and Quayle wasn't dumped, these men were willing to sway the public's attitude by means of a fake poll. They intended to rely on the fact that a skyrocketing number of Americans allow themselves to be swayed by real or concocted popular opinion.
The parallels to the Times' story and the consortium's study are obvious: once a decision has been made to promote a point of view, evidence must be conjured to support it. Once that support has been manufactured, the next step is to lend if credence, preferably through a mouthpiece of mainstream journalism. If that gains purchase in the public mind, all that is needed to complete the loop is proposed legislation to solve the "problem" from someone favorable to the cause.
Readers should therefore not be surprised if Senator Charles Schumer, the notorious anti-gunner from New York, would then offer a bill to close the loophole, in the name of mental illness, forcing states to report all such cases to the NCIS, and expanding background checks to everyone at the same time.
firearms Fraud George W. Bush Gun Control John Birch Society legislation Liberal media mental health mentally ill power Second Amendment the law War
This entry was posted	on Monday, December 23rd, 2013 at 2:09 pm	and is filed under Politics, Second Amendment. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

redpajama_set_name: RedPajamaCommonCrawl


A man, I've encountered on a beach by accident, who's suffering from Parkinson's disease.
Wayan is mostly walking along the beach collecting seashells and small coconuts. The first is a basis for his natural hand-made bracelets, each of those takes 1,5 — 2 hours, and the second — for coconut bracelets, each piece of which he cuts manually.
I say it again, Wayan has Parkinson's disease that means his head and arms are struggling to be calm and easy controlled. His speech also is pretty slurred. Surprisingly, he is able to communicate in English clearly though. I'd say he has to.
In spite of hurdles and difficulties, Wayan is spending hours on making bracelets. He's deeply immersed in this activity and really bothering to create items perfect, so each detail of his arms — a kind of masterpiece, as for me and not only for me.
If you are aware of Parkinson's affect the body and abilities, then you accurately realize how sometimes challenging to express emotions or do some motions for people with this disease. As a example, if you were a witness to Wayan's riding a bike, you would be immediately in shock, as he seems not to control anything ahead of and around – after all his head is always up.
Undoubtedly, this man could've complained about so many factors, he's not doing it at all though.
His eyes are full of life. Full of hope. Full of love to people.
To be open, every time I come to the beach I hope to encounter him. To ask him to unpack all goods and begin our dialogue where there's almost no place for bargain or something of that sort.
In the reality, some describe him as «in physical disorder», however it's more preferable to saying that «the inner order» is much more significant. Certainly, Wayan is in tremor outwardly, although inwardly he is in total quiet state. He has to make himself smile despite his facial muscles that are trying to limit. Moreover, he has to make himself interact with people being aware that there is a chance to be misunderstood.
Nevertheless, he doesn't have to make himself live a normal life as the life is not only physical process. And what is the normal?
Being beside him is seeing a pure bliss, a pure life. That passage is not about Parkinson's disease. It is about rather the man's inner strength.
The feeling of life, if you will.


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Cheating, tweaking the data and the view of academic biomedical output from industry
I talk occasionally with an exceptionally bright former Ph.D. student of mine who works now in pharma. I wanted my next post to be positive--there is no lack of good things to say about the nation's biomedical research enterprise--but a conversation I just had with him prompted this post instead.
My conversation with my former student exactly mirrored discussions I have had with other scientists in pharma and biotech in this regard: a high proportion of the output from academic labs can't be reproduced and is thus worse than useless. "Worse" because it sends companies down dead-end avenues, wasting money and scientific talent that otherwise could be pursuing potential disease therapies with a chance of working. An article in the Wall Street Journal, quoting Bruce Alberts (a prominent scientist and former editor of a prestigious research journal), puts it this way:
Two years ago, a group of Boston researchers published a study describing how they had destroyed cancer tumors by targeting a protein called STK33. Scientists at biotechnology firm Amgen Inc. quickly pounced on the idea and assigned two dozen researchers to try to repeat the experiment with a goal of turning the findings into a drug.
It proved to be a waste of time and money. After six months of intensive lab work, Amgen found it couldn't replicate the results and scrapped the project.
I was disappointed but not surprised," says Glenn Begley, vice president of research at Amgen of Thousand Oaks, Calif. "More often than not, we are unable to reproduce findings" published by researchers in journals.
This is one of medicine's dirty secrets: Most results, including those that appear in top-flight peer-reviewed journals, can't be reproduced. "It's a very serious and disturbing issue because it obviously misleads people" who implicitly trust findings published in a respected peer-reviewed journal, says Bruce Alberts, editor of Science. . . .
Drug manufacturers rely heavily on early-stage academic research and can waste millions of dollars on products if the original results are later shown to be unreliable. Patients may enroll in clinical trials based on conflicting data, and sometimes see no benefits or suffer harmful side effects.
The WSJ article cites a study by the pharmaceutical company Bayer that found that company scientists had to halt 64% of early drug projects based claims in the literature due to inability to replicate published results:
A lot has been written about scientific fraud and how (unsurprisingly) it is probably more prevalent in the highest-prestige journals, about how the scientific literature is biased towards positive results and about the pressures of "publish or perish." I don't have anything new to say about these pressures on academic scientists: pressures that underlie the problem of there being so much garbage in the literature. I will only say this: the "soft money" system that makes scientists' livelihood dependent on winning grants plus the current brutal funding environment is a perfect formula for ensuring increased levels of scientific cheating and the resulting waste and damage to efforts to cure diseases.
Posted by GrantSlave at 3:35 PM
This statistic really makes me curious. I mean, although I'm sure some fraud exists, I doubt it is as high as 64% of scientists. Do you have any ideas about this?
I've tried to think of a couple of answers for myself. Maybe it reflects the small sample sizes used (at least in animal work) in academia leading to false positives? Or grad students performing new techniques that they don't fully understand? But I am just speculating.
GrantSlave August 1, 2013 at 11:40 AM
Thanks for your comment. I agree that 64% seems too high to be accounted for by outright fraud, and I think your ideas as to why this happens are good ones. Also I think that biomedical scientists--given the various pressures (such as pressure from PIs on postdocs) may be too ready to disregard what they consider outlier data or outlier results or not attempt to spend the time and money to ensure that "good" results can be reproduced.
I am going to quote from a News Blog from the journal Nature below. First I want to provide the link because it also addresses this issue; interersted readers may want to skip my extended outake and go right to the article:
http://blogs.nature.com/news/2011/09/reliability_of_new_drug_target.html
"An unspoken industry rule alleges that at least 50% of published studies from academic laboratories cannot be repeated in an industrial setting, wrote venture capitalist Bruce Booth in a recent blog post. A first-of-its-kind analysis of Bayer's internal efforts to validate 'new drug target' claims now not only supports this view but suggests that 50% may be an underestimate; the company's in-house experimental data do not match literature claims in 65% of target-validation projects, leading to project discontinuation.
" 'People take for granted what they see published,' says John Ioannidis, an expert on data reproducibility at Stanford University School of Medicine in Palo Alto, California. 'But this and other studies are raising deep questions about whether we can really believe the literature, or whether we have to go back and do everything on our own.'
For the non-peer-reviewed analysis, Khusru Asadullah, Head of Target Discovery at Bayer, and his colleagues looked back at 67 target-validation projects, covering the majority of Bayer's work in oncology, women's health and cardiovascular medicine over the past 4 years. Of these, results from internal experiments matched up with the published findings in only 14 projects, but were highly inconsistent in 43 (in a further 10 projects, claims were rated as mostly reproducible, partially reproducible or not applicable; see article online here). 'We came up with some shocking examples of discrepancies between published data and our own data,' says Asadullah. These included inabilities to reproduce: over-expression of certain genes in specific tumour types; and decreased cell proliferation via functional inhibition of a target using RNA interference.
Irreproducibility was high both when Bayer scientists applied the same experimental procedures as the original researchers and when they adapted their approaches to internal needs (for example, by using different cell lines). High-impact journals did not seem to publish more robust claims, and, surprisingly, the confirmation of any given finding by another academic group did not improve data reliability. 'We didn't see that a target is more likely to be validated if it was reported in ten publications or in two publications,' says Asadullah.
Although the analysis is limited by a small sample size, and cannot itself be checked because of company confidentiality concerns, other studies point to similarly sobering conclusions. In one study researchers tried, and largely failed, to repeat the findings of published microarray gene expression analyses by working directly from the data sets the original conclusions were drawn from (Nature Genet. 41, 149–155; 2009). In another study, when an identical sample of proteins was sent to different proteomics laboratories, the vast majority failed to independently, and therefore reproducibly, identify all of the component proteins (Nature Methods 6, 423–430; 2009)."
Cheating, tweaking the data and the view of academ...
Learning from Spitzer and Weiner
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Maybe some doubts arising about the Medical Scient...


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Civil And Personal Injury Litigation; And Business Consulting
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Mr. Gailen has been practicing law since 1980 and has been a very successful trial attorney since the first week he became an attorney.
Over the course of the 40 years of practice as of May 2020, Mr. Gailen has litigated more than 200 trials — including jury trials and court trials in both civil and criminal cases, and court trials in Family Law matters in particular close to 30 of those years. Also, Mr. Gailen has litigated what could conservatively be considered to be thousands of court hearings in all areas of his practice including motions, orders to show cause, request for orders, restraining orders, arraignments, preliminary hearings, trial setting conferences, pretrial conferences, mandatory settlement conferences, final status conferences, readiness conferences, filings, hearings and trials in Los Angeles Superior Court (and almost all if not all the branch courts), Ventura Superior Court, Orange County Superior Court and most other Southern California Courts, Department of Children's Services courts, Juvenile Dependency hearings and other types of hearings in state court, the California Court of Appeal and U.S. District Court (9th Circuit). Mr. Gailen has also represented clients through the years in other states and federal court circuits throughout the United States — including Nevada, New Mexico, Oregon, Illinois, Minnesota and Colorado.
Although Mr. Gailen has been practicing law since 1980, he then formed Scott Gailen, Inc. a Professional Law Corporation in 1987 with the philosophy that clients are best served by providing them with the highest work ethic, diligence and skills to ensure the most successful results possible.
Mr. Gailen has earned the reputation for honesty and ethical behavior while zealously representing clients — and by filing the specific motions, documents and discovery — that are necessary to support their legal positions as the firm fights for their clients in each facet of their cases.
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TOKYO • What kind of financial blow has the widening scandal surrounding Carlos Ghosn delivered to Nissan Motor Co and Renault SA?
Investors are about to get a glimpse when closely watched earnings releases come out this week.
Then there's the sluggish sales in China and the US, Britain's potentially jarring exit from the European Union (EU) and huge investments in electric and autonomous vehicles hovering over the entire auto industry.
Taken together, these negatives could leave the alliance partners falling behind competitors such as Volkswagen AG and Toyota Motor Corp in the race to adapt to the changing terrain. The risks may be greater for Nissan since the lion's share of allegations against Ghosn reflect his tenure there, and its business challenges are tougher than Renault's.
Nissan is struggling in China and the US, and it owns the largest automotive plant in Britain. The Yokohamabased company reports earnings today, providing the first indications of its performance since Ghosn's arrest in November.
Renault's earnings are due two days later, just after an internal probe found Ghosn may have improperly used a company sponsorship deal to help pay for his Marie Antoinette themed wedding in Versailles.
"Automakers are starting 2019 with a hangover," said Pierre Quemener, an analyst at MainFirst Bank AG in Paris. As for the Renault-Nissan alliance, "there's not much upside to be expected from it at this point".
Nissan's operating profit is forecast to fall 10% to ¥517.1 billion (RM19.14 billion) in the fiscal year ending in March, the lowest in five years, according to analysts surveyed by Bloomberg.
On Thursday, Renault will probably report an 8.8% decline in operating profit for last year to €3.47 billion (RM16 billion).
"If it releases a profit warning for 2019, similar to Daimler's, we will most probably see the share price of both Renault and Nissan falling further," he wrote in an email.
For years, Nissan's earnings dwarfed Renault's, making a significant contribution to the French carmaker's bottom line. A bigger global footprint and sales 46% larger than Renault's may be motivating Nissan CEO Hiroto Saikawa's push to rebalance their alliance — which includes Mitsubishi Motors Corp — to give his company more say in strategic decisions.
Shares of both companies are down sharply since Ghosn's arrest on Nov 19. Renault was little changed at mid-afternoon in Paris yesterday, and has lost 31% in the past year. Nissan fell 1.5% earlier in Tokyo and has declined 19% over the last 12 months.
Sales for Nissan's Chinese joint venture dropped 4% in the October- December quarter as the world's largest auto market saw its first slowdown in decades. Nissan relies heavily on China, which is estimated to become its largest market.
The company plans to invest US$9 billion (RM36.65 billion) and introduce 20 electrified models there within three years.
Nissan has to fend off Honda Motor Co and Toyota, which are accelerating their China pushes. That's complicated by last month's departure of chief performance officer Jose Munoz, a Ghosn ally with responsibilities for China. Munoz hasn't been replaced.
Nissan's US sales plunged 19% in January after slumping 6.2% all of last year. Saikawa is renouncing Ghosn's strategy of juicing sales by lavishing incentives and instead wants to prioritise profitability. Nissan is cutting as many as 700 workers at a Mississippi factory because of slowing truck and van sales.
It also refrained from setting a sales target for the current midterm plan.
The carmaker is looking into the US business as part of its internal probe, with particular focus on how business was awarded to dealers.
Saikawa didn't attend last month's Detroit auto show, and his company didn't introduce any major new production models. Renault is absent from the US.
Brexit is a bigger risk for Nissan than most carmakers because its Sunderland plant makes three of every 10 cars in the UK. Nissan cited growing doubts about the UK's split from the EU in its decision to scrap plans to build the X-Trail SUV in the country. Instead, it will export them from Japan.
Renault said it wasn't building stocks in the UK, where it sold less than 3% of its cars last year. A bigger source of worry is Europe's pending stricter emission regulations, which weighed on sales and prompted carmakers to use discounts to reduce inventory.
In key technologies for the future, Nissan and Renault need to cooperate more. The alliance is working with China's Dongfeng Motor Group Co Ltd to locally produce an affordable electric crossover, based on a budget SUV Renault developed for India.
Nissan's battery-powered Leaf is the best-selling electric car, spawning a wave of competing models from traditional automakers and start-ups like Tesla Inc. Those rivals chipped away at the Leaf's lead with key advancements, and Ghosn's detention prompted Nissan to postpone the updated model's debut in Tokyo.
A deal between the three carmakers and Alphabet Inc's self-driving unit could include making driverless taxis, one of the people said.


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https://apnews.com/0b6cf6881e6a4f76b1aa0519093aada8
Abdelaziz Bouteflika
5 candidates for Algeria's contested presidential vote
By AOMAR OUALINovember 2, 2019 GMT
Algerian demonstrators take to the streets in the capital Algiers to protest against the government, in Algeria, Friday, Nov. 1, 2019. Police struggled Friday to contain thousands of Algerian demonstrators surging through the streets of the capital to protest next month's presidential election and celebrate 65 years since Algeria's war for independence from France. (AP Photo/Toufik Doudou)
ALGIERS, Algeria (AP) — Algeria's electoral body Saturday announced five candidates for the Dec. 12 presidential election, including two former prime ministers and all products of the system challenged by months of pro-democracy protests.
The electoral authority validated the candidacies of former prime ministers Ali Benflis and Abdelmadjid Tebboune, and two former ministers, one of them a moderate Islamist, plus the head of a small party.
The elections are to replace former longtime President Abdelaziz Bouteflika, forced to resign in April after protests and a stern warning from army chief Ahmed Gaid Salah, who has emerged as the country's authority figure.
Protesters had opposed Bouteflika's planned bid for a fifth term after 20 years in power and now want to dismantle the corruption-ridden system that kept him in office and the long-standing, if often shadowy, role of the military at the top. Bouteflika was Algeria's first civilian president since the nation's first leader after independence from France in 1962, Ahmed Ben Bella, was deposed in a coup.
Besides the two former prime ministers running in next month's presidential election, the other candidates are: former tourism minister and moderate Islamist, Abdelkader Bengrina; former culture minister and current interim secretary of the RND party that was in the governing coalition, Azzedine Mihoubi; and the head of the El Moustakbel (Future) party close to the FLN, also in the ruling coalition, Belaid Abdelaziz.
The announcement came a day after tens of thousands of Algerians marched for a 37th consecutive week to demand an end to Algeria's post-colonial political system. Protesters say they don't trust those currently in power to ensure democratic elections, citing their past links to Bouteflika.
The five who will run were among 23 people who tried to run for the presidency but fell short of the requirements. Rules for candidates included gathering 50,000 signatures from citizens on voting lists from at least 50 regions.


If you want to be in the know about what's going on at STAIR, you've come to the right place.
New Orleans, October 8, 2018 – The Board of Directors of Start the Adventure in Reading (STAIR) has announced the appointment of Shannon McCloskey Able as its new Executive Director, effective October 15.
Shannon has a wealth of nonprofit and volunteer leadership, communications experience as well as organizational, relationship building and strategic planning skills. As a native New Orleanian, she is acutely aware of the New Orleans educational system and its challenges.
Shannon served as President of the Junior League of New Orleans in 2015-16. In addition to her daily responsibilities as President, she developed programs and leveraged volunteers to meet the needs of the community. In addition, she worked closely with the Board and was the face of the organization to all key stakeholders and in the media. Shannon oversaw all grants, fundraisers and investments to ensure the financial success of the organization. Most recently, she chaired the very successful American Cancer Society Belles and Beaus Ball.
Since 1985 Start the Adventure in Reading (STAIR) has served more than 7,500 at-risk children from public elementary schools throughout the New Orleans area. Each school year, STAIR matches children with one-on-one volunteer reading tutors at no charge to their families or schools. To learn more about STAIR, please visit www.stairnola.org.
New Orleans Saints reveal of My Cause, My Cleats on November 28, 2017 for December 3 game against the Carolina Panthers. There is more information here.


How long have you been eco-friendly? I have been eco-friendly for about three and a half years now. The summer before my junior year of college in 2012, I was presented with a couple of documentaries that totally shifted my world views. I knew that with this new found information, I could no longer continue old habits. I had a responsibility to myself and to my environment to go vegan.
Why did you choose to be eco-friendly? I chose to become eco-friendly because I learned that when we destroy the land we live off of, we are essentially harming ourselves. Aside from the negative energies we internalize when consuming meats and dairies from animals that are abused, we are causing great harm to mother earth. Statistics say tat it takes 2,500 gallons of water to produce a pound of meat where it takes roughly 50 gallons to produce a pound of fruits or vegetables. Alongside that, we see that roughly forty pounds of soybeans are produced by the same amount of fossil fuels required to produce one pound of meat. As a result of all this, we are putting the planet through great stress and doing posterity a disservice.
I want for my great grandchildren to live in a green earth, and I knew that could be achieved if I did my part by not supporting a destructive lifestyle. Meats and dairy are no longer appealing after seeing what these animals went through and how much our environments hurts as a result of it.
What do you like about it? I like that I am not harming life by nourishing my body. I like that I have awareness that just because I am human, I am not the most important being on the planet. There was life that existed before I began my human experience that will also remain living after I transition on, and I need to respect that. I like that when I eat fruits and vegetables, I feel revitalized, positive, and thankful. I like that I can comprehend the inter-connectivity of all things in life on this rock and it's beautiful.
Did you face any challenges?If so, what was/is the biggest obstacle(s)? The only challenges I face when I went vegan was that I was criticized for sacrificing my culture and told that I would be at risk for being vitamin deficient. However, I quickly got over it by realizing that these are the same people who lead very unhealthy lifestyles. There is a saying, "misery loves company". Many times people would feel a lot more comfortable if you were doing what they are doing. When you reach a new space in the way you think and your conviction is strong, you will never concern yourself with misinformation and negativity.
Any tips/advice for someone looking to be more eco-friendly? I would tell that person to remain optimistic about the bigger picture. If you want to become eco-friendly, think about the ways in which posterity can benefit. Think about the life that shares the planet with you. Going vegan is just a small way you can be eco-friendlyand it is also a major first step. You are saving SO much when you become vegan. When you go vegan you are initiating a cycle of positive energy.
Going green can be complex. This discourages a lot of people. There's really no "right" way it's basically trying to do something than nothing at all. I sometimes feel like a green hypocrite. Do you feel that way sometimes? I totally understand where you are coming from. I never feel that way because I know that I am doing my part. Whether it be by going vegan it is a great effort on my part. I agree that a small action is better than no action at all. When one becomes aware, they will grow in their awareness and will want to do more. So I think we should be patient with ourselves and not be so judgmental.
You know I gotta ask, How long have you been natural and how do you keep it so FLY? HaHa! Thank You! I have been natural since October 2010. I have been through the whole "hair product junkie" phase for a year before realizing that I was natural for a reason. I need to keep things natural. So I only cleanse and condition with the AS I AM Coconut Co-Wash (effective and cruelty-free). I normally wash my hair in sections and air dry as much as possible.
During the drying phase, I grease my scalp and ends with a mixture of castor oil and vitamin E oil. For added moisture throughout the week, I spray my hair with a leave-in mixture of filtered water, lavender oil, peppermint oil, E.V. olive oil, and castor oil. I try to keep my hair stretched as much as possible as this helps prevent tangling and knotting. I also find that keeping it in one style for the week helps me maintain a detangled head of hair. That's pretty much it!
Is there anything you like to add? Well first off, thank you for allowing me to share your platform! I think that spreading awareness about eco-friendly lifestyles is a great way for people to really understand the gravity of the situation we are in on a global scale. I hope that your blog can continue to reach others for the better! Again, Thank You!


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Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern
Christian Hafner, Elena López-Knowles, Nuno M. Luis, Agustí Toll, Eulàlia Baselga, Alex Fernández-Casado, Silvia Hernández, Adriana Ribé, Thomas Mentzel, Robert Stoehr, Ferdinand Hofstaedter, Michael Landthaler, Thomas Vogt, Ramòn M. Pujol, Arndt Hartmann, and Francisco X. Real
PNAS August 14, 2007 104 (33) 13450-13454; https://doi.org/10.1073/pnas.0705218104
Christian Hafner
Elena López-Knowles
Nuno M. Luis
Agustí Toll
Eulàlia Baselga
Alex Fernández-Casado
Silvia Hernández
Adriana Ribé
Robert Stoehr
Ferdinand Hofstaedter
Michael Landthaler
Thomas Vogt
Ramòn M. Pujol
Arndt Hartmann
Francisco X. Real
For correspondence: preal@cnio.es
Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved July 2, 2007 (received for review June 5, 2007)
Activating mutations of the p110 α subunit of PI3K (PIK3CA) oncogene have been identified in a broad spectrum of malignant tumors. However, their role in benign or preneoplastic conditions is unknown. Activating FGF receptor 3 (FGFR3) mutations are common in benign skin lesions, either as embryonic mutations in epidermal nevi (EN) or as somatic mutations in seborrheic keratoses (SK). FGFR3 mutations are also common in low-grade malignant bladder tumors, where they often occur in association with PIK3CA mutations. Therefore, we examined exons 9 and 20 of PIK3CA and FGFR3 hotspot mutations in EN (n = 33) and SK (n = 62), two proliferative skin lesions lacking malignant potential. Nine of 33 (27%) EN harbored PIK3CA mutations; all cases showed the E545G substitution, which is uncommon in cancers. In EN, R248C was the only FGFR3 mutation identified. By contrast, 10 of 62 (16%) SK revealed the typical cancer-associated PIK3CA mutations E542K, E545K, and H1047R. The same lesions displayed a wide range of FGFR3 mutations. Corresponding unaffected tissue was available for four EN and two mutant SK: all control samples displayed a WT sequence, confirming the somatic nature of the mutations found in lesional tissue. Forty of 95 (42%) lesions showed at least one mutation in either gene. PIK3CA and FGFR3 mutations displayed an independent distribution; 5/95 lesions harbored mutations in both genes. Our findings suggest that, in addition to their role in cancer, oncogenic PIK3CA mutations contribute to the pathogenesis of skin tumors lacking malignant potential. The remarkable genotype–phenotype correlation as observed in this study points to a distinct etiopathogenesis of the mutations in keratinocytes occuring either during fetal development or in adult life.
senescence
benign tumor
Phosphatidylinositol 3-kinases (PI3Ks) are involved in the generation of the second-messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3). Three classes of PI3Ks are known. Class I PI3Ks are composed of a regulatory (p85) and a catalytic (p110) subunit. The Class IA subgroup proteins are involved in signaling from receptor tyrosine kinases upon growth factor binding, whereas class IB proteins signal from G-coupled receptors (1). The levels of PIP3 are also controlled by phosphatase and tensin homologue, a classical tumor suppressor protein with lipid phosphatase activity. PIP3 generated by the p110 catalytic subunit of class I PI3Ks is anchored to the cell membrane, leading to the binding of PKD through its plekstrin homology domain, its subsequent activation, and the downstream phosphorylation and activation of the survival kinase AKT. The PI3K pathway has been shown to play major roles in cell growth, proliferation, survival, and malignant transformation (2).
Four different p110 subunits (α, β, γ, and δ) have been identified, and all of them have transforming potential in vitro. Overexpression of WT p110 β, γ, or δ is oncogenic; by contrast, p110 α is oncogenic only when constitutively activated through point mutation (3). Indeed, activating somatic mutations have only been reported in the gene coding for the α isoform, PIK3CA, in a wide variety of human cancers, such as breast, colon, ovarian, and gastric cancer (4, 5). Somatic PIK3CA point mutations cluster in hotspots of exons 9 (helical domain) and 20 (kinase domain). These mutations result in a constitutive gain of function and confer oncogenic properties to mutated cells by deregulation of transcription and translation (6). The in vivo oncogenicity of mutant p110α carrying the most common hotspot mutations E542K, E545K, and H1047R has been recently demonstrated in a chicken model (7).
Epidermal nevi (EN) and seborrheic keratoses (SK) are keratinocyte-derived benign acanthotic skin tumors that never progress to acquire invasive features (Fig. 1). Both entities share clinical and histological characteristics. However, their natural history is very different. EN are congenital lesions that are present at birth or that develop early during childhood as localized epidermal thickening with hyperpigmentation (Fig. 1 A). EN follow frequently the lines of Blaschko and may vary in their extent from a single linear lesion to widespread and systematized involvement. It has been proposed that EN result from mosaicism in the skin (8). By contrast, SK are rare in young people. Their prevalence increases with age, and they can be identified by age 50 in 80–100% of healthy individuals (9), although there is wide variation in the number of lesions. SK present as well demarcated brownish plaques with a verrucous surface predominantly localized in the head, neck, and trunk (Fig. 1 B). EN and SK share many histological characteristics such as acanthosis, papillomatosis, and variable degrees of hyperkeratosis and hyperpigmentation (Fig. 1 C and D).
Morphological similarities of linear lesions of congenital EN from a child following Blaschko's lines (A) and SK from an elderly patient (B). At the microscopic level, both lesions are characterized by acanthosis, papillomatosis, and variable degrees of hyperkeratosis and hyperpigmentation (C, EN; D, SK).
Recently, activating mutations in the gene coding for FGF receptor 3 (FGFR3) were identified in both EN and SK (10, 11). The same mutations detected in these skin lesions have previously been identified as somatic alterations in several types of human cancer (12, 13) as well as in the germ-line in patients with short limb dysplasias (14). The reported FGFR3 mutations lead to a constitutive ligand-independent activation of the receptor tyrosine kinase activity, and a good correlation between the level of kinase activation and the severity of the skeletal phenotype has been observed (15). Because only ≈30% of EN (10, 16) and 25–85% of SK (11, 17, 18) harbor FGFR3 mutations, the involvement of additional genes has been postulated (16, 19). There is strong evidence indicating that the PI3K pathway is involved in FGFR signaling (20, 21). Therefore, genes in this pathway are potential candidates involved in the pathogenesis of EN and SK. Interestingly, the highest prevalence of FGFR3 mutations in cancer is found among superficial papillary bladder tumors (22–25). Activating PIK3CA mutations have also been reported in superficial papillary bladder tumors, often in association with FGFR3 mutations (26). These findings suggested that PIK3CA mutations might also occur in benign skin tumors. Therefore, we screened EN and SK for PIK3CA mutations in exons 9 and 20.
Here, we report that both types of benign acanthotic skin lesions indeed harbor somatic PIK3CA mutations in the hotspot codons as previously identified in malignant tumors. In addition, we demonstrate that the mutation spectrum of PIK3CA is different in EN and SK, indicating a remarkable genotype–phenotype correlation.
Table 1 summarizes mutational analyses. Supporting information (SI) Tables 2 and 3 provide detailed information on the clinical characteristics of the patients and molecular findings.
PIK3CA mutations in EN and SK
Activating PIK3CA Mutations Are Common in EN.
We sequenced exons 9 and 20 of PIK3CA in 33 EN. The E545G mutation was detected in nine cases (27%) (Fig. 2); no other alterations were found. In all cases, the WT sequence was also present, indicating heterozygosity. Codon 545 is a hotspot for activating mutations in a wide variety of tumors (5). However, in cancer, the E545K mutation is much more common than the E545G mutation, which has been reported only in a few carcinomas (4, 26) (www.sanger.ac.uk/genetics/CGP/cosmic). Mutations were not associated with sex, localization, or histological subtype. It has been proposed that EN result from somatic mutations occurring during development, leading to mosaicism, and evidence supporting this notion has been acquired in the case of FGFR3 mutations (10, 16). We analyzed six unaffected tissue samples from four patients with EN harboring mutant PIK3CA sequences and found that only the WT sequence was detectable. In an additional case, leukocyte DNA also displayed only the WT sequence. These findings provide evidence that PIK3CA mutations occur in mosaicism in the skin, analogous to FGFR3 mutations.
Mutational analysis of EN and SK. In all cases, the mutant sequence was accompanied by the presence of the WT allele, indicating heterozygosity.
Activating PIK3CA Mutations Occur in SK.
Because of the histological similarities between EN and SK and the recent demonstration that FGFR3 mutations occur in both types of lesions, we also analyzed exons 9 and 20 of PIK3CA in SK. Ten of 62 (16%) lesions analyzed were found to harbor PIK3CA mutations. Of them, eight displayed an acanthotic, one a hyperkeratotic, and one an adenoid histologic differentiation. The following amino acid substitutions were found: E542K (n = 7), E545K (n = 2), and H1047R (n = 1) (Table 1; Fig. 2). Analogous to the EN, all PIK3CA mutations detected in the SK were heterozygous. Corresponding normal skin, which was available from two patients with mutant SK, was found to be WT, confirming that PIK3CA mutations in SK are somatic events. Furthermore, multiple individual SK from three patients were analyzed (four, six, and eight SK per patient, respectively). In two patients, all SK were WT; in the third case, one of the SK was found to be mutated, whereas the other seven lesions from this patient displayed a WT sequence. PIK3CA mutations occurred preferentially in SK of the trunk (80%), but this association was not statistically significant (P = 0.29). Mutations were not associated with sex, age, or histologic subtype.
PIK3CA Mutations and FGFR3 Mutations in EN and SK.
Fig. 3 summarizes the mutational spectrum findings. The presence of FGFR3 mutations in this series of EN, and in a proportion of the SK studied, has been reported (10, 16–18). In seven of nine (78%) EN cases with mutant PIK3CA sequences, no mutations in FGFR3 were identified. In the remaining two cases, the R248C mutation in FGFR3 was associated with the E545G mutation in PIK3CA. Five EN showed the R248C hotspot mutation in the FGFR3 gene in the absence of detectable PIK3CA mutations. Similar to EN, 7 of 10 (70%) SK with a PIK3CA mutation did not harbor an additional FGFR3 mutation at the known hotspots. Nineteen of 62 (31%) SK showed activating FGFR3 mutations: R248C (n = 9), S249C (n = 2), Y375C (n = 2), A393E (n = 2), K652E (n = 1), and K652M (n = 4), one of them with two mutations. Three SK revealed simultaneous PIK3CA and FGFR3 mutations (in two cases, the E542K/R248C and in one case, the E542K/K652E combination was present). In 16 of 62 (26%) SK, an FGFR3 mutation was found in the absence of PIK3CA alterations.
Spectrum of mutations found in benign skin lesions in PIK3CA and FGFR3. The number of lesions with each mutation is indicated in the ordinates. EN display a very homogenous mutational pattern in both genes, whereas, in SK, a wide spectrum of mutations as found in malignant cancers is observed.
Taken together, PIK3CA and/or FGFR3 mutations were detected in 14 of 33 (42%) EN and in 26 of 62 (42%) SK in this study. Mutations in both genes showed an independent distribution (P = 0.908). In 5 of 95 (5%) of the benign skin lesions analyzed, the simultaneous occurrence of mutations in these two oncogenes was demonstrated.
An improved knowledge of the molecular basis of benign tumors is of fundamental importance to understand why benign tumors, unlike malignant ones, fail to progress and invade. Accordingly, a great deal of emphasis has been placed recently in investigating the cellular response to oncogenic stress as a defense mechanism against tumor progression.
Activating mutations in several oncogenes involved in malignant human tumors, such as K-ras or B-RAF, have been shown to occur frequently in benign lesions, such as colorectal adenomas or melanocytic nevi (27–29). These benign proliferative lesions carrying mutations show a variable risk for malignant transformation. In this report, we provide evidence that activating mutations in PIK3CA previously identified in a wide variety of human cancers also occur in two types of benign skin lesions that bear no relevant risk of progression to malignancy. These findings favor the notion that some benign lesions without malignant potential are initiated by oncogenic pathways shared with cancer. Why some types of benign lesions have the potential to progress to malignancy whereas others do not remains an important question (see below).
EN and SK are histologically similar but display a different natural history. EN are congenital lesions that have been proposed to result from mosaicism in the skin. Approximately 30% of EN display the R248C FGFR3 mutation in the absence of alterations in unaffected tissue (10, 16). However, there is no information on the genetic basis of the remaining cases. We show that ≈30% of EN display a specific mutation, E545G, in PIK3CA. This mutation has only exceptionally been reported in malignant tumors. By contrast, the E545K substitution in the same codon represents ≈25% of all PI3KCA mutations in cancers (4). Gymnopoulos et al. (30) have recently compared the activity of mutant PIK3CA proteins in vitro and have shown that the E545G substitution displays strong transforming activity on chicken embryo fibroblasts, although its effect is lower than that of the more common E542K and E545K substitutions.
The mutations identified in PIK3CA and FGFR3 in EN display a remarkable specificity: regarding the former, only the E545G amino acid substitution was present, and regarding the latter, the R248C mutation was almost exclusively found. This genetic homogeneity is in marked contrast with that reported among malignant tumors for both genes (4, 5, 12, 31). The E545G substitution results from an AT:GC transition, whereas the R248C substitution results from a CG:TA transition, suggesting that the biological nature of the mutation, rather than the mutagenic mechanism, plays a crucial role in the development of EN (32).
Unlike EN, SK display a wide spectrum of mutations in both genes (Fig. 3). Regarding PIK3CA, the three most common cancer-associated mutations (E542K, E545K, and H1047R) were found; as of FGFR3, the mutational spectrum showed even more diversity, including the R248C, S249C, G372C, S373C, Y375C, A393E, K652M, and K652E substitutions (19). Moreover, we have recently reported that, within a given individual with multiple SK, at least four different FGFR3 mutations were present in each case (18). The etiological and biological relevance of this genetic heterogeneity is currently unknown. However, it suggests that SK arise as a result of a wider range of mutagenic mechanisms than do EN. These observations may have implications for the understanding of the pathogenesis of other tumors in which genetic alterations have been proposed to occur during development.
Most of the mutations in PIK3CA present in SK were GC:AT transitions. The diversity of FGFR3 nucleotide substitutions reported in these lesions points to the selection of variants because of their biological properties rather than to a pivotal role of a carcinogen fingerprint associated with UV exposure in the skin (32).
This is a comprehensive study of PIK3CA mutations in human skin and, more generally, of point mutations in an oncogene of the PI3K pathway in benign lesions without malignant potential. The PI3K pathway is thought to play a predominant role in cell survival; mutations in genes coding for proteins acting upstream of PIKs, such as Ras genes or tyrosine kinase growth factor receptors, are thought to affect more directly cell proliferation. Pathologic activation of the FGFR3/PI3K/AKT pathway seems to be a frequent event in the pathogenesis of human EN and SK. That the majority of EN and SK in this study revealed a WT status in both PIK3CA and FGFR3 suggests that additional genes of this or of other pathways contribute to the pathogenesis of acanthotic skin tumors.
In addition, we report previously undescribed oncogenic mutations in two different genes occurring concomitantly in a completely benign lesion, whether congenital or acquired. That the majority of SK appear to be clonal (33) lends support to the notion that both mutations may occur in the same cell, although more work is required to conclusively establish this fact. Oncogenic germ-line FGFR3 mutations cause short limb dysplasia through the activation of Stat1 and the up-regulation of p21, thus leading to premature cell cycle exit in chondrocytes (34). We have proposed that this mechanism may, at least in part, be related to the association of FGFR3 mutations with good prognosis in patients with superficial papillary bladder tumors (25). In addition, we have proposed that, in bladder tumors, PIK3CA mutations may bypass a putative growth disadvantage effect provided by FGFR3 mutations (26). The findings in benign skin lesions reported here clearly indicate that, at least in keratinocytes, the presence of mutations in these two genes does not imply the malignant phenotype, supporting the notion that other genetic alterations, possibly in tumor suppressor genes, must occur to acquire a "progressor" phenotype. Furthermore, our findings suggest that the accumulation of mutations in oncogenes may effectively contribute to activate protective cellular mechanisms that act as a barrier for tumor development (35). Sarkisian et al. (36) have recently demonstrated the relevance of "the level of signaling" to the activation of senescence in a study using transgenic mice. In these mice, an oncogenic mutated Ras gene was expressed in the mammary gland under the control of a doxycycline-inducible promoter. Near-physiologic levels of oncogenic Ras led to hyperproliferation of epithelial cells, whereas high levels of Ras expression led to the activation of a senescence program. Importantly, high levels of oncogenic Ras failed to activate the senescence program in mice in which the Ink4a-Arf locus had been inactivated (36). Multiple mutations occurring in either a single oncogene, as is the case for FGFR3 or PIK3CA in benign skin tumors, or in multiple oncogenes may provide sufficient signals to activate a senescence program in humans as well. Interestingly, inhibition of the PI3K pathway has recently been shown to be required for Ras-induced senescence in vitro (37).
Our findings also bear evidence to the ability of abnormal PI3K signaling in the activation of senescence. Until now, genes located mainly upstream of PI3K have been reported to activate senescence (i.e., receptor tyrosine kinases, Ras, B-RAF, and NF1) (38, 39). This observation is in agreement with the activation of senescence upon acute Pten inactivation in the mouse (40). Mallette et al. (41) have reported that the DNA damage response (DDR) is involved in the induction of senescence mediated by oncogenic Ras and Stat5, and it will be important to determine whether aberrant PI3K signaling is also able to activate the DDR (41).
Overall, our findings extend the spectrum of proliferative lesions harboring PIK3CA mutations and underline the relevance of understanding the mechanisms involved in early steps of tumor development in human carcinogenesis. The skin provides a potent model for such studies given its ready accessibility for visual, pathological, and genetic examination.
Patients and Samples.
The files of the Department of Pathology of Hospital del Mar and Hospital de Sant Pau, the Department of Dermatology of the University of Regensburg, and the Department of Dermatohistopathology, Friedrichshafen, were searched to retrieve diagnostic slides corresponding to cases labeled as "epidermal nevus" (n = 33) and "seborrheic keratosis" (n = 62). Cases diagnosed as nonorganoid nonepidermolytic EN showing the "common" histopathological features (acanthosis, papillomatosis, and a variable degree of hyperkeratosis), as well as cases showing an acrokeratosis verruciformis-like findings, or an SK-like pattern were included in the study. For SK, the three major histologic subtypes (acanthotic, hyperkeratotic, and adenoid) were retrieved. H&E-stained sections were reviewed by an experienced dermatopathologist, and cases fulfilling criteria for the appropriate diagnoses were selected for study. The study was approved by the Ethics Committees of all participating institutions and was performed according to the Declaration of Helsinki.
PIK3CA and FGFR3 Mutation Analysis.
Microdissection, DNA extraction from formalin-fixed paraffin-embedded tissue, control samples, primers, and PCR conditions to amplify exons 9 and 20 of PIK3CA and exons 7, 10, and 15 of FGFR3 have been reported (16, 26). DNA from unaffected tissue was used to determine the somatic nature of the variants.
PCRs were done by using 10–50 ng of DNA/0.2 μmol/liter of each primer/200 μmol/liter deoxynucleotide triphosphates/3.5 mmol/liter MgCl2/1× PCR II buffer/1.5 units of Amplitaq Gold DNA Polymerase (Applied Biosystems, Foster City, CA). PCR conditions were as follows: 94°C (10 min) for one cycle; 94°C (40 sec), 60°C (40 sec), and 72°C (40 sec) for 42 cycles; and a final extension step of 72°C (10 min). In all experiments, several reactions were included in the absence of DNA to rule out contamination by PCR products. All mutations were confirmed by analyzing the products of a second independent PCR as well as by sequencing of both strands of PCR products. In addition, FGFR3 mutations for all SK in this study and 9 of 33 EN were analyzed by using a SNaPshot multiplex assay, as described (10, 42).
Statistical Analyses.
Independence of PIK3CA and FGFR3 mutational status was tested by applying χ2 Mantel–Haenszel test. The trend of PIK3CA mutational prevalence according to sex, age, localization, and histologic subtype was estimated by using Fisher's exact and Mann–Whitney tests.
We thank Manuel Serrano, Xavier Mayol, and Núria Malats for critical reading of the manuscript and helpful discussions; the Department of Pathology, Hospital del Mar, for valuable contributions; and Tania Lobato, Lydia Kuenzel, and Andrea Mueller for excellent technical support. This work was supported, in part, by Grants C03/010 and G03/174 from Instituto de Salud Carlos III, Ministerio de Sanidad, Spain; Grant SAF2004-01137 from Plan Nacional de I+D, Ministerio de Ciencia y Tecnología; and Grant SGR-00410 from Comissió Interdepartamental per la Recerca i Innovació Tecnològica–Generalitat de Catalunya. C.H. was supported by Deutsche Dermatologische Gesellschaft/Arbeitsgemeinschaft Dermatologische Forschung Research Grant 2007 and the ReForM-B grant of the University of Regensburg. E.L.-K. was supported by a Predoctoral Fellowship from Fundación Ramón Areces, Madrid, Spain. N.M.L. was supported by a Predoctoral Fellowship from Fundaçao para a Ciência e a Tecnologia, Portugal.
¶¶To whom correspondence should be addressed at the present address:
Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain.
E-mail: preal{at}cnio.es
Author contributions: C.H., E.L.-K., and N.M.L. contributed equally to this work; C.H., E.L.-K., N.M.L., R.M.P., A.H., and F.X.R. designed research; C.H., E.L.-K., N.M.L., A.T., A.F.-C., and S.H. performed research; E.B., A.R., T.M., R.S., F.H., M.L., and T.V. contributed new reagents/analytic tools; C.H., E.L.-K., N.M.L., A.T., R.M.P., A.H., and F.X.R. analyzed data; and C.H. and F.X.R. wrote the paper.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705218104/DC1.
EN,
epidermal nevus;
FGFR3,
FGF receptor 3;
PI3K,
phosphatidylinositol 3-kinase;
PIK3CA,
p110 α subunit of PI3K;
SK,
seborrheic keratosis.
© 2007 by The National Academy of Sciences of the USA
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You are going to email the following Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern
Christian Hafner, Elena López-Knowles, Nuno M. Luis, Agustí Toll, Eulàlia Baselga, Alex Fernández-Casado, Silvia Hernández, Adriana Ribé, Thomas Mentzel, Robert Stoehr, Ferdinand Hofstaedter, Michael Landthaler, Thomas Vogt, Ramòn M. Pujol, Arndt Hartmann, Francisco X. Real
Proceedings of the National Academy of Sciences Aug 2007, 104 (33) 13450-13454; DOI: 10.1073/pnas.0705218104


The Slowly Boiled Frog: Do we really need the Gay Games?
When I contacted Zeigler I was of the opinion that the Gay Games should be discontinued because we have the ability to compete openly in larger numbers. I knew that he would provide counterpoint. Then I realized that 49 openly gay athletes is minuscule. 11,178 athletes are participating in the Summer Games. Openly gay participants amount to a mere 0.4% of the total. Chances are that the closeted gays who are participating raise that number somewhat but it is still unacceptable. It is unacceptable that more gays cannot be safe in being themselves and it is unacceptable that more gays and lesbians are not competing.
The United States is considered to be a progressive country. Yet sometimes our sense of equality is illusory. Percentage wise there are as many gay kids in Alabama as there are in Massachusetts. There are many places, including the entire Muslim world and Russia, where gay people would trade places with someone in, say, Mississippi in a hot second. The Gay Games provides an all too brief respite for people who are oppressed due to their sexuality. They have an opportunity to excel and to be appreciated for their talent and dedication. That alone makes the Gay Games an important enterprise.
Cyd Zeigler is right in terms of the social values of the Gay Games which provide a safe and accepting environment. An estimated 10% of participants, by the way, are straight. There is also some prospective Olympic talent in the Gay Games. If nothing else the Games may serve as a confidence builder and a source of inspiration. Moreover, the diversity of included sports allows more people to compete.
The 2018 Gay Games will take place in Paris. I will be reading Cyd Zeigler's commentary (I am certain he will be there). More importantly I will be immensely proud of the dedicated men and women who participate. They will have worked very hard just to be there.