What?s a hero to do when he finds that his story is a pack of lies?
In an attempt to recapture the essence of Silkwood, it appears that Matt Damon and his buddies latched on to an environmental story of potentially deadly and disgusting gross water pollution by evil oil companies using ?Fracking,? an allegedly dangerous procedure to obtain more oil from oil-bearing lands. Sounds perfect for a modern day environmental hero to be played by Matt Damon. So what could go wrong? THE UNDERLYING STORY WAS BASED ON A LIE ? AND MANIPULATION BY THE EVIL ENVIRONMENTALISTS.
Hollywood celebrity Matt Damon has been forced to do dramatic rewrites of his anti-fracking movie Promised Land after a series of court cases found the film was inspired by a number of frauds. The rewrites - to ensure that the movie had an anti oil and gas company stance - are revealed in an op/ed in the New York Daily Post by a journalist and filmmaker Phelim McAleer:
McAleer reveals that the rewrites came after a series of findings that environmentalists opposed to fracking had committed perjury or misrepresented their situation. As the cases became publicly known Damon and his fellow screenwriter John Krasinski (Jim in NBC's The Office) went to ludicrous lengths to avoid putting the spotlight on environmentalists who had been caught committing fraud as part of lucrative multi-million dollar lawsuits.
So what is a fundamentally intellectually dishonest filmmaker going to do?
This is Hollywood, where the facts only serve as a framework for a story ? it doesn?t have to be true, it just has to sound believable and give the hero plenty of time to pose ?looking like a hero.? So deprived of version one, the evil oil companies are polluting the land, we go on to version two. Version two sees the evil environmentalists committing fraud ? but in a plot twist ? are actually paid by the evil oil companies.
Damon and Krasinski wrote a script where they admit that environmentalists lie but claim that this deception is paid for by oil and gas companies to discredit the environmental movement.
"Matt Damon really has jumped the shark with Promised Land," said McAleer who is making FrackNation, a documentary about fracking. "It seems Hollywood will go to any lengths to demonize the fossil fuel industry even making ludicrous assertions that they are funding the lawbreakers on the other side. It's crazy. Matt Damon is destroying what could be a good movie because of his environmental anti-business bias."
Bottom line ?
The public is being subtly conditioned to believe the environmentalists, a movement which has been infiltrated by ideological socialists and communists to continue their work of destroying America from within. With the help, of course, of ?useful idiots? in the Hollywood community who see only their own ability to gain media attention and big dollar rewards. Never once thinking about what they might be doing to the nation?s rather uneducated masses who actually believes what they are told by the Hollywood liberals.
In the final analysis, it is all about making a movie ? profits, recognition and the opportunity to speak as ?an expert? in various forums, including Congressional hearings where the bar for ?experts? providing testimony (especially without being sworn) is absurdly low.
Take a moment to read ?Matt Damon?s troubled frack attack?Phelim McAleer - NYPOST.com? and consider how the environmentalists are subverting our own laws to finance their political actions and to bring down the America we know and love.
Perhaps Matt Damon should reunite with Ben Affleck and write an original movie based on Hollywood?s ?useful idiots? and the propaganda they spew.
This topic is an Out Of Character part of the roleplay, ?Cultured?. Anything posted here will also show up there.
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Forum for completely Out of Character (OOC) discussion, based around whatever is happening In Character (IC). Discuss plans, storylines, and events; Recruit for your roleplaying game, or find a GM for your playergroup. Welcome to "Cultured"
Thankyou for viewing my roleplay, and I hope you will consider taking part. Here feel free to make reservations, ask questions and discuss the roleplay.
Please note, this is a literate, and advanced rp, so I will be rather strict on character profiles. My own characters stand as examples of what I am expecting. Since this is literate (again, pointing this out (: ) roleplay, if you are not willing/prepared to write around 600 words for each of your posts, please don't join. About the reservations, they last 24hours and people can reserve the same character and compete if needed.
Shan?
Member for 1 years
This could be interesting. Inspired by The Island I assume?
Staring real hard at the available slots. Might make a character should inspiration strike.
Seirei
Member for 2 years
Haha. I hope you find one you like, I tried to make all the spots as interesting as each other :) I actually haven't heard of that film though I'd assume that since cloning is a rather intriguing and controversial topic many different stories would be made about it.
Shan?
Member for 1 years
Oh please, please, please let me reserve The One in Denial! I really want to join this :)
I have this theory that, depending on your attitude, your life doesn't have to be this ridiculous charade that it seems so many people end up living.
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Death is more universal than life; everyone dies but not everyone lives.
raindrops_autumn
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A few weeks ago, Jenica Rogers, the library director at SUNY Potsdam, a small public college in upstate New York, wrote a blog post detailing how her library and chemistry department decided to cancel subscriptions to the journals published by the American Chemical Society due to unsustainable costs. Faculty at SUNY Potsdam agreed that it was worthwhile to forego immediate access to that content, even though it?s of high quality. Continued access to ACS journals would have used up 10% of the total library acquisitions budget. To make up for the loss of ACS journals they added subscriptions to journals from the Royal Society of Chemistry and other publishers.
The American Chemical Society is well known in library circles for having aggressive year-to-year price increases. Last year, my library cancelled its subscription to the ?all ACS journals? package in favor of a new, smaller, package of 16 ACS journals to avoid an effective 11% price jump on the ?all journals? package. The year before our cost for the ACS archive (pre-1995 journals) doubled as the ACS moved to a new pricing model. While prices for the smaller journal package held steady for us this year, I keep a list of things that we might need to cancel when (not if) prices increase faster than the library budget. I?m concerned that we will have to cancel this smaller journal package in favor of just a few ACS subscriptions sometime in the next few years. After several years of declining or steady library budgets, my library has made all of the ?easy? cuts we can in order to afford scholarly content from the ACS and other publishers: the book budget has been slashed, we?ve cancelled many magazines and newspapers, the student worker budget has been cut, we aren?t binding print journals anymore, etc. Other libraries are in a similar position where the only thing left to cut are journal subscriptions.
Many folks have responded to Potsdam?s move on library and chemistry blogs and other news sites (John Dupuis has a good list of posts and commentary). Some applaud their actions as standing up to the ?Goliath? of publishers. Others lament that their students will lose access to high quality research published by ACS. Few ask about the non-chemistry students who would loose access to their own discipline?s high quality research in order for Potsdam to afford the ACS subscriptions. Every time journal subscription costs go up faster than library budgets, something has to be cut.
For many folks, subscriptions to these journals were once considered un-cancelable. Perhaps we?ve been pushed to the point now where that is no longer the case.
In a recent article in the Chronicle of Higher Education the author talked to Jenica, a chemistry faculty member, and reached out to the ACS about the issue, expanding on some of the issues raised in Jenica?s original blog post. The ACS seemed to say that they aren?t going to talk to us about this in the places where we talk about this:
?We find little constructive dialogue can be had on blogs and other listservs where logic, balance, and common courtesy are not practiced and observed,? Glenn S. Ruskin, the group?s director of public affairs, said in an e-mail message. ?As a matter of practice, ACS finds that direct engagement via telephone or face-to-face with individuals expressing concern over pricing or other related matters is the most productive means to finding common ground and resolution.?
This statement infuriated many mild mannered librarians. Librarians use blogs, listservs, and other new-fangled online communication tools to discuss library issues, to help each other out and to engage with publishers on issues of mutual interest.
After several chemistry librarians politely expressed their outrage and disappointment in the ACS on the chemical information societies listerv, Mr. Ruskin emailed a response, stating that a final sentence had been left off his quote:
?Therefore, we will not be offering any response to this blog posting or the conversation that has ensued.?
His explanation suggested that the ACS was not going to respond to Jenica?s blog post and this particular issue. I?m not sure that Mr. Ruskin?s clarification seems to help the matter. Whatever your feelings about the tone of Jenica?s blog post (or her previous posts about the ACS in which she has described herself as ?feeling pointy?), Mr. Ruskin is still saying that they aren?t going to talk about this issue in the places where librarians talk about issues like this.
Personally, I don?t blame Jenica for using blunt language and the occasional curse word when talking about ACS with friends and colleagues. I became a librarian because I love information, and I?m passionate about teaching students to access, understand and use the scientific literature. When publishers make it more difficult for students to access it by charging fees that we can no longer afford, I feel ?pointy? too. Just ask the librarians whose cubicles are next to mine.
Those of us struggling to provide our students and faculty with high quality research are frustrated that we don?t have partners on the other side of the table willing to engage with us in honest conversation about journal prices. We are left with few options: renew at the prices ACS is charging or cancel something. It isn?t a nice position to be in.
Talk to us, ACS. And I don?t mean by calling me privately. Engage with librarians and chemists about this issue on listservs and blogs. Open a dialog on what a reasonable pricing model would include. We know that you have good content, and we?re not expecting to access it for free. But when we can?t afford it anymore we are left with few options, and almost everyone loses. I would love to see a greater variety of journal package options (a package of 8 or 12 journals, for example) at a lower cost. I would like to see some honest figures about why my college?s cost per download is about 10 times the cost per download of our nearby university. I would also love to hear about how the aggressive price increases and higher-than-other-scholarly-societies subscription costs mesh with the mission statement of the ACS ?to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and its people.?
Children ages 2-11 view an alarming amount of television shows that contain forms of social bullying or social aggression. Physical aggression in television for children is greatly documented, but this is the first in-depth analysis on children's exposure to behaviors like cruel gossiping and manipulation of friendship.
Nicole Martins, Indiana University, and Barbara J. Wilson, University of Illinois, Urbana-Champaign, published in the Journal of Communication a content analysis of the 50 most popular children's shows according to Nielsen Media Research. One hundred and fifty television shows were viewed and analyzed, and 92% of the programming contained some version of social aggression?approximately 14 times per hour. There was careful attention to what was portrayed in the cases of social aggression, whether the behavior was rewarded or punished, justified, or committed by an attractive perpetrator.
The findings suggested that some of the ways in which social aggression is contextualized make these depictions particularly problematic for young viewers. The study found that attractive characters who perpetrated social aggression were rarely punished for their behavior, and that socially aggressive scenes were significantly more likely than physically aggressive scenes to be presented in a humorous way. In some cases, social aggression on television may pose more of a risk than portrayals of physical aggression do.
"These findings should help parents and educators recognize that there are socially aggressive behaviors on programs children watch. Parents should not assume that a program is okay for their child to watch simply because it does not contain physical violence. Parents should be more aware of portrayals that may not be explicitly violent in a physical sense but are nonetheless antisocial in nature," Martins said.
"Martins and Wilson's research shows just how important it is to broaden our view of 'violence' beyond the physical; particularly as their findings indicate that social violence like insults and name calling occurs just as commonly in children's programming," said Amy Jordan, director of the Media and the Developing Child sector at the University of Pennsylvania and Chair of the Children, Adolescents and the Media Division of the International Communication Association.
"As a society, we need to acknowledge that our children are learning to be socially aggressive, and that one source of this learning may be the television shows they watch. We may not see physical manifestations of this type of violence, but children who are victims of social aggression from their peers may develop deep and lasting emotional scars."
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International Communication Association: http://Www.icahdq.org
Thanks to International Communication Association for this article.
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LONDON (Reuters) - The Financial Services Authority (FSA) delivered a 10-point plan to fix Libor but stopped short of scrapping the benchmark interest rate in a much-awaited reform of a system plagued by scandal.
"The system is broken and needs a complete overhaul," said Martin Wheatley, head of the FSA.
Wheatley acknowledged problems with London interbank offered rates, but said Libor is so deeply entrenched in the financial system that it cannot be easily replaced.
There are no better alternatives now and any transition to a new benchmark would be difficult, he said on Friday, adding that it made sense for market participants to examine whether there are other possible benchmark rates in the longer term.
The government sees the reform of Libor as critical to restoring global confidence in London as a financial centre.
"The longer the situation prevails that trust has been eroded, the more difficult it is to restore," financial services minister Greg Clark told Reuters.
The FSA plan, which includes oversight by a new panel from 2013, marks regulators' first effort to fix the tarnished benchmark, but rule makers have to thread the needle carefully.
On the one hand, they must restore confidence in the financial system; on the other, they cannot take steps that are too radical without creating big trouble with existing transactions that use the benchmark, with some home loans using Libor stretching out 65 years.
More than $300 trillion (185.2 trillion pounds) of contracts and loans ? from U.S. mortgages to Japanese interest-rate swaps - refer to Libor.
"Bringing Libor under an independent regulator will take away the notion that this was a system run by banks for the benefit of banks," said Matthew Fell, director for competitive markets at the Confederation of British Industry lobby group.
CHARGES OF MANIPULATION
Most responses to Wheatley's plan were supportive, but Stephen Gilchrist, head of regulatory law at Saunders Law, said regulation of individuals as proposed had not stopped abuses.
"The FSA only authorise persons in the financial services sector who pass a ?fit and proper' test which goes to probity and integrity. Where has that got us in the recent past?" Gilchrist said in an email.
Multiple banks have been accused of trying to manipulate Libor, a series of rates set daily in London. Barclays Plc in June agreed to pay $453 million to U.S. and British authorities to settle allegations that it tried to move Libor to help its trading positions.
Wheatley's programme for reform includes auditing banks that contribute data used to calculate the rates, to ensure they are not submitting false rates to benefit trading positions.
Libor, which is meant to reflect the rates at which banks borrow from one another, will include actual borrowing transactions. Previously, banks could estimate where they think they would borrow, which left room for manipulation.
Bank employees making Libor submissions will have to be approved by the FSA. Wheatley is looking for authorisation to criminally sanction those who attempt to manipulate the rate.
Wheatley said he had taken legal advice and does not expect a rash of legal disputes or any disruption in the transition to a new system, as there will be no change to the definition of Libor or to the timing or mechanism for submitting quotes.
Reuters parent company Thomson Reuters collects information from banks, and uses it to calculate Libor rates according to specifications drawn up by the British Bankers Association (BBA).
CULL OF RATES
The number of Libor rates will be culled from 150 to 20 with more banks required to contribute to the remaining ones.
As expected, the BBA, which had overseen the rate, will be replaced with a new, as-yet unidentified oversight panel.
The BBA said it worked closely with Wheatley on his review and had stated the need for greater regulatory oversight of Libor and tougher sanctions against manipulation.
A major remaining problem is that in financial crises, such as the one in 2008, banks cease lending to one another, effectively removing data needed to calculate Libor.
"More thought on how Libor operates during a stressed scenario is needed," said Kevin Burrowes, head of financial services at PricewaterhouseCoopers.
Mervyn King, governor of the Bank of England, said: "Over the medium to long term, further thinking will be needed to meet the challenge of benchmarks based on thinly traded markets, especially when they are quote-based."
The reforms come amid more crackdowns on the banks that submitted rates used to calculate Libor. Royal Bank of Scotland is expected to be next to settle Libor charges, with other banks to follow.
Britain's government commissioned Wheatley to report on reforming Libor and is expected to back the findings in full. Legislative changes will be inserted into a financial services bill now being approved by parliament.
(Additional reporting by Rick Rothacker in Charlotte, North Carolina and Carrick Mollenkamp and Jennifer Saba in New York; Writing by Dan Wilchins and Steve Slater; Editing by Edmund Klamann and David Holmes)
MEXICO CITY (AP) ? Mexico appeared to strike a major blow against one faction of the hyper-violent Zetas cartel, with the navy announcing it has captured one of the country's most-wanted drug traffickers, Ivan Velazquez Caballero, known as "El Taliban."
Velazquez Caballero has been fighting a bloody internal battle with top Zetas' leader Miguel Angel Trevino Morales, and officials have said the split was behind a recent surge in massacres and shootouts, particularly in northern Mexico.
"A person who is presumed to be, and acknowledges being, Ivan Velazquez Caballero, was captured in the state of San Luis Potosi" in north-central Mexico, the navy said in a statement on Wednesday.
Officials were presenting Velazquez Caballero to the media Thursday morning.
Also known as "Z-50," Velazquez Caballero has a 30 million peso ($2.3 million) reward on his head.
If confirmed, Velazquez Caballero's arrest could calm some of the brutal violence that has hit border cities like Nuevo Laredo, across from Laredo, Texas, in recent weeks.
On Sept. 14, eight men were found shot to death and one hanging from a bridge in Nuevo Laredo, territory traditionally controlled by Trevino Morales, alias "Z-40." Analysts say 14 bullet-ridden bodies stuffed in a van in mid-August in San Luis Potosi were men loyal to "El Taliban," and may have been left there as a warning by Trevino Morales' underlings.
Discussing recent fighting, a U.S. official in Mexico who could not be named for security reason said earlier this week that "I think right now the uptick that I'm seeing is between '40' and '50'," referring to Trevino Morales and Velazquez Caballero by their "Z'' aliases.
The Zetas cartel takes its name from a police radio code in which "Z'' means "commander," and a number refers to rank.
The official said Velazquez Caballero appeared to have formed an alliance of convenience with the Knights Templar cartel based in southern Michoacan state for his fight with Trevino Morales.
Banners signed by various elements of the Zetas and hung from overpasses in several Mexican states appeared to confirm mutual hatred between Trevino Morales and Velazquez Caballero. In the obscenity-laden banners, the two capos accused each other of betraying their fellow traffickers and preying on civilians.
If the man arrested as "El Taliban" is confirmed, the development could strengthen Trevino Morales, who shares leadership of the Zetas with Heriberto Lazcano, alias "El Lazca."
The U.S. official played down recent speculation that Trevino Morales and Lazcano had also fallen out.
"I'm not familiar with a fight between him (Trevino Morales) and Lazca," the official said. "I think he and Lazca ? Lazca is doing his thing and he is doing his, and they're still together from what I understand."
Lawmen and even competing drug capos picture Trevino as a brutal assassin who favors getting rid of foes by stuffing them into oil drums, dousing them with gasoline and setting them on fire, a practice known as a "guiso," a Spanish word for "stew."
The Zetas are already considered the hemisphere's most violent criminal organization. They have been blamed for a large share of the tens of thousands of deaths in Mexico's war on drugs, though other gangs also have repeatedly committed mass slayings.
Running gun battles between Navy personnel and gunmen broke out late Wednesday in the border city of Piedras Negras, across the border from Eagle Pass, Texas.
Officials in the border state of Coahuila confirmed the shootouts, and state security spokesman Sergio Cisbeles said the confrontation was serious, but he could not immediately confirm whether there anyone was wounded or dead.
The Zetas have been known to be active in Coahuila state, but it was unclear whether the confrontations in Piedras Negras were related in any way to the capture of Velazquez Caballero.
Deadly complication of stem cell transplants reduced in mice Public release date: 27-Sep-2012 [ | E-mail | Share ]
Contact: Julia Evangelou Strait straitj@wustl.edu 314-286-0141 Washington University School of Medicine
Studying leukemia in mice, researchers at Washington University School of Medicine in St. Louis have reduced a life-threatening complication of stem cell transplants, the only curative treatment when leukemia returns.
About 50 percent of leukemia patients who receive stem cells from another person develop graft-versus-host disease, a condition where donor immune cells attack the patient's own body. The main organs affected are the skin, liver and gut. Now, the scientists have shown they can redirect donor immune cells away from these vital organs. Steering immune cells away from healthy tissue also leaves more of them available for their intended purpose killing cancer cells.
"This is the first example of reducing graft-versus-host disease not by killing the T- cells, but simply by altering how they circulate and traffic," says John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine. "Donor T-cells do good things in terms of eliminating the recipient's leukemia, but they can also attack normal tissues leading to death in a number of patients. The goal is to minimize graft-versus-host disease, while maintaining the therapeutic graft-versus-leukemia effect."
The study is now available online in Blood.
Working with mice, Jaebok Choi, PhD, research assistant professor of medicine, showed that eliminating or blocking a particular protein the interferon gamma receptor on donor T-cells makes them unable to migrate to critical organs such as the intestines but still leaves them completely capable of killing leukemia cells.
"The fact that blocking the interferon gamma receptor can redirect donor T-cells away from the gastrointestinal tract, at least in mice, is very exciting because graft-versus-host disease in the gut results in most of the deaths after stem cell transplant," DiPersio says. "People can tolerate graft-versus-host disease of the skin. But in the GI tract, it causes relentless diarrhea and severe infections due to gut bacteria leaking into the blood, which can result in severe toxicity, reduction in the quality of life or even death in some patients."
Long known to be involved in inflammation, the roles of interferon gamma, its receptor and their downstream signaling molecules are just beginning to be described in the context of graft-versus-host disease, says DiPersio, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
The cascade begins when interferon gamma activates its receptor. The interferon gamma receptor then activates molecules known as JAK kinases, followed by STAT, and finally CXCR3. CXCR3 mediates the trafficking of donor T-cells to the GI tract and other target organs.
Since deleting the interferon gamma receptor from donor T-cells directs them away from target organs, the researchers asked whether they could produce the same beneficial effects by inhibiting some of the receptor's downstream signaling molecules. Indeed, Choi also found that knocking out CXCR3 reduces graft-versus- host disease, but not completely.
"There are probably additional downstream targets of interferon gamma receptor signaling other than JAKs, STATs and CXCR3 that are responsible for T-cell trafficking to the GI tract and other target organs," DiPersio says. "We're trying to figure out what those are."
To move their findings closer to possible use in humans, Choi and DiPersio also showed that they could mimic the protective effect of deleting the interferon gamma receptor with existing drugs that block JAK kinases. In this case, they tested two JAK inhibitors, one of which is currently approved by the U.S. Food and Drug Administration to treat myelofibrosis, a pre-leukemic condition in which the bone marrow is replaced with fibrous tissue.
While they showed that JAK inhibitors are effective in redirecting donor T-cells away from target organs and reducing graft-versus-host disease in mice with leukemia, they have not yet tested whether these drugs also preserve the desired anti-leukemia effect.
"The proof-of-principle behind these experiments is the exciting part," DiPersio says. "If you can change where the T-cells go as opposed to killing them, you prevent the life-threatening complications and maintain the clinical benefit of the transplant."
This work was supported by grants from the National Cancer Institute (R01 CA83845 and R21 grants CA110489, CA132269, CA141523 P01 CA101937, P50 CA94056, the Bryan Thomas Campbell Foundation, the Molecular Imaging Center Pilot Research Project 2010 Awards (P50 CA94056), the Translational Oncology Group at the Washington University School of Medicine, the Siteman Cancer Center Research Development Awards in Developmental Therapeutics, and the American Cancer Society Institutional Research Grant (IRG-58-010-53).
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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Deadly complication of stem cell transplants reduced in mice Public release date: 27-Sep-2012 [ | E-mail | Share ]
Contact: Julia Evangelou Strait straitj@wustl.edu 314-286-0141 Washington University School of Medicine
Studying leukemia in mice, researchers at Washington University School of Medicine in St. Louis have reduced a life-threatening complication of stem cell transplants, the only curative treatment when leukemia returns.
About 50 percent of leukemia patients who receive stem cells from another person develop graft-versus-host disease, a condition where donor immune cells attack the patient's own body. The main organs affected are the skin, liver and gut. Now, the scientists have shown they can redirect donor immune cells away from these vital organs. Steering immune cells away from healthy tissue also leaves more of them available for their intended purpose killing cancer cells.
"This is the first example of reducing graft-versus-host disease not by killing the T- cells, but simply by altering how they circulate and traffic," says John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine. "Donor T-cells do good things in terms of eliminating the recipient's leukemia, but they can also attack normal tissues leading to death in a number of patients. The goal is to minimize graft-versus-host disease, while maintaining the therapeutic graft-versus-leukemia effect."
The study is now available online in Blood.
Working with mice, Jaebok Choi, PhD, research assistant professor of medicine, showed that eliminating or blocking a particular protein the interferon gamma receptor on donor T-cells makes them unable to migrate to critical organs such as the intestines but still leaves them completely capable of killing leukemia cells.
"The fact that blocking the interferon gamma receptor can redirect donor T-cells away from the gastrointestinal tract, at least in mice, is very exciting because graft-versus-host disease in the gut results in most of the deaths after stem cell transplant," DiPersio says. "People can tolerate graft-versus-host disease of the skin. But in the GI tract, it causes relentless diarrhea and severe infections due to gut bacteria leaking into the blood, which can result in severe toxicity, reduction in the quality of life or even death in some patients."
Long known to be involved in inflammation, the roles of interferon gamma, its receptor and their downstream signaling molecules are just beginning to be described in the context of graft-versus-host disease, says DiPersio, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
The cascade begins when interferon gamma activates its receptor. The interferon gamma receptor then activates molecules known as JAK kinases, followed by STAT, and finally CXCR3. CXCR3 mediates the trafficking of donor T-cells to the GI tract and other target organs.
Since deleting the interferon gamma receptor from donor T-cells directs them away from target organs, the researchers asked whether they could produce the same beneficial effects by inhibiting some of the receptor's downstream signaling molecules. Indeed, Choi also found that knocking out CXCR3 reduces graft-versus- host disease, but not completely.
"There are probably additional downstream targets of interferon gamma receptor signaling other than JAKs, STATs and CXCR3 that are responsible for T-cell trafficking to the GI tract and other target organs," DiPersio says. "We're trying to figure out what those are."
To move their findings closer to possible use in humans, Choi and DiPersio also showed that they could mimic the protective effect of deleting the interferon gamma receptor with existing drugs that block JAK kinases. In this case, they tested two JAK inhibitors, one of which is currently approved by the U.S. Food and Drug Administration to treat myelofibrosis, a pre-leukemic condition in which the bone marrow is replaced with fibrous tissue.
While they showed that JAK inhibitors are effective in redirecting donor T-cells away from target organs and reducing graft-versus-host disease in mice with leukemia, they have not yet tested whether these drugs also preserve the desired anti-leukemia effect.
"The proof-of-principle behind these experiments is the exciting part," DiPersio says. "If you can change where the T-cells go as opposed to killing them, you prevent the life-threatening complications and maintain the clinical benefit of the transplant."
This work was supported by grants from the National Cancer Institute (R01 CA83845 and R21 grants CA110489, CA132269, CA141523 P01 CA101937, P50 CA94056, the Bryan Thomas Campbell Foundation, the Molecular Imaging Center Pilot Research Project 2010 Awards (P50 CA94056), the Translational Oncology Group at the Washington University School of Medicine, the Siteman Cancer Center Research Development Awards in Developmental Therapeutics, and the American Cancer Society Institutional Research Grant (IRG-58-010-53).
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
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Public release date: 27-Sep-2012
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