Coupling of proteins promotes glioblastoma development, researchers find

ScienceDaily (Oct. 21, 2011) ? Two previously unassociated proteins known to be overly active in a variety of cancers bind together to ignite and sustain malignant brain tumors, a research team led by scientists at The University of Texas MD Anderson Cancer Center reports this week in the journal Cancer Cell.

This research is the first to connect FoxM1 to a molecular signaling cascade that regulates normal neural stem cells, said senior author, Suyun Huang, M.D., Ph.D., associate professor in MD Anderson's Department of Neurosurgery.

"When FoxM1 binds to beta-catenin, we found that it also supports the self-renewal and differentiation of glioma-initiating cells, cancer stem cells thought to drive glioblastoma multiforme," Huang said.

Glioblastoma multiforme is the most common and lethal form of brain tumor. Glioma-initiating cells are prime suspects in the disease's resistance to treatment and ability to reoccur.

Protein's connection could be drug target

The scientists established the relationship between FoxM1 and beta-catenin in a series of cell line experiments and then confirmed their findings in mouse models of human glioblastoma and in an analysis of human tumors.

FoxM1 and beta-catenin separately so far have largely evaded targeting by drugs. Huang and her team are focusing on the details of the connection between the two proteins in search of small molecules that might block their binding.

"Our study might lead to the development of a new class of small-molecule anti-cancer drugs, including but not necessarily limited to glioblastoma multiforme," Huang said. Much preclinical work remains before such a drug can be identified and brought to clinical trial.

Blocking FoxM1 reduces glioblastoma in mice 100 percent

FoxM1 previously was known solely as a transcription factor -- a protein that binds to the DNA in a gene's promoter region to prompt the gene's expression of messenger RNA that is processed into a protein.

Structural analysis led Huang and her team to suspect FoxM1 might be a binding match for beta-catenin, a crucial protein in the Wnt signaling pathway, which regulates self-renewal and differentiation of neural stem cells. When a normal cell divides, it produces two copies of itself. A neural stem cell produces one copy of itself (self-renewal) and a copy of a functional brain cell, such as a neuron or an astrocyte (differentiation). Mutations occur in the Wnt pathway in other types of cancer, but are largely absent in glioblastoma.

Blocking either FoxM1 or beta-catenin function strongly influenced whether mice injected with glioblastoma cells developed brain tumors. Most dramatically, blocking FoxM1 with short hairpin RNA completely prevented development of brain tumors in 38 mice, while all 20 with unimpeded FoxM1 developed tumors.

In a series of cell line experiments leading to the mouse model research, the group found:

• FoxM1 is expressed at high levels in glioma and in glioma-initiating cells.
• FoxM1 and beta-catenin bind to each other in tumor cells.
• Wnt promotes the movement of both FoxM1 and beta-catenin to the cell nucleus.
• FoxM1 is required for beta-catenin to move to the cell nucleus in both neural stem cells and in tumor cells.
• The FoxM1 and beta-catenin connection is required for transcription and expression of beta-catenin Wnt-targeted genes in the nucleus.
• Interaction between the two proteins is critical to both cell renewal and differentiation in glioma stem cells.

The team analyzed 40 glioblastoma samples and found FoxM1 moderately expressed in 14 and highly expressed in 18. Levels of FoxM1 in the cell nucleus correlated directly with levels of beta-catenin expression and the expression of two Wnt target genes.

Additional analysis of eight tumors found the two proteins present together in the cell nuclei and a direct correlation with the presence of one protein marker for glioma-initiating cells.

Co-authors with Huang are first authors Nu Zhang, Ph.D., and Ping Wei, Ph.D., Aihua Gong, Ph.D., Wen-Tai Chiu, Ph.D, Hsueh-Te Lee, Ph. D, Jianfei Xue, Ph.D., Mingguang Liu, M.D., Yong Wang, Ph.D., and Raymond Sawaya, M.D. ,of MD Anderson's Department of Neurosurgery; Howard Colman, M.D., and W.K. Alfred Yung, M.D., of MD Anderson's Department of Neuro-Oncology. Keping Xie, M.D., Ph.D .,of MD Anderson's Department of Gastrointestinal Medical Oncology and the program in cancer biology at The University of Texas Graduate School of Biomedical Science at Houston; Rene Medema, M.D., of the Department of Medical Oncology, UMC Utrecht, Utrecht, The Netherlands; and Xi He, Ph.D., and He Huang, Ph.D., of the F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School.

Artwork chosen by Cell Press for the cover of Cancer Cell was designed by Huang's daughter Victoria Xie, a sophomore at Michael DeBakey High School for Health Professions in Houston.

This research was funded by grants from the National Cancer Institute, the National Institute of General Medical Sciences, a multidisciplinary research grant by MD Anderson, and the Leukemia and Lymphoma Society.

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Story Source:

The above story is reprinted from materials provided by University of Texas M. D. Anderson Cancer Center.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Nu Zhang, Ping Wei, Aihua Gong, Wen-Tai Chiu, Hsueh-Te Lee, Howard Colman, He Huang, Jianfei Xue, Mingguang Liu, Yong Wang, Raymond Sawaya, Keping Xie, W.K.?Alfred Yung, Ren??H. Medema, Xi He, Suyun Huang. FoxM1 Promotes ?-Catenin Nuclear Localization and Controls Wnt Target-Gene Expression and Glioma Tumorigenesis. Cancer Cell, 2011; 20 (4): 427 DOI: 10.1016/j.ccr.2011.08.016

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Source: http://www.sciencedaily.com/releases/2011/10/111021151609.htm

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US, Filipino marines hold drill near disputed area (AP)

SAN ANTONIO, Philippines ? More than 200 U.S. and Filipino marines have staged an amphibious assault on a beach as part of a combat drill near a South China Sea shoal disputed by China and the Philippines.

U.S. Marine Brig. Gen. Craig Timberlake says the exercise Sunday in the coastal town of San Antonio in Zambales province will allow the military allies to operate jointly in a range of scenarios, including responding to disasters.

He refused to discuss whether or not the drill was related to concerns over China's growing naval power.

A Marine spokesman says China is not an imaginary target in the annual exercise.

The Philippines has sought U.S. help to strengthen its military amid a territorial spat with China, including over the Scarborough Shoal off Zambales.

Source: http://us.rd.yahoo.com/dailynews/rss/asia/*http%3A//news.yahoo.com/s/ap/20111023/ap_on_re_as/as_philipines_us_military

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Shark kills American off Australian coast: police (Reuters)

PERTH, Australia (Reuters) ? A shark killed an American out diving off a popular Australian tourist island on Saturday, in the third fatal shark attack off the country's west coast in two months, police said.

The man, a U.S. national, was killed while diving alone off Rottnest Island, a popular getaway in the Indian Ocean about 20 km (12 miles) west of the Western Australia state capital, Perth.

A police spokesman told Reuters the body surfaced with "obviously traumatic fatal injuries."

Witnesses said the shark was a three-meter white pointer, the spokesman said. The victim, thought to have been 32 years old, has not been named.

Sharks are common in the waters around Australia. Attacks on humans are normally rare, but fatal attacks periodically occur.

(Editing by Sugita Katyal)

Source: http://us.rd.yahoo.com/dailynews/rss/pets/*http%3A//news.yahoo.com/s/nm/20111023/wl_nm/us_australia_shark

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Exclusive: Nasdaq hackers spied on company boards (Reuters)

(Reuters) ? Hackers who infiltrated the Nasdaq's computer systems last year installed malicious software that allowed them to spy on the directors of publicly held companies, according to two people familiar with an investigation into the matter.

The new details showed the cyber attack was more serious than previously thought, as Nasdaq OMX Group had said in February that there was no evidence the hackers accessed customer information.

It was not known what information the hackers might have stolen. The investigation into the attack, involving the FBI and National Security Agency, is ongoing.

"God knows exactly what they have done. The long term impact of such attack is still unknown," said Tom Kellermann, a well-known cyber security expert with years of experience protecting central banks and other high-profile financial institutions from attack.

The case is an example of a "blended attack," where elite hackers infiltrate one target to facilitate access to another. In March hackers stole digital security keys from EMC Corp's RSA Security division that they later used to breach the networks of defense contractor Lockheed Martin Corp.

Nasdaq had previously said that its trading platforms were not compromised by the hackers, but they attacked a Web-based software program called Directors Desk, used by corporate boards to share documents and communicate with executives, among other things.

By infecting Directors Desk, the hackers were able to access confidential documents and the communications of board directors, said Kellermann, chief technology officer at security technology firm AirPatrol Corp.

Investigators have learned that hackers were able to spy on "scores" of directors who logged onto directorsdesk.com before the malicious software was removed, said Kellermann and another person familiar with the investigation who was not authorized to discuss the matter publicly.

It was still unclear how long Nasdaq's system was breached before the attack was discovered last October.

A Nasdaq spokesman confirmed the investigation into the attack continues, but declined to give further details.

NSA HELPS NASDAQ

Executive Assistant FBI Director Shawn Henry said the financial services sector was losing hundreds of millions of dollars to hackers every year, and the attacks were increasingly "destructive" in nature.

"We know adversaries have full unfettered access to certain networks. Once there they have the ability to destroy data," he told Reuters in a phone interview. "We see that as a credible threat to all sectors, but specifically the financial services sector." Henry declined to comment on the Nasdaq attack.

U.S. Army General Keith Alexander, head of the National Security Agency and U.S. Cyber Command, said the NSA was working with Nasdaq to help protect its network against further attacks.

Alexander told security experts at a Baltimore conference that the United States was shoring up its defenses, but still had "tremendous vulnerabilities" to a growing number of increasingly destructive electronic attacks.

"Nation states, non-nation state actors and hacker groups are creating tools that are increasingly more persistent and threatening, and we have to be ready for that," he said.

Amid a spate of high-profile cyber crimes, the Obama administration wants Congress to pass comprehensive cyber-security legislation that would increase the government's ability to thwart the growing threat.

Alexander and other top officials held a classified meeting with lawmakers on Wednesday and Thursday to discuss the issue, according to sources familiar with the meeting.

Nasdaq CEO Robert Greifeld said in July that the exchange is under constant attack, requiring it to spend nearly a billion dollars a year on information security.

"As we sit here, there are people trying to slam into our system every day," Greifeld said in the interview. "So we have to be ever vigilant against an ever-changing foe."

(Reporting by Jim Finkle. Additional reporting by Jonathan Spicer in New York, Andrea Shalal-Esa in Baltimore and Diane Bartz in Washington. Editing by Tim Dobbyn, Tiffany Wu, and Bob Burgdorfer

Source: http://us.rd.yahoo.com/dailynews/rss/security/*http%3A//news.yahoo.com/s/nm/20111020/bs_nm/us_nasdaq_hacking

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Justice served by Gaddafi death, Lockerbie families say (Reuters)

NEW YORK (Reuters) ? Relatives of victims of the flight blown up over Lockerbie, Scotland, by Libyan agents 23 years ago said justice was served with the death of Libyan leader Muammar Gaddafi Thursday, but they also hoped it would reveal who else was behind the attack.

"I hope he's in hell with Hitler," said Kathy Tedeschi, whose first husband, Bill Daniels, was among the 270 people killed in the 1988 bombing of PanAm Flight 103.

"I saw it on the TV when I was ... (at the gym), I just can't stop crying, I am so thrilled," said Tedeschi, 62, who had three children with Daniels. "I am sure (Gaddafi) was the one who pushed to have this done, the bombing."

Gaddafi was killed Thursday, sparking wild celebrations that eight months of war in Libya may finally be over. Details of the fallen strongman's death were hazy but it was announced by several officials of the National Transitional Council (NTC) and backed up by a photograph of a bloodied face ringed by familiar, Gaddafi-style curly hair.

Bob Monetti, whose son Richard, 20, was killed in the Lockerbie bombing said: "The world is a much better place without Gaddafi and Libya is certainly much better off."

"I hope we can get some more information and get on with our lives," he said. "I am way past vengeance."

The PanAm airliner exploded as it flew to New York from London on December 21, 1988. All 259 people aboard the aircraft were killed and 11 others on the ground in the Scottish town of Lockerbie also died from falling wreckage.

Libyan agent Abdel Basset al-Megrahi was the only person found guilty of murder in the 1988 bombing of the airliner. He was convicted in January 2001 by a three-judge Scottish court sitting in the Netherlands. The court acquitted his co-defendant, Al-Amin Khalifa Fahima.

'GADDAFI HIMSELF ORDERED THIS'

"We know that there are more people involved, we're hoping that in the records and files that will turn up as a result of the overthrow of Gaddafi will give more evidence of other people's involvement," said Frank Duggan, president of the Victims of PanAm 103 group.

"But it was clear that Gaddafi himself ordered this."

Al-Megrahi was sentenced to life in prison but released by Scottish authorities on health grounds in August 2009, a decision that infuriated members of the victims' group.

"Sure the guy is supposedly dying, but he also knows who else is behind it and he should be in prison and that's where he should die," said Brian Flynn, vice president of the Victims of PanAm 103 group.

"There were other people behind the bombing, it wasn't just al-Megrahi and it wasn't just Gaddafi," said Flynn, whose brother J.P. Flynn was killed in the bombing.

But he said the families of the victims could feel a sense of accomplishment with the death of Gaddafi.

"We have been saying for more than 20 years ... that (Gaddafi) would continue to haunt the world until he was brought to justice," said Flynn. "We can take a certain sense of accomplishment that we were able to honor our loved ones and not give up."

(Editing by Mark Egan and Eric Beech)

Source: http://us.rd.yahoo.com/dailynews/rss/africa/*http%3A//news.yahoo.com/s/nm/20111020/wl_nm/us_libya_gaddafi_lockerbie

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Immigration debate intensifies in GOP race

Republican presidential candidates former Massachusetts Gov. Mitt Romney, left, and Texas Gov. Rick Perry speak during a Republican presidential debate Tuesday, Oct. 18, 2011, in Las Vegas. (AP Photo/Chris Carlson)

Republican presidential candidates former Massachusetts Gov. Mitt Romney, left, and Texas Gov. Rick Perry speak during a Republican presidential debate Tuesday, Oct. 18, 2011, in Las Vegas. (AP Photo/Chris Carlson)

WASHINGTON (AP) ? Neither Rick Perry nor Mitt Romney can claim conservative purity on illegal immigration ? and now both must deal with it.

Illegal immigration has emerged as a defining issue with remarkable staying power in a GOP presidential race that was expected to be primarily focused on the nation's struggling economy.

The heated clashes over illegal immigration between the two Republican presidential rivals in this week's debate made clear the issue isn't going away. It's a major fault line between them as they court a Republican primary electorate that generally takes a hard-line view against people who are in the country illegally.

At every turn, Perry, the Texas governor, has been forced to defend his signing of a law that allowed some illegal immigrants to get in-state college tuition. And now Romney is having to answer for the fact that some groundskeepers who had worked on his lawn were in the country illegally.

"Mitt, you lose all of your standing from my perspective because you hired illegals in your home, and you knew about it for a year," Perry told the former Massachusetts governor at Tuesday's debate in Las Vegas. "And the idea that you stand here before us and talk about that you're strong on immigration is, on its face, the height of hypocrisy."

Romney countered, "Rick, I don't think that I've ever hired an illegal in my life" and challenged his rival to show him the facts.

It was a preview of what Republicans can expect to hear in the coming weeks as the Jan. 3 leadoff Iowa caucuses inch closer, with Romney and Perry emerging as the two candidates with the best chances of winning the nomination. They're arguably the only Republicans with the money and organization necessary to go the distance.

For months now, immigration concerns have followed presidential contenders to town hall meetings from Nevada to Iowa to New Hampshire. And in some ways, immigration has shaped the increasingly bitter Republican nomination fight more than any other issue, particularly in a crowded field where the conservative candidates have more in common than not. And while conservative voters may be driving immigration chatter on the campaign trail, the candidates are stoking voter passions when given the opportunity.

"I'm not surprised that immigration is playing as big a role as it is," said Kevin Smith, a likely New Hampshire Republican gubernatorial candidate who has watched the candidates face repeated questions about the topic on the campaign trail. "This issue plays very well with Republican primary voters."

And it's clear they're listening.

Perry's sudden drop in the polls was largely attributed to weak debate performances involving his support for the Texas law. He suggested that Republicans who oppose the policy were heartless. And Romney fueled the tuition criticism every chance he got.

But Perry tried to neutralize the attacks this week. The outspoken Texan raised new questions at the debate about Romney's use of a landscaping company that employed illegal immigrants at his suburban Boston home several years ago.

For a moment, it looked as though Perry and Romney may come to blows as they debated the issue, with Romney at one point putting his hand on Perry's shoulder as the conversation began to heat up.

"The American people want the truth," Perry demanded. "They want to hear you say that you knew you had illegals working at your ..."

Romney cut in: "Would you please wait? Are you just going to keep talking, or are you going to let me finish with my ? what I have to say?"

For Romney, it was a frustrating return to an issue that played out in his 2008 presidential campaign.

At that time, and again Tuesday night, he said he had little control over whether a landscaping company he legally hired had illegal immigrants on the payroll. But the exchange provided one of the few moments in this presidential campaign in which the usually poised Romney showed flashes of anger.

That anger was apparent in campaign rhetoric from both sides the day after the debate.

"Gov. Perry is desperate to deflect from his liberal immigration record," Romney spokesman Ryan Williams said, calling Perry's launching of "a personal and untruthful attack" on Romney "unpresidential."

But don't expect Perry to back down from an issue that may have fueled his strongest debate performance.

Perry spokesman Ray Sullivan said, "Mr. Romney has been demagoguing and distorting these immigration and border control issues for months now." Sullivan argued that Romney was "exposed as someone who had illegal immigrants working in his lawn and cleaning his tennis court."

Sullivan would not say whether Perry might exploit the issue in television advertising, but he hinted that Romney has only seen the beginning of the new criticism.

There is danger is pushing too hard on immigration.

Polling suggests the issue may help the candidates score political points with Republican primary voters but could alienate the ballooning Hispanic population or hurt the candidates among independents in a general election matchup against President Barack Obama.

Obama campaign manager Jim Messina seized on the issue Wednesday.

"Romney's been taking hard-right positions on the campaign trail on immigration. He didn't object to having undocumented workers working for him because it's illegal; he objected because he thought it would hurt his political career," Messina said.

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/89ae8247abe8493fae24405546e9a1aa/Article_2011-10-20-Republicans-Immigration/id-1298475b28a148d38f4983db40c21c89

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Chris Rene will emerge a star, says "X Factor" judge (Reuters)

LOS ANGELES (Reuters) ? Recovering drug addict Chris Rene will become a star thanks to "The X Factor" but he needs to find the right material in order to win the TV singing contest, judge Antonio "L.A." Reid said on Thursday.

Reid told reporters he had faith that Rene, 28, a trash hauler who auditioned for the show just 70 days after leaving rehab, would stay clean during the contest.

The singer-rapper, whose audition video has been seen more than 6.4 million times on YouTube, is one of 17 finalists who will put their fate in the hands of the TV audience when live performances start next week.

Record producer Reid, who helped launch the careers of stars like Usher and Pink, picked Rene as one of the aspiring stars he will mentor for "X Factor."

"I have faith in Chris. I think he is going to emerge as a an amazing star and also a man we can be proud of who does have the strength to overcome the disease we call addiction," Reid told reporters on a conference call.

Rene told the judges at his first audition that he had been addicted for years to cocaine, methamphetamines and other drugs. But the single dad pledged to stay sober if he was picked for the show.

"Chris gave us his word that he will stay straight. I am going to take him at his word. When I see him, he looks amazing," Reid said.

"He has a very unique talent. Chris is somewhere between a singer and a rapper. He really just has to find the right material and give a compelling performance. If he gets into the moment, and he really feels comfortable with the material as he did with his own original material in his initial audition, then he is going to be fine," Reid said.

Created by Simon Cowell, "The X Factor" debuted on Fox television in September and offers an unprecedented $5 million prize plus a recording contract for the winner. The show is the latest in a crowded market of TV talent contests and has had a smaller than predicted U.S. audience of about 12 million viewers.

(Reporting by Jill Serjeant; Editing by Bob Tourtellotte)

Source: http://us.rd.yahoo.com/dailynews/rss/tv/*http%3A//news.yahoo.com/s/nm/20111020/tv_nm/us_xfactor

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