Looks like mobile OS allegiance will soon become part of the car buying decision: Hyundai and Kia will use Android to power in-car entertainment and navigation systems in all new models, starting with the new Kia Soul and Hyundai Genesis coming at the end of the year.
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Producer Janet Yang, who has long been involved in creating Hollywood-China partnerships, says studios need to be better engaged with the world's second-largest movie market.
Despite co-productions, partnerships like the one formed by DreamWorks Animation and studios incorporating Chinese actors and products into their films, "the studios are not doing that much right now," Yang told Reuters. "They are feeling it out."
PHOTOS: China's 10 Highest-Grossing Movies of All Time
She claims studios are mostly taking "defensive measures" to avoid alienating an important market.
"I've never seen so much talk about things with so few results. But that's going to change," Yang said. "It's two different systems trying to come together, so a lot of dating and few engagements and marriages but probably more on their way."
Yang has spent her career establishing partnerships between Hollywood and China since she advised on Steven Spielberg's 1987 film Empire of the Sun, shot partly in Shanghai. Since then she's produced The Joy Luck Club and Shanghai Calling, among other titles.
She also helped Disney adapt High School Musical for a Chinese audience.
She thinks studios should think about producing a homegrown film that would appeal to China and other markets.
"How about actually creating something that is appealing for the Chinese and also for the global market? I believe it's possible," Yang told Reuters.
The singer married her fiance in Tennessee! See more stars who made their romances official
Source: http://www.ivillage.com/celebrity-weddings-0/1-b-16623?dst=iv%3AiVillage%3Acelebrity-weddings-0-16623
Goldust vs. Seth Rollins: WWE Main Event, Oct. 23, 2013The Prime Time Players vs. The Real Americans: WWE Main Event, Oct. 23, 2013Dolph Ziggler vs. Damien Sandow: WWE Main Event, Oct. 23, 2013The Funkadactyls vs. Aksana & Alicia Fox: WWE Main Event, Oct. 23, 2013Seth Rollins & Roman Reigns want their gold back: WWE.com Exclusive, Oct. 21, 2013The Usos vs. The Shield: Raw, Oct. 21, 2013The Usos vs. The Shield continues: WWE App Exclusive, Oct. 21, 2013
BIRMINGHAM, Ala. – Just days away from WWE Hell in a Cell, WWE Main Event was chock full of action-packed matches, including Goldust battling Seth Rollins!
Seth Rollins def. Goldust
After a string of recent successes with his younger brother Cody Rhodes – including the duo winning the WWE Tag Team Titles – Goldust battled Shield member Seth Rollins on WWE Main Event. Still reeling from the loss of the tag titles to the Rhodes brothers, Rollins was seeking vengeance against the former Intercontinental Champion. . Nevertheless, the younger Rhodes sibling joined his face-painted kin as well in an effort to counteract Roman Reigns and keep the battle between the combatants inside the squared circle.
WWE Main Event photos | Watch Goldust battle Seth Rollins
The Hounds of Justice are certainly rabid and rely on controlled chaos as a unit, but Rollins is certainly a gifted competitor in his own right. Holding his own against Goldust – a Superstar with experience spanning three decades – the Shield member certainly displayed his abilities while also taking advantage of a distraction from Reigns.
With momentum in his favor, Rollins methodically attacked Goldust while taunting a helpless Cody Rhodes. However, Goldust has tussled with the likes of Roddy Piper and Triple H, buiding a resilience that has led him to a long, storied career and allowed him to battle back and keep Rollins at a disadvantage.
However, as the action spilled to the outside of the ring, Goldust exchanged words with Reigns. Cody took a more direct approach and attacked the Shield member as The Bizarre One returned to the ring to resume his struggle against Rollins. However, Reigns’ distraction was enough for Rollins to recover and roll up his opponent and steal a victory.
New York Jets head coach Rex Ryan stands on the sideline during the second half of an NFL football game against the New England Patriots on Sunday, Oct. 20, 2013, in East Rutherford, N.J. (AP Photo/Seth Wenig)
New York Jets head coach Rex Ryan stands on the sideline during the second half of an NFL football game against the New England Patriots on Sunday, Oct. 20, 2013, in East Rutherford, N.J. (AP Photo/Seth Wenig)
New England Patriots head coach Bill Belichick responds to a reporter's question during a media availability at the NFL football team's facility in Foxborough, Mass., Wednesday, Oct. 23, 2013. The Patriots will play the Miami Dolphins Sunday. (AP Photo/Stephan Savoia)
New England Patriots head coach Bill Belichick shakes hands with New York Jets head coach Rex Ryan after an NFL football game Sunday, Oct. 20, 2013 in East Rutherford, N.J. The Jets won the game 30-27. (AP Photo/Seth Wenig)
In this photo taken Sunday, Oct. 20, 2013, New England Patriots' Joe Vellano (72), Rob Ninkovich (50) and Chris Jones (94) watch as an official advances the ball after Jones was called for an unsportsmanlike penalty during overtime of an NFL football game against the New York Jets in East Rutherford, N.J. Jones was called for the penalty after pushing a teammate forward to try to block a Jets field goal, a new NFL rule. The Jets won the game 30-27 in overtime.(AP Photo/Seth Wenig)
In this photo taken Sunday, Oct. 20, 2013, New England Patriots coach Bill Belichick walks away from line judge Tom Stephan after the Patriots weres called for an unsportsmanlike penalty after New York Jets kicker Nick Foles missed a field goal during overtime of an NFL football game in East Rutherford, N.J. The Patriots' Chris Jones was called for the penalty after pushing a teammate forward to try to block the kick, a new NFL rule. The Jets won the game 30-27 in overtime. (AP Photo/Kathy Willens)
FLORHAM PARK, N.J. (AP) — Rex Ryan pushed back at Bill Belichick.
The New York coach vehemently denied the New England coach's claim that the Jets used similar push techniques on field goals against the Patriots on Sunday.
"That's not true!" Ryan said Wednesday.
During a conference call Tuesday with Boston reporters, Belichick was asked if he was bothered by a report that said the Jets alerted officials to the Patriots pushing on field goals. New England was called for the penalty — the first time it had been called in a game — to set up New York's winning field goal in overtime Sunday.
"Well, I mean, since they were using the play themselves, I don't even know about all that," Belichick said. "But, basically we're just moving on here."
Belichick was apparently referring to a play during Stephen Gostkowski's 44-yard field goal with 16 seconds left in regulation. Quinton Coples appeared to extend his right arm and slightly push teammate Muhammad Wilkerson from behind toward the Patriots' formation.
There was no call on that play, but it was also not as evident as what the Patriots did in overtime when Nick Folk was wide left on a 56-yarder, but had the miss was negated when New England's Chris Jones was called for unsportsmanlike conduct on a 15-yard penalty. Jones was penalized for pushing his teammate "into the opponents' formation."
Folk kicked a 42-yarder to win it a few minutes later, giving the Jets a 30-27 victory.
Belichick disagreed with the application of the rule after the game, saying, "You can't push in the second level. I didn't think we did that." Belichick backtracked Monday, saying he was mistaken in his interpretation.
But then came his accusatory comments on Tuesday.
"He's got to make up his mind," Ryan said. "Was he aware of this thing? Was it second-level, all this kind of jazz? Or, now the story is we did it? OK, I got you.
"The fact is, we're moving on. We earned that victory plain and simple, and we're focused on Cincinnati now."
NOTES: Wide receiver Santonio Holmes and tight end Jeff Cumberland both didn't practice with hamstring injuries. Ryan seemed optimistic Cumberland will be OK to play Sunday at Cincinnati. Holmes, however, has missed three straight games since being hurt at Tennessee last month. ... Backup QB David Garrard was activated Monday and added to the active roster after sitting out a few months while contemplating retirement because of a balky knee. Ryan said Garrard's conditioning is "good but I wouldn't call it great right now," but added that the veteran's arm is strong and could serve as a mentor to rookie Geno Smith. "He's been there and done it," Ryan said.
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AP NFL website: www.pro32.ap.org
Associated PressSource: http://hosted2.ap.org/APDEFAULT/347875155d53465d95cec892aeb06419/Article_2013-10-23-FBN-Patriots-Jets-Push-Penalty/id-22c2f0730ddc4ce7b0611e25d8719ed5From left, Aetna CEO Mark Bertolini, Humana CEO Bruce Broussard, Blue Cross Blue Shield of Florida CEO Patrick Geraghty, and other health care chief executive officers arrive at the White House in Washington, Wednesday, Oct. 23, 2013, to meet with White House officials regarding President Barack Obama's health care law. (AP Photo/Charles Dharapak)
From left, Aetna CEO Mark Bertolini, Humana CEO Bruce Broussard, Blue Cross Blue Shield of Florida CEO Patrick Geraghty, and other health care chief executive officers arrive at the White House in Washington, Wednesday, Oct. 23, 2013, to meet with White House officials regarding President Barack Obama's health care law. (AP Photo/Charles Dharapak)
House Speaker John Boehner of Ohio speaks during a new conference following a meeting at the Republican National Committee offices on Capitol Hill in Washington, Wednesday, Oct. 23, 2013. (AP Photo/Susan Walsh)
House Minority Leader Nancy Pelosi of Calif. gestures as she speaks to reporters during a news conference on Capitol Hill in Washington, Wednesday, Oct. 23, 2013. (AP Photo/Manuel Balce Ceneta)
House Speaker John Boehner of Ohio, left, and House Majority Leader Eric Canton of Va., right, walk away from the microphones following a news conference after a meeting at the Republican National Committee offices on Capitol Hill in Washington, Wednesday, Oct. 23, 2013. (AP Photo/Susan Walsh)
From left, Tufts Health Plan President and CEO James Roosevelt, Aetna CEO Mark Bertolini, Humana CEO Bruce Broussard, Blue Cross Blue Shield of Florida CEO Patrick Geraghty, Kaiser Permanente CEO Bernard Tyson, and other health care chief executive officers arrive at the White House in Washington, Wednesday, Oct. 23, 2013, to meet with White House officials regarding President Barack Obama's health care law. (AP Photo/Charles Dharapak)
WASHINGTON (AP) — On the defensive, the Obama administration acknowledged Wednesday its problem-plagued health insurance website didn't get enough testing before going live. It said technicians were deep into the job of fixing major computer snags but provided no timetable.
Democratic unhappiness with the situation began growing louder — including one call for President Barack Obama to "man up" and fire someone — as the president's allies began to fret about the political fallout. Democrats had hoped to run for re-election touting the benefits of the health care law for millions of uninsured Americans, but the computer problems are keeping many people from signing up.
The White House also signaled a change underway in the timeline for signing up for coverage. Consumers have until Dec. 15 to apply for coverage that's effective Jan. 1. Even though open enrollment lasts until March 31, people would face a penalty if they postpone buying coverage beyond mid-February. Calling that a "disconnect," the White House said officials will soon issue policy guidance so that if consumers sign up by the end of March they will not face a penalty. No action from Congress is needed to make that happen, the White House said.
Republican sniping about the website's flaws continued unabated, with House Speaker John Boehner declaring, "We've got the whole threat of Obamacare continuing to hang over our economy like a wet blanket."
Obama himself, though strongly defending the health care overhaul, has been increasingly willing to acknowledge extensive problems with the sign-up through online markets. Amid all that, the Health and Human Services Department on Wednesday provided its most specific accounting yet of the troubles with HealthCare.gov — an issue that is also about to get a lengthy, even-less-forgiving airing on Capitol Hill.
The first of several hearings is set for Thursday in the Republican-led House, with lawmakers ready to pounce on the contractors who built the balky online enrollment system.
Acknowledging what's been obvious to many outside experts, the administration said Wednesday that the system didn't get enough testing, especially at a high user volume. It blamed a compressed time frame for meeting the Oct. 1 deadline to open the insurance markets. Basic "alpha and user testing" are now completed, but that's supposed to happen before a launch, not after.
The Health and Human Services explanation identified some bugs that have gotten little outside attention.
For example, technical problems have surfaced that are making it hard for people to complete the application and plan-shopping functions. That's a big concern because those stages are further along in the signup process than the initial registration, where many consumers have been getting tripped up. The problems are being analyzed and fixes are planned, the department said.
The explanation, posted online in a department blog and accompanying graphic, identified other broad areas of problems and outlined fixes underway but in most cases incomplete:
— Unexpectedly high consumer interest that overwhelmed the system in its initial days. Equipment has been added to handle the load and system design has been improved. More fixes are in progress.
— Lack of a way for consumers to browse their health plan options without first having to set up a user account. A partial fix is in place.
— Incorrect or duplicate information in enrollments is being delivered to insurance companies. Some software fixes that should help address the issue have been completed, others are underway.
— Difficulties for consumers trying to create user accounts, including drop-down menus that didn't work. Design changes and software fixes should address the situation.
The new markets are supposed to be the portal to coverage for people who don't get health insurance on the job. Middle-class people are to pick from subsidized private insurance plans, while low-income people are steered to Medicaid in states that agreed to expand that safety-net program.
The federal government is running the online markets in 36 states, and its website has had more than its share of problems. As a result, even Obama has urged consumers to revert to low-tech approaches, by applying through the mail, telephoning federal call centers, or seeking in-person assistance.
On Thursday, the House Energy and Commerce Committee will line up contractors, including CGI Federal, the lead developer of the website, and QSSI, which designed a back-room operation known as the federal data services hub. The hub is integral to verifying applicants' personal information and income details, and the administration says it is working as designed.
Rep. Joe Pitts, R-Pa., chairman of the panel's health subcommittee, said he wants to focus on the administration's decision not to allow browsing, or window shopping. That's a standard feature of e-commerce sites, including Medicare.gov for seniors. Lack of a browsing capability forced all users to first go through the laborious process of creating accounts, overloading that part of the site.
"Who made that decision? When was it made? Why was it made?" said Pitts.
In prepared testimony, an executive of QSSI's parent company said the decision was made late in the game. It could have contributed to overloading the system, said the executive, Andy Slavitt.
CGI vice president Cheryl Campbell said the administration was the "quarterback" of the entire effort.
Meanwhile, Democrats are worrying aloud about persistent problems with the rollout. Rep. Richard Nolan of Minnesota emerged from a Wednesday morning meeting with administration health care officials on Capitol Hill and told The Associated Press the computer fiasco has "damaged the brand" of the health care law.
"The president needs to man up, find out who was responsible, and fire them," Nolan said. He did not name anyone.
Likewise in the Senate, Florida Democrat Bill Nelson said somebody should be fired over the computer problems. "That's the problem in government today," Nelson told ABC's Miami affiliate. "People are not held to account."
Obama says he's as frustrated as anyone and has promised a "tech surge" to fix the balky website. White House spokesman Jay Carney also said the administration will be more open about the problems. After more than 20 days without briefing the media, HHS will start regular sessions on Thursday, he said.
In light of the computer problems, some Democrats are saying Obama should consider extending open enrollment season beyond next March 31, and revisit the penalties for individuals who don't sign up and remain uninsured. Under the law virtually all Americans must carry health insurance starting next year or face fines.
House Democratic Leader Nancy Pelosi advised against the change.
"I think we should try to fix what we have, move forward with the deadline we have," the California Democrat told reporters. "What we want to do is fix it and go forward with it, not make policies that are predicated on its not working."
Even if the computer problems get ironed out, the Republicans are unlikely to end their criticism. Said Boehner on Wednesday: "When you look at the problems with Obamacare, all the focus here lately has been on the website. ... I would argue the problems go much further than that."
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Associated Press writers Josh Lederman, Laurie Kellman and Julie Pace contributed to this report.
Associated PressSource: http://hosted2.ap.org/APDEFAULT/3d281c11a96b4ad082fe88aa0db04305/Article_2013-10-23-Health%20Overhaul-Problems/id-80d55e134e81402cac6ea237a8a863bb
Part of the whole draw of gardening is watching your botanical efforts slowly bloom. But let's face it—most of us barely have time to water the houseplants regularly, much less manage a garden. Luckily, with these internet-enabled plant sensing systems, you'll be able to watch your garden grow from the couch.
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Chan Sung Jung is a cult favorite among MMA fans for his courageous and aggressive fighting style. When it comes to issues he cares about, the featherweight contender is just as committed outside the cage as he is inside it.
Earlier this year, the “Korean Zombie” sent an open letter to Georges St. Pierre, in an attempt to educate and chastise the welterweight champ for wearing a gi to the ring before his fight against Nick Diaz that had the rising sun symbol – a symbol used on the World War II Japanese war-time flag. Jung pointed out that to many people in Asian countries, the rising sun symbol brought up memories of atrocities committed by Japan during the second world war and that using the symbol was akin to someone using a Nazi swastika.
Jung’s letter made a difference. St. Pierre issued an apology to those offended and the maker of the gi also apologized and decided not to take the gi to market.
Viewers of this season’s Ultimate Fighter may have noticed bantamweight champion Ronda Rousey wearing a T-shirt sold by the UFC that also features the rising sun symbol, on a Pride Fighting Championships T-shirt. In response, Jung has written and sent out another letter, this time to one of his biggest fans – UFC president Dana White – asking that the UFC be more sensitive to what the symbol means to Koreans and others.
Bleacher Report obtained a copy of Jung’s letter. Here’s an excerpt from it.
“We have decided to take the time to speak up for what we know is right, because we do believe this is something that UFC management should absolutely be aware of. Let's get straight to the point.
It's about 'Rising Sun Flag' outfits. And our point is that this design is the symbol of war crimes, and that every single item designed after this symbol of war crimes should be kicked out of the UFC, firstly for justice, and then for the company.
... Let bygones be bygones? Get over it? Unjustified invasion, torture, massacre, military and sexual slavery, medical experiments on living prisoners of war and many other war crimes scarred too many people. It can never be forgotten. This is a tragic history for all of us. Furthermore, the Japanese government never gave a sincere apology, and is even trying to justify and distort their dirty, nasty history. Still to this day, so many victims are dying in pain, heartbroken, without being properly compensated.
... I was happy because I thought we have succeeded in educating a chunk of the world on a very important issue, and that we no longer have to see that symbol of war crimes, at least around the Octagon. But a few days later, another UFC champion and the symbol of [women's mixed martial arts], Ronda Rousey was seen in that 'Rising Sun Flag' outfit. Two UFC champions wearing the symbol of war crimes! Don't you think this will be an awful example for our company, which actually does a lot of charity stuff for troops as well?
This sport, mixed martial arts, is growing very fast. And on the top of everything is the UFC. It's been crossing borders with great ease. The event was a great success in Europe, Australia and Brazil, and now it's time for Asia. As a fighter, I'm really excited and happy to see the sport growing, but I don't even want to imagine UFC fighters in those outfits, especially in Asia. A lot of furious, heartbroken people will boycott the UFC, leading to a loss of a lot of (potential) fans, which will end up leaving a very bad impression on the Asian market. I mean, can you imagine our fighters in Nazi outfits in Europe? For us Asians, it’s nothing different.”
The UFC indeed is attempting to grow in Asian countries and Jung brings up an interesting point. Does enough of Asia agree with Jung about the symbolism of the rising sun emblem that it could hurt the UFC’s reputation in countries like South Korea?
We don’t ourselves know the answer but we’re glad anytime a thoughtful discussion about history and society arise in sports. So far, the UFC has not issued a formal response to Jung’s letter.
If you’ve got an interesting take on the issue, let us know in the comments section.
Source: http://sports.yahoo.com/blogs/mma-cagewriter/korean-zombie-says-ufc-needs-show-more-sensitivity-185751004--mma.htmlFILE -This Sunday, Oct. 23, 1983 file photo shows the aftermath of a suicide truck bombing of the U.S. Marines barracks in Beirut, Lebanon. The blast _ the single deadliest attack on U.S. forces abroad since World War II _ claimed the lives of 241 American service members. It was the single deadliest attack on U.S. forces abroad since World War II. (AP Photo/Jim Bourdier, File)
FILE -This Sunday, Oct. 23, 1983 file photo shows the aftermath of a suicide truck bombing of the U.S. Marines barracks in Beirut, Lebanon. The blast _ the single deadliest attack on U.S. forces abroad since World War II _ claimed the lives of 241 American service members. It was the single deadliest attack on U.S. forces abroad since World War II. (AP Photo/Jim Bourdier, File)
COMBO - This combination of two photographs shows the aftermath of a suicide truck bomb attack on the U.S. Marine barracks in Beirut, Lebanon on Sunday, Oct. 23, 1983, top, and the site of the blast as seen 30 years later on Wednesday, Oct. 23, 2013. The blast _ the single deadliest attack on U.S. forces abroad since World War II _ claimed the lives of 241 American service members. It was the single deadliest attack on U.S. forces abroad since World War II. (AP Photo/Mark Foley, Bilal Hussein)
FILE - In this Oct. 23, 1983 file photo, British soldiers give a hand in rescue operations at the site of the bomb-wrecked U.S. Marine command center near the Beirut airport, Lebanon. A bomb-laden truck drove into the center collapsing the entire four story building. The blast _ the single deadliest attack on U.S. forces abroad since World War II _ claimed the lives of 241 American service members. (AP Photo/Bill Foley, File)
FILE - This Oct. 23, 23, 1983 file photo shows the scene around the U.S. Marine barracks near Beirut airport following a massive bomb blast that destroyed the base, in Beirut, Lebanon. The blast _ the single deadliest attack on U.S. forces abroad since World War II _ claimed the lives of 241 American service members.(AP Photo, File)
FILE - This Oct. 23, 1983, file photo shows the scene of a truck bombing on a U.S. Marine base near Beirut airport in Beirut, Lebanon. This was a rock-solid structure that had withstood Israeli air and artillery attack during the Israeli invasion of 1982. Yet it had been blown to pieces by a truck bomb that exploded just before 6:30 a.m. that day, with the force of 21,000 pounds of TNT.(AP Photo, File)
It had been a massive, four-story building that had withstood air strikes and artillery — now reduced to a mountain of rubble. Enormous chunks of concrete, their twisted steel reinforcements ripped bare, balanced precariously on piles of debris. Only cracked concrete frames on the ground floor bore any semblance to what had stood there before.
As I watched crews struggle to remove wreckage from what remained of the U.S. Marine barracks in Beirut, I thought to myself, "My God. How did anyone survive?"
The Oct. 23, 1983 truck bombing that leveled the barracks near Beirut's airport claimed the lives of 241 American service members in the deadliest attack on U.S. forces abroad since World War II. The attack, amid Lebanon's civil war, was one of the United States' first experiences with the suicide bombings that over the past 30 years have become a trademark of Islamic militants.
By the time I arrived, the bodies were gone, and survivors evacuated. The day of the blast, I was in Cairo, where I was The Associated Press' bureau chief, and I traveled to Beirut in the immediate aftermath.
For me the shock was all the more intense because I had known that building — and doubtless some of the Marines who had perished inside.
During repeated assignments in Lebanon, I spent hours on the barracks' roof, along with other journalists, observing militias on the hills above hit their rivals and sometimes the Marines with artillery fire.
I recall watching visiting Marine generals scurrying for cover one afternoon when militias lobbed mortar shells near their convoy — to the amusement of some younger Marines.
The roof was also the site of the Marines' link to a radio network with the French and British to exchange information about battles around Beirut. If you could tolerate the blazing sun and long periods of boredom, it was a great place to track the fighting.
The structure — once an administrative building for the airport — was rock-solid. It had survived hits by Israeli air and artillery fire in 1982, well before the Marines moved in.
Yet it was pulverized by a truck bomb that exploded with the force of 21,000 pounds of TNT just before 6:30 a.m. on a Sunday. Minutes later, a second suicide bomber blasted the French military barracks a few miles north, killing 58 paratroopers and the wife and four children of the Lebanese janitor.
Shiite militias that were just starting to coalesce into what is now Hezbollah were behind the attacks.
The Marines, along with French and British troops, arrived in Beirut in August 1982. The Marines were to supervise the evacuation of Palestinian guerrillas under a deal to end Israel's invasion of Lebanon.
Instead, the experience became a textbook example of "mission creep."
After the Palestinians departed, the Marines did as well. But they were ordered back about two weeks later when the assassination of Lebanon's new Christian president sparked new fighting among the country's factions.
Syrian-backed militias frequently fired on the Marines' base and barracks, about 10 miles from downtown Beirut, to pressure the United States, which supported the Lebanese government.
A month before the bombing, U.S. warships fired on Syrian-backed militias, and French jets attacked militias in the Bekaa Valley.
Among anti-government factions, those attacks shattered any notion of neutrality.
The Marine commander, Col. Timothy Geraghty, recalled telling his staff that "we were going to pay in blood."
Within months after the bombing, the U.S. Marines were out of Lebanon. The civil war raged for another seven years.
Now on the site of the barracks is a large building of the Lebanese mail service, Liban Post, inside a closed military zone near the airport. On one side, access is barred by a military checkpoint and on the other, by a checkpoint of Hezbollah, now Lebanon's most powerful force.
The following is a gallery of images from the time of the Marine barracks bombing and today.
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Robert H. Reid, Berlin bureau chief, was chief of bureau for The Associated Press in Cairo from 1982-1986 and has covered Middle East events since 1978. Follow him at: http://twitter.com/rhreid .
Follow AP photographers and photo editors on Twitter: http://apne.ws/15Oo6jo
Associated PressSource: http://hosted2.ap.org/APDEFAULT/cae69a7523db45408eeb2b3a98c0c9c5/Article_2013-10-23-Lebanon-Marine%20Bombing-Photo%20Essay/id-978d88691e4a4ea29928ecf6f3a27201
Will Tony Stark's comic book brother take over for Robert Downey Jr. in the Marvel movie-verse?
By Alex Zalben
LinkedIn today is presenting an update on its mobile strategy, and as part of that, its parted the curtain a bit to show us how its planning to integrate Pulse into its platform. (Pulse, if you recall, was acquired for some $90 million in April of this year.) Ankit Gupta, Pulse’s co-founder said it would become the “content brand” for LinkedIn. As part of that, the app will start to offer users the ability for people to log in with their LinkedIn identities to receive recommended stories, and it will start to incorporate content from influencers.
The idea is that Pulse will be not just a place to read news, but a place for people to read news tailored to their professional lives. “We will be bringing better content experiences to empower users throughout their day and their careers,” he said. The app will be released later this year, Gupta said.
The concept of a single sign on and a user’s identity that will be used outside of LinkedIn’s own platform is an interesting one: it’s also something that LinkedIn’s acquisition of Rapportive is exploring with its new LinkedIn Intro app for iPhone. Currently invitation-only, Intro is effectively Rapportive gone mobile. It examines correspondence through your native iPhone mail app and then provides more insight into the sender and other content in the message.
LinkedIn today also announced a new a new iPad app that it says underscores its new approach to mobile with an updated feed with more visual images and video, as well incorporating its rebuilt search engine, introduced earlier this year on the desktop.
The company said that some 38% of all traffic is on mobile, and next year LinkedIn’s CEO Jeff Weiner said today that LinkedIn will cross its “mobile moment,” where mobile traffic will surpass that of desktop traffic.
The company has been on personalization tear over the last year, with improved search, more features in its mobile apps — including the ability to upload and edit resumes and apply for jobs, and a separate app to manage contacts — and updates of its user home page, LinkedIn Today, to include curated content (a place where we can expect more to come from its Pulse acquisition). The idea will be to ensnare all verticals as it goes on. One of these, to target universities in an effort started in August, now already has some 1,500 universities on board, Weiner said.
This is done with what the company says is a hands-off approach, with echoes of Google in its description of its philosophy on search than Facebook or Apple and their ecosystems. “We’d like there to be a professional profile for every one of the 3 billion-plus professional people in the world today,” said Weiner, “and then we’d like to step away.” He and LinkedIn see this as a potential economic boost.
“How is mobile allowing us to reinvent LinkedIn?” Weiner asked today. “The expectations of our users today is that those applications are going to continue to evolve… We can’t just take the desktop experience and port it over to mobile.” This includes taking into account screensize as well as user expectations and the need for users to find information faster.
During the presentation today Deep Nicer, SVP of Products and User Experience, admitted some of what LinkedIn learned along the way: from launching its first iPhone app in 2010, it thought it had everything sewn up. “Ten months later we had to completely rewrite it,” he said. And then it had to do it again, and again. That’s including needing to continue to staff and train existing staff to think and act mobile-first. That has included not just coding at the back end, but in terms of rethinking design.
“The magic of mobile is keeping simple simple. I have a five-second rule,” noted Kiran Prasad, Senior Director, Mobile Engineering. He noted that there is no way of putting the 500-odd distinct pages that LinkedIn offers on desktop into its mobile app. It’s a step away from trying to achieve parity in a single site, and a move towards a multiple-app strategy.
Wayne Kramer.
For the whys and whos of Detroit's Sense of Place in rock history, World Cafe host David Dye talks with Motor City music icon Wayne Kramer. In the 1960s, Kramer co-founded the MC5, the loud, passionate, radical rock band that served as the foundation of much of the Detroit rock that came later.
In this session, Kramer provides insight into how the economic woes of the city — and the consequent rise in crime — affected the music scene. He also describes the scene at the Grande Ballroom when shouts of "Kick out the jams!" led to the MC5's best-known song.
The rock veteran also takes some time to discuss his charity Jail Guitar Doors USA, which he founded with musician Billy Bragg to provide instruments for incarcerated musicians.
Pulling in some big names, we see!
Looks like Taylor Swift, queen of awards shows, will be performing a special version of her song Red with some HUGE country music names!
Alison Krauss, Vince Gill, bassist Edgar Meyer, Sam Bush, and percussionist Eric Darken will join the country cutie on stage during the Country Music Awards on November 6!
Sounds like it's gonna be a real good country-filled time! We can't wait!!
In addition to TSwift's performance, Jason Mraz will also be performing with Hunter Hayes and the Foo Fighters will be playing alongside Zac Brown Band!
Sounds like a cool fusion of country meets contemporary! So cool!!
We wonder when Swifty will start performing Sweeter Than Fiction on the awards circuit! Hopefully soon!
Maybe we'll see her perform it at the Oscars! Ya know, when she wins her Oscar along with Meryl Streep for her role in The Giver!?!
LOLz!!! Ya never know!
[Image via WENN.]
Tags: abc, alison strauss, awards, band, bassist, blake shelton, brad paisley, carrie underwood, country, country music, country music awards, cutie, foo fighters, huge, inspiration, jason aldean, jason mraz, music, music minute, nashville, nominations, nominees, november, on stage, perform, performance, performing, queen, red, singer, song, special, swifty, taylor swift, version, vince gill
Speaking at today's launch event in San Francisco, Phil Schiller announced the next iteration of the company's tablet. It's thinner, lighter and more powerful -- hence the new name: the iPad Air. (No more of that "new iPad" nonsense.) And Cupertino takes that moniker seriously; this slate weighs ...
Supreme Court Justice Sonia Sotomayor was named by 5 percent of respondents as "the most important Hispanic leader in the country today."
Supreme Court Justice Sonia Sotomayor was named by 5 percent of respondents as "the most important Hispanic leader in the country today."
While most Latinos believe it's important for their community to have a national leader, most of them can't pinpoint whom they think that leader is.
That's the new finding from a survey released today by the Pew Research Hispanic Trends Project. Survey participants were asked an open-ended question to name the person they think is "the most important Hispanic leader in the country today."
Sixty-two percent responded they didn't know and 9 percent said no one.
Only four leaders were named by more than 2 percent of the respondents:
— Supreme Court Justice Sonia Sotomayor — the high court's first Hispanic justice — was mentioned by 5 percent.
— Sen. Marco Rubio, a Florida Republican, was named by 5 percent.
— Former Los Angeles Mayor Antonio Villaraigosa was named by 3 percent.
— And Rep. Luis Gutierrez, an Illinois Democrat, was named by 2 percent.
Pew explains:
"The survey was conducted at a time when Latino political leaders and civic organizations have been pressing hard for legislation in Congress to create a pathway to citizenship for the estimated 11.7 million immigrants, the vast majority of them Latino, who are living in this country illegally.
"Even though most Latinos say their community needs a national leader to advance its concerns, the survey finds that not all Latinos agree that their community has shared values.
"Overall, four-in-ten (39%) respondents say that U.S. Latinos of different origins share 'a lot' of values, while another 39% say U.S. Latinos share 'some' values and an additional 19% say that they share few or no values. By similar shares, Latinos living in this country are divided about how many values they share with Latinos living in their families' country of origin."
Of course, these findings aren't totally surprising. Earlier this year, when the pace on immigration reform quickened, we explored the issue. We asked people who were among the thousands protesting in Washington, D.C., who was the leader of the movement. No one could come up with a name.
Walk around any city in Colombia and you'll find vendors selling counterfeit soccer jerseys. That came in handy for Bogota's Independiente Santa Fe team. They showed up for an away game in the wrong color, so a team official bought knockoffs from vendors.
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DAVID GREENE, HOST:
Good morning. I'm David Greene. Walk around any city in Colombia and you'll find vendors selling counterfeit soccer jerseys which came in handy for Bogota's Independiente Santa Fe team. They showed up for an away game in the wrong color jerseys. Their opponents could've helped by changing into another color, but they refused. So a Santa Fe team official went outside the stadium and bought knockoffs from vendors.
Players had their names and numbers scribbled on with a Sharpie and they won two-to-nothing. It's MORNING EDITION.
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WASHINGTON (AP) — A top White House economic adviser says the addition of 148,000 jobs in September is a sign of "solid" growth but forecasts worsening in October because of the 16-day partial government shutdown.
Jason Furman, who chairs the White House Council of Economic Advisers, says the policy focus has to return to achieving a faster pace of job growth by increasing certainty and investing in jobs instead of what he said were the "self-inflicted wounds" of the past few weeks.
Furman was referring to the shutdown. He says it increased uncertainty and hindered job creation.
The September unemployment report was released Tuesday, weeks later than usual, because of the shutdown. Furman said the report describes the economy more than a month ago. He says more recent indicators suggest worsening in October.
Associated PressSource: http://hosted2.ap.org/APDEFAULT/89ae8247abe8493fae24405546e9a1aa/Article_2013-10-22-US-Economy-White-House/id-f311e1099f184a98a863116ddc2c66d2![[ Back to EurekAlert! ]](http://www.eurekalert.org/images/back2e.gif){kind=small}
PUBLIC RELEASE DATE: 22-Oct-2013
ShareContact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research
BOSTON A functional biomarker that can predict whether BRAF-mutant melanomas respond to drugs targeting BRAF could help guide the treatment of patients with these cancers, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19 23.
Approximately 50 percent of melanomas harbor mutations in the BRAF gene, and the U.S. Food and Drug Administration has approved two drugs that target BRAF for the treatment of such cancers. However, not all patients with BRAF-mutant melanomas respond to treatment with these, and most of those patients who initially respond eventually relapse because their tumors become resistant to the effects of the BRAF-targeted drugs.
"Our study has identified decreased phosphorylation of the protein S6 after treatment with BRAF-targeted drugs as a functional biomarker that predicts sensitivity of BRAF-mutant melanomas to these drugs," said Ryan B. Corcoran, M.D., Ph.D., a Damon Runyon clinical investigator and assistant professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, Mass. "Importantly, we have developed a minimally invasive way to rapidly monitor post-treatment changes in S6 phosphorylation in patients' tumor cells. As a result, we think that we can quickly determine whether or not a patient is likely to respond to a BRAF-targeted drug and help speed up treatment decisions, although we need to verify this in larger clinical studies."
BRAF gene mutations lead to inappropriate BRAF protein activity, which, in turn, causes a cascade of inappropriate activation of numerous other proteins in the tumor cell. Corcoran and colleagues therefore examined whether there were differences in the activity of the proteins downstream of BRAF in BRAF-mutant melanoma cell lines responsive and resistant to the BRAF-targeted drug vemurafenib.
They found that decreased phosphorylation of the protein S6 after treatment with vemurafenib was associated with responsiveness of BRAF-mutant melanoma cell lines to the drug both in vitro and in mice.
They then analyzed S6 phosphorylation in tumor biopsies obtained from nine patients with BRAF-mutant melanomas before and after they had initiated treatment with a BRAF-targeted drug. Six patients had lower levels of tumor cell S6 phosphorylation after treatment compared with before treatment, and this was associated with an almost fivefold improvement in progression-free survival.
Finally, the researchers evaluated a method to rapidly monitor, in real time, levels of S6 phosphorylation in tumor cells. They found that they could reliably assess levels of S6 phosphorylation in tumor cells in fine-needle aspiration biopsies from patients before and during the first two weeks of treatment with a BRAF-targeted drug, and that in these patients, a decrease in S6 phosphorylation after treatment correlated with treatment response.
"Many of the signaling pathways known to drive various types of cancer regulate phosphorylation of S6, not just the BRAF pathway," said Corcoran. "Therefore, we are investigating whether S6 phosphorylation could be a biomarker of response to therapies that target these pathways in cancers other than melanoma."
###
This study was funded by a Damon Runyon Clinical Investigator Award, the National Institutes of Health, and the National Cancer Institute. Corcoran has no conflicts of interest to declare.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Guiding Treatment for BRAF- and BRCA-related Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 22 at 9 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
To interview Ryan Corcoran, contact Katie Marquedant at kmarquedant@partners.org or 617-314-3986. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.
About the National Cancer Institute
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the European Organisation for Research and Treatment of Cancer
The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.
EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org
Abstract Number: C137
Presenter: Ryan B. Corcoran, M.D., Ph.D.
Title: Rapid assessment of TORC1 suppression as a functional biomarker predicting responsiveness to RAF and MEK inhibitors in BRAF-mutant melanoma patients
Authors: Ryan B. Corcoran1, S. Michael Rothenberg1, Aaron N. Hata1, Anthony C. Faber1, Adriano Piris1, Rosalynn M. Nazarian1, Ronald D. Brown1, Jason T. Godfrey1, Daniel Winokur1, John Walsh1, Mari Mino-Kenudson1, Shyamala Maheswaran1, Jeffrey Settleman2, Jennifer A. Wargo1, Keith T. Flaherty1, Daniel A. Haber1, Jeffrey A. Engelman1. 1Massachusetts General Hosp. Cancer Ctr., Boston, MA; 2Genentech, South San Francisco, CA
The clinical development of selective RAF and MEK inhibitors has transformed the treatment of the ~50% of melanoma patients whose tumors harbor BRAF mutations. However, a substantial percentage of these patients fail to respond to therapy, and most responses are partial and short-lived. Although multiple mechanisms of resistance have been identified in BRAF-mutant melanoma, no clinically useful biomarkers have been established to predict which patients are most likely to demonstrate sensitivity or resistance to RAF or MEK inhibitors. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein-S6 (P-S6), was a functional biomarker that effectively predicted sensitivity in BRAF-mutant melanoma cell lines in vitro and in mouse tumor xenografts. In sensitive melanomas, TORC1 and P-S6 were suppressed in response to RAF or MEK inhibitors, but in resistant melanomas, TORC1 activity was maintained, in some cases despite robust suppression of MAPK signaling by these inhibitors. In mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response in vivo. Notably, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression was associated with significantly improved progression-free survival [HR 0.19, 95% CI 0.01-0.84, p=0.03]. Finally, we found that changes in P-S6 in patients' tumor cells could be readily monitored in real-time by multiplexed, quantitative immunofluorescence microscopy of serial fine-needle aspiration biopsies obtained from patients before and during the first 2 weeks of RAF inhibitor therapy. This approach provides a minimally-invasive means of rapidly monitoring the efficacy of treatment, before changes in tumor volume are apparent by traditional radiographic imaging. Together, these results establish suppression of P-S6 after initiation of RAF inhibitor therapy as a robust potential functional biomarker to guide the treatment of patients with BRAF-mutant melanoma, and present a powerful methodology for monitoring changes in potentially any signaling pathway in response to targeted therapies in patients.
Share
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.
PUBLIC RELEASE DATE: 22-Oct-2013
ShareContact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research
BOSTON A functional biomarker that can predict whether BRAF-mutant melanomas respond to drugs targeting BRAF could help guide the treatment of patients with these cancers, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19 23.
Approximately 50 percent of melanomas harbor mutations in the BRAF gene, and the U.S. Food and Drug Administration has approved two drugs that target BRAF for the treatment of such cancers. However, not all patients with BRAF-mutant melanomas respond to treatment with these, and most of those patients who initially respond eventually relapse because their tumors become resistant to the effects of the BRAF-targeted drugs.
"Our study has identified decreased phosphorylation of the protein S6 after treatment with BRAF-targeted drugs as a functional biomarker that predicts sensitivity of BRAF-mutant melanomas to these drugs," said Ryan B. Corcoran, M.D., Ph.D., a Damon Runyon clinical investigator and assistant professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, Mass. "Importantly, we have developed a minimally invasive way to rapidly monitor post-treatment changes in S6 phosphorylation in patients' tumor cells. As a result, we think that we can quickly determine whether or not a patient is likely to respond to a BRAF-targeted drug and help speed up treatment decisions, although we need to verify this in larger clinical studies."
BRAF gene mutations lead to inappropriate BRAF protein activity, which, in turn, causes a cascade of inappropriate activation of numerous other proteins in the tumor cell. Corcoran and colleagues therefore examined whether there were differences in the activity of the proteins downstream of BRAF in BRAF-mutant melanoma cell lines responsive and resistant to the BRAF-targeted drug vemurafenib.
They found that decreased phosphorylation of the protein S6 after treatment with vemurafenib was associated with responsiveness of BRAF-mutant melanoma cell lines to the drug both in vitro and in mice.
They then analyzed S6 phosphorylation in tumor biopsies obtained from nine patients with BRAF-mutant melanomas before and after they had initiated treatment with a BRAF-targeted drug. Six patients had lower levels of tumor cell S6 phosphorylation after treatment compared with before treatment, and this was associated with an almost fivefold improvement in progression-free survival.
Finally, the researchers evaluated a method to rapidly monitor, in real time, levels of S6 phosphorylation in tumor cells. They found that they could reliably assess levels of S6 phosphorylation in tumor cells in fine-needle aspiration biopsies from patients before and during the first two weeks of treatment with a BRAF-targeted drug, and that in these patients, a decrease in S6 phosphorylation after treatment correlated with treatment response.
"Many of the signaling pathways known to drive various types of cancer regulate phosphorylation of S6, not just the BRAF pathway," said Corcoran. "Therefore, we are investigating whether S6 phosphorylation could be a biomarker of response to therapies that target these pathways in cancers other than melanoma."
###
This study was funded by a Damon Runyon Clinical Investigator Award, the National Institutes of Health, and the National Cancer Institute. Corcoran has no conflicts of interest to declare.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Guiding Treatment for BRAF- and BRCA-related Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 22 at 9 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
To interview Ryan Corcoran, contact Katie Marquedant at kmarquedant@partners.org or 617-314-3986. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.
About the National Cancer Institute
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the European Organisation for Research and Treatment of Cancer
The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.
EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org
Abstract Number: C137
Presenter: Ryan B. Corcoran, M.D., Ph.D.
Title: Rapid assessment of TORC1 suppression as a functional biomarker predicting responsiveness to RAF and MEK inhibitors in BRAF-mutant melanoma patients
Authors: Ryan B. Corcoran1, S. Michael Rothenberg1, Aaron N. Hata1, Anthony C. Faber1, Adriano Piris1, Rosalynn M. Nazarian1, Ronald D. Brown1, Jason T. Godfrey1, Daniel Winokur1, John Walsh1, Mari Mino-Kenudson1, Shyamala Maheswaran1, Jeffrey Settleman2, Jennifer A. Wargo1, Keith T. Flaherty1, Daniel A. Haber1, Jeffrey A. Engelman1. 1Massachusetts General Hosp. Cancer Ctr., Boston, MA; 2Genentech, South San Francisco, CA
The clinical development of selective RAF and MEK inhibitors has transformed the treatment of the ~50% of melanoma patients whose tumors harbor BRAF mutations. However, a substantial percentage of these patients fail to respond to therapy, and most responses are partial and short-lived. Although multiple mechanisms of resistance have been identified in BRAF-mutant melanoma, no clinically useful biomarkers have been established to predict which patients are most likely to demonstrate sensitivity or resistance to RAF or MEK inhibitors. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein-S6 (P-S6), was a functional biomarker that effectively predicted sensitivity in BRAF-mutant melanoma cell lines in vitro and in mouse tumor xenografts. In sensitive melanomas, TORC1 and P-S6 were suppressed in response to RAF or MEK inhibitors, but in resistant melanomas, TORC1 activity was maintained, in some cases despite robust suppression of MAPK signaling by these inhibitors. In mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response in vivo. Notably, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression was associated with significantly improved progression-free survival [HR 0.19, 95% CI 0.01-0.84, p=0.03]. Finally, we found that changes in P-S6 in patients' tumor cells could be readily monitored in real-time by multiplexed, quantitative immunofluorescence microscopy of serial fine-needle aspiration biopsies obtained from patients before and during the first 2 weeks of RAF inhibitor therapy. This approach provides a minimally-invasive means of rapidly monitoring the efficacy of treatment, before changes in tumor volume are apparent by traditional radiographic imaging. Together, these results establish suppression of P-S6 after initiation of RAF inhibitor therapy as a robust potential functional biomarker to guide the treatment of patients with BRAF-mutant melanoma, and present a powerful methodology for monitoring changes in potentially any signaling pathway in response to targeted therapies in patients.
Share
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.
