‘Hobbit’ extends No. 1 journey with $36.7 million

LOS ANGELES (AP) — Tiny hobbit Bilbo Baggins is running circles around some of the biggest names in Hollywood.

Peter Jackson’s “The Hobbit: An Unexpected Journey” took in $ 36.7 million to remain No. 1 at the box office for the second-straight weekend, easily beating a rush of top-name holiday newcomers.

Part one of Jackson’s prelude to his “The Lord of the Rings” trilogy, the Warner Bros. release raised its domestic total to $ 149.9 million after 10 days. The film added $ 91 million overseas to bring its international total to $ 284 million and its worldwide haul to $ 434 million.

“The Hobbit” took a steep 57 percent drop from its domestic $ 84.6 million opening weekend, but business was soft in general as many people skipped movies in favor of last-minute Christmas preparations.

“The real winner this weekend might be holiday shopping,” said Paul Dergarabedian, an analyst for box-office tracker Hollywood.com.

Tom Cruise‘s action thriller “Jack Reacher” debuted in second-place with a modest $ 15.6 million debut, according to studio estimates Sunday. Based on the Lee Child best-seller “One Shot,” the Paramount Pictures release stars Cruise as a lone-wolf ex-military investigator tracking a sniper conspiracy.

Opening at No. 3 with $ 12 million was Judd Apatow’s marital comedy “This Is 40,” a Universal Pictures film featuring Paul Rudd and Leslie Mann reprising their roles from the director’s 2007 hit “Knocked Up.”

Paramount’s road-trip romp “The Guilt Trip,” featuring “Knocked Up” star Seth Rogen and Barbra Streisand, debuted weakly at No. 6 with $ 5.4 million over the weekend and $ 7.4 million since it opened Wednesday. Playing in narrower release, Paramount’s acrobatic fantasy “Cirque du Soleil: Worlds Away” debuted at No. 11 with $ 2.1 million.

A 3-D version of Disney’s 2001 animated blockbuster “Monsters, Inc.” also had a modest start at No. 7 with $ 5 million over the weekend and $ 6.5 million since opening Wednesday.

Domestic business was off for the first time in nearly two months. Overall revenues totaled $ 112 million, down 12.6 percent from the same weekend last year, when Cruise’s “Mission: Impossible — Ghost Protocol” debuted with $ 29.6 million, according to Hollywood.com.

Cruise’s “Jack Reacher” opened at barely half the level as “Ghost Protocol,” but with a $ 60 million budget, the new flick cost about $ 100 million less to make.

Starting on Christmas, Hollywood expects a big week of movie-going with schools out through New Year’s Day and many adults taking time off. So Paramount and other studios are counting on strong business for films that started slowly this weekend.

“‘Jack Reacher’ will end up in a very good place. The movie will be profitable for Paramount,” said Don Harris, the studio’s head of distribution. “The first time I saw the movie I saw dollar signs. It certainly wasn’t intended to be compared to a ‘Mission: Impossible,’ though.”

Likewise, Warner Bros. is looking for steady crowds for “The Hobbit” over the next week, despite the debut of two huge newcomers — the musical “Les Miserables” and the action movie “Django Unchained” — on Christmas Day.

“We haven’t reached the key holiday play time yet,” said Dan Fellman, head of distribution for Warner. “It explodes on Tuesday and goes right through the end of the year.”

In limited release, Kathryn Bigelow’s Osama bin Laden manhunt saga “Zero Dark Thirty” played to packed houses with $ 410,000 in just five theaters, averaging a huge $ 82,000 a cinema.

That compares to a $ 4,654 average in 3,352 theaters for “Jack Reacher” and a $ 4,130 average in 2,913 cinemas for “This Is 40.” ”The Guilt Trip” averaged $ 2,217 in 2,431 locations, and “Monsters, Inc.” averaged $ 1,925 in 2,618 cinemas. Playing just one matinee and one evening show a day at 840 theaters, “Cirque du Soleil” averaged $ 2,542.

Since opening Wednesday, “Zero Dark Thirty” has taken in $ 639,000. Distributor Sony plans to expand the acclaimed film to nationwide release Jan. 11, amid film honors and nominations leading up to the Feb. 24 Academy Awards.

Opening in 15 theaters from Lionsgate banner Summit Entertainment, Naomi Watts and Ewan McGregor’s tsunami-survival drama “The Impossible” took in $ 138,750 for an average of $ 9,250.

A fourth new release from Paramount, “The Sopranos” creator David Chase’s 1960s rock ‘n’ roll tale “Not Fade Away,” debuted with $ 19,000 in three theaters, averaging $ 6,333.

Universal’s “Les Miserables” got a head-start on its domestic release with a $ 4.2 million debut in Japan.

Estimated ticket sales for Friday through Sunday at U.S. and Canadian theaters, according to Hollywood.com. Where available, latest international numbers are also included. Final domestic figures will be released Monday.

1. “The Hobbit: An Unexpected Journey,” $ 36.7 million ($ 91 million international).

2. “Jack Reacher,” $ 15.6 million ($ 2.5 million international).

3. “This Is 40,” $ 12 million.

4. “Rise of the Guardians,” $ 5.9 million ($ 13.7 million international).

5. “Lincoln,” $ 5.6 million.

6. “The Guilt Trip,” $ 5.4 million.

7. “Monsters, Inc.” in 3-D, $ 5 million.

8. “Skyfall,” $ 4.7 million ($ 9 million international),

9. “Life of Pi,” $ 3.8 million ($ 23.2 million international).

10. “The Twilight Saga: Breaking Dawn — Part 2,” $ 2.6 million ($ 6.6 million international).

___

Estimated weekend ticket sales at international theaters (excluding the U.S. and Canada) for films distributed overseas by Hollywood studios, according to Rentrak:

1. “The Hobbit: An Unexpected Journey,” $ 91 million.

2. “Life of Pi,” $ 23.2 million.

3. “Rise of the Guardians,” $ 13.7 million.

4. “Skyfall,” $ 9 million.

5. “Wreck-It Ralph,” $ 7.3 million.

6. “The Twilight Saga: Breaking Dawn — Part 2,” $ 6.6 million.

7. “Pitch Perfect,” $ 6 million.

8. “Les Miserables,” $ 4.2 million.

9. “Love 911,” $ 3.2 million.

10. “De L’autre Cote du Periph,” $ 3.1 million.

___

Online:

http://www.hollywood.com

http://www.rentrak.com

___

Universal and Focus are owned by NBC Universal, a unit of Comcast Corp.; Sony, Columbia, Sony Screen Gems and Sony Pictures Classics are units of Sony Corp.; Paramount is owned by Viacom Inc.; Disney, Pixar and Marvel are owned by The Walt Disney Co.; Miramax is owned by Filmyard Holdings LLC; 20th Century Fox and Fox Searchlight are owned by News Corp.; Warner Bros. and New Line are units of Time Warner Inc.; MGM is owned by a group of former creditors including Highland Capital, Anchorage Advisors and Carl Icahn; Lionsgate is owned by Lions Gate Entertainment Corp.; IFC is owned by AMC Networks Inc.; Rogue is owned by Relativity Media LLC.

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Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

C.J. Gunther for The New York Times

Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.

No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.

And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”

At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.

Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.

“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.

The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.

The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”

Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.

Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.

The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?

In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.

But Nutlins did not work as drugs because they were not absorbed into the body.

Roche, Merck and Sanofi persevered, testing thousands of molecules.

At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.

The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.

Read More..

Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

C.J. Gunther for The New York Times

Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.

No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.

And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”

At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.

Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.

“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.

The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.

The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”

Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.

Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.

The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?

In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.

But Nutlins did not work as drugs because they were not absorbed into the body.

Roche, Merck and Sanofi persevered, testing thousands of molecules.

At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.

The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.

Read More..

6 die in Syria car bombing; gunman slays state journalist

BEIRUT — A car bomb exploded in eastern Damascus on Saturday, an insurgent spokeswoman said, and the Syrian government reported that a gunman killed a state television journalist in the capital.

The car bomb exploded in the capital's Kaboun area and left six people dead and 10 wounded, an opposition spokeswoman in Damascus identified as Lena Shami said by Skype.

There was no way to independently confirm the death toll.

The official Syria Arab News Agency also reported the bombing, blaming terrorists, the government's usual description of rebels seeking to overthrow President Bashar Assad. Shami the bombing on the government, which she said was targeting the area's Sunni residents. Sunnis make up a majority of the nation's population and also of the rebellion.

Meanwhile, a Syrian state television cameraman was slain outside his home in Damascus, SANA reported.

Haidar Smoudi was the ninth state-employed journalist killed by "armed terrorist groups," the news agency said. There was no claim of responsibility in the shooting, but anti-government groups have been suspected of carrying out attacks on state-employed journalists.

The 21-month-old rebellion has claimed as many as 40,000 lives, according to the opposition. A United Nations panel recently described the conflict as increasingly sectarian and gave details of abuses by both government forces and rebels.

Rami Abdul-Rahman, an activist with the London-based Syrian Observatory for Human Rights, a pro-opposition group, denounced the killing of Smoudi.

"We condemn completely the targeting of unarmed journalists who are considered pro-regime, just as we condemn the killing of any unarmed civilian, no matter their affiliation," he said.

On the diplomatic front, Russia, seen as one of Syria's chief supporters, indicated yet again that it was distancing itself from Assad. Russian Foreign Minister Sergei Lavrov told reporters late Friday that Moscow would not be opposed to any country offering Assad asylum, the Associated Press reported.

"If there is anyone willing to provide him guarantees, they are welcome," Lavrov told reporters on a plane returning from a Russia-European Union meeting in Brussels. "We would be the first to cross ourselves and say: 'Thank God, the carnage is over!' If it indeed ends the carnage, which is far from certain."

The remarks followed Russian President Vladimir Putin's comments Thursday making it clear that Russia saw Syria's stability, not "the fate of the Assad regime," as its priority.

ned.parker@latimes.com

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Facebook releases ‘Poke’ for the iPhone to compete with Snapchat

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Americans answer D.C.’s siren song of employment, strong economy

WASHINGTON (Reuters) – Thirteen years ago the band The Magnetic Fields crooned that the U.S. capital city is “the greatest place to be,” in the indie love song “Washington, D.C.”

Recently, a growing number of Americans are singing along as they move to the District in search of jobs, economic opportunity and cultural attractions.

In a study on migration provided exclusively to Reuters that is set to be released next month, United Van Lines found the District of Columbia tops all 50 states for the number of people moving in during 2012.

The city has held that spot for five years running, with 64 percent of the household moves in Washington coming from outside the city in 2012.

United Van Lines is the largest moving company in the country for households.

Oregon ranked second, followed by Nevada, North Carolina and South Carolina. Washington is a city that does not belong to a state, but is subject to loose control from the federal government.

“Washington, D.C., is unique because over the last five years its unemployment rate was not hit as hard by the Great Recession,” said Michael Stoll, chair and professor of public policy at the University of California at Los Angeles about the study. “But I think the other thing is that the city has remade itself from the one we knew 10 to 15 years ago.”

Washington has shed its reputation as the crime capital of the country, and it has developed a high technology corridor and other businesses that are both stable and hiring, said Stoll.

Also, many members of the Baby Boom generation are moving in as they retire, taking advantage of the free museums, monuments and cultural events the city has to offer, he said.

The rising popularity could yield a result also unthinkable less than two decades ago.

“D.C. will not just be a place of tourism. It will be a major economic engine, which many of us haven’t thought of it as being before,” Stoll said.

A U.S. Census report released on Thursday also showed the city is gaining new residents. Washington’s population increased 2.15 percent between July 2011 and July 2012, a rise second only to North Dakota.

The District’s population increase of 5.1 percent from 2010 to 2012 was the biggest in the country, the Census found. It had had 632,323 residents as of July 1.

The city has a large international community, largely due to the presence of foreign embassies and organizations such as the World Bank. The Census found people from other countries made up 32 percent of the net migration from 2011 to 2012.

According to a Labor Department report released on Friday, the District’s unemployment rate fell in November to 8.1 percent from 10.1 percent the year before. Local political leaders point to a development boom and one of the highest median incomes in the country – $ 63,124 – as other draws to the city.

On a national level, Stoll said, the migration patterns show Americans are seeking economic opportunity in places where new manufacturing and technology enterprises are building up. The patterns reveal a swelling group of aging people who are retiring and looking for affordable and comfortable places to live, as well.

He added that many people who wanted to move to California, but were put off by the state’s economic woes, turned their moving vans north to Oregon.

New Jersey topped states for outward moves, in 2012, the United Van Lines study showed, largely due to a shrinking factory sector. It was followed by Illinois, West Virginia, Michigan and New York.

Washington’s popularity surge recently created a paradox in the city’s economic success story. Last month, the Brookings Institution concluded three U.S. metropolitan areas are in economic recovery, but did not include Washington because its population burst drove down its gross domestic product on a per capita basis.

(Reporting By Lisa Lambert; Editing by Leslie Adler)

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Title Post: Americans answer D.C.’s siren song of employment, strong economy
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Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

C.J. Gunther for The New York Times

Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.

No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.

And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”

At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.

Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.

“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.

The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.

The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”

Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.

Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.

The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?

In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.

But Nutlins did not work as drugs because they were not absorbed into the body.

Roche, Merck and Sanofi persevered, testing thousands of molecules.

At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.

The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.

Read More..

Amazon Book Reviews Deleted in a Purge Aimed at Manipulation

Giving raves to family members is no longer acceptable. Neither is writers’ reviewing other writers. But showering five stars on a book you admittedly have not read is fine.

After several well-publicized cases involving writers buying or manipulating their reviews, Amazon is cracking down. Writers say thousands of reviews have been deleted from the shopping site in recent months.

Amazon has not said how many reviews it has killed, nor has it offered any public explanation. So its sweeping but hazy purge has generated an uproar about what it means to review in an era when everyone is an author and everyone is a reviewer.

Is a review merely a gesture of enthusiasm or should it be held to a higher standard? Should writers be allowed to pass judgment on peers the way they have always done offline or are they competitors whose reviews should be banned? Does a groundswell of raves for a new book mean anything if the author is soliciting the comments?

In a debate percolating on blogs and on Amazon itself, quite a few writers take a permissive view on these issues.

The mystery novelist J. A. Konrath, for example, does not see anything wrong with an author indulging in chicanery. “Customer buys book because of fake review = zero harm,” he wrote on his blog.

Some readers differ. An ad hoc group of purists has formed on Amazon to track its most prominent reviewer, Harriet Klausner, who has over 25,000 reviews. They do not see how she can read so much so fast or why her reviews are overwhelmingly — and, they say, misleadingly — exaltations.

“Everyone in this group will tell you that we’ve all been duped into buying books based on her reviews,” said Margie Brown, a retired city clerk from Arizona.

Once a populist gimmick, the reviews are vital to making sure a new product is not lost in the digital wilderness. Amazon has refined the reviewing process over the years, giving customers the opportunity to rate reviews and comment on them. It is layer after layer of possible criticism.

“A not-insubstantial chunk of their infrastructure is based on their reviews — and all of that depends on having reviews customers can trust,” said Edward W. Robertson, a science fiction novelist who has watched the debate closely.

Nowhere are reviews more crucial than with books, an industry in which Amazon captures nearly a third of every dollar spent. It values reviews more than other online booksellers like Apple or Barnes & Noble, featuring them prominently and using them to help decide which books to acquire for its own imprints by its relatively new publishing arm.

So writers have naturally been vying to get more, and better, notices. Several mystery writers, including R. J. Ellory, Stephen Leather and John Locke, have recently confessed to various forms of manipulation under the general category of “sock puppets,” or online identities used to deceive. That resulted in a widely circulated petition by a loose coalition of writers under the banner, “No Sock Puppets Here Please,” asking people to “vote for book reviews you can trust.”

In explaining its purge of reviews, Amazon has told some writers that “we do not allow reviews on behalf of a person or company with a financial interest in the product or a directly competing product. This includes authors.” But writers say that rule is not applied consistently.

In some cases, the ax fell on those with a direct relationship with the author.

“My sister’s and best friend’s reviews were removed from my books,” the author M. E. Franco said in a blog comment. “They happen to be two of my biggest fans.” Another writer, Valerie X. Armstrong, said her son’s five-star review of her book, “The Survival of the Fattest,” was removed. He immediately tried to put it back “and it wouldn’t take,” she wrote.

In other cases, though, the relationship was more tenuous. Michelle Gagnon lost three reviews on her young adult novel “Don’t Turn Around.” She said she did not know two of the reviewers, while the third was a longtime fan of her work. “How does Amazon know we know each other?” she said. “That’s where I started to get creeped out.”

Mr. Robertson suggested that Amazon applied a broad brush. “I believe they caught a lot of shady reviews, but a lot of innocent ones were erased, too,” he said. He figures the deleted reviews number in the thousands, or perhaps even 10,000.

The explosion of reviews for “The 4-Hour Chef” by Timothy Ferriss shows how the system has evolved from something spontaneous to a means of marketing and promotion. On Nov. 20, publication day, dozens of highly favorable reviews immediately sprouted. Other reviewers quickly criticized Mr. Ferriss, accusing him of buying supporters.

He laughed off those suggestions. “Not only would I never do that — it’s unethical — I simply don’t have to,” he wrote in an e-mail, saying he had sent several hundred review copies to fans and potential fans. “Does that stack the deck? Perhaps, but why send the book to someone who would hate it? That doesn’t help anyone: not the reader, nor the writer.”

As a demonstration of social media’s grip on reviewing, Mr. Ferriss used Twitter and Facebook to ask for a review. “Rallying my readers,” he called it. Within an hour, 61 had complied.

A few of his early reviews were written by people who admitted they had not read the book but were giving it five stars anyway because, well, they knew it would be terrific. “I am looking forward to reading this,” wrote a user posting under the name mhpics.

A spokesman for Amazon, which published “The 4-Hour Chef,” offered this sole comment for this article: “We do not require people to have experienced the product in order to review.”

The dispute over reviews is playing out in the discontent over Mrs. Klausner, an Amazon Hall of Fame reviewer for the last 11 years and undoubtedly one of the most prolific reviewers in literary history.

Mrs. Klausner published review No. 28,366, for “A Red Sun Also Rises” by Mark Hodder. Almost immediately, it had nine critical comments. The first accused it of being “riddled with errors in grammar, spelling and punctuation.” The rest were no more kind. The Harriet Klausner Appreciation Society had struck again.

Mrs. Klausner, a 60-year-old retired librarian who lives in Atlanta, has published an average of seven reviews a day for more than a decade. “To watch her in action is unbelievable,” said her husband, Stanley. “You see the pages turning.”

Mrs. Klausner, who says ailments keep her home and insomnia keeps her up, scoffs at her critics. “You ever read a Harlequin romance?” she said. “You can finish it in one hour. I’ve always been a speed reader.” She has a message for her naysayers: “Get a life. Read a book.”

More than 99.9 percent of Mrs. Klausner’s reviews are four or five stars. “If I can make it past the first 50 pages, that means I like it, and so I review it,” she said. But even Stanley said, “She’s soft, I won’t deny that.”

The campaign against Mrs. Klausner has pushed down her reviewer ratings, which in theory makes her less influential. But when everything is subject to review, the battle is never-ending.

Ragan Buckley, an aspiring novelist active in the campaign against Mrs. Klausner under the name “Sneaky Burrito,” is a little weary. “There are so many fake reviews that I’m often better off just walking into a physical store and picking an item off the shelf at random,” she said.

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Flawed data stall California's 911 upgrades

A three-year effort by California to improve 911 emergency service has been stymied by flawed data and aging computers at local fire departments and rescue agencies across the state, a Times investigation has found.

Since 2009, the state Emergency Medical Services Authority has been seeking to centralize reports on millions of emergency medical responses, a project that officials see as critical to improving life-saving practices.

State officials hoped to capture information from the moment dispatchers answer a call until the victim is transferred to a hospital. The program would for the first time give public officials, medical researchers and regulators the ability to compare response times and patient treatment across local jurisdictions.

But the project has floundered because many fire departments and ambulance operations have been unable to provide usable information.

One problem is that fire departments report basic information inconsistently, including how long it takes them to reach victims. Some begin counting the second a 911 call is answered. Others, including the Los Angeles Fire Department, start the clock when rescue crews are alerted at fire stations.

Moreover, nearly half of the state's 32 regional emergency medical agencies have failed to contribute reports to the system, officials said. And many of those who do file reports use paper records.

The shortcomings, officials and experts said, underscore how fire agencies lag behind police departments and the private sector in using technology to better manage and evaluate their performance.

"There's been a lot of benign neglect in the fire service as far as collecting data," said Robert Upson, a Connecticut fire marshal who has analyzed data for a nationwide group that sets performance standards for fire departments.

"There's so much sloppiness in recording data. It's just built into the system."

Similar troubles have fueled a months-long controversy over faulty response time data at the Los Angeles Fire Department. In March, top commanders admitted that the department had repeatedly published reports overstating how fast rescuers reached victims in need of help. The flawed reports have been blamed on the use of unqualified firefighters to analyze data and outdated computer systems.

In an effort to improve such data, California officials launched their program to collect rich, comparable details on medical emergencies statewide. Incident reports were to be gathered by regional regulatory agencies and forwarded to the state.

But three years and about $1.6 million later, the voluntary project is plagued by lack of participation, money problems and inconsistent information. The root of the problem is that some agencies rely on outmoded, "home-brewed" computer systems, said Tom McGinnis, the state official overseeing the project.

"We can't compare apples to apples. We compare apples to oranges and peaches," McGinnis said.

The state isn't forcing cash-strapped local agencies to participate because doing so would require many to replace computer systems, McGinnis said. "Really what it comes down to is money," he said.

Some experts say the state program won't be able to deliver on its promise until reporting standards are clarified and participation is mandatory.

"It should become a requirement tomorrow," said Bruce Wagner, the top administrator for the emergency medical services agency in Sacramento County.

His agency is among those that have not provided data to the state. That's because fire departments and ambulance firms under his jurisdiction are hesitant to spend time and money gathering records if they are not required to do so, Wagner said.

"It's hard for us to tell them they are going to incur additional costs if it's not mandated," he told The Times.

Los Angeles County, where a third of the state's 911 medical rescues take place, is a year behind in processing performance information because 28 of the county's 31 fire departments submit paper reports, said Cathy Chidester, the local oversight agency's top executive. Voluminous pages of information must be individually scanned into electronic files or manually typed into a county computer system.

"It's like sweeping sand off the beach," Chidester said.

Of the county's three largest fire departments — Los Angeles city, Los Angeles County and Long Beach — only the LAFD collects medical records electronically.

The county Fire Department has not filed reports on more than 300,000 incidents over the last two years because budget cuts eliminated employees working on the records, officials said. Next year, the agency is launching a test program in which paramedics will use iPads to create electronic reports, Chief Deputy Mike Metro said.

The state data project, known as CEMSIS, short for California Emergency Medical Services Information System, has also struggled for funding. It began as a $240,000-a-year demonstration project using federal grants and philanthropic donations. But no permanent funding has been secured.

Where possible, officials are attempting to use the partial records they have compiled for research. But thus far, they haven't been able to answer fundamental questions, including how different agencies' 911 response times compare, McGinnis said.

Ideally, McGinnis said, regulators could use the database to compare "the entire spectrum" of emergency medical care in California. "I want everybody to participate and see what we're doing statewide," he said.

Detailed data could improve understanding of what works best in the field. For example, researchers could examine how often rescuers are able to restore heartbeats after arriving on the scene, a key step in increasing cardiac-arrest survival rates, said Dr. Marc Eckstein, the medical director for the Los Angeles Fire Department.

"You have to really drill down to make sure we are talking about the right things," he said.

Slipping response times at the LAFD were only documented when outside experts, the city controller and The Times dug into the department's data. A series of Times reports found breakdowns and delays in processing 911 calls, dispatching units and summoning the nearest medical rescuers from neighboring jurisdictions.

Los Angeles Fire Commissioner Alan Skobin, who is overseeing a task force charged with overhauling the LAFD's data management, said programs such as California's fledgling 911 records system could help his agency compare its performance to other departments and improve service.

"There's a benefit to looking outside," Skobin said. "That's something the LAFD has to do."

Full coverage: Life on the line, 911 breakdowns at LAFD

Map: How fast is LAFD where you live?

Download: Open-source maps of California's emergency medical agencies

ben.welsh@latimes.com

robert.lopez@latimes.com

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TSX ends flat as RIM buckles, gold miners bounce

TORONTO (Reuters) – Canada‘s main stock index ended little changed on Friday as gold miners gained on safe-haven buying amid U.S. budget uncertainty, while BlackBerry maker Research In Motion Ltd plunged more than 20 percent.

The index’s materials sector, which includes miners, rose 0.4 percent. Even though the price of gold was near its lowest level in four months, the gold-mining sub-sector added 0.9 percent as investors fretted over stalled U.S. budget talks that could throw Canada’s largest trading partner back into recession.

“As our tiptoes are over the (U.S.) fiscal cliff and we’re looking over the abyss, the markets are upset obviously, and this is sort of putting a damper on the stocks,” said John Ing, president of Maison Placements Canada.

“But we’ve had a mixed reaction in Canada, mainly because the resources have been much better, like gold for example, which is hedging into the uncertainty (around the budget talks),” he said, noting gold miners had been under pressure for the last two weeks.

Miner Barrick Gold Corp edged up 0.2 percent to C$ 33.29. Centerra Gold Inc jumped more than 3 percent to C$ 9.10.

Gold miners are playing catch-up after underperforming throughout the year and could rise further in 2013, said Gavin Graham, president at Graham Investment Strategy.

Shares of RIM dropped 22.2 percent to C$ 10.86 on fears that a new fee structure for its high-margin services segment could put pressure on the business that has set the company apart from its competitors.

The Toronto Stock Exchange‘s S&P/TSX composite index <.gsptse> fell 3.01 points, or 0.02 percent, to end at 12,385.70. It gained 0.7 percent for the week.</.gsptse>

Efforts to avoid the looming U.S. “fiscal cliff” were thrown into disarray on Friday with finger-pointing lawmakers fleeing Washington for Christmas vacations even as the year-end deadline for action edged ever closer.

Graham said that until a deal is reached in the U.S. budget talks, investors will avoid economically sensitive Canadian stocks and those most closely tied to the U.S. economy: auto parts manufacturers, forestry companies and resource stocks generally.

“The resource sectors in Canada, which is half of the index, is going to be adversely affected, correctly or not,” he said.

“Chinese demand is likely to pick up somewhat now with the new leadership there but people will be focused on the U.S. given that it is still by far the most important export market for Canada.”

($ 1=$ 0.99 Canadian)

(Additional reporting by Claire Sibonney, Julie Gordon and Jeffrey Hodgson; Editing by Peter Galloway)

Gadgets News Headlines – Yahoo! News

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