E-Book Price War Has Yet to Arrive

Thor Swift for The New York Times

A Google e-reader is displayed at a bookstore. Sales of e-books for the devices have slowed this year.

Right about now, just as millions of e-readers and tablets are being slipped under Christmas trees, there was supposed to be a ferocious price war over e-books.

Last spring, the Justice Department sued five major publishers and Apple on e-book price-fixing charges. The case was a major victory for Amazon, and afterward there were widespread expectations — fueled by Amazon — that the price of e-books would plunge.

The most extreme outcome went like this: Digital versions of big books selling for $9.99 or less would give Amazon complete domination over the e-book market. As sales zoomed upward, even greater numbers of consumers would abandon physical books. The major publishers and traditional bookstores were contemplating a future that would pass them by.

But doomsday has not arrived, at least not yet. As four of the publishers have entered into settlements with regulators and revised the way they sell e-books, prices have selectively fallen but not as broadly or drastically as anticipated.

The $10 floor that publishers fought so hard to maintain for popular new novels is largely intact. Amazon, for instance, is selling Michael Connelly’s new mystery, “The Black Box,” for $12.74. New best sellers by David Baldacci and James Patterson cost just over $11.

One big reason for the lack of fireworks is that the triumph of e-books over their physical brethren is not happening quite as fast as forecast.

“The e-book market isn’t growing at the caffeinated level it was,” said Michael Norris, a Simba Information analyst who follows the publishing industry. “Even retailers like Amazon have to be wondering, how far can we go — or should we go — to make our prices lower than the other guys if it’s not helping us with market share?”

Adult e-book sales through August were up 34 percent from 2011, an impressive rate of growth if you forget that sales have doubled every year for the last four years. And there have been more recent signs of a market pausing for breath.

Macmillan, the only publisher that has not settled with the Justice Department, said last week as part of a statement from John Sargent, its chief executive, that “our e-book business has been softer of late, particularly for the last few weeks, even as the number of reading devices continues to grow.” His laconic conclusion: “Interesting.”

Mr. Norris said Simba, which regularly surveys e-book buyers, has been noticing what it calls “commitment to content” issues.

“A lot of these e-book consumers aren’t behaving like lab rats at a feeder bar,” the analyst said. “We have found that at any given time about a third of e-book users haven’t bought a single title in the last 12 months. I have a feeling it is the digital equivalent of the ‘overloaded night stand’ effect; someone isn’t going to buy any more books until they make a dent in reading the ones they have already acquired.”

Another, more counterintuitive possibility is that the 2011 demise of Borders, the second-biggest chain, dealt a surprising blow to the e-book industry. Readers could no longer see what they wanted to go home and order. “The print industry has been aiding and assisting the e-book industry since the beginning,” Mr. Norris said.

It is possible that Amazon, which controls about 60 percent of the e-book market, is merely holding back with price cuts for the right moment.

The next few weeks are when e-book sales traditionally take a big jump, as all those newly received devices are loaded up with content.

Amazon declined to comment beyond saying, “We have lowered prices for customers from the prices publishers set on a broad assortment of Kindle books.” Barnes & Noble declined to comment on its pricing strategy.

The question of the proper price for e-books has shadowed the industry ever since Amazon introduced the Kindle in late 2007 and created the first truly popular portable reading device. Amazon had a natural impulse to build a market and was an aggressive retailer in any case, so it took best sellers that cost $25 in independent bookstores and sold them for $9.99 as e-books. Consumers liked that. E-book adoption soared.

Read More..

Risks: Pedestrian Accidents More Deadly in Men

More than twice as many men as women die in pedestrian-vehicle accidents. Now researchers have partly determined why.

Writing online last month in the journal Injury Prevention, investigators considered the contribution of three factors: distance walked, number of accidents and fatalities per collision.

Researchers using data from a variety of sources found that men and women walk similar distances and that men are involved in slightly more accidents per mile. Only 1 percent of the difference in death rates is attributable to distance walked, they found, and 20 percent to an increased number of accidents among men.

The rest — 79 percent of the variation — owes to the fact that when there is a collision, men die at roughly twice the rate of women. According to the National Highway Traffic Safety Administration, 4,280 pedestrians died in traffic accidents in 2010, and 2,946 — 69 percent — were men.

Why? No one knows, but the lead author, Dr. Motao Zhu, an assistant professor of epidemiology at West Virginia University, suggested two possibilities: “Maybe males are more likely to cross roads with speed limits higher than 50 miles per hour,” he said. “Also, males may be more likely to be impaired by alcohol and drugs. Most people know it’s not safe to drive drunk, but it’s not safe to walk drunk either.”

Read More..

Risks: Pedestrian Accidents More Deadly in Men

More than twice as many men as women die in pedestrian-vehicle accidents. Now researchers have partly determined why.

Writing online last month in the journal Injury Prevention, investigators considered the contribution of three factors: distance walked, number of accidents and fatalities per collision.

Researchers using data from a variety of sources found that men and women walk similar distances and that men are involved in slightly more accidents per mile. Only 1 percent of the difference in death rates is attributable to distance walked, they found, and 20 percent to an increased number of accidents among men.

The rest — 79 percent of the variation — owes to the fact that when there is a collision, men die at roughly twice the rate of women. According to the National Highway Traffic Safety Administration, 4,280 pedestrians died in traffic accidents in 2010, and 2,946 — 69 percent — were men.

Why? No one knows, but the lead author, Dr. Motao Zhu, an assistant professor of epidemiology at West Virginia University, suggested two possibilities: “Maybe males are more likely to cross roads with speed limits higher than 50 miles per hour,” he said. “Also, males may be more likely to be impaired by alcohol and drugs. Most people know it’s not safe to drive drunk, but it’s not safe to walk drunk either.”

Read More..

E-Book Price War Has Yet to Arrive

Thor Swift for The New York Times

A Google e-reader is displayed at a bookstore. Sales of e-books for the devices have slowed this year.

Right about now, just as millions of e-readers and tablets are being slipped under Christmas trees, there was supposed to be a ferocious price war over e-books.

Last spring, the Justice Department sued five major publishers and Apple on e-book price-fixing charges. The case was a major victory for Amazon, and afterward there were widespread expectations — fueled by Amazon — that the price of e-books would plunge.

The most extreme outcome went like this: Digital versions of big books selling for $9.99 or less would give Amazon complete domination over the e-book market. As sales zoomed upward, even greater numbers of consumers would abandon physical books. The major publishers and traditional bookstores were contemplating a future that would pass them by.

But doomsday has not arrived, at least not yet. As four of the publishers have entered into settlements with regulators and revised the way they sell e-books, prices have selectively fallen but not as broadly or drastically as anticipated.

The $10 floor that publishers fought so hard to maintain for popular new novels is largely intact. Amazon, for instance, is selling Michael Connelly’s new mystery, “The Black Box,” for $12.74. New best sellers by David Baldacci and James Patterson cost just over $11.

One big reason for the lack of fireworks is that the triumph of e-books over their physical brethren is not happening quite as fast as forecast.

“The e-book market isn’t growing at the caffeinated level it was,” said Michael Norris, a Simba Information analyst who follows the publishing industry. “Even retailers like Amazon have to be wondering, how far can we go — or should we go — to make our prices lower than the other guys if it’s not helping us with market share?”

Adult e-book sales through August were up 34 percent from 2011, an impressive rate of growth if you forget that sales have doubled every year for the last four years. And there have been more recent signs of a market pausing for breath.

Macmillan, the only publisher that has not settled with the Justice Department, said last week as part of a statement from John Sargent, its chief executive, that “our e-book business has been softer of late, particularly for the last few weeks, even as the number of reading devices continues to grow.” His laconic conclusion: “Interesting.”

Mr. Norris said Simba, which regularly surveys e-book buyers, has been noticing what it calls “commitment to content” issues.

“A lot of these e-book consumers aren’t behaving like lab rats at a feeder bar,” the analyst said. “We have found that at any given time about a third of e-book users haven’t bought a single title in the last 12 months. I have a feeling it is the digital equivalent of the ‘overloaded night stand’ effect; someone isn’t going to buy any more books until they make a dent in reading the ones they have already acquired.”

Another, more counterintuitive possibility is that the 2011 demise of Borders, the second-biggest chain, dealt a surprising blow to the e-book industry. Readers could no longer see what they wanted to go home and order. “The print industry has been aiding and assisting the e-book industry since the beginning,” Mr. Norris said.

It is possible that Amazon, which controls about 60 percent of the e-book market, is merely holding back with price cuts for the right moment.

The next few weeks are when e-book sales traditionally take a big jump, as all those newly received devices are loaded up with content.

Amazon declined to comment beyond saying, “We have lowered prices for customers from the prices publishers set on a broad assortment of Kindle books.” Barnes & Noble declined to comment on its pricing strategy.

The question of the proper price for e-books has shadowed the industry ever since Amazon introduced the Kindle in late 2007 and created the first truly popular portable reading device. Amazon had a natural impulse to build a market and was an aggressive retailer in any case, so it took best sellers that cost $25 in independent bookstores and sold them for $9.99 as e-books. Consumers liked that. E-book adoption soared.

Read More..

Details of Stabbings Revive Chinese School Security Questions

BEIJING — The attacker’s first young target, a girl with a pink backpack, falls at the school gates as she tries to race away. She gets up, but stumbles again inside the gates as the man slashes at her with a meat cleaver. Two minutes later, dozens of students race out of the gates as the man rampages through the school, eventually wounding 23 children.

Perhaps most shocking is what the video of the attack 10 days ago shows about the school’s first line of defense: several children waving broomsticks try to block the man’s progress. Minutes later, local adults who had rushed into the building, also wielding brooms, chase the man from the school.

Such details were not in the immediate coverage of the attack, at the Chenpeng Village Primary School in Guangshan County, Henan Province, and the video was not released until days later.

The rampage came on Dec. 14, the same day a heavily armed 20-year-old man killed his mother and then opened fire at a school in Newtown, Conn., killing 20 first graders, 6 adults and then himself. Official Chinese news organizations had much more coverage of the Newtown massacre than of the Henan attack, and there was an outpouring of sympathy for the American tragedy as well as commentary drawing inevitable comparisons. Many Chinese Internet users pondered how many students at the Chenpeng school might have been killed if China had gun control laws as loose as those in the United States.

But now the Chinese video, circulating here on television and the Internet, has refocused attention on the Chenpeng attack, especially on security measures at the school and on local officials’ efforts to squelch coverage. Fury has been building because such rampages have recurred over the last three years, with intruders slashing at schoolchildren with knives and axes, including one who attacked with a hammer and then set himself on fire. Each case set off fear among parents across the country as well as criticism of government officials for not doing enough to protect children; each time, officials guaranteed schools would be secure. The video made blatant the gap between the official promises and reality.

“Did the government not say that no strangers can get into schools?” wrote one Internet user, Xia Ling, on a microblog. “Did the government not say that every school has security guards? Liars! You will eventually all face karma someday.”

Details were slow to filter out. Last Monday, the Internet operation of People’s Daily, the mouthpiece of the Communist Party, ran a report from a journalist who had traveled to Guangshan County. The article on the Web site, which is separate from the editorial operations of the print edition, said that even though school employees had asserted that a security guard was on the premises at the time, the attacker somehow managed to get to the third floor.

The same report said officials in Guangshan County appeared to be trying to cover up the attack. It said that the county propaganda office released details of the attack the day it occurred, but that someone later ordered the news removed from the county Web site. Officials canceled a news conference scheduled for the next day.

Reached by telephone, a county propaganda official told the reporter: “It takes time to check if the man with the knife has a mental disease. It’s pointless to discuss it. I need to eat first!”

The reporter found a deputy director of the education office playing a video game; that official refused to provide any answers. School officials and a village official also declined to discuss the attack. But the reporter unearthed the fact that two teenagers had been fatally stabbed in attacks in 2011 and last month at a high school across the street from the county education office.

On Tuesday, Xinhua, the state news agency, reported that six officials, including two school principals, had been fired.

Some other reports offered sketchy details about the arrested suspect, Min Yongjun, 36. Beijing News reported Wednesday that he felt deeply ashamed of his epilepsy. An article by Xinhua said Mr. Min believed in the ancient Mayan doomsday prophecy about the world ending on Dec. 21, implying that had somehow affected his behavior. Ouyang Mingguang, a deputy director of the Guangshan police, told Chinese reporters that Mr. Min had first attacked an elderly woman, Xiang Jiaying, and then decided that “he might as well just stab some students since he had already killed a person.” (Ms. Xiang was hospitalized but not fatally injured.)

The abiding question of why was asked by one person in charge of the official microblog of People’s Daily. “School killings happen over and over again, and murderers who have mental diseases are not the minority,” the person wrote. “Has any of the self-examination brought us any changes? These schoolchildren just started their lives; why is it that criminals always attack innocent children?”

Some commentators said the attackers feel they have been wronged by society. “Chinese society is full of anger and rage,” Murong Xuecun, a best-selling novelist and popular online commentator, said in a telephone interview. “Everybody has anger. Everybody has hate. Those who have been treated unfairly harm those who are even more vulnerable. It must be noted that every society has its share of sociopaths. But for China to have so many is no doubt abnormal.”

Mr. Murong said the only way to alleviate that was to establish a fair legal system and to “achieve real justice in society, so that the people won’t be mired in despair.”

Other critics blame the lack of proper mental health care in China; at least one man who carried out fatal attacks on schoolchildren in 2010 had exhibited clear signs of schizophrenia, but had not been given proper treatment.

On Friday, the English edition of Global Times, a populist newspaper, published an op-ed by a Chinese writer based in New York that looked at some of the same issues in the context of the Newtown massacre. The writer, Rong Xiaoqing, said the mental health system in the United States also had its shortcomings when dealing with potential killers, since they cannot easily be distinguished from other members of society.

“In the U.S., psychologists and psychiatrists have long followed specific criteria to screen for mental illness,” she wrote. “But the mercurial and mysterious human mind isn’t always that easy to categorize.”

Shi Da and Patrick Zuo contributed research.

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..

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..

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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At Western Wall, a Divide Over Prayer Deepens

Rina Castelnuovo for The New York Times

Members of Women of the Wall prayed this month while wearing tallits, fringed prayer shawls, and tefillin, leather prayer boxes, both of which Jewish men are told to wear.

JERUSALEM — The face-off at the security gate outside the Western Wall one Friday this month was familiar: for more than two decades, women have been making a monthly pilgrimage to pray at one of Judaism’s holiest sites in a manner traditionally preserved for men, and the police have stopped them in the name of maintaining public order.

But after a flurry of arrests this fall that set off an international outcry, the women arrived for December’s service to find a new protocol ordered by the ultra-Orthodox rabbi who controls the site. To prevent the women from defying a Supreme Court ruling that bars them from wearing ritual garments at the wall, they were blocked by police officers from bringing them in.

“How can you say this to me?” demanded a tearful Bonna Devora Haberman, 52, a Canadian immigrant who helped found the group Women of the Wall in 1988. “I’m a Jew. This is my state.”

The officer was unmoved. “At the Western Wall, you can’t pray with a tallit,” he said, referring to the fringed prayer shawl in Ms. Haberman’s backpack. “You can’t go in with it.”

After years of legislative and legal fights, the movement for equal access for people to pray as they wish at the site has become a rallying cause for liberal Jews in the United States and around the world, though it has long struggled to gain traction here in Israel, where the ultra-Orthodox retain great sway over public life.

This has deepened a divide between the Jewish state and the Jewish diaspora, in which some leaders have become increasingly vocal in criticizing Israel’s policies on settlements in the Palestinian territories; laws and proposals that are seen as antidemocratic or discriminatory against Arab citizens; the treatment of women; and the ultra-Orthodox control over conversion and marriage.

“When my kids start expressing frustration with Israel as a society because what they hear and see from a distance is not welcoming to them in their religious practice — that’s not good for the Jewish people, let alone for the state of Israel,” said Rabbi Steven C. Wernick, the director of the United Synagogue of Conservative Judaism.

Rabbi Levi Weiman-Kelman, an American immigrant who runs Kol Haneshama, a leading Reform synagogue here, said Women of the Wall “is an issue that really brings out the gap between Israeli Jews and American Jews.”

While more than 60 percent of Jews in the United States identify with the Reform or Conservative movements, where women and men have equal standing in prayer and many feminists have adopted ritual garments, in Israel it is one in 10. Instead, about half call themselves secular, and experts say that most of those consider Orthodoxy as the true Judaism, feel alienated from holy sites like the Western Wall, and view a woman in a prayer shawl as an alien import from abroad.

(Jewish law requires only men to pray daily, though many women have taken on the obligation voluntarily. It also says women should not dress like men.)

“Secular Israelis do not see this as their problem; to them it’s a bunch of crazy American ladies,” said Shari Eshet, who represents the New York-based National Council of Jewish Women here. “It’s embarrassing for Israel, it’s embarrassing for Jews, and the American Jewish community is beginning to understand that it’s a slippery slope here.”

The increased agitation around the wall is part of a broader clash over Judaism and gender that has roiled Israel in recent months. Women have won lawsuits against segregation on buses and sidewalks imposed in religious neighborhoods. But a bus line recently stopped accepting advertisements with images of people after religious vandals routinely blacked out women’s faces in the name of modesty.

In January, speakers at a conference on health and Jewish law canceled their appearances because women were barred from the podium — a demand of the most Orthodox — while the chief rabbi of the air force quit after religious soldiers were not excused from events where women sang.

These controversies concern the imposition of Orthodox doctrine in secular spheres. More complicated are questions of how Judaism itself should be practiced. This spring, the Supreme Court ruled that the government must pay the salary of a Reform rabbi along with hundreds of Orthodox ones. A small group of Jerusalem restaurants has been seeking an alternative kosher certification system to the one run by the government’s rabbinical council.

“The next chapter of what it means to be a Jewish state is being defined right now,” said Elana Sztokman, the director of the Jewish Orthodox Feminist Alliance, who is writing a book that includes a chapter about Women of the Wall. “We have to figure out what does Israel want, what role do we really want religion to have in this state? And it’s happening on the backs of women.”

Irit Pazner Garshowitz and Myra Noveck contributed reporting.

This article has been revised to reflect the following correction:

Correction: December 23, 2012

An earlier version of this article incorrectly identified the Jewish Agency as an arm of the Israeli government. It also misspelled the middle name of Sharon Graetz Strater as Gretz. 

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