Gun Makers Based in Connecticut Form a Potent Lobby

Gun owners packed a hearing room in the Connecticut capital, vowing to oppose a bill that would require new markers on guns so that they are easier to trace.

One after another, they testified that the technology, called microstamping, was flawed and would increase the cost of guns.

But the witness who commanded the most attention in Hartford that day in 2009 was a representative of one of Connecticut’s major employers: the Colt Manufacturing Company, the gun maker.

The Colt executive, Carlton S. Chen, said the company would seriously consider leaving the state if the bill became law. “You would think that the Connecticut government would be in support of our industry,” Mr. Chen said.

Soon, Connecticut lawmakers shelved the bill; they have declined to take it up since. Now, in the aftermath of the school massacre in Newtown, the lawmakers are formulating new gun-control measures, saying the state must serve as a national model.

But the failed effort to enact the microstamping measure shows how difficult the climate has been for gun control in state capitals. The firearm companies have played an important role in defeating these measures by repeatedly warning that they will close factories and move jobs if new state regulations are approved.

The companies have issued such threats in several states, especially in the Northeast, where gun control is more popular. But their views have particular resonance in Connecticut, a cradle of the American gun industry.

Like manufacturing in Connecticut over all, the state’s gun industry is not as robust as it once was. Still, Connecticut remains the seventh-largest producer of firearms in the country, according to federal data.

Colt, based in Connecticut since the 1800s, employs roughly 900 people in the state. Two other major gun companies, Sturm, Ruger & Company and Mossberg & Sons, are also based in the state. In all, the industry employs about 2,000 people in Connecticut, company officials said.

Gun-control advocates have long viewed Hartford, the capital, as hospitable terrain, because Connecticut is a relatively liberal state and already has more gun restrictions than most. Democrats control both houses of the legislature.

Yet lawmakers in Hartford did more than shelve the microstamping bill in 2009. They also declined to push a bill last year that would have banned high-capacity ammunition magazines — the very accessory used by Adam Lanza to kill 26 people, including 20 children, at Sandy Hook Elementary School in Newtown.

In several states, the gun companies have enlisted unions that represent gun workers, mindful that Democratic lawmakers who might otherwise back gun control also have close ties to labor.

In Connecticut, the United Automobile Workers, which represents Colt workers, has testified against restrictions. The union’s arguments were bolstered last year when Marlin Firearms, a leading manufacturer of rifles, closed a factory in Connecticut that employed more than 200 people. Marlin cited economic pressures, not gun regulation, for the decision, but representatives of the gun industry have said the combination of the two factors could spur others to move.

State law significantly restricts the ability of corporations to make political donations in Connecticut. Employees of Connecticut gun companies have contributed several thousand dollars in total in recent years to state candidates, mostly Republicans, according to an analysis of state records.

Financially, the gun companies and their employees in Connecticut have exerted influence by donating to national groups, especially the National Rifle Association, which have in turn helped Connecticut gun rights groups, according to interviews and financial records.

But it appears that in Hartford, the companies are relying largely on economic arguments.

Their strategy has been led by the industry’s trade group, the National Shooting Sports Foundation, which happens to have its national headquarters in Newtown, a few miles from the site of the shootings.

When Connecticut lawmakers held a hearing in 2011 on the measure to ban high-capacity ammunition magazines, the director of government regulations for the foundation, Jake McGuigan, opened his testimony with some statistics.

Mr. McGuigan told lawmakers that the state’s gun companies contributed $1.3 billion to the Connecticut economy, through their own operations and those of their suppliers.

“Each year, they get courted by other firearm-friendly states, like Idaho, Virginia, North Carolina,” Mr. McGuigan said. He later added, “It’s not an idle threat.”

The federation and Colt have declined to comment on gun-control legislation since the school killings.

“Our hearts go out to our fellow Connecticut residents who have suffered such unimaginable loss,” Colt said in a statement. “We do not believe it is appropriate to make further public statements at this very emotional time.”

Gun-control advocates in Hartford said the gun companies’ strategy was shrewd because it allowed Democratic lawmakers to oppose new regulations while proclaiming that they had not bowed to the National Rifle Association.

Michael Moss and Griff Palmer contributed reporting.

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The New Old Age Blog: Fudging the Facts, for Peace of Mind

Lou, my beloved grandfather, lived almost 101 years and obsessively worried every single day of his adult life — probably because his adult life began before it should have. As a child in Russia, he watched helplessly as his mother and sister were killed during a vicious pogrom in their village.

Lou (I called him Zadie) made his way to America, and immediately began imagining the worst about his fate, and his family’s fate, in his new country. I believe Zadie lived as long as he did because he was afraid of what would happen to his children, grandchildren, and great-grandchildren if he wasn’t here to protect them.

When I was a third-year medical student in New York City, he called from Denver very early one morning, waking me and my roommates. He had been listening to his transistor radio on one of his many sleepless nights of worry, and had heard that a Staten Island Ferry boat had crashed, injuring numerous passengers.

There were more than seven million people in the city, and Zadie called at 4 a.m. to make sure I wasn’t one of those injured. It was from him we learned the importance of telling white lies and omitting certain truths with our elderly parents and grandparents.

Before accusing me of infantilizing and patronizing my older family members, hear me out. Anxiety disorders can be debilitating for the elderly. A comprehensive review of the subject found 10 to14 percent of those 65 and older meet the criteria for these diagnoses, a significantly higher figure than for the more widely recognized depression syndromes in the same demographic.

Indeed, depression and anxiety disorders often occur together. Anxiety disorders are underdiagnosed in the elderly, largely because the symptoms are often assumed to be just another manifestation of aging. Additionally, the clinical assessment of the elderly for anxiety is more complicated than for younger patients because the signs may differ from those classically described in the diagnostic manuals.

A large national study showed an increased incidence of general anxiety disorder beginning after age 55, and the National Alliance on Mental Illness notes that, like depression, obsessive-compulsive disorder tends to worsen in old age. Factors contributing to the prevalence and severity of anxiety disorders in the elderly include a host of concomitant medical problems that interact with anxiety in a complicated way.

From the review article cited earlier:

The co-morbidity between medical illness and anxiety disorders poses difficulties for…diagnosis and detection of anxiety. Researchers have suggested that older adults may be more likely to attribute physical symptoms related to anxiety to medical issues… In turn, many physical conditions, such as cardiovascular disease, respiratory disease, hyperthyroidism, and pulmonary and vestibular difficulties, can mimic the symptoms of anxiety…making it difficult to establish the underlying cause…

Furthermore, the symptoms that result from medical illnesses may produce fearful bodily sensations that may result in the subsequent development of anxiety disorders.

As an example, more than 40 percent of patients with Parkinson’s disease meet the criteria for an anxiety disorder. Dementia is also associated with anxiety in a bidirectional way — anxiety can accelerate cognitive decline, which in turn can increase symptoms of anxiety. Added to this morass are the side effects, which can include anxiety, of many medications taken by older patients.

The elderly clearly are an at-risk population for anxiety disorders. Which brings us back to white lies. Zadie’s well-earned anxieties, obsessions and worries accelerated greatly as he got older, and we realized they could largely be prevented if we simply didn’t share the complete truth with him all the time. This became known in our family as the Zadie Filter.

When we took our children to the mountains, we told him we were headed to Colorado Springs; he’d been to Colorado Springs many times and knew it was a flat highway drive from Denver. No high mountain passes or narrow roads without guardrails.

When he begged my sons to become doctors so they would serve behind the front lines in the event they were drafted (this was long after the military draft ended, which was still not reassuring enough for Zadie), they so promised. When our daughter started driving, Zadie warned her it wasn’t safe for a girl to drive alone in case she had car trouble; she promised she would always have company in the car.

Zadie died when his great-grandchildren were still teenagers, and so he never had to know that the boys didn’t go into medicine and that his great-granddaughter drives alone.

My mother, Zadie’s daughter, inherited his anxieties, and as she has entered her mid-80s her symptoms have also markedly increased. On the other side of the family, my mother-in-law’s issues with anxiety began with her Parkinson’s disease and have worsened as her neurological condition has progressed.

With our mothers, we also rely on the Zadie Filter. Our white lies and omissions reduce their worries — which is not to say we can protect them from all triggers (they still read the newspaper and watch the nightly news), but even a bit of relief for them is relief for us as well.

Our parents live for the most part on fixed incomes, so when we’re able to cover some of their expenses without their knowing, we do so, and they worry a little less about their bills. All it takes is a little white lie: “The apartment manager waived your heating bill this month because you’ve been such a good long-term tenant,” or, “Of course I used your credit card when I paid for your medicines.”

My mother accidentally found out that our son broke his finger (playing flag football during finals week!) when a well-intentioned friend asked her how her grandson was doing after his injury. She was upset we hadn’t told her — but only for a few moments, until we explained that it had happened a week before, that he was all splinted up and was in no pain. All of which was 100 percent true, and she didn’t lose a minute of sleep worrying about it.

Last week, after pressing our law student son (he of the broken finger) about a school transcript issue I’ve been worried about for him, he assured me it had been taken care of. Our daughter in grad school goes into bars only when she’s with a large group of friends, and our college son is the designated driver for all of his fraternity functions.

And so it begins.

---

Dr. Harley A. Rotbart is professor and vice chairman of pediatrics at the University of Colorado School of Medicine and the author of “No Regrets Parenting.”

Read More..

The New Old Age Blog: Fudging the Facts, for Peace of Mind

Lou, my beloved grandfather, lived almost 101 years and obsessively worried every single day of his adult life — probably because his adult life began before it should have. As a child in Russia, he watched helplessly as his mother and sister were killed during a vicious pogrom in their village.

Lou (I called him Zadie) made his way to America, and immediately began imagining the worst about his fate, and his family’s fate, in his new country. I believe Zadie lived as long as he did because he was afraid of what would happen to his children, grandchildren, and great-grandchildren if he wasn’t here to protect them.

When I was a third-year medical student in New York City, he called from Denver very early one morning, waking me and my roommates. He had been listening to his transistor radio on one of his many sleepless nights of worry, and had heard that a Staten Island Ferry boat had crashed, injuring numerous passengers.

There were more than seven million people in the city, and Zadie called at 4 a.m. to make sure I wasn’t one of those injured. It was from him we learned the importance of telling white lies and omitting certain truths with our elderly parents and grandparents.

Before accusing me of infantilizing and patronizing my older family members, hear me out. Anxiety disorders can be debilitating for the elderly. A comprehensive review of the subject found 10 to14 percent of those 65 and older meet the criteria for these diagnoses, a significantly higher figure than for the more widely recognized depression syndromes in the same demographic.

Indeed, depression and anxiety disorders often occur together. Anxiety disorders are underdiagnosed in the elderly, largely because the symptoms are often assumed to be just another manifestation of aging. Additionally, the clinical assessment of the elderly for anxiety is more complicated than for younger patients because the signs may differ from those classically described in the diagnostic manuals.

A large national study showed an increased incidence of general anxiety disorder beginning after age 55, and the National Alliance on Mental Illness notes that, like depression, obsessive-compulsive disorder tends to worsen in old age. Factors contributing to the prevalence and severity of anxiety disorders in the elderly include a host of concomitant medical problems that interact with anxiety in a complicated way.

From the review article cited earlier:

The co-morbidity between medical illness and anxiety disorders poses difficulties for…diagnosis and detection of anxiety. Researchers have suggested that older adults may be more likely to attribute physical symptoms related to anxiety to medical issues… In turn, many physical conditions, such as cardiovascular disease, respiratory disease, hyperthyroidism, and pulmonary and vestibular difficulties, can mimic the symptoms of anxiety…making it difficult to establish the underlying cause…

Furthermore, the symptoms that result from medical illnesses may produce fearful bodily sensations that may result in the subsequent development of anxiety disorders.

As an example, more than 40 percent of patients with Parkinson’s disease meet the criteria for an anxiety disorder. Dementia is also associated with anxiety in a bidirectional way — anxiety can accelerate cognitive decline, which in turn can increase symptoms of anxiety. Added to this morass are the side effects, which can include anxiety, of many medications taken by older patients.

The elderly clearly are an at-risk population for anxiety disorders. Which brings us back to white lies. Zadie’s well-earned anxieties, obsessions and worries accelerated greatly as he got older, and we realized they could largely be prevented if we simply didn’t share the complete truth with him all the time. This became known in our family as the Zadie Filter.

When we took our children to the mountains, we told him we were headed to Colorado Springs; he’d been to Colorado Springs many times and knew it was a flat highway drive from Denver. No high mountain passes or narrow roads without guardrails.

When he begged my sons to become doctors so they would serve behind the front lines in the event they were drafted (this was long after the military draft ended, which was still not reassuring enough for Zadie), they so promised. When our daughter started driving, Zadie warned her it wasn’t safe for a girl to drive alone in case she had car trouble; she promised she would always have company in the car.

Zadie died when his great-grandchildren were still teenagers, and so he never had to know that the boys didn’t go into medicine and that his great-granddaughter drives alone.

My mother, Zadie’s daughter, inherited his anxieties, and as she has entered her mid-80s her symptoms have also markedly increased. On the other side of the family, my mother-in-law’s issues with anxiety began with her Parkinson’s disease and have worsened as her neurological condition has progressed.

With our mothers, we also rely on the Zadie Filter. Our white lies and omissions reduce their worries — which is not to say we can protect them from all triggers (they still read the newspaper and watch the nightly news), but even a bit of relief for them is relief for us as well.

Our parents live for the most part on fixed incomes, so when we’re able to cover some of their expenses without their knowing, we do so, and they worry a little less about their bills. All it takes is a little white lie: “The apartment manager waived your heating bill this month because you’ve been such a good long-term tenant,” or, “Of course I used your credit card when I paid for your medicines.”

My mother accidentally found out that our son broke his finger (playing flag football during finals week!) when a well-intentioned friend asked her how her grandson was doing after his injury. She was upset we hadn’t told her — but only for a few moments, until we explained that it had happened a week before, that he was all splinted up and was in no pain. All of which was 100 percent true, and she didn’t lose a minute of sleep worrying about it.

Last week, after pressing our law student son (he of the broken finger) about a school transcript issue I’ve been worried about for him, he assured me it had been taken care of. Our daughter in grad school goes into bars only when she’s with a large group of friends, and our college son is the designated driver for all of his fraternity functions.

And so it begins.

---

Dr. Harley A. Rotbart is professor and vice chairman of pediatrics at the University of Colorado School of Medicine and the author of “No Regrets Parenting.”

Read More..

Gadgetwise Blog: Q&A: Finding a Simplified Smartphone

Are there any smartphones designed for the eager-to-learn, but still-on-training-wheels senior citizen?

With the right amount of help and training, many people — regardless of age — can learn the basics of smartphone operation. To help make things easier for those who do not have a lot of experience or patience with modern gadgetry, some manufacturers are making smartphones specifically designed to be easier to use.

Such products include the Pantech Flex, an Android smartphone that offers an optional Easy Experience interface with larger text and home screen shortcut buttons. GreatCall, which makes the big-buttoned Jitterbug flip phone, now has a touch-screen smartphone, the Jitterbug Touch.

The Doro PhoneEasy 740, another simplified Android handset with a large touch screen and a keyboard, is scheduled for introduction in the United States next spring. The CNET site has an early review of the PhoneEasy 740.

If a bigger screen is the most desired feature, standard smartphones like Samsung’s Galaxy Note line, which has a 5.3-inch display and can be used with a stylus, may be easier to use than a smartphone with a smaller screen. Apple’s iPhone 5 model features a more petite four-inch screen, but Apple offers free workshops for new users at its Apple Stores in most major cities.

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In Aiding Quake-Battered Haiti, Lofty Hopes and Hard Truths

Damon Winter/The New York Times

Vegetable vendors worked recently amid rubble in Port-au-Prince, three years after an earthquake devastated the city. More Photos »

PORT-AU-PRINCE, Haiti — A few days after the Jan. 10, 2010, earthquake, Reginald Boulos opened the gates of his destroyed car dealership to some 14,000 displaced people who settled on the expansive property. Seven months later, eager to rebuild his business, he paid the families $400 each to leave Camp Boulos and return to their devastated neighborhoods.

At the time, Dr. Boulos, a physician and business magnate, was much maligned for what was portrayed as bribing the homeless to participate in their own eviction. But eventually, desperate to rid public plazas of squalid camps, the Haitian government and the international authorities adopted his approach themselves: “return cash grants” have become the primary resettlement tool.

This represents a marked deflation of the lofty ambitions that followed the disaster, when the world aspired not only to repair Haiti but to remake it completely. The new pragmatism signals an acknowledgment that despite billions of dollars spent — and billions more allocated for Haiti but unspent — rebuilding has barely begun and 357,785 Haitians still languish in 496 tent camps.

“When you look at things, you say, ‘Hell, almost three years later, where is the reconstruction?’ ” said Michèle Pierre-Louis, a former prime minister of Haiti. “If you ask what went right and what went wrong, the answer is, most everything went wrong. There needs to be some accountability for all that money.”

An analysis of all that money — at least $7.5 billion disbursed so far — helps explain why such a seeming bounty is not more palpable here in the eviscerated capital city, where the world’s chief accomplishment is to have finally cleared away most of the rubble.

More than half of the money has gone to relief aid, which saves lives and alleviates misery but carries high costs and leaves no permanent footprint — tents shred; emergency food and water gets consumed; short-term jobs expire; transitional shelters, clinics and schools are not built to last.

Of the rest, only a portion went to earthquake reconstruction strictly defined. Instead, much of the so-called recovery aid was devoted to costly current programs, like highway building and H.I.V. prevention, and to new projects far outside the disaster zone, like an industrial park in the north and a teaching hospital in the central plateau.

Meanwhile, just a sliver of the total disbursement — $215 million — has been allocated to the most obvious and pressing need: safe, permanent housing. By comparison, an estimated minimum of $1.2 billion has been eaten up by short-term solutions — the tent camps, temporary shelters and cash grants that pay a year’s rent.

“Housing is difficult and messy, and donors have shied away from it,” said Josef Leitmann, manager of the Haiti Reconstruction Fund.

Benefactors and Dysfunction

Beyond the numbers, the sluggish reconstruction has been the latest dispiriting chapter in the chronically dysfunctional relationship between Haiti and its benefactors.

After the earthquake, with good will and money pouring into Haiti, international officials were determined to use the disaster as a catalyst for transforming not only the intractably poor country but the world’s ineffectual strategies for helping it.

Bill Clinton, the United Nations special envoy for Haiti, invoked the “build back better” mantra he had imported from his similar role in South Asia after the tsunami. And Secretary of State Hillary Rodham Clinton cautioned donors to stop working around the government and instead work with it, and to stop financing “a scattered array of well-meaning projects” rather than making “deeper, long-term investments.”

But an examination by The New York Times shows that such post-disaster idealism came to be undercut by the enormousness of the task, the weakness and volatility of the Haitian government, the continuation of aid business as usual and the limited effectiveness of the now-defunct recovery commission that had Mr. Clinton as co-chairman.

André Paultre and Damon Winter contributed reporting.

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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..

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.

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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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India Ink: Protests Over Rape Turn Violent in India

Angry protests escalated into violence in India’s capital on Sunday, after thousands of people gathered to demand justice for the victim of a recent gang rape in New Delhi and improved safety for women.

Protesters flocked to the India Gate monument throughout the day, despite police attempts to deter them and a hastily enacted ban on protesting in New Delhi, where they taunted the police and attacked the car of a member of Parliament. The police, in turn, fired tear gas and water cannons, beat protesters with bamboo sticks and arrested dozens.

By late afternoon Sunday, political parties had joined the crowd, increasing the number of confrontational encounters with the police. Protesters overturned a car, and clashes turned fierce.

The crowd, made up predominantly of young people, surrounded India Gate but was prevented from marching to Rashtrapati Bhavan, the palatial home of the president. Hundreds of police officers, many in blue helmets from the country’s ”Rapid Action Force,” blocked their way.

The angry crowds jostled with the police, calling them ”cowardly,” ”corrupt” and ”inept,” as they tried to push through the cordon. ”Why don’t you come and join us?” one agitated protester asked a senior police officer. ”Aren’t you angry at what happened?”

Sunday marked the seventh day of protests in India after medical student was raped Dec. 16 on a moving bus by several men, the latest in a series of violent crimes against women in northern India. The victim of the gang rape suffered severe intestinal injuries after being attacked with an iron rod during the assault and was battling for her life, doctors said last week.

”We are not happy with this piecemeal, drop-in-the-ocean, inane response of the government” to concerns about women’s safety, said Albeena Shakil, 36, an activist who helped mobilize the protests. ”We want some big changes,” she said. ”If the administration will not do it, who will?”

Another protester, Kulsoom Rashid, 27, said she had been tear-gassed Sunday afternoon.

”This is how they are responding,” she said, seething, as she rubbed her eyes vigorously. ”Hundreds of rapists are running scot-free and the entire Delhi police is standing here to stop people like me?”

Women’s and students’ groups at the protests had compiled a list of four demands: They would like the courts to fast-track about 100,000 cases involving allegations of rape; for the Indian police to pledge to register complaints of rape when they happen; for Parliament to hold a special session to pass laws on rape, sexual harassment and child abuse; and for the Delhi police commissioner to be fired for his handling of the protests.

The police tried to prevent Sunday’s demonstration from taking place. Early in the morning, nearby subway stations were closed, and the roads leading to India Gate were blocked in an attempt to deter protesters.

Protesters who had camped in the area overnight were dragged away, and more than two dozen were arrested.

The police said in a statement on Sunday morning that they had also imposed Section 144, an emergency measure in the country’s criminal procedure code aimed at preventing riots, and had outlawed large gatherings of people in New Delhi. They asked protesters to go to the Ram Lila grounds, near the northern neighborhood of Old Delhi, instead.

Still, protesters poured into the India Gate area, which faces Delhi’s grand colonial-era government seat, throughout Sunday, arriving on foot. Several said that footage of the police dragging protesters away Sunday morning had inspired them to come.

”Many students who were protesting peacefully were attacked,” said Jayati Ghosh, a professor of economics at Jawaharlal Nehru University, who had joined the protest with her daughter. ”These are patriotic and respectable citizens. You cannot respond to them in this ham-handed manner,” she said.

The emergency measure remained in effect in New Delhi on Sunday afternoon, said Rajan Bhagat, a public relations officer with the Delhi police, but would not be invoked at Ram Lila. If protesters moved there, ”normal life of the city won’t be disturbed,” Mr. Bhagat said.

The protest Sunday paralyzed the Edward Lutyens-designed center of Delhi, where top government officials live in grand homes set on acres of land.

The president of the governing Congress party, Sonia Gandhi, and her son, Rahul, the party’s general secretary, met a few protesters Sunday morning at Ms. Gandhi’s residence, local news stations reported. ”I am with you,” Ms. Gandhi told protesters, adding that ”justice will be delivered,” according to the news agency ANI.

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