Reaction to the death of actor Jack Klugman


Celebrities on Monday reacted to the death of "Odd Couple" star Jack Klugman, who died Monday at age 90. Here are samples of sentiments expressed on Twitter:


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"R.I.P. Jack Klugman, Oscar, Quincy a man whose career spanned almost 50 years. I first saw him on the Twilight Zone. Cool guy wonderful actor." — Whoopi Goldberg.


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"You made my whole family laugh together." — Actor Jon Favreau, of "Swingers," ''Iron Man" and other films.


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"I worked with Jack Klugman several years ago. He was a wonderful man and supremely talented actor. He will be missed" — Actor Max Greenfield, of the "New Girl" on Fox.


___


"So sorry to hear that Jack Klugman passed away. I learned a lot, watching him on television" — Dan Schneider, creator of Nickelodeon TV shows "iCarly," ''Drake and Josh" ''Good Burger," ''Drake & Josh."


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Bill O’Reilly Has Top 2 Spots on Hardcover Best-Seller List





“Abe would have liked this book,” the Fox News television host Bill O’Reilly said confidently of his blockbuster best-seller “Killing Lincoln: The Shocking Assassination That Changed America Forever.” Even the ending?







Robert Wright for The New York Times

Bill O’Reilly is the co-author of “Killing Kennedy” (No. 1) and “Killing Lincoln” (No. 2).







Mr. O’Reilly reasoned that Lincoln would have liked this fast-paced, thrillerlike retelling of his death “because it is simple and he was a really simple guy, straightforward guy. He didn’t like a lot of subterfuge or a lot of nonsense.”


“I don’t know if Kennedy would have liked the book,” he added with a tad of reflection about “Killing Kennedy: The End of Camelot,” his other history book written with Martin Dugard that is currently dominating the nonfiction best-seller lists, “because it really lays him out as far as what he did, and some of it wasn’t very nice. But in the end he comes off as fairly heroic.”


No one could accuse Mr. O’Reilly, 63, of playing down his own appeal — and perhaps justifiably so. He anchors the highest-rated news program on cable, his political and personal writings like “A Bold, Fresh Piece of Humanity” (2008) and “Pinheads and Patriots” (2010) have been huge sellers, and now, in his latest franchise, he has become arguably the most popular history author in America.


In the 65 weeks since “Killing Lincoln” was released in fall 2011, Mr. O’Reilly has owned territory near the top of The New York Times’s best-seller list for hardcover nonfiction. It would have been an extraordinary run by itself, but in October he released “Killing Kennedy,” which has since sold about one million copies.


For the last full week of the year he snagged both the No. 1 and 2 spots on the list, a rare feat.


But few authors manage more than one book on the hardcover list because even regulars like the historian David McCullough and the journalist Michael Lewis do not grind it out at the pace of Mr. O’Reilly, who has produced about a book a year over the past decade and intends to keep going. Others have had two atop the paperback nonfiction best-seller list, an act most recently accomplished by President Obama, whose two memoirs “Dreams From My Father” (1995) and “The Audacity of Hope” (2006) both spiked with his election in 2008.


Of course few authors also have the television platform Mr. O’Reilly has and which he uses for 30 seconds nightly to promote his books to his nearly three million viewers.


In person Mr. O’Reilly sheds his on-air bellicosity but maintains the forward energy of a barreling freight train. During an interview, held at his corner office at Fox headquarters in Manhattan, Mr. O’Reilly barely looked up as he autographed a pile of bookplates to be put into copies to be sold on his Web site for a premium for charity. He is determined, he explained, to take advantage of the holiday season.


Thirty minutes later he pointed to the pile completed and said: “That’s about 10 grand for charity right in that pile. Not bad.” That money, he said, is likely to go to the Coalition for the Homeless, a New York-based group that has successfully sued the city and won a court-ordered “right to shelter” — just the kind of policy initiative that Mr. O’Reilly and might gleefully label “radical” or “leftist” on his program.


But Mr. O’Reilly appears to relish not playing to type. Both on and over his desk, for example, are pictures of him and his daughter standing cozily with President and Mrs. Obama. “Michelle was very nice to my daughter,” he said.


Not being predictable is how he turned to history, he said. He was urged by publishers to do another memoir. It was an idea he dismissed “because I was repeating myself.”


This article has been revised to reflect the following correction:

Correction: December 24, 2012

An earlier version of this article misstated the title of President Obama’s first memoir. It is “Dreams From My Father,” not “Dreams of Our Fathers.” 



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8 New Etiquette Rules for Using Gadgets in the Office






As the use of personal technology increases at work, it’s important to observe some new etiquette rules about how we use it. Here are eight of the most important rules to follow at work when it comes to cell phones, email, and other modern technology.


1. Using speaker phone when others can hear you. Playing back your voicemail messages on speaker phone or conducting an entire call on speaker phone is distracting to people trying to work around you. Even if you’re in an office with the door closed, speakerphone noises tend to travel. Don’t value your hands-free convenience over the ability of others to focus on their work.






2. Keeping your cell phone out so you can glance at it during meetings. Glancing down at your phone while you’re supposed to be focused on a meeting signals that you’re bored, not fully engaged, or don’t respect the time of the people you’re meeting with. If you must keep your phone out because you’re expecting an important call or text, explain that at the start of the meeting so that people don’t assume you’re just being rude.


3. Don’t overuse “reply all.” When multiple people are included on an email chain, they don’t all need to see your reply of “thanks” or “will do.” Only use “reply all” if everyone included truly needs to see your response; otherwise, stick with “reply” so your response goes only to the sender and doesn’t clutter multiple in-boxes.


4. Don’t email and phone with the same message; pick one or the other. Nothing is more annoying than starting to read an email, only to have the email’s sender pop his head in your office to repeat the same message.


5. Turn off your cell phone’s ringer if you leave it behind while you’re away from your desk. Ask any office worker, and you’ll hear stories about the annoying guy who leaves his phone behind with his ringer on full-volume while he goes to meetings … leaving his co-workers forced to hear repeated renditions of “Who Let the Dogs Out” or whatever else he’s chosen for his ringtone.


6. Placing calls from a noisy location. If you make a call, ensure you’re somewhere where you and the person you’re speaking with will be able to hear each other–and where you can give your full focus. It’s irritating to get a call from someone who immediately puts you on hold to order coffee because she just reached the front of the line.


7. Keep religious and political messages out of your email signature. Including religious or political messages is likely to offend or at least irritate some of your recipients, and introduces topics that don’t belong in a professional setting. Keep your sign-off neutral and professional.


8. Don’t use your work email as your personal email. In most offices, sending occasional personal emails from your work account is fine, but you should use your personal account for most personal things. If you treat your work email as your default personal account, chances are good that when you leave your job and your inbox and sent folder are full of personal messages, one of your co-workers will be stuck reading through all of them, as they clean out your account for your replacement. In the best case scenario, that’s merely a nuisance for a co-worker –but in the worst case scenario, it could lead to embarrassing revelations.


Alison Green writes the popular Ask a Manager blog, where she dispenses advice on career, job search, and management issues. She’s also the co-author of Managing to Change the World: The Nonprofit Manager’s Guide to Getting Results, and former chief of staff of a successful nonprofit organization, where she oversaw day-to-day staff management, hiring, firing, and employee development.


Wireless News Headlines – Yahoo! News





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Thousands sign US petition to deport Piers Morgan


LONDON (AP) — Tens of thousands of people have signed a petition calling for British CNN host Piers Morgan to be deported from the U.S. over his gun control views.


Morgan has taken an aggressive stand for tighter U.S. gun laws in the wake of the Newtown, Connecticut, school shooting. Last week, he called a gun advocate appearing on his "Piers Morgan Tonight" show an "unbelievably stupid man."


Now, gun rights activists are fighting back. A petition created Dec. 21 on the White House e-petition website by a user in Texas accuses Morgan of engaging in a "hostile attack against the U.S. Constitution" by targeting the Second Amendment. It demands he be deported immediately for "exploiting his position as a national network television host to stage attacks against the rights of American citizens."


The petition has already hit the 25,000 signature threshold to get a White House response. By Monday, it had 31,813 signatures.


Morgan seemed unfazed — and even amused — by the movement.


In a series of Twitter messages, he alternately urged his followers to sign the petition and in response to one article about the petition said "bring it on" as he appeared to track the petition's progress.


"If I do get deported from America for wanting fewer gun murders, are there any other countries that will have me?" he wrote.


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N.Y.U. and Others Offer Shorter Courses Through Medical School





Training to become a doctor takes so long that just the time invested has become, to many, emblematic of the gravity and prestige of the profession.




But now one of the nation’s premier medical schools, New York University, and a few others around the United States are challenging that equation by offering a small percentage of students the chance to finish early, in three years instead of the traditional four.


Administrators at N.Y.U. say they can make the change without compromising quality, by eliminating redundancies in their science curriculum, getting students into clinical training more quickly and adding some extra class time in the summer.


Not only, they say, will those doctors be able to hang out their shingles to practice earlier, but they will save a quarter of the cost of medical school — $49,560 a year in tuition and fees at N.Y.U., and even more when room, board, books, supplies and other expenses are added in.


“We’re confident that our three-year students are going to get the same depth and core knowledge, that we’re not going to turn it into a trade school,” said Dr. Steven Abramson, vice dean for education, faculty and academic affairs at N.Y.U. School of Medicine.


At this point, the effort involves a small number of students at three medical schools: about 16 incoming students at N.Y.U., or about 10 percent of next year’s entering class; 9 at Texas Tech Health Science Center School of Medicine; and even fewer, for now, at Mercer University School of Medicine’s campus in Savannah, Ga. A similar trial at Louisiana State University has been delayed because of budget constraints.


But Dr. Steven Berk, the dean at Texas Tech, said that 10 or 15 other schools across the country had expressed interest in what his university was doing, and the deans of all three schools say that if the approach works, they will extend the option to larger numbers of students.


“You’re going to see this kind of three-year pathway become very prominent across the country,” Dr. Abramson predicted.


The deans say that getting students out the door more quickly will accomplish several goals. By speeding up production of physicians, they say, it could eventually dampen a looming doctor shortage, although the number of doctors would not increase unless the schools enrolled more students in the future.


The three-year program would also curtail student debt, which now averages $150,000 by graduation, and by doing so, persuade more students to go into shortage areas like pediatrics and internal medicine, rather than more lucrative specialties like dermatology.


The idea was supported by Dr. Ezekiel J. Emanuel, a former health adviser to President Obama, and a colleague, Victor R. Fuchs. In an editorial in the Journal of the American Medical Association in March, they said there was “substantial waste” in the nation’s medical education. “Years of training have been added without evidence that they enhance clinical skills or the quality of care,” they wrote. They suggested that the 14 years of college, medical school, residency and fellowship that it now takes to train a subspecialty physician could be reduced by 30 percent, to 10 years.


That opinion, however, is not universally held. Other experts say that a three-year medical program would deprive students of the time they need to delve deeply into their subjects, to consolidate their learning and to reach the level of maturity they need to begin practicing, while adding even more pressure to a stressful academic environment.


“The downside is that you are really tired,” said Dr. Dan Hunt, co-secretary of the Liaison Committee on Medical Education, the accrediting agency for medical schools in the United States and Canada. But because accreditation standards do not dictate the fine points of curriculum, the committee has approved N.Y.U.’s proposal, which exceeds by five weeks its requirement that schools provide at least 130 weeks of medical education.


The medical school is going ahead with its three-year program despite the damage from Hurricane Sandy, which forced NYU Langone Medical Center to evacuate more than 300 patients at the height of the storm and temporarily shut down three of its four main teaching hospitals.


Dr. Abramson of N.Y.U. said that postgraduate training, which typically includes three years in a hospital residency, and often fellowships after that, made it unnecessary to try to cram everything into the medical school years. Students in the three-year program will have to take eight weeks of class before entering medical school, and stay in the top half of their class academically. Those who do not meet the standards will revert to the four-year program.


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Syrian Resort Town Is Stronghold for Alawites





TARTUS, Syria — Loyalists who support the government of President Bashar al-Assad are flocking to the Mediterranean port of Tartus, creating an overflowing boomtown far removed from the tangled, scorched rubble that now mars most Syrian cities.







The New York Times

The port city of Tartus is sheltered by a mountain range.






There are no shellings or air raids to interrupt the daily calm. Families pack the cafes lining the town’s seaside corniche, usually abandoned in December to the salty winter winds. The real estate market is brisk. A small Russian naval base provides at least the impression that salvation, if needed, is near.


Many of the new residents are members of the Alawite minority, the same Shiite Muslim sect to which Mr. Assad belongs. The latest influx is fleeing from Damascus, people who have decided that summer villas, however chilly, are preferable to the looming battle for the capital.


“Going to Tartus is like going to a different country,” said a Syrian journalist who recently met residents here. “It feels totally unaffected and safe. The attitude is, ‘We are enjoying our lives while our army is fighting overseas.’ ”


Should Damascus fall to the opposition, Tartus could become the heart of an attempt to create a different country. Some expect Mr. Assad and the security elite will try to survive the collapse by establishing a rump Alawite state along the coast, with Tartus as their new capital.


There have been various signs of preparations.


This month, the governor of Tartus Province announced that experts were studying how to develop a tiny local airfield, now used mostly by crop-dusters, into a full-fledged civilian airport “to boost transportation, business, travel and tourism,” as the official Syrian news agency, SANA, reported. The announcement coincided with the first attacks on the airport in Damascus, forcing it to close temporarily to international traffic.


More important, security forces are continuously tightening an extensive ring of checkpoints around the potential borders of an Alawite canton. The mountain heartland of the Alawites rises steeply to the east of Tartus, separating it from much of Syria. Across the mountains, the Orontes River creates a rough line separating Alawite territory from central Syria. Rebel military commanders from adjoining Hama Province said government soldiers vigorously maintain checkpoints on routes leading up into the mountains.


“If we bomb a checkpoint, it is back in place sometimes within hours,” said Basil al-Hamwi, a rebel fighter, speaking on the sidelines of a meeting of opposition military commanders in Turkey. “Once, in Hama Province, we destroyed five in one day and they were all back the next day. This area is even more important for them than Damascus.”


Mr. Hamwi and other rebel leaders said there were about 40 government checkpoints along more than 60 miles in Homs and Hama Provinces alone. Many Alawite commanders of Mr. Assad’s army have sent their families to their home villages, so they are particularly aggressive in protecting the area, said Hassan M. al-Saloom, a rebel battalion commander. They have formed committees to guard the outskirts of their villages, he said, and often negotiate local truces.


“Nobody goes inside, and they don’t come out,” he said.


There are widespread suspicions within the opposition that the military is shipping weapons into the Alawite hinterland, or has already positioned them. “The mountains and the coast make it hard to raid,” Mr. Saloom said.


Castles left by the Crusaders dot the coastal range, a testament to its strategic value.


If Mr. Assad fled to Tartus, he could seek protection from the Russian naval base here, or flee aboard a Russian vessel. Russia announced Tuesday that it was sending a small flotilla toward Tartus, possibly to evacuate its citizens who live in Syria. But Tartus residents said that the Russian families from the naval base had already left, while the officers do not leave the base, which is little more than an enclosure near the civilian port.


An employee of The New York Times reported from Tartus, and Neil MacFarquhar from Antakya, Turkey. Hania Mourtada contributed reporting from Beirut, Lebanon, and Hala Droubi from Dubai, United Arab Emirates.



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Without an ‘iTV,’ Apple’s growth could shrink to the single digits by 2015






Another analyst believes that Apple is losing its shine. Toni Sacconaghi of Bernstein Research on Thursday trimmed his price target for the company, citing concerns that growth may be slowing. The analyst believes that iPhone sales will remain strong for at least the next two years, however Apple (AAPL) is expected to lose overall market share “if it does not bring out a lower-price device” in the wake of a changing industry. Sacconaghi notes that the iPad should continue to see success in a tablet market that is “a rocket…an absolute juggernaut,” with tablet PC shipments estimated to more than triple over the next five years. It is believed, however, that Apple will likely become a single digit growth company by 2015, unless it releases a new major product such as an HDTV.


[More from BGR: RIM’s biggest problem: It’s still scrambling to catch yesterday’s hottest mobile app]






“That said, it will have a pristine balance sheet, and be generating a mind-boggling $ 49 billion in free cash flow a year after paying its current dividend,” Sacconaghi wrote in a note to investors, according to Forbes. “More importantly, we believe that Apple’s innovation offers significant option value, which is not in our forecast. Three years ago, the iPad did not exist. Today it generates $ 32 billon in annual revenues, and as a standalone business would be the 11th biggest U.S. tech company. Potential ‘options’ for Apple investors include a lower-end iPhone, a television ‘solution,’ a larger iPad or converged device and monetizing advertising, e-commerce and search from its iOS platform (and credit card database) of 435 million users.”


[More from BGR: WhatsApp goes free for iPhone for a limited time]


The analyst kept his Outperform rating on shares of Apple, although he trimmed his price target from $ 800 to $ 750 and lowered his 2013 fiscal year EPS forecast to $ 49.41 per share, from $ 50.57.


This article was originally published by BGR


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Ashton Kutcher files for divorce from Demi Moore


LOS ANGELES (AP) — Ashton Kutcher filed court papers Friday to end his seven-year marriage to actress Demi Moore.


The actor's divorce petition cites irreconcilable differences and does not list a date that the couple separated. Moore announced last year that she was ending her marriage to the actor 15 years her junior, but she never filed a petition.


Kutcher's filing does not indicate that the couple has a prenuptial agreement. The filing states Kutcher signed the document Friday, hours before it was filed in Los Angeles Superior Court.


Kutcher and Moore married in September 2005 and until recently kept their relationship very public, communicating with each other and fans on the social networking site Twitter. After their breakup, Moore changed her name on the site from (at)mrskutcher to (at)justdemi.


Kutcher currently stars on CBS' "Two and a Half Men."


Messages sent to Kutcher's and Moore's publicists were not immediately returned Friday.


Moore, 50, and Kutcher, 34, created the DNA Foundation, also known as the Demi and Ashton Foundation, in 2010 to combat the organized sexual exploitation of girls around the globe. They later lent their support to the United Nations' efforts to fight human trafficking, a scourge the international organization estimates affects about 2.5 million people worldwide.


Moore was previously married to actor Bruce Willis for 13 years. They had three daughters together — Rumer, Scout and Tallulah Belle — before divorcing in 2000. Willis later married model-actress Emma Heming in an intimate 2009 ceremony at his home in Parrot Cay in the Turks and Caicos Islands that attended by their children, as well as Moore and Kutcher.


Kutcher has been dating former "That '70s Show" co-star Mila Kunis.


The divorce filing was first reported Friday by People magazine.


___


Anthony McCartney can be reached at http://twitter.com/mccartneyAP.


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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..