Pagano back to coach Colts after cancer treatment

INDIANAPOLIS (AP) — Chuck Pagano stepped to the podium Monday, hugged his team owner, thanked his family for its support and wiped a tear from his eye.

He might, finally, turn out the lights in his office, too.

Nearly three months to the day after being diagnosed with leukemia, the Colts' first-year coach returned to a team eager to reunite with a boss healthy enough to go back to work.

"I told you my best day of my life was July 1, 1989," Pagano said, referring to his wedding date. "Today was No. 2. Getting to pull up, drive in, get out of my car, the key fob still worked. I was beginning to question whether it would or not. When I asked for Bruce to take over, I asked for him to kick some you-know-what and to do great. Damn Bruce, you had to go and win nine games? Tough act to follow. Tough act to follow. Best in the history of the NFL. That's what I have to come back to."

The comment turned tears into the laughter everyone expected on such a festive occasion.

For Pagano and the Colts, Monday morning was as precious as anyone could have imagined when Pagano took an indefinite leave to face the biggest opponent of his life, cancer.

In his absence, all the Colts was win nine of 12 games, make a historic turnaround and clinch a playoff spot all before Sunday's regular-season finale against Houston, which they pegged as the day they hoped to have Pagano back. If all goes well at practice this week, Pagano will be on the sideline for the first time since a Week 3 loss to Jacksonville.

Pagano endured three rounds of chemotherapy to put his cancer in remission.

That Pagano's return came less than 24 hours after Indy (10-5) locked up the No. 5 seed in the AFC and the day before Christmas seemed fitting, too.

"I know Chuck is ready for this challenge. In speaking to his doctor multiple times, I know that the time is right for him to grab the reins, get the head coaching cap on and begin the journey," owner Jim Irsay said. "It's been a miraculous story. It really is a book. It's a fairytale. It's a Hollywood script. It's all those things but it's real."

The reality is that he's returning to a vastly different team than the one he turned over to Arians, his long-time friend and first assistant coaching hire.

Back then, the Colts were 1-2 and most of the so-called experts had written them off as one of the league's worst teams. Now, they're ready to show the football world that they can be just as successful under Pagano as they were under Arians, who tied the NFL record for wins after a midseason coaching change.

Pagano also has changed.

The neatly-trimmed salt-and-pepper hair and trademark goatee that were missing in November have slowly returned, and the thinner man who appeared to be catching his breath during a postgame speech in early November, looked and sounded as good as ever Monday.

He repeatedly thanked fans for their prayers and letters, the organization and his family for their unwavering help and promised to provide comfort and support to other people who are facing similar fights. During one poignant moment that nearly brought out tears again, Pagano even recounted a letter sent to him by a 9-year-old child who suggested he suck on ice chips and strawberry Popsicles in the hospital and advised him to be nice to the nurses regardless of how he felt — and he never even paused.

"I feel great, my weight is back, my energy is back and again, it's just a blessing to be back here," Pagano said.

In the minds of Colts players and coaches, Pagano never really left.

He continually watched practice tape and game film on his computer, used phone calls and text messages to regularly communicate with players and occasionally delivered a pregame or postgame speech to his team.

"He texted me and called me so much, it was like he was standing there in my face every day," said receiver Reggie Wayne, who has been friends with Pagano since the two were working together at the University of Miami.

But the Colts found plenty of other ways to keep Pagano's battle in the forefront.

They began a fundraising campaign for leukemia research, calling it Chuckstrong. Players had stickers with the initials CP on their locker room nameplates, and Arians wore an orange ribbon on his baseball cap during games. Orange is the symbolic color for leukemia. At one point, nearly three dozen players shaved their heads to show their ailing coach they were with him.

That's not all.

Arians and first-year general manager Ryan Grigson decided to leave the lights on in Pagano's office until he returned. Pagano noted the team even installed plastic clips to make sure those lights were not mistakenly turned off while he was gone. Those clips were removed when Pagano arrived Monday morning.

And Arians said nobody sat in the front seat of the team bus.

"He's always been our head coach," Arians said.

So after getting medical clearance from his oncologist, Dr. Larry Cripe, to return with no restrictions, Pagano couldn't wait to get to the office Monday morning.

Arians arrived at 7 a.m., three hours early for the scheduled team meeting. By then, Pagano had already driven past the inflatable Colts player with the words "Welcome Back Chuck" printed on its chest and was back in his office preparing for the Texans.

Players showed up a couple of hours later, and when the torch was passed from Arians back to Pagano, players gave their returning coach a standing ovation that Wayne said was well-deserved.

All Pagano wants to do now is emulate the success Arians and his players have had this season.

"I asked him (Arians) if he would lead this team and this ballclub and this organization and take over the reins," Pagano said. "What a masterful, masterful job you did Bruce. You carried the torch and all you went out and did was win nine ballgames. You got us our 10th win yesterday and you got us into the playoffs. You did it with dignity and you did it with class. You're everything that I always knew you were and more."

___

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Gifts That Keep Giving (if Not Exploding)

Gregory Tobias/Chemical Heritage Foundation Collections

A Chemcraft set from the mid-1950s. More Photos »

Ask scientists of a certain age about their childhood memories, and odds are they’ll start yarning about the stink bombs and gunpowder they concocted with their chemistry sets. Dangerous? Yes, but fun.

“Admittedly, I have blown some things up in my time,” said William L. Whittaker, 64, a robotics professor at Carnegie Mellon University who unearthed his first chemistry set, an A. C. Gilbert, in a junkyard around age 8. By 16, he was dabbling in advanced explosives. “There’s no question that I burned some skin off my face,” he recalled.

Under today’s Christmas tree, girls and boys will unwrap science toys of a very different ilk: slime-making kits and perfume labs, vials of a fluff-making polymer called Insta-Snow, “no-chem” chemistry sets (chemical free!), plus a dazzling array of modern telescopes, microscopes and D.I.Y. volcanoes. Nothing in these gifts will set the curtains on fire.

“Basically, you have to be able to eat everything in the science kit,” said Jim Becker, president of SmartLab Toys, who recalled learning the names of chemicals from his childhood chemistry set, which contained substances that have long since been banned from toys.

Some scientists lament the passing of the trial-and-error days that inspired so many careers. “Science kits are a lot less open-ended these days,” said Kimberly Gerson, a science blogger who lives outside Toronto. “Everything is packaged. It’s either ‘yes’ or ‘no.’ If you don’t get the right result, you’ve done it wrong and you’re out of chemicals.”

Others, though, say the new crop of science toys — even with their cartoonish packaging and heavy emphasis on neon goo — actually represent progress. More entertaining, educational and accessible than earlier products, which relied heavily on a child’s inner motivation, these toys may actually help democratize the learning of science and introduce children to scientific methods and concepts at an earlier age.

“I grew up in the 1960s, and a lot of the chemistry sets were kind of boring,” said William Gurstelle, a science and technology writer. “You’d go through the book, and at the end of the experiment you’d get some light precipitate at the bottom of the beaker. Maybe at most it changes color or something.”

Mr. Gurstelle’s books, which include “Whoosh Boom Splat” and “Backyard Ballistics,” teach people how to make dangerous projectiles, like a potato cannon that uses hair spray as launching fluid. But he had high praise for commercial science kits, which show children (among other things) how to make slime.

Jeff Swensen for The New York Times

William L. Whittaker at the Planetary Robotics Lab at Carnegie Mellon University surrounded by the robots he has created.

“Well, that’s a pretty cool thing to have when you’re done,” Mr. Gurstelle said. “You’re not going to really learn to be a chemist from a chemistry set when you’re in seventh grade; you’re just going to be inspired. The point is that new chemistry sets and new toys are just better, because the manufacturers have figured out how to make them more fun.”

Some toy makers, like SmartLab, Mr. Becker’s company, have used this philosophy to give classic toys a makeover. One of SmartLab’s takes on a chemistry set, for instance, is the Extreme Secret Formula Lab, which comes with “squishy-lidded bubble test tubes” and “an abundance of glow-in-the-dark powder.” The game of Mousetrap has been re-envisioned as the Weird and Wacky Contraption Lab, meant to bring out children’s Rube Goldberg talents. And the slot car tracks that Mr. Becker recalls snapping together in his youth have been translated into a robot called ReCon 6.0, which children can program to roam around.

Mike Kane for The New York Times

Jim Becker of SmartLab Toys.

“What we do is give kids the opportunity to learn through problem solving,” Mr. Becker said.

Of course, technology has also remade the experience of learning science. Children may be more likely to click on a science app than to go play outside.

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Madrid Journal: Spain Turns Christmas Into a Season of Thrift

MADRID — This is the season when barren stone plazas and broad sidewalks here fill with Christmas markets peddling sweets, candles, holiday decorations and crafts. But alongside the festive stalls this year, another kind of market has sprung up in response to Spain’s hard times.

They are the “mercadillos,” or little markets, where the entrepreneurial-minded have found a niche by gathering and selling the unsold stock of more established retailers whose sales have plummeted, or unwanted clothing and other items from people in need of cash.

Buyers and sellers rely heavily on Facebook and other social networking sites to promote the improvised exchanges, which have transformed the way Spaniards shop for the holidays.

For the hard-pressed, the markets are a bargain hunters’ paradise, and for the jobless, they offer an economic lifeline and a chance to recast their fortunes.

Cristina Aresti and Sofía Bourne had never thought about working in fashion until they lost their jobs, joining the more than 25 percent of Spaniards who are unemployed. But this month they opened Abo Cool Market, a pop-up shop that sold secondhand women’s clothing over six days inside a Madrid furniture store.

The two women said they had intended to limit their sales to 500 items. But given the avalanche of offers from people wanting to sell off their wardrobes, they ended up selecting 800 pieces of clothing, with a combined retail value of more than $59,000.

“We just couldn’t believe how many people now want to sell clothing that they had hardly worn,” Ms. Bourne said. Among the most expensive items on sale — a totem of more prosperous times — was an unworn Gucci silk dress that still bore its original sales tag. It was on sale for $650, about a quarter of the original price.

Ms. Aresti and Ms. Bourne will keep 35 percent of their sales receipts; the rest will go to the women who supplied the clothing. The original owners then have the choice of either retrieving unsold items or donating them to charity groups.

Many of the people running this year’s mercadillos had little or no experience in retail sales. Ms. Bourne was laid off by a real estate company; Ms. Aresti lost her job as director of a company that organizes business conferences.

“I don’t yet know whether my future really lies in fashion,” Ms. Aresti said, “but there comes a point in such a hopeless job market when you’ve at least got to try to reinvent yourself.”

Even merchants with long experience in retail or fashion are borrowing some of the practices of the little markets as a way to lure customers.

“Store sales have been plummeting, so you need to go out of your way to make it fun and worthwhile for people to still do some shopping this Christmas,” said Cristina Terrón, a fashion stylist whose mercadillo sold some clothing she had initially selected for television and movie productions. “Something that started out of economic necessity is now also turning into a fashion.”

On average, Spanish households are set to spend $790 to $920 on Christmas shopping this year, down as much as 38 percent from 2007, before the onset of the economic crisis, according to a study published this month by Esade, a Spanish business school.

Jaime Castelló, a marketing professor and one of the authors of the study, said the crisis was not only reducing spending, but also speeding up changes in consumer habits.

About 70 percent of Spanish households said they would search online before buying any Christmas gifts, and 25 percent said they would not even step into a department store, according to the study. The mercadillos, Mr. Castelló suggested, were “another alternative in this crisis to the traditional buying channels.”

Ana María Menoyo Delgado, 26, said she had “lots of fun” searching the Christmas mercadillo Web sites as she worked her way through her holiday shopping list. At Abo Cool’s market, with her mother’s help, she ended up with two designer hand bags, a skirt and a coat, spending a total of $659.

While bargain hunting is part of the attraction, several buyers said they simply preferred the mercadillos to department stores.

“I can’t stand anymore walking into a conventional luxury store where you are likely to be welcomed by a pretty and young but utterly grumpy sales attendant,” Irene Trigueros, a commodities trader, said as she tried on a pair of secondhand sunglasses.

Some of the mercadillos have even been held in bars. “Having a cocktail while trying on some nice clothing seems to me a perfect way to end the day,” said Alberto Martínez, owner of the 1862 Dry Bar, who allowed his basement to become a mercadillo for three days this month.

Mr. Martínez did not charge any rent, but some of the larger mercadillos add to their revenue by renting out booths in their spaces to smaller sellers, normally for $200 to $400 a weekend.

In Alcobendas, on the outskirts of Madrid, a warehouse was transformed into La Galería del 32, a market that sold, among other things, wine, ham, sculpture, jewelry and handbags. The warehouse used to store electronics equipment and other goods until about three years ago, when the demand for storage space dried up as retail sales slumped.

“This kind of event is a great way for those who exhibit to attract more shoppers, while we earn something from renting the space rather than allowing it to stand empty,” said Leticia Martínez Rubio, one of the organizers.

A charity foundation, the Fundacíon Dar, also took part in the weekend event, encouraging shoppers to bring toys that the foundation would distribute to underprivileged children in the Madrid area.

“Beside having a successful weekend sale, I think it’s also important to keep some of the Christmas spirit,” Ms. Martínez Rubio said.

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Ravens beat Giants 33-14 to win AFC North

BALTIMORE (AP) — On their fourth try, the Baltimore Ravens finally got the victory they needed to win the AFC North.

Joe Flacco threw for 309 yards and two touchdowns, and the Ravens defeated the New York Giants 33-14 Sunday to capture their second straight division crown.

The Ravens (10-5) led 24-7 at halftime and cruised to the finish behind a short-handed defense that harassed quarterback Eli Manning and limited New York (8-7) to 186 yards.

Playing its second game with Jim Caldwell as offensive coordinator, Baltimore scored touchdowns on its first two possessions and amassed a season-high 533 yards — including 289 in the first half alone.

The victory ended a three-game skid for the Ravens and assured them of a home playoff game in the first weekend of January.

The defeat eliminated the defending Super Bowl champion Giants (8-7) from contention in the NFC East and severely damaged their chances of qualifying for a playoff berth.

New York has lost five of seven and was coming off a 34-0 defeat at Atlanta. New York has dropped five of seven and was coming off a 34-0 defeat at Atlanta.'

In this one, Manning went 14 for 28 for 150 yards and was sacked three times.

Flacco, meanwhile, rebounded from a stretch in which he committed two turnovers in each of Baltimore's three straight defeats. He completed 25 of 36 passes, ran for a score and did not throw an interception or lose a fumble.

Flacco repeatedly picked on New York cornerback Corey Webster, who simply couldn't contain Torrey Smith or Anquan Boldin. Smith caught five passes for 88 yards and a touchdown, and Boldin finished with seven receptions for 93 yards.

Ray Rice ran for 107 yards and caught six passes for 51 yards and a touchdown. Backup Bernard Pierce gained 123 yards rushing as part of a running attack that generated 224 yards.

Baltimore's defense was also impressive despite the absence of injured linebackers Ray Lewis and Jameel McClain, along with safety Bernard Pollard.

Now, after ending its longest losing streak since 2009, Baltimore is assured of hosting a first-round playoff game during the first weekend in January.

New York, on the other hand, fell out of a first-place tie in the NFC East and will need a win over Philadelphia next week — along with help from other teams — to squeeze into the postseason

Baltimore's first drive ended with a 6-yard touchdown pass from Flacco to Smith. The play came after officials overturned a fumble by Jacoby Jones at the New York 5 following a replay review.

The 73-yard march featured a few new wrinkles from the Ravens' offense, most notably an option pitch from Flacco to Rice and third-string running back Anthony Allen's first catch of the season, a first-down grab at the New York 40.

After the Giants went three-and-out for a second straight time, Smith made an outstanding catch behind Webster for a 43-yard gain before Flacco scored from the 1.

Manning followed with a four-play, 77-yard drive highlighted by a 43-yard completion to Rueben Randle and a 14-yard touchdown run by David Wilson.

That, however, would be the extent of the New York offense until Domenik Hixon caught a 13-yard touchdown pass with 3:18 left. After scoring 52 against New Orleans on Dec. 9, the Giants have totaled only 14 points in the past two weeks.

The Ravens went up 17-7 midway through the second quarter. After Boldin burned Webster for 39-yard gain on a third-and-19, a replay erased a 9-yard touchdown catch by Jacoby Jones and forced Baltimore to settle for a field goal.

Late in the half, the Ravens moved 76 yards in seven plays for a 24-7 lead. Flacco went 5 for 5 for 68 yards, including a 27-yard touchdown pass to Rice.

Baltimore opted for ball control in the second half, and the Giants were powerless to stop them. After an exchange of punts at the start of the third quarter, the Ravens moved 82 yards in 16 plays, holding the ball for just short of eight minutes, before Justin Tucker kicked a 20-yard field goal.

The lead became 30-7 with 11:08 left when Tucker concluded a 13-play, 62-yard drive with a 30-yard field goal.

___

Online: http://pro32.ap.org/poll and http://twitter.com/AP_NFL

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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.

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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..

Russia Says It Won’t Play Role in Ousting Syria’s Leader

Ahmed Jadallah/Reuters

The mother of a rebel with the Free Syrian Army mourned as his body was brought home during his funeral in Aleppo.

MOSCOW — The foreign minister of Russia, which is among Syria’s most reliable allies, said Saturday that several countries were offering asylum to President Bashar al-Assad to get him to leave Syria, but that Moscow would not mediate on their behalf, according to Russian news services.

“Some countries in the region have turned to us and suggested, ‘Tell Assad we are ready to fix him up,’ ” the foreign minister, Sergey V. Lavrov, told reporters who accompanied him on a flight home from the Russia-European Union summit meeting in Brussels, in comments carried by the Interfax and RIA Novosti news agencies. “And we answered, ‘What do we have to do with it? If you have such plans, approach him directly.’ ”

“If there are people wishing to give him some kind of guarantees, be our guest,” he said. “We will be the first to cross ourselves and say, ‘Thank God, the carnage is over.’ Whether this will end the carnage — that is far from obvious. It is not obvious at all.”

He also said that Syria’s government had brought together its chemical weapons from a large number of locations throughout the country to one or two central storage places to keep them out of rebel hands.

Mr. Lavrov’s comments follow recent signals from Russia that it sees the military balance shifting, though Moscow has not changed its strong opposition to international intervention in Syria. Rebel fighters are claiming gains in the war, pushing aggressively toward government strongholds near Damascus, the capital, and in the central Syrian city of Hama. Last week, opposition fighters tried to occupy the Yarmouk Palestinian refugee camp, which they said they had planned to use as a staging ground for attacks on central Damascus, setting off a fierce battle that caused most of the camp’s residents to flee.

On Saturday afternoon, a car bomb detonated in the Damascus suburb of Qaboun, killing at least six and destroying buildings and wounding scores of people on a commercial street.

Qaboun is less than two miles from central Damascus in a belt of restive suburbs where the rebels have had a presence for more than a year.

There was no immediate claim of responsibility for the bombing.

Fighting continued Saturday in central Syria, where rebels have been attacking government checkpoints and positions in an effort to cut the military’s supply routes to Idlib Province in the north. In a video posted online Friday, rebel fighters threatened violence against the residents of two Christian villages in Hama Province if they did not evict loyalist fighters known as shabiha.

In the video, an opposition fighter said that a rebel group that raided one village was attacked by “shabiha hiding behind houses” and that the rebels withdrew “to spare civilians.” If residents did not evict the government loyalists, the fighter warned, the rebels would “direct our artillery” at their hiding places.

The warning was met with alarm by a resident of one of the villages, al-Suqaylabiyah. The man, who is currently in Turkey, said that the village was 95 percent Christian and that the residents, some of whom, he said, had been given arms by the government, had chosen not to take sides. The appearance of the men in the video — “very Islamic and militarized,” he said — was unlikely to win the rebels any support. “They want to horrify the town,” said the man, a doctor. On Saturday, Mr. Lavrov said he believed both American and European supporters of the opposition coalition were losing their ability to influence antigovernment forces in Syria, according to news services.

“We ask the Americans, ‘You promised us that you would be able to draw them away from their militant and hard-line position,’ ” he said. “ ‘What have you done to make that happen?’ They are silent.

“We also asked our friends from the European Union, who also recognized that coalition as the representatives of the Syrian people,” he added. “They are also silent.”

Ellen Barry reported from Moscow, and Kareem Fahim from Beirut, Lebanon. Hala Droubi contributed from Jidda, Saudi Arabia, and Hwaida Saad from Beirut.

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

Title Post: Facebook releases ‘Poke’ for the iPhone to compete with Snapchat
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La.-Lafayette tops ECU in New Orleans Bowl, 43-34

NEW ORLEANS (AP) — Whether Terrance Broadway was throwing, running, or throwing on the run, he gave East Carolina fits and justified Louisiana-Lafayette coach Mark Hudspeth's decision to let his sophomore quarterback finish the season as his starter.

Broadway passed for 316 yards and ran for 108, helping Louisiana-Lafayette repeat as winners of the New Orleans Bowl with a 43-34 victory against East Carolina on Saturday.

The performance capped a 2012 campaign which opened with Broadway backing up senior Blaine Gautier, who broke a bone in his throwing hand in late September.

"Terrance comes in and just has a phenomenal season," Hudspeth said, describing the difficult decision not to give Gautier, the New Orleans Bowl MVP a year ago, his job back when he was healthy again late in the season. "We really had hit our stride and the best thing about Blaine is he understood."

Broadway had to sit out last season after transferring from Houston, and saw this year's New Orleans Bowl as his first real chance to add some kind of championship to his name after coming up short as a high school standout in Baton Rouge, La.

"My main goal was to get our team a big win in this bowl game and just to get that monkey off my back that I didn't have a ring from high school and last year," Broadway said. "I was very focused on that."

Alonzo Harris rushed for 120 yards, including touchdowns of 6 and 68 yards for the Ragin' Cajuns (9-4), who briefly squandered a three-touchdown lead before moving back in front for good on Broadway's 14-yard scoring pass to Javone Lawson late in the third quarter.

"Nothing fazes our team," said Broadway, who also ran for a 12-yard score. "Everybody on our team responds to adversity well. So when they came back on us and made a game out of it, our team is still upbeat and saying we're going to win this game."

And they did, with Brett Baer adding his second and third field goals in the fourth quarter to seal the victory.

Shane Carden passed for 278 yards and two touchdowns for East Carolina (8-5) but was intercepted in Cajuns territory by Jemarlous Moten in the fourth quarter as ECU drove for a potential tying or go-ahead score.

"They did a good job of changing, I guess, the coverage throughout the game," Carden said of ULL. "But I think our offense could execute a lot better. It was nothing really they were doing. It was a lot of us just not executing routine plays."

The Pirates' Reggie Bullock rushed for 104 yards and two touchdowns.

"The game plan was fine. We just needed the execution of the calls. We've always played hard. That was not a problem," East Carolina coach Ruffin McNeill said. "We had a chance there late in the game. ... I was proud of our guys."

Carden's touchdowns went to Justin Hardy for 19 yards and Danny Webster for 16 yards. Hardy finished with five catches for 59 yards. East Carolina's Andrew Bodenheimer had five catches for a team-high 65 yards, but could not secure a crucial fourth-down pass in the final minutes as defensive back T.J. Worthy ripped the ball away in ECU territory. That allowed the Cajuns to run the clock down to 15 seconds before setting up Baer's final field goal from 40-yards out.

Jamal Robinson had six catches for 116 yards for ULL, including a 39-yarder that was Broadway's longest completion. Lawson finished with four catches for 71 yards.

The Cajuns carried a 37-31 lead into the fourth quarter after Lawson juggled but secured the ball for a sprawling, rolling TD catch. The point-after kick failed, however, and East Carolina made it 37-34 on Warren Harvey's 26-yard field goal.

Broadway's interception on a tipped pass gave East Carolina the ball on the Cajuns 39, but Moten stepped in front of Carden's long pass over the middle to help preserve the slim lead.

Red-clad Ragin' Cajuns fans made up the bulk of a record New Orleans Bowl crowd of 48,828, and they were celebrating early.

Broadway's scoring run, his ninth rushing TD of the season, gave ULL a 7-0 lead and Harry Peoples' 10-yard scoring made it 14-0.

ECU didn't get a first down until early in the second quarter, when Carden converted on third-and-long with Jabril Solomon for a 45-yard gain. That set up Bullock's first touchdown from 5 yards out to make it 14-7.

Harris' two scores had the Cajuns seemingly in command at 28-7, but ECU responded with two touchdowns in a span of 13 seconds to make it a one-score game.

First came Hardy's leaping, outstretched grab in the back of the end zone. Then Darryl Surgent fumbled a kickoff return, giving ECU the ball on the Cajuns 16. Carden found Webster over the middle for a score on the next play.

Louisiana-Lafayette was able to regain some momentum in the final 37 seconds of the first half, driving 47 yards on five plays to set up Baer's 50-yard field goal, which was the same distance and direction as his game-winner at the end of last year's New Orleans Bowl.

The Pirates tied it in the third quarter on Harvey's 45-yard field goal and Bullock's 13-yard scoring run, capping a drive that included a converted fourth-and-3.

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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.

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