10 Talented Dogs Playing the Piano









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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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Gaza Cease-Fire Expands Fishing Area, but Risks Remain




Relaxed Rules Restore Old Opportunities:
As a part of last month's cease-fire agreement between Hamas and Israel, Gazans can now fish 6 miles off the coast, doubling the previous limit.







GAZA CITY — Khader Bakr, a 19-year-old fisherman, was thrilled to hear that he could now fish up to six nautical miles from the coast, up from the three-mile limit Israel had had in place since 2009. The change was part of the cease-fire deal that halted last month’s fighting in Gaza between Israel and Hamas.




But testing the waters late last month, Mr. Bakr apparently sailed out too far. An Israeli gunboat patrolling against arms smuggling ordered him to stop and strip to his underwear. As the Israelis sank his boat, he jumped into the sea, and was hauled aboard the Israeli vessel for questioning.


“I spent four hours trembling,” he said, before the Israelis ordered another Palestinian fishing boat to ferry Mr. Bakr back to shore.


Run-ins with Israeli patrols are still the bane of Gaza fishermen. But in most respects, the new arrangement has been a boon.


The fishermen have raced to take advantage of broader fishing grounds, farther from the shore where sewage is pumped into the water untreated. Catches have improved in quantity, quality and freshness, and thus price. The fish are bigger and include desirable species like grouper, red mullet and Mediterranean sea bass that were no longer present closer to land.


But the fisherman risk rapidly overfishing. “In the first few days, I caught fish worth $1,580 to $1,850,” said Yasser Abu al-Sadeq. “Today, I made around $1,050.” But the situation is still better, he said. “Before the cease-fire, I would barely catch $790.”


“It’s like when you come to a house that’s been abandoned for years and start cleaning it,” he said. “When you start cleaning, you get out a lot of trash, but when you clean daily, you get out only a little.” He and his crew go out for 24 hours at a time, he said, cooking the small crabs and squid they catch in the nets. He described an early trip out past the six-mile limit, when an Israeli gunboat circled his boat, shaking it in the wake, and ordered him back toward shore.


He remembers a golden time before the second Palestinian intifada in 2000, when he could go out as far as 12 nautical miles, where he could find sardines and what he called guitarfish, a small ray. “There, it’s a reserve protected by God,” he said.


The fishermen say they estimate their distance, since most of them lack precise navigational systems, but there is usually one indicator. “When we were allowed within 3 miles, the gunboats would attack us at 2.5 miles,” said Monzer Abu Amira, as he repaired his green nylon nets. “Today, they hit us when we are at 5.5 miles.”


The Israelis generally use loudspeakers and water cannons, but sometimes they shoot live ammunition at fishing gear, the motor or the boat itself. Gazans in principle can apply for compensation if boats are damaged or destroyed, but in practice few do.


A senior Israeli official said that there had never been an official announcement that the fishing limit had been extended from three miles to six, but he confirmed that six was the new reality. Israel is continuing to negotiate indirectly with Hamas, the Islamist movement that rules Gaza, with Egypt as an intermediary, to turn the cease-fire agreement into something more permanent, the official said.


“We have an interest in prolonging the longevity of the quiet,” the official said. “We understand that relaxation of some of the restrictions is conducive to that goal. Quiet is in our interest. So we have an interest in showing flexibility where we can, and to show the Egyptians that we’re serious.”


There were problems in the period immediately after the cease-fire, the Israeli official said, because “some in Gaza were interested in testing the limits and pushing the envelope,” and because the expansion of the fishing zone meant deploying more Israeli resources to cover more sea.


“But if people don’t exceed the six-mile limit, it’s O.K.,” he said.


The Israelis are not interested in the smuggling of small-caliber weapons like “Kalashnikovs and bullets,” he added, but in preventing Iran from resupplying longer-range missiles and preventing Hamas from smuggling in foreign experts to aid them in missile development and technology.


“The important thing for us is to prevent Hamas from rearming,” he said.


Ed Ou contributed reporting.



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Fifth-gen iPad reportedly due in March along with Retina iPad mini







Rumors that a second-generation iPad mini with a Retina display is set to launch ahead of Apple’s typical annual schedule next year have been swirling, and now it appears Apple’s (AAPL) full-size iPad may be sticking to its new semiannual release schedule. According to a report from Japanese blog Makotakra that cites an anonymous “inside source,” Apple plans to launch a new thinner, lighter 9.7-inch iPad as soon as March 2013. The fourth iPad model was just released last month alongside the iPad mini, but March was also suggested in recent Retina iPad mini rumors. Makotakra states that the new iPad will adopt styling queues from the current iPad mini model, unifying the look of Apple’s larger tablet with the iPad mini and iPhone 5.


[More from BGR: First photos of BlackBerry 10 ‘N-Series’ QWERTY smartphone leak]






This article was originally published by BGR


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Pagano back to coach Colts after cancer treatment


INDIANAPOLIS (AP) — Chuck Pagano was so eager to get back to work Monday, he was the first one to show up at team headquarters.


Long before meeting with his players, the Colts first-year coach drove quietly into the complex, walked into the office where the lights have remained on for nearly three months and began preparing for Sunday's game against AFC South champion Houston like it was another at the day office.


Hardly. It was the biggest milestone yet in an incredibly emotional season in which Pagano has beaten leukemia and the Colts have been a most pleasant surprise in reaching the playoffs under interim coach Bruce Arians.


"I asked him if he would ... take over the reins and what a masterful, masterful job you did Bruce," Pagano said with Arians nearby at the news conference. "You carried the torch and all you went out and did was win ballgames, you got our 10th win yesterday and you got us into the playoffs and you did it with dignity and you did it with class. I can't thank you enough."


Players, coaches and staff members had been anticipating this day from the moment they learned Pagano was taking an indefinite leave to fight cancer, Oct. 1.


So when the 52-year-old first-time head coach returned, the 24-hour rule was cast aside — giving the Colts (10-5) another 24 hours to celebrate something far more important than reaching the playoffs.


"I know Chuck is ready for this challenge," said Colts owner Jim Irsay. " I know the time is right for him to grab the reins and get the head coaching cap on and begin the journey.


"The great thing about the National Football League is that so much attention gets paid to it, so many other things happen beside win and losses and the inspiration Chuck has shown to others and the time Chuck has spent connecting with others, it really is miraculous. It's a fairytale story, its' a Hollywood script, it's all of those things."


When Pagano arrived, he drove past an inflatable Colts player with the words "Welcome Back Chuck" printed on its chest. Normally, that spot is reserved for a message for the Colts to beat their next opponent.


When he spoke at a private team meeting, cheering could be heard in the media room.


If all goes well at practice this week, Pagano will be back on the sideline for the first time since Jacksonville scored a last-minute touchdown on an 80-yard TD pass in Week 3, handing Indy it's only home loss this season.


Pagano began the first of three rounds of chemotherapy Sept. 26, after the team completed its final practice during a bye week.


Arians, a prostate cancer survivor, immediately established the goal: Play long enough so Pagano could return to the sideline this season.


Indianapolis did better than anyone could have expected under Arians, who had spent two decades as an NFL assistant but had never been in charge of an NFL team. The Colts went 9-4 under Arians, who tied the league record for wins after a midseason coaching change, joined the 2008 Miami Dolphins as the only teams in league history to lose 14 or more games one season and win 10 or more the next and became the fourth team in league history to win only two games one season and 10 or more the next.


___


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News Analysis: Scientists to Seek Clues to Violence in Genome of Gunman in Newtown, Conn.





In a move likely to renew a longstanding ethical controversy, geneticists are quietly making plans to study the DNA of Adam Lanza, 20, who killed 20 children and seven adults in Newtown, Conn. Their work will be an effort to discover biological clues to extreme violence.




The researchers, at the University of Connecticut, confirmed their plans through a spokeswoman but declined to provide details. But other experts speculated that the geneticists might look for mutations that might be associated with mental illnesses and ones that might also increase the risk for violence.


They could look at all of Mr. Lanza’s genes, searching for something unusual like gene duplications or deletions or unexpected mutations, or they might determine the sequence of his entire genome, the genes and the vast regions of DNA that are not genes, in an extended search for aberrations that could determine which genes are active and how active they are.


But whatever they do, this apparently is the first time researchers will attempt a detailed study of the DNA of a mass killer.


Some researchers, like Dr. Arthur Beaudet, a professor at the Baylor College of Medicine and the chairman of its department of molecular and human genetics, applaud the effort. He believes that the acts committed by men like Mr. Lanza and the gunmen in other rampages in recent years — at Columbine High School and in Aurora, Colo., in Norway, in Tucson and at Virginia Tech — are so far off the charts of normal behavior that there must be genetic changes driving them.


“We can’t afford not to do this research,” Dr. Beaudet said.


Other scientists are not so sure. They worry that this research could eventually stigmatize people who have never committed a crime but who turn out to have a genetic aberration also found in a mass murder.


Everything known about mental illness, these skeptics say, argues that there are likely to be hundreds of genes involved in extreme violent behavior, not to mention a variety of environmental influences, and that all of these factors can interact in complex and unpredictable ways.


“It is almost inconceivable that there is a common genetic factor” to be found in mass murders, said Dr. Robert C. Green, a geneticist and neurologist at Harvard Medical School. “I think it says more about us that we wish there was something like this. We wish there was an explanation.”


Scientists are well aware of the fraught history behind the questions of biology and violence.


In the early 20th century, claims that criminal behavior was inherited arose during the eugenics movement and led to sterilizations of mental patients and felons.


On Christmas Day in 1965, two researchers published a paper saying men with an extra Y chromosome, the chromosome that confers maleness, were “super males” and born criminals. The hypothesis was helped along by the fact that these men “fit the classic Hollywood criminal — big, awkward, thuglike and with low I.Q.’s,” said Dr. Philip Reilly, a lawyer and clinical geneticist who has studied this history.


The idea persisted for about 15 years, Dr. Reilly said, but eventually the epidemiological evidence convinced scientists that these men were no more violent than men without an extra Y chromosome.


In 1993, in a paper published in the journal Science, researchers reported that a mutation leading to a lack of the enzyme monoamine oxidase caused violence in a Dutch family. Every family member who inherited the mutation was a violent criminal; those without it had no criminal behaviors.


“It was a stunning piece of work,” said James Blair, the chief of the unit on affective cognitive neuroscience at the National Institute of Mental Health. But, he added, it turned out not to be generalizable. For the most part, “it was just this family,” he said.


The National Institutes of Health was embroiled in controversy about 20 years ago simply for proposing to study the biological underpinnings of violence. Critics accused researchers of racism and singling out minorities, especially black men.


Shortly after, the N.I.H. took back financing for a conference at the University of Maryland to examine genetics and criminal behavior. The conference was canceled.


But genetics has come of age in recent years with new and powerful methods to determine DNA sequences and analyze the results. Studies of people at the far end of a bell curve can be especially informative, because the genetic roots of their conditions can be stark and easy to spot, noted J. H. Pate Skene, a Duke University neurobiologist.


“I think doing research on outliers, people at an end of a spectrum on something of concern like violent behavior, is certainly a good idea,” he said, but he advised tempering expectations.


“I would call it a caution, not about whether to do this research but about what to expect,” he added.


Perhaps it will be fruitless to search for one or a few major gene mutations that always lead to extreme violence, Dr. Beaudet said. But what if a significant fraction of the shootings were linked to gene variants? What if scientists were to discover genes that were risk factors, increasing a person’s chance of violent behavior but not foreordaining it?


“If we know someone has a 2 percent chance or a 10 percent chance or a 20 percent chance of violent behavior, what would you do with that person?” Dr. Skene said. “They have not been convicted of anything — have not done anything wrong.”


But a genetic profile might play a role if someone were convicted of violent offenses, Dr. Beaudet countered. Criminals are routinely denied parole based solely on psychiatric evaluations. Perhaps a genetic test could add to the certainty of the decision, he said.


Ultimately, understanding the genetics of violence might enable researchers to find ways to intervene before a person commits a horrific crime. But that goal would be difficult to achieve, and the pursuit of it risks jeopardizing personal liberties. Some scientists shudder at the thought of labeling people potential violent criminals.


“The idea of screening with a view of preventing those kinds of incidents is basically unthinkable,” said Dr. Steven E. Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and M.I.T. “You would fail. You would stigmatize.”


Some day, he added, it might be important to know the phenotypes — the characteristics — of violent killers and have their DNA, but not for the reasons many think.


“I am always happy to store DNA and phenotype information and freeze cells, thinking that one day we would have usable clues,” Dr. Hyman added. “But that would be biology, not prevention.”


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As Egypt Constitution Passes, New Fights Lie Ahead


Tara Todras-Whitehill for The New York Times


Egyptian women walk into a polling station. Millions went to the polls to pass judgment on an Islamist-backed constitution, whose passage represented an important milestone in Egypt’s chaotic two-year transition to democracy. More Photos »







CAIRO — An Islamist-backed constitution was approved on Saturday, propelling Egypt’s deeply divided political factions into a new phase in the battle over the country’s future.




After millions went to the polls for the final round of a referendum, the charter’s approval, which had been predicted by all sides, marked an important milestone in Egypt’s chaotic two-year transition to democracy. A “yes” vote of 70 percent on Saturday brought the overall margin of passage to about 64 percent, according to the Muslim Brotherhood.


But the hastily drafted document leaves unresolved many questions about the character of that democracy, including the Islamists’ commitment to individual freedoms and their opposition’s willingness to accept the results of the political process without recourse to violent street protests.


The charter’s path to the referendum has also taken Egypt to the brink of civil strife, exposing the alienation of the Christian minority, the political opposition’s refusal to negotiate and the Muslim Brotherhood’s willingness to rely on authoritarian tactics.


How those tensions are managed and the new constitution is put into effect will determine whether Egypt returns to stability or plunges further into discord, and much of the region is watching the outcome of that definitive Arab Spring revolt.


Neither supporters nor opponents of the charter said they expected an immediate end to the partisan feuding that has torn at the country in the month before the vote.


The Islamists allied with President Mohamed Morsi said they intended to rebuild trust by using the new charter as a tool to battle remnants of former President Hosni Mubarak’s government. Old laws and prosecutors, the Islamists say, are protecting loyalists and holdovers while they obstruct change from within the bureaucracy and conspire with the opposition to stir up unrest. Leaders of the anti-Islamist opposition, however, said they hoped to carry the momentum of their struggle against the draft constitution into the parliamentary elections set to be held two months from now. They accused the Islamists of using the specter of a struggle against remnants of Mr. Mubarak’s government as a pretext to demonize the opposition and take over the machinery of the state.


“If we accept the legitimacy of working within the system, they have to agree that the opposition is legitimate,” said Amr Moussa, a former foreign minister under Mr. Mubarak and a presidential candidate who has re-emerged as an opposition leader during the constitutional debate. “The ancien rĂ©gime is finished. They are imagining things. They are imagining that if you say no to the constitution, as I have done, then you are part of a conspiracy to topple them.”


Both sides of the ideological divide appeared to dig in.


“A crack has emerged in Egypt; there’s a gap, there’s blood and deaths, there’s extremism,” said Ahmed Maher, who helped jump-start the revolution as a leader of the secular April 6 Youth Group and then served as a delegate in the constituent assembly that wrote a draft of the charter. “Something has happened between Egyptians that would make the results bad no matter what the outcome” of the constitutional vote, he said, predicting further clashes before the parliamentary elections.


Adding to the uncertainty about what may come next, Mr. Morsi’s vice president, Mahmoud Mekki, resigned Saturday. The draft constitution would eliminate his position, and Mr. Mekki, a former judge, said that he had originally submitted his resignation in early November before a series of crises postponed it.


“The nature of political work does not suit my nature as a judge,” he said.


The turnout for Saturday’s voting appeared to be low, as it was last week. At one polling place in the dense Mohandeseen district near Cairo, the station was empty at midday. The low turnout may have reflected a lack of enthusiasm or perhaps a consensus among Egyptians that after last week, the charter’s approval was a foregone conclusion.


Mr. Morsi’s advisers said that after the ballots were counted in the coming days he would deliver a televised address calling for unity and reconciliation. His critics said that to be credible he would need to strike a tone different from that of his previous address. In that speech, he blamed a conspiracy of foreign agents, Mubarak cronies and his political opponents for a deadly night of street fighting between his supporters and other protesters.


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Top Comments: Mashable Readers React to Instagram’s Terms of Service






Monday, Dec. 17: Instagram Updates TOS


Readers had varying reactions to Instagram‘s updates. Some felt that they were fair: If you don’t like the terms of service, argued some users, you have the option not to use the service. Others were far more outraged.


Click here to view this gallery.






[More from Mashable: Why xkcd Is Wrong About Instagram]


This week, the top comments on Mashable brought into focus both the state of the world around us and the constantly changing nature of our virtual lives. Our readers launched into debate when Instagram appeared to be making drastic changes to its privacy policy. Based on the wording of Instagram’s new Terms of Service, photographers worried that they may no longer own the rights to their own work, and that their photos could be used in advertising. As Mashable‘s Chris Taylor put it, the TOS as they stood early this week basically “signed your life away.”


Over the course of the week, we saw new privacy settings for Instagram users revealed, officially commented upon (while remaining unchanged) and then finally rescinded and apologized for.


[More from Mashable: Instagram Updates Its Terms of Service Based on User Feedback]


The Instagram controversy proved that users are, in fact, paying attention to the often glossed-over Terms of Service established by their favorite apps, and that a company’s response to public outcry has the potential to make or break their service.


Mashable‘s senior tech analyst, Christina Warren, compared Instagram’s actions to Netflix’s in the summer of 2011. Outraged users proved they weren’t bluffing about abandoning Instagram: Celebrities and power users threatened to quit the network, and downloads of rival apps such as Flickr and Aviary soared in the days surrounding the controversy. What was your take on this week’s events, involving photo-sharing and users’ right to ownership?


Even more commented upon, though less debated, were two Mashable stories that examined social media backlash in the wake of a tragedy. In the days following the horrific shooting at Sandy Hook Elementary in Newtown, Connecticut, we found ourselves contemplating, both online and off, the horrific nature of the event. Unsurprisingly, the two most-commented-upon stories this week both centered on Sandy Hook’s impact on the social web. Our commenters sounded off on the offensive tweets sent during Obama’s Newtown speech, as well as on the viral post, “I Am Adam Lanza’s Mother.”


Other stories our commenters flocked to this week included a viral video of a golden eagle snatching a baby (later proved to be a hoax), the hacking of the Westboro Baptist Church by hacktivist group Anonymous and the appalling revelation that Facebook’s interns make more money than all of us. We also prepared for the end of the world as brought forth by the Mayan Apocalypse — which never did happen.


What were your favorite moments on Mashable this week? You can be part of the discussion by signing up with one of your social networks, and joining the conversation on our site. Next week, your voice could be featured in the Top Comments.


Happy holidays to our community!


Image courtesy of flickr, Marc Wathieu


This story originally published on Mashable here.


Tech News Headlines – Yahoo! News





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Luck sets rookie record, rookie PK sets NFL mark


Andrew Luck has broken the NFL rookie record for yards passing, and rookie kicker Blair Walsh has broken the league mark for 50-yard plus field goals in a season.


On a Sunday featuring a slew of records, Luck topped Cam Newton's year-old mark for yards passing in the first half of Indianapolis' game at Kansas City. Newton's record was 4,051 yards. Luck entered the game needing 74 yards to break the mark, and had 123 at halftime.


Minnesota's Walsh kicked a 56-yard field goal in the second quarter against Houston, giving him a record ninth field goal of 50 yards or more.


Also, Redskins kicker Kai Forbath set the NFL record for consecutive field goals to begin a career with 17 straight. He had field goals of 45 and 42 yards in the first half against the Eagles. New Orleans' Garrett Hartley had 16 straight.


On Saturday, Detroit's Calvin Johnson broke Jerry Rice's single-season yards receiving record, and is at 1,892 with a game left. He also became the only NFL player with 100 yards receiving in eight straight games, and with 10-plus receptions in four straight games.


___


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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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