How to Get Free Last-Minute Shipping

First, the bad news: the cut off for free shipping on most online sites was Tuesday, Dec 18^th. But the good news – we’ve got some sneaky ways to finagle free rush shipping and a list of sites still offering free shipping guaranteed to arrive before December 25^th.

Free Rush Shipping
Some of the biggest online retailers are still offering free last minute shipping:

• Barnes & Noble – free shipping on Nook HD through Dec. 22


• MacMall – free 2-day shipping on orders over $ 299 and under 25lbs – through 6 p.m. PST Dec. 22.


• Macy’s – free shipping on orders over $ 99. Place order 11:59 p.m. EST Dec. 20.


• The Northface – free 2-day shipping on everything through 11:59 p.m. Dec. 19.


• Walmart.com has extended free shipping through December 19^th on some items (check product page for eligibility)


• Overstock.com – free shipping on select gifts. Place order by Dec. 22 to receive by Christmas.


• Newegg   Free 2-Day shipping on over 200 items


• Target – free shipping on Daily Deals


• Victoria’s Secret – free shipping on orders over $ 100 using code “SHIP12.” Order by 5 p.m. EST on Dec. 20.


• Zappos – free shipping for all items with guaranteed Christmas delivery if ordered by 11:59 p.m. PST Dec. 22.

And the biggest of the big online retailers, Amazon, has a limited set of items available for free expedited shipping. These include jewelry, watches, clothing, video games, laptops, headphones, and kitchen items.

[Related: Great Gifts for Under $ 25]

But since many of the above deals are limited to select items, take a look at…

How to Get Free 2-Day Shipping on Just About Everything
Amazon Prime is a yearly subscription service. In exchange for a $ 79 fee, you get free 2 day shipping all year long. And yes, that also applies at Christmas (must order by 3 p.m. EST Dec. 22 to receive on time). Best deal is that you can get a free 6-month trial.

And here’s the real sneaky surprise: Do you have a family member who already belongs to Prime? They can nominate up to four people for the same free shipping benefits. Prime members nominate someone by going to their account, clicking “Settings” and “Manage Prime Membership.”

Also, Amazon Student is a free 6-month membership to Prime with all the benefits, providing you have an email address that ends in .edu.

But you don’t have to limit yourself to Amazon. Shoprunner.com also offers free 2-day shipping, though the membership service costs $ 8.95 a month – so not entirely free, but if you have numerous items still to buy, you could save a bundle.  And Shoprunner has tons of participating online retailers like Toys R Us, Sports Authority, Claire’s, PetSmart and EMS. Say you want to buy something from PetSmart.com, if you sign in with Shoprunner, many of the items on the site will be eligible for free 2-day shipping. One more thing to try: I was able to sign up for a free 1-year membership to Shoprunner using the promo code RUNNER. The site implied I had to be an American Express member, but it never asked for my details about the credit card, and now I have a membership. Good luck.

Ship to Store
Finally, the best last-minute option for many is to ship to store. You peruse all the options from home, pay online, and then pick up your selection at your local store. Tons of big retailers offer this service, and it guarantees your item will be in stock and waiting for you at customer service. Major retailers offering free Ship to Store include:

• Best Buy


• Target


• Toys R Us


• Walmart


• Sears

[Related: Best E-Reader for Under $ 100]

Brad Marshland contributed to this story.

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Ravens beat Giants 33-14 to win AFC North

BALTIMORE (AP) — A celebration four weeks in the making featured laughs and hugs, a surprise appearance by team owner Steve Bisciotti and the distribution of hats announcing the Baltimore Ravens' stature as AFC North champions.

Joe Flacco threw for 309 yards and two touchdowns, and the Ravens defeated the New York Giants 33-14 Sunday to end a three-game losing streak to secure their second straight division crown.

"It feels good," wide receiver Torrey Smith said in the upbeat locker room. "I'm just glad we finally got it done."

The Ravens (10-5) led 24-7 at halftime and cruised behind a short-handed defense that harassed quarterback Eli Manning and limited New York 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 — 289 in the first half alone.

"It's about execution, man. It's a simple word, but it's a very tough task to do," said running back Ray Rice, who ran for 107 yards and caught six passes for 51 yards and a touchdown. "This was a championship game for us."

After ending their longest losing streak since 2009, the Ravens are assured a home playoff game on the first weekend of January.

"We know what's at stake. We want the AFC championship and it starts tonight," safety James Ihedigbo said. "We're not looking at regular season. Playoffs started for us and we're going to keep on playing."

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 the playoffs.

New York has lost 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.

"Obviously, we have a bad formula going on right here," coach Tom Coughlin said. "We're having trouble stopping people and our offense doesn't hold the ball at all to give the defense a chance to catch their breath. We've had two games in a row, pretty much the exact same scenario."

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.

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

Backup Bernard Pierce gained 123 yards as part of a running attack that generated 224 yards.

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

New York fell out of a first-place tie in the NFC East. The Giants will need a win over Philadelphia next week and help from other teams to squeeze into the postseason.

"I feel badly for everyone in that locker room because they can't turn this thing around either," Coughlin said. "What has happened over the course of the last couple of weeks is very difficult to explain. We just don't look like a well-oiled machine offensively at all."

Said Manning: "We knew we had to play our best football at the end of the season to get into the playoffs, and we haven't done that. When you're not playing your best, teams can come out and embarrass you."

Baltimore's first drive ended with a 6-yard touchdown pass from Flacco to Smith 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, 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 and Flacco scored from the 1.

Manning followed with a 43-yard completion to Rueben Randle before David Wilson ran 14 yards for a touchdown. New York didn't score again until Domenik Hixon caught a 13-yard touchdown pass with 3:18 left.

After racking up 52 points against New Orleans, the Giants have totaled 14 in the past two weeks.

"All we can do is go out and get back to playing better football," Manning said.

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 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, including a 27-yard touchdown pass to Rice.

Baltimore opted for ball control in the second half, and the Giants were powerless to stop it. 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 when Tucker concluded a 13-play, 62-yard drive with a 30-yard field goal. Tucker added his fourth field goal after a 78-yard run by Pierce.

NOTES: Flacco has thrown for a career-high 3,783 yards this season. ... New York defensive linemen Marvin Austin and Chris Canty both left with knee injuries. ... Boldin hurt his shoulder in the third quarter and did not return. ... Baltimore has won 10 straight regular-season home finales and has 13 consecutive home victories over NFC foes. ... It was only the fifth time in 47 games that New York did not force a turnover.

___

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

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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 the production of physicians, they say, it could eventually dampen a looming doctor shortage, although the number of doctors would not increase unless the schools admitted 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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E-Book Price War Has Yet to Arrive

Thor Swift for The New York Times

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

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

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

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

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

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

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

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

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

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

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

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

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

It is possible that Amazon, which controls about 60 percent of the e-book market, is merely holding back with price cuts for the right moment. The next few weeks are when e-book sales traditionally take a big jump, as all those newly received devices are loaded up with content.

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

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

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Clashes Break Out in India at a Protest Over a Rape Case

Anindito Mukherjee/European Pressphoto Agency

The police used water cannons on demonstrators gathered in India’s capital city on Saturday.

Protesters scuffled with the police throughout the day. Some police vehicles were damaged, and the police eventually used tear gas, water cannons and sticks to disperse the crowd. Officials said 35 protesters and 37 police officers had been injured, two officers seriously, and that six buses and several police vehicles were damaged.

Outrage over the crime has continued to build across the country and the protesters in New Delhi promised to return in even greater numbers on Sunday, prompting Home Minister Sushil Kumar Shinde to hold a news conference on Saturday night to plead for calm.

“The government is committed to ensuring the safety of women in the capital as well as in the rest of the country,” Mr. Shinde said. “I appeal to this media, to all those who have come to support this dedication, to withdraw.”

Mr. Shinde listed four steps the government would take immediately to improve security in New Delhi: increase the number of buses at night, track those buses with GPS devices, ensure drivers carry identity badges and increase the number of police officers on busy routes.

The police have arrested six suspects and Mr. Shinde said that the victim had given a statement to a magistrate on Friday night, and that the government had enough evidence to prosecute.

The woman was raped on Dec. 16 after she boarded a private bus with her boyfriend. A group of men onboard the bus, normally used to ferry schoolchildren, beat the couple with iron rods and raped the woman. The men then dumped them by the roadside.

The woman has had several rounds of surgery and a portion of her intestines had to be removed, doctors said. Mr. Shinde also said the government had canceled all permits for the transportation company that owns the bus on which the rape occurred. At the protest, people chanted “We want justice!” and held placards that said “Save Women Save India.”

“These rapists should be hanged publicly,” said Shaelly Tomar, a student at Delhi University who took part in the protest with several friends. “If that happens, nobody will dare to do it again.”

Tens of thousands of rapes are reported each year in India, while many more go unreported because rape victims are often shunned and unable to marry. Even so, reports of rape are on the rise, up about 25 percent in the past six years. Surveys have suggested that India is one of the most unsafe countries in the world for women.

The roots of the problem run deep in a conservative society that is having trouble adjusting to educational and economic advances by women, long confined to the home. Demographics also play a role, with half of India’s population under 25 and female infanticide and the neglect of girls creating a growing gender imbalance.

But India’s criminal justice system, riddled with incompetence, corruption and political meddling, seems unable to respond effectively.

Heather Timmons contributed reporting.

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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.

Read More..

Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

C.J. Gunther for The New York Times

Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.

No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.

And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”

At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.

Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.

“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.

The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.

The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”

Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.

Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.

The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?

In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.

But Nutlins did not work as drugs because they were not absorbed into the body.

Roche, Merck and Sanofi persevered, testing thousands of molecules.

At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.

The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.

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Obama Nominates Kerry for Secretary of State

WASHINGTON — With a patrician bearing, nearly three decades of service on the Senate Foreign Relations Committee, a highly decorated combat career in the Vietnam War, even a father who was a diplomat, John Kerry is the very picture of a secretary of state.

“In a sense, John’s entire life has prepared him for this role,” President Obama said on Friday at the White House, as he nominated Mr. Kerry to replace Hillary Rodham Clinton, the first step in filling out a national security team for his second term.

Mr. Obama praised Mr. Kerry, 69, a Massachusetts Democrat, for having been immersed in “every major foreign-policy debate for nearly 30 years.”

But though Mr. Kerry would bring even deeper experience to the job than Mrs. Clinton did, his appointment is likely to further centralize policy decisions in the White House, where for the past four years the president and a small circle of advisers have kept a tight grip on issues like Iran’s nuclear program, China, Pakistan, and the winding down of the war in Afghanistan.

“There’s every reason to believe that we’re going to have a very White House-centric foreign policy,” said David J. Rothkopf, the chief executive of the Foreign Policy Group. “Kerry is going to have to show his loyalty and willingness to work within the Obama system.”

In contrast to Mrs. Clinton, whom Mr. Obama named to his cabinet after they competed against each other in the 2008 presidential primaries, Mr. Kerry has been a loyal supporter of the Obama administration, guiding an arms-reduction treaty with Russia to ratification in the Senate and playing diplomatic troubleshooter for the White House in Afghanistan, Pakistan and Sudan.

He has also figured at critical moments in Mr. Obama’s career. At the 2004 Democratic National Convention that nominated him for president, Mr. Kerry gave the keynote speaking slot to Mr. Obama, then a little-known Illinois state senator, catapulting him to national prominence. In early 2008, Mr. Kerry endorsed him over Mrs. Clinton, and this fall he played the role of Mitt Romney in mock debates — sessions that by some accounts put the president’s teeth on edge.

“Nothing brings two people closer together than weeks of debate prep,” said Mr. Obama on Friday, looking at a grinning Mr. Kerry. “John, I’m looking forward to working with you instead of debating you.”

However lavish Mr. Obama’s praise, his instinctive choice for secretary of state was Susan E. Rice, the ambassador to the United Nations, who withdrew her name from consideration after Republicans threatened to block her nomination because of statements she made after the lethal attack on the American Mission in Benghazi, Libya.

Mr. Obama, his aides said, likes Ms. Rice’s blunt style and is in sync with her view of foreign policy, which places a premium on aggressively defending human rights.

As a result, Ms. Rice, who is staying in her post, remains a candidate for a major foreign-policy post in the second term, according to administration officials. Thomas E. Donilon, the national security adviser, is expected to stay on for a year or so, but Ms. Rice could be named to his job.

If she were to move into the White House, analysts said, that would pose a test for Mr. Kerry, given her access to Mr. Obama and their shared views on many foreign policy issues.

“The easiest model to see developing is one in which Kerry is on the road a lot, interfacing with foreign leaders, but the decision-making is done at the White House,” said Elliott Abrams, who held foreign-policy posts in the administrations of Ronald Reagan and George W. Bush.

Mr. Obama expressed confidence that Mr. Kerry would be confirmed by his Senate colleagues, a prediction that seemed safe, given that at a recent news conference, Senator John McCain, Republican of Arizona, one of Ms. Rice’s fiercest critics, jokingly referred to Mr. Kerry as “Mr. Secretary.”

Mrs. Clinton has not announced her resignation, but she has made it clear she would not stay beyond a single term. Because she is recovering from a concussion, she did not appear at the midday announcement. Mr. Obama said that he spoke to her on Friday morning, and reported that she was “in good spirits.”

In a statement, Mrs. Clinton said Mr. Kerry was a leader of the “highest caliber,” who had advocated on behalf of diplomacy and development in Congress.

Mr. Kerry is working with her to adopt the recommendations of a recent report that harshly criticized the State Department for lapses in security in Benghazi, she said. The Benghazi attack, analysts said, underscored the management challenge for a longtime senator like Mr. Kerry in taking over a sprawling worldwide bureaucracy. Former aides to Mr. Kerry point out that he did oversee a huge, if temporary, campaign operation in 2004, which, though criticized for tactical missteps, was not viewed as poorly managed.

Although Mr. Kerry is not a global celebrity like Mrs. Clinton, his background as a presidential nominee and his chairmanship of the Foreign Relations Committee have made him well known abroad, accustomed to meeting monarchs and presidents.

In October 2009, he was viewed as instrumental in persuading President Hamid Karzai of Afghanistan to accept the need for a runoff election. Mr. Kerry spent 20 hours over five days with Mr. Karzai, telling him over dinner and in long walks in the garden of the presidential palace in Kabul of his own frustrations at the ballot box in 2004.

“I told him, ‘Sometimes there are tough things,’ ” Mr. Kerry said in an interview at the time.

Before Syria exploded in violence, Mr. Kerry met several times with its president, Bashar al-Assad, hoping to draw him into a more constructive role in the Middle East. His failed effort at engagement may elicit some tough questions from Mr. McCain and other Senate hawks.

As a senator, Mr. Kerry compiled a strong record on climate change, and environmental groups issued enthusiastic responses to his nomination. But Mr. Obama, pressed at a recent news conference, said climate change would take a back seat to the economy, at least for now.

For Mr. Kerry, exerting influence internally is likely to be the greatest challenge of the job he has long coveted. Friends and former aides predicted he would carve out a role, just as Mrs. Clinton did.

“John was someone who from an early age dreamed of being president,” said Jim Gomes, a former chief of staff to Mr. Kerry. “As someone who grew up in a Foreign Service family, who testified before Senate Foreign Relations after coming home from Vietnam and who wanted to serve on Foreign Relations, this is a pretty terrific Plan B.”

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Brain Benefits for the Holidays? Stuff the Stocking with Video Games

Title Post: Brain Benefits for the Holidays? Stuff the Stocking with Video Games
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