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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Barbra Streisand goes on a “Guilt Trip” with Seth Rogen

LOS ANGELES (Reuters) – Road-trip movies have been dominated by teenagers on wild adventures or “Hangover” style bro-mances, but Barbra Streisand and Seth Rogen are driving the genre into new territories with mother-son comedy “The Guilt Trip” to usher in the holiday season.

“The Guilt Trip,” which hits U.S. theaters this week, follows struggling novice inventor Andy (Seth Rogen), who is guilted in to bringing his mother on a work-related road-trip across the country.

Streisand, 70, who broke out as an actress in 1968′s comedy “Funny Girl,” returns to her comedic roots as Joyce, Andy’s overbearing mother, who becomes closer to her son over the duration of their tense and comedic adventures on the road.

The actress told reporters at a recent press conference that it was her son Jason Gould who convinced her to do the project after reading the script with her, and Streisand found a deeper connection to the story.

“Mothers develop guilt trips,” Streisand said. “(When my own son was young) I was working a lot and I felt guilty as a parent that I cannot pick (up) my son everyday from school, bake him cookies, that kind of thing. And so you try and compensate.”

“I thought it was interesting to investigate this – trying to be his friend versus a mother…this movie, it hit on all those things that I thought I could explore.”

Rogen, 30, also related closely to the mother-son storyline, saying that while he has a “good relationship” with his own mom, even she can drive him “crazy” sometimes.

“That dynamic where your mother is trying and the more she tries, the more it bugs you, the more it bugs you, the more she tries….All that is very, at times, real to my relationship with my mother,” Rogen said.

STAYING OUT OF THE SPOTLIGHT

Streisand, who is one of the few actresses to win a Tony, Emmy, Grammy and Oscar award over her six-decade career, last took a leading role in 1996′s “The Mirror Has Two Faces,” which she also directed and produced.

The actress initially had reservations about signing onto the movie and said she gave the movie studio numerous clauses “because I kept wanting an out some way.”

Her requests included having a set “no more than 45 minutes away from my house” and later morning starts, as “my husband (James Brolin) and I stay up until two or three in the morning so we don’t function…at six in the morning.”

Streisand’s requests were granted, and thus came about a road trip movie where the actors never actually went on the road. The film ended up largely being shot on a sound stage with Streisand and Rogen in a car against a green screen while backdrops of landmarks such as the Grand Canyon, were added in later.

With the exception of a supporting role as Ben Stiller’s mother in 2004′s “Meet The Fockers” and 2010′s “Little Fockers,” Streisand has stayed out of the spotlight in recent years, and attributes that as one of the keys to her long-standing success.

“I don’t make many movies and I don’t make that many appearances. Less is more. Maybe that keeps a little mystery,” Streisand said, adding that she likes to “stay at home a lot.”

While she hasn’t signed onto another project just yet, she said what keeps her satisfied as an artist is engaging in work that is “private” as opposed to being on public display.

“I love recording and I love making films as a filmmaker,” she said. “Because it uses every bit of what you have experienced or know, whether it’s graphics, composition, decorating, psychology, storytelling, whatever it is. It’s a wonderful thing.”

(Editing by Piya Sinha-Roy and Lisa Shumaker)

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Tepid Sales of Microsoft’s Windows 8 Point to Shaky Market

Mario Tama/Getty Images

Plenty of consumers already own PCs and seem content to make do with what they have.

BELLEVUE, Wash. — It used to be that a new version of the Windows operating system was enough to get people excited about buying a new computer, giving sales a nice pop.

Ted S. Warren/Associated Press

Earlier versions of Windows all came out during periods when the PC’s status as the center of computing seemed far more secure.

Not this time. Windows 8, the latest edition of Microsoft’s software, failed to pack shoppers into a Microsoft store in a mall here last week, at a time when parking lots in the area were overflowing. The trickle of shopping bags leaving the store with merchandise was nothing like the steady stream at a bustling Apple store upstairs.

Claude Ballard was among the customers at the Microsoft store who tried out Surface, a new Microsoft-designed Windows tablet. Mr. Ballard, who described himself as a “semiretired” computer systems manager for a real estate firm, said he was intrigued by the eye-catching design of Windows 8 — but not enough to scrimp to buy a new computer this year.

“It’s economics, really,” he said. “It’s going to be a better year for my mechanic than it is for me.”

Weak PC sales this holiday season suggest that the struggles of Microsoft and other companies that depend heavily on the computer business will not abate soon. Plenty of consumers already own PCs and seem content to make do with what they have, especially in a shaky economy in which less expensive mobile devices are bidding for a share of their wallets.

While there are also many tablets running Microsoft’s new, touch-friendly Windows, they have so far failed to emerge from the shadow of competing products from Apple and Amazon and other devices that are being snapped up by holiday shoppers.

Emmanuel Fromont, president of the Americas division of Acer, the world’s No. 4 PC maker, said sales of the company’s Windows 8 PCs had been lower than expected. He said one factor was the system’s unfamiliar design, which appeared to be making consumers cautious.

“There was not a huge spark in the market,” Mr. Fromont said. “It’s a slow start, there’s no question.”

The clearest evidence of Windows 8’s disappointing introduction comes from the research firm NPD, which estimates that sales of Windows machines have actually dropped from a year ago.

According to NPD, stores in the United States sold 13 percent fewer Windows devices from late October, when Windows 8 made its debut, through the first week in December, than in the same period last year.

Those figures do not include sales in Microsoft’s own stores, which were the only place to buy a Surface tablet during that period, but because the stores are scarce, analysts believe it is unlikely they made a big difference.

“I think everybody would have hoped for a better start,” said Stephen Baker, an analyst at NPD. “The thing is, this market is not the same market that Windows 7 or Vista or even XP launched into.”

Those earlier versions of Windows all came out during periods when the PC’s status as the center of computing seemed far more secure. In the intervening years, smartphones and tablets have become much more serious rivals for a share of consumer spending on technology. Sales of PCs have been declining for much of the year.

While most people are not getting rid of their PCs altogether in favor of mobile devices, analysts believe they are postponing purchases of new ones.

“What you’re seeing is not a retirement of PCs, but a push-out in the replacement cycle,” said A. M. Sacconaghi, an analyst at Sanford C. Bernstein. “If people used to buy PCs every four years and are now buying them every five years, that could lower PC sales by 20 percent over time. That’s substantial.”

Mr. Sacconaghi predicted that global PC shipments would be down 3 percent in 2012.

The shift in spending to tablets is one reason that Windows 8 is so critical for Microsoft’s future. The company overhauled its operating system with a radically different, tile-based interface that is easier to navigate on touch-screen devices. Microsoft intends the software to be flexible enough that it can still be used on conventional laptops and desktops, including newer models with touch screens.

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Meat company owner sues USDA for right to slaughter horses

Rick de los Santos wants to reopen an animal slaughter business that's been banned in the U.S. for years. Along the way, he's also opened a can of worms.

The Roswell, N.M., meat company owner sued the federal government last week, alleging that officials ignored his application to resume domestic horse slaughter for food because the practice had become an emotional political issue throughout the West.

After waiting a year for permits, De los Santos, 52, says he's using the courts to force the U.S. Department of Agriculture to resume inspections necessary to open what would be the nation's first new horse slaughterhouse since 2007.

"I've submitted all the paperwork and have been told all along 'Oh, it won't be long now,'" said De los Santos, who owns Valley Meat Co. "I followed all their guidelines. I put more than $100,000 in upgrades and additions on my facilities to handle equine slaughter. And then the government comes back and tells me, 'We can't give you the permits. This horse issue has turned into a political game.'

"So what else do you do? I figured it was time to go to court."

The slaughterhouse owner, whose business had been slaughtering cattle, is also suing the Humane Society of the United States, Front Range Equine Rescue and Animal Protection of New Mexico, accusing those groups of defamation and causing loss of income during the dispute.

The dispute over killing horses has raged for years. Equine advocates have accused the Bureau of Land Management of failing to protect tens of thousands of mustangs that wander government-owned land in 10 Western states. Many of the animals are corralled each year and sent to long-term holding facilities. And reports surfaced this fall that the BLM was knowingly selling wild horses for slaughter, an outcome banned annually by Congress. The agency is investigating the claim.

In 2007, the last three domestic slaughterhouses in the United States were closed. Since then, unwanted domestic animals have been shipped to Mexico and Canada for slaughter.

Many animal protection groups and public officials were outraged at the idea of resuming domestic horse slaughter, including New Mexico Gov. Susana Martinez, a Republican, who has opposed the plan.

Many animal advocates says horse slaughter has no business in the U.S.

"Everything is wrong with this idea," said Sally Summers, founder of Horse Power, a Nevada-based equine advocacy group. "The economy has done just fine without this type of slaughter. And these plants are toxic to the community. They hurt these towns; they don't help them."

Summers said that many of the drugs that U.S. owners give their horses to ensure longevity and peak performance are carcinogenic. "This stuff gets into the water table through the drains," she said. "It's a nightmare. This man is smoking a pipe and I don't know what's in it."

The USDA declined to comment last week on the pending litigation. The agency has until January to respond to the suit, filed in federal court in late October.

De los Santos says his lawsuit will show that a recent "marked change in cooperation" by the USDA is due to pressure the government is receiving on the horse issue.

Some support a return to domestic horse slaughter. The American Quarter Horse Assn. says a 2011 report from the federal Government Accountability Office shows horse abuse and abandonment have been increasing since Congress essentially banned horse slaughter by cutting funding for USDA inspection programs in 2006.

The number of U.S. horses sent to other countries for slaughter has nearly tripled since domestic horse slaughter ceased. Most animal advocacy groups agree that some of the worst abuse occurs in the slaughter pipeline that often takes horses to inhumane facilities in Mexico.

Last year, 68,429 horses were shipped to Mexico and 64,652 to Canada, according to USDA statistics compiled by the Equine Welfare Alliance, a nonprofit group dedicated to ending horse slaughter. That compares with total exports of 37,884 of the animals in 2006.

De los Santos says he is tired of sitting in southern New Mexico and watching countless truckloads of horses en route to Mexico for slaughter.

"I've seen 130,000 horses a year on their way to Mexico — they go right through our backyard — and I wanted to tap into the market," he said. "I could have hired 100 people by now. Everyone in our community agrees we need this type of service. And I'm tired of waiting."

De los Santos says he is ready to start killing horses humanely.

"Everything that has four legs that walks can be slaughtered the same way, but we're ready to do this humanely," he said. "We've upgraded our knocking chutes for giving them that lethal hit."

He says he can't understand why everyone is so upset. Americans kill cows; why not horses?

"My wife says horse is on the menu all over Europe, but the moment you mention horse slaughter in the U.S., you've got a problem," he says.

john.glionna@latimes.com

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Facebook Poke App Is Frustrating as Hell

Facebook Poke: Startup Screen

Poke, the new iPhone app from Facebook, lets you send short messages, photos and videos to friends that automatically self destruct after a few seconds. If you have the Facebook app on your phone already, logging in is effortless.

Click here to view this gallery.

[More from Mashable: 2012′s Biggest Winners and Losers]

I was never a big poker on Facebook. When I joined the social network in 2007, giving someone a “poke” was still pretty common. It was a connection that stopped short of an actual friend request, a way to test the waters of a reconnection with, say, an ex.

The new app, Facebook Poke (as it’s listed in the App Store), doesn’t have much in common with poking of old. It’s essentially a clone of other texting apps where all the messages have a built-in self-destruct. It’s ideal for clandestine activities, shall we say.

[More from Mashable: Facebook Introduces Snapchat Competitor, Poke]

Here’s how it works: Let’s say you have a sudden urge to send one of your Facebook friends a photo of a, er, cucumber. But you don’t want to just send them a cucumber pic that they could post and re-share to the world. Poke lets you send the pic, but the recipient will only have 1, 3, 5 or 10 seconds to view your majestic vegetable. And they need to press and hold the screen while viewing, or the pic goes away.

You can send photos, videos or text messages via Poke, although you can’t use it for anything too elaborate since the message content lasts 10 seconds maximum. After that, boom. The message, whatever it was, is gone forever. There isn’t even a record on the sender’s phone (although a log of who you’ve poked and who’s poked you still remains).

Poke is pretty unforgiving. The recipient must press and hold the notification to see the content. Once you touch, the countdown starts, and there’s no going back — even if you let go. Videos just stop, with no chance of re-watching. You slip, and you’re done.

I suspect Poke will engender a lot of frustration because of this limitation. You feel as if it should at least pause the countdown when you remove your finger.

The app also lets you just “poke” people — meaning send a message with no content — about the only way the app is similar to the old act of poking. Those are just simple notifications, and don’t expire.

It gets more annoying: All your poke recipients need to download the app to see them. Poking only works on mobile right now, and Facebook’s been careful to ensure notifications for incoming pokes only appear in its mobile apps.

Checking out your profile on the web won’t reveal any trace of poking. On a smartphone, a note appears that encourages pokees to download the app.

What if someone does a screengrab of your poke, turning it into something more permanent? There’s nothing you can do, but the app will inform you if someone does that, with a “flash” icon beside their name in your feed. If you see your ephemeral wild moment appear on Tumblr the next day, at least you’ll know who to blame.

Poke isn’t that intuitive. It displays some basic instructions when you first log in, but would benefit greatly from one of those tutorial overlays that have become ubiquitous among iOS apps. Also, I find it odd that your front-facing camera isn’t selected by default. But maybe my expectation for the subject material of most pokes is off the mark.

You can add text and colored line drawings to any pics you send. That’s helpful to get the attention on the thing in the photo you really want the person to look at in those three seconds of poke life.

At first I found it frustrating that Poke doesn’t let you take horizontal photos or videos. But that’s actually a good idea. If you think about it, if the only people seeing this content are people glancing at their phones for a few seconds, so vertical pics make total sense. In the time it took a person to turn their phone and the accelerometer to react, the message will probably be gone. If you want masterpieces, try Flickr.

Bottom line: Poke is an annoying app, but it probably has more to do with the nature of what it’s trying to do than any design flaws. How do you like Poke? Let us know in the comments.

Image courtesy of iStockphoto, jcsmily

This story originally published on Mashable here.

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Reports: Rolling Stones guitarist Wood ties knot

LONDON (AP) — Two British newspapers say Rolling Stones guitarist Ronnie Wood has married his fiancee Sally Humphreys at a ceremony at London‘s Dorchester Hotel.

The Sun and the Daily Mirror carried photographs of the 65-year-old rocker with a pale boutonniere and a dark blue suit, and his 34-year-old bride in a traditional white gown and a clutch of matching white flowers.

The Sun quoted Wood as saying “I’m feeling great” as he and his bride kissed and posed for pictures outside the exclusive hotel in London’s upscale Mayfair district.

The newspapers said the guests included singer Rod Stewart and his wife Penny Lancaster as well as ex-Beatle Paul McCartney and his wife Nancy Shevell.

A call and an email to Wood’s U.S.-based agent weren’t immediately returned Saturday.

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

C.J. Gunther for The New York Times

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Read More..

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

C.J. Gunther for The New York Times

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Read More..

Violence in America? We're all responsible

For years, the National Rifle Assn. has been telling us that guns don't kill people, people kill people.

In the wake of the Newtown shootings, the group has added a twist. Guns don't kill people; television, film and video games do.

Breaking its days-long silence, the NRA on Friday offered its solution to making American schools safer — armed guards — and laid the blame for the seemingly endless cycle of mass shootings on "a callous, corrupt and corrupting shadow industry that sells, and sows, violence against its own people."

PHOTOS: Mourning after the massacre

That would be the entertainment industry, which as Wayne LaPierre, the NRA's vice president, went on to explain, creates violent video games, films and television shows that inundate our youth with "the filthiest form of pornography."

Citing, rather inexplicably, old films including "American Psycho" (which was an adaptation of a novel), the NRA condemned Hollywood for its addiction to violence.

This is a complete cultural contradiction. If we are to be a society that celebrates firepower, that believes the answer to violence is violence, then it would follow that our art forms would reflect that.

Which, of course, we are and which, of course, they do. As far apart as the NRA and Hollywood may seem from each other politically, they are two of the more powerful forces affecting popular culture. Intentionally or not, their relationship is symbiotic.

As we have been told repeatedly during the last week, the gun lobby is among the most powerful in Washington, able to cow politicians and presidents into policy often in direct opposition to their personal and publicly stated opinions.

The ban on assault weapons was allowed to lapse because even President Obama, so often labeled as ultra-liberal, didn't want to waste his currency of compromise in a fight he didn't think he could win. And so, as pointed out in a Times opinion piece by U.S. District Judge Larry Alan Burns, who made a conservative jurist's case for an assault weapons ban after sentencing Tucson shooter Jared Lee Loughner, half of the nation's deadliest shootings occurred after the ban expired, including the massacre at Sandy Hook Elementary.

FULL COVERAGE: Connecticut school shooting

Yet to the NRA, the real villain is the entertainment industry, with its serial-killer serials, bang-bang franchises and first-person shooter video games. Never mind the wide availability of military-style assault weapons; "Batman" and "Call of Duty," the gun lobby would have us believe, is more to blame for all the recent mass shootings. Reality is merely imitating art.

There is no denying that there is too much violence in film and television today, too many video games centered around high and bloody body counts. But how could this not be the case? We live in a country where the suggestion that civilians should not be able to own weapons designed to kill a large number of people quickly is inevitably dubbed as unconstitutional.

The NRA believes that the ability to own guns and use guns defines us as Americans. So how can it blame Hollywood for creating the kind of films and television shows that do precisely the same thing?

No doubt Hollywood will respond swiftly with words we've heard before — violence is essential to drama, art is a way to diffuse the aggressive tendencies we naturally have, imagery cannot become reality if the weapons aren't available, etc., etc. We will be treated, no doubt, to the sight of two self-important, overly influential groups standing on either side of 26 utterly inexcusable graves, pointing fingers at each other.

Accusations of making a national tragedy political have already begun, but it's actually worse than that. We're just making it theatrical, with all the usual suspects reciting all the usual lines, criminally diminishing the lives taken at Sandy Hook to a posturing rerun.

We have all failed. As Americans, as adults, as human beings. As creators and consumers, as politicians and voters. If 20 first-graders shot in their classroom is not proof that things have gotten out of control, then it's hard to imagine what is. Both sides, all sides, need to take responsibility.

Trumpeting a "more is more" mentality, Americans find it increasingly difficult to contemplate the restriction of anything; many of us can't even lose the weight that threatens our lives. The NRA's suggestion that what we really need is armed guards at schools sacrifices not just the notion of a peacetime nation (the terrorists have indeed won, except the terrorists are us) but of civilization itself. Are we really willing to return to the days of the Wild West?

But their point about our art forms, though posed rather hysterically, is not without truth. Too many of our prestige TV shows, our blockbuster films and our popular games revolve around violence. More important, they celebrate people and actions we would deplore in real life.

And while there is value in exploring the outer limits of both human valor and depravity, there is also such a thing as wallowing, of substituting shock for illumination. A high body count, a charming psychopath, should not be a prerequisite for a hit film or show.

In Ang Lee's beautiful film "The Ice Storm," adults argue and engage in endlessly self-absorbed drama while one of their children, unnoticed, forgotten, walks down an empty frozen street, where a power line falls and electrocutes him.

This is not the time for the grown-ups to argue; we have been arguing for far too long, and while we argue, our children die. This is the time for us all to take responsibility, make it not so easy for a young man to imagine a hideous act of violence, and not so easy for him to actually commit it.

mary.mcnamara@latimes.com

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