Caught in the act: Researchers capture key moments in cell death

Feb. 2, 2013 ? Scientists at the Walter and Eliza Hall Institute have for the first time visualised the molecular changes in a critical cell death protein that force cells to die.

The finding provides important insights into how cell death occurs, and could lead to new classes of medicines that control whether diseased cells live or die.

Cell death, called apoptosis, is important for controlling the number of cells in the body. Defects in cell death have been linked to the development of diseases such as cancer and neurodegenerative conditions. Insufficient cell death can cause cancer by allowing cells to become immortal while excessive cell death of neurons may be a cause of neurodegenerative conditions.

Dr Peter Czabotar, Professor Peter Colman and colleagues in the institute's Structural Biology division, together with Dr Dana Westphal from the institute's Molecular Genetics of Cancer division, made the discovery which is published in the latest edition of the journal Cell.

Dr Czabotar said activation of the protein Bax had long been known to be an important event leading to apoptosis, but until now it was not known how this activation occurred. "One of the key steps in cell death is that holes are punched into a membrane in the cell, the mitochondrial membrane," Dr Czabotar said. "Once this happens the cell is going to go on and die. Bax is responsible for punching the holes in the mitochondrial membrane and visualising its activation brings us a step closer to understanding the mechanics of cell death."

Using the Australian Synchrotron, Dr Czabotar and colleagues were able to obtain detailed three-dimensional images of Bax changing shape as it moved from its inactive to active form. The active form ruptures mitochondrial membranes, removing the cell's energy supply and causing cell death.

"By using the powerful X-ray beams created by the synchrotron, we obtained structures of Bax that were really exciting," Dr Czabotar said. "Bax is activated when small protein fragments called BH3-peptides bind to it. We saw that these peptides open up the Bax molecule like a key unlocking a padlock. This unlocked form of Bax can bind to another Bax molecule, which can then form larger Bax complexes that can go on to break up membranes in the cell.

"As well as explaining the detail of how cell death occurs, our research could provide clues about how to design potential new therapeutic agents that target Bax," Dr Czabotar said. "Now that we can see how Bax changes its shape to move from the inactive to the active form, it may be possible to block Bax activation, to prevent cell death in conditions such as neurodegenerative disorders, where illness is caused by excessive cell death. Similarly, agents that drive Bax into its active form could force immortal cells such as cancer cells to die, providing the basis for a potential new class of anti-cancer agents."

The research was supported by the National Health and Medical Research Council, the Australian Research Council, the Australian Cancer Research Foundation, Cancer Council Victoria, the German Research Foundation, the Leukemia and Lymphoma Society (US) and the Victorian Government.

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Story Source:

The above story is reprinted from materials provided by Walter and Eliza Hall Institute.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Peter?E. Czabotar, Dana Westphal, Grant Dewson, Stephen Ma, Colin Hockings, W.?Douglas Fairlie, Erinna?F. Lee, Shenggen Yao, Adeline?Y. Robin, Brian?J. Smith, David?C.S. Huang, Ruth?M. Kluck, Jerry?M. Adams, Peter?M. Colman. Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis. Cell, 2013; 152 (3): 519 DOI: 10.1016/j.cell.2012.12.031

Note: If no author is given, the source is cited instead.

Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/top_environment/~3/IHLdgIdih0Q/130203085132.htm

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"Great Rotation"- A Wall Street fairy tale?

NEW YORK (Reuters) - Wall Street's current jubilant narrative is that a rush into stocks by small investors has sparked a "great rotation" out of bonds and into equities that will power the bull market to new heights.

That sounds good, but there's a snag: The evidence for this is a few weeks of bullish fund flows that are hardly unusual for January.

Late-stage bull markets are typically marked by an influx of small investors coming late to the party - such as when your waiter starts giving you stock tips. For that to happen you need a good story. The "great rotation," with its monumental tone, is the perfect narrative to make you feel like you're missing out.

Even if something approaching a "great rotation" has begun, it is not necessarily bullish for markets. Those who think they are coming early to the party may actually be arriving late.

Investors pumped $20.7 billion into stocks in the first four weeks of the year, the strongest four-week run since April 2000, according to Lipper. But that pales in comparison with the $410 billion yanked from those funds since the start of 2008.

"I'm not sure you want to take a couple of weeks and extrapolate it into whatever trend you want," said Tobias Levkovich, chief U.S. equity strategist at Citigroup. "We have had instances where equity flows have picked up in the last two, three, four years when markets have picked up. They've generally not been signals of a continuation of that trend."

The S&P 500 rose 5 percent in January, its best month since October 2011 and its best January since 1997, driving speculation that retail investors were flooding back into the stock market.

Heading into another busy week of earnings, the equity market is knocking on the door of all-time highs due to positive sentiment in stocks, and that can't be ignored entirely. The Standard & Poor's 500 Index <.spx> ended the week about 4 percent from an all-time high touched in October 2007.

Next week will bring results from insurers Allstate and The Hartford , as well as from Walt Disney , Coca-Cola Enterprises and Visa .

But a comparison of flows in January, a seasonal strong month for the stock market, shows that this January, while strong, is not that unusual. In January 2011 investors moved $23.9 billion into stock funds and $28.6 billion in 2006, but neither foreshadowed massive inflows the rest of that year. Furthermore, in 2006 the market gained more than 13 percent while in 2011 it was flat.

Strong inflows in January can happen for a number of reasons. There were a lot of special dividends issued in December that need reinvesting, and some of the funds raised in December tax-selling also find their way back into the market.

During the height of the tech bubble in 2000, when retail investors were really embracing stocks, a staggering $42.7 billion flowed into equities in January of that year, double the amount that flowed in this January. That didn't end well, as stocks peaked in March of that year before dropping over the next two-plus years.

MOM AND POP STILL WARY

Arguing against a 'great rotation' is not necessarily a bearish argument against stocks. The stock market has done well since the crisis. Despite the huge outflows, the S&P 500 has risen more than 120 percent since March 2009 on a slowly improving economy and corporate earnings.

This earnings season, a majority of S&P 500 companies are beating earnings forecast. That's also the case for revenue, which is a departure from the previous two reporting periods where less than 50 percent of companies beat revenue expectations, according to Thomson Reuters data.

Meanwhile, those on the front lines say mom and pop investors are still wary of equities after the financial crisis.

"A lot of people I talk to are very reluctant to make an emotional commitment to the stock market and regardless of income activity in January, I think that's still the case," said David Joy, chief market strategist at Columbia Management Advisors in Boston, where he helps oversee $571 billion.

Joy, speaking from a conference in Phoenix, says most of the people asking him about the "great rotation" are fund management industry insiders who are interested in the extra business a flood of stock investors would bring.

He also pointed out that flows into bond funds were positive in the month of January, hardly an indication of a rotation.

Citi's Levkovich also argues that bond investors are unlikely to give up a 30-year rally in bonds so quickly. He said stocks only began to see consistent outflows 26 months after the tech bubble burst in March 2000. By that reading it could be another year before a serious rotation begins.

On top of that, substantial flows continue to make their way into bonds, even if it isn't low-yielding government debt. January 2013 was the second best January on record for the issuance of U.S. high-grade debt, with $111.725 billion issued during the month, according to International Finance Review.

Bill Gross, who runs the $285 billion Pimco Total Return Fund, the world's largest bond fund, commented on Twitter on Thursday that "January flows at Pimco show few signs of bond/stock rotation," adding that cash and money markets may be the source of inflows into stocks.

Indeed, the evidence suggests some of the money that went into stock funds in January came from money markets after a period in December when investors, worried about the budget uncertainty in Washington, started parking money in late 2012.

Data from iMoneyNet shows investors placed $123 billion in money market funds in the last two months of the year. In two weeks in January investors withdrew $31.45 billion of that, the most since March 2012. But later in the month money actually started flowing back.

(Additional reporting by Caroline Valetkevitch; Editing by Kenneth Barry)

Source: http://news.yahoo.com/great-rotation-wall-street-fairy-tale-012451222--sector.html

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US gains 157K jobs; jobless rate rises to 7.9 pct.

In this Tuesday, Jan. 22, 2013 photo, job seekers fill a room at the job fair in Sunrise, Fla. U.S. employers added 157,000 jobs in January, and hiring was much stronger at the end of 2012 than previously thought, providing reassurance that the job market held steady even as economic growth stalled, according to Labor Department reports, Friday, Feb. 1, 2013. (AP Photo/J Pat Carter)

In this Tuesday, Jan. 22, 2013 photo, job seekers fill a room at the job fair in Sunrise, Fla. U.S. employers added 157,000 jobs in January, and hiring was much stronger at the end of 2012 than previously thought, providing reassurance that the job market held steady even as economic growth stalled, according to Labor Department reports, Friday, Feb. 1, 2013. (AP Photo/J Pat Carter)

In this Tuesday, Jan. 22, 2013 photo, Fernando Rames answers questions on a job application at the job fair in Sunrise, Fla. U.S. employers added 157,000 jobs in January, and hiring was much stronger at the end of 2012 than previously thought, providing reassurance that the job market held steady even as economic growth stalled, according to Labor Department reports, Friday, Feb. 1, 2013. (AP Photo/J Pat Carter)

WASHINGTON (AP) ? U.S. employers added 157,000 jobs in January, and hiring was much stronger at the end of 2012 than previously thought, providing reassurance that the job market held steady even as economic growth stalled.

The Labor Department report Friday showed a jump in hiring in the final two months of last year, just when the economy was sputtering and facing the threat of deep government spending cuts and tax increases from the fiscal cliff. The department revised up the estimated job gains for November from 161,000 to 247,000 and for December from 155,000 to 196,000.

The mostly encouraging jobs report included one negative sign: The unemployment rate rose to 7.9 percent from 7.8 percent in December. The rate is calculated from a survey of households, and more people in that survey said they were unemployed.

The monthly job gains are derived from a separate survey of employers.

The hiring picture over the past two years also looked stronger after the department's annual revisions. The revisions showed that employers added an average of roughly 180,000 jobs a month in 2012 and 2011. That was up from previous estimates of about 150,000.

"The significantly stronger payroll gains tell us the economy has a lot more momentum than what we had thought," Joseph LaVorgna, chief U.S. economist at Deutsche Bank, said in a research note.

Stocks surged immediately after trading began at 9:30 a.m. Eastern time, an hour after the jobs report was released. The Dow Jones industrial average jumped 130 points and briefly touched 14,000 for the first time in more than five years, before falling back.

Other economic news Friday contributed to the stock rally. Manufacturing expanded at a much faster pace in January compared with December, a private survey found. Ford, Chrysler and General Motors all reported double-digit sales gains for January. And construction spending rose in December at a healthy pace.

The employment report revealed a notable shift in the job market: More hiring by construction companies. They added 28,000 jobs in January and nearly 100,000 over the past four months. Those job gains are consistent with a rebound in home construction and a broader recovery in housing.

Retailers added 33,000 positions. Health care gained 23,000 jobs. Manufacturers reported a small increase of 4,000. Restaurants and hotels added 17,000.

The solid hiring in retail, construction, restaurants and hotels suggested that such companies expect consumer spending to hold up in coming months.

"The strong and steady job gains from retail trade and construction look a lot more like a normal economic expansion," said Scott Anderson, chief economist at Bank of the West. "This is a sign that consumer spending is playing a far more important role in this expansion than it has so far."

Average hourly wages rose 4 cents to $23.78 and have risen an encouraging 2.1 percent in the past 12 months. That's slightly above the inflation rate, which was 1.7 percent.

Last month's hiring should cushion the impact of the higher Social Security taxes that most consumers are paying this year. And it would help the economy resume growing after it shrank at an annual rate of 0.1 percent in the October-December quarter.

Higher Social Security taxes are reducing take-home pay for most Americans. A person earning $50,000 a year will have about $1,000 less to spend in 2013. A household with two high-paid workers will have up to $4,500 less. Taxes rose after a 2 percent cut, in place for two years, expired Jan. 1.

Analysts expect the Social Security tax increase to shave about a half-point off economic growth in 2013, since consumers drive about 70 percent of economic activity.

The hit to consumers is coming at a precarious moment for the economy. It contracted in the fourth quarter for the first time in 3? years. The decline was driven largely by a steep cut in defense spending and a drop in exports. Analysts generally think those factors will prove temporary and that the economy will resume growing.

Still, the contraction last quarter points to what are likely to be key challenges for the economy this year: the prospect of sharp government spending cuts and uncertainty over whether Congress will agree to raise the federal borrowing cap.

Most analysts predict that the economy will grow again in the January-March quarter, though likely at a lackluster annual rate of around 1 percent. They expect the economy to expand about 2 percent for the full year.

Two key drivers of growth improved last quarter: Consumer spending increased at a faster pace. And businesses invested more in equipment and software.

In addition, homebuilders are stepping up construction to meet rising demand. That could generate even more construction jobs.

And home prices are rising steadily. That tends to make Americans feel wealthier and more likely to spend. Housing could add as much as 1 percentage point to economic growth this year, some economists estimate.

Auto sales reached their highest level in five years in 2012 and are expected to keep growing this year. That's boosting production and hiring at U.S. automakers and their suppliers.

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/f70471f764144b2fab526d39972d37b3/Article_2013-02-01-Economy/id-e2b6aab8c91d484982da948eba75c53c

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Video: The Night Hannah Hill Disappeared, Part 5

Dateline NBC

'Dateline NBC,' the signature broadcast for NBC News in primetime, premiered in 1992. Since then, it has been pioneering a new approach to primetime news programming. The multi-night franchise, supplemented by frequent specials, allows NBC to consistently and comprehensively present the highest-quality reporting, investigative features, breaking news coverage and newsmaker profiles.

Source: http://www.nbcnews.com/id/3032600/vp/50674045#50674045

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Negotiators talking to Ala. captor through pipe

MIDLAND CITY, Ala. (AP) ? Speaking into a 4-inch-wide ventilation pipe, hostage negotiators tried Thursday to talk a man into releasing a kindergartener and ending a standoff in an underground bunker that stretched into its third day.

The man identified by multiple neighbors and witnesses as 65-year-old retired truck driver Jimmy Lee Dykes was accused of pulling the boy from a school bus on Tuesday and killing the driver. The pair was holed up in a small room on his property that authorities compared to tornado shelters common in the area.

James Arrington, police chief of the neighboring town of Pinckard, said the shelter was about 4 feet underground, with about 6-by-8 feet of floor space and a PVC pipe that negotiators were speaking through.

There were signs that the standoff could continue for some time: A state legislator said the shelter has electricity, food and TV. The police chief said the captor has been sleeping and told negotiators that he has spent long periods in the shelter before.

"He will have to give up sooner or later because (authorities) are not leaving," Arrington said. "It's pretty small, but he's been known to stay in there eight days."

Midland City Mayor Virgil Skipper said he has been briefed by law enforcement and visited with the boy's parents.

"He's crying for his parents," he said. "They are holding up good. They are praying and asking all of us to pray with them."

The normally quiet red clay road was teeming Thursday with more than a dozen police cars and trucks, a fire truck, a helicopter, officers from multiple agencies, media and at least one ambulance near Midland City, population 2,300.

Dykes was known around the neighborhood as a menacing figure who neighbors said once beat a dog to death with a lead pipe, threatened to shoot children for setting foot on his property and patrolled his yard at night with a flashlight and a firearm.

The chief confirmed that Dykes held anti-government views, as described by multiple neighbors: "He's against the government ? starting with Obama on down."

"He doesn't like law enforcement or the government telling him what to do," he said. "He's just a loner."

Authorities say the gunman boarded a stopped school bus Tuesday afternoon and demanded two boys between 6 and 8 years old. When the driver tried to block his way, the gunman shot him several times and took a 5-year-old boy off the bus.

The bus driver, Charles Albert Poland Jr., 66, was hailed by locals as a hero who gave his life to protect the 21 students aboard the bus.

No motive has been discussed by investigators, but the police chief said the FBI had evidence suggesting it could be considered a hate crime. Federal authorities have not released any details about the standoff or the investigation. The mayor said he hasn't seen anything tying together Dykes' anti-government views and the allegations against him.

Dykes had been scheduled to appear in court Wednesday to answer charges he shot at his neighbors in a dispute last month over a speed bump. Neighbor Claudia Davis said he yelled and fired shots at her, her son and her baby grandson over damage Dykes claimed their pickup truck did to a makeshift speed bump in the dirt road. No one was hurt.

The son, James Davis Jr., believes Tuesday's shooting was connected to the court date. "I believe he thought I was going to be in court and he was going to get more charges than the menacing, which he deserved, and he had a bunch of stuff to hide and that's why he did it."

Neighbors described a number of other run-ins with Dykes in the time since he moved to this small town near the Georgia and Florida borders, in a region known for peanut farming.

A neighbor directly across the street, Brock Parrish, said Dykes usually wore overalls and glasses and his posture was hunched-over. He said Dykes usually drove a run-down "creeper" van with some of the windows covered in aluminum foil.

Parrish saw him often digging in his yard, as if he was preparing a spot to lay down a driveway or a building foundation. He lived in a small camping trailer on the site. He patrolled his lawn at night, walking from corner to corner with a flashlight and an assault rifle.

Mike and Patricia Smith, who also live across the street from Dykes and whose two children were on the bus, said their youngsters had a run-in with him about 10 months ago.

"My bulldogs got loose and went over there," Patricia Smith said. "The children went to get them. He threatened to shoot them if they came back."

Another neighbor, Ronda Wilbur, said Dykes beat her 120-pound dog with a lead pipe for coming onto his side of the dirt road. The dog died a week later.

"He said his only regret was he didn't beat him to death all the way," Wilbur said. "If a man can kill a dog, and beat it with a lead pipe and brag about it, it's nothing until it's going to be people."

Court records showed Dykes was arrested in Florida in 1995 for improper exhibition of a weapon, but the misdemeanor was dismissed. The circumstances of the arrest were not detailed in his criminal record. He was also arrested for marijuana possession in 2000.

___

Associated Press writers Jay Reeves, Melissa Nelson-Gabriel, Bob Johnson in Montgomery and AP researcher Rhonda Shafner in New York contributed to this report.

Source: http://news.yahoo.com/negotiators-talking-ala-captor-pipe-181459029.html

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Penalty for running a red light - Road Traffic Law

Penalty For Running A Red Light

For most drivers running a red light might not seem to be a big issue. Obviously the inherent dangers surrounding running a red light are clear to all and do not need to be stated here but what happens to you if you run a red light and you already have 9 penalty points on your licence?

Under ?Totting Up? provisions you will be banned from driving for 6 months unless you can demonstrate that ?Special Reasons? existed at the time of the offence or ?Exceptional Hardship? would occur if banned.

What Are The Special Reasons To Avoid Disqualification?

Special reasons are relevant if you are convicted of a road traffic offence which has a penalty of obligatory disqualification, or obligatory endorsement.  Although special reasons are not technically a defence, they can significantly reduce the sentence you receive.

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Obligatory disqualification

The court may shorten the period of disqualification or remove it altogether if it considers that there are special reasons   to do so. So running a red light does NOT always mean that 3 penalty points will be endorsed on your licence!

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Obligatory endorsement for Running a Red Light

Imposed for a range of offences, including speeding, but also including running a red light and using a mobile phone, not having insurance, as well as more serious offences where disqualification can also be imposed.

The court may impose anything up to 11 penalty points.

If the court thinks that there are special reasons  for doing so, they will decide not to endorse your licence (it cannot reduce the number of points it imposes).

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Special reasons can only relate to the facts and circumstances of the offence itself, such as the reason why it was committed. Your personal circumstances, for example the effect that the disqualification/endorsement will have on you or others, or the fact that the offence was (for example if you only slightly exceeded the speed limit) do not count as special reasons.

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Examples of special reasons

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Medical emergency

If you can show that you committed the offence only because of a medical emergency, then this will amount to a special reason. However, the emergency must be genuine and unforeseen. You must also show that you drove only as a last resort: you must have exhausted all other possibilities of dealing with the emergency, including contacting the emergency services. For example, if a driver who lived in a rural area drove (whilst over the legal limit) to take his seriously sick child to hospital because no ambulance was available, then this would probably amount to a special reason for not disqualifying.

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The penalty for running a red light might mean a 6 month ban (Under Totting Up Procedures) but the least you can expect is a 3 penalty points endorsement and a fine of £60. It might not seem obvious to you as a driver that a technical defence may exist and therefore we would suggest that you always contact a specialist road traffic solicitor as soon as possible as it may be that they can win your case at trial depending upon the facts and circumstances of your particular case. It might even be done without you having to give evidence. Technical defences often depend upon an evidential issue and a legal submission made by the lawyer and therefore it is unnecessary for the accused to testify.

In our experience it is seldom a clear cut issue and you may be surprised at what can amount to a defence in relation to these charges.

You always have to weigh up the costs against the benefits of fighting such a case as they involve a considerable amount of time involved in court attendances and legal fees as they are seldom charges that will entitle you to Legal Aid to fund your defence.

For more information about Penalties for Running a Red Light please get in touch today for a free case consultation on 0800 612 9597 or email enquiries@roadtrafficlaw.com

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Source: http://www.roadtrafficlaw.com/penalty-for-running-a-red-light

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How cancer cells rewire their metabolism to survive

Friday, February 1, 2013

Cancer cells need food to survive and grow. They're very good at getting it, too, even when nutrients are scarce. Many scientists have tried killing cancer cells by taking away their favorite food, a sugar called glucose. Unfortunately, this treatment approach not only fails to work, it backfires?glucose-starved tumors actually get more aggressive. In a study published January 31 in the journal Cell, researchers at Sanford-Burnham Medical Research Institute discovered that a protein called PKC? is responsible for this paradox. The research suggests that glucose depletion therapies might work against tumors as long as the cancer cells are producing PKC?.

PKC?: critical regulator of tumor metabolism

According to this study, when PKC? is missing from cancer cells, tumors are able to use alternative nutrients. What's more, the lower the PKC? levels, the more aggressive the tumor.

"We found an interesting correlation in colon cancers?if a patient's tumor doesn't produce PKC?, he has a poorer prognosis than a similar patient with the protein. We looked specifically at colon cancer in this study, but it's likely also true for other tumor types," said Jorge Moscat, Ph.D., a professor in Sanford-Burnham's National Cancer Institute-designated Cancer Center. Moscat led the study in close collaboration with Sanford-Burnham colleague Maria Diaz-Meco, Ph.D.

PKC? keeps tumors addicted to glucose, and under control

Although most cancer cells love glucose, tumors lacking PKC? grow even better in the absence of this nutrient. Using human tumor samples and a mouse model of colon cancer, Moscat and his team determined this growth-without-glucose paradox is because PKC?-deficient tumors are able to reprogram their metabolism to use glutamine, another nutrient, instead.

Without PKC? around to keep them addicted to glucose, these tumors kick-start a new metabolic pathway. This altered metabolism helps PKC?-deficient cancer cells survive in conditions that would otherwise be lethal.

"If we can find an effective way to add PKC? back to tumors that lack it, we'd make them less suited for survival and more sensitive to current therapies," Moscat said.

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Sanford-Burnham Medical Research Institute: http://www.burnham-inst.org

Thanks to Sanford-Burnham Medical Research Institute for this article.

This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.

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Source: http://www.labspaces.net/126579/How_cancer_cells_rewire_their_metabolism_to_survive

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