Friday, May 25, 2012

Cancer may require simpler genetic mutations than previously thought

ScienceDaily (May 25, 2012) ? Chromosomal deletions in DNA often involve just one of two gene copies inherited from either parent. But scientists haven't known how a deletion in one gene from one parent, called a "hemizygous" deletion, can contribute to cancer.

A research team led by Stephen Elledge, a professor in the Department of Genetics at Harvard Medical School, and his post-doctoral fellow Nicole Solimini, has now provided an answer. The most common hemizygous deletions in cancer, their research shows, involve a variety of tumor suppressing genes called STOP genes (suppressors of tumorigenesis and proliferation) that scatter randomly throughout the genome, but that sometimes cluster in the same place on a chromosome. And these clusters, said Elledge, who is also a professor of medicine at Brigham and Women's Hospital, tend to be deleted as a group. "Eliminating the cluster gives a bigger bang for the deletion buck," he said.

This finding is especially interesting in light of the two-hit model of cancer formation, which holds that both copies of a recessive gene need to be inactivated to trigger a biological effect. Thus the loss of a single tumor suppressor copy should have little or no influence on tumor cell proliferation because the remaining copy located on the other chromosome is there to pick up the slack.

Elledge's research points to a different hypothesis, namely that STOP genes in a hemizygous deletion aren't recessive but are instead haploinsufficient, meaning that they depend on two copies to function normally. "If a tumor suppressor is haploinsufficient, then a single gene copy lacks the potency needed to fully restrain tumorigenesis," Elledge explained, who is also a Howard Hughes Medical Institute Investigator. "So by removing clusters of haploinsufficient genes all at once, the cancer cell immediately propels its growth forward without having to wait for the other copies to also be lost."

Angelika Amon, a professor of biology at the Massachusetts of Technology, said she's surprised by the findings. "We've known from a lot of human syndromes that haploinsufficiency is widespread in the development of complex multicellular organisms," she said. "But these data show it's also critical for individual cells and cell proliferation."

The results also offer a different take on the two-hit model in carcinogenesis, Amon said. Being remarkably unstable, cancer cells can delete gene copies at every turn of the corner. If the loss of a single tumor suppressor copy provides no survival advantage for the tumor, then the tumor has no incentive to retain the cell with that deletion. But if the loss of that copy boosts proliferation, then the probability of a second hit later is greatly increased. "So haploinsufficiency is a way for the cancer cell to dramatically accelerate the acquisition of growth beneficial mutations," Amon said.

In other words, all it takes is a 50 percent reduction in gene activity for a cancer cell to grow. "That tells us it's a lot easier to get cancer than we might have hoped," Amon said.

According to Elledge, the number of hemizygotic deletions averages roughly six per tumor, with some tumors -- breast and pancreatic, for instance -- averaging up to ten. Each deletion involves 25 to 40 genes, many of them STOP genes, but also a few GO genes (growth enhancers and oncogenes) that enhance proliferation. That the STOP genes substantially outnumber their GO counterparts is important, Elledge explained, because it means cancer cells can tilt scales toward proliferation without also compromising it at the same time.

"The data reveal a lot of haploinsufficient players that have small effects individually, but large effects in combination," Elledge said. "Unfortunately, it's not easy to see how to take advantage of that chemotherapeutically."

What's important about the results, he emphasized, is that they open up new views on how tumors evolve. Moreso, they underscore the importance of proliferation as a fundamental feature of tumor growth, he added.

The challenge now, Elledge said, will be to find out which of the genes in a recurring deletion are haploinsufficient. "At the moment, we estimate roughly 25 percent," he said. "So these findings could also have important ramifications for other human diseases in addition to cancer."

This work was supported by grants from the NCI/NHGRI funded Cancer Genome Atlas (TCGA) project, from the NIH (U54CA143798) to R.B. and by grants from the NIH, SU2C, and DOD.

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The above story is reprinted from materials provided by Harvard Medical School.

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


Journal Reference:

  1. N. L. Solimini, Q. Xu, C. H. Mermel, A. C. Liang, M. R. Schlabach, J. Luo, A. E. Burrows, A. N. Anselmo, A. L. Bredemeyer, M. Z. Li, R. Beroukhim, M. Meyerson, S. J. Elledge. Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential. Science, 2012; DOI: 10.1126/science.1219580

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

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Just How Big Was the Biggest Earthquake?

chile earthquake 1960, eartquake, Image: Unknown, Courtesy of NOAA

Showcasing more than fifty of the most provocative, original, and significant online essays from 2011, The Best Science Writing Online 2012 will change the way...

Read More??

This week marks the anniversary of the largest earthquake ever recorded ? a magnitude-9.5 earthquake that ripped along the coast of southern Chile on May 22, 1960.

The colossal quake and the powerful tsunami that followed killed more than 1,400 people and left 2 million homeless in Chile. And its devastation reached far beyond South America.

The tsunami swept across the Pacific Ocean, wreaking havoc in Hawaii, the Philippines and Japan; a day after the earthquake, walls of water up to 18 feet (5.5 meters) high rushed ashore at Honshu, Japan's main island, destroying 1,600 homes and killing 138 people.

The colossal quake was what is known as a megathrust earthquake. These giant quakes, the most powerful quakes the planet is capable of unleashing, occur along subduction zones, where one tectonic plate dives beneath another. [The 10 Biggest Earthquakes in History]

In this case, the quake was caused when a 620-mile-long (1,000 kilometers) stretch of the Nazca plate, an oceanic plate that forms a large swath of the Pacific Ocean floor, lurched deeper beneath the South American plate, producing the only 9.5-magnitude quake on record.

So just how big is a 9.5? An earthquake magnitude video, created with an animation from Nathan Becker, an oceanographer at the Pacific Tsunami Warning Center, offers a simple way to understand the vast differences between one magnitude and the next.

Essentially, each successive magnitude is 33 times larger than the last. That means a magnitude-8.0 earthquake is 33 times stronger than a 7.0, and a magnitude-9.0 earthquake is 1,089 (33 x 33) times more powerful than a 7.0 ? the energy ramps up fast.

Magnitude measures
Although figuring out an earthquake's power requires lots of complicated math and lots of data, magnitude boils down to three basic factors: area, distance and friction.

"It's about the physical properties of the fault," said Paul Earle, a seismologist with the U.S. Geological Survey.

To get the magnitude, Earle told OurAmazingPlanet, you multiply the area of the fault that slipped ? how much real estate moved ? by the distance it moved and by the amount of friction on the fault.

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Romney campaign outlines 'day 1' of his presidency

(AP) ? Mitt Romney's campaign has released a new ad promoting "Day One" of a potential Romney presidency, describing which of President Barack Obama's policies the Republican will reverse first if he wins the White House.

The ad promises that in his first day in the Oval Office, Romney will announce deficit reductions, ending what the campaign calls "the Obama era of big government."

It says Romney will stand up to China on trade and demand "they play by the rules."

And the ad says Romney will repeal what it calls "job-killing regulations that are costing the economy billions."

Associated Press

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Commonly used pesticide turns honey bees into 'picky eaters'

Thursday, May 24, 2012

Biologists at UC San Diego have discovered that a small dose of a commonly used crop pesticide turns honey bees into "picky eaters" and affects their ability to recruit their nestmates to otherwise good sources of food.

The results of their experiments, detailed in this week's issue of the Journal of Experimental Biology, have implications for what pesticides should be applied to bee-pollinated crops and shed light on one of the main culprits suspected to be behind the recent declines in honey bee colonies.

Since 2006, beekeepers in North America and Europe have lost about one-third of their managed bee colonies each year due to "colony collapse disorder." While the exact cause is unknown, researchers believe pesticides have contributed to this decline. One group of crop pesticides, called "neonicotinoids," has received particular attention from beekeepers and researchers.

The UC San Diego biologists focused their study on a specific neonicotinoid known as "imidacloprid," which has been banned for use in certain crops in some European countries and is being increasingly scrutinized in the United States.

"In 2006, it was the sixth most commonly used pesticide in California and is sold for agricultural and home garden use," said James Nieh, a professor of biology at UC San Diego who headed the research project with graduate student Daren Eiri, the first author of the study. "It is known to affect bee learning and memory."

The two biologists found in their experiments that honey bees treated with a small, single dose of imidacloprid, comparable to what they would receive in nectar, became "picky eaters."

"In other words, the bees preferred to only feed on sweeter nectar and refused nectars of lower sweetness that they would normally feed on and that would have provided important sustenance for the colony," said Eiri. "In addition, bees typically recruit their nestmates to good food with waggle dances, and we discovered that the treated bees also danced less."

The two researchers point out that honey bees that prefer only very sweet foods can dramatically reduce the amount of resources brought back to the colony. Further reductions in their food stores can occur when bees no longer communicate to their kin the location of the food source.

"Exposure to amounts of pesticide formerly considered safe may negatively affect the health of honey bee colonies," said Nieh.

To test how the preference of sugary sources changed due to imidacloprid, the scientists individually harnessed the bees so only their heads could move. By stimulating the bees' antennae with sugar water, the researchers were able to determine at what concentrations the sugar water was rewarding enough to feed on. Using an ascending range of sugar water from 0 to 50 percent, the researchers touched the antennae of each bee to see if it extended its mouthparts. Bees that were treated with imidacloprid were less willing to feed on low concentrations of sugar water than those that were not treated.

The biologists also observed how the pesticide affected the bees' communication system. Bees communicate to each other the location of a food source by performing waggle dances. The number of waggle dances performed indicates the attractiveness of the reward and corresponds to the number of nestmates recruited to good food.

"Remarkably, bees that fed on the pesticide reduced the number of their waggle dances between fourfold and tenfold," said Eiri. "And in some cases, the affected bees stopped dancing completely."

The two scientists said their discoveries not only have implications for how pesticides are applied and used in bee-pollinated crops, but provide an additional chemical tool that can be used by other researchers studying the neural control of honey bee behavior. The study was funded by the North American Pollinator Protection Campaign and the National Science Foundation.

###

University of California - San Diego: http://www.ucsd.edu

Thanks to University of California - San Diego 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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Thursday, May 24, 2012

Staff bled $44M from heiress Clark, suit says

W.A. Clark Memorial Library

Huguette Clark with one of her dolls.

NEW YORK ? The nurses, doctors, hospital, attorney and accountant for the reclusive heiress Huguette Clark coerced or influenced her to give them more than $44 million in gifts, the executor of her estate claimed in a remarkable legal petition filed Tuesday in Manhattan. The executor asked the court to order all the money to be repaid.

The executor doesn't deny that Clark authorized nearly all of these gifts, relentlessly writing hundreds of checks in her own steady hand until her eyesight gave out at the age of?102.

The accusations were vigorously denied by Clark's attorney, whose representative said, "To suggest that these gifts were not from Mrs. Clark's generous heart is to denigrate the person who gave these gifts,?as well as the?recipients who cared for her with their love."

The most-favored object of Clark's generosity was her registered nurse, Hadassah Peri, an immigrant from the Philippines who had been randomly assigned in 1991 by a home healthcare agency. For 20 years Peri was the daytime private nurse, working 12-hour shifts, five or six days a week, taking care of Clark's health, her hygiene and her purchases of dolls at auctions. She was paid at an annual salary of $131,040. In addition, she and her family received $31 million in gifts, including the money to buy five homes, jewelry, dolls and a Stradivarius violin (though not Clark's best Stradivarius).


Another $6.3 million, including a $6 million painting by Manet, was given to Beth Israel Medical Center, which allowed Clark to live in the hospital although she was quite healthy for most of her last two decades.

Clark's two physicians and their families received gifts of $3.1 million.

The night nurse and her family got $1.1 million.

The accountant, $375,000.

The attorney, just $60,000 ? in addition to $1,850,000 given after the terror attacks of Sept. 11, 2001, for a security system for the attorney's daughter's Israeli community on the West Bank.

All of these amounts were gifts on top of salaries.

If the judge in Surrogate's Court agrees with the executor, all will?have to?be repaid.

The legal petition filed late Tuesday afternoon, available here from msnbc.com, is an attempt to claw back into the estate millions that the executor claims was bled away by undue influence or fraud. Two other petitions are expected to be filed Wednesday by the executor, to beat the deadline of a year since Clark's death. Those petitions are expected to accuse Clark's attorney and accountant of malpractice and breaches of fiduciary duty, possibly opening the door for some of the claims to be covered by professional liability insurance policies.

Should they have to give back the gifts?

Huguette (pronounced "hue-GET") Marcelle Clark, born in Paris in 1906, inherited her fortune from William A. Clark, a U.S. senator from Montana who was among the richest men of the Gilded Age, a copper miner, a banker, a builder of railroads, and founder of the city of Las Vegas.

His youngest daughter attracted the attention of msnbc.com in 2009 because of her vacant but well-manicured mansions and questions about the management of her money. She lived her last 20 years in spartan hospital rooms in New York City, dying in May 2011 just weeks before her 105th birthday. (The archive of Clark stories, photos and videos is at http://clark.msnbc.com/.)

'Virtually no visitors'
The executor's petition draws a picture of a woman isolated and controlled by others from 1991, when she was admitted to Doctors Hospital, until 2011, when she died at Beth Israel Medical Center, One of her former attorneys represented her for 20 years without meeting her face to face, instead talking to her on the phone and through a closed door.

"Mrs. Clark had virtually no visitors other than persons who were on her payroll," wrote Peter S. Schram, outside counsel for the Public Administrator of New York County. That official, Ethel J. Griffin, was appointed by the court as the temporary executor of the Clark estate after questions were raised about the actions of Clark's attorney and accountant, whom Clark had named as executors.

"Mrs. Clark," Schram wrote, "was completely dependent for her physical and emotional needs on a small group of individuals, who were her only contacts with the world outside of her hospital room."

The executor claims that this close circle of caregivers exerted undue influence and control over Clark, making her unable to make free and intelligent decisions. The executor claims that the attorney and accountant never fully informed Clark of the tax ramifications of her gift-giving. The executor also says that Clark suffered from various unspecified "physical and mental infirmities," and by 2009, at age 102, she was suffering from severe loss of sight and hearing along with episodes of "hallucinations and confusion."

Those claims will be countered by documents showing that Clark, while a recluse who saw few visitors, was never diagnosed with any mental illness, paid close attention to her financial affairs through the years, and rebuffed or ignored the advice of attorneys and accountants, even as they warned her that the gifts were making her cash poor, running up a tab of millions in unpaid gift taxes.

The petition's claims were rejected by Clark's attorney, Wallace Bock, whose own attorney issued a statement.

The filing by the executor "reflects a total disloyalty and lack of fiduciary care to Mrs. Clark," attorney John D. Dadakis of the firm of Holland & Knight said in a written statement to msnbc.com. "Our client, Wallace Bock, has honored Mrs. Clark's wishes during his career and handled her affairs with the utmost duty of loyalty to her. Mrs. Clark understood each and every gift she made, and they were made with the love that she had for those who were close to her.

"To suggest that these gifts were not from Mrs. Clark's generous heart is to denigrate the person who gave these gifts,?as well as the?recipients who cared for her with their love," Dadakis wrote. "All of the records reflect that Mrs. Clark actively enjoyed her generosity and fully understood what she was giving. Mr. Bock will vigorously defend the acts of Mrs. Clark and we fully expect that the record will prove that all the gifts of Mrs. Clark were made by her, being fully aware of what she was doing."

Hadassah Peri has not spoken publicly about Clark, but a press agent issued a statement on her behalf in June after she was named in the will: "I saw Madame Clark virtually every day for the 20 years. I was her private duty nurse but also her close friend. I knew her as a kind and generous person, with whom I shared many wonderful moments and whom I loved very much. I am profoundly sad at her passing, awed at the generosity she has shown me and my family, and eternally grateful. Just as Madame Clark demonstrated kindness toward others in her actions, so, too, will I and my family devote a substantial portion of this bequest toward making the world a better place for all people."

All the parties named in the court papers have until Aug. 8 to respond in Surrogate's Court.

The gifts claimed by the executor as not valid include the following:

  • $17,117,326.03 given by Clark to the nurse, Peri, in more than 200 personal checks written by Clark from 1991 to 2001.
  • $5 million paid to Peri, funded by a line of credit from JPMorgan because Clark had insufficient liquid assets. The executor acknowledges that the attorney, Bock, had a signed authorization from Clark for this payment and nearly all the others listed here, and by 2009 she had signed over to him a document called a durable power of attorney, giving him authority over certain financial affairs.
  • $3,883,685.78 given to Peri to purchase five homes: a co-op apartment on the Upper West Side of Manhattan, two condos on the Upper East Side, a house in the borough of Brooklyn, and a vacation home in Ocean, N.J., as disclosed by msnbc.com in 2010.
  • $1,935,200 in other tangible gifts to Peri, including 84 pieces of jewelry worth $667,300, a doll worth $64,400; a Stradivarius violin worth $1.2 million (not Clark's $6 million Strad, which was sold); and three harpsichords worth $3,500.
  • $60,000 in a check written by Clark's attorney in 2009 to Peri.
  • $3.4 million to Peri's family, including $1,503,813 to her husband, Daniel Peri, $706,550 to her son David, $628,250 to her son Abraham, and $632,450 to her daughter, Guela.
  • $685,000 given to Clark's licensed practical nurse on the night shift, Geraldine Coffey, who also worked from 1991 to 2011 at an annual salary of $131,040.
  • $358,327 to help Coffey buy two condo apartments on the Upper East Side.
  • $85,554 for tuition of Coffey's children.
  • $30,000 given to Coffey by the attorney.
  • $10,000 given to Erlinda Ysit, a licensed practical nurse for Clark for seven years.
  • $6 million Manet painting sold to benefit Beth Israel Medical Center, which allowed Clark to live in the hospital, even though for most of her two-decade stay "there was no medical need." This gift, and $295,000 in other gifts, was made on top of the $300,000 to $400,000 a year she paid to the hospital to live there. "At no time did Beth Israel, its staff, or any other physician or expert conduct a neurological examination or psychological examination of Mrs. Clark or otherwise ensure that she possessed the capacity required to make a gift to Beth Israel," Schram wrote.
  • $500,000 given to the Corcoran Gallery of Art in Washington, D.C. The executor did not yet ask for this money to be returned, but asked for the court to order an inquiry.
  • $1,168,000 given to Dr. Jack Rudick, one of her physicians, and his wife, Irene Rudick.
  • $1 million lent by Clark to Dr. Rudick, on which he made no payments, and which she forgave.
  • $667,951 given to Dr. Henry Singman, her primary treating physician for 20 years.
  • $33,857 paid by attorney Bock to cover Singman's professional liability insurance premiums. (Not authorized in writing by Clark, the executor said.)
  • $200,000 paid to Singman's family.
  • $1,850,000 paid to an Israeli community on the West Bank where the family of attorney Bock lives. Documents show that Bock asked Clark in 2000 if she wanted to contribute to a security system. The total amount to be raised was $1,850,000, and Clark wrote in that amount, agreeing to pay the entire cost. Only five days earlier, according to the court records, Bock and accountant Irving Kamsler had written letters to Clark, warning that her gifts were out of hand, that she would owe $12.5 million in gift taxes, and that she might have to sell assets to raise cash. The executor accuses Bock of failing to remind her, when he solicited the gift benefitting his family, of this earlier warning about her financial situation, as well as failing to advise her of the right to seek independent counsel, nor arranging a medical evaluation to confirm that she had sufficient capacity to make the gift.
  • A $60,000 check written by Bock to himself in December 2009. Bock testified at his deposition in March that this check was authorized by a letter signed by Clark a month earlier. That letter was prepared by Bock, who gave $48,000 of the gift to his law firm, in line with his partnership agreement. The executor wants that money back as well, claiming that Clark never intended to make any gift to Collier, Halpern, Newberg, Nolletti & Bock.
  • $375,000 in checks written by Clark to Kamsler, a felon and registered sex offender, from 2000 to 2008, on top of his monthly salary, and a $60,000 check written by Bock to Kamsler in 2009, authorized by a letter from Clark. (Bock at the same time wrote checks to nurses, doctors and others, mostly in line with payments that she had made previously.)

Other gifts are not being challenged by the executor. For example, Clark gave $10 million in 2000 to her friend Suzanne Pierre, now deceased, but Pierre might not be considered to have a confidential or fiduciary relationship with Clark.

Criminal investigation
Originally the executors of the Clark estate were Clark's attorney and accountant, but the court revoked the accountant's authority, and suspended the attorney from his role, leaving only the public official to manage the estate. The judge, Surrogate Kristin Booth Glen, acted after the public administrator's attorney revealed that Kamsler failed to file gift tax returns from 1997 through 2003, and falsely claimed on later returns that all taxes had been paid, leaving Clark owing millions in gift taxes plus interest and possible penalties. (See the earlier story.)

Though a criminal investigation was launched in August 2010 into the handling of Clark's finances by Bock and Kamsler, no one has been charged. Both men have maintained that they did nothing more than carry out the wishes of a woman who wanted to protect her privacy. The investigation continues by the Elder Abuse Unit of the New York County District Attorney's Office. The investigation was prompted in part by reports at msnbc.com about the sale of property owned by Clark, including a Stradivarius violin and a Renoir painting.

To direct her $400 million fortune, at age 98 the heiress signed two wills.

The first will favored the relatives from her father's first marriage. They were not named: The will left the money to the "intestate distributees," legal language for the people who would inherit her money if she died without a will. (Clark had been married only briefly, and had no children.) And the will gave $5 million to the nurse, Peri.

Just six weeks passed before she signed a new will, cutting out the family, which claims that this will was the product of fraud. The new document? leaves the largest share of her money to a museum for her art collection in her oceanfront estate in Santa Barbara, Calif. Millions more (an estimated $27 million after taxes) and a doll collection will go to Peri, and lesser amounts to a godchild, the hospital, and doctor, as well as $500,000 each to the attorney and accountant. (See the earlier story and read the documents: A twist: Heiress Huguette Clark signed two wills.)

The $400 million heavyweight battle over the wills is about to begin, with the $44 million in gifts providing the preliminary bout.

Clark's jewelry collection sold in April for $18.3 million. That money will be held by the estate during the contest over the wills. Her three apartments overlooking Central Park and Fifth Avenue, a total of 15,000 square feet, are on the market for $55 million; one of the three has found a buyer. Her country estate in New Canaan, Conn., is for sale for $17 million. Her $100 million estate in Santa Barbara, which the Clarks had not visited for half a century, is being carefully maintained, awaiting the court's decision on the will's plan for an art museum.

A twist: If the executor is successful in recovering for the estate millions from the nurse, doctor, hospital, attorney and accountant, and if the second of Clark's written wills is the one to be upheld, those same millions can then be paid out to the beneficiaries, including the nurse, doctor, hospital, attorney and accountant.

The full story
More on the Huguette Clark mystery is at http://clark.msnbc.com/.

Do you have information on the Clark family?
Reporter Bill Dedman is writing a nonfiction book about the Clark family. If you have documents or information, you can reach him at bill.dedman@msnbc.com.

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