Research in brief

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Major differences in protocols used to determine brain death

A survey of some of the top hospitals in the country has found that the protocols followed to determine brain death differ significantly among those institutions. In the Jan. 22 issue of the journal Neurology, a team of researchers reports finding that brain death protocols at hospitals cited as top neurology and neurosurgery centers by U.S. News and World Report often do not follow the standards established by the American Academy of Neurology (AAN). The paper has been released online.

The concept of brain death — irreversible loss of function in the entire brain — was first established in the 1960s, and in 1981 a presidential commission confirmed that brain death was the legal equivalent of more traditional standards, such as the cessation of heart and lung function. The Uniform Determination of Death Act, which has been ratified by most states, specifies that guidelines for determining death “be made in accordance with accepted medical standards,” and in 1995 the AAN published practice guidelines based on an evidence-based review of the literature and best practices.

“We were surprised to find such significant differences among … hospitals in terms of their specified guidelines for brain-death determination,” said study leade4r David Greer of the Massachusetts General Hospital (MGH) Neurology Service. “In reviewing the protocols, we would have anticipated more consistency with the American Academy of Neurology practice parameters.”

Harvard researchers achieve stem cell milestone

Harvard researchers have successfully turned back the clock on human skin cells, causing them to revert to an embryonic stem-cell-like state from which they can become any cell in the body.

The work, published online on Dec. 23 by the journal Nature, is an independent report similar to the stem cell breakthrough announced in November simultaneously by scientists in Japan and at the University of Wisconsin. That work, too, induced skin cells to revert to cells very similar to embryonic stem cells, called “induced pluripotent stem cells” (iPS).

Pluripotency, or the ability to develop into any other cell in the body, is a much-desired trait of embryonic stem cells, which are extracted from several-day-old embryos and then cultured in the lab.

George Daley, associate professor of biological chemistry and molecular pharmacology and associate professor of pediatrics, noted that “despite success in generating iPS cells, we are not abandoning our efforts to derive new human stem cell lines by nuclear transfer.”

The collaborative work was led by Daley and conducted by researchers at the Harvard Stem Cell Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, Harvard Medical School, and Brigham and Women’s Hospital.

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Consortium links chromosome abnormality to autism disorders

Researchers have fitted another piece into the complex genetic puzzle that is autism, finding DNA deletions and duplications on a specific chromosome that they say explains 1 to 2 percent of the 1.5 million cases of autism and related disorders in the United States today.

The genetic changes were discovered in DNA scans of more than 3,000 people, both with and without autism spectrum disorder, a category of developmental disability that includes autism disorder, Asperger’s syndrome, and a broad category called “pervasive developmental disorder not otherwise specified.”

Autism spectrum disorders, which typically begin before age 3, are characterized by impaired abilities to communicate and interact socially, as well as unusual behaviors and interests. Those with the disorder can range in mental ability from severely challenged to gifted, according to the Centers for Disease Control and Prevention (CDC). CDC statistics indicate that autism spectrum disorders affect roughly one in 150 children under the age of 3.

The work, published online Jan. 9 by the New England Journal of Medicine, was conducted by the Autism Consortium, a group of 14 Boston-area universities and medical centers that, together with families, researchers, and clinicians, aims to accelerate research and advance care for those with autism spectrum disorders. The consortium includes several Harvard-affiliated institutions, including Massachusetts General Hospital, Children’s Hospital Boston, Harvard Medical School, Beth Israel Deaconness Medical Center, the Cambridge Health Alliance, McLean Hospital, and the Broad Institute of MIT and Harvard.

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Blocking HIV infection

By coaxing the HIV-1 protein to reveal a hidden portion of its protein coat, scientists at Dana-Farber Cancer Institute and Harvard Medical School have provided a newly detailed picture of how protective, or so-called broadly neutralizing, antibodies block HIV-1 infection.

In a study in the January issue of Immunity, the investigators report that the discovery may help researchers overcome two of the main stumbling blocks that have arisen on the road to an HIV vaccine: the fact that the virus’s envelope protein — the target for any antibody-based vaccine — varies greatly from one viral strain to the next and is strewn with sugar molecules, which make it difficult for the immune system to select the virus for destruction. The paper was posted on the journal’s Web site on Jan. 10 in advance of the print publication.

“Not surprisingly, only a handful of broadly neutralizing antibodies (BNAbs) have been identified, and they are rarely elicited during natural human infection,” says the study’s senior author, Ellis Reinherz, who is the faculty director of the Cancer Vaccine Center at Dana-Farber and a professor of medicine at Harvard Medical School.

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Oral osteoporosis meds appear to reduce the risk of jaw degradation

Athanasios Zavras began receiving messages from distraught patients in 2005 after case reports linked oral osteoporosis meds to bone death in the jaw. A number of doctors and dentists advised women and men taking these drugs to postpone dental work, fearing that procedures such as tooth extractions would exacerbate the problem. That’s when Zavras, an associate professor in the Harvard School of Dental Medicine, decided to take a closer look at the purported link.

After analyzing the medical claims of 714,217 people, Zavras, along with Vassiliki Cartsos at the Tufts University School of Dental Medicine and Shao Zhu of Ingenix—i3 Drug Safety (the company that provided medical claims data), have concluded that oral osteoporosis meds seem to reduce the risk of jaw degradation. Clinical studies are needed to replicate and clarify the results, which appear in the January issue of the Journal of the American Dental Association.

“This is good news for the roughly 3 million Americans who take Fosamax, Actonel, Boniva, or similar osteoporosis meds orally,” says Zavras, who is also director of dental public health in the Department of Oral Health Policy and Epidemiology.

The drugs, which are called bisphosphonates, inhibit cells that break down bone tissue, and a growing number of Americans with osteoporosis or low bone mass ingest them orally to halt bone loss. In fact, they have been used for this purpose since 1977. Some cancer patients also rely on bisphosphonates to prevent bone fragility and metastasis, but these individuals typically receive potent intravenous versions of the drugs.

Six new genetic variants linked to heart-disease risk factor

Using new techniques for rapidly scanning the human genome, researchers have associated levels of cholesterol and triglycerides, two fats in the blood, to 18 genetic variants, six of which represent new DNA regions never before associated with the traits. The findings, which appeared in the Jan. 13 advance online issue of Nature Genetics, help explain some of the variability in cholesterol and triglyceride levels that arises from genes. With the potential to help predict a patient’s genetic risk of heart disease, the six new loci may point to novel aspects of cholesterol metabolism and could also spur new cholesterol-lowering drugs.

“By uncovering the genetic determinants of cholesterol levels and, in turn, heart-disease risk, we may be able to identify high-risk patients who can benefit from early interventions, in addition to expanding our knowledge of cholesterol biology and opening doors to new treatments,” said first author Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and a genetics researcher in the Program in Medical and Population Genetics at the Broad Institute of Harvard and MIT.

Gene variation may elevate risk of liver tumor in some patients

A particular gene variation appears to significantly increase the risk that individuals with cirrhosis of the liver will go on to develop hepatocellular carcinoma (HCC), a liver tumor that is the third leading cause of cancer death. In the Jan. 2 Journal of the American Medical Association, researchers from Massachusetts General Hospital (MGH) Cancer Center and colleagues in France describe finding that a single alteration in the epidermal growth factor (EFG) gene may greatly increase the risk of developing HCC.

“If these results are confirmed, this EGF variation could be used to determine which cirrhotic patients should be screened more intensively for tumor development,” said Kenneth Tanabe, chief of surgical oncology at the MGH Cancer Center and the study’s lead author. “In addition, the molecular pathway controlled by EGF and its receptor, EGFR — which is known to be important in several types of cancer — appears to be an excellent target for chemoprevention studies. This is a deadly cancer and so progress in prevention and early detection is critically important.”

HCC is the sixth most common solid tumor worldwide and most commonly develops in individuals with cirrhosis, which may be caused by infection with the hepatitis B or C viruses. There are currently no effective treatments for most HCC patients, so there is considerable interest in strategies that may prevent development of the tumor.

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Cancer stem cells can be targeted for destruction

It’s increasingly believed among scientists that nearly every cancer contains small populations of highly dangerous cells — cancer stem cells — that can initiate a cancer, drive its progression, and create endless copies of themselves. On the theory that targeting these cells might be an effective therapeutic strategy, researchers around the world have begun isolating stem cells from various kinds of cancers. Now, for the first time, researchers at Children’s Hospital Boston and Brigham and Women’s Hospital (BWH) have found a strategy that selectively targets cancer stem cells for destruction, successfully halting one of the deadliest cancers — melanoma — in mice.

The findings, reported in a cover article in the Jan. 17 issue of Nature, also add credence to the hypothesis that stem cells drive cancer progression.

Melanoma is a highly aggressive and difficult-to-treat cancer because it is resistant to virtually all drugs. In 2007, an estimated 59,940 cases were diagnosed in the United States with about 8,110 deaths, according to the National Cancer Institute, and the percentage of people developing melanoma in the United States has more than doubled in the past 30 years.

Markus Frank, a researcher in the Transplantation Research Center of Children’s and BWH who conducted the study in collaboration with George Murphy, chief of dermatopathology at BWH, said, “This study lays the groundwork for a possible treatment, showing that targeting stem cells may be a viable strategy in cancer.”

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