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Sun 1 Apr 2007 03:55 PM

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Research matters

News from the Harvard Medical School research community.


Technology offers practical method of obtaining tumors' ‘genetic profile' to guide treatment, scientists report

A study led by researchers at Dana-Farber Cancer Institute and Broad Institute of the Massachusetts Institute of Technology and Harvard University provides the first demonstration of a practical method of screening tumors for cancer-related gene abnormalities that might be treated with "targeted" drugs.

The findings, published online on the Nature Genetics Web site, may help relieve a bottleneck between scientists' expanding knowledge of the genetic mutations associated with cancer and the still nascent ability of doctors to use that knowledge to benefit patients. The results constitute an important step toward the era of "personalized medicine," in which cancer therapy will be guided by the particular set of genetic mutations within each patient's tumor, the authors suggest.

"It's universally recognized that cancer is a disease of the genome, of mutations within genes responsible for cell growth and survival, and a great deal of effort has gone into finding those mutations, to the point where several hundred to a thousand are now known," said the study's senior author, Levi Garraway, MD, PhD, of Dana-Farber and the Broad Institute. "The challenge has been how to determine which of them are involved in each of the hundreds of kinds of cancer that occur in humans - and to develop accurate, affordable methods of detecting key mutations in tumor samples. This study suggests that such a method is feasible on a large scale."

The authors took advantage of a scientific serendipity to devise a simple test to detect important cancer mutations. Mutations in oncogenes (genes linked to cancer) do not occur randomly; rather, they seem to arise most frequently in certain regions of the oncogenes. As a result, researchers didn't necessarily have to scan the entire length of each gene, but could focus instead on the sections most likely to harbor mutations.

They performed these screenings with a technology known as high-throughput genotyping, a fast, relatively inexpensive way of profiling gene mutations within cells. It involves extracting DNA from a tumor sample, copying this material thousands of times, depositing segments of it in tiny "wells" on a small plate, and mixing in reagents that reveal whether each segment carries a specific mutation. Automated equipment then reads the plates to determine which mutations are present in each sample. In the study, the researchers scanned 1,000 human tumor samples for 238 known mutations in 17 specific oncogenes. (Those 17 were chosen because they are mostly "classic, well-known" contributors to cancer, Garraway stated.) They found at least one mutation in 298 of the samples, or 30 percent of the entire group, which was in keeping with the rates reported in scientific literature for the types of cancer examined.

"Mutations were identified in the percentages we expected," Garraway said, "which indicates this technique is on-target for the mutations we were interested in. Overall, the technique worked very well: we were able to obtain mutation profiles that were accurate, sensitive, and cost-effective." The cost of processing each sample was between $50 and $100, although the figure would probably be somewhat higher if the technology were used in cancer clinics to test for large numbers of oncogene mutations.

The scans produced some surprises as well. Mutations were found in several types of tumors where they had not been previously recognized. Researchers also discovered an unexpectedly large number of instances where the same set of mutations co-occurred within tumor cells, suggesting that oncogenes often work in partnership. As promising as high-throughput genotyping is for cancer treatment and research, its capacity will need to be expanded so it can handle larger numbers of mutations. The next step, Garraway explained, would be to work with clinical investigators to explore whether use of the technology is feasible in a clinical setting and whether it actually improves doctors ability to classify and treat individual tumors.

"We've shown the practical potential of this technique," observed Garraway, who is also an instructor in medicine at Harvard Medical School. "It is a step toward the day when cancer patients will routinely have their tumors scanned for specific mutations, and treatment will be based on the cancer's particular genetic profile."


Study recommends greater attention to spiritual needs of advanced cancer patients

People with advanced cancer felt they received little or no spiritual support from religious communities and the medical system, according to a new survey. However, those who did receive such support reported a better quality of life.

The study, led by researchers at Dana-Farber Cancer Institute and Harvard Medical School and published in the Feb. 10 issue of the Journal of Clinical Oncology, drew on data from the Coping with Cancer study, a multi-institutional investigation of advanced cancer patients and their main caregivers. Of 230 patients surveyed, the vast majority - 88 percent - considered religion to be at least somewhat important. But nearly half said their spiritual needs were largely or entirely unmet by a religious community, and 72 percent felt those needs were similarly unaddressed by the medical system.

The findings also indicated that greater spiritual support from religious organizations and medical service providers was strongly linked to better quality of life for patients, even after other factors were taken into account. Intriguingly, patients who considered themselves religious were more likely to want all possible measures taken to extend their lives.

"This study examined how much spiritual support advanced cancer patients received from religious organizations, as well as hospital-based doctors, nurses, and chaplains," said the study's lead author, Tracy Balboni, MD, a senior resident in the Harvard Radiation Oncology Program. "Our findings suggest that such support can help improve patients' quality of life at the end of life."

The infrequent recognition of the spiritual components of illness on the part of many hospitals may reflect a debate over the medical system's proper role in this area, the authors stated. Numerous barriers deter physicians from helping procure spiritual support services for patients at the end of life. Among these is a separation of the realms of medical science and religion that exists within many hospital cultures. Another is concern that physicians might try to impose a specific set of religious beliefs on patients.

Given religious faith's ability to help people cope with illness, physicians' reluctance to inquire about spiritual issues may deprive patients of an important force for healing and wholeness, the authors asserted. This does not mean that physicians should be spiritual counselors, "but they can participate appropriately in spiritual care by recognizing spiritual needs and advocating for attention to them," the authors wrote.

They advocate making a "spiritual history" - an account of a patient's religious upbringing and evolution - a routine part of patient care. "It's a way of saying to patients that we acknowledge their illness may have a spiritual dimension for them," Balboni stated. "It may make it easier for patients to bring up spiritual issues later in the course of their illness and may cue doctors and nurses into special concerns that may arise."

The study also tracked how patients' religious observances changed as a result of disease. In general, there was a shift from public to more private forms of spirituality, possibly because people with advanced illness are less able to attend services in a house of worship.

The finding that highly religious patients were the most likely to desire life-extending measures came as something of a surprise, said Balboni. Such individuals might be expected to submit to the natural unfolding of a divine plan, rather than want heroic measures. But, the authors suggested, "Religious individuals may feel that because their illness is in divine hands, there is always hope for a miraculous intervention. Religious individuals also may place a value on life that supersedes potential harms of aggressive attempts to sustain life."


New Risk Assessment Tool More Accurately Predicts Women's Cardiovascular Risk

Using data collected from over 24,000 initially healthy American women, researchers from Brigham and Women's Hospital (BWH) have devised a new Web-based formula called the Reynolds Risk Score, that for the first time more accurately predicts risk of heart attack or stroke among women. In addition to usual risk factors like cholesterol, blood pressure, and smoking, the new Reynolds Risk Score adds information on two new factors, family history of heart attack prior to age 60 and blood level of C-reactive protein (CRP), a measure of artery inflammation. Using the new risk assessment tool, the researchers found that nearly 50 percent of women in the study who were estimated to be at "intermediate risk" for heart attack or stroke based on current guidelines were in fact at significantly higher or lower risk levels.

For the 10 million American women currently classified at "intermediate risk," use of the Reynolds Risk Score provides doctors and their patients a much clearer picture of who should or should not receive drug therapies such as statins or aspirin, and highlights the critical impact that can be made on heart disease prevention by diet, exercise, and smoking cessation. The findings appear in the February 14, 2007 issue of the Journal of the American Medical Association and are available in a user-friendly format for both physicians and their patients at


"Women as well as men suffer premature heart attacks and stroke, but our standard methods for risk prediction have not been as effective in preventing disease among women," said cardiologist Paul Ridker, director of the Center for Cardiovascular Disease Prevention at BWH and lead author of the study. "One of the problems cardiologists and preventive physicians face is that we often underestimate women's risk for heart disease and stroke. With the new Reynolds Risk Score, we found many women to be at substantially higher risk than anticipated. That's an enormous opportunity for prevention because if physicians can accurately tell a women in her 30's or 40's about true lifetime risk, they've got a much better chance of motivating her to stop smoking, get regular exercise, reduce her blood pressure, and where indicated, start a statin or aspirin regimen."

The Reynolds Risk Score was derived from a study of 24,558 initially healthy women enrolled in the Women's Health Study in 1992 who were followed more than a decade for the occurrence of heart attack, stroke, and other major cardiovascular events. The researchers first evaluated 35 different risk factors to come up with the best possible prediction tool for clinical use and then directly compared the new prediction tool to traditional approaches currently in use. Two new risk factors proved crucial to understanding cardiovascular risk in these women, each representing an important advance in the biology of heart disease. The first was a simple blood test for C-reactive protein (CRP) reflecting inflammation in the artery wall. The second was whether or not a patient's parents had suffered a heart attack before age 60, a measure of genetic risk. "When information on CRP and family history were incorporated into our prediction models, they improved the fit and predicted risk more accurately" said Nancy Cook, the study statistician. "For some women, changes were striking enough to potentially affect treatment decisions or alter behavior" she continued.

"Using the Reynolds Risk Score, we found that many women were correctly re-classified at high risk, while others had their level of risk reduced" Ridker explained. "Correctly classifying risk is crucial for those of us trying to get the right preventive drug to the right patient and to do so as cost-effectively as possible. Preventing heart disease among high-risk women while avoiding drug toxicity in low risk women is a win-win situation for everyone."

Women and their physicians can freely access the Reynolds Risk Score at www.ReynoldsRiskScore.org. In addition to providing each woman with an estimate of her risk of suffering a future heart attack, stroke, or other major cardiovascular event over the next 10 years, the Reynolds Risk Score website simultaneously shows each woman what her risk would be if she improved each of her individual risk factors to optimal levels. For young women, risk may appear low over the next 10-years, yet can be very high over a lifetime. The Reynolds Risk Score also allows each woman to calculate risk as she ages, demonstrating the impact that risk reduction early in life can have on future events. The Reynolds Risk Score website provides useful links to prevention programs for women from the National Heart Lung and Blood Institute, the American Heart Association, and the American College of Cardiology.


Study finds how common anesthetic may induce cell death and generation of Alzheimer's-associated protein

A new study has found how one of the most commonly used anesthetics may produce Alzheimer's-like changes in the brain. Previous studies have shown that applying the anesthetic isoflurane to cultured neural cells can lead to generation of amyloid-beta protein - the key component of senile plaques seen in the brains of Alzheimer's patients - and to the cell-death process known as apoptosis. In the Feb. 7 Journal of Neuroscience, researchers from Massachusetts General Hospital (MGH) and colleagues describe how isoflurane may set off a process in which A-beta generation and apoptosis interact with and magnify each other. Since this work was done in cell cultures, it is unknown whether the findings reflect a possible effect of the anesthetic on human brains.

"Our studies have shown that isoflurane may induce a vicious cycle of apoptosis, amyloid-beta generation, and further rounds of apoptosis leading to cell death," says Zhongcong Xie, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), the study's lead author. "If future studies support these findings, they suggest that caution be used in choosing this anesthetic for elderly patients, who already are at increased risk for Alzheimer's and for postoperative cognitive dysfunction." Xie is also associated with the MGH Department of Anesthesia and Critical Care.

Alzheimer's disease is characterized by plaques within the brain of amyloid-beta protein (A-beta), which is toxic to brain cells. A-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes - beta-secretase, also known as BACE, and gamma-secretase - to release the A-beta fragment. Normal processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.

Some studies have indicated that general anesthesia may increase the risk of developing Alzheimer's disease. It also is known that a small but significant number of surgical patients experience a form of dementia in the postoperative period, but there is insufficient evidence of a direct connection between anesthesia and the risk of dementia. Previous articles - including a recent report from the same research team - have shown that isoflurane increases both A-beta generation and apoptosis in several types of cultured cells. The current study was designed to investigate the relationship between isoflurane-induced apoptosis and A-beta generation.

In a series of experiments, the researchers first found that applying isoflurane to cultured neural cells increased the activation of the enzyme caspase - a key player in a pathway leading to apoptosis - with no change in A-beta generation or APP processing. When they applied isoflurane to neural cells that express APP and had been treated with a caspase inhibitor, the expected changes in APP processing and A-beta generation were significantly reduced, indicating that caspase activation is essential to the pathway leading to A-beta generation and aggregation.

The researchers also found that isoflurane appears to raise levels of the A-beta-releasing enzymes BACE and gamma secretase and that generation of A-beta plaques further increases isoflurane-induced caspase activation. In addition, adding A-beta to neuronal cells that do not express APP also increased caspase activation in response to isoflurane. Overall, the study's results define molecular pathways by which isoflurane induces deposition of A-beta, both directly and via caspase activation, and by which A-beta deposits lead to further caspase activation and apoptosis.

"Even though our findings and those from other studies suggest that isoflurane may affect Alzheimer's pathogenesis, these experiments were performed in cultured cells only," says Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging Research Unit and senior author of the current paper. "We need to conduct in vivo studies before we can determine whether these results might be relevant to the development of delirium or Alzheimer's disease in human patients." Tanzi is a professor of Neurology at Harvard Medical School, where Xie is an assistant professor of Anesthesia. The researchers also plan to investigate whether other anesthetic agents may produce the same results seen with isoflurane, which is the only anesthetic tested in previous studies.

Infectious disease

Discovery could lead to better control of hemorrhagic fever viruses

Researchers report discovering the receptor through which a group of life-threatening hemorrhagic fever viruses enter and attack the body's cells, and show that infection can be inhibited by blocking this receptor. The findings, published online by the journal Nature on February 7, give a clue to the high lethality of New World arenaviruses, suggest a way of reducing the severity of infection, and point the way toward a sorely needed treatment strategy.

The four viruses, known as the Machupo, Guanarito, Junin and Sabia viruses, cause Bolivian, Venezuelan, Argentine and Brazilian hemorrhagic fever, respectively, with mortality rates of about 30 percent. No vaccine is available, though a weakened form of Junin virus has been given to Argentinean farmers with some success. In addition to causing occasional disease outbreaks, mostly in poor, rural areas of South America, the viruses are of U.S. government interest because of their potential as bioterrorism agents.

Because of TfR1's essential function in transporting iron into cells, it is found on the surface of virtually every cell of the body. It is abundant on endothelial cells, which line blood vessels, a fact that may help account for the bleeding and organ damage caused by the viruses. TfR1 is also especially abundant on activated immune cells -- the very cells that mobilise to fight the viruses -- making them especially vulnerable to infection. "This may help explain why mortality is so high," says Hyeryun Choe, the study's senior author.

Choe now hopes to translate these findings into treatments to contain natural or intentional outbreaks of New World hemorrhagic fever. Serendipitously, several anti-TfR1 antibodies have already been developed as anticancer therapeutics (cancer cells are also high in TfR1), and some have already been through clinical trials. Choe's lab will test these antibodies, hoping to find one that inhibits virus entry without compromising TfR1's essential function in cellular iron uptake.

"If some of these antibodies work, they could be used clinically fairly soon," Choe says.

Coincidentally, Stephen Harrison, PhD, a structural biologist and Howard Hughes Medical Institute investigator at Children's, had crystallized TfR1 and determined its 3-dimensional structure in 1999. Knowledge of TfR1's structure will speed up the Choe lab's efforts to pinpoint the parts of the molecule that are exploited by New World hemorrhagic fever viruses, which is necessary for the development of targeted antiviral drugs that block those parts, but not the parts involved in iron uptake.

The findings of Choe and colleagues also suggest that iron supplements may reduce the severity of New World virus infections. Past studies have shown that when the iron level in the body is low, the number of transferrin receptors in tissues increases. Consistent with these findings, Choe's team found that New World arenaviruses infect cells more efficiently when iron levels are low, and that adding iron to cultured cells makes them less susceptible to infection. Choe notes that New World hemorrhagic fever outbreaks mostly occur in poor rural areas, where people are often deficient in micronutrients, including iron, possibly predisposing them to more severe infection when exposed to the rodents that carry the viruses. Choe's lab is now trying to find the cellular receptor for other viruses that cause hemorrhagic fever in humans. In 2003, Choe's lab collaborated with Farzan's lab to identify angiotensin converting enzyme 2 (ACE2) as the receptor for the SARS virus.

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