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Microbiology: Uncovering the Secrets of Bacterial Division Leadership: New HSPH Dean Sketches Vision of Public Health Genetics: Mutant Genes May Cooperate To Override Errors Research Briefs: Radial Scars Join List of Breast Cancer Risk Factors Gene Involved in Heart Chamber Specification Looking Beyond Pressure Problems in Glaucoma Designer Drug Safe and Effective Against Rheumatoid Arthritis Knockout Mice Bridge Divide in Diabetes Research Seed Grants: Seed Grants Nurture Collaborative Research Bulletin: Dean's Awards Honor Women Faculty Support In Memoriam: John Penney Countway Rare Books Closed To Public HMI Contracts with One of Brazil's Largest Medical Groups Call for Services Award Nominees Division of Medical Ethics to Award Fellowship, Prize Forum: HMS Develops Multilingual Phrase Books Front page: Go back to the Focus front page Current Issue: Go back to the first page of the current Focus

February 19, 1999 RESEARCH BRIEFS Radial Scars Join List of Breast Cancer Risk Factors Pathologists scrutinizing a woman's breast biopsies for signs of malignancy should add a new feature to their mental list of histological trouble spots. It is called the radial scar. This conclusion emerges from a study by Stuart Schnitt, HMS associate professor of pathology at Beth Israel Deaconess Medical Center, and four other Harvard scientists. In the February 11 New England Journal of Medicine, the researchers report that radial scars constitute an independent histological risk factor for breast cancer. These scars are abnormalities in which breast ducts and lobules exhibiting precancerous changes radiate from a central fibrous core. Pathologists commonly see radial scars in biopsies taken from women with benign breast disease, and have noted their morphological similarity to cancer as early as 1928. Some scientists suspect the scars may represent an early phase of some types of breast cancer, yet studies trying to link radial scars to an increased risk of breast cancer were small and yielded conflicting results. Schnitt and his colleagues addressed this question by inspecting breast biopsy slides from 1,396 participants of the Nurses' Health Study, 255 of whom later developed breast cancer. They found that, overall, the presence of a radial scar almost doubled a woman's risk for developing breast cancer. The risk varied depending on which histological category of benign breast disease a woman fell into. The scientists also found that the risk increased with the number and size of the radial scars found in benign lesions. The researchers recommend that pathologists report the presence of radial scars, and that affected women undergo the same clinical and mammographic follow-up as recommended for women with a moderately increased risk. In this study, the researchers evaluated mostly scars about one-eighth inch long. Yet larger scars routinely show up in mammograms, raising the question whether these also carry the same predictive power. Gene Involved in Heart Chamber Specification How an organ develops and acquires its characteristic shape is a fundamental question in biology. Now a team of HMS researchers has gotten to the heart of the problem--literally, that is. They identified a gene called Irx-4 that will open new doors to understanding how the heart chambers form. Their findings appear in the Feb.19 issue of Science. Scientists knew that some genes were expressed either in the future ventricles or the future atria of the developing heart, but no one really knew how these genes remained confined to their respective chambers or whether their restricted expression reflected a role in setting up the heart chambers.With Irx4, researchers will now be able to ask these questions. As shown by Connie Cepko, HMS professor of genetics, and colleagues, Irx4--which is specifically expressed in the ventricle--can induce the expression of a ventricle-specific gene, ventricle myosin heavy chain-1 (VMHC1), and prevent the expression of an atrium-specific gene, atrial myosin heavy chain-1 (AMHC1). These findings suggest that Irx4 works to maintain the boundaries between the heart chambers. Looking Beyond Pressure Problems in Glaucoma Here's an observation that has passed the test of time. In 1622, the British oculist Richard Banister wrote, "if one feele ... by rubbing upon the eie-lids that the eye be growne more solid and hard than naturally it should be ... the humour growne to any solid or hard substance, it is not possible to be cured." To this day, most ophthalmologists consider increased pressure inside the eye a defining factor in glaucoma, and acknowledge that standard therapy geared toward lowering that pressure is insufficient. Normal optic nerve with healthy neural tissue (left) and glaucomatous optic nerve (right). A new approach may finally relegate Banister's statement to history, Stuart Lipton hopes. Lipton, HMS associate professor of surgery (neuroscience) at Brigham and Women's Hospital, works on amending standard therapy with neuroprotective agents. In the January 27 Journal of the American Medical Association, he discusses recent work on programmed cell death of the retinal ganglion cells in glaucoma patients, suggesting it provides a new tack for experimental treatments. For example, researchers led by Lipton showed that glutamate--an amino acid known to promote apoptosis by overstimulating so-called NMDA receptors--is elevated to toxic levels in the vitreous humor of glaucoma patients. Glaucoma is a leading cause of blindness worldwide. Lipton suggests that the disease might be treatable with the experimental drug memantine, which blocks excessive NMDA receptor activity while sparing physiological receptor activity. This selectivity gives memantine an edge over other glutamate antagonists that have failed in clinical trials, Lipton says. Currently in advanced clinical studies for other neurodegenerative diseases, memantine will soon be tested in a large trial of glaucoma patients aimed at preserving vision in people who fail standard therapy. Designer Drug Safe and Effective Against Rheumatoid Arthritis Handing physicians a new tool to fight rheumatoid arthritis, researchers led by Michael Weinblatt, HMS professor of medicine at Brigham and Women's Hospital, found that a genetically engineered drug called etanercept is safe and effective in treating the disease. In the January 28 New England Journal of Medicine, Weinblatt and scientists from six other medical centers describe a double-blind, six-month trial in which they administered etanercept together with methotrexate--the standard treatment for rheumatoid arthritis--to 89 men and women aged 26 to 71. Many patients continue to have active disease despite receiving methotrexate. In patients receiving both drugs, the median number of tender joints dropped by 75 percent; the number of swollen joints decreased by 78 percent. The corresponding improvements for patients receiving methotrexate and placebo were 39 percent and 33 percent. Thirty-nine percent of etanercept patients and 3 percent of control patients improved by 50 percent using criteria set by the American College of Rheumatology. A slight rash at the injection site was the only common side effect attributable to etancercept, and previous studies have shown the drug to be safe when given for 18 months, the authors note. Etanercept is designed to inhibit the inflammatory cytokine tumor necrosis factor alpha (TNF alpha). Approved by the FDA last November, the drug is a recombinant protein consisting of two TNF alpha receptors fused with part of a human antibody. As a protein drug, however, it comes with certain disadvantages: it is expensive to manufacture and must be injected twice a week. A similar drug, infliximab, is awaiting FDA approval. Knockout Mice Bridge Divide in Diabetes Research Despite intensive study, scientists still lack a unifying hypothesis for the development of type 2 diabetes, a disease that afflicts more than 100 million people worldwide. In a report in the February 5 Cell, HMS researchers now offer such an explanation. Research into type 2, or non-insulin dependent, diabetes has long been divided into two camps: those researchers who focus on how muscle, fat and the liver become insulin resistant over time, and those who study the pancreatic beta cells' increasing inability to churn out enough of the hormone to compensate for the peripheral tissues' numbness to insulin. But it has never been clear how these two pathological processes are connected. In this study, researchers led by C. Ronald Kahn, the Mary K. Iacocca professor of Medicine at HMS and director of Joslin Diabetes Center, created "conditional knockout" mice, in which the gene of interest is disrupted only in a specific tissue. The mice lacked the gene for the insulin receptor only in their pancreatic beta cells, allowing Kahn's team to look at insulin signaling apart from its confusing web of body-wide interactions and study it at the suspected source of the disease, pancreas. The engineered mice were unable to release an initial burst of insulin in response to glucose. Like humans with early stage disease, the mice developed a progressive inability to handle a glucose challenge. The researchers suggest that a twofold insulin defect is at play in the pancreas: beta cells themselves become resistant to insulin, which in turn impairs their ability to secrete insulin. Coupled with insulin resistance in peripheral tissues, these defects could result in the classical pathology of this disease, the authors write.