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RESEARCH BRIEFSAlcohol Gives Broad Protection Against Heart AttackResearch has demonstrated that moderate alcohol consumption diminishes a man's risk for having a heart attack, but many questions remain. How much is enough or too much? Does the type of alcohol matter? Findings from a 12-year study at HSPH and HMS may shed light on the issue. Researchers have found that in male professionals, aged 40 to 75 years, neither amount consumed per drinking day nor beverage type significantly altered the protective effect. Also, whether or not food accompanied alcohol intake had little effect on the association. The results were derived from the range and pattern of alcohol intake reported by 38,077 men enrolled in the Health Professionals Follow-Up Study based at HSPH. Using validated questionnaires, the team assessed frequency, average amount, and timing of consumption. "The inverse relationships between risk of myocardial infarction and alcohol consumption were strongest for beer and liquor, moderate for white wine, and weakest for red wine. Surprisingly, even relatively modest amounts per drinking day may be protective if consumed frequently," explained Kenneth Mukamal, lead author and HMS assistant professor of medicine at Beth Israel Deaconess Medical Center. Senior author on the study was Eric Rimm, HSPH associate professor of nutrition and epidemiology. The study, which appeared in the Jan. 9 New England Journal of Medicine, also found that men who increased consumption over time by an average of one drink per day had a 22 percent lower risk of having a heart attack afterward. Furthermore, intake of small to moderate quantities at least three times a week conferred a reduced risk. While the correlation between quantity and frequency of consumption and the non-alcohol-related differences among participants could influence the results, the study accounted for other variables, such as diet, exercise, and family history. Few participants reported drinking more than 50 grams of alcohol per day, the equivalent of four drinks, so examination of heavy drinking was limited. "Our results are not intended to encourage increased alcohol intake per se, since we know that alcohol has adverse health effects when consumed in excess. Men should discuss appropriate alcohol consumption with their physicians," said Mukamal.
Modified AIDS Vaccine Shows Heightened Immunity in MiceVaxGen's protein subunit vaccine AIDSVAX is the only AIDS vaccine to enter phase III trials. But even as researchers await the trial results expected this year, many have already turned their attention to other strategies, believing that AIDSVAX is not optimally immunogenic. Taking a different tack, Lawrence Paoletti, HMS assistant professor of medicine at Brigham and Women's Hospital, has looked for ways to improve the existing vaccine. Paoletti applied a strategy used to create conjugate vaccines for group B Streptococcus. By covalently coupling the capsular polysaccharide (CPS) antigen of group B Streptococcus to an immunogenic protein carrier like tetanus toxoid, the antibody response to CPS dramatically improves. As reported in the Dec. 1 Journal of Infectious Diseases, Paoletti, working with Ronald Kennedy, professor and chair of microbiology and immunology at Texas Tech University Health Sciences Center, created a similar conjugate vaccine for HIV-1 by coupling the HIV envelope protein gp120 and tetanus toxoid to CPS. They also devised vaccines using the nonglycosylated form of gp120, env2-3, as well as one that carried both proteins. The vaccines were then tested in a mouse strain known to respond poorly to gp120 alone. The conjugate vaccines all boosted levels of gp120-specific immunoglobulin G. The combined gp120/env2-3 conjugate vaccine performed best, raising levels nearly 100-fold. Serum taken from the mice neutralized both lab-adapted and primary HIV-1 isolates in vitro. Though the method has yet to demonstrate effectiveness against HIV infection in vivo, Paoletti pointed out that it would be no great leap to carry this vaccine strategy into clinical trials, unlike more untested approaches. All of the individual pieces of this vaccine have been through at least phase II clinical trials, and the conjugation method is also well tested. --Courtney Humphries
Mouse Model Enables Research on Rare Tumor, Other CancersA clearer understanding of a rare, aggressive childhood cancer, malignant rhabdoid tumor, is on the horizon thanks to HMS researchers. Lead author and instructor in pediatrics Charles Roberts and colleagues have created a mouse model to study a key tumor suppressor gene, SNF5. Based on a technique new to tumorigenesis research, the model may aid work on other cancer-related genes. SNF5 codes for the protein Snf5, a core component of the SWI/SNF chromatin remodeling complex that regulates gene expression by binding to the DNA-protein aggregate chromatin. Previous research has linked SWI/SNF with tumor suppression, but knockout studies of SNF5 have been unable to circumvent mouse death caused by excising the gene. The power of the model is in its conditional targeting approach, which instead of completely knocking out a gene allows it to flip back and forth and then randomly settle in the active or inactive orientation. "We were able to produce mice that had enough cells with normal SNF5 to live longer and enough cells with inactivated SNF5 to give rise to cancers," said Stuart Orkin, a Howard Hughes Medical Institute investigator and the David G. Nathan professor of pediatrics at HMS and the Dana-Farber Cancer Institute, in whose lab the model was constructed. The team observed that SNF5 was required for nonmalignant cells to live, but its loss gave rise to highly lethal malignancies. All mice with induced inactivation of normal SNF5 rapidly developed tumors, many of which closely resembled human rhabdoid tumors. Roberts explained, "It is possible that cells without SNF5 are supposed to die, but rare cells that contain additional mutations escape death and progress to cancer." Since SNF5 exists in all SWI/SNF complexes, conditional models could help identify the genetic and biochemical basis of the complexes' tumor suppression. Furthermore, uncovering the pathways of SNF5-related diseases may lead to future therapies for cancer. The study appears in the November Cancer Cell.
Method Captures Early Culprit in Alzheimer'sFor more than a century, the symptoms of Alzheimer's disease were thought to be largely the handiwork of plaques--the dense deposits, consisting of A-beta protein fibrils and other substances, that surround sick neurons. Recently, researchers have begun to suspect that the plaque precursors, protofibrils and oligomers, may be even nimbler and deadlier agents of disease. But actually pinning down the potential culprits has been difficult. "Oligomers are not stable and do not last long," said David Teplow, HMS associate professor of neurology. In the Jan. 7 Proceedings of the National Academy of Sciences, Gal Bitan, HMS research fellow in neurology, Teplow, and colleagues report that they have devised a way to capture the shifty precursors. The method, photo-induced cross-linking of unmodified proteins (PICUP), consists of chemically stabilizing oligomers in a cross-linked state. Using the technique, they have been able to gain glimpses not only of how the oligomers assemble into protofibrils but also how they might wreak destruction in the brain. Aleksey Lomakin and George Benedek, both at MIT, were collaborators on the study. Researchers have long known that the A-beta protein comes in two forms, long (42 amino acids) and short (40 amino acids). A-beta-42 is the deadlier of the two--indeed, it is a main component of plaques. Yet it was not clear how the A-beta-42 polypeptide forms aggregates. It now appears that molecules of A-beta-42 band together to form spherical blobs that are structurally distinct from the oligomers initially formed by A-beta-40. Further, it appears that the spherical blobs associate, like beads on a string, to form chains that eventually mature into fibrils. As for how the other precursors might gain their deadly foothold in the brain, "one hypothesis is that these oligomers interact with receptors on the surface of the cell to cause a change in the normal physiology of the neuron, either killing it or making it more susceptible to insults that affect its function, such as inflammation and oxidative stress," Teplow said. Oligomers might also launch their attack from inside the cell. In either case they would provide an attractive drug target. "If you could understand structurally how this peptide exists in nature," he said, "you would be in a better position to design therapeutic agents that could be used to control its assembly." --Misia Landau |
