How Papillomavirus Proteins Brew Genetic Errors, Cancer
Though most cancers are not caused by viruses, at least 90 percent of cervical cancers are associated with infections of the human papillomavirus (HPV). Yet like other cancers, cervical cancers often develop when cells become genetically unstable, taking on extra copies of some genes and losing copies of others. The question is, how does a virus cause cells to do this?
In the Aug. 29 PNAS, Karl Munger, HMS associate professor of pathology, and his team headed by research fellow Stefan Duensing presented some new findings that help explain how HPV interferes with genomic integrity.
After the virus infects a cell, it expresses two viral proteins, E6 and E7. E6 inactivates the tumor suppressor protein p53, which normally keeps a cell from dividing when its DNA is damaged. The viral E7 protein inactivates the retinoblastoma tumor suppressor and plays a role in establishing genomic instability. Munger and his colleagues have found that E7 may do this by increasing production of the cell's centrosomes.
Right before normal cell division, two centrosomes sit at opposite ends of the cell. After the genetic material is duplicated, each centrosome reels in a complete set of chromosomes, ensuring an equal distribution of genes when the cell splits in two.
Researchers in Munger's lab noticed that due to the E7 protein, cervical cancer cells have an abundance of centrosomes. With all of these centrosomes floating around, chromosomes are drawn in multiple directions.
This type of chaos can result in some very abnormal sets of chromosomes and genes once the cell splits. And since the viral E6 protein blocks p53's tumor suppressor activity, division continues despite the genetic aberration. Consequently, HPV effectively sets the stage for the emergence of abnormal cells that can progress to a cancerous state.
Paper Suggests Why Hens Don't Have Teeth
Everyone knows that birds have sharp beaks, but they once had sharp teeth to go with them. That was about 60 million years ago, and researchers have been wondering how today's toothless versions came about. In the Aug. 29 PNAS, Richard Maas, HMS associate professor of medicine at Brigham and Women's Hospital, and his colleagues report that evolution in birds may have shut down the genetic pathway that is responsible for tooth formation.
A normal cell (left) has one centrosome (red) that separates into two prior to cell division. Expression of the human papillomavirus protein E7 causes the formation of multiple centrosomes (right), rendering the accurate separation of chromosomes impossible. Courtesy of Karl Munger
By looking at various marker genes, the researchers found that the genetic program regulating tooth initiation is partly functional in the avian embryonic jaw. A couple of key genes, Msx1 and Msx2, are not expressed, though.
In support of these findings, when Maas and his team knocked out the Msx1 gene in mice, tooth development was arrested. Yet the story seems to be more complex than the simple loss of Msx1 expression. Another gene, BMP4, controls the expression of Msx1 in the dental epithelium. Maas and his group found that chicken cells could, indeed, express Msx1 and Msx2 when the BMP4 protein was provided artificially. It is unlikely that true teeth could form, however, because birds have almost certainly lost additional genes during evolution that are required to make the hard mineralized dentition characteristic of other vertebrates.
Interestingly, in their mouse studies, Maas and his group also found that the Msx gene products are required for expression of BMP4 in the dental mesenchyme. In this case, recombinant BMP4 is able to rescue Msx1-mutant tooth germs all the way to definitive stages of dentin and enamel formation. So Msx1-mutant mice appear to approximate the interruption in the molecular pathways controlling tooth development that has occurred naturally during the evolution of modern birds.
Residency Directors And Managed Care Medical Directors Agree on Training
Managed care in one form or another appears to be here to stay. But is medical education preparing young doctors for this kind of practice?
In a study published in the Sept. 6 JAMA, Gordon Moore, HMS professor of ambulatory care and prevention at Harvard Pilgrim Health Care, and collaborators at New York University found that residency directors and managed care medical directors, two groups that may be expected to have disparate perspectives on the practice of medicine, value mastery of many of the same clinical competencies important to treating patients.
Both groups ranked the following areas as among the top 10: time management, case management, ethics, practice guidelines, cost-effective clinical decision-making, clinical epidemiology, disease management, referral management, and patient satisfaction. The one difference in opinion was that residency program directors valued evidence-based medicine, while managed care medical directors found practice profiling (comparing one's own practice to that of peers) more important.
The study also showed that residents who participated in managed care training courses were more confident than their counterparts in performing tasks in these competency areas.
Briefs above by Tracy Hampton
Is the Food Pyramid Healthy?
For as long as the U.S. Food and Drug Administration's food pyramid has been standing, fat, at the peak, has been targeted for weight loss. Despite decreases in dietary fat intake, however, obesity remains a major medical problem in the U.S. Recent evidence suggests that the pyramid may need to be redesigned with glycemic index, not fat content, determining its tiers.
Leslie Spieth, HMS instructor in psychology; David Ludwig, HMS assistant professor of pediatrics; and their colleagues at the Optimal Weight for Life Program at Children's Hospital report in the September Archives of Pediatrics and Adolescent Medicine that obese children prescribed a diet with a low glycemic index show a significant decrease in body mass compared with children prescribed a low-fat diet. Sixty-four outpatients in the low glycemic index group were given recommendations to eat and snack to satiety, avoiding foods that cause dramatic peaks in blood glucose levels, such as potatoes, refined carbohydrates, and sugar. These patients had an average reduction in body mass index of 1.53 kg/m2 after 18 to 19 weeks, compared to 0.06 kg/m2 seen in the 43 outpatients who received recommendations to avoid fatty foods in an effort to reduce their caloric intake. Body weight likewise decreased more in the low glycemic index group, and these findings remained significant after age, sex, ethnicity, baseline weight, participation in behavioral therapy, and treatment duration were controlled for.
Ludwig and his colleagues have long been interested in the relationship between a food's glycemic index and body weight. This project followed a study published in the March 3, 1999 Pediatrics, which showed that 12 obese boys had a reduced appetite after consuming low glycemic index meals (see Focus March 19, 1999). Blood tests on the boys who ate high glycemic index meals showed an insulin surge after consumption which resulted in a quick depletion of circulating blood glucose and reduced accessibility to the body's energy stores. These boys became hungry again more quickly than their counterparts who received a low glycemic index meal.
Though longer term, prospective clinical trials need to be conducted for more conclusive evidence, the attention now being drawn to the glycemic index may set the familiar food pyramid on its head.