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Chromosomes Tangled in Stem Cells Present Cancer Risk

Stem cells will attempt cell division in the presence of entangled chromosomes, increasing their risk of becoming cancerous, says new research published in the December issue of Cancer Cell.

Because mistakes in cell division can produce chromosomal abnormalities, cells closely monitor the process with several checkpoints. One, the decatenation checkpoint, delays mitosis if the chromosomes haven’t been disentangled.

Faced with entangled chromosomes, normal stem and progenitor cells, however, tend to
Chromosomes Tangled in Stem Cells Present Cancer Risk
The natural tendency of stem cells to divide in the presence of entangled chromosomes may give rise to abnormal chromosomes in cancer stem cells. On the left, chromosomes as they normally look during division; on the right, entangled chromosomes in stem cells treated with inhibitor.
skip through this checkpoint, according to research by Timothy Bestor, Ph.D, professor of genetics and development, and Marc Damelin, Ph.D., a postdoctoral research fellow of the Damon Runyon Cancer Research Foundation.

The researchers treated different types of cells with topoisomerase II inhibitor, a drug that prevents chromosomes from untangling. While the differentiated cells stopped dividing, the stem and progenitor cells (mouse embryonic stem cells, mouse neural progenitors, and human bone marrow cells) proceeded with cell division in the presence of entangled chromosomes.

This inherent property of stem cells may explain how a tumor-initiating cell, also known as a cancer stem cell, arises from a normal stem cell with no pre-existing mutations. “Stem cells don’t divide with entangled chromosomes all the time – otherwise we wouldn't be here – but in cases where there is an abnormal division, it could give rise to cancer,” Dr. Damelin says.

It may also explain how a cancer stem cell acquires additional mutations that increase tumor malignancy. Chromosomal imbalances of the type expected to arise from an inefficient decatenation checkpoint are a universal feature of cancer cells.

The research was supported by the NIH.

Researchers Find B Cells Get Special Delivery

Immunology’s understanding of how B cells respond to invaders may be due for an overhaul, according to recent discoveries made by the lab of Raphael Clynes, M.D., Ph.D., assistant professor of medicine and microbiology. The discovery should provide important information for the creation of new vaccines.

When viruses, bacteria, or microbes enter our bodies, B cells unleash a slew of antibodies that neutralize the invaders or direct an attack by other parts of the immune system.

B cells begin their attack only after detecting antigens from the invaders, but it’s unclear how the antigens ever come into contact with the cells. The presumption has been that antigens will eventually float by the lymph nodes where the B cells reside. However, this mechanism is highly inefficient and unlikely to account for all the antigens detected by B cells.

Dr. Clynes and graduate student Amy Bergtold have now discovered that delivery by dendritic cells may be more important. Dendritic cells were known to deliver antigens to T cells, but it was unclear how they could deliver antigens to B cells. Unlike the small, processed antigens that are delivered to T cells, antigens delivered to B cells must be whole and intact. Dr. Clynes and Ms. Bergtold’s work reveals how dendritic cells can engulf antigens, carry them whole to the lymph nodes, and present the whole antigens to B cells.

Since dendritic cells continually migrate from the body’s tissues to the lymph nodes, they may represent a more reliable source of antigens for B cells than random encounters.

Dr. Clynes and Ms. Bergtold are also investigating whether HIV uses the pathway to find its way to the lymph nodes, where the virus primarily infects T cells.

The research was published in the November issue of Immunity and supported by the NIH, the Speaker Fund of the City Council of New York, the Cancer Research Institute, and the Arthritis Foundation.

Antioxidant Prevents Emphysema in Mice

Each cigarette puff contains an estimated 100 trillion oxidants, molecules that destroy the lung’s air sacs during the course of emphysema.

Now researchers have shown, for the first time, that antioxidants can prevent the disease in an animal model. “Our animal study is proof of principle that antioxidants – delivered correctly – can protect against the development of emphysema,” says the study’s senior author, Jeanine D’Armiento, M.D., Ph.D., assistant professor of medicine. The findings were published ahead of print on the American Journal of Respiratory and Critical Care Medicine Web site.

Despite laboratory studies that suggest antioxidants may prevent the damage caused by smoke, a recent large clinical trial showed that one antioxidant, N-acetylcysteine, could not slow the disease’s progression. However, the dosage of N-acetylcytein used in the trial did not effectively augment the antioxidant defenses within the lung.

Dr. D’Armiento and her colleagues investigated a different antioxidant called superoxide dismutase (SOD) that is produced naturally in the lung. The researchers created transgenic mice that expressed four-fold levels of human SOD in their lungs and then exposed the mice to cigarette smoke six hours a day for one year.

The excess SOD inside the lungs protected the mice from developing smoke-induced emphysema. Dr. D’Armiento says the antioxidant worked by preventing an influx of neutrophils into the lung that inflames the airways and initiates the disease.

Because it is difficult to deliver superoxide dismutase as a drug, the researchers are now looking for similar-acting antioxidants that can be delivered to the lungs.

The research was supported by the Flight Attendant Medical Research Institute and the Alpha-1 Anti-trypsin Foundation.

Can’t Keep the Weight Off? Here’s Why.

If you belong to the vast majority of dieters who have successfully lost weight only to regain every single pound, you may be able to place the blame squarely on the hormone leptin, new research reveals.

Leptin is produced solely by fat cells, so when dieters attempt to maintain a lower weight, they are also attempting to maintain lower levels of leptin. However, the new research found that these attempts to keep leptin down may provoke numerous changes in metabolic, endocrine, and neurological systems that conspire to fight the weight loss and restore leptin to its pre-weight loss levels.

The study, led by Michael Rosenbaum, M.D., associate professor of medicine and pediatrics, tested the hypothesis that restoration of leptin to pre-weight loss levels would reverse some of the metabolic opposition to keeping weight off. In 10 human subjects the researchers found that a 10 percent weight loss increased the efficiency with which muscles burn calories and resulted in an overall decline in energy expenditure of about 23 percent. When the researchers injected each volunteer with enough leptin to bring the hormone back to its pre-weight-loss level, the metabolic changes disappeared.

Though the study was not designed as a clinical trial of leptin (which must be injected to work) it does suggest that drugs affecting the leptin signaling pathway may be a key to successful long-term weight loss therapy. Dr. Rosenbaum says that drugs designed to help people sustain weight loss may be more effective than treatments designed to induce weight loss.

The research was supported by the NIH.