Experimental drug helps kids with neuroblastoma

Two new studies offer hope for babies and toddlers suffering from neuroblastoma, a rare but often deadly cancer of the nervous system that strikes about 750 children a year.

Both therapies offer better, safer treatments for the disease, and belong to the emerging field of "personalized" cancer therapy, with medications tailored to the specific genetic profiles of a patient's tumor, says co-author John Maris of the Children's Hospital of Philadelphia.

Children diagnosed with neuroblastoma, which grows in nerve cells in the neck, chest and abdomen, are typically only about 17 months old, Maris says. About have an aggressive form of disease that relapses despite the best therapy.

A study of 226 children focused on an experimental, man-made antibody, called ch14.18, given as a cocktail with other immune stimulants. Doctors randomly assigned half of children to get standard care and half to receive the new antibody, according to the study in today's New England Journal of Medicine.

This type of antibody is the "holy grail" of cancer therapy, Maris says, because it targets a protein found only on cancer cells, but rarely on healthy ones. Scientists first identified this protein in the 1980s, he says.

The new therapy cut the risk of relapse from 66% to 46% after two years Because most relapses occur in the first two to three years, these children have likely been cured, Maris says. About 86% of those given the new therapy were alive after two years, compared to 75% of those given standard care.

"This is the biggest improvement we've ever seen in neuroblastoma," Maris says. "It's not a magic bullet, but it's the biggest result we've seen in a long time.. .. This is the culmination of 20 years of work."

Mechanism uncovered behind Salmonella virulence and drug susceptibility

Researchers have discovered a novel mechanism in Salmonella that affects its virulence and its susceptibility to antibiotics by changing its production of proteins in a previously unheard of manner. This allows Salmonella to selectively change its levels of certain proteins to respond to inhospitable conditions.

Although the mechanism had not been recognized before, the scientists were intrigued to find evidence of a similar mechanism in all five kingdoms of life — animals, plants, fungi, protista, and monera.

The findings were published today, July 29, in Molecular Cell. The senior author of the study is Dr. Ferric C. Fang, professor of microbiology, laboratory medicine, and medicine at the University of Washington (UW). Fang also directs the Clinical Microbiology Laboratory at Harborview Medical Center in Seattle. The lead author is William Wiley Navarre, who began the study as a postdoctoral fellow in the Fang lab and is now an assistant professor at the University of Toronto.

Salmonella enters the gut when people eat contaminated food, and can sometimes spread to other parts of the body. Illness outbreaks and grocery recalls related to Salmonella are often in the news. Babies, young children, the elderly, and people with cancer or HIV are especially prone to severe illness from Salmonella.

Salmonella is adaptable and can withstand many of the body’s attempts to fight it. The bacteria live and multiply in a special compartment inside the cells of an infected person or animal. Salmonella can alter its physiology as it moves from a free-swimming life to its residence in a host cell. Salmonella’s metabolism also changes over time to make use of the nutrients available in the host cell, and to survive damage from the build-up of oxidants and nitric oxide in the infected cell.

While screening mutant Salmonella that were resistant to a form of nitric oxide that normally stops the bacteria from dividing, Navarre, Fang and their research collaborators found mutations in two little-known genes. These are the closely linked poxA and yjeK genes. In a number of bacteria, these two genes are associated with a third gene that encodes the Bacterial Elongation Factor P, which is involved in protein production.

The researchers discovered that these three genes operate in a common pathway that is critical for the ability of the Salmonella bacteria to cause disease and resist several classes of antibiotics. Salmonella with mutations in either the poxA gene or the yjeK genes, the study noted, appear to be nearly identical and show similar changes in proteins involved in metabolism. Strains with mutations in both genes resemble the single mutant strains, an observation that suggests the two genes work in the same pathway.

The mutant strains exhibited many abnormalities under stressful conditions.

Drug Resistant HIV spreading globally

Drug resistant HIV is striking back against the antiretroviral drugs that keep it largely in check in rich countries, thanks both to its over-exposure to the major drugs and to individuals who don't realise (or care) they're infected and so spread resistant strains to new partners.

Its not new
Drug-resistant strains of HIV have already been documented in San Francisco and elsewhere in the US, and Europe. Now a model of their transmission, based on studies of gay San Francisco men, forecasts a rapid upsurge in the next five years.

What's more, as access to antiretroviral therapy is expected to expand in poorer countries, they could experience a rise in resistance too, predicts Sally Blower of the University of California, Los Angeles, lead author on the analysis.

Cocktail of resistance
Currently, people with HIV tend to be given a cocktail of drugs, making it less likely that resistance will emerge. That's because even if a strain evolves resistance to one of the drugs, it will still succumb to the others.

Short Term Thinking
However, the virus can evolve resistance nonetheless. Currently, about 15 per cent of new infections in San Francisco are from resistant strains, some of them resistant to all three major classes of drug used to combat the virus.

To see how this might increase in future, Blower's team created a model of HIV transmission that predicts how and when resistant strains will emerge. When they fed in data from San Francisco, it correctly predicted how drug-resistant HIV has already evolved and spread among gay men there over the past 20 years. It also predicted how quickly it will spread globally.

Full article here .....

Journal reference: Science, DOI: 10.1126/science.1180556