While previous research has shown that bupropion is an effective smoking cessation aid, smokers experience variability in response to this drug and only 30-45 percent remain abstinent. By identifying the genetic factors that influence response to bupropion, researchers hope to aid in the development of more effective treatment strategies that are tailored to individual smokers.
Lead author Dr. Caryn Lerman, associate director for Cancer Control and Population Science at the Abramson Cancer Center and professor in the School of Medicine and the Annenberg Public Policy Center, led a research team that examined 426 smokers enrolled in a randomized clinical trial of bupropion for smoking cessation.
The researchers found that participants with a decreased activity variant of the CYP2B6 gene reported greater increases in cravings for cigarettes following the quit date and were about one and a half times more likely to relapse during the treatment phase.
"This study provides an important first step toward utilizing genotype to identify smokers who are more vulnerable to relapse and who may benefit most from more intensive smoking cessation treatment," said Dr. Lerman.
The research was funded by the National Cancer Institute and the National Institute on Drug Abuse and was conducted by the University of Pennsylvania/Georgetown University Transdisciplinary Tobacco Use Research Center.
Parkinson's Disease in Fruit
The result suggests a new approach to the treatment of human disorders including Parkinson's and Alzheimer's diseases. Penn professor of biology and investigator with the Howard Hughes Medical Institute Dr. Nancy M. Bonini and graduate student Pavan K. Auluck reported the finding in the November issue of Nature Medicine.
Parkinson's--the second most common human neurodegenerative disorder-- is characterized by tremors, postural rigidity and progressive deterioration of dopaminergic neurons in specific areas of the brain. Despite the evolutionary gulf separating humans and fruit flies, neurotoxicity unfolds in a similar manner in both species. Like humans, Drosophila melanogaster experiences neuronal loss upon expression of alpha-synuclein, a protein implicated in the onset of Parkinson's disease in both species.
Dr. Bonini and Mr. Auluck fed flies a naturally occurring antibiotic called geldanamycin. When fed geldanamycin-supplemented food as adults, flies with a genetic susceptibility to neurodegenerative disease--flies that would normally experience a 50 percent loss of dopaminergic neurons by 20 days of age--maintained normal numbers of these neurons.
Geldanamycin tweaks the activity of Hsp90, one of a class of proteins known as molecular chaperones. Dr. Bonini, Mr. Auluck and colleagues showed last year that molecular chaperones can block the progression of neurodegenerative disease in Drosophila, suggesting that diseases like Parkinson's and Alzheimer's may result from reduced chaperone levels and might be averted by pharmacologically boosting chaperone activity.
Dr. Bonini and Mr. Auluck's work is funded by grants from the David and Lucile Packard Foundation, the National Institute on Aging, the NIH and the Alzheimer's Association.
the Way Race is Used in Research
According to Dr. Pawela Sankar, assistant professor of bioethics in the department of Medical Ethics and Center for Bioethics, the recent debate over race in genetic research has focused on whether or not race exists. This is misguided for two reasons. First, the term race is understood in different ways; some assume that "race" refers to historically racist theory of human subspecies, while others assume it refers to genetic differences that are associated with population history, and is simply descriptive.
The second issue is that researchers use race in very different ways. Some use it as a proxy for environmental exposures, and others as a way of selecting subjects that are more or less genetically similar to one another. The fact that race is used in so many different ways in genetic research is one of the reasons that ethnicity or genetic markers cannot simply replace race, as some have suggested.
The paper comes at a time when new research efforts are unfolding, now that the human genome has been completely sequenced. The paper asks researchers to carefully consider for what purpose they are using race, to define the term and then use it consistently. "The practice of science requires a precise language and oddly, the word race,' although used frequently in the literature, has escaped the kind of scientific scrutiny that other words have had," said Dr. Sankar. "In one paper researchers will have used the term three different ways and not defined it."
Stanford University researcher Dr. Mildred. K. Cho--formerly of Penn's Center for Bioethics--was also involved in this study.
Pneumonia by a Nose
"We wanted to further explore using the e-nose after the exciting results of an initial study we conducted back in 1997 with only 20 patients," said Dr. C. William Hanson, III, professor of anesthesia, surgery and internal medicine, and lead author of the study. When it comes to lower pulmonary infections, especially in critically ill patients, time is of the essence for disease control.
The e-nose contains an array of sensors consisting of carbon-black/polymer composites. The patient's exhaled breath gas was passed over these sensors which interact with volatile molecules to produce unique patterns that are displayed in two-dimensional "maps," or dot patterns on a computer screen. The results were analyzed using pattern recognition algorithms and assessed for a correlation between the actual CPIS scores and the one predicted by the nose. Dr. Hanson and his colleagues found that the e-nose made clear distinctions between the patients who were infected and those who were not. Cyrano Sciences, Inc., donated a "Cyranose" electronic nose for use in this study.
the West Nile Virus
The Penn researchers first began studying WNV-Cp when they noticed a striking similarity between the gene that encodes for it and that of an HIV regulatory protein. "We hope to extend the lessons they have learned in trying to develop therapeutics for HIV in fighting West Nile," said Dr. Weiner. "In addition to the possibility of creating a vaccine for West Nile, our results support the idea that a specific portion of the capsid protein-- called the 3' terminal region--is required for the protein's pathogenicity. If we can find a way to block that region's function, this might help slow the virus down."
By itself, the WNV-Cp protein can cause inflammation. Dr. Weiner and his colleagues found that WNV-Cp drives apoptosis in cell cultures through what is called the mitochondrial pathway. The protein begins the process of cell suicide by somehow disrupting the membrane potential of the cell's mitochondria, which then leads to the activation of proteins such as caspase-9 and caspase-3 that start a cascade of reactions to subsequently cause the cell to digest itself.
Since the protein enters the nucleus of the cell, it is possible that WNV-Cp changes the host cell's transcriptional machinery, resulting in an over production of certain proteins related to an apoptotic program, which consequently feed back to the mitochondria. Alternatively, as WNV-Cp moves from the cytoplasm to the nucleus, it may inactivate an important part of the cell's natural control system that keeps apoptosis in check--overpowering the guard as it were--thus inducing the cell suicide. Funding for this work was supported by grants from the NIH.
Almanac, Vol. 49, No. 17, January 14, 2003