Research Roundup
May 1, 2007, Volume 53, No. 32	Print Issue

Gene-Environment Interactions in Lung Cancer

The Penn School of Medicine, in association with Pennsylvania State University Medical College and Lincoln University, has received $4.2 million to study gene-environment interactions that increase the risk of lung cancer in African American and Caucasian smokers and non-smokers. The funds were awarded from Pennsylvania’s share of the national tobacco settlement for 2006-2007.

The award will fund the establishment of a Center for Gene-Environment Interactions in Lung Cancer directed by Dr. Steve Whitehead, professor of pharmacology. The study will be conducted under the Gene-Environment Initiative of Penn’s Center of Excellence in Environmental Toxicology (CEET), directed by Dr. Trevor M. Penning, professor of pharmacology, obstetrics and gynecology, and biochemistry and biophysics. 

Lung cancer is the leading cause of cancer deaths in the adult U.S. population. “This year alone 174,500 new cases of lung cancer will be diagnosed and almost as many deaths will result,” notes Dr. Penning. “Eighty-five to 90 percent of all lung cancer is seen in individuals who smoke cigarettes, yet only ten-percent of those who smoke will succumb to the disease. These statistics suggest that a significant gene-environment interaction exists.”

Cigarette smoke contains two major classes of cancer-causing chemicals: those derived from nicotine and those derived from polycyclic aromatic hydrocarbons (PAHs). PAHs are also produced by burning fossil fuels and are ubiquitous environmental pollutants. “PAHs are present in soot that is found at relatively high concentrations in the air we breathe in urban environments,” explains Dr. Penning. “Exposure to environmental PAHs may also account for lung-cancer incidence in people who have never smoked.”

The researchers aim to enroll and compare 600 lung-cancer patients from Philadelphia, which has high concentrations of air pollutants, and 600 patients from Hershey, PA, which has comparatively unpolluted air. In addition, for the 600 recruits in the Philadelphia-based part of the project, the investigators hope to recruit 300 African Americans and the same number of Caucasians to study possible racial differences in gene-environment causes of lung cancer.

Each site will also recruit 600 control individuals who do not have lung cancer, even though they have the same smoking behavior and exposures to pollutants.

The study subjects will answer questions about their smoking history and exposure to airborne pollutants. These pollutants will also be mapped cartographically using GIS technologies to ascertain distribution in each study location.

Exposure to air pollutants for each subject will be analyzed together with their individual variation in approximately 100 genes. “The genes to be tested are considered to be very important for dealing with the carcinogens that are known to cause lung cancer and include many of those responsible for the metabolism and detoxification of carcinogens and for repairing DNA damage caused by carcinogens,” explains Dr. Whitehead.

Additionally, current exposure to nicotine and PAHs will be estimated by measuring molecules called biomarkers produced from these chemicals in the body. This is an important component to the study, especially for estimating carcinogen levels in participants who have never smoked but have Dr. Whitehead and Dr. Penning both note that urban areas that are most polluted are very often occupied by residents of lower socio-economic status and issues of health-disparity and environmental justice exist. Faculty and student interns from Lincoln University will conduct questionnaire-based surveys to identify health-care disparities between the various populations to be enrolled. In addition, they will examine how information about genetic risk is understood and acted upon by the various participating groups.

“Once lung cancer is diagnosed, the five-year survival rate is less than 15 percent,” notes Dr. Penning. “This study provides the opportunity to identify those individuals who may be genetically pre-disposed to lung cancer. This genetic information could provide the impetus for high-risk individuals to enter smoking cessation programs. In addition, a better understanding of the relationship between pollution and genetic factors in lung cancer would inform agencies involved in urban planning and facilitate the formulation and implementation of environmental health policies.”

Link Between Autism and Abnormal Blood-Vessel Function and Oxidative Stress

Researchers at Penn’s School of Medicine discovered that children with autism showed signs of abnormal blood-vessel function and damaging levels of oxidative stress compared to healthy children. The children with autism possessed levels of biochemicals that indicate the presence of constricted blood vessels via the endothelium (the cells that line vessels) with a higher tendency to form clots (through cells called platelets). Exploring the relationship between oxidative stress and blood-vessel function in autistic patients, may lead to new therapeutic options for this syndrome. The researchers, led by Dr. Domenico Pratico, associate professor of pharmacology, published their findings in the August issue of the Archives of Neurology.

According to the Autism Society of America, the reported number of autism cases is increasing 10 to 17 percent per year in the U.S. Autism, an early onset neurological disorder, is characterized by impaired social interactions, limited verbal and nonverbal communication, and repetitive and restricted behavioral patterns. Patients with autism can differ in the severity and scope of their symptoms, suggesting that multiple factors contribute to explaining the disorder’s symptoms. Previous studies at other institutions have shown that autistic patients have reduced cerebral blood flow, presumably due to constricted blood vessels in the brain, versus healthy controls.

Dr. Pratico’s team measured isoprostane, a biomarker for oxidative stress; thromboxane, an index of platelet activation; and prostacyclin, a measure of blood vessel activation in the samples. Compared with controls, children with autism had significantly higher urinary levels of isoprostane, thromboxone, and prostacyclin.

Oxidative stress is the result of an excessive formation of chemically unstable byproducts, called free radicals, within the cell. Under normal conditions, the cell is able to destroy the free radicals. However, when excessive free radicals accumulate, these molecules mount an attack against the cell in search of chemical stability.

Autism is a complex neurological disorder and oxidative imbalance is one feature of the autistic syndrome. Several lines of evidence support the hypothesis that oxidative imbalance may also play a role in this disease: autism is characterized by an impaired anti-oxidant defense system, higher free-radical production, and improvement of behavioral symptoms after taking anti-oxidants.

Meditation Helps Congestive Heart Failure

According to a first-of-its-kind randomized study conducted by researchers from Penn’s division of geriatric medicine, a widely practiced, stress-reducing meditation technique can significantly reduce the severity of congestive heart failure. The study appears in the Winter 2007 issue of Ethnicity & Disease.

“The results of this study indicate that transcendental meditation can be effective in improving the functional capacity and quality of life of congestive heart failure patients,” said Dr. Ravishankar Jayadevappa, lead author and research assistant professor in the division of geriatric medicine. “These results also suggest long-term improvements in survival in these individuals.”

Dr. Jayadevappa and fellow researchers from Penn evaluated 23 African American men and women, average age 64, who were recently hospitalized with New York Heart Association class II or III congestive heart failure. Participants were randomized to either the Transcendental Meditation ® (TM) technique or health education—in addition to standard medical treatment.  According to Dr. Jayadevappa, the TM group significantly improved on a six-minute walk test after both three and six months of TM practice compared to the control group. The TM group also showed improvement in quality of life measurements, depression, and had fewer re-hospitalizations.

This present finding is consistent with previous research demonstrating that TM reduces factors that contribute to the cause or progression of heart failure, such as high blood pressure, stress, metabolic syndrome, left ventricular hypertrophy (enlargement of the heart) and severity of atherosclerosis (hardening of the arteries).  Further validation of the outcomes of this study is planned via a large, multi-center trial with long-term follow-up. According to the study authors, TM most likely improves heart failure by reducing sympathetic nervous system activation associated with stress that is known to contribute to the failing heart.