Gene Profiles of Lung Cancer Biopsies Predict Prognosis
Researchers at Columbia have found a way to predict who is most likely to respond to treatment for lung cancer by monitoring the activity of 42 genes from small biopsies taken from the tumors. The findings represent a step toward personalized treatment for lung cancer, in which patients will receive the most effective treatment for their particular type of cancer.
"The gene signatures of the tumors should help us improve lung cancer survival by identifying the patients most likely to benefit from current treatments and giving us ideas for alternative therapies for the other patients," says Charles Powell, M.D., assistant professor of clinical medicine at P&S.
The research was published in the July 15, 2004, issue of American Journal of Respiratory and Critical Care Medicine. Dr. Powell and his colleagues are now conducting trials to test the utility of the genetic testing in the clinic.

Parkinson's Disease: New Vaccine and Cell Implants Show Promise
CUMC and University of Nebraska scientists have designed a vaccine that successfully prevents the death of brain cells in a Parkinson's disease mouse model. The findings were published in the June 22, 2004, issue of the Proceedings of the National Academy of Sciences.
The new vaccine uses an agent to stimulate brain chemicals that mediate inflammatory events implicated in the destruction of neurons in Parkinson's. "The research is very exciting," says Serge Przedborski, M.D., Ph.D., professor of neurology and pathology in the Center for Neurobiology and Behavior at Columbia. "Using this approach, the harmful aspects of inflammation associated with Parkinson's disease could be eliminated."
In another study, published in the June 2004 issue of the Archives of Neurology, researchers reported success in Parkinson's patients who underwent implantation of embryonic cells. The patients had better motor performance following the surgery than patients who didn't receive the cells. The investigators, led by Seth Pullman, M.D., associate professor of clinical neurology, and Paul Gordon, M.D., assistant professor of neurology, reported on data collected from the 2001 double-blind, placebo-controlled trial of embryonic cell implants (not embryonic stem cells) for Parkinson's disease. The main results of that study, published in the New England Journal of Medicine, showed a slight improvement in Parkinson's symptoms among younger patients who got the implants but also found that many developed additional movement problems a year after the surgery.
In the current study, Dr. Pullman and colleagues measured patient reaction and motor times before the surgery and four and 12 months after surgery. The results showed that the implants stopped deterioration of motor performance seen in older (patients over age 60) control patients who did not receive the implant. After one year, older patients who received implants maintained the level of motor skills they had before surgery, while the motor skills of older control patients deteriorated.

Alzheimer's Proteins May Promote Cell Growth
In a stem cell study, researchers found that beta-amyloid, the peptide that builds up in the brain and is thought to play a major role in Alzheimer's disease, may also be involved in repairing the brain in the disease. Better knowledge of the negative and positive roles of these proteins will be critical to exploiting the regenerative potential of the brain in preventing and treating Alzheimer's. The study, published in the June 9, 2004, issue of the Journal of Neuroscience, was led by Michael Shelanski, M.D., Ph.D., co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and professor and chairman of pathology at P&S.
Dr. Shelanski and colleagues cultured embryonic neural stem cells from rodents and introduced beta-amyloid proteins at various stages. Under normal circumstances, neural stem cells differentiate into neurons. Based on earlier research, the scientists believed that neural stem cells would be negatively affected by the amyloid proteins. The researchers found instead that, if introduced early enough, beta-amyloid promoted the generation of neurons from the stem cells. This represents the first time that a potential positive role has been found for these proteins.

Drug Combo Extends Life Span in Prostate Cancer
Combining the breast cancer drug Taxotere (docetaxel) with the prostate cancer drug estramustine helped men with a certain type of metastatic prostate cancer survive 20 percent longer than similar patients receiving standard therapy, according to a landmark Phase III study authored by physician-scientists at Columbia. The study was presented in June 2004 at the American Society of Clinical Oncology's 40th annual meeting.
In this multi-center clinical trial, approximately 650 patients with androgen-independent prostate cancer were treated with docetaxel and estramustine, a breast cancer-prostate cancer drug combination therapy, or standard chemotherapy treatment (mitoxantrone/prednisone). The men receiving docetaxel and estramustine lived an average of 18 months, compared with 16 months for the men treated with standard chemotherapy. In addition, cancer progression was slowed by half in the docetaxel/estramustine group (six vs. three months). "The findings show that docetaxel can effectively treat hormone-refractory metastatic prostate cancer and docetaxel/ estramustine can now be considered a benchmark for future clinical trials," says Daniel P. Petrylak, M.D., associate professor of medicine.

Aspirin Users May Be at Lower Risk for Breast Cancer
Women who regularly take aspirin seem to be at lower risk of the most common type of breast cancer than those who do not take aspirin, report researchers from Columbia and Weill Cornell Medical College. The study, conducted with nearly 3,000 women from the Long Island Breast Cancer Study Project, was reported in the May 26, 2004, issue of JAMA.
Mary Beth Terry, Ph.D., assistant professor of epidemiology at Columbia's Mailman School of Public Health, and colleagues analyzed data collected in 1996 and 1997 from 1,442 breast cancer patients and 1,420 healthy women. When the researchers compared women with breast cancer to women who were cancer-free, they found that those who took aspirin regularly had a 26 percent lower risk of hormone receptor positive breast cancer, a type of cancer making up about 60 percent to 70 percent of all breast cancer cases, compared with women who did not take aspirin. The association was strongest in women who took seven or more aspirin tablets per week and was greater in menopausal women than in their premenopausal counterparts.

Low Dose Arsenic May Be Treatment for Skin Cancer
Melanoma, once it spreads from its initial site, is extremely resistant to treatment and is usually fatal. But a new study indicates that short term treatment with low doses of arsenic, coupled with an inhibitor of a specific cell signaling pathway, might be able to stop melanoma by making tumor cells self-destruct.
Vladimir Ivanov, Ph.D., associate research scientist, and Tom K. Hei, Ph.D., professor of radiation oncology and environmental health sciences, both in Columbia's Center for Radiological Research, found that arsenic alone was able to induce cell death in 40 percent of some melanomas in cell cultures and less than 10 percent in others while causing no harm to normal cells. When they applied preclinical drugs known to inhibit certain cell signal pathways, they achieved a 90 percent kill rate even among the most resilient tumor cells. "Further research is necessary, first in animals and then in clinical trials, but this approach could have a profound impact on melanoma treatment," says Dr. Hei. The research was reported in the May 21, 2004, issue of the Journal of Biological Chemistry.

Nicotine Aids Concentration
Nicotine jams some of the background noise sent through the brain's neurons while letting more important messages pass through, a new study finds. The new research was published in the June 2004 issue of Nature Neuroscience.
"Nicotine ends up being a filter and that may explain why it helps increase concentration and memory of people with attention deficit disorder and Alzheimer's disease and why so many people with schizophrenia smoke," says David Sulzer, Ph.D., associate professor of neurology and psychiatry at P&S. "Smoking has always been suspected to be a form of self-medication in schizophrenia and now we have evidence for that idea."
At levels typically experienced by smokers, nicotine acts as a filter, the researchers found, by stopping slow-firing neurons, which are carrying less important signals, from releasing dopamine into the brain. The drug allows only more rapidly firing neurons, which are related to acts of concentration and to short-term memory,
to release dopamine, which then transmits the information to other parts of the brain.
Dr. Sulzer and co-author Hui Zhang, Ph.D., do not advocate smoking to improve concentration, because the harm from smoking far outweighs any benefit from nicotine. They suggest instead that nicotine or similar drugs delivered in a safer manner could be used to improve concentration, memory, or reduce hallucinations.

Imaging Finds Brain Network Affected by Lack of Sleep
Researchers know that sleep deprivation acts as a brake on the brain, slowing alertness, reaction time, and memory. But until recently, scientists have been looking at the brain section by section to see which areas are affected by lack of sleep.
Now, researchers taking a more holistic approach have used functional magnetic resonance imaging in two studies to determine which brain areas change their activity levels together to form a network associated with sleep deprivation. In the study, Yaakov Stern, Ph.D., professor of clinical neuropsychology, Christian Habeck, Ph.D., postdoctoral research scientist in Columbia's Taub Institute, and colleagues examined the effects of sleep deprivation on the short-term memory of 19 young adults who went two days without sleep. The researchers identified a network of brain areas whose activity levels dropped after sleep deprivation and correlated with diminished memory performance.
"Our findings suggest which brain regions need to be stimulated during sleep deprivation to overcome the cognitive effects of sleep loss," says Dr. Habeck. The research was published in the May 2004 issue of Cerebral Cortex.

New Drug Prevents Arrhythmias That Cause Sudden Cardiac Death
Heart researchers have developed and tested a unique heart arrhythmia drug that could prevent the sudden death of millions of people with heart failure and individuals with an inherited heart disorder exacerbated by exercise. The drug represents one of the first molecular-based therapies for cardiac arrhythmias and heart failure and avoids the toxicity of current treatments. Results of the initial animal test were published in the April 9, 2004, issue of Science.
In the study, investigators tested the experimental drug in mice that had the same molecular defect as people with heart failure and some otherwise healthy people who develop fatal arrhythmias during exercise. (The defect causes a tiny channel in the heart muscle to leak calcium ions into heart cells, triggering arrhythmias in both types of patients). The researchers found that the drug completely prevented sudden death from arrhythmia. All 10 mice that received the drug thrived and never developed the problem, while 8 out of 9 untreated mice became arrhythmic and died.
"The drug will be an incredible advance if it works in patients," says Andrew Marks, M.D., chairman of physiology and cellular biophysics at P&S, director of the Center for Molecular Cardiology, and leader of the study. "It represents the beginning of an era when drugs will directly fix the molecular defects in heart failure. While our drug is one of the first molecular-based therapies for heart failure and arrhythmias,
it won't be the last."

Researchers Bypass a Spinal Cord Injury to Restore Motor Function
An innovative surgical procedure that restores a connection to limbs paralyzed by spinal cord injury has passed its first test, reports a study published in the March 3, 2004, Journal of Neuroscience. Within weeks after a spinal cord injury, an impenetrable scar forms, preventing any hope of re-establishing connections through the damaged site. While other researchers work on ways to prevent the scar from forming, Columbia's John Martin, David Chiu, and Richard Ambron decided to leap over it.
Their unique procedure redirects a nerve that normally travels from the spinal cord to abdominal muscles and tells these muscles to contract. In rats with paralyzed rear legs, the researchers detached the nerve from the abdominal muscles and inserted the end into the spinal cord below the injury site. The inserted nerve sprouted new connections into the cord and restored mobility in the leg when the nerve was electrically stimulated. The rats must be trained to move the leg on their own, but if they pass this next test, the authors hope continued work on the technique will lead to clinical trials within the next few years.

ILLUSTRATIONS: CLAUDIA BRANDENBURG

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