Microbiology:
Findings Recommend Herpes Vaccine for Human Trials
Immunology:
Genetic Battleground Marked Between HIV and Host
Biological Chemistry:
Disparate Proteins Structurally Identical
Neuroscience:
Brain Region Senses Setbacks, Redirects Action
Faculty Development:
First African-American Pediatrics Professor at HMS Asserts Value of Mentoring
Anti-angiogenesis Drug Improves Response To Radiation Therapy
Brain Wave Abnormalities May Explain Schizophrenic Hallucinations
Extended Shifts Raise Interns’ Risk of Having A Car Wreck
Cancer Institute Announces Awards to Speed Cancer Biomarker Discovery
MD-PhD Program Splits into Two Tracks
Faculty Applications Sought for Fellowship in Medical Education
Dale Named Dean for Research Integrity
News Brief
Honors and Advances
Baghdad to Boston and Back
Anti-angiogenesis Drug Improves Response to Radiation Therapy
Investigators from Massachusetts General Hospital have discovered a new use for the cancer drug DC101, an antibody against vascular endothelial growth factor receptor 2. Originally designed to destroy tumor vasculature, DC101 can actually normalize tumor blood vessels and improve tumor response to radiation therapy during a specific time window after treatment, according to their paper in the December Cancer Cell. The study was led by co–first authors Frank Winkler and Sergey Kozin, research fellows in the laboratory of Rakesh Jain, the Andrew Werk Cook professor of radiation oncology (tumor biology) at MGH.
A therapeutic window. Low doses of the angiogenesis inhibitor DC101 make abnormal tumor vessels more normal in their form, cell structure, and thickness, rendering tumors more vulnerable to radiation. (Image by Jeff Cleary)
While a high dose of anti-VEGF (vascular endothelial growth factor) antibodies can kill most tumor blood vessels, it causes too much toxicity. Previous work demonstrated that low-dose DC101 treatment can, for a short while, change abnormal tumor vasculature to better resemble that of normal tissue. This led Jain to a novel hypothesis. “Radiotherapy depends on the creation of toxic oxygen radicals,” he said, “so improving tumor oxygenation during a specific time window might also improve the response to radiotherapy during that window.”
Winkler and Kozin treated human glioblastoma xenografts in the brains of mice with combinations of DC101 and gamma radiation. In most cases, the effects of combined treatment were additive, but when radiotherapy was given on days 4 to 6 after DC101 treatment, the effect on tumor growth was synergistic. This window of maximum effectiveness was correlated with increased tumor oxygenation, reduced tumor blood vessel density, and the degradation of the pathologically thick basement membranes of tumor vessels. In addition, DC101 therapy led to upregulation of angiopoietin-1, which increased the recruitment of pericytes to tumor vessels; these cells coat the outside of mature blood vessels.
“We have shown that there is an optimal time of tumor vascular normalization at which to administer radiotherapy after DC101 treatment,” said Jain. Future work will examine whether vascular normalization can also benefit chemotherapy patients. “We are moving very actively to test this concept in the clinic for patients with brain, head, and neck tumors,” he added.
More information about vascular normalization after anti-angiogenic treatments appears in Jain’s review in the Jan. 7 Science.
—Jillian Lokere
Brain Wave Abnormalities May Explain Schizophrenic Hallucinations
Abnormalities in the brain waves of schizophrenic patients may be responsible for the visual hallucinations and delusions that characterize this disease, according to a study in the Dec. 7 Proceedings of the National Academy of Sciences. Researchers at Boston Veterans Affairs Medical Center found through EEG recordings that the brains of schizophrenic patients produced abnormally low-frequency waves when responding to a perception task, indicating a dysfunction in brain synchronization. The extent of the improper response correlated with the severity of the symptoms.
The Gestalt perception task used in the study, whose lead author is Kevin Spencer, HMS instructor in psychiatry, required subjects to press a button if they saw an illusory square in an image. Healthy subjects’ brains respond in two stages: stimulus-locked and response-locked gamma activity. Immediately upon receiving input from the image, neurons in the occipital cortex, the visual center of the brain, fire a synchronous burst of gamma frequency waves (30 to 80 Hz), which constitute the stimulus-locked activity. These appear to be responsible for bringing diverse features into a single perception.
“When you see a fire truck, that’s how your brain puts together the color red, the shape of the truck, the movement, the siren, and the smell of diesel into a single percept,” said senior author Robert McCarley, HMS professor of psychiatry and head of that department at the Boston VA. The next stage, response-locked gamma activity, occurs about 250 milliseconds before the button press response. McCarley said that “this may represent a reactivation of the neurons responsible for putting together the original percept.”
Earlier work found that schizophrenic subjects failed to exhibit stimulus-locked gamma activity when presented with the Gestalt images. Here, the authors found that schizophrenic subjects also failed to exhibit response-locked gamma activity, showing a response-locked burst of low-frequency activity instead. “This may indicate less efficient communication among neurons,” said McCarley, because the strongest nongamma activity was shown by patients with the most severe schizophrenia symptoms.
Although all the subjects with schizophrenia were on medication, none of these affected the gamma activity. “We need to look elsewhere for medications that might influence gamma activity to better treat these patients,” McCarley said.
—Jillian Lokere
Extended Shifts Raise Interns’ Risk of Having
A Car Wreck
Medical interns who work extended shifts of 24 hours or more are more likely to be involved in motor vehicle crashes and near misses, according to a study in the Jan. 13 New England Journal of Medicine. This latest evidence adds fuel to the debate over resident hours and suggests that the long shifts residents routinely work pose a safety hazard to them and others.
The study was conducted by the Harvard Work Hours, Health, and Safety Group, headed by Charles Czeisler, the Frank Baldino, Jr., Ph.D. professor of sleep medicine at HMS and Brigham and Women’s. The researchers conducted a prospective, Web-based survey of 2,737 interns across the country who submitted monthly reports of work hours, shift length, and documentation of any motor vehicle crashes or near-miss incidents they experienced over the year. The researchers assessed whether their number of scheduled extended shifts correlated with the subsequent occurrence of crashes. “From that analysis, we found that for each extended-duration shift they work per month, there was a 16 percent increase in the monthly risk of a motor vehicle crash driving home from work, and they could be scheduled for as many as 10 extended shifts per month by current guidelines,” Czeisler said.
The team, led by Laura Barger, HMS clinical fellow in medicine at BWH, also examined whether each subject was more likely to experience an incident on the road after an extended shift. The analysis showed that interns had more than double the odds of having a motor vehicle wreck on the commute home from an extended shift and more than five times the odds of having a near-miss incident than they did after working a shift of 12 hours or less.
Czeisler’s group has previously conducted research at the Brigham showing that interns who worked longer shifts exhibited more fatigue and committed more medical errors (see Focus, Nov. 12, 2004). This latest evidence raises the stakes of the debate by demonstrating that long shifts may not only harm residents and possibly patients, but pedestrians and other drivers. Czeisler believes the study underestimates the true risk because it compared acute sleep deprivation after a long shift and could not measure the effects of chronic sleep deprivation. Previous studies have found that sleep deprivation is similar to alcohol in its impairment of driving.
Last summer, the Accreditation Council for Graduate Medical Education (ACGME) set guidelines that limit resident hours for the first time, setting caps on the maximum shift length and hours worked per week. But these guidelines allow for scheduled shifts of up to 30 hours and a workweek of up to 80 hours. Czeisler says these caps do not place adequate limits on resident work hours and, in fact, make dangerously long work hours official. “The ACGME is the only nationally recognized regulatory body of any kind that continues to sanction 30-hour shifts,” he said. “Unfortunately, this establishes as a national standard a practice that endangers these trainees as they drive home from work.”
—Courtney Humphries