Research Round-up- Clinical & Research News - For and about the Physicians and Researchers of Brigham and Women's HospitalResearch Round-up- Clinical & Research News - For and about the Physicians and Researchers of Brigham and Women's Hospital

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Research Round-up

Proteins and Plaques


Tracy Young-Pearse, PhD

A research team led by Tracy Young-Pearse, PhD, BWH assistant professor, and senior study author is the first to report a biochemical interaction between two specific proteins involved in cortical brain development. In the study, the researchers used mass spectrometry screening technology to identify factors that bind to amyloid precursor protein. This protein is concentrated in nerve cells and is the precursor to amyloid plaques, which are found in the brains of patients with Alzheimer's disease.

The researchers identified an interaction between amyloid precursor protein and pancortins, which are proteins expressed during cerebral cortex development. Further experiments showed that pancortins act together with amyloid precursor protein to mediate migration of cells in the developing cerebral cortex.

"It is important to identify factors that affect the generation of amyloid through cleavage of amyloid precursor protein," said Young-Pearse. "Our study identifies a previously unappreciated interaction between pancortins and amyloid precursor protein, shows that these proteins interact functionally to mediate migration, and that this interaction inhibits the generation of amyloid. Future studies will investigate how this interaction leads to decrease amyloid production, and perhaps give us clues to how we can prevent amyloid accumulation in the brain."

The study was published in the September 19, 2012 online issue of Development. 

Tumor-fighting Drug Induces High Blood Pressure


Benjamin Humphreys, MD, PhD

Previous research has shown that antiangiogenic therapies-a rapidly growing class of cancer therapy that is highly effective-causes hypertension in 10 percent to 40 percent of patients. Although the mechanisms are not completely understood, studies have implicated endothelin-1, a protein that constricts blood vessels and raises blood pressure, and nitric oxide, a molecule that dilates blood vessels and lowers blood pressure.

Now a new study led by Benjamin Humphreys, MD, PhD, BWH Renal Division, Department of Medicine, has found that regorafenib, an antiangiogenic therapy induces a coordinated and reversible suppression of nitric oxide and stimulation of endothelin-1, providing further insight about how this class of cancer therapy causes hypertension in patients. 

After administering regorafenib to 32 research participants with gastrointestinal stromal tumor, the researchers noticed that 63 percent of the participants developed regorafenib-induced hypertension, as well as an increase in endothelin-1 plasma levels and a decrease in nitric oxide levels.

"These results suggest that systemic vasoconstriction, caused by increased endothelin-1 and decreased nitric oxide, underlies the hypertension experienced by many patients on these drugs," said Humphreys. "This knowledge will help us to prescribe appropriate blood pressure medications so patients can safely continue this effective class of cancer therapy, and it also suggests that endothelin-1 and nitric oxide changes could help us predict which patients are most likely to have a favorable response to therapy."

The study is published in the October 2012 issue of the American Journal of Hypertension.

Modeling Dynamic Changes in Human Gut Microbial Populations

Georg Gerber, MD, PhD, MPH and Lynn Bry, MD, PhD in the BWH Center for Clinical and Translational Metagenomics developed a new computational method that models how human microbial ecosystems respond over time to disturbances; for instance, such as when an individual is treated with antibiotics. These rich microbial ecosystems play important roles in health and disease.

After applying their computational method to a large publicly available dataset, the researchers observed sub-populations of microbes across human subjects that share specific physiological roles and responses. These findings offer new insights into the diversity of dynamic responses to antibiotics among microbes in the human body.


Georg Gerber, MD, PhD, MPH

According to the researchers, the study has provided an integrated computer-based method for automatically discovering patterns of change over time in the microbes that live in our bodies. The work will help the research community design future experiments to help identify causative communities that promote human health or contribute to development of disease.

The study was published in the August 2012 issue of PLoS Computational Biology.

Helping Chile's Children


MaryCatherine Arbour, MD, MPH

BWH researchers have conducted a study that may help Chile expand its system for early childhood development, an expansion that had been stymied by lack of consensus about how to identify at-risk children. The study facilitated a process for incorporating local priorities and best practices to choose a child assessment instrument that would accurately assess developmental risk.

Using the priority-setting method of the Child Health and Nutrition Research Initiative, researchers engaged local experts to weigh ideal assessment instrument characteristics and used those weights to rank existing instruments under different inclusion criteria, such as instrument quality, administration site, cost, time and prior use in Chile. Ideal instruments were those that would reliably assess language, socioemotional well-being, mental health and parenting abilities; as well as those that could be administered at school or at home by teachers or parents.

Three instruments met 11 of 13 criteria. The researchers concluded that the findings from this study will allow for informed instrument selection with explicit negotiation and trade-offs by Chilean decision-makers; and the Child Health and Nutrition Research Initiative method provided a useful process for identifying instruments that best meet local needs and priorities.

"An estimated 200 million children around the world are not meeting their full developmental potential, and there is no single established, standardized instrument for assessing child development," said MaryCatherine Arbour, MD, MPH, BWH Division of Global Health Equity, and first study author. "There is growing consensus that decisions about how to assess developmental risk among children must be informed by local contexts, needs and priorities, but there are few examples of how to apply such principles.  While the findings from this study are specific to Chile, the process, methods and data have important implications for the selection of appropriate child assessment instruments across diverse contexts."

The study is published in the October 2012 issue of the Journal of Developmental & Behavioral Pediatrics.