March 2017

Complexity variability assessment of nonlinear time-varying cardiovascular control

Theories from advanced mathematics and physics have long been applied to gain knowledge on cardiovascular control (how the nervous system controls the heart) in health and heart-related disease. However, previous attempts could account for one single measure in time only, which limits scientific results and conclusions. This study applied multiple advanced math measures of cardiovascular control over time. In considering the variability of these novel measures, authors discovered a potential biomarker of physiological well-being (similarly to a thermometer that detects fever). This biomarker was proven effective in detecting heart failure, as well as mental and neurological diseases including depression, Parkinson's, and post-traumatic stress disorder.

Summary provided by Riccardo Barbieri, PhD, of the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital, and senior author of the study.

Dopamine in the medial amygdala network mediates human bonding

Healthy mothers watched a film of their own infant and a film of an infant they didn’t know during simultaneous fMRI and PET brain scanning. When mothers watched films of infants, their brains produced a chemical called dopamine that supports motivation and effort. When watching their own infants (as compared to infants they didn’t know), mothers who produced more dopamine were more likely to provide optimal care for their infants, be more sensitive to their infants’ needs and adjust their own behavior to meet those needs. Our findings suggest that mothers who produce more dopamine will be more motivated to care for their infants (i.e., they will pay more attention and work harder to care for their infants), which may result in healthy infant development and better outcomes for their child.

Summary provided by Lisa Feldman Barrett, PhD, of the Martinos Center for Biomedical Imaging at Mass General and of Northeastern University, and the corresponding author of the study.

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

Those with the genotype APOE-e44 are at increased risk for Alzheimer's dementia. Statistical models have estimated that the risk of these individuals developing the disease could be as high as 67%, thus such individuals are targeted in prevention studies. To better estimate risk based on direct observation, we examined data from 16,844 individuals (292 with APOE-e44) from four different samples followed over time. The risk of developing dementia or Mild Cognitive Impairment (MCI, a milder condition that often leads to dementia) at five years varied widely across the samples, but in general was close to 0 at age 60 and rose to ~20% with age. Lifetime risk (assessed in the two samples with sufficient follow-up) was ~40%. Overall, less education, memory problems and family history of dementia increased the risk, and differences in these factors, along with varying study methodologies, likely accounted for differences across the samples. The study showed that the risk of Alzheimer's dementia with APOE-e44 is lower than previously estimated, and that risk estimates are critically dependent on a specific study's methodology.

Summary provided by Deborah Blacker, MD, SCD, Director of the Gerontology Research Unit in the Department of Psychiatry at Massachusetts General Hospital, and senior author of the study.

Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition

William Dean Carlson, MD, PhD, used the structure of BMP7 (a protein in the body that is critical for the formation of vital organs and promotes cartilage and bone growth) to design a number of compounds that could mimic its function. These compounds can manipulate pre-existing stem cells, resulting in the repair of damaged organs such as the heart, lung, kidney and liver. Knowing that the formation of cancer stem cells leads to recurrences in breast and prostate cancer, Dr. Carlson wondered whether the compounds he designed could be used to control cancer stem cells which are associated with higher rates of metastasis and poor patient outcomes. Results, recently published in Biochemical Society Transactions, show that one of the compounds can both prevent the formation of cancer stem cells and also reverse the process, driving cancer stem cells back to a state that is less resistant to standard chemotherapy. These results demonstrate how harnessing the BMP pathway could lead to the development of novel therapies to treat metastatic breast and prostate cancer.

Genetics of coronary artery disease: discovery, biology and clinical translation

A family history was first recognized as a major risk factor for having a heart attack, caused by coronary artery disease, in work led by MGH cardiologist Paul Dudley White in the 1950s. Since then, tremendous effort has gone into carefully dissecting out the genetic drivers of this increased risk. Drs. Amit V. Khera and Sekar Kathiresan of the MGH Center for Genomic Medicine recently outlined this tremendous progress and provided a framework for ongoing work to integrate human genetics into drug development, risk prediction, and precision medicine.

Summary provided by Sekar Kathiresan, MD, the Director of the Center for Genomic Medicine at Massachusetts General Hospital, and lead author of the study.

Six degree-of-freedom knee joint kinematics in obese individuals with knee pain during gait

One-third of US adults are obese and many of them suffer from knee pain. However, walking is often prescribed as part of weight management programs. With our dual-fluoroscopic imaging system accurately measuring joint movements, we found obese individuals kept their knees more flexed when walking with reduced overall range of motion in the six-degree-of-freedom kinematic movement analysis. Increasing knee joint range of motion while walking should be addressed. This could potentially better distribute contact stress to prevent local stress concentration.

Summary provided by Jing-Sheng Li is corresponding author. Guoan Li, PhD, Director of the Bioengineering Laboratory at Massachusetts General Hospital, and Tsung-Yuan Tsai, PhD, from the Bioengineering Laboratory, are co-authors of the study.

High risk, high reward: An analysis of outcomes for candidates awaiting hepatic re-transplantation

Liver transplantation is the best treatment option for patients with chronic liver failure. A second liver transplantation is a feasible option for recipients who experience liver failure after their first transplant. However, given the technical complexity of liver re-transplantation and the scarce availability of donor organs, the decision to pursue a second liver transplant is challenging from multiple standpoints. Researchers demonstrated that when re-transplantation is performed in an experienced and skilled care center, patients can achieve long-term survival and avoid the nearly guaranteed and often swift death that comes with liver transplant failure.

Summary provided by Parsia Vagefi, MD, senior author of this study and Associate Surgical Director of Liver Transplantation and the Surgical Director of Living Donor Liver Transplantation at Massachusetts General Hospital.

Patient-identified events implicated in the development of body dysmorphic disorder

Body dysmorphic disorder (BDD) is a distressing and impairing illness characterized by a preoccupation with a perceived flaw in appearance. Stressful events during childhood may contribute to the onset of BDD. In this study, 165 adults with BDD were asked whether they attribute the onset of symptoms to a life event; 37.6% of patients answered yes. The most common event was being bullied during grade school or middle school, highlighting the importance of prevention programs that reduce childhood bullying.

Summary provided by Hilary Weingarden, PhD, of the Department of Psychiatry at Massachusetts General Hospital, and corresponding author of the study.

Fracture risk after bariatric surgery: Roux-en-Y gastric bypass versus adjustable gastric banding

The long-term consequences of weight-loss surgery on bone health are unclear but likely vary by procedure type. Our study compared fracture rates after two common weight-loss surgeries, Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB). We found that RYGB is associated with increased risk of non-spine fracture in obese adults compared with AGB. In particular, RYGB was associated with a higher risk of hip and wrist fractures. Fracture risk should be considered in risk/benefit discussions of these surgeries, particularly for patients at high risk for weak or brittle bones.

Summary provided by Elaine W. Yu, MD, MMSc, the Co-Director of the Bone Density Center at Massachusetts General Hospital, and lead author of the study.

Functions of replication protein A as a sensor of R loops and a regulator of RNaseH1

Genome instability is a hallmark of cancers that leads to an increase in genetic alterations, which enables cancer progression. Replication Protein A (RPA) is a protein complex that senses different types of DNA damage and prevents genome instability. Massachusetts General Hospital researchers reported a novel function of RPA where it can sense R loops (a RNA:DNA hybrid transcription intermediate that is a major source of genomic instability) and regulate R loop levels in cells through its interaction with RNaseH1, an enzyme that suppresses R loops. Thus, in addition to RPA’s known roles in sensing DNA damage and replication stress, the authors extend the versatile function of RPA to the suppression of genome instability.

ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. Mutations in these genes result in an increased risk for breast and ovarian cancers (i.e. BRCA cancers). PARP helps repair DNA when it becomes damaged and PARP inhibitors are used to treat BRCA cancers; however, most tumors become resistant to this targeted therapy. This study shows that BRCA1 deficient tumors become resistant by bypassing two functions of BRCA1 and simultaneously becoming more dependent on ATR, a DNA damage response protein, for survival. Thus, ATR inhibition can overcome PARP inhibitor resistance in BRCA cancers. These results will likely be applicable to treatment of many breast and ovarian cancers.

Summaries provided by Lee Zou, MD, PhD, corresponding author of both studies.


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