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Snapshot of Science

Overview

Welcome to the July 2017 Snapshot of Science, a quick look at recent research publications, press releases and articles featuring investigators from Massachusetts General Hospital.

This month, we highlight:

This is just a small snapshot of the incredible research that takes place at Mass General each day—there's lots more to find at massgeneral.org/research/news.


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Publications List

PROTECTING AGAINST TUBERCULOSIS
A Small-Molecule Allosteric Inhibitor of Mycobacterium Tuberculosis Tryptophan Synthase 
Wellington, S., Nag, P.P., Michalska, K., Johnston, S.E., Jedrzejczak, R.P., Kaushik, V.K., [et al.] Hung, D.T.
Published in Nature Chemical Biology on July 3, 2017 | Summary available


PSYCHOPATHY AND DECISION MAKING
Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy Hosking, J.G., Kastman, E.K., Dorfman, H.M., Samanez-Larkin, G.R., Baskin-Sommers, A., Kiehl, K.A., Newman, J.P., Buckholtz, J.W.
Published in Neuron on July 5, 2017


CHILDHOOD OBESITY AND COMMUNITY RESOURCES
A Community Resource Map to Support Clinical-Community Linkages in a Randomized Controlled Trial of Childhood Obesity, Eastern Massachusetts, 2014-2016
Fiechtner, L., Puente, G.C., Sharifi, M., Block, J.P., Price, S., Marshall, R., Blossom, J., Gerber, M.W., Taveras, E.M.
Published in Preventing Chronic Disease on July 6, 2017 | Summary available


MOLECULE SHAPE AND ALZHEIMER'S DISEASE
Isoform and cell type-specific structure of apolipoprotein E lipoparticles as revealed by a novel forster resonance energy transfer assay
Kara, E., Marks, J.D., Fan, Z., Klickstein, J.A., Roe, A.D., Krogh, K.A., [et al.] Hyman, B.T.
Published in Journal of Biological Chemistry on July 6, 2017 | Summary available


HIGH RESOLUTION IMAGES AND LYMPH NODES
Murine chronic lymph node window for longitudinal intravital lymph node imaging
Meijer, E.F.J., Jeong, H.S., Pereira, E.R., Ruggieri, T.A., Blatter, C., Vakoc, B.J., Padera, T.P.
Published in Nature Protocols on July 6, 2017 | Summary available


GENETIC MUTATIONS AND BREAST CANCER
Recurrent and functional regulatory mutations in breast cancer
Rheinbay, E., Parasuraman, P., Grimsby, J., Tiao, G., Engreitz, J.M., Kim, J., [et al.] Getz, G.
Published in Nature on July 6, 2017 | Summary available


LYMPH NODES AND METASTASES
Origins of lymphatic and distant metastases in human colorectal cancer
Naxerova, K., Reiter, J.G., Brachtel, E., Lennerz, J.K., van de Wetering, M., Rowan, A., [et al.] Jain, R.K.
Published in Science on July 7, 2017 | Summary available


GENE EXPRESSION AND SEX CHROMOSOME PAIRING
Par-Terra directs homologous sex chromosome paring
Chu, H.P., Froberg, J.E., Kesner, B., Oh, H.J., Ji, F., Sadreyev, R., Pinter, S.F., Lee, J.T.
Published in Nature Structural and Molecular Biology on July 10, 2017 | Summary available


CELLULAR CATALYSTS AND CANCER TREATMENT
Nano-palladium is a cellular catalyst for in vivo chemistry 
Miller, MA, Askevold, B, Mikula H, Kohler RH, Pirovich D, Weissleder R.
Published in Nature Communications on July 12, 2017 | Summary available


ENVIRONMENTAL AND HUMAN MICROBIOTA
Impact of environmental microbiota on human microbiota of workers in academic mouse research facilities: An observational study
Lai, P.S., Allen, J.G., Hutchinson, D.S., Ajami, N.J., Petrosino, J.F., Winters, T., [et al.] Christiani, D.C.
Published in PLOS ONE on July 13, 2017 | Summary available


PERIPHERAL NERVE STIMULATION IN MRI
Predicting Magnetostimulation Thresholds in the Peripheral Nervous System using Realistic Body Models
Davids, M., Guerin, B., Malzacher, M, Shad, L. and Wald, L.L.
Published in Scientific Reports on July 13, 2017


CANCER-KILLING VIRUSES AND BRAIN TUMORS
Stem Cell-Released Oncolytic Herpes Simplex Virus Has Therapeutic Efficacy in Brain Metastatic Melanomas
Du, W., Seah, I., Bougazzoul, O., Choi, G., Meeth, K., Bosenberg, M.W., Wakimoto, H., Fisher, D., Shah, K.
Published in PNAS on July 14, 2017 | Summary available


VACCINE RESPONSE AND INFRARED LASERS
Near-Infrared 1064 nm Laser Modulates Migratory Dendritic Cells To Augment the Immune Response to Intradermal Influenza Vaccine 
Morse, K., Kimizuka, Y., Chan, M.P.K., Shibata, M., Shimaoka, Y., Takeuchi, S., [et al.] Kashiwagi, S.
Published in the Journal of Immunology on July 14, 2017 | Summary available


CORONARY ARTERY DISEASE AND THE HUMAN GENOME
Genetic Analysis in UK Biobank Links Insulin Resistance and Transendothelial Migration Pathways to Coronary Artery Disease
Klarin, D., Zhu, Q.M., Emdin, C.A., Chaffin, M., Horner, S., McMillan, B.J.,...Kathiresan, S.
Published in Nature Genetics on July 17, 2017


METABOLISM, McARDLE DISEASE AND MITOCHONDRIAL MYOPATHY
Metabolic Profiles of Exercise in Patients with McArdle Disease or Mitochondrial Myopathy
Delaney, N.F., Sharma, R., Tadvalkar, L., Clish, C.B., Haller, R.G., Mootha, V.K. Published in PNAS on July 17, 2017 | Summary available


CHEMOTHERAPY-INDUCED PAIN
Gut Microbiota is Critical for the Induction of Chemotherapy-Induced Pain
Shen, S., Lim, G., You, Z., Ding, W., Huang, P., Ran, C., [et al.] Mao, J.
Published in Nature Neuroscience on July 17, 2017 | Summary available


GENES AND STARVATION RESISTANCE
Genome-wide RNAi screen for fat regulatory genes in C. elegans identifies a proteostasis-AMPK axis critical for starvation survival
Webster, C.M., Pino, E.C., Carr, C.E., Wu, L., Zhou, B., Cedillo, L., [et al.] Soukas, A.A.
Published in Cell Reports on July 18, 2017 | Summary available


HUMAN BRAIN NETWORKS
Parallel interdigitated distributed networks within the individual estimated by intrinsic functional connectivity
Braga, R.M., Buckner, R.L.
Published in Neuron on July 19, 2017 | Summary available


SYNAPSE DEVELOPMENT
Retrograde synaptic inhibition Is mediated by α-neurexin binding to the α2δ subunits of n-yype calcium channels
Tong XT, Lopez-Soto J, Li L, Liu H, Nedelcu D, Lipscombe D, Hu Z, Kaplan JM.
Published in Neuron on July 19, 2017


FRONTOTEMPORAL DEMENTIA
Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia
She, A., Kurtser, S.A., Reis, K.H., Lai,J., Lang, A., Zhao, W., Mazitschek, R., Dickerson, B.C., Herz, J., Haggarty, S.J.
Published in Cell Chemical Biology on July 20, 2017


ZEBRAFISH AORTA FORMATION TGF-β
Signaling Is Necessary and Sufficient for Pharyngeal Arch Artery Angioblast Formation
Abrial, M., Paffett-Lugassy, N., Jeffrey, S., Jordan, D., O’Loughlin, E., Frederick 3rd, C.J., Burns, C.G., Burns, C.E.
Published in Cell Reports on July 25, 2017  | Summary available


ANESTHETIC DRUGS AND CONSCIOUSNESS
Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness
Flores, F.J., Kartnack, K. E., Fath, A.B., Kim, S., Wilson, M.A., Brown, E. N., Purdon, P.L.
Published in PNA on July 25, 2017 | Summary available


EMBRYONIC STEM CELL DEVELOPMENT
Prolonged Mek1/2 Suppression Impairs the Developmental Potential of Embryonic Stem Cells
Choi, J., Huebner, A.J., Clement, K., Walsh, R.M., Savol, A., Lin, K., [et al.] Hochedlinger, K.
Published in Nature on July 26, 2017 | Summary available


TREATING GIANT-CELL ARTERITIS WITHOUT STEROIDS
Trial of Tocilizumab in Giant-Cell Arteritis
Stone, J.H., Tuckwell, K., Dimonaco, S., Klearman, M., Aringer, M., Blockmans, D., [et al.] Collinson, N.
Published in New England Journal of Medicine on July 27, 2017 | Summary available


GENETICS AND VASCULAR DISEASE
A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
Gupta, R.M., Hadaya, J., Trehan, A., Zekavat, S.M., Roselli, C., Klarin, D. [et al]. Kathiresan, S.
Published in Cell on July 27, 2017

Publication Summaries

PROTECTING AGAINST TUBERCULOSIS
A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase
Wellington, S., Nag, P.P., Michalska, K., Johnston, S.E., Jedrzejczak, R.P., Kaushik, V.K., [et al.] Hung, D.T.
Published in Nature Chemical Biology on July 3, 2017

Scientists in the Hung lab discovered a new inhibitor against Mycobacterium tuberculosis, the causative agent of tuberculosis, which is the leading cause of infection-related deaths worldwide. There is a desperate need for new TB antibiotics in the face of rising drug resistance. The small molecule functions by inhibiting tryptophan biosythesis, a process that has not been previously targeted by antibiotics. Importantly, tryptophan biosynthesis is essential for the survival of M tuberculosis in animal models. The unique and complex mechanism of the molecule suggests general strategies for the design and discovery of new inhibitors.

(Summary submitted by Deborah Hung, MD, PhD, Center for Computational and Integrative Biology)


CHILDHOOD OBESITY AND COMMUNITY RESOURCES
A community resource map to support clinical-community linkages in a randomized controlled trial of childhood obesity, Eastern Massachusetts, 2014-2016
Fiechtner, L., Puente, G.C., Sharifi, M., Block, J.P., Price, S., Marshall, R., Blossom, J., Gerber, M.W., Taveras, E.M.
Published in Preventing Chronic Disease on July 6, 2017

Giving families information on healthy and affordable community resources through novel mapping tools can lead to increased parental satisfaction and positive childhood obesity interventions. Interviewing parents, community partners and experts on child obesity and the "built environment," researchers created an online interactive map to identify healthy resources in environments with high rates of childhood obesity. Parents identified poor access to healthy food and easy access to fast-food as barriers to healthy weight in their community. Researchers also found that nutrition resources, physical activity and social support were important for success in reducing childhood obesity. Using the map, families were physically active at new locations, shopped at new locations and reported a high satisfaction level with the information they received.

(Summary submitted by Lauren Fiechtner, MD, MPH, Director for the Center for Pediatric Nutrition at Massachusetts General Hospital for Children)


MOLECULE SHAPE AND ALZHEIMER'S DISEASE
Isoform and cell type-specific structure of Apolipoprotein E lipoparticles as revealed by a novel Forster Resonance Energy Transfer assay
Kara, E., Marks, J.D., Fan, Z., Klickstein, J.A., Roe, A.D., Krogh, K.A., [et al.] Hyman, B.T.
Published in Journal of Biological Chemistry on July 6, 2017

Apolipoprotein E is a molecule that is present in both the blood and the brain. It can be inherited in one of 3 forms, called E2, E3, or E4. While people who inherit E2, E3 or E4 are completely normal in almost every way, individuals who have the E4 gene have a 3 times higher chance of getting Alzheimer's disease as they age. To understand what is different between E2, E3, and E4, Dr. Eleanna Kara in Dr. Brad Hyman's lab developed a way to measure the shape of the molecules, which she found differ from one another in a substantial way. This may be the first step to understanding how E4 increases the risk for Alzheimer's, and a tool to develop drugs to change the shape of E4 to something that is more like E3 and E2.

(Summary submitted by Bradley Hyman, MD, PhD, Alzheimer's Unit Director for the Mass General Institute for Neurodegenerative Disease)


HIGH RESOLUTION IMAGES AND LYMPH NODES
Murine chronic lymph node window for longitudinal intravital lymph node imaging
Meijer, E.F.J., Jeong, H.S., Pereira, E.R., Ruggieri, T.A., Blatter, C., Vakoc, B.J., Padera, T.P.
Published in Nature Protocols on July 6, 2017

Chronic imaging windows in mice have been developed to allow high resolution images of multiple organs in living animals. These techniques have proven to be of paramount importance in advancing our knowledge of normal and disease processes. However, no model system that allowed long-term, live animal imaging of lymph nodes had been developed. This has been a major limitation in the study of cell behavior in lymph nodes during the generation of immune responses as well during the spread of cancer to lymph nodes. This manuscript describes a novel surgical preparation to facilitate long-term, live animal imaging of a lymph node in mice.

(Summary submitted by Timothy Padera, PhD, Edwin L. Steele Laboratories for Tumor Biology in the Department of Radiation Oncology)


GENETIC MUTATIONS AND BREAST CANCER
Recurrent and Functional Regulatory Mutations in Breast Cancer
Rheinbay, E., Parasuraman, P., Grimsby, J., Tiao, G., Engreitz, J.M., Kim, J., [et al.] Getz, G.
Published in Nature on July 6, 2017

Previous genomic analyses of many tumors have discovered hundreds of cancer genes with mutations in protein-coding regions. By contrast, we do not yet know much about cancer-causing mutations in non-coding regions that regulate important genes. This study found that breast cancers hide potentially important mutations in the promoters of at least nine genes. Promoters are noncoding stretches of DNA just before genes, where the cell’s DNA-reading machinery latches on to start the transcription process. In addition to highlighting several genes not previously thought to be involved in breast cancer, the team’s findings offer new insights into how one known cancer gene may help breast tumors thrive in the face of treatment.

(Summary submitted by Gad Getz, PhD, Director of Bioinformatics at the Cancer Center and Department of Pathology)


LYMPH NODES AND METASTASES
Origins of lymphatic and distant metastases in human colorectal cancer
Naxerova, K., Reiter, J.G., Brachtel, E., Lennerz, J.K., van de Wetering, M., Rowan, A., [et al.] Jain, R.K.
Published in Science on July 7, 2017

Cancer patients who have metastases in the lymph nodes surrounding the tumor have a worse prognosis than patients whose lymph nodes are cancer-free. This observation has traditionally been explained by a progression model in which lymph node metastases come before lethal organ metastases. However, no conclusive evidence for this model existed so far. In this study, researchers investigated the "family tree" of metastases in colorectal cancer and found that in most cases, lymph node metastases did not come before organ metastases. They concluded that lymph node metastases are indicators of an aggressive primary tumor, but not necessarily the cause of distant metastases.

(Summary submitted by Kamila Naxerova, PhD, Edwin L. Steele Laboratories for Tumor Biology in the Department of Radiation Oncology)


GENE EXPRESSION AND SEX CHROMOSOME PAIRING
PAR-TERRA directs homologous sex chromosome pairing
Chu, H.P., Froberg, J.E., Kesner, B., Oh, H.J., Ji, F., Sadreyev, R., Pinter, S.F., Lee, J.T.
Published in Nature Structural and Molecular Biology on July 10, 2017

When only one allele of a gene is actively transcribed, how is this expression established through sex chromosome pairing, and how do these chromosomes find each other in the 3D nucleus? This paper shows that sex chromosomes of both male and female embryonic stem cells briefly pair when they develop from a less specialized cell to a more specialized cell type. This pairing is critical for inactivating the X chromosome and is directed by a transcription made from the homologous sex-linked ends of the sex chromosomes, called PAR-TERRA. PAR-TERRA tethers the sex chromosomes together via the ends of the chromosomes (telomeres) at the nuclear periphery. The telomeres in turn enable the inactivated X chromosomes to find each other by constraining the space around them. This work demonstrates the essential nature of long RNA in 3D nuclear dynamics that is transcribed from DNA but not translated into proteins.

(Summary submitted by Jeannie Lee, MD, PhD, Department of Molecular Biology)


CELLULAR CATALYSTS AND CANCER TREATMENT
Nano-palladium is a cellular catalyst for in vivo chemistry
Miller, M.A., Askevold, B., Mikula, H., Kohler, R.H., Pirovich, D., Weissleder, R.
Published in Nature Communications on July 12, 2017

What does a catalytic converter have to do with drugs? A lot, it turns out. Catalytic converters in our cars convert toxic gas emissions into acceptable ones. A key element is the metal palladium, which catalyses the oxidation of pollutants like carbon monoxide to carbon dioxide. In this article, we describe the development of a medical version of nano-palladium to enable chemistry to take place inside cells in our body. The discovery allows the administration of harmless prodrugs, which then get specifically activated at sites of cancer. This work demonstrates the possibility of using palladium as a catalyst for treatment of disease in mammals.

(Summary submitted by Miles Miller, PhD, Center for Systems Biology


ENVIRONMENTAL AND HUMAN MICROBIOTA
Impact of environmental microbiota on human microbiota of workers in academic mouse research facilities: An observational study.
Lai, P.S., Allen, J.G., Hutchinson, D.S., Ajami, N.J., Petrosino, J.F., Winters, T., [et al.] Christiani, D.C.
Published in PLOS ONE on July 13, 2017

The millions of bacteria living in our body, called the human microbiome, play a key role in both keeping us healthy and putting us at risk for chronic diseases. But how do these bacteria get there? In a study focused on workers who care for mice in research facilities, Dr. Lai and her collaborators demonstrate that just as there is a human microbiome, there is also a microbiome in our external environment. A small part of the human microbiome in these workers was traced to the environmental microbiome of their workplace. More research is needed to better understand the health implications of these findings.

(Summary submitted by Peggy Lai, MD, Division of Pulmonary and Critical Care)


CANCER-KILLING VIRUSES AND BRAIN TUMORS
Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas
Du, W., Seah, I., Bougazzoul, O., Choi, G., Meeth, K., Bosenberg, M.W., Wakimoto, H., Fisher, D., Shah, K.
Published in PNAS on July 14, 2017

Our team has developed stem cells that can deliver cancer-killing oncolytic viruses and applied them to metastatic tumors in the brain of clinically relevant mouse models which his team built in parallel to developing the therapeutic strategy. The investigators report the elimination of metastatic skin cancer cells from the brain of these preclinical models, resulting in prolonged survival. The study also describes a strategy of combining this therapy with immune check point inhibitors. This work will have direct implications for designing clinical trials using oncolytic viruses for metastatic tumors in the brain.

(Summary submitted by Khalid Shah, PhD, formerly from the Center for Stem Cell Therapeutics and Imaging in the Department of Radiology)


VACCINE RESPONSE AND INFRARED LASERS
Near-infrared 1064 nm laser modulates migratory dendritic cells to augment the immune response to intradermal influenza vaccine
Morse, K., Kimizuka, Y., Chan, M.P.K., Shibata, M., Shimaoka, Y., Takeuchi, S., [et al.] Kashiwagi, S.
Published in the Journal of Immunology on July 14, 2017

Traditional adjuvants that increase the effectiveness of vaccines for infectious diseases may induce inflammatory reactions in tissues that mobilize and activate immune cells that may result in local and systemic adverse reactions. This study shows for the first time that a non-damaging, low-dose infrared laser delivered to the skin for just one minute, can both activate and enhance migration of a type of skin-resident immune cells called dendritic cells, which can lead to enhancement of vaccine responses without inflammation. The team's laser vaccine adjuvant has proved safe in initial human studies. The next steps are to test the efficacy of this new technology in the context of vaccination in the clinic under the direction of Dr. Gelfand and Dr. Poznansky.

(Summary submitted by Satoshi Kashiwagi, PhD, MD, Assistant Professor of Medicine in the Vaccine and Immunotherapy Center; and Marc C. Poznansky, MD, PhD, Director of the Vaccine and Immunotherapy Center)


METABOLISM, McARDLE DISEASE AND MITOCHONDRIAL MYOPATHY
Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy
Delaney, N.F., Sharma, R., Tadvalkar, L., Clish, C.B., Haller, R.G., Mootha, V.K.
Published in PNAS on July 17, 2017

Human metabolism is "wired" to allow us to go from rest to running by efficiently burning sugars, fats and proteins to harness their energy. However, patients with certain genetic conditions like McArdle disease who cannot access glycogen stores or mitochondrial disease who have broken respiratory chains have symptoms that are exacerbated by exercise. We studied the exercise-induced changes that occur in hundreds of plasma metabolites in healthy individuals, patients who have McArdle disease and mitochondrial disease patients. By comparing these disorders they shed light on the typical metabolic processes that allow us to exercise and also revealed potential disease biomarkers.

(Summary submitted by Rohit Sharma, PhD, from the Department of Molecular Biology)


GUT MICROBIOTA AND CHEMOTHERAPY-INDUCED PAIN
Gut microbiota is critical for the induction of chemotherapy-induced pain
Shen, S., Lim, G., You, Z., Ding, W., Huang, P., Ran, C., [et al.] Mao, J.
Published in Nature Neuroscience on July 17, 2017

Gut microbiota is a collective term for the diverse consortium of microorganisms residing in the gastrointestinal tract. Accumulating evidence supports previously unrecognized roles for gut microbiota in many physiological and pathological processes, for example, gut microbiota is critical to determine the tumor killing effects of many chemotherapy drugs. In this paper, our team provides evidence that chemotherapy-induced pain, a major dose-limiting side effect of many chemotherapy drugs, is fueled by gut microbiota. Findings from this study may lead to new mechanistic insight on chemotherapy-induced pain, and new therapeutic avenues to treat this devastating pain symptom.

(Summary submitted by Jianren Mao, MD, PhD, Chief of the Division of Pain Medicine)


GENES AND STARVATION RESISTANCE
Genome-wide RNAi screen for fat regulatory genes in C. elegans identifies a proteostasis-AMPK axis critical for starvation survival
Webster, C.M., Pino, E.C., Carr, C.E., Wu, L., Zhou, B., Cedillo, L., [et al.] Soukas, A.A.
Published in Cell Reports on July 18, 2017

To better understand how body fat is regulated, a team led by Dr. Alexander Soukas performed a genome-wide screen in the microscopic roundworm Caenorhabditis elegans, identifying 475 fat regulatory genes, most of which are shared with humans. The study found that high fat genes tend to lead to starvation resistance, while low fat genes promote early death from starvation. With this information, the Soukas laboratory can now determine how starvation defenses developed during ancient times of feast or famine now, in times of nutritional excess, lead to the development of obesity, diabetes, and associated cardiometabolic diseases.

(Summary submitted by Alexander Soukas, MD, PhD, from the Center for Genomic Medicine and Diabetes Unit)


HUMAN BRAIN NETWORKS
Parallel interdigitated distributed networks within the individual estimated by intrinsic functional connectivity
Braga, R.M., Buckner, R.L.
Published in Neuron on July 19, 2017

The elegant organization of brain networks important to thought and remembering was revealed in a new study. By examining the details of brain organization in individuals, Rodrigo Braga and Randy Buckner were able to reveal that the human brain possesses multiple networks that connect regions distributed throughout the brain. Strikingly, the multiple networks are intertwined like threads in a tapestry. Prior work blurred over this orderly pattern by averaging across individuals. The newly discovered structure sets a foundation for analysis of the functional properties of the multiple networks as well as clinical endeavors that seek to modulate the networks to treat psychiatric illness.

(Summary submitted by Randy Buckner, PhD, Director of the Psychiatric Neuroimaging Research Division)


ZEBRAFISH AORTA FORMATION
TGF-β signaling is necessary and sufficient for pharyngeal arch artery angioblast formation
Abrial, M., Paffett-Lugassy, N., Jeffrey, S., Jordan, D., O’Loughlin, E., Frederick 3rd, C.J., Burns, C.G., Burns, C.E.
Published in Cell Reports on July 25, 2017

The aorta and its branches are large arteries in the human body that carry oxygen-rich blood from the heart to the rest of the circulatory system. Structural malformations of the aorta are common birth defects that even in the mildest cases require life-saving surgery at birth. During fetal life, the aorta is built from transient blood vessels termed the pharyngeal arch arteries (PAAs). However, the mechanisms regulating formation of the PAAs remain poorly understood. This paper reports that TGFb signaling, a molecular pathway that controls cellular proliferation and differentiation in other contexts, initiates and is essential for PAA development in zebrafish. Despite this important advance, further research is needed to identify additional molecular pathways that control PAA establishment and to learn if mutations that affect TGFb signaling in humans result in similar aortic deficiencies. This information can be leveraged to develop new therapies for preventing or treating congenital malformations that involve the aorta and its branches.

(Summary provided by Caroline Burns, PhD, d'Arbeloff MGH Research Scholar and researcher in the Cardiovascular Research Center)


ANESTHETIC DRUGS AND CONSCIOUSNESS
Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

Flores, F.J., Kartnack, K. E., Fath, A.B., Kim, S., Wilson, M.A., Brown, E. N., Purdon, P.L.
Published in PNA on July 25, 2017

This study finds evidence that propofol, an anesthetic drug frequently used in clinical practice, disrupts activity in the parts of the brain responsible for awareness and coordination by inducing highly synchronized oscillations within and between these brain structures. The study also found that during recovery of consciousness, these synchronized oscillations dissipate in a distinct “boot-up” sequence, one that did not simply mirror loss of consciousness. This implies that recovering consciousness is not just a passive process, but an active one involving a different set of brain areas responsible for “waking up” the brain. Overall, this study advances understanding of what it means to be unconscious under anesthesia, and establishes principled neurophysiological markers to monitor and manage this state.

(Summary provided by Patrick Purdon, PhD, from the Department of Anesthesia, Critical Care, and Pain Medicine)


EMBRYONIC STEM CELL DEVELOPMENT
Prolonged Mek 1/2 suppression impairs the developmental potential of embryonic stem cells

Choi, J., Huebner, A.J., Clement, K., Walsh, R.M., Savol, A., Lin, K. [et al...], Hochedlinger,K.
Published in Nature on July 26, 2017

Inhibition of the kinases Mek1 and Mek2 helps to maintain cultured embryonic stem cells in a primitive state, which closely resembles cells of the early embryo. This approach is widely used in the field to study the molecular basis of stem cell self-renewal and early development. This study found that capturing embryonic stem cells in a dish comes at a cost. Jiho Choi and Aaron Huebner from Konrad Hochedlinger’s lab discovered that prolonged suppression of these kinases in mouse cells leads to irreversible epigenetic and genomic changes that impair their developmental potential. Further exploration of Mapk signaling could shed light on epigenetic regulation of embryonic development and lead to strategies to generate stable, human embryonic stem cells for research or clinical applications.

(Summary provided by Konrad Hochedlinger, PhD, of the Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine)


TREATING GIANT-CELL ARTERITIS WITHOUT STEROIDS
Trial of Tocilizumab in Giant-Cell Arteritis
Stone, J.H., Tuckwell, K., Dimonaco, S., Klearman, M., Aringer, M., Blockmans, D., [et al.] Collinson, N.
Published in New England Journal of Medicine on July 27, 2017

Giant cell arteritis (GCA) is the most common form of blood-vessel inflammation. Complications include blindness and aneurysm. Up to now, the only known effective treatment was a steroid called prednisone which caused many complications. Now a phase 3 clinical trial has confirmed for the first time in the history of this disease that regular treatment with a drug called tocilizumab successfully reduces the need for high-dose steroid treatment. Patients who received tocilizumab plus a prednisone taper were nearly four times more likely to achieve disease remissions compared to those who received prednisone alone. Results of the trial were the basis for the Food and Drug Administration’s approval of tocilizumab to treat GCA in May 2017.

(Summary provided by John Stone, MD, MPH, Director of the Clinical Rheumatology in the Rheumatology Unit)


ROLE OF GENE EXPRESSION IN PROMOTING CANCER CELLS
IGF2 mRNA Binding Protein-2 is a Tumor Promoter that Drives Cancer Proliferation Through its Client mRNAs IGF2 and HMGA1
Dai, N., Ji, F., Wright, J., Minichiello, L., Sadreyev, R., Avruch, J.
Published in eLife on July 28, 2017

The gene encoding the protein IMP2 is amplified and overexpressed in many human cancers, accompanied by a poorer prognosis. Mice lacking IMP2 exhibit a longer lifespan and a reduced tumor burden at old age. However, the underlying molecular mechanism for this is not known. We discovered that IMP2 overexpression stimulates and IMP2 elimination diminishes proliferation by 50-80% in a diverse array of human cancer cells. In addition to its known ability to promote production of Insulin-like Growth Factor 2 (IGF2), IMP2 strongly promotes IGF action by binding and stabilizing the mRNA encoding HMGA1, a gene that can transform a cell into a tumor cell.

(Summary provided by Ning Dai, PhD, Department of Molecular Biology)

Press Releases

Incorporating 12-step program elements improves substance use disorder treatment in adolescents
Featuring John Kelly, PhD

A treatment program for adolescents with substance-use disorder that incorporates the practices and philosophy of 12-step programs like Alcoholics Anonymous produced even better results than the current state-of-the art treatment approach in a nine-month, randomized trial.


"Safe Genes" award to Mass General team aims to improve precision, safety of gene-editing technologies
Featuring J. Keith Joung, MD, PhD

A Massachusetts General Hospital-based research team is one of seven nationwide receiving contracts under the DARPA Safe Genes program, which is designed to improve the safety of gene drives.


Phase 3 trial confirms superiority of tocilizumab to steroid treatment for giant cell arteritis
Featuring John Stone, MD, MPH

A phase 3 clinical trial has confirmed that regular treatment with tocilizumab, an inhibitor of interleukin-6, successfully reduced both symptoms of and the need for high-dose steroid treatment for giant cell arteritis, the most common form of blood-vessel inflammation. Results of the trial are being published in the New England Journal of Medicine and were the basis for the Food and Drug Administration’s approval of tocilizumab to treat giant cell arteritis in May.


Researchers develop new methods to generate human antibodies
Featuring Facundo Bastista, PhD

An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory.


fMRI, EEG may provide early detection of consciousness in patients with severe brain injury
Featuring Brian Edlow, MD

The use of functional magnetic resonance imaging and electroencephalography may be able to identify ICU patients with severe traumatic brain injuries who have a level of consciousness not revealed by the standard bedside neurological examination.


Setting the record straight: PPIs do not cause dementia
Featuring Andrew Chan, MD, MPH

Several studies have reported associations between proton-pump inhibitor use and dementia. New research published in Gastroenterology, the official journal of the American Gastroenterological Association, puts these claims to rest.


Antibiotic-releasing polymer may help eradicate joint implant infection
Featuring Orhun Muratoglu, PhD

A team of Massachusetts General Hospital investigators has developed an antibiotic-releasing polymer that may greatly simplify the treatment of prosthetic joint infection.


Nipple-sparing mastectomy has low rate of breast cancer recurrence
Featuring Barbara Smith, MD, PhD, FACS

Women with breast cancer who undergo nipple-sparing mastectomy have a low rate of the cancer returning within the first five years, when most recurrences in the breast are diagnosed, findings of a single-center study show.


Immunosuppression underlies resistance to anti-angiogenic therapy
Featuring Rakesh K. Jain and Kamilia Naxerova, PhD


Lymph node metastases may not always be the source of cancer's spread to other organs
featuring Rakesh K. Jain, PhD, and Kamila Naxerova, PhD

A study led by Massachusetts General Hospital investigators has found that the traditional model for the spread of carcinoma, the deadliest form of cancer—from the primary tumor, to nearby lymph nodes, to other organs—may not apply in all cases.


Liquid biopsies offer a non-invasive look at treatment response
Featuring Aparna Parikh, MD, MS

A new study shows that so-called "liquid biopsies," blood tests that detect circulating tumor DNA, may not only sound an early alarm that a treatment's effect is diminishing, but may also help to explain why—sometimes offering clues about what to do next.


The breast cancer genome's "dark matter" starts to give up some secrets
Featuring Gad Getz, PhD

While mutations in protein-coding genes have held the limelight in cancer genomics, those in non-coding genome (home to the regulatory elements that control gene activity) may also have powerful roles in driving tumor growth. A new study reveals recurrent mutations in nine such non-coding elements in breast cancer.

Blog posts

What triggers our scratching and how we can make it stop
Featuring Sarina Elmariah, MD, PhD, and Ethan Lerner, MD, PhD

Everyone itches. But there’s a big difference between a tingle that a quick flick of the fingernail can remedy and a chronic and uncomfortable sensation for which deep scratching only provides temporary relief.


New study demonstrates the benefits of Tai Chi in Chinese Americans suffering from depression
Featuring Albert Yeung, MD, ScD

New research from Mass General has found that practicing the Chinese martial art tai chi significantly reduced symptoms of mild to moderate depression in Chinese Americans, which could prove especially helpful for a patient population that tends to avoid traditional forms of psychiatric treatment.


The elephant in the waiting room: survey data helps address racial and ethnic disparities in healthcare
Featuring Joseph Betancourt, MD, MPH

A new report, published in the June issue of Health Affairs, identifies challenges to and strategies for addressing disparities in healthcare organizations, a topic that can be uncomfortable to address.


Could a technique echoing an ancient Greek military strategy point the way to more effective cancer treatments?
Featuring Miles Miller, PhD

An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory.


Grant program encourages innovation and creativity among nurses and staff
Featuring Guardia Banister, RN, PhD, NEA-BC, FAAN

What does a device that helps to keep patients stable when using the bathroom have in common with a chart that tracks the days since the last infection in the intensive care unit? These projects were the first recipients of the Innovation Design Excellence Awards (IDEA) at Massachusetts General Hospital last year.


Artificial intelligence makes waves in healthcare
Featuring Keith Dreyer, DO, PhD

Keith J. Dreyer, DO, PhD, Vice Chairman of Radiology and Executive Director of the MGH & BWH Center for Clinical Data Science, says AI and machine learning have the potential to impact health care as profoundly as the discovery of the microscope.


Studying the many impacts of water imbalance in the body
Featuring Dennis Brown, PhD

Just as an ecosystem relies on a river for life, so does the body rely on proper water transport through its cells in order to function. Whether there is too much or too little water being transported, or if it is not getting to the right places, it is incredible how much our health can be affected by issues with water transport.


High risk pregnancy complication leads to significant health and cost burdens for mothers and their babies
Featuring Anupam B. Jena, MD, PhD

What should be a joyous and exciting time for soon-to-be parents can sometimes take a turn for the worse if the mother develops a blood pressure related condition called preeclampsia. Because little is known about the extent of the health and cost burden of preeclampsia in the United States, a team of researchers recently sought to quantify its impact.


Research Awards and Honors for July 2017
Featuring Dennis Brown, PhD, Kim Francis, PhD, PHCNS-BC, Amit V. Khera, MD, Alan Mullen, MD, PhD, and Joseph H. Schwab, MD

Massachusetts General Hospital’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. In this series, we highlight a few individuals who have recently received awards or honors for their achievements.


Team effort finds first definitive answers to complex genetic basis of Tourette syndrome
Featuring Jeremiah Scharf, MD, PhD

A large scale analysis of genetic information from individuals with Tourette syndrome led by researchers at Massachusetts General Hospital and UCLA has identified alterations in two genes that significantly increase the risk of developing the disorder.

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