Snapshot of Science for January 2019

Welcome to our Snapshot of Science for January 2019

Here's a quick look at some recent publications, press releases and stories about the Mass General Research Institute community.

In this issue we highlight:

22 new studies published in high impact journals, along with 15 summaries submitted by the research teams
9 posts from the Mass General Research Institute blog

Publications

EXPANDING BIOBANKING TO AFRICA
The NeuroDev Study: Phenotypic and Genetic Characterization of Neurodevelopmental Disorders in Kenya and South Africa
de Menil V, Hoogenhout M, Kipkemoi P, Kamuya D, Eastman E [et al.], Robinson E.
Published in Neuron on January 2, 2019 | *Summary available

A NEW POTENTIAL ANGLE FOR HIV THERAPIES
HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early after Mucosal Transmission
Usmani SM, Murooka TT, Deruaz M, Koh WH, Sharaf RR [et al.], Mempel TR.
Published in Cell Host & Microbe on January 9, 2019 | *Summary available

EXPLORING NEW TREATMENTS FOR MAJOR DEPRESSIVE DISORDER
A Phase 2, Double-blind, Placebo-controlled Study of NSI-189 Phosphate, a Neurogenic Compound, Among Outpatients with Major Depressive Disorder
Papakostas GI, Johe K, Hand H, Drouillard A, Russo P [et al.], Fava M.
Published in Molecular Psychiatry on January 9, 2019 | *Summary available

DEVELOPING AN ALGORITHM TO SURVEY BACTERIAL GENOMES
Invertible Promoters Mediate Bacterial Phase Variation, Antibiotic Resistance, and Host Adaptation in the Gut
Jiang X, Hall AB, Arthur TD, Plichta DR, Covington CT [et al.], Xavier RJ.
Published in Science on January 11, 2019

NEW AVENUES FOR HEART TISSUE REGENERATION
Endocardial Notch Signaling Promotes Cardiomyocyte Proliferation in the Regenerating Zebrafish Heart Through Wnt Pathway Antagonism
Zhao L, Ben-Yair R, Burns CE, Burns CG.
Published in Cell Reports on January 15, 2019 | *Summary available

RESEARCHERS SUGGEST RETESTING FOR PENICILLIN ALLERGIES
Evaluation and Management of Penicillin Allergy: A Review
Shenoy ES, Macy E, Rowe T, Blumenthal KG.
Published in JAMA on January 15, 2019 | *Summary available

CLIMATE'S EFFECTS ON HEALTH
Climate Change - A Health Emergency
Solomon CG, LaRocque RC.
Published in New England Journal of Medicine on January 17, 2019 | *Summary available

LOSARTAN SHOWN TO IMPROVE SURVIVAL OF PATIENTS WITH OVARIAN CANCER
Losartan Treatment Enhances Chemotherapy Efficacy and Reduces Ascites in Ovarian Cancer Models by Normalizing the Tumor Stroma
Zhao Y, Cao J, Melamed A, Worley M, Gockley A [et al.], Xu L.
Published in PNAS on January 18, 2019 | *Summary available

OBSERVING PANCREATIC CANCER RECURRENCE PATTERNS
Timing But Not Patterns of Recurrence Is Different Between Node-negative and Node-positive Resected Pancreatic Cancer
Honselmann KC, Pergolini I, Castillo CF, Deshpande V, Ting D [et al.], Ferrone CR.
Published in Annals of Surgery on January 18, 2019 | *Summary available

ESTABLISHING THE EFFICACY OF RAMUCIRUMAB TREATMENT FOR LIVER CANCER
Ramucirumab After Sorafenib in Patients with Advanced Hepatocellular Carcinoma and Increased α-fetoprotein Concentrations (REACH-2): A Randomised, Double-blind, Placebo-controlled, Phase 3 Trial
Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR [et al.], Kudo M.
Published in Lancet Oncology on January 18, 2019 | *Summary available

CHROMATIN REMODELING ON THE INACTIVE X CHROMOSOME
Xist RNA Antagonizes the SWI/SNF Chromatin Remodeler BRG1 on the Inactive X Chromosome
Jégu T, Blum R, Cochrane JC, Yang L, Wang CY [et al.], Lee JT.
Published in Nature Structural & Molecular Biology on January 21, 2019

UNCOVERING MECHANISMS OF THE ALTERNATIVE LENGTHENING OF TELOMERES
Alternative Lengthening of Telomeres Through Two Distinct Break-induced Replication Pathways
Zhang JM, Yadav T, Ouyang J, Lan L, Zou L.
Published in Cell Reports on January 22, 2019

COMBATING INFLAMMATION OF THE HEART
Self-reactive CD4+ IL-3+ T Cells Amplify Autoimmune Inflammation in Myocarditis by Inciting Monocyte Chemotaxis
Anzai A, Mindur JE, Halle L, Sano S, Choi JL [et al.], Swirski FK.
Published in Journal of Experimental Medicine on January 22, 2019 | *Summary available

UNRAVELING THE EFFECTS OF THE CROHN'S DISEASE RISK ALLELE
The Crohn's Disease Polymorphism, ATG16L1 T300A, Alters the Gut Microbiota and Enhances the Local Th1/Th17 Response
Lavoie S, Conway KL, Lassen KG, Jijon HB, Pan H [et al.], Xavier RJ.
Published in eLife on January 22, 2019

IMPROVING LUPUS OUTCOMES WITH TIMELY KIDNEY TRANSPLANTS
Renal Transplantation and Survival Among Patients with Lupus Nephritis: A Cohort Study
Jorge A, Wallace ZS, Lu N, Zhang Y, Choi HK.
Published in Annals of Internal Medicine on January 22, 2019 | *Summary available

EXAMINING THE VISUAL CORTEX OF MACAQUES
Submillimeter fMRI Reveals a Layout of Dorsal Visual Cortex in Macaques, Remarkably Similar to New World Monkeys
Zhu Q, Vanduffel W.
Published in PNAS on January 23, 2019

PHYSICAL ACTIVITY ASSOCIATED WITH LOWER RISK OF DEPRESSION
Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study
Choi KW, Chen CY, Stein MB, Klimentidis YC, Wang MJ [et al.], Smoller JW.
Published in JAMA Psychiatry on January 23, 2019 | *Summary available

PINPOINTING GENES ASSOCIATED WITH INTELLECTUAL DISABILITY
Contribution of Rare and Common Variants to Intellectual Disability in a Sub-isolate of Northern Finland
Kurki MI, Saarentaus E, Pietiläinen O, Gormley P, Lal D [et al.], Palotie A.
Published in Nature Communications on January 24, 2019 | *Summary available

UNCOVERING ADDITIONAL FUNCTIONS OF CTCF
Exploration of CTCF Post-translation Modifications Uncovers Serine-224 Phosphorylation by PLK1 at Pericentric Regions During the G2/M Transition
Del Rosario BC, Kriz AJ, Del Rosario AM, Anselmo A, Fry CJ [et al.], Lee JT.
Published in eLife on January 24, 2019

USING TROPONIN TO DETERMINE CARDIOVASCULAR RISK
Single-Molecule hsTnI and Short-Term Risk in Stable Patients with Chest Pain
Januzzi JL Jr, Suchindran S, Hoffmann U, Patel MR, Ferencik M [et al.], Douglas PS.
Published in Journal of the American College of Cardiology on January 29, 2019 | *Summary available

HOW IMMUNE CELLS COULD AFFECT METABOLISM
Gut Intraepithelial T Cells Calibrate Metabolism and Accelerate Cardiovascular Disease
He S, Kahles F, Rattik S, Nairz M, McAlpine CS [et al.], Swirski FK.
Published in Nature on January 30, 2019 | *Summary available

Summaries

There is much to be learned about genetic causes of neurodedevelopmental disorders, such as autism, attention deficit, and intellectual disability, by studying Africans, because they have more genetic variation than any other population. The NeuroDev study is collecting data in South Africa and Kenya from over 5,000 individuals, including at least 500 mother-father-child trios. The study will pair DNA with assessments of cognition, development, and medical history, as well as photos, to uncover new genetic causes and understand their expression in Africans. Samples will be banked through NIMH and data published on controlled-access databases to make a public scientific resource.

(Summary submitted by Victoria de Menil, PhD, Broad Institute)

A NEW POTENTIAL ANGLE FOR HIV THERAPIES
HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early After Mucosal Transmission
Usmani SM, Murooka TT, Deruaz M, Koh WH, Sharaf RR [et al.], Mempel TR.
Published in Cell Host & Microbe on January 9, 2019

The human immunodeficiency virus (HIV) infects T lymphocytes and uses these migratory immune cells as vehicles to spread the infection throughout the body. This new study revealed that, unexpectedly, the viral protein Nef slows down the rate of infectious spread following genital infection in humanized mice by impairing the motility of infected T cells. However, the underlying function of Nef later on protects the virus from attack by the immune system. These findings could be the basis for new strategies to render the virus more vulnerable to therapies that use the immune system to combat the infection.

(Summary submitted by Thorsten Mempel, MD, PhD Center for Immunology and Inflammatory Diseases)

This study examined NSI-189, a medication that promotes nerve growth in experimental conditions (test tube), in treating depression. It was the second study ever to do so. Similar to the older study, while there was no difference from placebo in treating these symptoms as measured by scales administered by doctors, nearly all patient-scored scales were in favor of NSI-189. This suggests that the effects of NSI-189 may not be completely captured by doctor-administered scales, developed more than half a century ago, and that future studies are needed to better understand how this drug differs from existing antidepressants.

(Summary submitted by George Papakostas, MD, Department of Psychiatry)

New therapies that stimulate heart regeneration and suppress scarring are needed to improve outcomes for patients who experience a heart attack. Lower vertebrates, such as the zebrafish, naturally regenerate their hearts after injury, thereby providing a roadmap for achieving successful heart muscle regrowth. The Burns Lab discovered that zebrafish hearts must activate a particular pathway termed Notch signaling which, in turn, dampens a second pathway termed Wnt signaling to achieve successful heart regeneration. Since Notch signaling is also activated in the human heart following injury, our data suggest that harnessing and repurposing this natural response could provide a novel therapeutic inroad for treating heart attacks.

(Summary submitted by Caroline Burns, PhD, Cardiovascular Research Center)

RESEARCHERS SUGGEST RETESTING FOR PENICILLIN ALLERGIES
Evaluation and Management of Penicillin Allergy: A Review
Shenoy ES, Macy E, Rowe T, Blumenthal KG.
Published in JAMA on January 15, 2019

Thirty-two million Americans report a penicillin allergy, but most are not allergic. These patients receive broader-spectrum and often less-effective antibiotics, with increased risk of treatment failure, healthcare-associated infections, and antimicrobial resistance. This paper describes how the allergy history can be used to risk stratify patients with penicillin allergy histories and provides toolkits to implement skin testing and drug challenges in clinical practice.

(Summary submitted by Kimberly Blumenthal, MD, MSc, Department of Allergy and Immunology)

CLIMATE'S EFFECTS ON HEALTH
Climate Change - A Health Emergency
Solomon CG, LaRocque RC.
Published in New England Journal of Medicine on January 17, 2019

Drs. Caren Solomon and Regina LaRocque call for physician action to address the tremendous harms to human health associated with greenhouse gas (GHG) emissions. These health harms are outlined in the recent Fourth National Climate Assessment as well as in an accompanying NEJM review article. Among the actions they recommend: working with health institutions to cut emissions (Mass General Brigham is currently working toward carbon neutrality); individual actions to reduce energy use and food waste; education of colleagues, students, and patients; engagement in legislative advocacy; and financial divestment from the fossil fuel industry.

(Summary submitted by Regina LaRocque, MD, MPH, Division of Infectious Diseases)

Treatment with losartan, an FDA-approved anti-hypertensive that blocks angiotensin signaling, enhanced the efficacy of paclitaxel chemotherapy and reduced ascites in ovarian cancer models. A retrospective analysis of patients who received standard treatment for ovarian cancer at Massachusetts General Hospital or Brigham and Women’s Hospital, while being treated for hypertension, found that those patients taking losartan or other angiotensin-targeting drugs had 30 months longer overall survival than those receiving other anti-hypertensives. These new findings provide both the rationale and supporting data for a clinical trial planned to begin later this year.

(Summary submitted by Lei Xu, MD, PhD, Department of Radiation Oncology)

OBSERVING PANCREATIC CANCER RECURRENCE PATTERNS
Timing But Not Patterns of Recurrence Is Different Between Node-negative and Node-positive Resected Pancreatic Cancer
Zhao Honselmann KC, Pergolini I, Castillo CF, Deshpande V, Ting D [et al.], Ferrone CR.
Published in Annals of Surgery on January 18, 2019

Patterns of recurrence (the site of disease reoccurrence after resection) in patients with positive and negative loco-regional lymph nodes were evaluated after resection of their pancreatic adenocarcinoma. This study demonstrates that tumor recurrence occurred later in patients with lymph node negative disease compared to patients with lymph node positive disease. However, if tumors recurred, the patterns of recurrence were very similar. The majority of lymph node positive and negative patients presented with distant metastases as their first site of metastatic disease. Patients who received neoadjuvant therapy continued to present with distant metastases as their first site of disease. These findings emphasize the need for effective systemic therapy in the perioperative setting.

(Summary submitted by Kim Honselmann, MD, Department of Gastrointestinal Surgery and Pathology)

Patients with advanced hepatocellular carcinoma (HCC) and an elevated α-fetoprotein level carry a poor prognosis with limited treatment options. REACH-2 is the first positive phase 3, randomized, placebo-controlled trial done in patients with HCC enrolled based on a biomarker. We demonstrated overall survival was significantly improved in patients with α-fetoprotein concentrations of at least 400 ng/mL who received second-line ramucirumab, an anti-VEGFR2 antibody. Treatment with ramucirumab was well tolerated, with a clinically acceptable safety profile. The positive results of REACH-2 support VEGFR2 as a therapeutic target in HCC.

(Summary submitted by Andrew Zhu, MD, PhD, Mass General Cancer Center)

Myocarditis is an inflammatory disease of the heart muscle that can be triggered by infections, immunological syndromes, drugs, or toxins. Combating inflammation brought upon by myocarditis is crucial to prevent life-threatening complications, including cardiac dysfunction, heart failure and sudden death. In this study, the Swirski Lab uncovered how interleukin-3 (IL-3), an inflammatory mediator, promotes myocarditis. They found that T cells in the inflamed heart produce IL-3, causing the recruitment of monocytes that perpetuate heart inflammation and dysfunction. They also found that blocking IL-3 reduces monocyte recruitment and heart inflammation. Therefore, the study highlights IL-3 as a pathological player and potential therapeutic target in myocarditis.

(Summary submitted by John E. Mindur, PhD Candidate, Center for Systems Biology)

Lupus nephritis can cause kidney failure that must be treated with dialysis or kidney transplant. Patients with kidney failure due to lupus have high rates of premature death. Our study used a large database of patients with kidney failure due to lupus in the US. We found that receiving a kidney transplant was associated with much improved survival compared with continuing long-term dialysis. There were fewer deaths due to cardiovascular disease and infections. Our study suggests that patients with renal failure due to lupus nephritis should undergo early referral to transplant centers to be considered for this potentially life-saving intervention.

(Summary submitted by April Jorge, MD, Department of Medicine and Division of Rheumatology)

Does physical activity help reduce risk for depression, or does depression simply lead to reduced physical activity? To answer these questions, we used Mendelian randomization, a research method that harnesses genetic variation as a natural experiment to test possible causal relationships between physical activity and depression. We found that physical activity (measured using wrist-worn activity trackers, but not with self-report) showed a protective effect on depression. Overall, this study supports the hypothesis that enhancing physical activity is an effective prevention strategy for depression.

(Summary submitted by Karmel Choi, PhD, Psychiatric & Neurodevelopmental Genetics Unit)

Intellectual disability (ID), characterized by deficits in both intellectual functioning and adaptive behaviors, is a relatively common disorder affecting 1-3% of the population. In this study, researchers focused on elucidating the genetics of mild and severe forms of ID by sequencing the genes of 442 Finnish patients, of which >50% had the most common mild form of ID. The results show that both rare, high-impact genetic variants and an accumulation of common genetic risk variants contribute to ID. Rare, damaging mutations are more common in the severe ID patients while the contribution of polygenic load is higher in patients having milder ID forms.

(Summary submitted by Mijta Kuri, PhD, Psychiatric & Neurodevelopmental Genetics Unit)

When patients present with acute severe chest pain, their blood is tested for a heart protein called troponin, and if elevated, this typically signifies the presence of a heart attack. New, so-called “high sensitivity” tests are now able to measure the marker in the blood of normal people. Among a low risk ambulatory population of patients with stable chest symptoms with and without coronary disease, we found that concentrations of high sensitivity troponin were not only able to identify which patients had underlying coronary artery disease, but also strongly predicted which patients were most likely to suffer a major cardiovascular complication within 90 days of presentation.

(Summary submitted by James Januzzi, MD, Department of Cardiology)

HOW IMMUNE CELLS COULD AFFECT THE METABOLISM
Gut Intraepithelial T Cells Calibrate Metabolism and Accelerate Cardiovascular Disease
He S, Kahles F, Rattik S, Nairz M, McAlpine CS [et al.], Swirski FK.
Published in Nature on January 30, 2019

The Swirski Lab at the Mass General Center of Systems Biology identified a subset of immune cells in the gut that modulates metabolism. The team shows that gut intraepithelial T leukocytes (IELs) modulate systemic metabolism. Mice lacking natural IELs are metabolically hyperactive and, when fed a high fat and sugar diet, resist obesity, hypercholesterolemia, hypertension, diabetes and atherosclerosis. The phenomenon depends on the incretin GLP-1, which IELs normally control via IEL GLP-1 receptor expression. While its function may prove advantageous when food is scarce, overabundance of diets high in fat and sugar render this metabolic checkpoint inimical to health.

(Summary submitted by Filip Swirski, PhD, Center for Systems Biology)

Blog Posts

Mass General Research Wrapped

To bring this year to a close and to celebrate the beginning of a new year, we chose a few of our proudest accomplishments and most meaningful milestones to give you Mass General Research Wrapped.

Mass General Researcher Resolutions

In the spirit of New Year's resolutions, we reached out to a few of our top researchers at Mass General to hear about their proudest moments from 2018 and what they look forward to accomplishing in 2019.

MGRI Image Contest: Meet Our Winner and the Top 10!

We recently had an image contest to see what research at Mass General looks like. Meet our winner and the researchers behind the top 10!

Research Finds a Little Bit of Empathy Makes a Big Difference
Featuring Helen Riess, MD

Helen Riess, MD, Mass General researcher and practicing psychiatrist, conducted research and developed a training to teach clinicians empathy skills to use in their practice.

New Protocol Could Improve Early Autism Diagnosis Through Eye Tracking
Featuring Xue-Jun (June) Kong, MD

Researchers from the Martinos Center for Biomedical Imaging at Mass General have developed a new testing protocol to screen infants, toddlers and young children for autism spectrum disorder (ASD) using eye tracking software. The tool could increase early detection rates and reduce the time and cost of current screening techniques.

How the Cocoanut Grove Fire Survivors Gave a Mass General Psychiatrist Insights into Acute Grief
Featuring Erich Lindemann, MD

A recent article in the Harvard Crimson took an in-depth look at how treating the victims of the Cocoanut Grove Fire in Boston contributed to a Mass General psychiatrist’s research and clinical work into how people experience and process losses due to death or injury.

Do Lifestyle Factors Such as Stress Affect the Onset and Progression of Alzheimer’s Disease?
Featuring Matthias Nahrendorf, MD, PhD and Filip Swirski, PhD

A team of researchers from Mass General are exploring the role of lifestyle factors such as stress in the onset and progression of Alzheimer’s disease.

These Three Happiness Exercises Could Help Promote Recovery from Substance Use Disorder
Featuring Bettina B. Hoeppner, MS, PhD

A team of researchers from the Mass General Recovery Research Institute conducted a study published in The Journal of Substance Abuse Treatment that found positive psychology exercises could boost the happiness levels of those recovering from substance abuse.

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Snapshot of Science for January 2019