Snapshot of Science for March 2019

Welcome to our Snapshot of Science for March 2019

Welcome to the March 2019 edition of Snapshot of Science. 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 16 summaries submitted by the research teams
9 posts from the Mass General Research Institute blog

Publications

EXPLORING GENETIC LINKS TO INSOMNIA
Biological and Clinical Insights from Genetics of Insomnia Symptoms
Lane JM, Jones SE, Dashti HS, Wood AR, Aragam KG [et al.], Saxena R.
Published in Nature Genetics on February 25, 2019 | *Summary available

EFFECTS OF MICRORNA MUTATIONS
Gain-of-function Mutation of microRNA-140 in Human Skeletal Dysplasia.
Grigelioniene G, Suzuki HI, Taylan F, Mirzamohammadi F, Borochowitz ZU [et al.], Kobayashi T.
Published in Nature Medicine on February 25, 2019 | *Summary available

ANALYZING THE FUNCTIONAL IMPORTANCE OF THE C2A DOMAIN
Heterodimerization of UNC-13/RIM Regulates Synaptic Vesicle Release Probability but Not Priming in C. Elegans
Liu H, Li L, Nedelcu D, Hall Q, Zhou L [et al.], Hu Z.
Published in ELife on February 25, 2019

FINDING A BETTER SCAFFOLD FOR PET TRACER DEVELOPMENT
Half-curcumin Analogues as PET Imaging Probes for Amyloid Beta Species
Yang J, Cheng R, Fu H, Yang J, Kumar M [et al.], Ran C.
Published in Chemical Communications on February 25, 2019 | *Summary available

CRISPERESSO2 ALLOWS FOR FASTER AND MORE ACCURATE ANALYSIS OF GENOME EDITING
CRISPResso2 Provides Accurate and Rapid Genome Editing Sequence Analysis
Clement K, Rees H, Canver MC, Gehrke JM, Farouni R [et al.], Pinello L.
Published in Nature Biotechnology on February 26, 2019 | *Summary available

RHIZOBIUM CAUSES A GENOME INSTABILITY PHENOTYPE
Rhizobium Induces DNA Damage in Caenorhabditis Elegans Intestinal Cells
Kniazeva M, Ruvkun G.
Published in PNAS on February 26, 2019

INSIGHTS INTO NERVOUS SYSTEM TOXICITY CAUSED BY IMMUNOTHERAPY
Clinical Presentation, Management, and Biomarkers of Neurotoxicity After Adoptive Immunotherapy with CAR T-cells
Karschnia P, Jordan JT, Forst DA, Arrillaga-Romany IC, Batchelor TT [et al.], Dietrich J.
Published in Blood on February 26, 2019 | *Summary available

ASSESSING OUTCOMES OF OVERLAPPING SURGERIES
Association of Overlapping Surgery With Perioperative Outcomes
Sun E, Mello MM, Rishel CA, Vaughn MT, Kheterpal S [et al.], Jena AB.
Published in JAMA on February 26, 2019 | *Summary available

CROSS-TALK BETWEEN TUMOR CELLS AND REACTIVE STROMAL CELLS
COX-2 Mediates Tumor-stromal Prolactin Signaling to Initiate Tumorigenesis
Zheng Y, Comaills V, Burr R, Boulay G, Miyamoto DT [et al.], Haber DA.
Published in PNAS on February 28, 2019 | *Summary available

IDENTIFYING AN RNA MOTIF FOR RNA SPREADING AND POLYCOMB TARGETING
Xist Deletional Analysis Reveals an Interdependency Between Xist RNA and Polycomb Complexes for Spreading Along the Inactive X.
Colognori D, Sunwoo H, Kriz AJ, Wang CY, Lee JT.
Published in Molecular Cell on February 28, 2019

EVALUATING NEEDS FOR DIABETES CARE IN LOW AND MIDDLE INCOME COUNTRIES
Health System Performance for People with Diabetes in 28 Low- and Middle-income Countries: A Cross-sectional Study of Nationally Representative Surveys
Manne-Goehler J, Geldsetzer P, Agoudavi K, Andall-Brereton G, Aryal KK [et al.], Jaacks LM.
Published in PLOS Medicine on March 1, 2019 | *Summary available

BUILDING A NEW SYSTEM FOR CRISPR-CAS9
A Singular System with Precise Dosing and Spatiotemporal Control of CRISPR-Cas9.
Choudhary A, Manna D, Maji B, Gangopadhyay SA, Cox KJ [et al.], Mazitschek R.
Published in Angewandte Chemie International Edition on March 4, 2019

RESEARCH FINDS HPV IS NOT NECESSARY FOR THE DEVELOPMENT OF CERVICAL CANCER
A Human Papillomavirus-Independent Cervical Cancer Animal Model Reveals Unconventional Mechanisms of Cervical Carcinogenesis
He C, Lv X, Huang C, Angeletti PC, Hua G [et al.], Wang C.
Published in Cell Reports on March 5, 2019 | *Summary available

INVESTIGATING THE ROLE OF AGING IN HEART FAILURE
Activin Type II Receptor Signaling in Cardiac Aging and Heart Failure
Roh JD, Hobson R, Chaudhari V, Quintero P, Yeri A [et al.], Rosenzweig A.
Published in Science Translational Medicine on March 6, 2019 | *Summary available

PINPOINTING GENETIC LINKS TO SLEEP DURATION
Genome-wide Association Study Identifies Genetic Loci for Self-reported Habitual Sleep Duration Supported by Accelerometer-derived Estimates
Dashti HS, Jones SE, Wood AR, Lane JM, van Hees VT [et al.], Saxena R.
Published in Nature Communications on March 7, 2019 | *Summary available

MONITORING CALCIUM ACTIVITY IN LEARNING AND MEMORY
Cholinergic Modulation of Hippocampal Calcium Activity Across the Sleep-wake Cycle
Zhou H, Neville KR, Goldstein N, Kabu S, Kausar N [et al.], Gomperts SN.
Published in eLife on March 7, 2019 | *Summary available

DETERMINING THE MAKEUP OF ACUTE MYELOID LEUKEMIA CELLS
Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity
van Galen P, Hovestadt V, Wadsworth Ii MH, Hughes TK, Griffin GK [et al.], Bernstein BE.
Published in Cell on March 7, 2019 | *Summary available

ASSESSING PARENTAL SMOKING AND E-CIGARETTE USE
Parental Smoking and E-cigarette Use in Homes and Cars
Drehmer JE, Nabi-Burza E, Hipple Walters B, Ossip DJ, Levy DE [et al.], Winickoff JP.
Published in Pediatrics on March 11, 2019 | *Summary available

HIGHER TRAMADOL PRESCRIPTION RATES LINKED TO HIGHER MORTALITY
Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis
Zeng C, Dubreuil M, LaRochelle MR, Lu N, Wei J [et al.], Zhang Y.
Published in JAMA on March 12, 2019 | *Summary available

UNDERSTANDING IMPLICATIONS OF MUTATIONS IN THE HUNTINGTON'S GENE
Hypomorphic Mutation of the Mouse Huntington's Disease Gene Orthologue.
Murthy V, Tebaldi T, Yoshida T, Erdin S, Calzonetti T [et al.], Biagioli M.
Published in PLOS Genetics on March 21, 2019

NATRIURETIC PEPTIDE LEVELS IN MEN
Effect of Testosterone on Natriuretic Peptide Levels.
Bachmann KN, Huang S, Lee H, Dichtel LE, Gupta DK [et al.], Finkelstein JS.
Published in Journal of American College of Cardiology on March 26, 2019

EFFECTS OF SACUBITRIL/VALSARTAN TREATMENT ON ATRIAL NATRIURETIC PEPTIDE CONCENTRATIONS
Effect of Neprilysin Inhibition on Various Natriuretic Peptide Assays
Ibrahim NE, McCarthy CP, Shrestha S, Gaggin HK, Mukai R [et al.], Januzzi JL Jr.
Published in Journal of American College of Cardiology on March 26, 2019 | *Summary available

Summaries

Insomnia, difficulty falling and staying asleep, is a common ailment. Genetics plays a role in your risk of insomnia. We conducted a study to find regions of the genome contributing to increased risk of insomnia using data from the UK Biobank. We find 57 regions of the genome associated with insomnia and confirm these results in two other studies. We also find there are shared genetic factors between insomnia and restless legs syndrome, cardio-metabolic disorders, and psychiatric traits, with insomnia playing a causal role in coronary artery disease, depressive symptoms and overall well-being.

(Summary submitted by Jacqueline Lane, PhD, Center for Genomic Medicine and Department of Anesthesia)

microRNAs regulate gene expression by binding target RNAs. This study reports the first human genetic disease caused by a gain-of-function mutation of a microRNA. A single-base substitution in the microRNA, miR-140 was found in a novel skeletal dysplasia, characterized by short stature, depressed nose bridge and small epiphyses. Analysis of a mouse model showed that this mutation caused both loss-of-function and unusually strong gain-of new function effects. This strong effect of the mutant miR-140 appears partly due to its interference to RNA binding protein (RBP)-mediated gene regulation, providing insight into interactions between these regulatory systems.

(Summary submitted by Tatsuya Kobayashi, MD, PhD, Endocrine Unit and Department of Medicine)

Evidence suggests that the abnormal levels of amyloid beta (Aβ) species in brains appear as early as 30 years before symptoms start in Alzheimer’s disease (AD) patients. However, the first-generation positron emission tomography (PET) probes can only detect the abnormal Ab deposits close to the onset of clinical AD syndrome. It is revealed that CRANAD-101, a half-curcuminoid based second generation probe, has significant responses to both soluble and insoluble Aβs in fluorescent spectral tests. PET imaging results indicate that both 14-month and five-month APP/PS1 AD mice have higher signals in brains than the age-matched wild type mice, indicating the PET probe has the potential to detect Aβ species at the early stages of AD.

(Summary submitted by Chongzhao Ran, PhD, Martinos Center for Biomedical Imaging and Department of Radiology)

Clustered regularly interspaced short palindromic repeats (CRISPR) genome editing has revolutionized the ability to modify a genome of interest in a targeted and programmable way. This system has accelerated biological discovery and clinical treatments and new genome editing variants with different editing properties are being introduced at a rapid pace. The computational tools to analyze genome editing outcomes has been unable to accurately measure the activity rates and editing properties of many recent genome editors, particularly base editors. This publication details the advances made in our tool, CRISPResso2 which allows for faster and more accurate analysis of genome editing, including the development of a novel biologically-aware alignment algorithm and visualizations.

(Summary submitted by Luca Pinello, PhD, Mass General Cancer Center and Department of Pathology)

Chimeric antigen receptor T-cell (CAR-T) therapies are a promising new class of immunotherapy in cancer patients with high response rates even in patients who previously failed several chemotherapies. However, the treatment is associated with an unusually high frequency of neurological complications that can be fatal. Researchers summarized their findings from a large cohort of affected patients and identified potential risk factors and biomarkers that may predict either a good or poor outcome. The findings provide novel insights into the pattern of nervous system toxicity caused by immunotherapy and is an important step forward to improve patient management.

(Summary submitted by Jorg Dietrich, MD, PhD, Mass General Cancer Center and Department of Neurology)

Surgeons performing overlapping surgeries has raised concerns because of potential adverse outcomes. This study analyzed 66,000 operations and found that overlapping surgeries did not increase the risk for post-surgical complications and patient death in the period following the procedure. However, there were two important caveats: patients deemed high risk experienced higher mortality and complication rates, and overlapping procedures ran slightly longer by about a half hour. Overall, the authors argued that the practice of overlapping surgery appears safe for most patients though additional consideration of the practice may be warranted in patients at high risk of post-operative complications.

(Summary submitted by Anupam B. Jena, MD, PhD, Departments of Medicine and Primary Care)

The efficacy of COX-2 inhibitors in cancer prevention and in suppressing metastatic cancer recurrence has been attributed to their anti-inflammatory effects. This study, using single cell RNA sequencing in immune deficient mouse models and human cancer tissue analyses, identifies a signaling cross-talk between tumor cells and reactive stromal cells in the cancer microenvironment. Prostaglandin E2, produced by tumor cells expressing COX-2, induces prolactin secretion by adjacent stromal fibroblasts. Prolactin activates growth factor signaling in early micro-metastases, which express the prolactin receptor. Together, these findings point to a novel mechanism of cancer suppression by COX-2 inhibitors and suggests potential biomarkers to help guide their selective application.

(Summary submitted by Daniel A Haber, MD, PhD, Mass General Cancer Center)

We harmonized and analyzed information on 800,000 adults in 28 low-income and middle-income countries. Our study found that 8.8% of these adults had diabetes, with more than half being undiagnosed. About 77% of these individuals had some form of unmet need for diabetes care. People living with diabetes in upper-middle income countries received more services than those in the lowest income countries, but across all countries less than one-quarter achieved control of their disease. Our study showed that diabetes is an epidemic with global reach and that there is much more work to be done to provide care for all adults with diabetes.

(Summary submitted by Jennifer Manne-Goehler, MD, Infectious Disease Unit and Department of Medicine)

This paper reports the first ever HPV-independent cervical cancer animal model, which indicates that HPV is not necessary for the development of cervical cancer. The new findings in this study challenge the dogma that HPV is a necessary agent for the development of cervical cancer, provide new mechanism for the cervical carcinogenesis, and put a new insight into the role of HPV in cervical cancer development. Results in this study suggest that combined targeting of the Hippo/YAP signaling pathway and HPV represents a new strategy to improve preventative screening and treatment of cervical cancer.

(Summary submitted by Cheng Wang, MD, Vincent Center for Reproductive Biology and Department of Obstetrics and Gynecology)

Advanced age is a dominant risk factor for heart failure. However, the mechanisms by which aging contributes to the development of heart failure are largely unclear. This study found that catabolic ActRII signaling increases with age and heart failure severity in humans. Moreover, inhibiting this pathway with either clinical-stage inhibitors or genetic ablation improved the function of the heart in multiple mouse models of heart failure. This study identified increased ActRII signaling as a causal link between aging and heart failure, and suggests that targeted inhibition of this pathway may offer a new strategy for treating heart failure.

(Summary submitted by Jason D Roh, MD, Department of Cardiology)

While we spend about a third of our life asleep, we have little knowledge of the specific genes and pathways that regulate the amount of sleep people get. Family studies have suggested that 10 to 40 percent of the variation in sleep duration may be inherited. In the current study, we analyzed genetic data from more than 446,000 participants in the UK Biobank and identified 78 gene regions — including the two previously known regions — as associated with sleep duration. Our study suggests that many of the genes important for sleep in animal models may also influence sleep in humans. This opens the door to better understanding of the function and regulation of sleep.

(Summary submitted by Hassan Dashti, PhD, RD, Center for Genomic Medicine)

Calcium is a critical second messenger in neurons that contributes to learning and memory. To determine how dynamic calcium activity changes across network states and evaluate the contribution of acetylcholine inputs, we acquired simultaneous calcium imaging and electrophysiological recordings in the hippocampus of freely behaving mice. Calcium activity changed markedly across network states and was greatest in “theta” states (exploratory behavior, REM sleep) associated with high acetylcholine levels. Cholinergic neuron activation increased calcium activity; this was reduced with muscarinic acetylcholine receptor inhibition. These results implicate cholinergic- and state-dependent dynamic calcium activity in memory formation and inform understanding of hippocampal failure in disease.

(Summary submitted by Stephen Gomperts, MD, PhD, Department of Neurology)

Acute myeloid leukemia (AML) patients have poor outcome due to the difficulty of eradicating all cancer cells. We used new single-cell technologies and computer algorithms to study the makeup of cells in AML patient samples. Our analysis showed how leukemia progression is influenced by developmental stages of the leukemia cells, by underlying genetic mutations, and by interactions with the immune system. Our single-cell atlas of AML cells can be used to develop more precise and effective therapies.

(Summary submitted by Peter van Galen, PhD, Department of Pathology)

Little is known about how often parents have policies that prohibit the use of e-cigarettes inside their homes and cars. Parents were interviewed at five U.S. pediatric practices that were participating in a clinical trial of the Clinical Effort Against Secondhand Smoke Exposure (CEASE) program. The majority of e-cigarettes users reported vaping inside their home and car, and e-cigarettes were often used inside cars with children present. Parents who were dual users of cigarettes and e-cigarettes were more likely to have a smoke-free policy for their home than a vape-free policy, suggesting many believe e-cigarettes can be safely used inside homes where children live.

(Summary submitted by Jeremy Drehmer, MPH, CPH, Mass General for Children and Mass General Tobacco Research and Treatment Center)

Tramadol is one of the most commonly prescribed pain-relief medications for the management of osteoarthritis. Several professional organizations have recommended tramadol as a first-line therapy for patients with osteoarthritis. Using data collected from the participants at a general practice in the United Kingdom, we found that tramadol prescription increased more than three-fold from 2000 to 2013 among the patients with osteoarthritis, and the initial prescription of tramadol was associated with a 70-104% higher mortality over one-year compared with commonly prescribed NSAIDs. These findings, if confirmed by future studies, raise a concern for the safety profile of tramadol and call for a revisit of the osteoarthritis treatment guidelines.

(Summary submitted by Chao Zeng MD, PhD, Division of Rheumatology, Allergy, and Immunology and Clinical Epidemiology Unit)

Sacubitril/valsartan is a new angiotensin receptor-neprilysin inhibitor used in the treatment of patients with heart failure with reduced ejection fraction (HFrEF). In 23 sequential stable ambulatory patients with HFrEF we examined the effect of sacubitril/valsartan. We demonstrated initiation and titration of sacubitril/valsartan led to consistent and substantial increase in atrial natriuretic peptide (ANP) concentrations, but with varying effects on other natriuretic peptides. Our results provide important insights into the effects of sacubitril/valsartan treatment on individual patients and suggest the benefit of neprilysin inhibition may be partially explained by increased ANP concentrations.

(Summary submitted by Nasrien E Ibrahim, MD, Department of Cardiology)

Blog Posts

Mass General Researchers Create Program to Ease Emotional Stress in Stroke Patients and Caregivers
Featuring Jessica McCurley, PhD, MPH, and Ana-Maria Vranceanu, PhD

Researchers at Massachusetts General Hospital recently conducted a study to identify the factors that contribute to emotional stress after stroke, identify tools and strategies that would provide the most help, and determine an effective timeline and delivery system for an intervention program aimed at preventing chronic depression, anxiety and post traumatic stress in this high risk population.

A Coordinated Effort to Improve Pediatric Emergency Care
Featuring Krislyn Boggs, MPH

Researchers at Massachusetts General Hospital have been collaborating on a grassroots campaign to increase the appointment rates of pediatric emergency care coordinators in Massachusetts emergency departments.

Mass General Celebrates Women’s History Month and International Women’s Day 2019

The month of March is Women’s History Month, and every year on March 8th we recognize International Women’s Day to celebrate the achievements of women, support gender equality and raise awareness against gender bias.

Ensuring Adequate Measles Protection is Key to Stopping Outbreaks in United States
Featuring Emily Hyle, MD, MSc

The measles outbreaks in the states of Washington and New York have generated a lot of headlines in recent weeks, but the good news is that measles remains relatively rare in the United States – and that is because most people have been vaccinated with the measles-mumps-rubella (MMR) vaccine.

From the Gut to the Brain: Exploring a New Pathway for the Onset of Alzheimer’s Disease
Featuring Deepak Vijaya Kumar, PhD

A research project led by Massachusetts General Hospital’s Deepak Vijaya Kumar, PhD, will seek to untangle the connections between microbes in the gut and the onset of Alzheimer’s disease.

Photo Filters Spark the Need for a Guide to Help Cosmetic Surgeons Recognize Body Dysmorphic Disorder
Featuring Jennifer Greenberg, PsyD, Hilary Weingarden, PhD, and Sabine Wilhelm, PhD

While flipping through filters can be a fun way to kill time or lighten a mood, researchers are beginning to find the way they artificially alter appearances might have negative consequences such as triggering body dysmorphic disorder.

Mass General Investigators Dig Deeper into the Science of Sleep
Featuring Filip Swirski, PhD, John Kelly, PhD, and Hassan Saeed Dashti, PhD, RD

Three recent studies from researchers at Massachusetts General Hospital that look at the connections between sleep and health.

Ketamine Approval Offers New Hope for Treatment-Resistant Depression, but Questions Remain
Featuring Cristina Cusin, MD

While the FDA’s approval of the first ketamine-based drug for treatment-resistant depression is encouraging, there are still a lot of details to work out, says Cristina Cusin, MD.

Researchers Find Immune Cells in the Gut May Affect the Speed of Your Metabolism
Featuring Filip Swirski, PhD

Researchers from Mass General recently published a study in Nature that found how certain immune cells in the gut could regulate metabolism and possibly contribute to diseases like obesity, diabetes, high blood pressure and heart disease.

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Snapshot of Science for March 2019