Snapshot of Science for August 2020

Welcome to our Snapshot of Science for August 2020

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:

47 new studies published in high impact journals, along with 28 summaries submitted by the research teams
21 new research-related press releases from the Mass General Public Affairs office
3 posts from the Mass General Research Institute blog

Publications

IMPROVING IMAGE QUALITY IN LOW-FIELD MRI
High-sensitivity In Vivo Contrast for Ultra-low Field Magnetic Resonance Imaging Using Superparamagnetic Iron Oxide Nanoparticles
Waddington DEJ, Boele T, Maschmeyer R, Kuncic Z, Rosen MS.
Published in Science Advances on July 17, 2020 | *Summary available | Press release

DEFINING A MOLECULAR BASIS FOR CARDIOMETABOLIC STRESS
Molecular Signature of Multisystem Cardiometabolic Stress and Its Association with Prognosis
Murthy VL, Yu B, Wang W, Zhang X, Alkis T [et al.], Shah R.
Published in JAMA Cardiology on July 22, 2020

CLOTTING COMPLICATIONS IN COVID-19
COVID-19 and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV-2 Infection
Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE [et al.], Rosovsky RP.
Published in Blood on July 23, 2020 | *Summary available

USING CLOUD-BASED TECHNOLOGY FOR LARGE-SCALE DATA ANALYSIS
Cumulus Provides Cloud-based Data Analysis for Large-scale Single-cell and Single-nucleus RNA-seq
Li B, Gould J, Yang Y, Sarkizova S, Tabaka M [et al.], Regev A.
Published in Nature Methods on July 27, 2020 | *Summary available

EXPANDING THE ENCYCLOPEDIA OF DNA ELEMENTS
Expanded Encyclopaedias of DNA Elements in the Human and Mouse Genomes
Sato T, Verma S, Castro Andrade CD, Omeara M, Campbell N [et al.], Wein MN.
Published in Nature on July 29, 2020

IDENTIFYING AND CORRECTING MISLABELED SAMPLES
Detecting Sample Swaps in Diverse NGS Data Types Using Linkage Disequilibrium
Javed N, Farjoun Y, Fennell TJ, Epstein CB, Bernstein BE, Shoresh N.
Published in Nature Communications on July 29, 2020

SEX DIFFERENCES IN PHYSICIAN INCOME AND PRACTICE COMPOSITION
Practice Composition and Sex Differences in Physician Income: Observational Study
Whaley CM, Arnold DR, Gross N, Jena AB.
Published in The BMJ on July 30, 2020

VARYING ANTIBODY RESPONSES IN COVID-19
Distinct Early Serological Signatures Track with SARS-CoV-2 Survival
Ateyo C, Fischinger S, Zohar T, Slein MD, Burke J [et al.], Alter G.
Published in Immunity on July 30, 2020 | *Summary available

INSIGHTS INTO MITOCHONDRIAL FUNCTION AND MICRONUTRIENT METABOLISM
Lysosomal Activity Regulates Caenorhabditis Elegans Mitochondrial Dynamics Through Vitamin B12 Metabolism
Wei W, Ruvkun G.
Published in PNAS on July 31, 2020

STRATEGIES FOR SAFE REOPENING OF COLLEGE CAMPUSES
Assessment of SARS-CoV-2 Screening Strategies to Permit the Safe Reopening of College Campuses in the United States
Paltiel AD, Zheng A, Walensky RP.
Published in JAMA Network Open on July 31, 2020 | *Summary available

SELECTIVELY TARGETING HYPERACTIVE CANCER CELLS
Synthetic Lethality by Targeting the RUVBL1/2-TTT Complex in mTORC1-Hyperactive Cancer Cells
Shin SH, Lee JS, Zhang J, Choi S, Boskovic ZV [et al.], Byun S.
Published in Science Advances on July 31, 2020 | *Summary available

ORAL CHOLERA VACCINE FOR PREVENTION IN HAITI
Achieving Coordinated National Immunity and Cholera Elimination in Haiti Through Vaccination: A Modelling Study
Lee EC, Chao DL, Lemaitre JC, Matrajt L, Pasetto D [et al.], Ivers LC.
Published in Lancet Global Health on August 1, 2020

RECURRENCE IN PANCREATIC CANCER PATIENTS
Timing But Not Patterns of Recurrence Is Different Between Node-negative and Node-positive Resected Pancreatic Cancer
Honselmann KC, Pergolini I, Fernandez-Del Castillo F, Deshpande V, Ting D [et al.], Ferrone C.
Published in Annals of Surgery on August 1, 2020

EXPERIENCE WITH ECMO THERAPY IN COVID-19 PATIENTS
Veno-venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19 Patients: Early Experience From a Major Academic Medical Center in North America
Osho AA, Moonsamy P, Hibbert KA, Shelton KT, Trahanas JM [et al.], Funamoto M.
Published in Annals of Surgery on August 1, 2020

MULTIDISCIPLINARY CARE TEAM FOR COVID-19 PATIENTS
Design and Impact of a COVID-19 Multidisciplinary Bundled Procedure Team
Albutt K, Luckhurst CM, Alba GA, El Hechi M, Mokhtari A [et al.], Kaafarani H.
Published in Annals of Surgery on August 1, 2020

COVID-19 AND GASTROINTESTINAL COMPLICATIONS
Gastrointestinal Complications in Critically Ill Patients With COVID-19
Kaafarani HMA, El Moheb M, Hwabejire JO, Naar L, Christensen MA [et al.], Velmahos GC.
Published in Annals of Surgery on August 1, 2020 | *Summary available

IMPACT OF COVID-19 ON BREAST CANCER PREVENTION AND CARE
Breast Imaging, Breast Surgery, and Cancer Genetics in the Age of COVID‐19
Yin K, Singh P, Drohan B, Hughes KS.
Published in Cancer on August 4, 2020 | *Summary available

VITAMIN D SUPPLEMENTS AND DEPRESSION
Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial
Okereke OI, Reynolds CF, Mischoulon D, Chang G, Vyas CM [et al.], Manson JE.
Published in JAMA on August 4, 2020 | *Summary available | Press release

NEW BREAKTHROUGH FOR ULTRAFAST BEDSIDE CANCER DIAGNOSIS
CytoPAN-Portable Cellular Analyses for Rapid Point-of-Care Cancer Diagnosis
Min J, Chin LK, Oh J, Landeros C, Vinegroni C [et al.], Weissleder R.
Published in Science Translational Medicine on August 5, 2020 | *Summary available

MOTIVATION AND LEARNING IN MACAQUES
Selective Mesoaccumbal Pathway Inactivation Affects Motivation but Not Reinforcement-based Learning in Macaques
Vancraeyenest P, Arsenault JT, Li X, Zhu Q, Kobayashi K [et al.], Vanduffel W.
Published in Neuron on August 5, 2020 | *Summary available

CIRCULATING TUMOR DNA AND DISEASE BURDEN
Association Between Circulating Tumor DNA Burden and Disease Burden in Patients with ALK-positive Lung Cancer
Zhang EW, Dagogo-Jack I, Kuo A, Rooney MM, Shaw AT, Digumarthy SR.
Published in Cancer on August 5, 2020 | *Summary available

BIOMARKERS FOR NONALCOHOLIC FATTY LIVER DISEASE
Epoxygenase-derived Epoxyeicosatrienoic Acid (EET) Mediators Are Associated with NAFLD, NASH and Fibrosis
Arvind A, Osganian SA, Sjoquist JA, Corey KE, Simon TG.
Published in Gastroenterology on August 5, 2020

METABOLIC MECHANISMS BEHIND CANCER RESISTANCE
Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance
van Gastel N, Spinelli JB, Sharda A, Schajnovitz A, Baryawno N [et al.], Scadden DT.
Published in Cell Metabolism on August 6, 2020 | *Summary available

THYROID STIMULATING HORMONE-ASSOCIATED VARIANTS
GWAS of Thyroid Stimulating Hormone Highlights Pleiotropic Effects and Inverse Association with Thyroid Cancer
Zhou W, Brumpton B, Kabil O, Gudmundsson J, Thorleifsson G [et al.], Asvold BO.
Published in Nature Communications on August 7, 2020

POTENTIAL NEURAL MARKERS FOR CHRONIC BACK PAIN
Distinct Thalamocortical Network Dynamics are Associated with the Pathophysiology of Chronic Low Back Pain
Tu Y, Fu Z, Mao C, Falahpour M, Gollub RL [et al.] Kong J.
Published in Nature Communications on August 7, 2020 | *Summary available

DNA VARIANTS ASSOCIATED WITH CORONARY ARTERY DISEASE IN SOUTH ASIANS
Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians
Wang M, Menon R, Mishra S, Patel AP, Chaffin M [et al.], Khera AV.
Published in Journal of the American College of Cardiology on August 11, 2020

SOCIAL DISTANCING AND COVID-19
Social Distancing to Slow the US COVID-19 Epidemic: Longitudinal Pretest-Posttest Comparison Group Study
Siedner MJ, Harling G, Reynolds Z, Gilbert RF, Haneuse S [et al.], Tsai AC.
Published in PLOS Medicine on August 11, 2020 | *Summary available | Press release

PATHOGENIC MUTATIONS OF MITOCHONDRIAL DNA
Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells
Walker MA, Lareau CA, Ludwig LS, Karaa A, Sankaran VG [et al.], Mootha VK.
Published in New England Journal of Medicine on August 12, 2020 | Press release

DISEASE-CAUSING MUTATIONS IN SODIUM AND CALCIUM ION CHANNELS
Predicting Functional Effects of Missense Variants in Voltage-gated Sodium and Calcium Channels
Heyne HO, Baez-Nieto D, Iqbal S, Palmer DS, Brunklaus A [et al.], Daly MJ.
Published in Science Translational Medicine on August 12, 2020 | *Summary available

MODIFIABLE FACTORS FOR DEPRESSION PREVENTION
An Exposure-Wide and Mendelian Randomization Approach to Identifying Modifiable Factors for the Prevention of Depression
Choi KW, Stein MB, Nishimi KM, Ge T, Coleman JRI [et al.], Smoller JW.
Published in American Journal of Psychiatry on August 14, 2020 | Press release

CREATING REALISTIC SIMULATIONS OF RNA COPYING
Potentially Prebiotic Activation Chemistry Compatible with Nonenzymatic RNA Copying
Zhang SJ, Duzdevich D, Szostak JW.
Published in Journal of the American Chemical Society on August 14, 2020

A CRITICAL ENZYME FOR X CHROMOSOME INACTIVATION
Decapping Enzyme 1A Breaks X-Chromosome Symmetry by Controlling Tsix Elongation and RNA Turnover
Aeby E, Lee H, Lee Y, Kriz A, Del Rosario BC [et al.], Lee JT.
Published in Nature Cell Biology on August 17, 2020 | Press release

GENETIC LINKS TO HYPERTENSIVE DISORDERS OF PREGNANCY
Genetic Variation in Cardiometabolic Traits and Medication Targets and the Risk of Hypertensive Disorders of Pregnancy
Honigberg MC, Chaffin M, Aragam K, Bhatt DL, Wood MJ [et al.], Natarajan P.
Published in Circulation on August 17, 2020 | *Summary available

OSCILLATORY PATTERNS IN DAILY REPORTED COVID-19 CASES
Periodic Oscillations in Daily Reported Infections and Deaths for Coronavirus Disease 2019
Bukhari Q, Jameel Y, Massaro JM, D'Agostino RB, Khan Sheraz.
Published in JAMA Network Open on August 17, 2020 | *Summary available

AAV VECTOR FOR ALZHEIMER'S GENE THERAPY
Gene Therapy for Alzheimer's Disease Targeting CD33 Reduces Amyloid Beta Accumulation and Neuroinflammation
Griciuc A, Federico AN, Natasan J, Forte AM, McGinty D [et al.], Maguire CA.
Published in Human Molecular Genetics on August 17, 2020 | *Summary available

GERMINAL CENTER LOSS IN COVID-19
Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19
Kaneko N, Kuo H, Boucau, Farmer JR, Allard-Chamard [et al.], Pillai S.
Published in Cell on August 19, 2020 | *Summary available | Press release

POLYGENIC BACKGROUND MODIFIES PENETRANCE OF MONOGENIC MUTATIONS
Polygenic Background Modifies Penetrance of Monogenic Variants for Tier 1 Genomic Conditions
Fahed AC, Wang M, Homburger JR, Patel AP, Bick AG [et al.], Khera AV.
Published in Nature Communications on August 20, 2020 | *Summary available

TUMOR CELLS FAIL TO SPATIALLY SEGREGATE ACTIVE CHROMATIN
Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer
Johnstone SE, Reyes AR, Qi Y, Adriaens C, Hegazi E [et al.], Bernstein BE.
Published in Cell on August 24, 2020 | *Summary available

THE IMPACT OF HOSPITAL ACQUISITION BY PRIVATE EQUITY
Changes in Hospital Income, Use, and Quality Associated with Private Equity Acquisition
Bruch JD, Gondi S, Song Z.
Published in JAMA Internal Medicine on August 24, 2020 | *Summary available

BRAIN CONNECTIVITY PATTERNS ASSOCIATED WITH MANIA
Mapping Mania Symptoms Based on Focal Brain Damage
Cotovio G, Talmasov D, Barahona-Correa JB, Hsu J, Senova S [et al.], Fox MD.
Published in Journal of Clinical Investigation on August 24, 2020

INSIGHTS INTO ANTIBODY ADAPTABILITY
A Single Human VH-gene Allows for a Broad-Spectrum Antibody Response Targeting Bacterial Lipopolysaccharides in the Blood
Sangesland M, Yousif AS, Ronsard L, Kazer SW, Zhu AL [et al.], Lingwood D.
Published in Cell Reports on August 25, 2020 | *Summary available

FECAL MICROBIOTA TRANSPLANTATION FOR CROHN'S DISEASE
Linking Strain Engraftment in Fecal Microbiota Transplantation with Maintenance of Remission in Crohn's Disease
Kong L, Lloyd-Prince J, Vatanen T, Seksik P, Beaugerie L [et al.], Xavier RJ.
Published in Gastroenterology on August 26, 2020 | *Summary available

VIRAL RESERVOIRS IN ELITE CONTROLLERS OF HIV
Distinct Viral Reservoirs in Individuals with Spontaneous Control of HIV-1
Jiang C, Lian X, Gao C, Sun X, Einkauf KB [et al.], Walker BD, Lichterfield M, Yu XG.
Published in Nature on August 26, 2020 | *Summary available | Press release

RISK ASSESSMENT SCORES FOR PATIENTS WITH ACUTE PULMONARY EMBOLISM
Comparison of 4 Acute Pulmonary Embolism Mortality Risk Scores in Patients Evaluated by Pulmonary Embolism Response Teams
Barnes GD, Muzikansky A, Cameron S, Giri J, Heresi GA [et al.], Kabrhel C.
Published in JAMA Network Open on August 26, 2020

POTENTIAL TARGET FOR ALLERGY PREVENTION
Increased IgE-mediated Food Allergy with Food Protein-induced Allergic Proctocolitis
Martin VM, Virkud YV, Phadke NA, Su K, Seay H [et al.], Yuan Q.
Published in Pediatrics on August 26, 2020 | *Summary available

BRAIN DYNAMICS UNDER ANESTHESIA
Neural Signatures of α2-Adrenergic Agonist-induced Unconsciousness and Awakening by Antagonist
Ballesteros JJ, Briscoe JB, Ishizawa Y.
Published in eLife on August 28, 2020

NOVEL DUAL CAR T CELL TO TARGET THE HIV RESERVOIR
Dual CD4-based CAR T Cells with Distinct Costimulatory Domains Mitigate HIV Pathogenesis In Vivo
Maldini CR, Claiborne DT, Okawa K, Chen T, Dopkin DL [et al.], Allen TM.
Published in Nature Medicine on August 31, 2020 | *Summary available | *Summary available | Press release

Summaries

Traditional MRI machines work at high magnetic fields and use superconducting magnets that are big, bulky and expensive. Recently, a new generation of versatile, portable and low-cost MRI scanners operating at low magnetic fields has started to be used in hospitals. The trade-off for this type of machine has been the quality and resolution of the medical scans. This study developed a technique using iron oxide nanoparticles to improve the image quality and contrast of medical scans acquired by these low-field MRI machines. This development can help improve access to diagnostic imaging worldwide.

(Summary submitted by Matthew Rosen, PhD, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology)

COVID-19 may result in excessive blood clotting, particularly in critically ill patients. The mechanism of this clotting propensity is unknown, but extreme levels of inflammation may be an important contributing factor. In this study, we examined outcomes of 400 patients with COVID-19. Both clotting and bleeding manifestations contributed significantly to the morbidity of this disease, particularly in the critically ill. Significant elevations of the D-dimer assay (commonly used to evaluate clotting activity) drawn at initial presentation was predictive of bleeding complications, clotting complications, critical illness, and death. The D-dimer correlated with many other clinical markers of inflammation, providing evidence for the hypothesis that clotting complications may be related to inflammation in COVID-19.

(Summary submitted by Hanny Al-Samkari, MD, Division of Hematology, Mass General Cancer Center)

Single-cell and single-nucleus RNA sequencing technology enables systematic tissue atlases to be built for health and disease studies. As the scale of data generation is growing, researchers need computational pipelines for scaled analysis. We developed Cumulus, a cloud-based framework to tackle this challenge. With the power of cloud computing and improvements in algorithms and implementation, Cumulus can handle the analysis on large-scale data well at a low cost. Moreover, it provides a user-friendly interface with a comprehensive set of features for a better experience of users with no computational background. In a benchmark on a large human bone marrow dataset, we demonstrate that Cumulus not only improves efficiency over conventional frameworks, but also maintains and improves the quality of results.

(Summary submitted by Bo Li, PhD, Center for Immunology and Inflammatory Diseases, Department of Medicine)

Using a proprietary antibody profiling approach, Systems Serology, we observed striking differences in the antibody response in individuals that survived or died from COVID-19. Responses to the external spike protein, involved in viral attachment and infection, during the first few days after symptoms were linked to survival. Responses to the internal nucleocapsid protein, involved in protecting the viral genome, was associated with death. These data point to the balance of immunity to viral antigens in the first few days of infection as critical predictors of survival, have important implications for vaccine development and offer clues for new diagnostics to support those at highest risk from COVID-19.

(Summary submitted by Rachel Leeson, MS, Ragon Institute of MGH, MIT and Harvard)

We sought to investigate how to safely offer in-person learning in the context of the COVID pandemic using the methods of epidemic modeling and cost-effectiveness analysis. Using SARS-CoV2 test performance and disease dynamics data, we demonstrate that safely opening residential colleges is possible and can be cost-effective if a high cadence of testing (every student every 2-3 days) is performed along with strict adherence to other preventive practices (e.g. masking, distancing). Symptomatic screening of students alone led to uncontrolled outbreaks in all of the scenarios we examined. We acknowledge that the findings of this study set a high bar—logistically, financially, behaviorally—that may be beyond the reach of many universities and the students in their care.

(Summary submitted by Rochelle Walensky, MD, MPH, Infectious Diseases Division, Department of Medicine)

Targeting the mTOR pathway through the mTOR inhibitor only generates moderate and limited clinical outcome. Thus, there is a demand for new approaches that specifically target mTOR-hyperactive cancers. We found piperlongumine (PL) could selectively kill mTOR-hyperactive cancer cells through disrupting the formation of RUVBL1/2-TTT, and blocking its function in DNA repair signaling. Cancer cells with high mTORC1 activity endure c-Myc-dependent higher level of DNA damage stress, and it makes the cells dependent on RUVBL1/2 for survival. The study demonstrated that RUVBL1/2-TTT complex can be used as a target for selectively killing cancer cells addicted to the mTOR pathway.

(Summary submitted by Jiamin Zhang, PhD, Department of Medicine, Mass General Cancer Center)

In this study, we sought to describe the complications affecting the abdominal organs of critically ill patients with COVID-19. We found that 74% of patients admitted to the intensive care unit developed at least one abdominal complication: 67% had high circulating levels of liver enzymes which are markers for liver damage, and 56% had a severe ileus, a condition in which the bowels do not contract properly. Several patients developed life threatening dead bowel with highly atypical features that required emergency surgery and bowel resection, some developed a paralytic colon while others developed inflammation of their gallbladder or pancreas. Front line clinicians should keep a high index of suspicion for abdominal symptoms warranting surgical consultation.

(Summary submitted by Mohamad El Moheb, MD, Division of Trauma, Emergency Surgery & Surgical Critical Care, Department of Surgery)

IMPACT OF COVID-19 ON BREAST CANCER PREVENTION AND CARE
Breast Imaging, Breast Surgery, and Cancer Genetics in the Age of COVID-19
Yin K, Singh P, Drohan B, Hughes KS.
Published in Cancer on August 4, 2020

The COVID-19 pandemic caused many elective health care services to shut down. This has far-reaching consequences on health care delivery in the U.S. By analyzing data from a cancer risk assessment company, we demonstrated that from February 2 to April 11, 2020, the number of women having a mammogram dropped by 94.6%, breast surgery consultations decreased by 59.9%, and genetics consultations dropped by 60.1%. These findings suggest that the COVID-19 pandemic has had a significant impact on breast cancer prevention, screening, diagnosis and treatment. The long-term consequences of missed and delayed cancer diagnoses remain to be seen.

(Summary submitted by Kanhua Yin, MD, MPH, Division of Surgical Oncology, Department of Surgery)

The study was a randomized trial that addressed the question: Can long-term supplementation with vitamin D3 prevent depression in the general adult population? There were 18,353 men and women, aged 50 years or above, who were without depression when the study began. Participants were randomized to receive either vitamin D3 supplementation or a matching placebo. After an average of five-and-a-half years of randomized treatment, there was no significant difference between vitamin D3 and placebo in the risk of developing depression or clinically relevant depressive symptoms, and there were no differences in overall mood quality during the course of the study. Therefore, although vitamin D is essential for bone health and may be still be important for other health purposes, the broad use of vitamin D3 supplements in generally healthy adults has no benefit for preventing depression.

(Summary submitted by Olivia Okereke, MD, Department of Psychiatry)

Rapid, automated, and point-of-care cellular diagnosis of cancer remains difficult in resource-limited settings due to lack of specialists and medical infrastructure. We developed an automated image cytometry system (CytoPAN) that allows rapid breast cancer diagnosis and receptor subtyping in one hour using as few as 50 cells obtained by fine needle aspiration (FNA). The combination of FNA and CytoPAN offers an alternative strategy for faster, minimally invasive cancer diagnosis in both developed and developing countries. Coupled with recently developed cycling technologies for FNA, this will enable rapid molecular and cellular profiling of serial tumor samples in clinical trials.

(Summary submitted by Hyungsoon Im, PhD, Center for Systems Biology)

We inactivated specific connections between two ventral brain structures implicated in reinforcement-based learning. However, contrary to this assumption, inactivation of this pathway in monkeys did not affect performance in a learning task. In contrast, the monkeys lost their motivation to perform trials requiring high but not low effort levels. Moreover, functional imaging revealed increased functional connectivity between many brain areas. Besides the unpredicted behavioral and functional findings, the study confirmed the translational potential of pathway-selective manipulations. Indeed, motivational imbalances play a major role in many psychiatric diseases, including depression, obsessive compulsive behavior, addiction, etc. The present study provides clues as how to precisely affect motivational behavior, without affecting learning in such patients.

(Summary submitted by Wim Vanduffel, PhD, Martinos Center for Biomedical Imaging, Department of Radiology)

Cancer cells shed circulating tumor DNA (ctDNA) into the bloodstream and analysis of this genetic material can determine the alterations driving cancers and conferring resistance to treatment. However, for reasons not well understood, there is variability in ctDNA detection. In this study, we correlated tumor burden estimated on imaging studies in ALK-positive lung cancer with ctDNA derived from peripheral blood. A correlation was found between ctDNA burden and overall tumor and extrathoracic tumor burden, and disease in the liver, bone and adrenals. Patients with exclusive intrathoracic disease had insignificant/absent ctDNA. These results can help in patient selection for ctDNA testing.

(Summary submitted by Eric Zhang, MD, Department of Radiology)

Blood cancers like leukemia can be effectively treated with chemotherapy, but relapse usually occurs due to resistant cancer cells that evade the original drug regimen. We have identified a unique characteristic of resistant cancer cells: a temporary change in their metabolism or how they use nutrients. Specifically, resistant leukemia cells consumed more glutamine to fuel nucleotide production. During a short time after chemotherapy, the cancer cells are extremely vulnerable to targeting of these metabolic changes. We propose using drugs that inhibit glutamine or nucleotide metabolism at the right time after chemotherapy to eliminate resistant cells and improve patient outcomes.

(Summary submitted by Nick van Gastel, PhD, Center for Regenerative Medicine)

To date, treatment for non-specific chronic low back pain (cLBP), a common disorder, remains unsatisfactory. The underlying mechanisms for this disorder are unclear due to both its non-specific etiology and complexity. Using functional magnetic resonance imaging (fMRI) on the brains of patients and pain-free controls, we found that abnormal brain connectivity between different thalamic nuclei and cortical regions (e.g., primary somatosensory area, insula and default mode network) were associated with cLBP pathophysiology. Our results may provide a neural marker as well as a potential therapeutic target (e.g., brain stimulation) for cLBP.

(Summary submitted by Yiheng Tu, PhD, Department of Psychiatry, Martinos Center for Biomedical Imaging)

We found that government-issued social distancing orders in the U.S. played a significant role in reducing cases and deaths from COVID-19. Just prior to their implementation, the epidemic was doubling approximately every 3 days. Three weeks later, the doubling rate had dropped to approximately every 8 days, corresponding to a reduction in an estimated 600,000 cases of COVID-19 over that period. The reduction was seen across most states, regardless of population density or stage of the epidemic when implementation occurred. These results support the use of state-mandated mitigation policies to confront the COVID-19 epidemic in the U.S. in areas with active outbreaks.

(Summary submitted by Mark Siedner, MD, MPH, Infectious Diseases Division, Department of Medicine, Center for Global Health)

Sodium and calcium ion channels (Nav/Cavs) are key mediators of cell communication in many tissues and as a result, genetic mutations in those channels can lead to different diseases affecting the brain, heart, muscle or eye. We developed a computational tool that predicts whether disease-causing mutations in Nav/Cavs would increase or decrease channel activity, as the two states often result in different disease conditions. We tested our tool on genetic data of individuals with epilepsy or autism as well as EEG electrophysiology data and learned new aspects about function and dysfunction of Nav/Cavs. Our work aims to better diagnose and treat diseases caused by mutations in these channels.

(Summary submitted by Henrike Heyne, MD, Analytic & Translational Genetics Unit, Department of Medicine and the Broad Institute)

We know women with hypertensive disorders of pregnancy (HDP), have elevated long-term risk of chronic hypertension, diabetes, obesity, and heart disease. However, it’s been unclear whether there is a causal relationship between these “cardiometabolic traits” and HDP. We used an approach called “Mendelian randomization,” which uses genetics as a tool to infer causality, among ~214,000 women in the UK Biobank who had given birth. We found that genetically determined blood pressure and body-mass index (BMI) were strongly associated with HDP. This finding implies that blood pressure and BMI may be causal for development of HDP and that strategies to lower blood pressure and BMI in at-risk women may prevent these pregnancy complications and improve long-term cardiovascular health.

(Summary submitted by Michael Honigberg, MD, MPP, Division of Cardiology, Department of Medicine)

COVID-19 is a global pandemic that has devastated countries across the world. While the pandemic phase (growth and decline), is dissimilar across nations, a closer look reveals an astounding pattern of oscillations with a periodicity of approximately a week in the daily reported new cases and deaths. We discussed the periodicity of these oscillations across the world and their possible origins. These oscillations should be accounted for in the estimation of the effective reproduction number R(t). Moreover, an in-depth understanding of this periodicity in COVID-19 cases and deaths might lead to improved hospital capacity management.

(Summary submitted by Sheraz Khan, PhD, Department of Radiology, Martinos Center for Biomedical Imaging)

Our study stemmed from work by the Tanzi lab showing that CD33 is an Alzheimer’s Disease (AD) risk gene, leading to neuroinflammation and plaque formation. We designed an adeno-associated virus vector gene therapy approach to target CD33 mRNA, and we demonstrated that CD33 knockdown reduced plaque size as well as markers of neuroinflammation in the AD mouse brain.

(Summary submitted by Casey Maguire, PhD, Department of Neurology)

Thoracic lymph nodes and spleens from COVID-19 autopsies lacked germinal centers—transient Darwinian anatomic structures where B cells that make high-affinity antibodies are selected and immortalized during an immune response. Increased local TNF-a in COVID-19 lymph nodes may cause the observed block in T follicular helper cell differentiation that prevents germinal center formation. The lack of germinal centers may compromise a patient’s ability to develop a high quality, long-lasting antibody response and ultimately negatively impact immunological memory. It is very unlikely that this type of defect would be seen in a vaccine-induced immune response.

(Summary submitted by Rachel Leeson, MS, Ragon Institute of MGH, MIT and Harvard)

Many people with a high-risk genetic mutation remain healthy. We asked whether the polygenic background plays a role. We studied the interplay of monogenic and polygenic risk in more than 80,929 individuals focusing on three ‘Tier 1’ genomic diseases: Familial Hypercholesterolemia linked to heart attack, BRCA1/BRCA2 mutations linked to breast cancer, and Lynch syndrome linked to colorectal cancer. Among carriers of mutations for all three conditions, we identified a striking gradient of risk. The probability of disease by age 75 ranged between 17%-78% for heart attack 13%-76% for breast cancer, and 11%-80% for colorectal cancer. Polygenic background modifies penetrance of monogenic mutations. The future of genome interpretation should look at both monogenic and polygenic risk.

(Summary submitted by Akl Fahed, MD, MPH, Division of Cardiology, Department of Medicine)

Pathologists have long described abnormalities of tumor cell nuclei. However, the molecular underpinnings of these morphological changes have remained unknown. We mapped the 3D structure of the genome in colon cancer and show that tumor cells fail to spatially segregate active chromatin from repressed chromatin. This loss of organization also occurs in normally aging cells and, surprisingly, serves to repress stemness and invasion programs. Cancer cells are able to circumvent these tumor suppressive changes to facilitate tumor growth. Modulating tumor cell sensitivity to these tumor suppressive effects could lead to a new therapeutic approach in cancer.

(Summary submitted by Sarah Johnstone, MD, PhD, Department of Pathology)

Empirical evidence describing the relationship between private equity acquisition and changes in hospital spending and quality is lacking. In this analysis of 204 private equity-acquired hospitals and 532 similar hospitals that were not acquired by private equity, net income, charges, charge to cost ratios and the case mix index differentially increased for private equity-acquired hospitals after acquisition relative to control hospitals. Some quality measures improved among a subset of private equity-acquired hospitals relative to control hospitals. Medicare’s share of discharges decreased for private equity-acquired hospitals after acquisition relative to controls. Heterogeneity in some findings was observed between private equity-owned Hospital Corporation of America (HCA) hospitals and non-HCA private equity-owned hospitals.

(Summary submitted by Joseph Bruch, Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health)

Antibodies target pathogens via their binding surfaces, which are formed by hypervariable and gene-encoded loops called complementarity determining regions (CDR). Diversity in the binding surfaces must keep pace with diverse pathogens and this is thought to be achieved by the hypervariable CDRs. However, using transgenic mice bearing human-like CDR diversity, we showed that specific gene-encoded CDRs were needed for antibodies to recognize diverse forms of lipopolysaccharide (LPS), a key danger signal and bacterial component. These antiseptic responses were also directed against the non-variable features of LPS, demonstrating that specific human gene-encoded CDRs are ‘innate-like’ and tune for immune-recognition of conserved microbial patterns.

(Summary submitted by Daniel Lingwood, PhD, Ragon Institute of MGH, MIT and Harvard)

Transplantation of gut microbes from healthy donors, such as fecal microbiota transplantation (FMT), is emerging as a promising approach for treating patients with Crohn's disease (CD). We published the first metagenomic sequencing-based study of FMT engraftment dynamics in CD patients. We found that the engraftment of particular microbial species and strains correlated with clinical remission, that donors' microbes often end up co-existing alongside patients' (as opposed to replacing them completely), and that it may be possible to match donors and recipients based on metagenomic microbial signatures.

(Summary submitted by Ramnik Xavier, MD, PhD, Division of Gastroenterology, Department of Medicine, Center for Computational and Integrative Biology)

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals, known as elite controllers (EC). We analyzed the genomes of ECs and found, in contrast to individuals on long-term antiretroviral therapy, viral reservoirs in ECs were preferentially located in gene deserts. These data suggest that quality rather than quantity of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, one EC had no intact viral genomes detected, raising the possibility that a sterilizing cure of HIV-1 infection may be feasible in rare instances.

(Summary submitted by Rachel Leeson, MS, Ragon Institute of MGH, MIT and Harvard)

POTENTIAL TARGET FOR ALLERGY PREVENTION
Increased IgE-mediated Food Allergy With Food Protein-induced Allergic Proctocolitis
Martin VM, Virkud YV, Phadke NA, Su K, Seay H [et al.], Yuan Q.
Published in Pediatrics on August 26, 2020

Food protein-induced allergic proctocolitis (FPIAP) is an early, common form of food allergy treated with milk avoidance and not thought to be associated with IgE-mediated food allergy (IgE-FA). With IgE-FA on the rise and its association with lack of early antigen exposure, we prospectively evaluated the relationship between FPIAP and subsequent IgE-FA in a large healthy cohort. We found that children with FPIAP were more likely to develop IgE-FA, suggesting it may be an important target for allergy prevention. We recommend judicious use of the Milk Allergy in Primary Care (iMAP) guidelines, earlier attempts at milk reintroduction and considering early peanut and egg introduction for infants with FPIAP.

(Summary submitted by Victoria Martin, MD, MPH, Division of Pediatric Gastroenterology and Nutrition, Mass General for Children)

We explored whether chimeric antigen receptor (CAR) T cells can mitigate HIV-induced pathogenesis in humanized mice. Through an iterative process we developed a novel Dual CAR T cell that simultaneously expresses two CD4-based CARs, one encoding the 4-1BB costimulatory domain to sustain cellular division, and one encoding CD28 to enhance effector function. CAR T cells were further engineered to express the C34 fusion inhibitor to protect them from infection. In mice, Dual CAR T cells reduced viremia, limited CD4 T cell loss and diminished tissue viral burden, highlighting their therapeutic potential to target the HIV reservoir towards a functional cure.

(Summary submitted by Rachel Leeson, MS, Ragon Institute of MGH, MIT and Harvard)

Press Releases

First Participants Enrolled in the Groundbreaking Trial Led by the Sean M. Healey & AMG Center for ALS at Mass General
Featuring Merit Cudkowicz, MD, and Sabrina Paganoni, MD, PhD

As the first ever platform trial for ALS, the HEALEY ALS Platform Trial is testing three proposed drug regimens and will add two more over the next several months.

Massachusetts General Hospital, University of Minnesota to Co-lead Collaboration Focused on Preserving Cells, Tissue, Organs, Organisms
Featuring Mehmet Toner, PhD, Martin Yarmush, MD, PhD, and Korkut Uygun, PhD

The National Science Foundation has awarded a $26 million grant to an ambitious collaboration involving the Mass General Center for Engineering in Medicine & Surgery (CEMS) to establish an engineering research center (ERC) that will develop, refine and expand technologies to “stop biologic time” by preserving, stabilizing and suspending living material.

Large Study Confirms Vitamin D Does Not Reduce Risk of Depression in Adults
Featuring Olivia I. Okereke, MD, MS

In a study of 18,000+ participants, the risk of depression was not significantly different between those receiving vitamin D and those on placebo.

New Study Supports More Frequent HIV Screening Among High-risk Young Men Who Have Sex with Men
Featuring Anne Neilan, MD, MPH

Screening every three months compared to current recommendations of annual screening would improve clinical outcomes and be cost-effective.

Aspirin May Accelerate Progression of Advanced Cancers in Older Adults
Featuring Andrew Chan, MD, MPH

Aspirin use in older adults was associated with an approximately 20% higher risk of the cancer spreading through the body and of a stage four (advanced) cancer diagnosis.

Mass General Study Shows Physical Distancing Slowed Growth of COVID-19 in US
Featuring

Researchers found that the average daily COVID-19-attributed death rate also began declining after the implementation of physical distancing measures.

AI-assisted Mammography Must Move into a Critical New Phase of Prospective Clinical Evaluation
Featuring Connie Lehman, MD, PhD

To impact and improve patient care, the study of artificial intelligence tools to support screening mammography must now shift from simulated research trials to robust clinical evaluations, according to Constance Lehman, MD, PhD.

No Increased Skin Cancer Risk with Topical Immunosuppressant Ointments, Study Finds
Featuring Maryam Asgari, MD

Two topical ointments commonly prescribed to treat atopic dermatitis do not appear to increase the risk for the most common forms of skin cancer.

Single-cell Analysis Provides New Insights into Mitochondrial Diseases
Featuring Melissa Walker, MD, PhD

Single-cell analysis provides new insights into mitochondrial diseases.

Study of More than 100 Modifiable Factors for Depression Identifies Social Connection as the Strongest Protective Factor
Featuring Jordan Smoller, MD, and Karmel Choi, PhD

Researchers from Mass General have identified a set of modifiable factors from a field of over 100 that could represent valuable targets for preventing depression in adults.

Study Reveals How Two Sex Chromosomes ‘Talk’ to Each Other to Make a Critical Decision During Development of the Female Embryo
Featuring Jeannie T. Lee, MD, PhD

In a breakthrough study, Mass General researchers discovered the role of a critical enzyme in the phenomenon known as X chromosome inactivation, which is essential for normal female development.

Clinical and Sociodemographic Features of Early COVID-19 Patients in Massachusetts: MGH Study Suggests Vulnerable Populations are Hardest Hit
Featuring Jason Wasfy, MD

Data from the first COVID-19 patients treated at three large Massachusetts hospitals reveal important trends, including high rates of disease-related complications, and the need for post-discharge care and monitoring.

COVID-19 Cytokine Storms May Prevent a Durable Immune Response
Featuring Shiv Pillai, MD, PhD

Researchers found a mechanism that could explain a lower-quality immune response in some COVID-19 patients.

Mass General Study Finds Children Have High COVID-19 Viral Load Despite Mild or No Symptoms
Featuring Alessio Fasano, MD, and Lael M. Yonker, MD

Study provides critical data suggesting that children may play a larger role in the community spread of COVID-19 than previously thought.

Mass General Researchers Create Bioluminescent Tag to Detect DNA Break Repair
Featuring Christian Elias Badr, PhD

The system can be used to monitor DNA repair pathways directly in animals as well as cell lines. These pathways play a crucial role in multiple conditions, including cancer.

Massachusetts General Hospital First in New England to Perform New Procedures for Tricuspid Valve Disease
Featuring Sammy Elmariah, MD, MPH, and Ignacio Inglessis-Azuaje, MD

These procedures provide new options for patients who have had limited treatments and been suffering the ill effects of tricuspid valve disease.

MGH Researchers Gain Insight into Mechanism of Promising Therapy to Reduce Liver Fat and Prevent Fibrosis Progression in Common Form of Liver Disease
Featuring Steven Grinspoon, MD

Through genetic analysis, researchers have identified how one promising therapy may work to improve the adverse effects of non-alcoholic fatter liver disease.

Unique HIV Reservoirs in Elite Controllers
Featuring Xu Yu, MD, and Bruce Walker, MD

Researchers find that in elite controllers—a small group of individuals who are able to control HIV infection without antiretroviral medication—HIV is hidden in parts of the cell's DNA where it can not be used to create new copies of the virus.

Mass General Study Shows the Benefits of Inhaled Nitric Oxide Therapy for Pregnant Patients with Severe and Critical Covid-19
Featuring Lorenzo Berra, MD

The delivery of the therapeutic gas to six COVID-19 pregnant patients admitted to Mass General resulted in a rapid and sustained improvement in cardiopulmonary function and decreased inflammation.

Strong, Durable Responses to Selpercatinib in Ret-driven Medullary Thyroid Cancer
Featuring Lori Wirth, MD

The drug was effective both in patients with no prior treatment with targeted anti-cancer drugs and in those who had disease progression following treatment with other multitargeted agents.

Novel Dual Car T Cell Immunotherapy Holds Promise for Targeting the HIV Reservoir
Featuring Todd Allen, PhD

A recent study published in the journal Nature Medicine, describes a new Dual CAR T cell immunotherapy that can help fight HIV infection.

Blog Posts

Non-White Patients Hospitalized for COVID-19 More Likely to Show Severe Disease in Chest X-Rays
Featuring Efren J. Flores, MD

Severity in chest x-rays increase the likelihood of admission to the intensive care unit, intubation and death.

Everything You Need to Know About COVID-19 Tests
Featuring David Louis, MD, Anthony John Iafrate, MD, and Eric Rosenberg, MD

Widespread testing and tracing are crucial to managing the spread of COVID-19, but there are several different kinds of tests that each have a specific use. Learn more about which test may be best for you.

Science Rehashed: A Podcast on a Mission
Featuring Mehdi Jorfi, PhD

Mass General investigator Mehdi Jorfi, PhD, created the Science Rehashed podcast to give back to the community and share the latest scientific research in an accessible way. Learn more about Dr. Jorfi and the creative team behind the podcast.

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Snapshot of Science for August 2020