Snapshot of Science for June 2020

Welcome to our Snapshot of Science for June 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:

36 new studies published in high impact journals, along with 20 summaries submitted by the research teams
12 new research-related press releases from the Mass General Public Affairs office
6 posts from the Mass General Research Institute blog

Publications

TAM-AVID NANOTHERAPY TO BLOCK TUMOR-MACROPHAGE SIGNALING
Efficient Blockade of Locally Reciprocated Tumor-Macrophage Signaling Using a TAM-avid Nanotherapy
Wang SJ, Li R, Ng TSC, Luthria G, Oudin MJ [et al.], Miller MA.
Published in Science Advances on May 22, 2020 | *Summary available

MEMBRANE OXYGENATION IN COVID-RELATED RESPIRATORY FAILURE
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 May 25, 2020 | *Summary available

EVOLUTIONARY DEVELOPMENT OF LYMPH NODE METASTASES
Lymph Node Metastases Develop Through a Wider Evolutionary Bottleneck Than Distant Metastases
Reiter JG, Hung W, Lee I, Nagpal S, Giunta P [et al.], Naxerova K.
Published in Nature Genetics on May 25, 2020 | *Summary available | Press Release

ENHANCING TYPE 1 IMMUNIZATION RESPONSE
Targeting Lymph Node Niches Enhances Type 1 Immune Responses to Immunization
Lian J, Ozga AJ, Sokol CL, Luster AD.
Published in Cell Reports on May 26, 2020 | *Summary available

IDENTIFYING AN ENZYME THAT PROTECTS MALIGNANT CELLS
Aldehyde Dehydrogenase 3a2 Protects AML Cells From Oxidative Death and the Synthetic Lethality of Ferroptosis Inducers
Yusuf RZ, Saez B, Sharda A, van Gastel N, Yu V [et al.], Scadden DT.
Published in Blood on May 26, 2020 | *Summary available

RACIAL AND ETHNIC DISPARITIES IN OPIOID USE DISORDER TREATMENT IN PREGNANT WOMEN
Assessment of Racial and Ethnic Disparities in the Use of Medication to Treat Opioid Use Disorder Among Pregnant Women in Massachusetts
Schiff DM, Nielsen T, Hoeppner BB, Terplan M, Hansen H [et al.], Taveras EM.
Published in JAMA Open Network on May 26, 2020 | Press Release

UNDERLYING CHEMICAL RATIO OF METABOLIC TRAIT VARIATION
Hepatic NADH Reductive Stress Underlies Common Variation in Metabolic Traits
Goodman RP, Markhard AL, Shah H, Sharma R, Skinner OS [et al.], Mootha VK.
Published in Nature on May 27, 2020 | *Summary available | Press Release

GENOME ANALYSIS YIELDS LARGEST-EVER MAP OF STRUCTURAL VARIANTS
A Structural Variation Reference for Medical and Population Genetics
Collins RL, Brand H, Karczewski KJ, Zhao X, Alfoldi J [et al.], Talkowski ME.
Published in Nature on May 27, 2020 | *Summary available

GENOME AGGREGATION DATABASE (gnomAD) CONSORTIUM RELEASES LARGEST CATALOG OF HUMAN GENETIC DATA VARIATION TO DATE | *Summary available

Characterising the Loss-Of-Function Impact of 5' Untranslated Region Variants in 15,708 Individuals
Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ [et al.], Ware JS.
Published in Nature Communications on May 27, 2020
Landscape of Multi-Nucleotide Variants in 125,748 Human Exomes and 15,708 Genomes
Wang Q, Pierce-Hoffman E, Cummings BB, Alfoldi J, Francioli LC, Gauthier LD [et al.], MacArthur DG.
Published in Nature Communications on May 27, 2020
The Effect of LRRK2 Loss-Of-Function Variants in Humans
Whiffin N, Aremean IM, Kleinman A, Marshall JL, Minikel EV [et al.], MacArthur DG.
Published in Nature Medicine on May 27, 2020
Transcript Expression-Aware Annotation Improves Rare Variant Interpretation
Cummings BB, Karczewski KJ, Kosmicki JA, Seaby EG, Watts NA [et al.], MacArthur DG.
Published in Nature on May 27, 2020
The Mutational Constraint Spectrum Quantified From Variation in 141,456 Humans
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J [et al.], MacArthur DG.
Published in Nature on May 27, 2020
Evaluating Drug Targets Through Human Loss-Of-Function Genetic Variation
Minikel EV, Karczewski KJ, Martin HC, Cummings BB, Whiffin N [et al.], MacArthur DG.
Published in Nature on May 27, 2020

MITOCHONDRIAL DYSFUNCTION & INTEGRATED STRESS RESPONSE
Distinct Mitochondrial Defects Trigger the Integrated Stress Response Depending on the Metabolic State of the Cell
Mick E, Titov DV, Skinner OS, Sharma R, Jourdain AA, Mootha VK.
Published in eLife on May 28, 2020

CRISPR EDITOR ENABLES EDITING OF ADENINE AND CYTOSINE
A Dual-Deaminase CRISPR Base Editor Enables Concurrent Adenine and Cytosine Editing
Gruenewald J, Zhou R, Lareau CA, Garcia SP, Iyer S [et al.], Joung JK.
Published in Nature Biotechnology on June 1, 2020

BLEEDING AND THROMBOSIS IN COVID-19
COVID and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection
Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JC, Fogerty AE [et al.], Rosovsky RP.
Published in Blood on June 3, 2020 | *Summary available

CIRCADIAN EFFECTS ON NEUROPROTECTIVE FAILURE
Potential Circadian Effects on Translational Failure for Neuroprotection
Esposito E, Li W, Mandeville ET, Park J, Sencan I [et al.], Lo EH.
Published in Nature on June 3, 2020

MRNA MODIFICATION TO PROMOTE HOMOLOGOUS DNA RECOMBINATION
M5 C Modification of mRNA Serves a DNA Damage Code to Promote Homologous Recombination
Chen H, Yang H, Zhu X, Yadav T, Ouyang J [et al.], Lan L.
Published in Nature Communications on June 3, 2020 | *Summary available

ELECTRONIC RECORDING OF PSYCHIATRIC ASSESSMENTS IN MA DURING COVID-19
Electronic Health Record Documentation of Psychiatric Assessments in Massachusetts Emergency Department and Outpatient Settings During the Coronavirus Disease 2019 (COVID-19) Pandemic
Castro VM, Perlis RH.
Published in JAMA Open Network on June 8, 2020

TRIAL OF HOSPICE EDUCATIONAL VIDEO FOR CANCER PATIENTS AND CAREGIVERS
Randomized Trial of a Hospice Video Educational Tool for Patients With Advanced Cancer and Their Caregivers
El-Jawahri A, Traeger L, Greer JA, Vanbenschoten O, Markovitz N [et al.], Temel JS.
Published in Cancer on June 8, 2020 | *Summary available

CONTEMPORARY GUIDELINES FOR HIGH-RISK CORONARY ARTERY PATIENTS
Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease
Aragam KG, Dobbyn A, Judy R, Chaffin M, Chaudhary K [et al.], Natarajan P.
Published in Journal of the American College of Cardiology on June 9, 2020 | Press Release

CANCER DRUG ATLAS REVEALS VULNERABILITIES
A Cancer Drug Atlas Enables Synergistic Targeting of Independent Drug Vulnerabilities
Narayan RS, Molenaar P, Teng J, Cornelissen FMG, Roelofs I [et al.], Westerman BA.
Published in Nature Communications on June 10, 2020 | *Summary available

XIST RNA ACCOUNTS FOR TWO PHASES OF X INACTIVATION
Xist Repeats A and B Account for Two Distinct Phases of X Inactivation Establishment
Colognori D, Sunwoo H, Wang D, Wang C, Lee JT.
Published in Developmental Cell on June 10, 2020 | Press Release

ISMA GENE AIDS IN CHOLESTEROL METABOLISM
Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level
Kenny DJ, Plichta DR, Shungin D, Koppel N, Hall AB [et al.] Xavier RJ.
Published in Cell Host Microbe on June 15, 2020 | *Summary available

TIMING AND DOSAGE OF CORTICOSTEROIDS ON CARDIAC OUTCOMES
Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis
Zhang L, Zlotoff DA, Awadalla M, Mahmood SS, Nohria A [et al.] Neilan TG.
Published in Circulation on June 16, 2020 | *Summary available

HEART TRANSPLANT SURVIVAL AFTER MECHANICAL CIRCULATORY SUPPORT
Survival After Heart Transplantation in Patients Bridged With Mechanical Circulatory Support
Moonsamy P, Axtell AL, Ibrahim NE, Funamoto M, Tolis G [et al.], Villavicencio-Theoduloz MA.
Published in Journal of the American College of Cardiology on June 16, 2020 | *Summary available

FAN1 MAY ALTER HUNTINGTON’S DISEASE ONSET
Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects
Kim K, Hong EP, Shin JW, Chao MJ, Loupe J [et al.], Lee J.
Published in American Journal of Human Genetics on June 16, 2020 | *Summary available

DISTAL NEPHRON GENES PROTECT AGAINST RENAL FIBROSIS
AP-2ß/KCTD1 Control Distal Nephron Differentiation and Protect Against Renal Fibrosis
Marneros AG.
Published in Developmental Cell on June 17, 2020 | *Summary available | Press Release

INSIGHTS INTO EARLY FORMS OF RNA-BASED LIFE
Template-directed Copying of RNA by Non-Enzymatic Ligation
Zhou L, O'Flaherty DK, Szostak JW.
Published in Angewandte Chemie on June 18, 2020

USING A MOBILE APPLICATION TO TRACK COVID SYMPTOMS
Rapid Implementation of Mobile Technology for Real-Time Epidemiology of COVID-19
Drew DA, Nguyen LH, Steves CJ, Menni C, Freydin M [et al.], Chan AT.
Published in Science on June 19, 2020

MULTIPLE MOLECULAR DRIVERS OF ALZHEIMER’S HIGHLIGHT NEED FOR PERSONALIZED THERAPIES
Tau Molecular Diversity Contributes to Clinical Heterogeneity in Alzheimer's Disease
Dujardin S, Commins C, Lathuiliere A, Peerepoot P, Fernandes AR [et al.], Hyman BT.
Published in Nature Medicine on June 22, 2020 | Press Release

EVALUATING SOMATICALLY ACQUIRED BRCA1/2 MUTATIONS
Identification of Somatically Acquired BRCA1/2 Mutations by cfDNA Analysis in Patients With Metastatic Breast Cancer
Vidula N, Dubash TD, Lawrence MS, Simoneau A, Niemierko A [et al.], Bardia A.
Published in Clinical Cancer Research on June 22, 2020 | *Summary available

INSIGHTS INTO GENES CRUCIAL TO DNA METHYLATION AND EPIGENETIC REGULATION
Identification of Distinct Loci for De Novo DNA Methylation by DNMT3A and DNMT3B During Mammalian Development
Yagi M, Kabata M, Tanaka A, Ukai T, Ohta S [et al.], Yamada Y.
Published in Nature Communications on June 24, 2020 | *Summary available

INHIBITION OF SCLEROSTIN MAY ELEVATE CARDIOVASCULAR RISK
Evaluating the Cardiovascular Safety of Sclerostin Inhibition Using Evidence From Meta-Analysis of Clinical Trials and Human Genetics
Bovijn J, Krebs K, Chen C, Boxall R, Censin JC [et al.], Holmes MV.
Published in Science Translational Medicine on June 24, 2020

USING AUTOPHAGY TO REDUCE TAU BURDEN IN HUMAN NEURONS
Prolonged Tau Clearance and Stress Vulnerability Rescue by Pharmacological Activation of Autophagy in Tauopathy Neurons
Silva MC, Nandi GA, Tentarelli S, Gurrell IK, Jamier T [et al.], Haggarty SJ.
Published in Nature Communications on June 26, 2020 | *Summary available

Summaries

Cancer drugs are designed to kill tumor cells but can elicit wound-healing responses as the body repairs dying tissue. We collaborated with MIT researchers to understand how this response promotes drug resistance often seen in patients. Tumor cells were discovered to adopt a program of wound healing related to the clearance of debris from dying cells and signaling co-amplified between tumor and immune cells to cause drug resistance. This discovery opens the door for new drug strategies, as the team showed by designing a nanotherapy that co-opted the wound healing response to overcome resistance.

(Summary submitted by Miles Miller, PhD, Center for Systems Biology and Department of Radiology)

In the most severe cases, COVID-19 can lead to respiratory failure that is refractory to maximal ventilator management. In these patients, veno-venous extracorporeal membrane oxygenation (VV-ECMO) can be utilized to provide oxygenation while the lungs recover. This therapy involves establishing a continuous circuit through which the patient’s blood is removed, oxygenated and then returned to the body. This study reports selection criteria and early experiences with VV-ECMO at Mass General during the COVID-19 pandemic. Data suggest that VV-ECMO can be successfully utilized in appropriately selected COVID-19 patients with advanced respiratory failure.

(Summary submitted by Asishana Osho, MD, MPH, Department of Surgery)

It is unknown whether lymph node and distant metastases are only distinguished by their different prognostic implications or whether the biology underlying their formation is also distinct. In this study, we show that lymph node metastases are a genetically highly diverse group. Their heterogeneity indicates that they can be seeded by many different primary tumor sub-lineages. In contrast, distant metastases are homogeneous. They typically resemble each other and have a recent common ancestor, suggesting that fewer primary tumor subclones possess the ability to form lesions in distant organs. Thus, the selective pressures shaping metastasis development in different anatomical sites differ substantially.

(Summary submitted by Kamila Naxerova, PhD, Center for Systems Biology)

Generating a robust T cell helper response is important for protective vaccine-induced immunity. We found that emulsifying an immunogen in oil improved its delivery to specific regions within lymph nodes, called interfollicular regions, that we had found specialize in generating protective immune responses. Activation of this region resulted in the production of the chemokine CXCL10 by inflammatory monocytes that recruited T cells into these areas, which promoted their differentiation into polyfunctional helper T cells and the generation of stronger protective immune responses. Formulations able to deliver immunogens to this specialized region of the lymph node and activate the immune system in a similar manner may improve vaccine efficacy.

(Summary submitted by Andrew Luster, MD, PhD, Department of Rheumatology, Allergy and Immunology, and Center for Immunology & Inflammatory Diseases)

Our work started with a genetic screening of stem cells in leukemia and in normal bone marrow. We studied key metabolic enzymes, the kind we all study in biochemistry pathways, and identified one called aldehyde dehydrogenase 3a2 (Aldh3a2), which when depleted, killed leukemia stem cells but spared normal ones; the exact properties you want in an effective therapy for leukemia. The leukemia cells lacking Adh3a2 seem to die through a novel mechanism called ferroptosis and triggering this mode of death can synergize with Aldh3a2 inhibition to increase the rate of cell death.

(Summary submitted by Rushdia Yusuf, MD, Mass General Cancer Center and Department of Medicine)

By using a new genetically encoded tool, we have been able to study for the first time how directly manipulating liver levels of NADH — sources of electrons for chemical reactions — impacts metabolic physiology. This led to the discovery that a common genetic variant in humans increases NADH levels in the liver. These elevated NADH levels, called "reductive stress," in turn influence multiple important metabolic traits, such as insulin resistance and risk factors for cardiovascular disease like triglyceride levels. This study identifies hepatic reductive stress as a common denominator for many metabolic traits, and shos that it is influenced by genetics and environment.

(Summary submitted by Russell Goodman, MD, Dphil, Division of Gastroenterology, Department of Medicine)

Structural variants (SVs) are large rearrangements of DNA involving more than 50 nucleotides, including deletions, duplications, inversions and other, more complex changes. We analyzed the genomes of nearly 15,000 individuals from populations around the world to identify more than 433,000 SVs, forming the largest-ever map of SVs. This unprecedented genetic map revealed new insights into an entire class of genetic variation, including that roughly one-quarter of all rare gene-inactivating events per genome are contributed by SVs, that nearly 4% of individuals in the general population carry a very large, rare rearrangement involving over one million nucleotides and that complex forms of SVs that involve intricate flips and swaps of DNA are abundant in all individuals and across populations. Our findings will have broad utility in population genetics, disease-association studies and diagnostic screening.

(Summary submitted by Ryan Collins and Michael Talkowski, PhD, Center for Genomic Medicine)

GENOME AGGREGATION DATABASE (gnomAD) CONSORTIUM RELEASES LARGEST CATALOG OF HUMAN GENETIC DATA VARIATION TO DATE

Characterising the Loss-Of-Function Impact of 5' Untranslated Region Variants in 15,708 Individuals
Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ [et al.], Ware JS.
Published in Nature Communications on May 27, 2020
Landscape of Multi-Nucleotide Variants in 125,748 Human Exomes and 15,708 Genomes
Wang Q, Pierce-Hoffman E, Cummings BB, Alfoldi J, Francioli LC, Gauthier LD [et al.], MacArthur DG.
Published in Nature Communications on May 27, 2020
The Effect of LRRK2 Loss-Of-Function Variants in Humans
Whiffin N, Aremean IM, Kleinman A, Marshall JL, Minikel EV [et al.], MacArthur DG.
Published in Nature Medicine on May 27, 2020
Transcript Expression-Aware Annotation Improves Rare Variant Interpretation
Cummings BB, Karczewski KJ, Kosmicki JA, Seaby EG, Watts NA [et al.], MacArthur DG.
Published in Nature on May 27, 2020
The Mutational Constraint Spectrum Quantified From Variation in 141,456 Humans
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J [et al.], MacArthur DG.
Published in Nature on May 27, 2020
Evaluating Drug Targets Through Human Loss-Of-Function Genetic Variation
Minikel EV, Karczewski KJ, Martin HC, Cummings BB, Whiffin N [et al.], MacArthur DG.
Published in Nature on May 27, 2020

An international consortium led by Mass General Research Institute and Broad Institute faculty and trainees recently published the largest catalog of human genetic data variation to date, known as the Genome Aggregation Database (gnomAD) consortium. This vast genetic atlas includes alterations to DNA sequences ranging from short single nucleotide variants to large structural variants in over 141,000 individuals across major global populations. In a series of seven papers, the gnomAD consortium identified genes that are intolerant to losing a functional copy, evaluated proposed drug targets, described rare and understudied forms of genetic variation and improved diagnostics for individuals with rare genetic diseases. The gnomAD dataset, which was released four years prior to publication, has already become one of the most widely accessed resources in biomedical research, with over 20 M page views from 184 countries worldwide, and the resource has been used in publications from basic, translational and clinical genomics research.

(Summary submitted by Ryan Collins and Michael Talkowski, PhD, Center for Genomic Medicine)

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 thrombotic 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, including the C reactive protein, erythrocyte sedimentation rate, procalcitonin and ferritin, providing evidence for the hypothesis that clotting complications may be related to inflammation in COVID-19.

(Summary submitted by Hanny Al-Samkari, MD, Mass General Cancer Center and Department of Medicine)

Oxidative DNA damage, which is frequently caused by exogenous exposures (radiation or chemicals) and endogenous oxygen radicals, is a key component of the pathogenesis of tumorigenesis. We found that oxidative DNA damage elicits the mRNA modification methl-5-cytosine (m5C) in a transcription-dependent manner. We uncovered the role of m5C in regulating transcription-dependent homologous recombination (HR) in the damage repair and cell survival. Loss of the m5C writer, TRDMT1, compromises HR and confers sensitivity to PARP inhibitor (PARPi) and ionizing radiation (IR) in cells and in cancer patients. These findings will significantly change the future studies on HR and its implications in cancer and cancer therapy.

(Summary submitted by Li Lan, MD, PhD, Mass General Cancer Center and Department of Radiation Oncology)

TRIAL OF A HOSPICE EDUCATIONAL VIDEO FOR CANCER PATIENTS AND CAREGIVERS
Randomized Trial of a Hospice Video Educational Tool for Patients With Advanced Cancer and Their Caregivers
El-Jawahri A, Traeger L, Greer JA, Vanbenschoten O, Markovitz N [et al.], Temel JS.
Published in Cancer on June 8, 2020

In a recent randomized clinical trial, we found that an educational video about hospice care can provide valuable information for patients with advanced cancer and their caregivers, improve their knowledge and perceptions about hospice, and can result in increase in hospice utilization. This work highlights the potential benefits of using video educational tools to better inform patients about their end of life care options and impact the care they receive at the end of life.

(Summary submitted by Areej El-Jawahri, MD, Mass General Cancer Center and Department of Medicine)

We present a new approach to identify effective drug combinations, called the Drug-atlas. The method is based on the Voronoi diagram, a mathematical application extensively used in science, technology and visual arts. Mapping the complementarity of the effects thousands of drugs over dozens tumor models resulted in this Drug-atlas. When a tumor model is particularly sensitive to two drugs that have combination effects, synergistic effects can be predicted. We have validated our results in tissue culture models as well as in mouse models where six out of eight models showed more than additive effects, indicating the clinical value of this atlas.

(Summary submitted by Jian Teng, MD, Department of Neurology, and Bart Westerman, PhD, Amsterdam Free University Medical Center)

High cholesterol levels constitute a risk factor for the country's number one cause of death: heart disease. We sequenced nearly six million microbial genes from the gut bacteria of 3,097 people, looking for genes present only in people who excrete a cholesterol breakdown product called coprostanol. We identified one such gene, Intestinal Sterol Metabolism A (ismA), and showed it encodes an enzyme that metabolizes cholesterol. People with the ismA gene in their microbiomes have lower blood cholesterol levels than those without any copies of ismA. This discovery could lead to new therapeutics that help people manage their blood cholesterol levels.

(Summary submitted by Isabel Latorre, PhD, Center for Computational and Integrative Biology)

Myocarditis is an uncommon toxicity associated with the use of immune checkpoint inhibitors (ICIs); however, the morbidity and mortality associated with ICI-associated myocarditis is very high. Corticosteroids are the first-line treatment for ICI myocarditis, but guidelines vary widely on the optimum dose. We found an inverse relationship between initial corticosteroids dose and timing, and the morbidity and mortality associated with ICI-myocarditis. High-dose corticosteroids was associated with 73% lower risk of major adverse cardiac events. In parallel, patients receiving corticosteroids early, within 24 hours, had a significantly lower rate of major adverse cardiac events compared with those treated between 24-72 hours and >72 hours. Therefore, we concluded that higher initial dose and earlier initiation of corticosteroids are associated with improved cardiovascular outcomes among patients with myocarditis related to an ICI.

(Summary submitted by Lili Zhang, MD, and Tomas G. Neilan, MD, MPH, Cardiovascular Imaging Research Center, Division of Cardiology and Department of Medicine)

We examined the trends in modes of temporary circulatory support used in adults in a nationwide database and compared post-transplant survival among patients bridged to transplant with TCS-VAD, ECMO and LVAD. Overall, survival in patients bridged to transplant with TCS-VAD appears to be superior to those bridged with ECMO and similar to those bridged with LVADs. Our study may help clinicians make more informed decisions about bridge to transplant strategies, especially in the context of the new 6-tier UNOS heart allocation system where ECMO and biventricular TCS-VAD are both prioritized as Status 1.

(Summary submitted by Philicia Moonsamy, MD, Department of Surgery)

Huntington's disease (HD) is a neurodegenerative disease involving neurological changes that typically appear in mid-life and progressively worsen, resulting in loss of independence and premature death. We found that age at clinical onset is determined by the size of the CAG trinucleotide repeat in the Huntingtin gene, not by polyglutamine, in a manner that appears to be modified by genes known to be involved in DNA handling. Now, we have delved into one of these genetic loci, FAN1, and have discovered that the HD modifier effects are due to changes that alter either the amount of the FAN1 protein or its DNA-binding function. This provides molecular insights to guide the development of interventions that may hasten or delay HD onset based on FAN1 and repeat instability in general, a mutational mechanism that underlies a host of other unstable repeat disorders.

(Summary submitted by Jong-Min Lee, PhD, Center for Genomic Medicine)

I show that the transcription factor AP-2ß induces differentiation of distal tubule precursors into early stage distal convoluted tubules (DCTs), whereas its downstream target KCTD1 is required for their terminal differentiation into mature DCTs. KCTD1 loss causes immature DCTs, leading to a salt-losing tubulopathy followed by renal fibrosis via ß-catenin hyperactivation.

(Summary submitted by Alexander Marneros, MD, PhD, Department of Dermatology and Cutaneous Biology Research Center)

We describe a cohort of patients with metastatic breast cancer, in whom BRCA1/2 mutations were identified using cell-free DNA (cfDNA) genotyping (liquid biopsy). In selected cases, functional assays in cultured circulating tumor cells (CTCs) were conducted. Up to 13.5% of patients with metastatic breast cancer harbor somatic BRCA1/2 mutations in cfDNA; 4% are known germline-pathogenic variants. In CTC-derived models, certain cell lines with somatic BRCA1/2 mutations demonstrate increased sensitivity to PARP inhibitors. This work suggests that some somatic BRCA1/2 mutations may respond to PARP inhibitors. A trial is ongoing at MGH (PI Dr. Vidula) to study a PARP inhibitor in patients with metastatic breast cancer who have somatic BRCA1/2 mutations.

(Summary submitted by Neelima Vidula, MD, Mass General Cancer Center and Department of Medicine)

DNA methylation plays critical roles during mammalian development and is accomplished by DNMT3A and DNMT3B. Here, we found that DNMT3A is exclusively required for the acquisition of DNA methylation at Polycomb group (PcG) target genes, while DNMT3B has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes was substantially reduced in DNMT3A knockout embryos. Finally, we found that human patients with DNMT3 mutations exhibit reduced DNA methylation at DNMT3 target regions. Our findings have important implications regarding the roles of DNA methyltransferases in epigenetic regulation of development and diseases.

(Summary submitted by Masaki Yagi, PhD, Department of Molecular Biology and Mass General Cancer Center)

Diseases such as Alzheimer’s disease and frontotemporal dementia are caused by accumulation of abnormal tau protein in the brain. We describe a drug screen in patient neurons that led to the identification of three molecules that promote degradation of tau by a mechanism known as autophagy. These three molecules target a master regulator of autophagy, mTOR, and reduce the levels of tau protein and associated toxicity, improving neuronal viability. These therapeutic candidates were more potent than other available FDA-approved drugs in the same class and had a prolonged effect on tau and neuronal health. Our results, together with evidence for brain penetration at tolerable doses, highlight the potential for these drugs and respective targets in the development of therapeutics.

(Summary submitted by Maria Catarina Silva, PhD, Department of Neurology)

Press Releases

Genetic Risk Scores May Improve Clinical Identification of Patients at Increased Heart Attack Risk
Featuring Krishna Aragam, MD, MS

Genetic variants have been linked with a higher risk of having a heart attack, permitting the calculation of polygenic risk scores that quantify patients’ inherited susceptibility based on the number of variants they have.

Model Projects Sharp Rise in Alcohol-Related Liver Disease
Featuring Jagpreet Chhatwal, PhD

A new analysis by researchers at Mass General, Harvard Medical School and Georgia Tech indicates that cases of alcohol-related liver disease will rise dramatically in the coming years without drastic steps to reduce high-risk drinking rates.

Mass General Researchers Identify a Promising Treatment for Deadly Cancer
Featuring Priscilla Brastianos, MD

Breast cancer is the most common malignancy to metastasize to the leptomeninges. “LMD is typically deadly and patients may live only a few weeks after a diagnosis of LMD,” says Priscilla Brastianos, MD, director of the Central Nervous Metastasis Center at Mass General.

Mass General Study Finds That Older Physicians and Those of Asian Ancestry Are at Highest Risk of Suicide
Featuring Yisi Daisy Ji, DMD

Health care professionals who die by suicide are more likely to be older and nearing the end of their careers, or be of Asian or Pacific Islander ancestry, or confronting physical, mental health or medical malpractice issues, according to a new study from Mass General.

Study Identifies Mechanism Affecting X Chromosome That Could Lead to Novel Therapies for Rare and Common Diseases
Featuring Jeannie T. Lee, MD, PhD

Researchers at Mass General have identified a key mechanism in X chromosome inactivation, a phenomenon that may hold clues that lead to treatments for certain rare congenital disorders.

Study Examines the Prevalence of COVID-19 Infections in Pregnant Women About to Give Birth
Featuring Ilona Goldfarb, MD, and Erica Shenoy, MD, PhD

Universal testing of pregnant women admitted to labor and delivery units is part of a multipronged approach to reducing transmission of the virus that causes COVID-19 in hospitals and clinics. A team led by investigators at Mass General has now provided a report on the prevalence of infections with the virus in women admitted to such units in several Boston hospitals.

Discovery of Key Steps in Kidney Development Offers New Clues About Improving Treatments for Chronic Kidney Disease
Featuring Alexander G. Marneros, MD, PhD

The discovery of how certain key structures in the kidneys are formed could have important implications for treating renal fibrosis (or scarring), a feature of chronic kidney disease, according to a new study.

Information Recorded Over Time in Medical Records Tells More About Diseases
Featuring Hossein Estiri, PhD

A new study describes an approach that uses machine learning, a type of artificial intelligence, to carefully track patients’ medical records over time in electronic health records to predict their likelihood of having or developing different diseases.

Different "Subtypes" of Alzheimer's May be Linked to Different Modifications of the Tau Protein, Mass General-led Team Finds
Featuring Bradley T. Hyman, MD, PhD

A new study reveals a possible biological reason that Alzheimer’s Disease progresses at different rates in different patients.

Simple Bed-side Test Detects Bleeding Risk in Patients After Surgery or Major Injury
Featuring Seemantini K. Nadkarni, PhD

A team of investigators has developed a novel, inexpensive and portable device that can quickly and accurately measure the ability of blood to properly clot.

Mass General Study Finds That Many Hospitalized Patients With a Presumed Penicillin Allergy Are Given Less Effective or More Harmful Antibiotics
Featuring Kimberly Blumenthal, MD, MSc, and Rochelle Walensky, MD, MPH

Hospitalized patients who report an allergy to penicillin are often prescribed alternative antibiotics for infection that can be harmful, even though diagnostic testing or evaluations would show that the vast majority of these reported allergies could be disproven, according to new research.

New Treatment Strategy May Benefit Patients With Brain Cancer
Featuring Daniel Cahill, MD, PhD, and Julie Miller, MD, PhD

A team of investigators has uncovered a potentially promising strategy to target and improve treatment for gliomas with mutations in isocitrate dehydrogenase (IDH) genes, the most common brain tumors diagnosed in younger adults ages 18 to 45 years.

Blog Posts

A Guide to Understanding Clinical Trials: Part 1 - What They Are and How They Work

When a new disease such as COVID-19 is discovered, it is up to doctors and scientists to investigate how the disease behaves so treatments can be developed and tested.

A Guide to Understanding Clinical Trials: Part 2 - Five Factors to Consider When Evaluating Results
Featuring Maurizio Fava, MD

Since the start of the SARS-CoV-2 (COVID-19) outbreak, scientists have repeatedly advocated for the use of well-structured clinical trials in testing new treatments for the disease. But what does a well-structured trial look like?

STEM in the Time of COVID: Science Experiments for Kids
Featuring Nitya Jain, PhD

Nitya Jain, PhD, shares several kid-friendly science experiments to promote STEM learning while abiding by stay-at-home orders during the COVID-19 pandemic.

Contact Tracing Relies on Individual Trust to Advance the Public Good
Featuring Louise Ivers, MD, MPH

Contact tracing is a strategy that seeks to break the chain of transmission of infectious diseases such as COVID-19 by rapidly identifying, notifying and isolating individuals who have recently been in contact with a newly diagnosed patient.

Lessons from the Backcountry in Finding a Potential COVID-19 Treatment
Featuring Brian Strickland, MD

Brian Strickland, MD, traveled to Nepal to conduct research on high altitude pulmonary edema, but was recalled to help treat patients with similar respiratory issues due to COVID-19.

Mass General Emergency Room Physician Details the Toll of Racial Disparities in COVID-19 Crisis
Featuring Alister F Martin, MD, MPP

For Mass General’s Alister Martin, MD, MPP, working as a Black emergency room doctor during the COVID-19 pandemic has felt like “walking on a tightrope during a hurricane.”

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Snapshot of Science for June 2020