Snapshot of Science for May 2021

Welcome to our Snapshot of Science for May 2021

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:

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

Publications

TAILORED PUBLIC HEALTH COVID-19 MESSAGING FOR BLACK AND LATINX COMMUNITIES
Comparison of Knowledge and Information-Seeking Behavior After General COVID-19 Public Health Messages and Messages Tailored for Black and Latinx Communities: A Randomized Controlled Trial
Alsan M, Stanford FC, Banerjee A, Breza E, Chandrasekhar AG [et al.], Duflo E
Published in Annals of Internal Medicine on April 17, 2021 | *Summary available

PE RNA-PROTEIN COMPLEXES INDUCE TARGETED ALTERATIONS IN HUMAN CELLS
CRISPR Prime Editing with Ribonucleoprotein Complexes in Zebrafish and Primary Human Cells
Petri K, Zhang W, Ma J, Schmidts A, Lee H [et al.], Yeh JJ
Published in Nature Biotechnology on April 21, 2021 | *Summary available

B CELL AND ANTIBODY BEHAVIOR IN SARS-COV-2
B Cell Genomics Behind Cross-Neutralization of SARS-CoV-2 Variants and SARS-CoV
Scheid JF, Barnes CO, Eraslan B, Hudak A, Keeffe JR [et al.], Xavier RJ
Published in Cell on April 23, 2021 | *Summary available

CHLORIDE MICRODOMAINS ARE NOT UNIFORM AT GABA SYNAPSES
Unique Actions of GABA Arising from Cytoplasmic Chloride Microdomains
Rahmati N, Normoyle KP, Glykys J, Dzhala VI, Lillis KP, Kahle KT, Raiyyani R, Jacob T, Staley KJ
Published in The Journal of Neuroscience on April 26, 2021 | *Summary available

CHARACTERIZING PROPOFOL-INDUCED UNCONSCIOUSNESS
Neural Effects of Propofol-induced Unconsciousness and Its Reversal Using Thalamic Stimulation
Bastos AM, Donoghue JA, Brincat SL, Mahnke M, Yanar J [et al.], Miller EK
Published in eLife on April 27, 2021

BLOOD-ONLY LIQUID BIOPSY FOR RESIDUAL DISEASE IN COLORECTAL CANCER
Minimal Residual Disease Detection Using a Plasma-Only Circulating Tumor DNA Assay in Colorectal Cancer Patients
Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A [et al.], Corcoran RB
Published in Clinical Cancer Research on April 29, 2021 | *Summary available

HOW SARS-COV-2 AFFECTS DIFFERENT CELL TYPES
COVID-19 Tissue Atlases Reveal SARS-CoV-2 Pathology and Cellular Targets
Delorey TM, Ziegler CGK, Heimberg G, Normand R, Yang Y [et al.], Regev A
Published in Nature on April 29, 2021 | *Summary available

FUNCTIONAL OUTCOMES AFTER POUCH SURGERY
Patients Undergoing Ileoanal Pouch Surgery Experience a Constellation of Symptoms and Consequences Representing a Unique Syndrome: A Report From the Patient Reported Outcomes After Pouch Surgery (PROPS) Delphi Consensus Study
Cavallaro P, Fearnhead N, Bissett I, Brar M, Cataldo T [et al.], Bordeianou L; PROPS Delphi Study Expert Panels
Published in Annals of Surgery on April 30, 2021 | *Summary available

RISKS AND BENEFITS OF WAITING FOR LUNG CANCER SURGERY
Estimating the Impact of Extended Delay to Surgery for Stage I Non-small-cell Lung Cancer on Survival
Mayne NR, Elser HC, Darling AJ, Raman V, Liou DZ [et al.], Yang CJ
Published in Annals of Surgery on May 01, 2021 | *Summary available

FIRST DEGREE RELATIVES OF PATIENTS WITH COLORECTAL POLYPS AT HIGH RISK FOR CANCER
Risk of Colorectal Cancer in First Degree Relatives of Patients with Colorectal Polyps: Nationwide Case-Control Study in Sweden
Song M, Emilsson L, Roelstraete B, Ludvigsson JF
Published in The BMJ on May 04, 2021

SETDB1 MAY BE A TARGET FOR IMMUNOTHERAPY
Epigenetic Silencing by SETDB1 Suppresses Tumour Intrinsic Immunogenicity
Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J [et al.], Bernstein BE
Published in Nature on May 05, 2021

SMOKING CESSATION INTERVENTION FOLLOWING HOSPITAL DISCHARGE
Sustained Care Smoking Cessation Intervention for Individuals Hospitalized for Psychiatric Disorders: The Helping HAND 3 Randomized Clinical Trial
Brown RA, Minami H, Hecht J, Kahler CW, Price LH [et al.], Rigotti NA
Published in JAMA Psychiatry on May 05, 2021 | *Summary available

MANIPULATING NUTRIENT SIGNALING TO IMPROVE DELIVERY OF ALBUMIN-BINDING DRUGS
Therapeutically Reprogrammed Nutrient Signalling Enhances Nanoparticulate Albumin Bound Drug Uptake and Efficacy in KRAS-Mutant Cancer
Li R, Ng TSC, Wang SJ, Prytyskach M, Rodell CB [et al.], Miller MA
Published in Nature Nanotechnology on May 06, 2021 | *Summary available

BISULFITE SEQUENCING FOR TARGETED PROFILING OF DNA METHYLATION
Extended-representation Bisulfite Sequencing of Gene Regulatory Elements in Multiplexed Samples and Single Cells
Shareef SJ, Bevill SM, Raman AT, Aryee MJ, van Galen P [et al.], Bernstein BE
Published in Nature Biotechnology on May 06, 2021

NEW SOFTWARE FOR ANALYZING PROTEIN INTERACTIONS
Genoppi Is an Open-Source Software for Robust and Standardized Integration of Proteomic and Genetic Data
Pintacuda G, Lassen FH, Hsu YH, Kim A, Martín JM [et al.], Lage K
Published in Nature Communications on May 10, 2021 | *Summary available

MECHANISTIC MANIPULATION OF PLACEBO AND NOCEBO EFFECTS
Manipulating Placebo Analgesia and Nocebo Hyperalgesia by Changing Brain Excitability
Tu Y, Wilson G, Camprodon J, Dougherty DD, Vangel M [et al.], Kong J
Published in PNAS on May 11, 2021

NEW FORM OF TREATMENT FOR GLIOBLASTOMA
Targeting Treg Cells with GITR Activation Alleviates Resistance to Immunotherapy in Murine Glioblastomas
Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW [et al.], Jain RK
Published in Nature Communications on May 11, 2021 | *Summary available | Press Release

EFFECT OF LOCAL TRANSCRIPTION ON HOMOLOGOUS RECOMBINATION
RNA Transcripts Stimulate Homologous Recombination by Forming DR-loops
Ouyang J, Yadav T, Zhang JM, Yang H, Rheinbay E [et al.], Zou L
Published in Nature on May 12, 2021 | *Summary available

CONNECTION BETWEEN ADVERSE CHILDHOOD EXPERIENCES AND ADULT MENTAL HEALTH
Adverse Childhood Experiences, Adult Depression and Suicidal Ideation in Rural Uganda: A Cross-sectional, Population-based Study
Satinsky EN, Kakuhikire B, Baguma C, Rasmussen JD, Ashaba S [et al.], Tsai AC
Published in PLoS Medicine on May 12, 2021 | *Summary available

UNDERPINNINGS OF PTC INCIDENCE IN AREAS SURROUNDING CHERNOBYL
Radiation-related Genomic Profile of Papillary Thyroid Carcinoma after the Chernobyl Accident
Morton LM, Karyadi DM, Stewart C, Bogdanova TI, Dawson ET [et al.], Chanock SJ
Published in Science on May 14, 2021 | *Summary available

CARDIOVASCULAR AND KIDNEY OUTCOMES ACROSS THE GLYCEMIC SPECTRUM
Cardiovascular and Kidney Outcomes across the Glycemic Spectrum: Insights from the UK Biobank
Honigberg MC, Zekavat SM, Pirruccello JP, Natarajan P, Vaduganathan M
Published in Journal of the American College of Cardiology on May 17, 2021 | *Summary available

NEW RECOMMENDATIONS FOR COLORECTAL CANCER SCREENING
Colorectal Cancer Screening: An Updated Modeling Study for the US Preventive Services Task Force
Knudsen AB, Rutter CM, Peterse EFP, Lietz AP, Seguin CL [et al.], Lansdorp-Vogelaar I
Published in JAMA on May 18, 2021 | *Summary available

PATHWAYS MODULATED BY MULLERIAN INHIBITING SUBSTANCE
Single-Cell Sequencing Reveals Suppressive Transcriptional Programs Regulated by MIS/AMH in Neonatal Ovaries
Meinsohn MC, Saatcioglu HD, Wei L, Li Y, Horn H [et al.], Pépin D
Published in PNAS on May 18, 2021 | *Summary available | Press Release

PHYSICIAN MENTAL HEALTH AND MEDICAL LICENSES
Consistency Between State Medical License Applications and Recommendations Regarding Physician Mental Health
Saddawi-Konefka D, Brown A, Eisenhart I, Hicks K, Barrett E, Gold JA
Published in JAMA on May 18, 2021 | *Summary available

NEW INSIGHT INTO DEVELOPMENT OF ALZHEIMER'S DISEASE
Axonal Generation of Amyloid-β From Palmitoylated App in Mitochondria-associated Endoplasmic Reticulum Membranes
Bhattacharyya R, Black SE, Lotlikar MS, Fenn RH, Jorfi M [et al.], Tanzi RE
Published in Cell Reports on May 18, 2021 | *Summary available | Press Release

NOT ENOUGH PEDIATRIC EMERGENCY PHYSICIANS TO TREAT CHILDREN VISITING ER
Evaluation of the 2020 Pediatric Emergency Physician Workforce in the US
Bennett CL, Espinola JA, Sullivan AF, Boggs KM, Clay CE [et al.], Camargo CA Jr
Published in JAMA Network Open on May 18, 2021 | *Summary available

AI PREDICTS CARDIOVASCULAR DISEASE
Deep Learning Predicts Cardiovascular Disease Risks From Lung Cancer Screening Low Dose Computed Tomography
Chao H, Shan H, Homayounieh F, Singh R, Khera RD [et al.], Yan P
Published in Nature Communications on May 20, 2021 | *Summary available

COMMUNITY HEALTH WORKER INTERVENTIONS REDUCE HOSPITAL READMISSIONS
Effect of Community Health Workers on 30-Day Hospital Readmissions in an Accountable Care Organization Population
Carter J, Hassan S, Walton A, Yu L, Donelan K, Thorndike AN
Published in JAMA Network Open on May 20, 2021 | *Summary available | Press Release

GLUTEN AND COGNITIVE FUNCTION
Long-term Intake of Gluten and Cognitive Function Among US Women
Wang Y, Lebwohl B, Mehta R, Cao Y, Green PHR [et al.], Chan AT
Published in JAMA Network Open on May 21, 2021 | *Summary available

IDENTIFYING ANTIBODIES AS POTENTIAL THERAPEUTIC TARGETS FOR HIV
Mining HIV Controllers for Broad and Functional Antibodies to Recognize and Eliminate HIV-infected Cells
Rossignol ED, Dugast AS, Compere H, Cottrell CA, Copps J [et al.], Julg B
Published in Cell Reports on May 25, 2021 | *Summary available

INSIGHTS INTO HYPOXIC BRAIN INJURY
Sulfide Catabolism Ameliorates Hypoxic Brain Injury
Marutani E, Morita M, Hirai S, Kai S, Grange RMH [et al.], Ichinose F
Published in Nature Communications on May 25, 2021 | *Summary available

TARGETS FOR TREATING AND PREVENTING MIS-C IN CHILDREN
Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-dependent Loss of Gut Mucosal Barrier
Yonker LM, Gilboa T, Ogata AF, Senussi Y, Lazarovits R [et al.], Fasano A
Published in Journal of Clinical Investigation on May 25, 2021 | *Summary available

PROTECTIVE ASSOCIATION WITH MORNING PREFERENCE AND MAJOR DEPRESSIVE DISORDER
Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder
Daghlas I, Lane JM, Saxena R, Vetter C
Published in JAMA Psychiatry on May 26, 2021 | *Summary available

UTILIZING CELL FREE DNA IN METASTATIC CANCER
Cell-free DNA Captures Tumor Heterogeneity and Driver Alterations in Rapid Autopsies with Pre-Treated Metastatic Cancer
Pereira B, Chen CT, Goyal L, Walmsley C, Pinto CJ [et al.], Juric D
Published in Nature Communications on May 27, 2021

Publication Summaries

TAILORED PUBLIC HEALTH COVID-19 MESSAGING FOR BLACK AND LATINX COMMUNITIES
Comparison of Knowledge and Information-Seeking Behavior After General COVID-19 Public Health Messages and Messages Tailored for Black and Latinx Communities : A Randomized Controlled Trial
Alsan M, Stanford FC, Banerjee A, Breza E, Chandrasekhar AG [et al.], Duflo E
Published in Annals of Internal Medicine on April 17, 2021

Black and Latinx communities have been disproportionately affected by COVID-19. The disparities in prevalence and health outcomes reflect a complex set of factors (i.e., systemic racism, access to health services, discrepancies in educational opportunities and occupational differences) as well as knowledge gaps—perhaps reflecting the lack of effort to design COVID-19 public health messaging with minority communities in mind. We formed a "COVID-19 Messaging Working Group" and developed COVID-19 video health messages to address the specific concerns of these communities. Regardless of physician race, public health messages directly improved knowledge of symptoms, asymptomatic transmission and preventative practices for both Black and Latinx respondents. For Black respondents, video messages delivered by Black physicians spurred an increased interest in health information-seeking, suggesting the importance of race concordance in spurring these behaviors.

(Summary submitted by Fatima Cody Stanford, MD, MPH, MPA, MBA, Department of Medicine, Mass General Weight Center)

PE RNA-PROTEIN COMPLEXES CAN INDUCE TARGETED ALTERATIONS IN HUMAN CELLS
CRISPR Prime Editing with Ribonucleoprotein Complexes in Zebrafish and Primary Human Cells
Petri K, Zhang W, Ma J, Schmidts A, Lee H [et al.], Yeh JJ
Published in Nature Biotechnology on April 21, 2021

CRISPR prime editing (PE) is a recently described gene editing platform that can flexibly create a wide range of targeted alterations. We show that purified RNA-protein complexes of PE components can induce targeted edits in the model organism zebrafish, generating useful models of human disease. We also show that PE RNA-protein complexes can induce targeted alterations in human cells, including therapeutically relevant primary T cells. These findings extend PE applications to an important model organism and demonstrate the feasibility of delivering PE complexes for potential therapeutic use.

(Summary submitted by Jing-Ruey Joanna Yeh, PhD, Department of Medicine, Cardiovascular Research Center)

Inside the body of a person with COVID-19, the immune system's B cells are engaged in a full-scale battle with the SARS-CoV-2 virus. We studied blood samples from 14 people who recovered from COVID-19 and revealed distinct patterns of gene expression in B cells that produce antibodies that bind tightly to and neutralize SARS-CoV-2. We also discovered a new antibody, BG10-19, which neutralizes the virus, variants of concern such as ones first identified in the U.K. and South Africa, and the coronavirus that caused the 2003 SARS outbreak. These findings could help scientists better understand why some people don't respond as well to existing COVID-19 vaccines or therapies, a first step toward improving vaccines and treatments.

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

Variations in the concentration of chloride in the cytoplasm of neurons is a predictable consequence of the uneven distribution of large, charged molecules such as actin, tubulin and nucleic acid polymers. Here, we demonstrate the existence and stability of these variations in chloride concentrations, which we termed "chloride microdomains." We found that chloride microdomains are not uniform at GABA synapses. This enabled each interneuron to impart a unique degree of charge accumulation and consequent inhibition of neural activity. Our findings open a new dimension of complexity for inhibitory GABA signaling, demonstrating new ways that the brain can store and process information. The findings also introduce novel targets for treatment of pathological states, such as intractable epilepsy.

(Summary submitted by Negah Rahmati Andami, PhD, Department of Neurology)

BLOOD-ONLY LIQUID BIOPSY FOR RESIDUAL DISEASE IN COLORECTAL CANCER
Minimal Residual Disease Detection using a Plasma-Only Circulating Tumor DNA Assay in Colorectal Cancer Patients
Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A [et al.], Corcoran RB
Published in Clinincal Cancer Research on April 29, 2021

For early-stage colorectal cancer, surgery is the mainstay of curative treatment though some patients may require additional treatment. However, despite surgery and additional treatment, many cases will ultimately recur. Liquid biopsies are a tool to identify patients with residual disease who are at highest risk for recurrence and may benefit most from additional treatment by detecting recurrence before standard-of-care imaging. Our study evaluated and reported data from the first blood-only liquid biopsy test for the detection of residual disease in colorectal cancer. This contrasts with other tests available currently, which require sequencing of the patient's tumor in order to design a personalized liquid biopsy test.

(Summary submitted by Aparna Parikh, MD, MS, Division of Hematology/Oncology, Department of Medicine, Mass General Cancer Center)

We studied tissue samples of 17 individuals who succumbed to COVID-19 and investigated how the SARS-CoV-2 virus interferes with the function of cells and their genetic programs. Using single-cell RNA sequencing data from tissue samples taken from 11 organ systems, we built a comprehensive "cell atlas" showing how COVID-19 can lead to organ failure and death, and how infected cells exhibited a range of molecular and genomic changes. We also saw signs of multiple, unsuccessful attempts by the lungs to repair themselves in response to respiratory failure. Our cell atlas is freely and openly available, providing a resource for other scientists to explore and use in future studies to ask specific questions.

(Summary submitted by Alexandra-Chloé Villani, PhD, Department of Medicine, Center for Immunology and Inflammatory Diseases)

Previous studies of ulcerative colitis patients with J pouches have focused on symptoms that surgeons find important, with little input from patients. We engaged in virtual meetings with hundreds of patients and clinicians in what is called a “Delphi consensus process.” At the end of the study, the group developed a patient-centered definition of “Ileoanal Pouch Syndrome” - the collection of symptoms that describe the full range of expected function after creation of an ileoanal pouch, while highlighting those symptoms that may have an impact on the quality of life of pouch patients and thus need recognition, education, and treatment.

(Summary submitted by Paul Cavallaro, MD, Department of Surgery)

This study evaluated the outcomes of patients with two types of stage I lung cancer (adenocarcinoma and squamous cell carcinoma) who underwent surgery quickly after diagnosis (within 30 days of diagnosis) or delayed surgery (90-120 days after diagnosis). For small stage I tumors, delayed surgery had similar outcomes to early surgery. However, for larger stage I tumors, delayed surgery was associated with worse outcomes. The findings can be used to help patients and doctors figure out the risks and benefits of waiting for surgery for lung cancer.

(Summary submitted by Chi-Fu Jeffrey Yang, MD, Division of Thoracic Surgery, Department of Surgery, Mass General Cancer Center)

People with serious mental illnesses have lifespans 25 years shorter than the general U.S. population, partly because they have high rates of smoking and low rates of success when trying to quit. This randomized clinical trial tested a sustained care intervention designed to help smokers admitted to an inpatient psychiatric hospital stop smoking. The 353 smokers in the trial received nicotine patches and stop-smoking counseling in the hospital that continued after discharge. Six months after discharge, the program nearly doubled the participants' quit rate compared to usual care. The program demonstrated that its effectiveness extends to people hospitalized for psychiatric disorders, a particularly vulnerable population.

(Summary submitted by Nancy Rigotti, MD, Department of Medicine, Tobacco Research and Treatment Center)

MANIPULATING NUTRIENT SIGNALING TO IMPROVE DELIVERY OF ALBUMIN-BINDING DRUGS
Therapeutically Reprogrammed Nutrient Signalling Enhances Nanoparticulate Albumin Bound Drug Uptake and Efficacy in KRAS-mutant Cancer
Li R, Ng TSC, Wang SJ, Prytyskach M, Rodell CB [et al.], Miller MA
Published in Nature Nanotechnology on May 06, 2021

Albumin has long been used to improve drug circulation and targeting in the body. In principle, this concept has been attractive for treating tumors with appetites for protein nutrients that fuel malignant growth. Nonetheless, albumin-based delivery mechanisms in cancer remain difficult to understand. We demonstrated how oncogenic KRAS signaling controls albumin-drug uptake in mouse tumor models and discovered that therapeutically manipulating nutrient signaling could enhance efficacy of the albumin-formulated chemotherapeutic, nab-paclitaxel. These results offer new possibilities to improve delivery of albumin-binding drugs in patients.

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

NEW SOFTWARE FOR ANALYZING PROTEIN INTERACTIONS
Genoppi Is an Open-source Software for Robust and Standardized Integration of Proteomic and Genetic Data
Pintacuda G, Lassen FH, Hsu YH, Kim A, Martín JM [et al.], Lage K
Published in Nature Communications on May 10, 2021

Genetic variation can impact protein complexes and interaction networks, but reconciling genetic and proteomic information remains challenging. To address this challenge, the Lage group developed Genoppi (https://www.lagelab.org/genoppi/), an open-source tool for integrating cell-type-specific proteomic data with genetics. By applying Genoppi to protein interaction data of four proteins in human neurons and three cancer cell lines, they observed a general pattern of both cell-type-independent and cell-type-specific interactions for these proteins. In particular, their results suggest that the neuron-specific interactions of BCL2 and TDP-43 are mediating their genetic involvement in amyotrophic lateral sclerosis.

(Summary submitted by Nadine Fornelos Martins, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

Glioblastoma (GBM) shows high level of resistance to currently available treatments including the standard of care and immunotherapy, representing the most fatal cancer type. Our study revealed that immune suppression by regulatory T cells (Treg) secondary to therapy with immune checkpoint blocker (anti-PD1) confers this resistance. By selectively targeting Treg using antibodies specific for a molecule on GBM Treg, the function of these cells could be converted from immune suppressors to tumor killers without adverse events. This Treg reprogramming strategy synergized with conventional immunotherapy and the standard of care. This finding highlights Tregs as an untapped resource for GBM therapy.

(Summary submitted by Rakesh Jain, PhD, Department of Radiation Oncology, Mass General Cancer Center)

Homologous recombination (HR) is a DNA repair pathway essential for repairing DNA breaks. Recent studies suggested that HR is stimulated by transcription, but the underlying mechanism remains unknown. Our study reveals that the local RNA transcripts at DNA breaks directly hybridize with homologous DNA, forming a novel intermediate called DR-loop to stimulate HR. This finding provides a mechanistic explanation for the stimulatory effect of transcription on HR, offering new opportunities to identify repair defects and therapeutic targets in cancer cells.

(Summary submitted by Jian Ouyang, PhD, Department of Medicine, Mass General Cancer Center)

CONNECTION BETWEEN ADVERSE CHILDHOOD EXPERIENCES AND ADULT MENTAL HEALTH
Adverse Childhood Experiences, Adult Depression, and Suicidal Ideation in Rural Uganda: A Cross-sectional, Population-based Study
Satinsky EN, Kakuhikire B, Baguma C, Rasmussen JD, Ashaba S [et al.], Tsai AC
Published in PLoS Medicine on May 12, 2021

Studies from sub-Saharan Africa have shown that depression is common among adolescents and young adults with adverse childhood experiences (ACEs). To address the research gap on ACEs and adult mental health, we estimated the associations between ACEs, depression and suicidal ideation in a population-based sample of adults in rural Uganda. The cumulative number of ACEs had statistically significant associations with all outcome measures. Additionally, depression symptom severity and major depressive disorder had statistically significant associations with all nine types of ACEs. These findings raise implications for the development of policies and programs that promote mental health.

(Summary submitted by Emily Satinsky, MSc, Mass General Global Health)

The 1986 Chernobyl nuclear accident released massive amounts of radiation, with a significant rise in the number of children from the region who developed papillary thyroid cancers (PTCs) over the ensuing years. In collaboration with Dr. Stephen Chanock’s team at NCI, we created a comprehensive genomic landscape of these PTCs and found radiation dose–dependent enrichment of gene-fusion drivers and structural alterations in the DNA that bore hallmarks of repair pathways. Overall, the data suggest that exposure-related double-stranded breaks in the DNA were an early carcinogenic event, enabling PTC growth later in life.

(Summary submitted by Mendy Miller, PhD, Broad Institute of MIT and Harvard)

Treatment guidelines for pre-diabetes focus on blood sugar control and lifestyle management, but few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population. This study evaluated cardiovascular and kidney disease risk across spectrum of blood sugar levels with a focus on the range below type 2 diabetes. Pre-diabetes and type 2 diabetes were each independently associated with atherosclerotic cardiovascular disease, chronic kidney disease, and heart failure. However, a substantial gradient of risk was evident across blood sugar levels in the pre-diabetic range and below. These findings highlight the need for specific risk-reduction strategies across the glycemic spectrum, including below thresholds for diabetes.

(Summary submitted by Michael Honigberg, MD, MPP, Division of Cardiology, Department of Medicine, Cardiovascular Disease Prevention Center)

NEW RECOMMENDATIONS FOR COLORECTAL CANCER SCREENING
Colorectal Cancer Screening An Updated Modeling Study for the US Preventive Services Task Force
Knudsen AB, Rutter CM, Peterse EFP, Lietz AP, Seguin CL [et al.], Lansdorp-Vogelaar I
Published in JAMA on May 18, 2021

The U.S. Preventive Services Task Force commissioned a modeling study to help inform its 2021 colorectal cancer screening recommendation. The modelers provided estimates of how the benefits, burden and harms of different screening tests vary by the ages to begin and end screening. We estimated that lowering the age to begin screening from 50 to 45 would lead to better health outcomes with only a small increase in the burden and harms of screening. Our findings, together with new data showing increasing rates of colorectal cancer in people younger than 50, informed the Task Force's recommendation to start colorectal cancer screening at age 45.

(Summary submitted by Amy Knudsen, PhD, Institute for Technology Assessment, Department of Radiology)

PATHWAYS MODULATED BY MULLERIAN INHIBITING SUBSTANCE
Single-cell Sequencing Reveals Suppressive Transcriptional Programs Regulated by MIS/AMH in Neonatal Ovaries
Meinsohn MC, Saatcioglu HD, Wei L, Li Y, Horn H [et al.], Pépin D
Published in PNAS on May 18, 2021 | Press Release

Mullerian inhibiting substance (MIS) is a hormone produced by the ovary which keeps eggs dormant; however, its mechanism of action was unknown. Our study used single cell RNA-sequencing to elucidate the pathways modulated by MIS in neonatal rodent ovaries. MIS was found to suppress proliferation in granulosa cells, surface epithelial cells and stromal cells, and repress pathways associated with differentiation of these cell types. Interestingly, MIS further enhanced a transcriptional signature found to be associated with primordial follicle quiescence. This study may have multiple clinical applications in contraception and the treatment of infertility.

(Summary submitted by David Pépin, PhD, Department of Surgery)

Despite higher rates of burnout, depression and other mental health conditions, physicians infrequently seek mental health care, often fearing that it will result in loss of their medical license. In 2018, the Federation of State Medical Boards (FSMB) published recommendations to limit medical license application questions regarding mental health to only what is necessary and relevant, and to provide supportive language. Only 1 of 54 U.S. state and territory medical licensing applications evaluated in the study fully adopted the FSMB recommendations (North Carolina), and five states were not consistent with any of the recommendations

(Summary submitted by Daniel Saddawi-Konefka, MD, MBA, Department of Anesthesia, Critical Care and Pain Medicine)

NEW INSIGHT INTO DEVELOPMENT OF ALZHEIMER'S DISEASE
Axonal Generation of Amyloid-β From Palmitoylated App in Mitochondria-Associated Endoplasmic Reticulum Membranes
Bhattacharyya R, Black SE, Lotlikar MS, Fenn RH, Jorfi M [et al.], Tanzi RE
Published in Cell Reports on May 18, 2021 | Press Release

A key feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain decades before symptoms of dementia occur. It has been known for over three decades that the key component of the plaques, a protein cell called amyloid-beta, is derived from a larger protein known as APP. A key question has been how amyloid-beta is generated in neuronal processes leading to synaptic damage. We found a chemically modified form of APP in specific cholesterol-rich "rafts", known as "MAM's", which we showed to be the source of amyloid-beta within neuronal axons. Next steps will include devising ways to safely reduce this most dangerous pool of amyloid beta around neuronal axons so as to prevent the loss of synapses leading to dementia.

(Summary submitted by Rudolph E. Tanzi, PhD, Genetics and Aging Research Unit, Department of Neurology)

NOT ENOUGH PEDIATRIC EMERGENCY PHYSICIANS TO TREAT ALL CHILDREN WHO COME TO ER
Evaluation of the 2020 Pediatric Emergency Physician Workforce in the US
Bennett CL, Espinola JA, Sullivan AF, Boggs KM, Clay CE [et al.], Camargo CA Jr
Published in JAMA Network Open on May 18, 2021

Given that nearly 30 million emergency department visits are made by children annually, access to pediatric emergency physicians (EP) is likely important. In 2020, there were only 2,403 pediatric EPs, who compromised only 4.9% of all clinically active emergency physicians. Nearly all pediatric EPs (99%) were in urban areas, and pediatric EPs in urban areas were younger than those in rural areas. Three states (Montana, South Dakota and Wyoming) and 87% of U.S. counties had no pediatric EPs. At their current numbers, pediatric EPs cannot be expected to provide most pediatric emergency care.

(Summary submitted by Krislyn Boggs, MPH, Department of Emergency Medicine)

Coronary artery disease and lung cancer are among the leading cause of morbidity and mortality in the United States, and they share important risk factors such as smoking. Low-dose CT (LDCT) is used for screening patients at risk of developing lung cancer. We developed a tool that can help screen patients for cardiovascular disease while a patient is already being screened for lung cancer with LDCT. This tool can help with diagnosis, initiate treatment and improve outcomes in some patients with coronary artery disease. In collaboration with engineers from Rensselaer Polytechnic Institute (RPI), we developed an artificial intelligence-based tool to assess patient's risk of cardiovascular disease from LDCT scan used to screen for lung cancer.

(Summary submitted by Mannudeep Kalra, MD, Department of Radiology)

The Community CAre Transitions (C-CAT) clinical trial, pairing community health workers (CHWs) with patients admitted to Massachusetts General Hospital, found that fewer intervention group participants (12.6) were readmitted within 30 days than control group participants (24.5%). This effect was seen in intervention vs. control participants discharged to rehabilitation (5.0% vs 37.3%) but not in those discharged home (14.7% vs 20.4%). In addition, fewer intervention than control participants had missed appointments (22.0% vs. 33.7%). These results indicate that CHW interventions may help reduce hospital readmissions and improve preventive care among clinically complex patients within an accountable care organization.

(Summary submitted by Jocelyn Carter, MD, MPH, Department of Medicine)

Gluten, a protein present in certain grains like wheat and barley, has been linked to cognitive symptoms among patients with celiac disease. However, despite the lack of data on individuals without celiac disease, gluten-free products have become increasingly popular over the past decades. In this study, we leveraged longitudinal dietary data from 13,494 Nurses’ Health Study II participants, who were free of celiac disease and had completed a computerized cognitive assessment. We found that long-term gluten intake was not associated with cognitive function. Our findings suggest that restricting dietary gluten to maintain or improve cognition is not warranted in the absence of celiac disease or established gluten sensitivity.

(Summary submitted by Yiqing Wang, PhD, Clinical and Translational Epidemiology Unit, Department of Medicine)

IDENTIFYING ANTIBODIES AS POTENTIAL THERAPEUTIC TARGETS FOR HIV
Mining HIV Controllers for Broad and Functional Antibodies to Recognize and Eliminate Hiv-infected Cells
Rossignol ED, Dugast AS, Compere H, Cottrell CA, Copps J [et al.], Julg B
Published in Cell Reports on May 25, 2021

A small number of people living with HIV, called "HIV controllers," are able to naturally suppress the virus in their bodies. Interestingly, highly functional anti-HIV antibodies are enriched in these individuals and such antibodies might be useful for treatment strategies. In this study, we isolated 185 HIV envelope-specific monoclonal antibodies from HIV controllers and down-selected antibodies based on their ability to broadly recognize HIV-infected cells and potently drive killing of these cells by the immune system. Using this approach, we identified several promising antibodies that are now being further evaluated as potential novel therapeutics against HIV-1.

(Summary submitted by Boris Juelg, MD, PhD, Division of Infectious Diseases, Department of Medicine)

The mammalian brain is exquisitely vulnerable to lack of oxygen. When oxygen levels become low, hydrogen sulfide, also known as "sewer gas," accumulates in brain cells and impairs their ability to use the remaining, available oxygen to produce energy. We found that hibernating ground squirrels, which can withstand very low levels of oxygen, have high levels of an enzyme that catabolizes hydrogen sulfide in the brain. Upregulating this enzyme, or administrating drugs that scavenge hydrogen sulfide, makes the brains of mice resistant to the adverse effects of decreased oxygen. Drugs that scavenge hydrogen sulfide may prove to be an effective approach to the treatment of patients experiencing brain injury caused by stroke or cardiac arrest.

(Summary submitted by Fumito Ichinose, MD, PhD, Department of Anesthesia, Critical Care and Pain Medicine, Corrigan Minehan Heart Center)

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but acute response that occurs weeks after a COVID-19 infection. MGfC researchers and collaborators have identified the mechanism of how it develops and effectively tested a proof-of-concept oral treatment in an infant. Research published in the Journal of Clinical Investigation shows that viral particles can remain in the gut long after initial infection and travel into the bloodstream, triggering a hyperinflammatory response and the “cytokine storm” typical of acute COVID-19 infections. The group successfully treated a 17-month-old infant with larazotide acetate, which is in Phase II clinical trials for celiac disease.

(Summary submitted by Susie Flaherty, MA, Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Mass General for Children)

Using data from over 840,000 individuals of European ancestry, we found that a lifelong genetic predisposition to being an early riser was associated with a reduced risk of depression. This suggests that sleep timing has a cause-and-effect relationship with depression, however clinical trials are needed to determine whether sleep timing interventions may have a role in preventing or treating depression.

(Summary submitted by Iyas Daghlas, MD, Department of Neurology, Center for Genomic Medicine)

Press Releases

Researchers Identify Protein Signature of Severe COVID-19
Featuring Michael Filbin, MD, MS, and Marcia Goldberg, MD

Researchers at Mass General have identified the protein signature of severe COVID-19.

Team Cracks Century-old Mystery over the Health Struggles of Explorer Ernest Shackleton
Featuring Oscar Benavidez, MD, Lauren Fiechtner, MD, and Paul Firth, MBChB

Researchers from Mass General appear to have solved the 120-year-old mystery surrounding the failing health of famed Antarctic explorer Sir Ernest Shackleton over the course of his daring expeditions to Antarctica in the early part of the twentieth century.

A Trait of the Rare Few Whose Bodies Naturally Control HIV: "Trained" Immune Cells
Featuring Xu Yu, MD

Elite controllers, a rare subset of people whose immune system can control HIV without the use of drugs, have myeloid dendritic cells that display traits of a trained innate immune cell.

New Understanding of Ovarian Follicle Development May Lead to Novel Reproductive Therapies
Featuring David Pépin, PhD

Mullerian inhibiting substance keeps follicles dormant until they are ready to release eggs during ovulation. Targeting this hormone could preserve follicles and eggs lost to aging or chemotherapy, improve the harvesting of eggs during IVF, or create a new contraceptive.

New Test Detects Residual Cancer DNA in the Blood Without Relying on Tumor Data
Featuring Aparna R. Parikh, MD

A team led by investigators at Mass General has evaluated the first "tumor-uninformed" test that detects cancer DNA circulating in the blood of patients following treatment.

Scientists Discover How to Trick Cancer Cells to Consume Toxic Drugs
Featuring Sareh Parangi, MD, and Ralph Weissleder, MD, PhD

New research led by a team at Mass General points to a promising strategy to boost tumors' intake of cancer drugs, thereby increasing the effectiveness of chemotherapy treatments.

Tumor-promoting Immune Cells Retrained to Fight Most Aggressive Type of Brain Cancer
Featuring Rakesh K. Jain, PhD

New research shows regulatory T cells in the brain can be reprogrammed from guarding glioblastoma tumors to attacking them from within.

Anesthetic May Affect Tau Spread in the Brain to Promote Alzheimer's Disease Pathology
Featuring Zhongcong Xie, MD, PhD

Research provides new insights on mechanisms behind tau spread and how it promotes cognitive impairment.

Epigenetic Changes Drive the Fate of a B Cell
Featuring Shiv Pillai, MD, PhD

Scientists at the Ragon Institute of MGH, MIT and Harvard discover epigenetic changes unique to B cells and B cell subtypes.

Study Solves Mystery of How Amyloid Beta, a Key Player in Alzheimer's, Forms in Brain Nerve Cells
Featuring Rudolph Tanzi, PhD

A new study solves the mystery of how amyloid beta, a key player in Alzheimer's, forms in brain nerve cells

Colorectal Cancer Screening Past Age 75 Lowers Cancer Death Risk for Most
Featuring Andrew Chan, MD, MPH

A team of Mass General investigators finds colonoscopy or sigmoidoscopy after age 75 reduced colorectal cancer incidence and death related to colorectal cancer in all but those with cardiovascular disease or multiple health conditions.

Wearable Devices Show That Physical Activity May Lower Atrial Fibrillation and Stroke Risk
Featuring Steven Lubitz, MD, MPH

A new generation of smart devices with diagnostic capabilities could open the door to low-cost, highly effective disease prevention programs.

A Community Health Worker Intervention Reduces Hospital Readmissions
Featuring Jocelyn Carter, MD, MPH

A clinical trial that paired community health workers with inpatients found that fewer intervention group participants were readmitted within 30 days than were control group participants.

Serendipitous Discovery Could Lead to Treatment for Strokes, Cardiac Arrest
Featuring Fumito Ichinose, MD, PhD

Researchers at Mass General identified a mechanism that protects the brain from the effects of hypoxia, a potentially lethal deprivation of oxygen.

Researchers Uncover Mechanism Related to Severe Post-COVID-19 Disease in Children
Featuring Alessio Fasano, MD, and Lael Yonker, MD

A multidisciplinary team from Mass General for Children and other institutions have identified the mechanism of how an extremely rare but serious post-COVID-19 complication develops in children and adolescents.

Blog Posts

Not Just a Matter of Appearance: How Alopecia Affects Patients Throughout Life
Featuring Maryanne Senna, MD

In a recent study, Mass General researchers detailed the negative physical, psychological, social and financial effects of alopecia areata from the perspective of cumulative life course impairment.

Mass General Research Institute 5-Year Celebration Video

The Mass General Research Institute was formed to help unify and support researchers of all disciplines across Mass General as well as promote and share their science with the world.

Conversations with Margarita: It Stays with You
Featuring Margarita Alegría, PhD

In this month's "Conversations with Margarita," Margarita Alegría, PhD, discusses the rise in violence and racism toward the Asian American and Pacific Islander community and what we can do to move forward.

World Medical Innovation Forum Outlines a Patient-Centric Vision for Gene and Cell Therapies

What role will investigators in the Mass General Brigham system play in the growing field of gene and cell therapy?

Humans of MGRI: Alba Miranda-Ribera, PhD

Alba Miranda-Ribera, PhD, is an instructor at the Mucosal Immunology and Biology Research Center.

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Snapshot of Science for May 2021