Welcome to our Snapshot of Science for February 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 25 summaries submitted by the research teams
  • 15 new research-related press releases from the Mass General Public Affairs office
  • 9 posts from the Mass General Research Institute blog
Publications

SCAR ENABLES CRISPR-BASED STUDIES OF TUMOR-IMMUNE INTERACTIONS
In Vivo Screens Using a Selective CRISPR Antigen Removal Lentiviral Vector System Reveal Immune Dependencies in Renal Cell Carcinoma
Dubrot J, Lane-Reticker SK, Kessler EA, Ayer A, Mishra G [et al.], Manguso RT
Published in Immunity on January 20, 2021


HIGH DOSE BLOOD THINNERS DO NOT LOWER COVID-19 DEATH RISK
Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients with COVID-19
Al-Samkari H, Gupta S, Leaf RK, Wang W, Rosovsky RP [et al.], Leaf DE
Published in Annals of Internal Medicine on January 26, 2021 | *Summary available | Press Release


INDIVIDUAL NEURONS ARE CRITICAL FOR SOCIAL REASONING
Single-neuronal Predictions of Others' Beliefs in Humans
Jamali M, Grannan BL, Fedorenko E, Saxe R, Báez-Mendoza R, Williams ZM
Published in Nature on January 27, 2021 | *Summary available | Press Release


PLASMA-BASED GENOTYPING ASSOCIATED WITH POTENTIAL IMPROVEMENTS IN MBC OUTCOMES
Tumor Tissue- Versus Plasma-based Genotyping for Selection of Matched Therapy and Impact on Clinical Outcomes in Patients with Metastatic Breast Cancer
Vidula N, Niemierko A, Malvarosa G, Yuen M, Lennerz JK [et al.], Bardia A
Published in Clinical Cancer Research on January 27, 2021 | *Summary available


AI TO MEASURE CORONARY ARTERY CALCIUM AS PREDICTOR OF CV EVENTS
Deep Convolutional Neural Networks to Predict Cardiovascular Risk from Computed Tomography
Zeleznik R, Foldyna B, Eslami P, Weiss J, Alexander I [et al.], Aerts JWL
Published in Nature Communications on January 29, 2021 | *Summary available


IMPACT OF COMMON AND RARE COPY NUMBER VARIANTS
Polygenic Burden Has Broader Impact on Health, Cognition, and Socioeconomic Outcomes Than Most Rare and High-Risk Copy Number Variants
Saarentaus EC, Havulinna AS, Mars N, Ahola-Olli A, Kiiskinen TTJ [et al.], Palotie A
Published in Molecular Psychiatry on February 01, 2021 | *Summary available


HEALTHY LIFESTYLE COULD ADD SUBSTANTIAL BENEFIT FOR COLORECTAL CANCER PREVENTION
Healthy Lifestyle, Endoscopic Screening, and Colorectal Cancer Incidence and Mortality in the United States: A Nationwide Cohort Study
Wang K, Ma W, Wu K, Ogino S, Chan AT, Giovannucci EL, Song M
Published in PLOS Medicine on February 01, 2021 | *Summary available


NEED FOR DIVERSITY IN VACCINE TRIALS
Assessment of the Inclusion of Racial/Ethnic Minority, Female, and Older Individuals in Vaccine Clinical Trials
Flores LE, Frontera WR, Andrasik MP, Del Rio C, Mondríguez-González A [et al.], Silver JK
Published in JAMA Network Open on February 01, 2021 | *Summary available


DATA SUGGEST INCREASED SAFETY OF XFAL ANTICOAGULANT
Clinical Characteristics and Outcomes Associated with Oral Anticoagulant Use Among Patients Hospitalized with Intracerebral Hemorrhage
Xian Y, Zhang S, Inohara T, Grau-Sepulveda M, Matsouaka RA [et al.], Schwamm LH
Published in JAMA Network Open on February 01, 2021 | *Summary available


COVID-19 ANTIBODIES PERSIST MORE THAN 4 MONTHS POST ILLNESS
Orthogonal Immunoassays for IgG Antibodies to SARS-CoV-2 Antigens Reveal That Immune Response Lasts Beyond 4 Mo Post Illness Onset
Sasisekharan V, Pentakota N, Jayaraman A, Tharakaraman K, Wogan GN, Narayanasami U
Published in Proceedings of the National Academy of Sciences on February 02, 2021 | *Summary available


EMR INFORMATION TO PREDICT POOR COVID-19 OUTCOMES
Predicting COVID-19 Mortality with Electronic Medical Records
Estiri H, Strasser ZH, Klann JG, Naseri P, Wagholikar KB, Murphy SN
Published in npj Digital Medicine on February 04, 2021 | *Summary available | Press Release


GENES PREDICTIVE OF SURVIVAL CAN HELP SELECT PDAC TREATMENT COURSE
Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma
Birnbaum DJ, Begg SKS, Finetti P, Vanderburg CR, Neyaz A [et al.], Liss AS
Published in Clinical Cancer Research on February 05, 2021 | *Summary available


MANIPULATING P53 DYNAMICS TO IMPROVE CANCER THERAPY
P53 Dynamics Vary Between Tissues and Are Linked with Radiation Sensitivity
Stewart-Ornstein J, Iwamoto Y, Miller MA, Prytyskach MA, Ferretti S [et al.], Lahav G
Published in Nature Communications on February 09, 2021 | *Summary available


GENETIC BASIS FOR DAYTIME NAPPING
Genetic Determinants of Daytime Napping and Effects on Cardiometabolic Health
Dashti HS, Daghlas I, Lane JM, Huang Y, Udler MS [et al.], Saxena R
Published in Nature Communications on February 10, 2021 | *Summary available | Press Release


PERSONALIZED GROCERY INCENTIVES INCREASES HEALTHY FOOD PURCHASING
Effect of Personalized Incentives on Dietary Quality of Groceries Purchased: A Randomized Crossover Trial
Vadiveloo M, Guan X, Parker HW, Perraud E, Buchanan A [et al.], Thorndike AN
Published in JAMA Network Open on February 10, 2021 | *Summary available


HIV-INFECTED MACROPHAGES RESIST NATURAL KILLER CELLS
HIV-infected Macrophages Resist Efficient NK Cell-Mediated Killing While Preserving Inflammatory Cytokine Responses
Clayton KL, Mylvaganam G, Villasmil-Ocando A, Stuart H, Maus MV [et al.], Walker BD
Published in Cell Host & Microbe on February 10, 2021


HUMORAL IMMUNE RESPONSE MAY DRIVE COVID-19 OUTCOMES
Humoral Signatures of Protective and Pathological SARS-CoV-2 Infection in Children
Bartsch YC, Wang C, Zohar T, Fischinger S, Atyeo C [et al.], Alter G
Published in Nature Medicine on February 12, 2021 | *Summary available | Press Release


GENE EXPRESSION IN GLIOMA-INFILTRATING T CELLS
Inhibitory CD161 Receptor Identified in Glioma-infiltrating T Cells by Single Cell Analysis
Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM [et al.], Wucherpfennig KW
Published in Cell on February 15, 2021 | *Summary available


SEVERITY OF COVID-19 INFECTION CORRESPONDS TO LEVEL OF ANTIBODIES AND FUTURE PROTECTION
Discrete SARS-CoV-2 Antibody Titers Track with Functional Humoral Stability
Bartsch YC, Fischinger S, Siddiqui SM, Chen Z, Yu J [et al.], Alter G
Published in Nature Communications on February 15, 2021 | *Summary available | Press Release


NEW SOFTWARE FOR PRECISE GENE EDITING
PrimeDesign Software for Rapid and Simplified Design of Prime Editing Guide RNAs
Hsu JY, Grünewald J, Szalay R, Shih J, Anzalone AV [et al.], Pinello L
Published in Nature Communications on February 15, 2021 | *Summary available


AI TO IDENTIFY REPURPOSED DRUGS FOR AD
Machine Learning Identifies Candidates for Drug Repurposing in Alzheimer's Disease
Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA [et al.], Sokolov A
Published in Nature Communications on February 15, 2021


CORTICAL NEURONS HAVE STRONG INCREASE IN FIRING DURING SPINDLES
Travelling Spindles Create Necessary Conditions for Spike-timing-dependent Plasticity in Humans
Dickey CW, Sargsyan A, Madsen JR, Eskandar EN, Cash SS, Halgren E
Published in Nature Communications on February 15, 2021


PROGRESSION OF TRICUSPID REGURGITATION AFTER HEART SURGERY
Progression of Tricuspid Regurgitation After Surgery for Ischemic Mitral Regurgitation
Bertrand PB, Overbey JR, Zeng X, Levine RA, Ailawadi G [et al.], Hung J
Published in Journal of the American College of Cardiology on February 16, 2021 | *Summary available


RETAINING WOMEN PARTICIPANTS IN CLINICAL TRIALS
Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials
Lau ES, Braunwald E, Morrow DA, Giugliano RP, Antman EM [et al.], O'Donoghue ML
Published in Circulation on February 16, 2021 | *Summary available


COSMETIC LASERS AS A SCC THERAPY
Epitope Spreading Toward Wild-type Melanocyte-lineage Antigens Rescues Suboptimal Immune Checkpoint Blockade Responses
Lo JA, Kawakubo M, Juneja VR, Su MY, Erlich TH [et al.], Fisher DE
Published in Science Translational Medicine on February 17, 2021 | *Summary available | Press Release


SOCIAL SUPPORT IMPROVES STEM CELL TRANSPLANT OUTCOMES
Sharing and Caring: The Impact of Social Support on Quality of Life and Health Outcomes in Hematopoietic Stem Cell Transplantation
Amonoo HL, Johnson PC, Dhawale TM, Traeger L, Rice J [et al.], El-Jawahri A
Published in Cancer on February 17, 2021 | *Summary available


COLLAGENOUS COLITIS ASSOCIATED WITH INCREASED RISK FOR SEVERE COVID-19
Association Between Collagenous and Lymphocytic Colitis and Risk of Severe COVID-19
Khalili H, Zheng T, Söderling J, Larsson E [et al.], Ludvigsson JF
Published in Gastroenterology on February 18, 2021


SPECIFIC CELLS DRIVE CANCER GROWTH
A Unique Subset of Glycolytic Tumour-propagating Cells Drives Squamous Cell Carcinoma
Choi JE, Sebastian C, Ferrer CM, Lewis VA, Sade-Feldman M [et al.], Mostoslavsky R
Published in Nature Metabolism on February 21, 2021 | *Summary available


INFLAMMATORY MOLECULE CONTRIBUTES TO SKIN AND PANCREATIC CANCERS
Nuclear Il-33/SMAD Signaling Axis Promotes Cancer Development in Chronic Inflammation
Park JH, Ameri AH, Dempsey KE, Conrad DN, Kem M [et al.], Demehri S
Published in The EMBO Journal on February 22, 2021 | *Summary available | Press Release


EMBOLIC PROTECTION DEVICES LOWER ODDS OF IN-HOSPITAL STROKE
Cerebral Embolic Protection and Outcomes of Transcatheter Aortic Valve Replacement: Results from the TVT Registry
Butala NM, Makkar R, Secemsky EA, Gallup D, Marquis-Gravel G [et al.], Cohen DJ
Published in Circulation on February 23, 2021 | *Summary available


ATHEROSCLEROSIS CAN ACCELERATE THE DEVELOPMENT OF CLONAL HEMATOPOIESIS
Increased Stem Cell Proliferation in Atherosclerosis Accelerates Clonal Hematopoiesis
Heyde A, Rohde D, McAlpine CS, Zhang S, Hoyer FF [et al.], Naxerova K
Published in Cell on February 25, 2021 | Press Release


BIOLOGICAL INSIGHTS INTO PERINEURAL INVASION
Pan-Cancer Transcriptomic Predictors of Perineural Invasion Improve Occult Histopathological Detection
Guo JA, Hoffman HI, Shroff S, Chen P, Hwang PG [et al.], Hwang WL
Published in Clinical Cancer Research on February 25, 2021


BINIMETINIB NOT PROMISING FOR NRAS-MUTATED CANCERS
Differential Outcomes in Codon 12/13 and Codon 61 NRAS-Mutated Cancers in the Phase 2 NCI-MATCH Trial of Binimetinib in Patients with NRAS-Mutated Tumors
Cleary JM, Wang VX, Heist RS, Kopetz S, Mitchell EP [et al.], Flaherty KT
Published in Clinical Cancer Research on February 26, 2021


HOUSEHOLD COVID-19 INFECTION RISK
Household Transmission of SARS-CoV-2
Metlay JP, Haas JS, Soltoff AE, Armstrong KA
Published in JAMA Network Open on February 26, 2021 | *Summary available


Publication Summaries

HIGH DOSE BLOOD THINNERS DO NOT LOWER COVID-19 DEATH RISK
Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients with COVID-19
Al-Samkari H, Gupta S, Leaf RK, Wang W, Rosovsky RP [et al.], Leaf DE
Published in Annals of Internal Medicine on January 26, 2021 | Press Release

COVID-19 infection causes an increased propensity for blood clotting, which can be fatal. This study evaluated the rates of blood clotting and bleeding complications, as well as the impact of empiric high-dose blood thinner use, on 3239 critically ill patients with COVID-19 at 67 geographically-diverse hospitals throughout the United States. The major finding of the study was that high-dose blood thinner use did not reduce the risk of death in critically ill patients with COVID-19, suggesting that doctors should use standard preventive doses of blood thinners in these patients.

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


INDIVIDUAL NEURONS ARE CRITICAL FOR SOCIAL REASONING
Single-neuronal Predictions of Others' Beliefs in Humans
Jamali M, Grannan BL, Fedorenko E, Saxe R, Báez-Mendoza R, Williams ZM
Published in Nature on January 27, 2021 | Press Release

Our ability to reason about the thoughts and beliefs of others, often termed "theory of mind," is crucial to social behavior. By using single-neuronal recording from the human dorsomedial prefrontal cortex, this study identifies neurons that reliably encode information about others’ beliefs across richly varying scenarios and that distinguish self- from other-belief related representations. It also shows how these cells represent the other-belief contents and accurately predict whether they are true or false. Together, these findings provide a rare look into the cellular-level processing that underlie human theory of mind and a potential platform by which to begin studying social reasoning and its dysfunction in humans.

(Summary submitted by Ziv Williams, MD, Department of Neurosurgery, Mass General Cancer Center, MassGeneral Hospital for Children)


PLASMA-BASED GENOTYPING ASSOCIATED WITH POTENTIAL IMPROVEMENTS IN MBC OUTCOMES
Tumor Tissue- Versus Plasma-based Genotyping for Selection of Matched Therapy and Impact on Clinical Outcomes in Patients with Metastatic Breast Cancer
Vidula N, Niemierko A, Malvarosa G, Yuen M, Lennerz JK [et al.], Bardia A
Published in Clinical Cancer Research on January 27, 2021

We conducted a comprehensive analysis of patients with metastatic breast cancer to determine the utility of tissue-based and plasma-based genotyping for the identification of actionable mutations, the selection of matched therapy targeted to an actionable mutation, and impact on overall survival. Both tests detected high rates of actionable mutations and relevance for matched therapy. For cell-free DNA patients with actionable mutations, matched therapy was associated with better overall survival. Plasma-based genotyping may identify high rates of actionable mutations, with relevance for matched therapy and a potential improvement in outcomes.

(Summary submitted by Neelima Vidula, MD, Division of Hematology/Oncology, Mass General Cancer Center)


AI TO MEASURE CORONARY ARTERY CALCIUM AS PREDICTOR OF CV EVENTS
Deep Convolutional Neural Networks to Predict Cardiovascular Risk from Computed Tomography
Zeleznik R, Foldyna B, Eslami P, Weiss J, Alexander I [et al.], Aerts JWL
Published in Nature Communications on January 29, 2021

This study used 20,000 CT scans of the heart from four NIH trials (FHS, NLST, ROMICAT and PROMISE) to develop and validate a deep learning system to automatically measure coronary artery calcium, a strong predictor of adverse cardiovascular events. The automated calcium scores highly correlated with the manual calcium scores from human experts and independently predicted major adverse cardiovascular events. The tool is open source and freely available to help physicians and patients to make more informed decisions about cardiovascular prevention.

(Summary submitted by Udo Hoffmann, MD, Department of Radiology, Cardiac Imaging)


IMPACT OF COMMON AND RARE COPY NUMBER VARIANTS
Polygenic Burden Has Broader Impact on Health, Cognition, and Socioeconomic Outcomes Than Most Rare and High-Risk Copy Number Variants
Saarentaus EC, Havulinna AS, Mars N, Ahola-Olli A, Kiiskinen TTJ [et al.], Palotie A
Published in Molecular Psychiatry on February 01, 2021

Both common and rare genetic variation contributes to disease susceptibility. Copy number variants (CNVs) are rare, large genomic rearrangements that can cause syndromic and severe neurological and psychiatric disorders, such as intellectual disability, epilepsy, schizophrenia and autism. Although considered high-impact, CNVs are also observed in seemingly healthy individuals. We estimated the impact of rare disease-associated CNVs on long term health and well-being among healthy participants. The results imply that for healthy CNV carriers, the quality of life is expected to be comparable to that of the general population. Furthermore, the combined effect of common low-impact variants was broader and often more substantial than that of rare CNVs.

(Summary submitted by Elmo Saarentaus, MD, University of Helsinki, and Aarno Palotie, MD, PhD, Department of Psychiatry, Analytic and Translational Genetics Unit, Center for Genomic Medicine)


HEALTHY LIFESTYLE COULD ADD SUBSTANTIAL BENEFIT FOR COLORECTAL CANCER PREVENTION
Healthy Lifestyle, Endoscopic Screening, and Colorectal Cancer Incidence and Mortality in the United States: A Nationwide Cohort Study
Wang K, Ma W, Wu K, Ogino S, Chan AT, Giovannucci EL, Song M
Published in PLOS Medicine on February 01, 2021

An adoption of healthy lifestyle and screening represent two major approaches to colorectal cancer prevention, but it remains an open question how an integration of healthy lifestyle with endoscopic screening can improve colorectal cancer prevention compared with endoscopic screening alone. Leveraging data from three large U.S. cohorts, we found that, even among individuals having undergone endoscopic screening, adoption of healthy lifestyle could still confer a substantial benefit for colorectal cancer prevention, and the incremental benefit was particularly strong for proximal colon cancer. Our data highlight the potential of healthy lifestyle to complement endoscopic screening for optimal colorectal cancer prevention.

(Summary submitted by Mingyang Song, MD, ScD, Clinical & Translational Epidemiology Unit, Department of Medicine)


NEED FOR DIVERSITY IN VACCINE TRIALS
Assessment of the Inclusion of Racial/Ethnic Minority, Female, and Older Individuals in Vaccine Clinical Trials
Flores LE, Frontera WR, Andrasik MP, Del Rio C, Mondríguez-González A [et al.], Silver JK
Published in JAMA Network Open on February 01, 2021

In the largest study to date on diversity and inclusion in clinical trials, a diverse team of researchers from multiple academic institutions in the United States and Puerto Rico examined 230 studies on ClinicalTrials.gov from 2011-2020. We hypothesized that people who identified with underrepresented racial/ethnic groups, women, and individuals aged 65 and older would be underrepresented as participants. Our hypotheses were confirmed with the exception that women were overrepresented. We also discovered that there was a lot of missing data suggesting that federal recommendations regarding data collection and transparency are not being followed. The findings suggest that diversity enrollment targets are needed and compliance with reporting guidelines should be strengthened.

(Summary submitted by Julie K. Silver, MD, Department of Physical Medicine and Rehabilitation)


DATA SUGGEST INCREASED SAFETY OF XFAL ANTICOAGULANT
Clinical Characteristics and Outcomes Associated with Oral Anticoagulant Use Among Patients Hospitalized with Intracerebral Hemorrhage
Xian Y, Zhang S, Inohara T, Grau-Sepulveda M, Matsouaka RA [et al.], Schwamm LH
Published in JAMA Network Open on February 01, 2021

Patients who require chronic anticoagulation to prevent stroke or other disorders due to excess clotting are prescribed either warfarin or newer medications called Factor Xa Inhibitors (FXaI). The FXaI cause lower rates of brain bleeding in clinical trials, but real-world data were limited. Among >200,000 patients admitted to >1800 hospitals from 2013-2018 in the Get with the Guidelines-Stroke registry, we found that patients taking FXaI prior to admission had ~25% lower odds of dying and 18% higher odds of going directly home compared to those taking warfarin, though both groups unsurprisingly had worse outcomes than those not taking any anticoagulation. These data support the increased safety of FXaI.

(Summary submitted by Lee Schwamm, MD, Department of Neurology, Vascular Center, Center for TeleHealth)


COVID-19 ANTIBODIES PERSIST MORE THAN 4 MONTHS POST ILLNESS
Orthogonal Immunoassays for IgG Antibodies to SARS-CoV-2 Antigens Reveal That Immune Response Lasts Beyond 4 Mo Post Illness Onset
Sasisekharan V, Pentakota N, Jayaraman A, Tharakaraman K, Wogan GN, Narayanasami U
Published in Proceedings of the National Academy of Sciences on February 02, 2021

As the COVID-19 pandemic continues to cause havoc worldwide, understanding immune response to SARS-CoV-2 is of immense importance. Herein, a multidisciplinary team of researchers used an orthogonal quantitative approach to SARS-CoV-2 antibody testing using distinct viral antigens in a community-based analysis of patients with symptomatic and asymptomatic COVID-19 infection. This study showed correlation of S1, NP and neutralization antibody titers to each other and to clinical features such as length and severity of COVID-19 illness. Also, contrary to reports of rapid decay of antibody levels, this study shows persistence of antibodies for more than four months post onset of COVID-19 illness.

(Summary submitted by Uma Narayanasami, MD, Division of Hematology/Oncology, Mass General Cancer Center)


EMR INFORMATION TO PREDICT POOR COVID-19 OUTCOMES
Predicting COVID-19 Mortality with Electronic Medical Records
Estiri H, Strasser ZH, Klann JG, Naseri P, Wagholikar KB, Murphy SN
Published in npj Digital Medicine on February 04, 2021 | Press Release

We analyzed demographics, diagnosis labels and medications stored in the electronic health record for over 16,000 patients who would eventually be diagnosed with COVID-19. Based only on the data entered prior to their diagnosis, we built robust and accurate models for predicting an individual’s risk of death. We then analyzed what the models prioritized as the most significant features for predicting poor outcomes. While age was the most important feature, we were surprised to find a prior diagnosis of pneumonia as the second most important. Additionally, the models could be used to determine individual risk and theoretically help allocate limited resources like vaccines.

(Summary submitted by Zachary Strasser, MD, Laboratory of Computer Science, Department of Medicine)


GENES PREDICTIVE OF SURVIVAL CAN HELP SELECT PDAC TREATMENT COURSE
Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma
Birnbaum DJ, Begg SKS, Finetti P, Vanderburg CR, Neyaz A [et al.], Liss AS
Published in Clinical Cancer Research on February 05, 2021

Characterizing the molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) has been confounded by the abundance of non-cancerous stromal cells in tumors. In this study, we performed laser capture microdissection to physically separate the cancer and stromal cells and defined their transcriptional subtypes. We identified 13 genes expressed in cancer cells that were predicative of survival which could help select patients with operable disease for either immediate surgery or neoadjuvant chemotherapy. From a wider perspective, our findings help elucidate the complex nature of PDAC molecular subtypes and expand our understanding of global gene expression programs in the stroma.

(Summary submitted by Andrew Liss, PhD, Division of General and Gastrointestinal Surgery, Department of Surgery)


MANIPULATING P53 DYNAMICS TO IMPROVE CANCER THERAPY
P53 Dynamics Vary Between Tissues and Are Linked with Radiation Sensitivity
Stewart-Ornstein J, Iwamoto Y, Miller MA, Prytyskach MA, Ferretti S [et al.], Lahav G
Published in Nature Communications on February 09, 2021

The tumor suppressor p53 governs cell response to stressors such as radiation, but it has been unclear how in vivo p53 dynamics unfold over time to influence cell fate in tissue. In our study, differences in temporal p53 levels were associated with varying radiation sensitivities in tissue. This led to use of an inhibitor of the p53 regulator, MDM2, to block p53 levels from declining and oscillating in tumors following radiation. Combining MDM2 inhibition with localized radiation slowed tumor progression, thus opening new directions for potentially manipulating p53 dynamics in patients to improve cancer therapy.

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


GENETIC BASIS FOR DAYTIME NAPPING
Genetic Determinants of Daytime Napping and Effects on Cardiometabolic Health
Dashti HS, Daghlas I, Lane JM, Huang Y, Udler MS [et al.], Saxena R
Published in Nature Communications on February 10, 2021 | Press Release

Daytime napping is a common behavior, but very little is known about its genetic basis. Understanding the genetics of daytime napping can reveal biological drivers and clarify links to health. In our study, the largest of its kind, we studied the genetics of 452,633 adults in the UK Biobank and 541,333 adults in 23andMe and found 123 genetic regions that may regulate how often adults nap. Those findings indicated at least three potential mechanisms that drive napping: increased need for sleep, disrupted nighttime sleep and early morning awakening. Results suggested possible links between more frequent napping and both larger waist circumference and higher blood pressure, however these links differed based on subtypes of napping.

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


PERSONALIZED GROCERY INCENTIVES INCREASES HEALTHY FOOD PURCHASING
Effect of Personalized Incentives on Dietary Quality of Groceries Purchased: A Randomized Crossover Trial
Vadiveloo M, Guan X, Parker HW, Perraud E, Buchanan A [et al.], Thorndike AN
Published in JAMA Network Open on February 10, 2021

Food purchased in grocery stores influences the dietary intake and health of the entire household. Many factors contribute to unhealthy choices, including taste preferences, food marketing, and nutrition knowledge. We tested a semi-automated, personalized healthy food incentive and nutrition education intervention to promote healthier purchases in a Rhode Island supermarket. Shoppers received coupons for healthy foods (e.g., whole grain bread, low fat milk) that were personalized based on prior purchases and individual preferences (e.g., specific brands). We found the intervention resulted in a modest increase in healthy purchases over nine months. In the future, personalized grocery incentives hold promise for promoting healthier dietary choices at the population level.

(Summary submitted by Anne Thorndike, MD, MPH, Department of Medicine)


HUMORAL IMMUNE RESPONSE MAY DRIVE COVID-19 OUTCOMES
Humoral Signatures of Protective and Pathological SARS-CoV-2 Infection in Children
Bartsch YC, Wang C, Zohar T, Fischinger S, Atyeo C [et al.], Alter G
Published in Nature Medicine on February 12, 2021 | Press Release

There is currently no way to predict COVID-19 disease severity or if a child will develop MIS-C, a rare but serious syndrome that can develop following SARS-CoV-2 exposure. Using systems serology to examine the immune response of adults with severe or mild COVID-19, and children with mild COVID-19 and MIS-C, we found, unexpectedly, that children and adults with mild COVID-19 have similar antibody profiles. However, adults with severe disease showed elevated levels of IgA antibodies, while children who developed MIS-C had elevated levels of IgG antibodies. These findings suggest that the humoral immune response may be driving disease outcome.

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


GENE EXPRESSION IN GLIOMA-INFILTRATING T CELLS
Inhibitory CD161 Receptor Identified in Glioma-infiltrating T Cells by Single Cell Analysis
Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM [et al.], Wucherpfennig KW
Published in Cell on February 15, 2021

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Performing single-cell RNA-sequencing on glioma-infiltrating T cells, we identify subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes as potential effectors of anti-tumor immunity. Analysis of clonally expanded T cells further identifies the CD161 protein, encoded by the KLRB1 gene, as a potential inhibitory receptor. We then used CRISPR/Cas9 gene-editing technology or blocking antibodies to show that CD161 inhibits the tumor cell-killing function of T cells. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.

(Summary submitted by Mario L. Suvà, MD, PhD, Department of Pathology, Mass General Cancer Center)


SEVERITY OF COVID-19 INFECTION CORRESPONDS TO LEVEL OF ANTIBODIES AND FUTURE PROTECTION
Discrete SARS-CoV-2 Antibody Titers Track with Functional Humoral Stability
Bartsch YC, Fischinger S, Siddiqui SM, Chen Z, Yu J [et al.], Alter G
Published in Nature Communications on February 15, 2021 | Press Release

In a longitudinal analysis of a cohort of over 4300 SpaceX employees, we identified 120 with previously unknown SARS-CoV-2 exposure. Using our systems serology technique on those with mild to asymptomatic cases, we found that individuals who reported more COVID-19 related symptoms were more likely to reach a specific threshold of SARS-CoV-2 antibodies, and to have functional adaptive immune responses, which may confer protective immunity. This suggests the mere presence of SARS-CoV-2 antibodies isn’t enough to determine whether an individual develops protective immunity upon mild infection; rather, protection may depend on the levels of antibodies developed in response to infection.

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


NEW SOFTWARE FOR PRECISE GENE EDITING
PrimeDesign Software for Rapid and Simplified Design of Prime Editing Guide RNAs
Hsu JY, Grünewald J, Szalay R, Shih J, Anzalone AV [et al.], Pinello L
Published in Nature Communications on February 15, 2021

In this paper, we describe PrimeDesign, a flexible and user-friendly tool for designing customized components needed to practice targeted CRISPR-based prime editing. Prime editing is a novel, recently described gene editing method with significant translational potential that enables the introduction of precise insertion, deletion and substitution edits of interest. PrimeDesign automates the complex design of prime editing guide RNA (pegRNA) and nicking sgRNA (ngRNA) constructs needed for users to make their desired edits and is generalizable for both individual and combinatorial edits. This tool can be accessed online through a user-friendly web application at primedesign.pinellolab.org or off-line as a command line utility.

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


PROGRESSION OF TRICUSPID REGURGITATION AFTER HEART SURGERY
Progression of Tricuspid Regurgitation After Surgery for Ischemic Mitral Regurgitation
Bertrand PB, Overbey JR, Zeng X, Levine RA, Ailawadi G [et al.], Hung J
Published in Journal of the American College of Cardiology on February 16, 2021

In mitral valve surgery, it remains unclear whether a tricuspid valve repair for tricuspid regurgitation (TR) is needed at the same time. We therefore studied the progression of TR after cardiac surgery for ischemic mitral regurgitation in 492 patients included in two prospectively randomized trials. Our findings show that TR progression at two years is not as common as previously reported. Factors associated with progression of TR were analyzed to help guide therapy for these patients.

(Summary submitted by Philippe B. Bertrand, MD, PhD, Division of Cardiology, Department of Medicine)


RETAINING WOMEN PARTICIPANTS IN CLINICAL TRIALS
Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials
Lau ES, Braunwald E, Morrow DA, Giugliano RP, Antman EM [et al.], O'Donoghue ML
Published in Circulation on February 16, 2021

Women are consistently underrepresented in clinical trials, but whether women are more likely to prematurely discontinue a study drug or withdraw consent once enrolled in a clinical trial is unknown. Using data from 187,691 participants enrolled across 11 cardiovascular clinical trials conducted by the Brigham and Women’s Hospital Thrombolysis in Myocardial Infarction (TIMI) Study Group, we found that women are more likely than men to prematurely stop taking the study drug and withdraw consent from study participation. Differences in baseline characteristics and adverse events did not explain these findings. Our work highlights an unmet need to better understand the barriers to clinical trial retention for women.

(Summary submitted by Emily Lau, MD, Division of Cardiology, Department of Medicine)


COSMETIC LASERS AS A CANCER THERAPY
Epitope Spreading Toward Wild-type Melanocyte-lineage Antigens Rescues Suboptimal Immune Checkpoint Blockade Responses
Lo JA, Kawakubo M, Juneja VR, Su MY, Erlich TH [et al.], Fisher DE
Published in Science Translational Medicine on February 17, 2021 | Press Release

Immune checkpoint inhibitors are key medications that boost immune responses against various cancers, but only a minority of patients benefit from these drugs. This study identified a previously unrecognized inflammation-inducing role for mutations in the genomes of the cancers, and thereby revealed a new treatment strategy based upon stimulating localized inflammation within a tumor. Our research team exposed melanomas or pancreatic cancers in mice to a cosmetic laser invented at Mass General, followed by immune checkpoint inhibitors, and observed dramatically enhanced cures for these otherwise incurable cancers.

(Summary submitted by David E. Fisher MD, PhD, Department of Dermatology, Mass General Cancer Center, Cutaneous Biology Research Center)


SOCIAL SUPPORT IMPROVES STEM CELL TRANSPLANT OUTCOMES
Sharing and Caring: The Impact of Social Support on Quality of Life and Health Outcomes in Hematopoietic Stem Cell Transplantation
Amonoo HL, Johnson PC, Dhawale TM, Traeger L, Rice J [et al.], El-Jawahri A
Published in Cancer on February 17, 2021

Social support is essential for successful recovery following hematopoietic stem cell transplantation (HSCT). In this study, we examined the relationship between HSCT patients’ perception of their social support and quality of life (QOL), psychological distress, posttraumatic stress symptoms, fatigue and health care utilization. Our results suggest that patients with higher pre-HSCT perception of their social support experience better QOL and lower psychological distress at six months post-HSCT. These findings emphasize the importance of social support and raise the possibility that supportive care interventions targeting social support may improve outcomes in patients with hematologic malignancies undergoing HSCT population.

(Summary submitted by Hermioni Lokko Amonoo, MD, MPP, Department of Psychiatry, Brigham and Women's Hospital)


SPECIFIC CELLS DRIVE SCC GROWTH
A Unique Subset of Glycolytic Tumour-propagating Cells Drives Squamous Cell Carcinoma
Choi JE, Sebastian C, Ferrer CM, Lewis VA, Sade-Feldman M [et al.], Mostoslavsky R
Published in Nature Metabolism on February 21, 2021

Head and neck squamous cell carcinoma is an aggressive form of cancer that is challenging to treat. Although metabolic adaptations have emerged in recent years as unique features in tumors, the metabolic characteristics of SCCs and their roles in tumor progression remain unknown. We found that a unique group of tumor propagating cells (TPCs) exhibit exquisite reliance on their ability to burn glucose through aerobic glycolysis (the Warburg effect). Contrary to previous models, we found that this is an early adaptation in only a subset of TPCs, indicating that metabolic adaptations are a heterogeneous characteristic in tumors. We also showed that inhibition of glycolysis significantly reduced tumor burden, suggesting that these new findings could be exploited for therapeutic purposes.

(Summary submitted by Raul Mostoslavsky, MD, PhD, Mass General Cancer Center, Center for Cancer Research)


IMFLAMMATORY MOLECULE CONTRIBUTES TO SKIN AND PANCREATIC CANCERS
Nuclear Il-33/SMAD Signaling Axis Promotes Cancer Development in Chronic Inflammation
Park JH, Ameri AH, Dempsey KE, Conrad DN, Kem M [et al.], Demehri S
Published in The EMBO Journal on February 22, 2021 | Press Release

Chronic inflammation is a critical predisposing factor for cancer development in several organs. Cancer-prone chronic inflammation includes inflammatory bowel disease-associated colorectal cancer, pancreatitis-associated pancreatic cancer and skin cancers associated with several skin inflammatory diseases. We have previously demonstrated that Interleukin (IL)-33 is a key cytokine in establishing a tumor-promoting immune environment in chronic inflammation. Considering that IL-33 is expressed by the epithelial cells in the skin and pancreas, we now report that IL-33 has a novel function in cancer as a nuclear protein. Induction of nuclear IL-33 in chronic inflammatory conditions of skin and pancreas regulates SMAD signaling within cancer-initiating cells to promote cancer development. This study reveals a previously unrecognized function for IL-33, independent of its cytokine function, and provide a novel therapeutic target to prevent skin and pancreatic cancer.

(Summary submitted by Shawn Demehri, MD, PhD, Department of Dermatology, Mass General Cancer Center, Center for Cancer Immunology, Cutaneous Biology Research Center)


EMBOLIC PROTECTION DEVICES LOWER ODDS OF IN-HOSPITAL STROKE
Cerebral Embolic Protection and Outcomes of Transcatheter Aortic Valve Replacement: Results from the TVT Registry
Butala NM, Makkar R, Secemsky EA, Gallup D, Marquis-Gravel G [et al.], Cohen DJ
Published in Circulation on February 23, 2021

Stroke remains a devastating complication of transcatheter aortic valve replacement (TAVR). While cerebral embolic protection devices (EPDs) have been developed to reduce risk of stroke, data regarding their impact on stroke and other outcomes after TAVR are limited. In this large nationally-representative observational study, we did not find an association between EPD use for TAVR and a meaningful reduction in-hospital stroke. Thus, more definitive data from ongoing randomized trials are necessary to support routine use of EPDs in TAVR to prevent stroke.

(Neel Butala, MD, Division of Cardiology, Department of Medicine)


HOUSEHOLD COVID-19 INFECTION RISK
Household Transmission of SARS-CoV-2
Metlay JP, Haas JS, Soltoff AE, Armstrong KA
Published in JAMA Network Open on February 26, 2021

SARS-CoV-2 has resulted in an unprecedented level of global morbidity and mortality. The primary mode of transmission of SARS-CoV-2 is person to person via respiratory droplets. While much attention has focused on transmission in schools, workspaces and public venues, an important amount of transmission occurs in homes. In this study, we linked patients based on their address in our electronic medical records in order to measure the risk that a COVID-19 patient would transmit the infection to someone else living at the same address. The overall risk of household transmission was 10% but was significantly higher for certain household members, including those with diabetes, cardiovascular disease, and cancer.

(Summary submitted by Joshua Metlay, MD, PhD, Division of General Internal Medicine, Department of Medicine)


Press Releases

Novel Software Tool Facilitates Inclusion of Individuals of Diverse Ancestry in Large-scale Genetics Studies
Featuring Elizabeth Atkinson, PhD

Researchers at Mass General, the Broad Institute of MIT and Harvard, and other institutions around the world have now developed a free-access software package called Tractor that increases the discovery power of genomics in understudied populations.


Automated Imaging Detects and Tracks Brain Protein Involved in Alzheimer's Disease
Featuring Justin Sanchez

A team led by investigators at Mass General has now developed an automated method that can identify and track the development of harmful tau deposits in a patient’s brain, which could lead to earlier diagnoses of Alzheimer’s disease.


Preventive Anti-clotting Therapy Does Not Improve Survival of Critically Ill Adults with COVID-19
Featuring Hanny Al-Samkari, MD

Although abnormal blood clotting has been identified as one of the primary causes of death from COVID-19, early treatment in an intensive care unit with therapeutic anticoagulation for adults does not appear to improve chances of survival and could do more harm than good by increasing the risk for major bleeding, a multicenter research group cautions.


Electronic Health Records Can Be a Valuable Predictor of Those Likeliest to Die from COVID-19
Featuring Hossein Estiri, PhD

Medical histories of patients collected and stored in electronic health records can be rapidly leveraged to predict the probability of death from COVID-19, information that could prove valuable in managing limited therapeutic and preventive resources to combat the devastating virus.


Study Reveals How Air Pollution May Increase the Risk of Cardiovascular Disease
Featuring Michael Osborne, MD

New research led by investigators at Mass General reveals that fine particulate matter has a detrimental impact on cardiovascular health by activating the production of inflammatory cells in the bone marrow, ultimately leading to inflammation of the arteries.


Artificial Intelligence Model Bests Previous Methods in Predicting Breast Cancer Risk
Featuring Constance "Connie" Lehman, MD, PhD

Investigators at MIT and Mass General have collaborated to develop a new AI model to predict a woman’s future risk of breast cancer based on her mammogram alone and performed validation trials in patient populations in Europe and Asia.


The Science of Siestas: New Research Reveals the Genetic Basis for Daytime Napping
Featuring Hassan S. Dashti, PhD, RD

How often a person takes daytime naps, if at all, is partly regulated by their genes, according to new research led by investigators at Mass General.


New Tool Helps Clinicians Assess Patients Who Develop COVID-19 Symptoms
Featuring Emily Hyle, MD, and Erica Shenoy, MD, PhD

A team led by investigators at Mass General has now created a tool to guide frontline clinicians through diagnostic evaluations of such patients so that they’ll know when it’s safe to discontinue precautions.


Exhaled Respiratory Droplets Increase in Number with the Onset of COVID-19 Infection—and with Aging and Obesity
Featuring Dennis Ausiello, MD

Researchers from Harvard University, Tulane University, MIT and Mass General found that a critical factor in super spreader and other transmission events is the propensity of certain individuals to exhale large numbers of small respiratory droplets. The researchers found that age, obesity and COVID-19 infection all correlate with a propensity to breathe out more respiratory droplets.


Ragon and BWH Researchers Collaborate with SpaceX to Identify Humoral Immune Features Which May Track with Lasting Protection Against Sars-cov-2
Featuring Galit Alter, PhD

This study found that while antibodies against SARS-CoV-2 may be a good way to measure exposure to the virus, their presence alone wasn’t enough to determine if a person had long-lasting protection.


Cosmetic Laser May Boost Effectiveness of Certain Anti-Cancer Therapies
Featuring David E. Fisher, MD, PhD

Use of a cosmetic laser invented at Mass General may improve the effectiveness of certain anti-tumor therapies and extend their use to more diverse forms of cancer.


Antibody Response May Drive COVID-19 Outcomes
Featuring Galit Alter, PhD, and Lael Yonker, MD

Discovering how the immune system’s response shapes the disease and its outcome in both children and adults can help researchers develop treatments that can prevent or modulate the immune response, keeping its protective functions but lessening the unintentional, yet harmful, ones.


New Insights on How Inflammatory Molecule Contributes to Skin and Pancreatic Cancers
Featuring Shawn Demehri, MD, PhD

Investigators at Mass General who previously demonstrated high expression levels of an immune molecule called interleukin-33 (IL-33) during cancer-promoting inflammation have now uncovered the details behind the molecule’s effects.


What to Do When a Mammogram Reveals Swollen Lymph Nodes in Women Recently Vaccinated for COVID-19
Featuring Helen D'Alessandro, MD, Leslie Lamb, MD, MSc, and Connie Lehman, MD, PhD

Swelling of lymph nodes in the armpit area is a normal response to COVID-19 vaccinations, but when they are seen on mammograms, they can be mistaken for nodes that are swollen because of cancer. Radiologists at Mass General have published an approach to manage what is expected to be a fairly common occurrence as vaccination programs ramp up to help patients and avoid delays in cancer treatments.


Two New Models Boost Accuracy in Assessing Which COVID-19 Patients Face the Greatest Risk of Mechanical Ventilation and Death
Featuring Rajeev Malhotra, MD, MS

Two novel calculators for predicting which patients admitted to the hospital with COVID-19 are at greatest risk of requiring mechanical ventilation or of in-hospital death have been developed and validated by Mass General.


Blog Posts

Nursing Research Day Highlights Opportunities to Improve Patient Care

Short summaries of the winning abstracts from the 2020 Nursing Research Day at the Yvonne L. Munn Center for Nursing Research.


Nurse Researcher Seeks a Better Way to Identify Signs of Pain in Preterm Infants
Featuring Kim Francis, PhD, RN, PHCNS-BC

Dr. Francis and team are investigating how changes in facial temperature could be connected to facial expressions associated with pain in premature infants. The goal is to find a more objective way to assess and relieve pain.


Humans of MGRI: Ishan Bhatia, BA

Profile of Ishan Bhatia, BA, a research technician in Dr. Nitya Jain’s group at the Mucosal Immunology and Biology Research Center (MIBRC).


Mass General Honors Black History Month 2021

Events and resources for Black History Month 2021 at Mass General.


Heart Month 2021: Spotlighting Mass General Cardiology Researchers
Featuring Sawalla Guseh, MD, Michael Honigberg, MD, MPP, and Judy Hung, MD

Since every February is dedicated to heart health awareness, we reached out to some of our cardiology researchers to see what they’re currently working on.


Mass General-MIT Team Create an Online COVID-19 Testing Calculator for Schools and Businesses
Featuring Paul Tessier

A team from Mass General and Massachusetts Institute of Technology (MIT) has created a free online tool to help organizations calculate the costs and benefits of different COVID-19 testing and mitigation strategies.


ICON Center Explores How Essential Connections Between the Heart and the Brain Differ by Sex
Featuring Jill M. Goldstein, PhD

Jill M. Goldstein, PhD, founder and executive director of the Innovation Center on Sex Differences in Medicine (ICON) and the Helen T. Moershner Endowed MGH Research Institute Chair in Women’s Health, is focused on understanding sex differences in the shared causes of disorders of the heart and brain.


Humans of MGRI: Shannon Stratton, BFA
Featuring Shannon Stratton, BFA

Profile of Shannon Stratton, BFA, a grant administrator in the Center for Genomic Medicine.


Spotlight on Rare Disease Research at Massachusetts General Hospital
Featuring Alexander Marneros, MD, PhD, and Susan Cotman, PhD

Rare Disease Day takes place on the last day of February each year to raise awareness about rare diseases and their impact on patients’ lives.