Snapshot of Science for April 2022

Welcome to our Snapshot of Science for April 2022.

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:

43 new studies published in high-impact journals, along with 43 summaries submitted by the research teams
16 new research-related press releases from the Mass General Public Affairs office
5 posts from the Mass General Research Institute blog

Publications

Women With Infertility Are at Greater Risk of Developing Heart Failure
Infertility and Risk of Heart Failure in the Women’s Health Initiative
Lau ES, Wang D, Roberts M, Taylor CN, Murugappan G [et al.], Ho JE
Published in Journal of the American College of Cardiology on Tuesday, April 26, 2022 | *Summary available | Press Release

Two Very Similar Proteins Regulate the Function of Two Distinct Segments of the Distal Nephron
Transcription Factors AP-2α and AP-2β Regulate Distinct Segments of the Distal Nephron in the Mammalian Kidney
Lamontagne JO, Zhang H, Zeid AM, Strittmatter K, Rocha AD [et al.], Marneros AG
Published in Nature Communications on Monday, April 25, 2022 | *Summary available | Press Release

Shared Immune Pathways Between Coronary Artery Disease and Pneumonia
Genome-wide Pleiotropy Analysis of Coronary Artery Disease and Pneumonia Identifies Shared Immune Pathways
Yu Z, Zekavat SM, Haidermota S, Bernardo R, MacDonald BT [et al.], Natarajan P
Published in Science Advances on Friday, April 22, 2022 | *Summary available

Liquid Biopsy for Pancreatic Cancer
Single-EV Analysis (sEVA) of Mutated Proteins Allows Detection of Stage 1 Pancreatic Cancer
Ferguson S, Yang KS, Zelga P, Liss AS, Carlson JCT, Del Castillo CF, Weissleder R
Published in Science Advances on Friday, April 22, 2022 | *Summary available

New CAR T Design to Attack Acute Myeloid Leukemia
Non-Cleavable Hinge Enhances Avidity and Expansion of CAR-T Cells for Acute Myeloid Leukemia
Leick MB, Silva H, Scarfò I, Larson R, Choi BD [et al.], Maus MV
Published in Cancer Cell on Thursday, April 21, 2022 | *Summary available | Press Release

Potential Pathway to Show Origins of Life
Freeze-Thaw Cycles Enable a Prebiotically Plausible and Continuous Pathway From Nucleotide Activation to Nonenzymatic RNA Copying
Zhang SJ, Duzdevich D, Ding D, Szostak JW
Published in PNAS on Thursday, April 21, 2022 | *Summary available

Considerations for a Clinical Competency Committee
Reimagining the Clinical Competency Committee to Enhance Education and Prepare for Competency-based Time-variable Advancement
Goldhamer MEJ, Martinez-Lage M, Black-Schaffer WS, Huang JT, Co JPT, Weinstein DF, Pusic MV
Published in Journal of General Internal Medicine on Wednesday, April 20, 2022 | *Summary available

New Drug for Patients With Pyruvate Kinase Deficiency
Mitapivat Versus Placebo for Pyruvate Kinase Deficiency
Al-Samkari H, Galactéros F, Glenthøj A, Rothman JA [et al.], van Beers EJ; ACTIVATE Investigators
Published in New England Journal of Medicine on Thursday, April 14, 2022 | *Summary available | Press Release

Rilzabrutinib for Blood Disorder Shows Promise in Phase 1–2 Clinical Trial
Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia
Kuter DJ, Efraim M, Mayer J, Trněný M, McDonald V [et al.], Cooper N
Published in New England Journal of Medicine on Thursday, April 14, 2022 | *Summary available | Press Release

Use of CAR T-Cells to Treat Primary Central Nervous System Lymphoma
Safety and Efficacy of Tisagenlecleucel in Primary CNS Lymphoma: A Phase 1/2 Clinical Trial
Frigault MJ, Dietrich J, Gallagher K, Roschewski M, Jordan JT [et al.], Chen YB
Published in Blood on Thursday, April 14, 2022 | *Summary available

CAR T-Cells Need to Be Sticky to Treat Solid Tumors
CAR T Cell Killing Requires the IFNγR Pathway in Solid But Not Liquid Tumours
Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM [et al.], Maus MV
Published in Nature on Wednesday, April 13, 2022 | *Summary available

Behavior of Extracellular Vesicle-Encapsulated Cargo
Uptake, Functionality, and Re-Release of Extracellular Vesicle-Encapsulated Cargo
O'Brien K, Ughetto S, Mahjoum S, Nair AV, Breakefield XO
Published in Cell Reports on Tuesday, April 12, 2022 | *Summary available

New Clinical Trial for Non-Small Cell Lung Cancer
Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data From Patients With KRASG12C-Mutant Non-Small Cell Lung Cancer
Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS [et al.], Wakimoto H
Published in Clinical Cancer Research on Monday, April 11, 2022 | *Summary available

Genetic Underpinnings of Bipolar Disorder Identified in AKAP11
Exome Sequencing in Bipolar Disorder Identifies AKAP11 as a Risk Gene Shared With Schizophrenia
Palmer DS, Howrigan DP, Chapman SB, Adolfsson R, Bass N [et al.], Neale BM
Published in Nature Genetics on Monday, April 11, 2022 | *Summary available

Risk Variants for Schizophrenia in Ten Genes
Rare Coding Variants in Ten Genes Confer Substantial Risk for Schizophrenia
Singh T, Poterba T, Curtis D, Akil H, Al Eissa M [et al.], Daly MJ
Published in Nature on Friday, April 8, 2022 | *Summary available

Less Experienced Physicians Have Lower First-Pass Success Rate and Higher Adverse Event Rate Performing Tracheal Intubation
Association of Number of Physician Postgraduate Years With Patient Intubation Outcomes in the Emergency Department
Goto T, Oka S, Okamoto H, Hagiwara Y, Watase H, Hasegawa K
Published in JAMA Network Open on Friday, April 8, 2022 | *Summary available

A Healthy Virome Is Protective but an Altered Virome Autonomously Drives Disease
Human Enteric Viruses Autonomously Shape Inflammatory Bowel Disease Phenotype Through Divergent Innate Immunomodulation
Adiliaghdam F, Amatullah H, Digumarthi S, Saunders TL, Rahman RU [et al.], Jeffrey KL
Published in Science Immunology on Friday, April 8, 2022 | *Summary available | Press Release

Common Genetic Variation May Cause QT Interval Prolongation
Monogenic and Polygenic Contributions to QTc Prolongation in the Population
Nauffal V, Morrill VN, Jurgens SJ, Choi SH, Hall AW [et al.], Lubitz SA
Published in Circulation on Thursday, April 7, 2022 | *Summary available

AI Able to Accurately Label Chest X-Ray Images
Accurate Auto-labeling of Chest X-Ray Images Based on Quantitative Similarity to an Explainable AI Model
Kim D, Chung J, Choi J, Succi MD, Conklin J [et al.], Do S
Published in Nature Communications on Wednesday, April 6, 2022 | *Summary available

Mutation in STAG2 Leads to Cancer
STAG2 Regulates Interferon Signaling in Melanoma via Enhancer Loop Reprogramming
Chu Z, Gu L, Hu Y, Zhang X, Li M [et al.], Zheng B
Published in Nature Communications on Wednesday, April 6, 2022 | *Summary available

Potential Causal Relationships Across CHIP and LTL Toward Preventing CAD
Mendelian Randomization Supports Bidirectional Causality Between Telomere Length and Clonal Hematopoiesis of Indeterminate Potential
Nakao T, Bick AG, Taub MA, Zekavat SM, Uddin MM [et al.] Natarajan P
Published in Science Advances on Wednesday, April 6, 2022 | *Summary available

Repurposed Cancer Drug May Be Used as Contraceptive
A Screen of Repurposed Drugs Identifies AMHR2/MISR2 Agonists as Potential Contraceptives
Li Y, Wei L, Meinsohn MC, Suliman R, Chauvin M [et al.], Pepin D
Published in PNAS on Tuesday, April 5, 2022 | *Summary available

Greater Tau Burden Associated With Early-Onset Alzheimer’s Disease
Amyloid-β and Tau Pathologies Relate to Distinctive Brain Dysconnectomics in Preclinical Autosomal-dominant Alzheimer's Disease
Guzmán-Vélez E, Diez I, Schoemaker D, Pardilla-Delgado E, Vila-Castelar C [et al.], Quiroz YT
Published in PNAS on Tuesday, April 5, 2022 | *Summary available | Press Release

Starting Multikinase Inhibitor Treatment Sooner Leads to Longer Survival in Advanced Thyroid Cancer
Impact of Baseline Tumor Burden on Overall Survival in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer Treated With Lenvatinib in the SELECT Global Phase 3 Trial
Kiyota N, Tahara M, Robinson B, Schlumberger M, Sherman SI [et al.], Wirth LJ
Published in Cancer on Tuesday, April 5, 2022 | *Summary available

Unique Patterns of tRNAs Generated by Stress on Cells
Distinct Stress-dependent Signatures of Cellular and Extracellular tRNA-derived Small RNAs
Li G, Manning AC, Bagi A, Yang X, Gokulnath P [et al.], Das S
Published in Advanced Science on Monday, April 4, 2022 | *Summary available | Press Release

Certain Subtypes of Hydrocephalus May Be Caused by Abnormal Neurodevelopment
Impaired Neurogenesis Alters Brain Biomechanics in a Neuroprogenitor-based Genetic Subtype of Congenital Hydrocephalus
Duy PQ, Weise SC, Marini C, Li XJ, Liang D [et al.], Kahle KT
Published in Nature Neuroscience on Monday, April 4, 2022 | *Summary available | Press Release

Most Seizures End Synchronously
Quantifying Seizure Termination Patterns Reveals Limited Pathways to Seizure End
Salami P, Borzello M, Kramer MA, Westover MB, Cash SS
Published in Neurobiology of Disease on Friday, April 1, 2022 | *Summary available

Simulation Study Predicts COVID-19 Deaths Will Rebound After Relaxing Restrictions
Projecting COVID-19 Mortality as States Relax Nonpharmacologic Interventions
Linas BP, Xiao J, Dalgic OO, Mueller PP, Adee M [et al.], Chhatwal J
Published in JAMA Health Forum on Friday, April 1, 2022 | *Summary available | Press Release

Radiation Oncology Involvement in Lung Cancer Screening Increases Access to Safe and Effective Oncologic Care
Incidence of Radiation Therapy Among Patients Enrolled in a Multidisciplinary Pulmonary Nodule and Lung Cancer Screening Clinic
Milligan MG, Lennes IT, Hawari S, Khandekar MJ, Colson Y [et al.], Keane FK
Published in JAMA Network Open on Thursday, March 31, 2022 | *Summary available

Lung Cancer Diagnosed Earlier, but Not in Minority Patients
Association of Computed Tomography Screening With Lung Cancer Stage Shift and Survival in the United States: Quasi-experimental Study
Potter AL, Rosenstein AL, Kiang MV, Shah SA, Gaissert HA [et al.], Yang CJ
Published in BMJ on Wednesday, March 30, 2022 | *Summary available

Changes in Vaginal Microbiota in Postmenopausal People
Impact of Topical Interventions on the Vaginal Microbiota and Metabolome in Postmenopausal Women: A Secondary Analysis of a Randomized Clinical Trial
Srinivasan S, Hua X, Wu MC, Proll S, Valint DJ [et al.], Mitchell CM
Published in JAMA Network Open on Wednesday, March 30, 2022 | *Summary available

Physiology and Pharmacology of GABA_A Receptors
Differential Assembly Diversifies GABA_A Receptor Structures and Signaling
Sente A, Desai R, Naydenova K, Malinauskas T, Jounaidi Y [et al.], Aricescu AR
Published in Nature on Wednesday, March 30, 2022 | *Summary available

Differences in COVID-19 Vaccines Provide Options for Future Vaccine Development
mRNA-1273 and BNT162b2 COVID-19 Vaccines Elicit Antibodies With Differences in Fc-mediated Effector Functions
Kaplonek P, Cizmeci D, Fischinger S, Collier AR, Suscovich T [et al.], Alter G
Published in Science Translational Medicine on Tuesday, March 29, 2022 | *Summary available

Injectable Hydrogels Improve Iron Chelation Therapy of Nanochelators
Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators
Park SH, Kim RS, Stiles WR, Jo M, Zeng L [et al.], Choi HS
Published in Advanced Science on Sunday, March 27, 2022 | *Summary available

A Robust Animal Model for Hereditary Spastic Paraplegia
Transverse Endoplasmic Reticulum Expansion in Hereditary Spastic Paraplegia Corticospinal Axons
Zhu PP, Hung HF, Batchenkova N, Nixon-Abell J, Henderson J [et al.], Blackstone C
Published in Human Molecular Genetics on Saturday, March 26, 2022 | *Summary available

New Opportunities for the Study of Human Brain Pathways
Tracing Modification to Cortical Circuits in Human and Non-Human Primates from High Resolution Tractography, Transcription, and Temporal Dimensions
Charvet CJ, Ofori K, Baucum C, Sun J, Modrell MS [et al.], van der Kouwe AJ
Published in The Journal of Neuroscience on Thursday, March 24, 2022 | *Summary available

Cancer Drug Helps Prevent ALL Relapse
Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation for B-Lineage Acute Lymphoblastic Leukemia
Gaballa MR, Banerjee P, Milton DR, Jiang X, Ganesh C [et al.], Kebriaei P
Published in Blood on Thursday, March 24, 2022 | *Summary available

3TC Treatment in Metastatic Colorectal Cancer
Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer
Rajurkar M, Parikh AR, Solovyov A, You E, Kulkarni AS [et al.], Ting DT
Published in Cancer Discovery on Wednesday, March 23, 2022 | *Summary available | Press Release

Route to Understand Differences in the Brain Cell Types That Underlie the Different Symptoms of HD
Genetic Modifiers of Huntington Disease Differentially Influence Motor and Cognitive Domains
Lee JM, Huang Y, Orth M, Gillis T, Siciliano J [et al.], Gusella JF
Published in American Journal of Human Genetics on Wednesday, March 23, 2022 | *Summary available

A Model for the Paradoxical Association of Repressor Proteins to Active Genes
Unveiling RCOR1 as a Rheostat at Transcriptionally Permissive Chromatin
Rivera C, Lee HG, Lappala A, Wang D, Noches V [et al.], Andrés ME
Published in Nature Communications on Wednesday, March 23, 2022 | *Summary available

Lower Brain Activity in Locus Coeruleus Could Lead to Alzheimer's Disease
Lower Novelty-related Locus Coeruleus Function Is Associated With Aβ-related Cognitive Decline in Clinically Healthy Individuals
Prokopiou PC, Engels-Domínguez N, Papp KV, Scott MR, Schultz AP [et al.], Jacobs HIL
Published in Nature Communications on Wednesday, March 23, 2022 | *Summary available

Major Depressive Symptoms and Gun Ownership
Prevalence of Firearm Ownership Among Individuals With Major Depressive Symptoms
Perlis RH, Simonson MD, Green J, Lin J, Safarpour A [et al.], Baum MA
Published in JAMA Network Open on Monday, March 21, 2022 | *Summary available

Publication Summaries

Infertility affects nearly one in five U.S. women, but its link with heart failure has not been well studied. Using data from 38,528 women enrolled in the Women’s Health Initiative, we found that women with infertility were at greater risk of developing heart failure, specifically heart failure with preserved ejection fraction, a form of heart failure that is more common among women. Traditional cardiovascular risk factors or other infertility-related conditions did not explain this relationship. These findings highlight the importance of asking a woman about her reproductive history when assessing her risk of developing heart failure and heart disease.

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

The distal nephron is particularly important for the ability of the kidney to concentrate urine, regulate blood pressure, and control calcium and magnesium blood levels. How the development and function of specific segments of the distal nephron are regulated on a molecular level remains poorly understood. Here, it is shown that two very similar proteins, the transcription factors AP-2α and AP-2β, regulate the function of two distinct segments of the distal nephron in mice. While AP-2β function in the kidney is required for survival by regulating the development and function of distal convoluted tubules, AP-2α is important for the proper function of a different segment of the distal nephron, called the collecting duct, which is involved in the kidney’s ability to concentrate urine.

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

Coronary artery disease (CAD) and acute respiratory infections have a high co-occurrence rate, providing an opportunity to examine shared mechanisms. Using summary statistics from GWAS for CAD, and pneumonia and individual data from participants in the UK Biobank, we conducted a genome-wide scan and zeroed in on ADAMTS7, IL6R, and related genes. We found that increased ADAMTS7 expression was linked to decreased risk for CAD but increased risk for pneumonia; IL6R showed the opposite. These findings provide new insights into reducing CAD risk via immune modulation and emphasize the need for careful prioritization of therapeutic targets.

(Summary submitted by Zhi Yu, PhD, Broad Institute)

Pancreatic cancers are often hard to detect until it is too late. One of the reasons is that there are no sensitive or specific blood tests for early pancreatic cancer. We describe a new liquid biopsy method (sEVA). The technique accurately tests for tumor-shed vesicles by analyzing every vesicle in a blood sample. Preliminary feasibility studies showed that sEVA detected 15/16 stage 1 pancreatic cancer cases at Mass General. The single vesicle detection method has the potential to transform early pancreatic cancer research and clinical practice.

(Summary submitted by Scott Ferguson, PhD, Center for Systems Biology)

Acute myeloid leukemia (AML) is a highly aggressive cancer and the most common acute leukemia in adults. Chimeric antigen receptor (CAR) T-cell therapy, in which the patient’s own immune cells are collected, given new DNA to attack the tumor, and reinfused into the patient, has been tremendously successful in other blood cancers, with seven FDA approvals in the last few years. Targeting AML has been more challenging. Here we optimize a new CAR T design to attack an AML-specific target, CD70, and show synergy with a drug that is already used in the treatment of AML, azacitidine. We discovered a flaw in the previous design that resulted in the CARs getting cleaved at the surface of the T cells, rendering them ineffective; our new design overcomes this flaw and makes the CARs more stable and effective in eliminating AML in mice. This is a readily translatable strategy that could be brought to patients and have significant impact.

(Summary submitted by Marcela Maus, MD, PhD, Division of Hematology/Oncology, Department of Medicine, Mass General Cancer Center)

The replication of RNA without the aid of evolved enzymes may have enabled the inheritance of useful molecular functions during the origin of life. Several key steps on the path to RNA replication have been studied in isolation, including chemical nucleotide activation, synthesis of a key reactive intermediate and nonenzymatic RNA copying. Here we report a prebiotically plausible scenario under which these reactions can happen together under mutually compatible conditions. Thus, this pathway could potentially have operated in nature without the complicating requirement for exchange of materials between distinct environments.

(Summary submitted by Jack W. Szostak, PhD, Department of Molecular Biology)

The Clinical Competency Committee (CCC) is a key mechanism for ensuring that residency programs meet or exceed competency standards for each resident. We propose a “Bow-tie” model for the CCC process to ensure the developmental assessment of all residents. These ideas were generated through work on a pilot project at Mass General Brigham, which is one of a handful of institutions in the country piloting competency-based time-variable graduate medical education, where graduation from residency is based on demonstration of competence rather than completion of a fixed duration of training. This article describes the revised processes and considerations for CCCs to make fine-tuned decisions about readiness for graduation and unsupervised practice based on each individual resident's competency. It emphasizes the importance of focusing on each trainee’s developmental trajectory to individualize education and emphasizes that each resident should cultivate the ability to self-assess—a skill critical to life-long learning.

(Summary submitted by Mary Ellen J. Goldhamer MD, MPH, Department of Medicine)

New Drug Approved for Patients With Pyruvate Kinase Deficiency
Mitapivat Versus Placebo for Pyruvate Kinase Deficiency
Al-Samkari H, Galactéros F, Glenthøj A, Rothman JA [et al.], van Beers EJ; ACTIVATE Investigators
Published in New England Journal of Medicine on Thursday, April 14, 2022

Pyruvate kinase deficiency is a lifelong, debilitating hereditary blood disorder characterized by reduced energy in red blood cells, causing them to break up prematurely in the bloodstream, and causing anemia and complications in many organs including the liver, heart, and bones. In this global clinical trial, a brand-new medication called mitapivat that works by increasing energy in red blood cells was compared with placebo in patients with pyruvate kinase deficiency. Mitapivat was highly effective in reducing red cell breakdown and improving or eliminating anemia in patients with pyruvate kinase deficiency compared with placebo (which, as expected, had no significant effect). As a result of this work, the FDA approved mitapivat as the very first treatment for pyruvate kinase deficiency.

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

In people with immune thrombocytopenia (ITP), the body produces destructive antibodies against platelets that reduces their numbers in the blood and increases the risk of bruising, bleeding, hospitalization, death, fatigue, and an impaired quality of life. In an international phase 1–2 clinical trial of patients with immune thrombocytopenia, an oral investigational drug called rilzabrutinib was effective in raising the platelet count and associated with only low-level toxic effects at all dose levels. Additional clinical trials are underway to verify that rilzabrutinib can safely boost platelet levels in patients with this autoimmune disease characterized by an increased risk of bleeding.

(Summary submitted by David J. Kuter, MD, DPhil, Division of Hematology/Oncology, Department of Medicine, Mass General Cancer Center)

Primary central nervous system lymphoma (PCNSL) is a rare but aggressive disease that can affect any part of the brain or central nervous system. Despite optimal management with high-dose chemotherapy, most patients have disease progression that is associated with poor survival. Immunotherapies with CAR T-cells have shown impressive results in patients with lymphoma but have not been studied in PCNSL. We here report the first prospective clinical trial of using CAR T-cells in PCNSL. Treatment was safe and well tolerated and most patients showed a response to therapy, with a subset of patients with complete remission, paving the path for a novel and promising therapy option in this challenging disease.

(Summary submitted by Matthew J. Frigault, MD, Mass General Cancer Center)

CAR T-Cells Need to be Sticky to Treat Solid Tumors
CAR T Cell Killing Requires the IFNγR Pathway in Solid But Not Liquid Tumours
Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM [et al.], Maus MV
Published in Nature on Wednesday, April 13, 2022

CAR T-cell therapy uses cancer patients’ immune cells and reprograms them to attack their tumor. This study asked why CAR T-cells are so successful in treating patients with liquid tumors (like leukemia and lymphoma) but haven’t worked as well yet in solid tumors (like brain and pancreatic cancer). We discovered that a protein secreted by CAR T-cells, interferon gamma, was necessary for killing solid tumors but not liquid tumors, and the way it worked was by making the T cells stickier to the solid tumors. Liquid tumors didn’t need the interferon gamma to be killed by CAR T-cells. This is important because it suggests that T cells kill tumor cells in different ways, and that making them stickier may be helpful for solid tumors.

(Summary submitted by Marcela Maus, MD, PhD, Division of Hematology/Oncology, Department of Medicine, Mass General Cancer Center)

Extracellular Vesicle-Encapsulated Cargo Behavior
Uptake, Functionality, and Re-Release of Extracellular Vesicle-encapsulated Cargo
O'Brien K, Ughetto S, Mahjoum S, Nair AV, Breakefield XO
Published in Cell Reports on Tuesday, April 12, 2022

This paper studies the paths of extracellular vesicles (EVs) upon entering recipient cells. EVs are naturally secreted nanoparticles that are widely studied for their promise as therapeutic delivery vehicles and in this paper, we show that EVs can deliver cargo in a functional manner. However, we also demonstrate that EVs can be rendered “non-functional” when the cell retains them in compartments for up to 24 hours. Most interestingly though, we also provide evidence for EVs and their cargo being released back out of the cells. Overall, this study shows the many fates of EVs in the recipient cell, from functional delivery to being re-released.

(Summary submitted by Killian O'Brien, PhD, Department of Neurology)

New Clinical Trial Design for Non-Small Cell Lung Cancer
Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data From Patients With KRASG12C-Mutant Non-Small Cell Lung Cancer
Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS [et al.], Wakimoto H
Published in Clinical Cancer Research on Monday, April 11, 2022

Effective treatments are lacking for patients with non-small cell lung cancer (NSCLC) that has metastasized to the brain. In this collaborative work with Mirati Therapeutics and NYU, we showed that over 40% of patients with KRAS-mutant NSCLC developed brain metastasis. The KRAS-G12C specific inhibitor adagrasib mediated tumor regression and extended survival in multiple preclinical models of brain metastasis. Furthermore, we present clinical evidence of CSF penetration and intracranial activity in two patients with KRAS-G12C NSCLC brain metastasis. This work has paved the way for the design of a national clinical trial testing adagrasib for patients with KRAS-G12C mutant brain metastases (Alliance #A071701).

(Summary submitted by Hiroaki Wakimoto, MD, PhD, Brain Tumor Stem Cell Lab, Department of Neurosurgery)

An international collaborative effort to identify the genetic underpinnings of bipolar disorder has identified loss of function mutations in AKAP11 as a strong risk factor. These mutations are exceedingly rare, occurring at a rate of approximately one in ten thousand in population surveys of genetic variation but are found at about a rate of one in a thousand in individuals with bipolar disorder. The protein product of AKAP11 has been shown to bind to GSK3-beta, the hypothesized target of lithium therapy, one of the few approved treatments for bipolar disorder. AKAP11 mutations are also seen at a higher rate in individuals diagnosed with schizophrenia suggesting that rare coding risk variants may follow a similar pattern of sharing between these two disorders as has been documented for common genetic influences.

(Summary submitted by Ben Neale, PhD, Analytical and Translational Genetic Unit, Center for Genomic Medicine)

Schizophrenia is a severe and debilitating psychiatric disorder with a notable genetic component. By analyzing the whole exomes of 24,248 individuals with schizophrenia and 97,322 without, we identify ultra-rare protein-coding variants in 10 genes as conferring substantial risk for schizophrenia, with effects that range from 3- to 50-fold. These genes have diverse functions in the brain that include the formation, structure, and function of the synapse. Two genes encode components of glutamate receptor complexes. We find that some genetic signal is shared with other neurodevelopmental disorders, while some genes are uniquely associated with schizophrenia. Using the approach in our study, many more risk genes for schizophrenia await discovery.

(Summary submitted by Tarjinder Singh, PhD, Analytic and Translational Genetics Unit, Center for Genomic Medicine)

Less Experienced Physicians Have Lower First-pass Success Rate and Higher Adverse Event Rate Performing Tracheal Intubation
Association of Number of Physician Postgraduate Years With Patient Intubation Outcomes in the Emergency Department
Goto T, Oka S, Okamoto H, Hagiwara Y, Watase H, Hasegawa K
Published in JAMA Network Open on Friday, April 8, 2022

In the emergency department (ED), critically ill patients often require airway management, including tracheal intubation. Tracheal intubation is frequently performed by trainees, such as resident physicians, under supervision. However, in this study of 11,297 patients in Japan, we found that tracheal intubations performed by a resident physician had a significantly lower first-pass success rate and higher adverse event rate compared with those by attending physicians. The +20% lower success rate by postgraduate year-1 physicians observed here is not acceptable for ED patients. Our findings underscore the importance of improving both resident training and current airway management strategies for critically ill patients in the ED.

(Summary submitted by Tadahiro Goto, MD, Department of Clinical Epidemiology and Health Economics, School of Public Health, University of Tokyo)

Billions of viruses perpetually reside within healthy people, particularly in the intestine (i.e., the virome). Perturbations in this virome are observed in disease, including inflammatory bowel disease (IBD) but we were stalled at correlations. Our work found that viruses enriched from normal colon tissue elicited anti-inflammatory immune responses and were protective to the gut. In contrast, the collective viruses isolated from colon resections post-surgery of ulcerative colitis or Crohn’s disease patients actively provoked inflammation and intestinal damage. Both scenarios were dependent on the host innate immune system. Thus, our work demonstrates that a healthy virome is protective but an altered virome autonomously drives disease, revealing a new biomarker and therapeutic strategy for IBD.

(Summary submitted by Kate Jeffrey, PhD, Division of Immunology, Department of Medicine)

Disparities in U.S. Medical Faculty Persist
Intersectional Analysis of U.S. Medical Faculty Diversity Over Four Decades
Kamran SC, Winkfield KM, Reede JY, Vapiwala N.
Published in New England Journal of Medicine on Thursday, April 7, 2022 | *Summary available

The United States is becoming more racially and ethnically diverse every day, but those changes are not reflected in the makeup of clinical faculty and leadership of medical schools in this country. Our analysis of full-time faculty in 18 clinical academic departments over 42 years found some positive trends, most notably for women, but the overall picture suggests that U.S. academic medical programs must not only recruit more underrepresented clinical faculty candidates, but also find ways to support them throughout the academic pipeline to build diversity at leadership levels in medicine.

(Summary submitted by Sophia Kamran, MD, Department of Radiation Oncology, Mass General Cancer Center)

Common Genetic Variation May Cause QT Interval Prolongation

Monogenic and Polygenic Contributions to QTc Prolongation in the Population
Nauffal V, Morrill VN, Jurgens SJ, Choi SH, Hall AW [et al.], Lubitz SA
Published in Circulation on Thursday, April 7, 2022

Rare genetic variation causes the long QT syndrome but the contributions of rare genetic variation to QT interval duration in the general population is unclear. We studied ~28,000 individuals with paired whole genome sequencing data and electrocardiograms from the Trans-Omics for Precision Medicine Program (TOPMed). We identified a rare genetic cause in 3.4% of individuals with pronounced QT prolongation (QTc>480 milliseconds). In contrast, a high value for a polygenic risk score comprising 1,110,494 common genetic variants was present in 21% of individuals with pronounced QT prolongation. These findings imply that assessment for common genetic variation may be warranted when testing for genetic causes of QT interval prolongation in the future.

(Summary submitted by Victor D. Nauffal, MD, Brigham and Women's Hospital)

AI Able to Accurately Labe Chest X-Ray Images
Accurate Auto-labeling of Chest X-Ray Images Based on Quantitative Similarity to an Explainable AI Model
Kim D, Chung J, Choi J, Succi MD, Conklin J [et al.], Do S
Published in Nature Communications on Wednesday, April 6, 2022

The inability to accurately, efficiently label large, open-access medical imaging datasets limits the widespread implementation of artificial intelligence (AI) models in healthcare. There have been few attempts, however, to automate the annotation of such public databases. Here we: (1) developed and demonstrated a generalizable method for automated labeling of five different CXR imaging features at a user selected, quantitative level of confidence, and (2) showed that, by retraining the original model using the automatically labeled exams, performance could be preserved or improved. These results were accomplished by human expert annotation of only 100 exams, suggesting the approach may provide highly accurate labels, regardless of the size of the open-source database studied, and could reduce the need for labor-intensive manual labeling by human experts.

(Summary submitted by Michael H. Lev, MD. FAHA. FACR, Department of Radiology, Vascular Center)

The human genome is folded within the nucleus in a highly organized fashion to allow proper regulation of gene expression. The tumor suppressor STAG2, which generates DNA loops and participates in this 3D organization of the genome, is frequently mutated in cancers. But how the loss of STAG2 contributes to cancer is mostly unknown. In this study, we showed that STAG2 regulates the 3D genome organization and proper expression of IRF9, a key player in an immune signaling pathway that helps cancer cells evade the immune system’s attack in the body. This immune evasion of cancer cells that lose STAG2 may explain why a mutation in STAG2 leads to cancer. Moreover, our findings also suggest that mutations in STAG2 could be used as a biomarker to guide the selection of cancer patients for immune checkpoint blockade therapies.

(Summary submitted by Bin Zheng, PhD, Cutaneous Biology Research Center, Department of Dermatology)

Both clonal hematopoiesis of indeterminate potential (CHIP) and leukocyte telomere length (LTL) have been related to mortality, cancer, and cardiovascular disease. We investigated the observational and causal associations between LTL and CHIP, which predisposes hematologic malignancy and coronary artery disease (CAD). We observed longer LTL increasing the propensity to develop CHIP, but CHIP then, in turn, hastens to shorten LTL. We also demonstrated modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward preventing CAD.

(Summary submitted by Tetsushi Nakao, MD, PhD, Broad Institute)

Mullerian inhibiting substance (MIS, also known as AMH) is an ovarian hormone that inhibits folliculogenesis. Unlike all other hormonal contraceptives, MIS works by blocking follicle development far upstream of ovulation, giving it unique therapeutic opportunities. We screened a repurposed drug library to find small molecules capable of activating the MIS receptor, MISR2. We found that four molecules, including ruxolitinib which is approved for human use, and could recapitulate the function of MIS in vitro and in vivo. This study represents an important first step in the development of new safe and effective oral female contraceptives targeting MISR2 and raises important questions on possible off-target effects of ruxolitinib on female fertility.

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

Greater Tau Burden Associated With Early-onset Alzheimer’s Disease
Amyloid-β and Tau Pathologies Relate to Distinctive Brain Dysconnectomics in Preclinical Autosomal-dominant Alzheimer's Disease
Guzmán-Vélez E, Diez I, Schoemaker D, Pardilla-Delgado E, Vila-Castelar C [et al.], Quiroz YT
Published in PNAS on Tuesday, April 5, 2022

Amyloid-β and tau, hallmark pathologies of Alzheimer’s disease (AD), are thought to spread through brain functional networks that are critical for neural communication. Using high-resolution network analyses and positron emission tomography (PET), researchers showed that greater tau burden was associated with reduced functional connectivity of regions that are important for memory and increased connectivity of structures that help integrate information, in cognitively-unimpaired presenilin-1 E280A carriers, who will develop early-onset AD dementia. Findings enlighten how amyloid-β and tau pathologies distinctly relate to patterns of functional connectivity in regions that are essential for memory. Findings may help identify individuals at risk for AD years before cognitive impairment and predict disease progression.

(Summary submitted by Edmarie Guzman-Velez, PhD, Department of Psychiatry, and Ibai Diez, PhD, Gordon Center for Medical Imaging, Department of Radiology)

Starting Multikinase Inhibitor Treatment Sooner Leads to Longer Survival in Advanced Thyroid Cancer
Impact of Baseline Tumor Burden on Overall Survival in Patients With Radioiodine-refractory Differentiated Thyroid Cancer Treated With Lenvatinib in the SELECT Global Phase 3 Trial
Kiyota N, Tahara M, Robinson B, Schlumberger M, Sherman SI [et al.], Wirth LJ
Published in Cancer on Tuesday, April 5, 2022

When is the best time to start treatment with a multikinase inhibitor treatment in patients with radioiodine-refractory metastatic thyroid cancer? This treatment can cause side effects that may impact on a patient’s quality of life. Therefore, holding off on starting has become a standard approach. This analysis of the impact of tumor burden on survival endpoints in advanced thyroid cancer patients treated with the multikinase inhibitor lenvatinib showed that patients derive a longer survival benefit when lenvatinib is started earlier in the disease process, rather than later. This analysis therefore gives us important information to discuss with patients regarding the best time to initiate therapy based on the factors that are most important to each individual patient.

(Summary submitted by Lori Wirth, MD, Division of Hematology/Oncology, Department of Medicine, Mass General Cancer Center)

Transfer RNAs (tRNAs) are important in the process of translating genetic code into proteins. However, tRNAs can also be cut into smaller pieces called tRNA-derived small RNAs (tDRs) that have distinct roles, particularly in helping cells adapt to stress. In this study, we show that different patterns of stress, such as lack of oxygen or nutrients, lead to unique patterns of tDRs generated both within cells and released from cells. Some of these patterns we found in cells are replicated in the blood of patients during cardiac surgery when the heart is deprived of nutrients. Understanding patterns of tDRs may lead to new markers for tracking different diseases and for understanding key disease processes.

(Summary submitted by Saumya Das, MD, Division of Cardiology, Department of Medicine)

As the leading reason for brain surgery in children, hydrocephalus has been historically characterized by dilation of fluid-filled cavities in the brain that can increase pressure inside the skull and injure neural tissue. The primary treatment is neurosurgical shunting to reduce fluid volume, but not all patients benefit and there are risks of complications and morbidity from surgery. We combined integrative genomic studies of hydrocephalus patients with functional investigations in mouse and stem cell models to show that gene mutations associated with hydrocephalus disrupt development of brain neural stem cells. This causes poor brain growth and leads to mechanical instability of the brain tissue and secondary fluid accumulation. This suggests certain subtypes of hydrocephalus may be caused by abnormal neurodevelopment rather than altered “brain fluid plumbing,” and future treatment strategies could look toward optimizing brain growth.

(Summary submitted by Phan Q. Duy, PhD, Yale University School of Medicine)

The study involves looking at the voltage signals at the end of the seizure to examine seizure termination patterns across 710 seizures recorded from 104 patients. We found that most seizures end synchronously, and show block-like termination patterns, often terminating with burst suppression regardless of if they are focal versus generalized. Our work highlights a surprising finding in that, even though epilepsy is varied and complex with numerous causes and symptoms, there may be a limited number of ways that seizures end. This could have significant implications for therapies in interrupting or stopping seizures.

(Summary submitted by Yangling Chou, PhD, Department of Neurology)

The study evaluated if it is possible to avoid trade-offs between returning to pre-pandemic lifestyles—with no mask mandates or restrictions on social gatherings—and increasing COVID-19–related deaths. The analysis found that in most states, relaxing masking mandates and other restrictions resulted in some “rebound” in COVID-19–related deaths; however, delaying the date of lifting mandates did little to lessen the eventual rise in deaths. The inevitable rebound in mortality was directly attributable to the Omicron variant. One of the strongest predictors of the extent of the rebound surge in mortality after relaxing mandates was the degree of immunity in the community at the time of lifting the mandate. Therefore, communities with a high percentage of residents who are vaccinated and/or who have had COVID-19 are likely to have lower death rates.

(Summary submitted by Jagpreet Chhatwal, PhD, Institute for Technology Assessment)

Current guidelines recommend lung cancer screening only for qualifying patients who would be able to undergo surgery should a tumor be found. However, the experiences of the multidisciplinary Pulmonary Nodule and Lung Cancer Screening Clinic (PNLCSC) at Mass General suggest these recommendations should be broadened. After the inclusion of radiation oncologists in the clinic in 2015, the percentage of patients treated with stereotactic body radiation therapy (SBRT)—rather than surgery—increased from 6.9% to 32.7%. 25% of patients requiring treatment for screen-detected nodules were not candidates for surgery and received SBRT. Radiation oncology involvement in the management of screen-detected pulmonary nodules increases access to safe and effective oncologic care for patients with early-stage lung cancer.

(Summary submitted by Michael G. Milligan, MD, Department of Radiation Oncology)

In December 2013, the U.S. Preventive Services Task Force first recommended lung cancer screening for high-risk individuals. The real-world impact of the introduction of lung cancer screening on lung cancer stage shift and survival remains unknown. In this study using data from two large-scale U.S. clinical registries, we found that the introduction of lung cancer screening in the U.S. was associated with a beneficial stage shift toward stage 1 lung cancer and improvements in survival. However, these benefits did not appear to extend to racial minorities and more deprived patients, illustrating the need for efforts to increase access to screening.

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

In this secondary analysis of samples from a randomized trial of vaginal estrogen or low-pH vaginal moisturizer vs. placebo for postmenopausal vaginal discomfort, we found that only people using vaginal estradiol had substantial changes in their vaginal microbiota and metabolome. There were increases in the abundance of lactobacilli and bifidobacteria, and metabolites such as lactate among the estradiol users compared to the placebo group. Such changes were not observed among participants using vaginal moisturizer despite both groups showing reductions in vaginal pH. This study demonstrated that a decrease in vaginal pH alone was insufficient to change the vaginal microbiota in postmenopausal people.

(Summary submitted by Caroline M. Mitchell, MD, MPH, Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology & Reproductive Biology)

GABA(A) receptors control excitability in the brain. Mutations in them lead to epilepsy, schizophrenia, cognitive disfunction, anxiety disorders and autism. GABA(A)Rs have five separate subunits arranged in a circle around a conducting channel. There are nineteen different subunits. Major classes of GABA(A)R are: 1) synaptic that respond to brief pulses of GABA, and 2) extrasynaptic that respond to paracrine GABA. Here single particle Cryo–EM shows that extrasynaptic receptors assemble βββαδ whereas synaptic receptors assemble βαβαγ. The subunit arrangement is important because GABA binds only in β/α interfaces and many drugs (anti-epileptics, tranquilizers, antidepressants and general anesthetics) bind between specific pairs of subunits.

(Summary submitted by Keith W. Miller, MA, DPhil, Department of Anesthesia, Critical Care & Pain Medicine)

While phase 3 data pointed to nearly identical levels of immunity conferred by both Moderna and Pfizer mRNA vaccines, real world data has begun to show differences in efficacy. These data point to the possibility that mRNA vaccines may induce different immune responses, driven by differences in dose, interval in vaccination, or lipid nanoparticle chemistry. We deeply profiled the humoral immune response induced by both mRNA vaccine platforms and found significantly differences in antibody profiles. These differences point to two exciting prospects in vaccine development: 1) vaccine-induced immunity may be tunable in the future by simply tweaking vaccine dose/intervals/chemistry, and 2) mix-and-match across platforms may drive enhanced immunity as the vaccines are seen “differently” by the immune system. The differences are not bad—in fact, they give us more options for training the immune system.

(Summary submitted by Galit Alter, PhD, Ragon Institute of MGH, MIT and Harvard)

Deferoxamine (DFO) has been widely used to remove excess toxic iron from patients with secondary iron overload; however, its short blood half-life presents challenges such as the need for repeated injections or continuous infusions. We developed injectable thermosensitive hydrogels for the long-term release of nanochelators for iron chelation therapy. The injectable hydrogel is composed of FDA-approved polymers to load a high dose of nanochelators and diminish the initial burst release. This hydrogel could improve the therapeutic efficacy of nanochelators as well as the potential toxicity by offering a long-term release of iron nanochelators with a short-term residence in non-target tissues. Considering the need for lifelong administrations of chelators in patients with iron overload, hydrogel-based nanochelators offer significant advantages over the current chelation therapies.

(Summary submitted by Homan Kang, PhD, and Hak Soo Choi, PhD, Gordon Center for Medical Imaging, Department of Radiology)

Hereditary spastic paraplegias (HSPs) are genetic disorders characterized by spasticity in the legs and difficulty walking due to impairment of very long spinal cord nerves, with axons that can measure up to one meter. Specific treatments are lacking but modeling this disease of long axons in small rodents has been challenging. Our international, multidisciplinary team has simultaneously mutated two different genes to produce a vigorous mouse model for HSPs. Using a cutting-edge type of electron microscopy, we have been able to identify a new and highly specific type of endoplasmic reticulum abnormality within the affected axons. This mouse model will be ideal for pre-clinical studies testing new HSP therapies.

(Summary submitted by Craig Blackstone, MD, PhD, Movement Disorders Division, Department of Neurology)

New Opportunities for the Study of Human Brain Pathways
Tracing Modification to Cortical Circuits in Human and Non-Human Primates From High Resolution Tractography, Transcription, and Temporal Dimensions
Charvet CJ, Ofori K, Baucum C, Sun J, Modrell MS [et al.], van der Kouwe AJ
Published in The Journal of Neuroscience on Thursday, March 24, 2022

Diffusion MR tractography is an exciting method to explore pathways, but its accuracy is uncertain. We developed a multi-scale approach to integrate state-of-the art diffusion MR scans with transcriptional variation from comparisons of human, macaque, and mouse brains. The authors also aligned ages across species, building on Translating Time (www.translatingtime.org). While frontal cortex circuitry development is extended and unusual in humans compared to mice, there is relatively little difference between studied primates. Expanding the repertoire of tools available for use with diffusion MR tractography generates new opportunities for the study of human brain pathways

(Summary submitted by Christine Charvet, PhD, College of Veterinary Medicine, Auburn University, and Andre van der Kouwe, PhD, Martinos Center, Department of Radiology)

We investigated the use the blinatumomab after allogeneic hematopoietic cell transplantation (HCT) to mitigate the risk of relapse in patients with high-risk acute lymphoblastic leukemia (ALL). The study included 21 patients and showed that this approach is feasible and well-tolerated with no excess grade 3-4 acute graft-versus-host disease. Outcomes were similar to a matched cohort, however, patients who responded were found to have a specific healthier immune profile compared to non-responders. These results set the foundation for future studies that may integrate immune profiling for patients to identify those who are more likely to benefit from blinatumomab.

(Summary submitted by Mahmoud R. Gaballa, MD, Division of Hematology/Oncology, Department of Medicine, Mass General Cancer Center)

Most of the human genome is made up of repeat sequences formerly thought to be “junk DNA,” but these repeat elements have been found to replicate and move in cancer genomes through a viral-like process called retrotransposition. We show the nucleoside reverse transcriptase inhibitor 3TC disrupts the life cycle of repeats in colorectal cancer pre-clinical models. 3TC suppressed reverse transcriptional products, enhanced DNA damage, and diminished invasive behavior in these models. We then translated these findings into a phase 2 clinical trial of 3TC treatment in metastatic colorectal cancer with disease stability in eight of 32 (25%) patients.

(Summary submitted by David T. Ting, MD, Center for Cancer Research, Mass General Cancer Center)

Huntington’s disease (HD) is a neurodegenerative disorder caused by the inheritance of an expanded repeat of CAG nucleotides in a gene on chromosome 4. The length of the repeat determines age at disease onset. We have previously identified other genes that modify this onset. In this study, we used other disease landmarks, defined by integrating information from multiple measures of abnormal movement and cognitive decline, to discover that each genetic modifier has its own pattern of effect, which can preferentially influence either movement disorder or cognitive function. These findings not only offer the potential for targeted therapies aimed at the modifiers, but also provide a route to understand differences in the brain cell types that underlie the different symptoms of HD.

(Summary submitted by James Gusella, PhD, Center for Genomic Medicine)

RCOR1 represses the expression of neuronal genes in non-neuronal cells by recruiting enzymes that erase histone modifications associated with active transcription. We aimed to explore the organization of this complex in heterochromatin domains. However, our multidisciplinary approach showed that RCOR1 preferentially localizes to actively expressed genes and uncovered a novel mechanism of repression whereby RCOR1 gets recruited to the transcriptional machinery to promote deacetylation of the carboxy-terminal domain of RNA polymerase II. We suggest that this non-canonical activity is linked to the regulation of POL-II transcription pause-release and/or elongation, proposing a model for the paradoxical association of repressor proteins to active genes.

(Summary submitted by Carlos Rivera Álvarez, PhD, Department of Molecular Biology)

Alzheimer's disease involves the misfolding of tau and amyloid-β proteins, which disrupt normal brain function and contribute to cognitive decline. A minuscule region deep in the brain, the locus coeruleus, is important for cognition and one of the first regions to accumulate tau. To examine this region, we used magnetic resonance imaging in older individuals while they were learning new information. Individuals showed faster Alzheimer's disease-related cognitive decline when their locus coeruleus was less active during learning. These findings suggest that examining locus coeruleus function may be valuable to individuals at-risk for Alzheimer's disease-related cognitive decline at an earlier point in life.

(Summary submitted by Heidi I. L. Jacobs, PhD, Gordon Center for Medical Imaging, Department of Radiology)

Two major modifiable risk factors for suicide are major depression and firearm ownership. We used data from a survey conducted in all 50 states and the District of Columbia, the Covid States Project, to understand how often these two risk factors occur together. We found that about one-third of people who reported moderate or greater depression symptoms also owned firearms— a proportion similar to that among people who were not depressed. But people with depression were more likely to have purchased a firearm during the COVID-19 pandemic, and more likely to be considering a future firearm purchase. We hope that our findings will help to inform focused strategies to reduce suicide risk in this otherwise high-risk group.

(Summary submitted by Roy Perlis, MD, MSc, Center for Quantitative Health, Center for Genomic Medicine, Department of Psychiatry)

Press Releases

Brain Connectivity Changes Revealed in Individuals With Pre-Clinical Alzheimer’s Disease
Featuring Yakeel Quiroz-Gaviria, PhD

Accumulation of amyloid-β and tau proteins are related to brain network changes years before symptoms.

Simulation Study Predicts COVID-19 Deaths Will Rebound Sooner or Later When All Restrictions Are Lifted
Featuring Jagpreet Chhatwal, PhD

Model provides detailed projections for each state.

Diversity in U.S. Medicine Is Not Keeping Pace With Population Changes, Analysis Finds
Featuring Sophia Kamran, MD

Women see gains in representation, but minority groups remain underrepresented.

Molecules Produced by Cells in Response to Stress May Be Indicators of Various Diseases
Featuring Saumya Das, MD, PhD

Signatures of certain RNA molecules may help improve diagnostics.

HIV Drug Stabilizes Disease Progression in Metastatic Colorectal Cancer
Featuring David T. Ting, MD

Using reverse transcriptase inhibitors raises the possibility of a new therapeutic strategy in cancer.

Non-English-Speaking Patients Hospitalized With COVID-19 Are at Risk of Worse Health Outcomes
Featuring Priscilla Wang, MD

Researchers at Mass General Brigham report that racial and ethnic minority patients continue to be disproportionally affected by COVID-19

Some Gut Viruses Promote Intestinal Health, While Others Contribute to Inflammatory Bowel Disease
Featuring Kate L. Jeffrey, PhD

Like bacteria, viruses in the body can be helpful or harmful.

Research in Human Kidney Organoids Reveals Target to Prevent Irreversible Kidney Damage
Featuring Ryuji Morizane, MD, PhD

Activating a DNA repair mechanism may help preserve kidney function in people with chronic kidney disease.

New Approach for Delivery of Anti-HIV Antibody Therapy Shows Promise in Phase I Clinical Trial
Featuring Alejandro B. Balazs, PhD

Treatment using adeno-associated viral vector is poised to move into larger, later-phase trials.

Phase 3 Clinical Trial Results Lead to Approval of Oral Drug for Red Blood Cell Disorder
Featuring Hanny Al-Samkari, MD

ACTIVATE trial generated positive safety and efficacy data for mitapivat.

Rilzabrutinib for Blood Disorder Shows Promise in Phase 1–2 Clinical Trial
Featuring David J. Kuter, MD, DPhil

Drug may safely boost platelet levels in patients with immune thrombocytopenia.

Genetic Analysis Provides Insights Into the Cause of Hydrocephalus, or “Water on the Brain”
Featuring Kristopher T. Kahle, MD, PhD

Research indicates that hydrocephalus does not result from a defect of cerebrospinal fluid “plumbing” but rather arises because primitive cells in the brain do not behave properly during development.

Study Finds Infertility History Linked with Increased Risk of Heart Failure
Featuring Emily Lau, MD, MPH

A woman’s reproductive history can help predict her future risk of heart disease.

Researchers Identify Key Regulators of Urinary Concentration in the Kidney
Featuring Alexander G. Marneros, MD, PhD

The finding could have implications in the treatment of kidney diseases.

New Details Behind the Body’s Response to Tuberculosis Could Lead to a More Effective Vaccine
Featuring Alex K. Shalek, PhD

Researchers uncover how the immune system clears, or in some cases helps, bacteria after infection.

CAR T Drives Acute Myeloid Leukemia Into Submission in Pre-Clinical Studies
Featuring Mark Leick, MD, and Marcela Maus, MD, PhD

A chimeric antigen receptor (CAR) T-cell construct designed to overcome difficulties with prior attempts showed good efficacy against Acute Myeloid Leukemia (AML) in mouse models.

Blog Posts

Mass General Brigham Investigators Can Now Access First Dataset of Nearly 100,000 Whole Genome Sequences Released by All of Us Research Program
The National Institutes of Health’s All of Us Research Program has reached an important milestone with the release of its initial genomic dataset.

More Action is Needed to Reduce Disparities in Osteoporosis Screening, Prevention and Care
Featuring Karina N. Ruiz-Esteves, MD, Jimmitti Teysir, MD, and Sherri-Ann Burnett-Bowie, MD, MPH

Despite being a treatable disease, osteoporosis remains underdiagnosed and undertreated, with Black women experiencing the most disparities.

Humans of MGRI: Daniel Ruiz, MD
Featuring Daniel Ruiz, MD

Dr. Ruiz is studying the interactions of the immune system with tumor cells in the brain and neck. He also loves dancing and bike riding.

How a New Service is Helping Mass General Researchers Go Green One Lab at a Time`
Featuring Ann-Christine Duhaime, MD

A unique collaborative effort seeks to reduce the environmental impact of biomedical research.

Gabriela Apiou, PhD, Named Inaugural Incumbent of the Endowed MGH Research Institute Chair in Translational Sciences
Featuring Gabriela Apiou, PhD

Dr. Apiou’s focus is on teaching and practicing unique models of innovation through collaboration across academia and industry.

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Snapshot of Science for April 2022