Snapshot of Science for July 2022

Welcome to our Snapshot of Science for July 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:

35 new studies published in high-impact journals, along with 29 summaries submitted by the research teams
14 new research-related press releases from the Mass General Public Affairs office
4 posts from the Mass General Research Institute blog

Publications

Mechanistic Insight to Guide Therapeutic Strategies Targeting KRAS
KRASG12C-independent Feedback Activation of Wild-type RAS Constrains KRASG12C Inhibitor Efficacy
Ryan MB, Coker O, Sorokin A, Fella K, Barnes H [et al.], Corcoran RB
Published in Cell Reports on June 21, 2022

Impact of Firearm Injuries Runs Deeper Than Deaths
Changes in Health Care Spending, Use, and Clinical Outcomes After Nonfatal Firearm Injuries Among Survivors and Family Members: A Cohort Study
Song Z, Zubizarreta JR, Giuriato M, Paulos E, Koh KA
Published in Annals of Internal Medicine on June 21, 2022 | *Summary available

New Insights into the Gene Expression Profile of Heart Failure
Single-Nucleus Profiling of Human Dilated and Hypertrophic Cardiomyopathy
Chaffin M, Papangeli I, Simonson B, Akkad AD, Hill MC [et al.], Ellinor PT
Published in Nature on June 22, 2022 | *Summary available

Communication Between Advanced Lung Cancer Patients, Their Caregivers, and Oncologists
Prognostic Communication About Lung Cancer in the Precision Oncology Era: A Multiple-perspective Qualitative Study
Petrillo LA, Shimer SE, Zhou AZ, Sommer RK, Feldman JE [et al.], Temel JS
Published in Cancer on June 22, 2022 | *Summary available

New Tool for Observation of Dynamic Cellular Interactions and Therapeutic Responses In Vivo
In Vivo Click Chemistry Enables Multiplexed Intravital Microscopy
Ko J, Lucas K, Kohler R, Halabi EA, Wilkovitsch M, Carlson JCT, Weissleder R
Published in Advanced Science on June 24, 2022 | *Summary available | Press Release

A New Strategy to Extend Survival in Patients with Pancreatic Ductal Adenocarcinoma
Remediating Desmoplasia With EGFR-targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer
Obaid G, Bano S, Thomsen H, Callaghan S, Shah N [et al.], Hasan T
Published in Advanced Science on June 24, 2022 | *Summary available

Health System-based Smoking Cessation Model Improves on Community Model
Comparative Effectiveness of Postdischarge Smoking Cessation Interventions for Hospital Patients: The Helping HAND 4 Randomized Clinical Trial
Rigotti NA, Chang Y, Davis EM, Regan S, Levy DE [et al.], Tindle HA
Published in JAMA Internal Medicine on June 27, 2022 | *Summary available

Postoperative and Long Term Outcomes of Parenchyma-Sparing Resections vs Oncologic Resections in PNET Patients
Long Term Outcomes of Parenchyma-sparing and Oncologic Resections in Patients With Non-Functional Pancreatic Neuroendocrine Tumors <3cm in a Large Multi-Center Cohort
Bolm L, Nebbia M, Wei AC, Zureikat AH, Fernández-Del Castillo C [et al.], Ferrone CR; PAncreatic Neuroendocrine Disease Alliance (PANDA)
Published in Annals of Surgery on June 27, 2022

COVID-19 Vaccinations and Boosters in Pregnant Women
Maternal Immune Response and Placental Antibody Transfer After COVID-19 Vaccination Across Trimester and Platforms
Atyeo CG, Shook LL, Brigida S, De Guzman RM, Demidkin S [et al.], Edlow AG
Published in Nature Communications on June 28, 2022 | *Summary available

Increased Risk of Thrombosis When Taking Abemaciclib for Breast Cancer
Venous and Arterial Thrombosis Associated With Abemaciclib Therapy for Metastatic Breast Cancer
Watson NW, Wander SA, Shatzel JJ, Al-Samkari H
Published in Cancer on June 29, 2022 | *Summary available

Women Surgical Residents Have Better Outcomes With Women Mentors
Impact of a Virtual Professional Development Coaching Program on the Professional Fulfillment and Well-Being of Women Surgery Residents: A Randomized Controlled Trial
Palamara K, McKinley SK, Chu JT, Merrill A, Yu L [et al.], Stein SL
Published in Annals of Surgery on June 29, 2022 | *Summary available

Fat Distribution Has Important Inherited Component
Inherited Basis of Visceral, Abdominal Subcutaneous and Gluteofemoral Fat Depots
Agrawal S, Wang M, Klarqvist MDR, Smith K, Shin J [et al.], Khera AV
Published in Nature Communications on June 30, 2022 | *Summary available

New Understanding of PPM1D Biology
Allosteric Inhibition of PPM1D Serine/Threonine Phosphatase Via an Altered Conformational State
Miller PG, Sathappa M, Moroco JA, Jiang W, Qian Y [et al.], Ebert BL
Published in Nature Communications on June 30, 2022 | *Summary available

Proton Pump Inhibitor Patients Not at Greater Risk of Death
Association of Proton Pump Inhibitor Use With All-Cause and Cause-specific Mortality
Lo CH, Ni P, Yan Y, Ma W, Joshi AD [et al.], Chan AT
Published in Gastroenterology on June 30, 2022 | *Summary available | Press Release

Suicide in Children
Prevalence and Correlates of Suicide and Nonsuicidal Self-Injury in Children: A Systematic Review and Meta-Analysis
Liu RT, Walsh RFL, Sheehan AE, Cheek SM, Sanzari CM
Published in JAMA Psychiatry on July 1, 2022 | *Summary available

Adult Carriers of Rare LMNA Variants at Increased Risk for Heart Disease
LMNA Variants and Risk of Adult-onset Cardiac Disease
Lazarte J, Jurgens SJ, Choi SH, Khurshid S, Morrill VN [et al.], Lubitz SA
Published in Journal of the American College of Cardiology on July 5, 2022

Cortisone Shots Do Not Increase COVID-19 Risk
The Relationship of Imaging-guided Corticosteroid Injections to COVID-19 Incidence in the Pandemic Recovery Period
Vicentini JRT, Habibollahi S, Staffa SJ, Simeone FJ, Kheterpal AB [et al.], Chang CY
Published in Radiology on July 5, 2022 | *Summary available

Increased Tau Can Lead to Post Surgery Delirium
Preoperative Plasma Tau-PT217 and Tau-PT181 Are Associated With Postoperative Delirium
Liang F, Baldyga K, Quan Q, Khatri A, Choi S [et al.], Xie Z
Published in Annals of Surgery on July 6, 2022 | *Summary available | Press Release

Inhaled Nitric Oxide Shortens Hospital Stays in Pregnant COVID-19 Patients
High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia
Valsecchi C, Winterton D, Safaee Fakhr B, Collier AY, Nozari A [et al.], Berra L; DELiverly oF iNO (DELFiNO) Network Collaborators
Published in Obstetrics & Gynecology on July 7, 2022 | *Summary available | Press Release

Motor Proteins Respond When Close Together, Not Just When Touching
Motor Guidance by Long-range Communication on the Microtubule Highway
Wijeratne SS, Fiorenza SA, Neary AE, Subramanian R, Betterton MD
Published in PNAS on July 7, 2022 | *Summary available

New Approach to Study Gene-Environment Interactions in Cardiometabolics
Variance-quantitative Trait Loci Enable Systematic Discovery of Gene-Environment Interactions for Cardiometabolic Serum Biomarkers
Westerman KE, Majarian TD, Giulianini F, Jang DK, Miao J [et al.], Cole JB
Published in Nature Communications on July 9, 2022 | *Summary available

Two Different White Blood Cell Types Have Opposite Effects on Heartbeat Irregularities After Heart Attack
Neutrophils Incite and Macrophages Avert Electrical Storm After Myocardial Infarction
Grune J, Lewis AJM, Yamazoe M, Hulsmans M, Rohde D [et al.], Nahrendorf N
Published in Nature Cardiovascular Research on July 11, 2022 | *Summary available | Press Release

Virus-specific Responses to HIV Suppression in Tissue Sanctuaries During Suppressive ART
CD8 Lymphocytes Mitigate HIV-1 Persistence in Lymph Node Follicular Helper T Cells During Hyperacute-treated Infection
Baiyegunhi OO, Mann J, Khaba T, Nkosi T, Mbatha A [et al.], Ndhlovu ZM
Published in Nature Communications on July 12, 2022

New Blocking Antibody Therapy for Brain Tumors in Children
A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma
Saulnier Sholler G, Duda DG, Bergendahl G, Ebb D, Snuderl M [et al.], Jain RK
Published in Clinical Cancer Research on July 14, 2022 | *Summary available | Press Release

New Drug Treatment for Breast Cancer
AMEERA-1 Phase 1/2 Study of Amcenestrant, SAR439859, in Postmenopausal Women With ER-positive/HER2-negative Advanced Breast Cancer
Bardia A, Chandarlapaty S, Linden HM, Ulaner GA, Gosselin A [et al.], Campone M
Published in Nature Communications on July 15, 2022 | *Summary available

New Strategy Extends the Preservation Time of Organs Without Damage
Partial Freezing of Rat Livers Extends Preservation Time by 5-Fold
Tessier SN, de Vries RJ, Pendexter CA, Cronin SEJ, Ozer S [et al.], Toner M
Published in Nature Communications on July 15, 2022 | *Summary available | Press Release
Featured as one of Nature’s Best Images for July!

Most Adverse Events in Breast Reconstruction Occur Within 60 Days
The Timing of Acute and Late Complications Following Mastectomy and Implant-based Reconstruction
Jimenez RB, Packowski K, Horick N, Rosado N, Chinta S [et al.], Liao EC
Published in Annals of Surgery on July 15, 2022 | *Summary available

New Strategy to Measure Oxygen Levels in the Tumor Microenvironment
Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation During Antiangiogenesis and Angiotensin Signaling Inhibition
Martin JD, Lanning RM, Chauhan VP, Martin MR, Mousa AS [et al.], Jain RK
Published in Clinical Cancer Research on July 15, 2022 | *Summary available | Press Release

Alzheimer’s-defying Brain Offer Clues to Treatment and Prevention of Dementia
Distinct Tau Neuropathology and Cellular Profiles of an APOE3 Christchurch Homozygote Protected Against Autosomal Dominant Alzheimer's Dementia
Sepulveda-Falla D, Sanchez JS, Almeida MC, Boassa D, Acosta-Uribe J [et al.], Quiroz YT
Published in Acta Neuropathologica on July 15, 2022 | Press Release

New Test for Mutation in Blood of Patients With Glioma
Highly Sensitive EGFRvIII Detection in Circulating Extracellular Vesicle RNA of Glioma Patients
Batool SM, Muralidharan K, Hsia T, Falotico S, Gamblin AS [et al.], Carter BS
Published in Clinical Cancer Research on July 18, 2022 | *Summary available | Press Release

Odor Enrichment Lowers Post-operative Cognitive Impairment
Odor Enrichment Attenuates the Anesthesia/Surgery-induced Cognitive Impairment
Zhang C, Han Y, Liu X, Tan H, Dong Y [et al.], Xie Z
Published in Annals of Surgery on July 18, 2022 | *Summary available | Press Release

Wide Variability in Developmental Progress in Autism
Developmental Variability in Autism Across 17,000 Autistic Individuals and 4,000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis
Kuo SS, van der Merwe C, Fu JM, Carey CE, Talkowski ME, Bishop SL, Robinson EB
Published in JAMA Pediatrics on July 18, 2022 | *Summary available

Heart Failure Drug Does Not Improve Exercise Capacity
Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial
Lewis GD, Voors AA, Cohen-Solal A, Metra M, Whellan DJ [et al.], Felker GM
Published in JAMA on July 19, 2022 | *Summary available

A Promising Role for Patient-generated Feedback in Surgical Resident Assessment
Inpatient Satisfaction With Surgical Resident Care After Elective General and Oncologic Surgery
McKinley SK, Wojcik BM, Witt EE, Hamdi I, Mansur A [et al.], Phitayakorn R
Published in Annals of Surgery on July 20, 2022 | *Summary available

Discrimination Took A Toll on the Mental Health of Racial and Ethnic Minority Groups During the COVID-19 Pandemic
Association of Everyday Discrimination With Depressive Symptoms and Suicidal Ideation During the COVID-19 Pandemic in the All of Us Research Program
Lee YH, Liu Z, Fatori D, Bauermeister JR, Luh RA [et al.], Smoller JW
Published in JAMA Psychiatry on July 27, 2022 | Press Release

Publication Summaries

Impact of Firearm Injuries Runs Deeper Than Deaths
Changes in Health Care Spending, Use, and Clinical Outcomes After Nonfatal Firearm Injuries Among Survivors and Family Members : A Cohort Study
Song Z, Zubizarreta JR, Giuriato M, Paulos E, Koh KA
Published in Annals of Internal Medicine on June 21, 2022

For every firearm death in the U.S., more than two people survive a firearm injury. In this study of 6,498 gunshot survivors and 32,490 matched controls, medical spending increased four-fold in the first year after firearm injury ($30,000 per survivor in additional spending). Survivors experienced a 51% increase in psychiatric disorders and 85% increase in substance use disorders compared to controls. Among 12,489 family members of survivors, there was a 12% increase in psychiatric disorders compared to 62,445 matched controls. The ripples of firearms run deeper than deaths, and family members are not unscathed. Employers and Medicare paid 96% of the additional spending, which ultimately falls on taxpayers and workers through wages foregone.

(Summary submitted by Zirui Song, MD, PhD, Department of Medicine)

Heart failure (HF) is a growing public health concern encompassing a wide range of clinical features. To investigate the molecular basis of HF, we performed single-nucleus RNA sequencing of hearts from two forms of HF, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Broadly, gene expression of DCM and HCM hearts converged across cell types. Further, we identified a population of activated fibroblasts from a subset of DCM and HCM patients. We then experimentally implicated genes from this population as playing a mechanistic role in fibroblast activation. Our findings provide new insights into the gene expression profile of HF as well as new potential therapeutic targets for HF.

(Summary submitted by Mark Chaffin, MS, Broad Institute of MIT and Harvard)

Targeted therapies—drugs that precisely target molecular drivers of tumor growth—have transformed treatment for a subset of patients with lung cancer, though advanced lung cancer remains incurable and individual benefit varies. We explored how patients with advanced lung cancer receiving targeted therapy, their caregivers, and oncologists communicate about what to expect from these novel therapies. We found that uncertainty makes it difficult for oncologists to discuss prognosis with patients. We also found that oncologists’ optimism leads to high expectations of targeted therapy among patients, which affects their medical decision making, particularly at the end of life.

(Summary submitted by Laura Petrillo, MD, Division of Palliative Medicine, Department of Medicine)

New Tool for Observation of Dynamic Cellular Interactions and Therapeutic Responses in Vivo
In Vivo Click Chemistry Enables Multiplexed Intravital Microscopy
Ko J, Lucas K, Kohler R, Halabi EA, Wilkovitsch M, Carlson JCT, Weissleder R
Published in Advanced Science on June 24, 2022

It has long been a goal to characterize the molecular make-up of living cells and tissues nondestructively, identifying key players and watching them as they work. We recently developed scission accelerated fluorophore exchange (SAFE), the first biocompatible chemical tools capable of multiplexed temporospatial analyses in living systems. Here, we demonstrate that SAFE can be further adapted for highly multiplexed immunofluorescence imaging in living mice, achieving bioorthogonal multiplexing in vivo. This SAFE-IVM method enables longitudinal immunoprofiling of complex microenvironments, allowing observation of dynamic cellular interactions and therapeutic responses as they occur.

(Summary submitted by Ralph Weissleder, MD, PhD, Center for Systems Biology)

A New Strategy to Extend Survival in Patients With Pancreatic Ductal Adenocarcinoma
Remediating Desmoplasia With EGFR-targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer
Obaid G, Bano S, Thomsen H, Callaghan S, Shah N [et al.], Hasan T
Published in Advanced Science on June 24, 2022

Pancreatic cancer has a dismal prognosis with less than 10% of patients surviving five years beyond diagnosis. We developed small, light-responsive packages–targeted photoactivable multi-inhibitor liposomes (TPMILs) that target pancreatic tumors with multiple anti-cancer agents simultaneously. When activated by light, the tumors are imaged, and, in a process called photodynamic therapy, these TPMILs loosen the tumor scaffold by remodeling collagen to improve the delivery of the anti-cancer agents within pancreatic tumors and simultaneously destroy cancer cells, often synergistically with the anticancer agents. The result is an unprecedented shrinkage of tumors and a doubling of overall survival in mice models.

(Summary submitted by Tayyaba Hasan, PhD, Wellman Center for Photomedicine)

For cigarette smokers, a hospital admission provides a unique opportunity to start the process of quitting smoking because they must abstain from tobacco in the hospital. Smoking cessation treatment that starts in the hospital increases long-term quit smoking rates but only if treatment continues after hospital discharge. The best way for hospitals to provide this is uncertain. This multi-site randomized controlled trial compared two models for delivering post-discharge care: health system-based care or referral to a community-based quitline. Health system-based care produced better treatment use and more tobacco abstinence throughout the three months of active treatment, but the difference narrowed and did not differ significantly six months after discharge. Extending treatment beyond three months may have sustained end-of-treatment superiority of the health system-based model.

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

This collaboration between investigators at Mass General, the Ragon Institute, and Brigham and Women’s Hospital examined maternal antibody responses and transfer of antibody across the placenta to the neonate, examining vaccination in all three trimesters of pregnancy, and across all three vaccine platforms (Janssen’s adenovirus-based Ad26.COV2.S, Moderna’s mRNA-based mRNA-1273, and Pfizer-BioNTech’s mRNA-based BNT162b2). Maternal antibody responses were evaluated in 158 pregnant individuals, and transfer of antibody was evaluated in 175 mother-neonate pairs. We found that, in comparison to Ad.26.COV2.S, mRNA vaccine-induced antibodies had higher levels and functionality against SARS-CoV-2 ancestral strain, as well as against variants of concern, such as Alpha, Beta, Delta, and Gamma. Vaccine-induced antibodies had neutralizing activity against Omicron. First and third trimester vaccination led to enhanced maternal immune responses relative to second trimester. Transfer of SARS-CoV-2-specific antibodies to the fetus was most efficient following first and second trimester vaccination. These data suggest that if individuals have not yet received the COVID-19 vaccine prior to pregnancy, they should have the initial vaccine series early in pregnancy, with boosting later in pregnancy to optimize protective antibody titers for both mother and neonate.

(Summary submitted by Andrea G. Edlow, MD, MSc, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Biology)

Abemaciclib is an important therapeutic agent for patients with metastatic breast cancer but has a black box warning from the FDA for increased risk of abnormal blood clots (thrombosis) after high rates of thrombosis were observed in clinical trials. In our study, which evaluated 364 patients with breast cancer receiving abemaciclib, we found a thrombosis risk 2-to-3-fold greater than the already elevated rates seen in clinical trials that earned the drug its black box warning. Additionally, patients developing thrombosis on abemaciclib had a significantly higher risk of death than those who did not. Given this data, providers need to closely consider the thrombotic risk factors of each patient they consider for abemaciclib therapy. Studies evaluating the role of routine use of blood thinners in some or all patients receiving abemaciclib are needed as a next step.

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

In the first known published randomized controlled trial of professional development coaching for residents, women surgical residents coached by women surgical faculty in this Association of Women Surgeons coaching program showed significant improvements in professional fulfillment, burnout, well-being, and self-valuation. Faculty coaches underwent three hours of training plus two virtual refresher trainings and met virtually up to three times per year with their coaches using a positive psychology coaching curriculum. Coached and uncoached residents differed significantly in resilience, self-valuation, and tolerance of uncertainty.

(Summary submitted by Kerri Palamara McGrath, MD, Department of Medicine)

Beyond overall measures of adiposity, such as body mass index, the distribution of fat in various depots is an important driver of risk for diabetes and other important health conditions. Using precise measurements of fat volume in specific areas of the body in nearly 40,000 individuals, we set out to understand the relationship between inherited DNA variants and amount of fat in visceral, abdominal subcutaneous, and gluteofemoral regions. We found that (1) the genetic basis of each fat depot is unique from the others, and (2) these fat depot-specific common variants can be aggregated to construct depot-specific polygenic scores that have divergent associations with type 2 diabetes and coronary artery disease. These results confirm fat distribution has an important inherited component and has implications for our understanding of risk and biology of cardiometabolic health outcomes.

(Summary submitted by Saaket Agrawal, Broad Institute of MIT & Harvard)

PPM1D is a gene that is mutated in a variety of cancers. When this occurs, the tumors become increasingly resistant to chemotherapy and radiation. In our recent study, we sought to understand how drugs that target PPM1D and reverse cancer resistance to therapy may work. We discovered that PPM1D exists in two 3D conformations; in one conformation the protein is active and in the other the protein is inactive. We then found that drugs that bind to a specific part of the protein “lock” it into the inactive conformation and inhibit PPM1D’s function. This study not only deepens our understanding of PPM1D biology but also paves the way for new drug discovery efforts.

(Summary submitted by Peter Miller, MD, PhD, Center for Cancer Research, Department of Medicine)

Proton pump inhibitor (PPI) use has increased over the past two decades, which called into question the long-term effects of these medications. In this prospective cohort study, we examined the association between PPI use and mortality. Our analysis showed that PPI use was associated with increased risks of all-cause mortality and mortality due to cardiovascular diseases, cancer, respiratory diseases, and digestive diseases. After utilizing a lag-time approach to adjust for reverse causation, these associations were no longer statistically significant. Our study adds to the existing literature that patients who use PPI are not at a greater risk of death.

(Summary submitted by Chun-Han Lo, MD, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, Department of Medicine)

Suicide is the fifth leading cause of death among preadolescent children. Yet, little is known about preadolescent suicide, partly due to the common misconception that young children are incapable of suicidal thoughts. This study sought to synthesize all research conducted to date on self-harm. We found that suicidal thoughts are common, with 15% of preadolescent children in the general community experiencing these thoughts within their lifetime, and 17% of suicidal children eventually attempt suicide. Current findings suggest that depression, ADHD, and child maltreatment may be associated with risk for suicidal thoughts, whereas parental support may be protective.

(Summary submitted by Richard T. Liu, PhD, Department of Psychiatry)

Corticosteroid injections, or “cortisone shots,” are commonly used to treat joint or spine pain. Corticosteroids are absorbed from the joint or spine into the rest of the body and may temporarily impair the ability of our immune system to fight infections such as COVID-19. We followed 1,960 patients who underwent injections guided by X-ray or ultrasound in 2020-2021, and we found no increased risk of infection by COVID-19 among these patients. The results of our study provide reassurance to patients and providers who rely on corticosteroid injections to treat joint or back pain, even in potential new COVID-19 surges or in places with low vaccination rates.

(Summary submitted by Joao R.T. Vicentini, MD, Department of Radiology)

Increase Tau Can Lead to Post Surgery Delirium
Preoperative Plasma Tau-PT217 and Tau-PT181 Are Associated With Postoperative Delirium
Liang F, Baldyga K, Quan Q, Khatri A, Choi S [et al.], Xie Z
Published in Annals of Surgery on July 6, 2022

Postoperative delirium, one of the most common postoperative complications in older patients, is associated with postoperative adverse effects and the development of Alzheimer’s disease and related dementia. Phosphorylation of tau protein at threonine 217 (Tau-PT217) and threonine 181 (Tau-PT181) are blood biomarkers that can detect early-stage Alzheimer’s disease. In the present study, we reported that blood Tau-PT217 and Tau-PT181 amounts, detected by a newly developed nanoneedle technology, could predict postoperative delirium in patients. These findings will promote more research to identify biomarkers of postoperative delirium and investigate the cellular and molecular mechanisms of postoperative delirium in patients and animals.

(Summary submitted by Zhongcong Xie, MD, PhD, FASA, Department of Anesthesia, Critical Care and Pain Medicine)

COVID-19 pneumonia in pregnancy is associated with high risk of severe illness, maternal death, preterm delivery and stillbirth. Inhaled nitric oxide (iNO) is a lifesaving gas-therapy for infants with persistent pulmonary hypertension and used in adults with hypoxic respiratory failure to improve oxygenation. Based on laboratory studies showing antiviral activity of nitric oxide when used at high concentrations, we tested the use of 200 parts-per-millions of iNO in pregnant patients with severe COVID-19 pneumonia. iNO improved oxygenation and shortened the hospital length of stay.

(Summary submitted by Lorenzo Berra, MD, Department of Anesthesia)

Within a cell, the cytoskeleton, a network of protein polymers, form a highway system linking distant sites. Motor proteins walk on these cytoskeletal highways for processes like intracellular transport. It is typically assumed that motor proteins sense and respond to each other only when physically confined in close proximity along microtubules (i.e., traffic jam). Here, we show that nanometer-sized motors separated by several microns can sense and respond to each other. Thus, contrary to a long-held paradigm, microtubule is not a concrete highway, but responsive like a wooden bridge, where movement from one person can influence others on the bridge.

(Summary submitted by Sitara Wijeratne, PhD, Department of Molecular Biology)

Both genetics and environment (e.g., lifestyle, demographic) influence risk for common, complex diseases, but their interaction (whether the effect of one depends on the other) is not well understood. We describe an approach to study these gene-environment interactions by (1) narrowing the search space of genetic variants, and (2) testing a broader array of environmental exposures than had been previously examined. Using this approach in the UK Biobank cohort, we identify more than 800 gene-environment interactions impacting 20 cardiometabolic blood biomarkers. These findings could support the development of genetics-based precision medicine approaches for cardiometabolic health.

(Summary submitted by Kenneth E. Westerman, PhD, Department of Medicine)

Sudden cardiac death is triggered by fast, chaotic electrical currents that disrupt the usual orderly contractions. As a result, the heart ceases to pump blood, a condition that is treated with electric shocks. However, defibrillation does not prevent arrhythmia recurrence, and current options to treat such conditions with drugs are limited. Because arrhythmia often occurs in inflamed hearts, we investigated leukocytes’ roles in acute myocardial infarction. We found that neutrophils promote arrhythmia, likely by hurting stressed cardiomyocytes, while heart resident macrophages are protective. Such insight may provide the foundation for the development of a new class of immuno-modulatory antiarrhythmic drugs.

(Summary submitted by Matthias Nahrendorf, MD, PhD, Center for Systems Biology)

Effective and safe treatments are needed for medulloblastoma—the most common type of brain tumor in children—especially for patients whose cancer has spread to the spinal cord. A recent phase I clinical trial led by researchers at Atrium Health Levine Children’s Hospital and Mass General has generated promising results for a new blocking antibody therapy (TB403) that targets placental growth factor (PlGF), a protein critical to medulloblastoma cells’ ability to multiply and spread. TB403 treatment was well tolerated and induced stable disease in some medulloblastomas in a setting with no effective treatments available, warranting further studies alone or with other therapies.

(Summary submitted by Rakesh K. Jain, PhD, Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology)

Endocrine therapy is the mainstay of management of hormone receptor (HR)+ breast cancer. Amcenestrant (SAR439859) is a novel, oral, selective estrogen receptor degrader (SERD) being developed for HR+ breast cancer. In a phase 1/2 open-label single-arm study evaluating once-daily amcenestrant, in postmenopausal women with HR+ advanced breast cancer (NCT03284957), evidence of ER occupancy and degradation, based on paired functional 18F-fluoroestradiol positron emission tomography and tumor biopsies. The overall clinical benefit rate was 13/46 (28.3%). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. Further evaluation is ongoing in randomized phase 2 and phase 3 clinical trials.

(Summary submitted by Aditya Bardia, MD, MPH, Mass General Cancer Center, Department of Hematology/Oncology)

Replacing organs with transplantation is a life-saving procedure. However, not all patients who need an organ can receive one because of a global organ shortage. One of the reasons for the shortage is the limited time organs can live outside the body during transport. Currently, organs are immersed in an ice-cold solution that is designed to help the organ survive for a couple hours outside the body. To give patients and surgeons more time, we developed a way to preserve livers at colder temperatures by mimicking the techniques used by frogs that freeze solid in the winter without sustaining damage. This protocol could allow organs to be stored for five times longer and potentially help alleviate the organ shortage.

(Summary submitted by Shannon N. Tessier, PhD, Center for Engineering in Medicine & Surgery, Department of Surgery)

Implant-based reconstruction following mastectomy is a common procedure among patients with breast cancer and those at risk of breast cancer. While the acute and late complications of this procedure are well characterized, the natural history of when complications are likely to occur has not been previously described. In this study of >2,400 reconstructed breasts, the authors identified a discrete temporal distribution for complications, with 94% of hematomas, 85% of skin necrosis events, and 75% of seromas occurring within defined periods inside 60 days of surgery. Half of all related infections and implant losses occurred during this period. In contrast, 94% of capsular contracture events and 93% of implant rippling occurred more than 60 days from surgery. Characterizing the timing of adverse post-operative events has important implications for clinical management and can inform the appropriate timing and frequency of both clinical follow-up and research studies.

(Summary submitted by Rachel B. Jimenez, MD, Mass General Cancer Center, Department of Radiation Oncology)

Low oxygen levels in tumors–resulting from abnormal blood vessels–promote invasion and metastasis and confer resistance to various treatments. We previously developed two approaches to improve the function of tumor vessels and oxygenation. Here, we developed a novel microscopy technique to assess blood vessels and oxygen levels at a high resolution in preclinical models of tumors. We found that treatment using an antiangiogenic agent versus losartan–a drug approved for controlling blood pressure–affects blood vessels and oxygen delivery differently. Our findings suggest ways to improve the use of these approaches alone and in combination to improve cancer treatment.

(Summary submitted by Rakesh K. Jain, PhD, Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology)

New Blood Test Could Improve Treatment and Monitoring of Glioma Patients
Highly Sensitive EGFRvIII Detection in Circulating Extracellular Vesicle RNA of Glioma Patients
Batool SM, Muralidharan K, Hsia T, Falotico S, Gamblin AS [et al.], Carter BS
Published in Clinical Cancer Research on July 18, 2022

Liquid biopsy is a simple, minimally invasive alternative to surgical tissue biopsy. Currently, glioma tumors are diagnosed based on pathological findings on tumor tissue biopsy which is invasive, involves considerable risk and does not allow monitoring or response to therapy or progression. EGFRvIII is a mutation that occurs frequently in high grade gliomas and is present only in the tumor. Here we developed a robust test that can detect the presence of the mutation in the blood of patients with glioma. EGFRvIII is found on the surface of tumor cells and novel therapeutics are also being developed to target this tumor specific mutation. Our blood test would allow diagnostics as well patient stratification and monitoring in clinical trials targeting EGFRvIII.

(Summary submitted by Leonora Balaj, PhD, Brain Tumor Research Center, Department of Neurosurgery)

The underlying mechanisms and interventions of perioperative neurocognitive disorder (PND), one of the most common postoperative complications in older adults, remain largely unknown. In the clinical portion of the present study, we demonstrated that patients with PND had impaired pre- and postoperative olfactory function. In the animal studies, we reported that anesthesia/surgery caused olfactory and cognitive impairment, increased amounts of interleukin-6 in blood and nasal epithelium, decreased amounts of olfactory receptor neurons in the nasal epithelium, and reduced amounts of synapse markers in the brain tissues of mice. Significantly, these changes were mitigated by odor enrichment in the mice.

(Summary submitted by Zhongcong Xie, MD, PhD, FASA, Department of Anesthesia, Critical Care and Pain Medicine)

Wide Variability in Developmental Progress in Autism
Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis
Kuo SS, van der Merwe C, Fu JM, Carey CE, Talkowski ME, Bishop SL, Robinson EB
Published in JAMA Pediatrics on July 18, 2022

Autistic children frequently reach developmental milestones later than children without autism, yet few studies have evaluated how much milestone timing varies in autistic children. We evaluated developmental progress across 17,000+ autistic children and 4,000+ non-autistic siblings. We found that developmental delays in autistic children spanned from 1-20 months on average and were more variable in autistic children who had co-occurring intellectual disability, were diagnosed early, or carried a rare genetic variant associated with neurodevelopmental disorders. These findings can provide useful clinical information about how much autistic children’s early life experiences can vary.

(Summary submitted by Susan S. Kuo, PhD, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Center for Genomic Medicine)

Existing medications to treat heart failure do not consistently improve exercise capacity, which is among the most prominent symptoms of heart failure. Omecamtiv mecarbil is a novel cardiac myosin activator specifically developed to safely improve heart performance. METEORIC-HF was an international, randomized, double-blind, placebo controlled clinical trial in 276 patients with heart failure that did not show a significant improvement in exercise capacity with omecamtiv mecarbil, though other studies with this novel drug have indicated improvement in outcomes such as heart failure hospitalizations. Improving exercise capacity with medications for heart failure remains an important unmet need.

(Summary submitted by Gregory D. Lewis, MD, Division of Cardiology, Department of Medicine)

A Promising Role for Patient-Generated Feedback in Surgical Resident Assessment
Inpatient Satisfaction with Surgical Resident Care After Elective General and Oncologic Surgery
McKinley SK, Wojcik BM, Witt EE, Hamdi I, Mansur A [et al.], Phitayakorn R
Published in Annals of Surgery on July 20, 2022

Surgical trainees are often the primary providers of care to surgical inpatients, yet patient satisfaction with this care is not well characterized or routinely assessed. We surveyed hospitalized patients recovering from elective general surgery to determine their satisfaction with the care they received from their surgical resident physicians. In general, patients were willing and able to provide satisfaction ratings of surgical residents at a high frequency. This suggests a promising role for patient-generated feedback in surgical resident assessment. Future work should investigate how to best incorporate patient experience feedback into surgical training to improve residents’ ability to provide high-quality, patient-centered care.

(Summary submitted by Roy Phitayakorn, MD, MHPE (MEd), FACS, Department of Surgery)

Press Releases

Alzheimer’s Disease Biomarkers Can Predict Postoperative Delirium
Featuring Zhongcong Xie, MD, PhD

Research also provides new mechanistic insights into how this delirium occurs.

Older Adults With Superior Memories May Have Built-In Protection Against Delirium Following Surgery
Featuring Alexandra Touroutoglou, PhD, Yuta Katsumi, PhD, and Bonnie Wong, PhD

Because the size of the anterior mid-cingulate cortex is greater in SuperAgers than in typical older adults, it could be a marker for strategies to mitigate the risk and consequences of post-operative delirium.

Inhaled Nitric Oxide Reduces Hospital Stay and Improves Oxygenation in Pregnant Patients With COVID-19 Pneumonia
Featuring Lorenzo Berra, MD

Findings from a Mass General-led study could offer a new treatment approach for pneumonia combining high dose inhaled nitric oxide gas with careful patient monitoring.

Researchers Assess the Risk of Monkeypox Transmission Following Exposure in Healthcare Settings
Featuring Kimon C. Zachary, MD, and Erica Shenoy, MD, PhD

Analysis of articles published from 2000 up until the current outbreak uncovers only a single reported case of transmission following exposure.

New Antibody Therapy Shows Promising Phase I Clinical Trial Results for Advanced, Treatment-refractory Pediatric Brain Cancer
Featuring Rakesh K. Jain, PhD

The new agent, called TB-403, was well tolerated and induced stabilization of the disease in some medulloblastoma patients.

Two Different White Blood Cell Types Play Opposing Roles in Affecting Heartbeat Irregularities After Heart Attack
Featuring Matthias Nahrendorf, MD, PhD

The team’s experiments revealed that two different white blood cell types—neutrophils and macrophages—have opposite effects on heartbeat irregularities after a heart attack, suggesting that targeting these cells may help reduce the risk of sudden cardiac death.

Investigational Blood Test Can Detect Multiple Signs of Brain Cancer to Help Improve Diagnosis and Monitoring
Featuring Leonora Balaj, PhD, and Bob S. Carter, MD, PhD

Researchers who previously developed a blood test for mutations in a gene linked to gliomas, the most common type of adult brain tumors, have now applied their technology to detect additional mutations, in this case in the gene that codes for epidermal growth factor receptor.

Emoji are Shown to be as Effective as Numerical Pain Scales in Judging Patient Pain Levels in the Hospital
Featuring Shuhan He, MD, and Jarone Lee, MD, MPH

A Mass General study is seen as an important step in making Emoji a mainstream clinical tool for understanding the severity of patient pain.

Best Available Therapy for AIDS-associated Karposi Sarcoma is Cost Effective in Africa
Featuring Emily Hyle, MD, and Esther Freeman, MD, PhD

New research indicates that the best available chemotherapy for Kaposi sarcoma, which is infrequently used in Africa, would improve clinical outcomes and be cost-effective at its current price compared with therapies most frequently provided in the region.

Odor Enrichment Attenuates Postoperative Cognitive Impairment in Mice
Featuring Zhongcong Xie, MD, PhD

A new study in patients and rodents reveals the association between postoperative olfactory impairment and postoperative cognitive impairment. The findings indicate that olfactory enrichment may mitigate the anesthesia/surgery-induced olfactory and cognitive impairment in rodents.

Scientists at Massachusetts General Hospital and Harvard Medical School Succeed in Freezing Rodent Livers and Preserving at Subzero Temperatures for Five Days
Featuring Shannon Tessier, PhD, Korkut Ugyun, PhD, and Mehmet Toner, PhD

For the first time, scientists succeeded in successfully freezing rodent livers to extend preservation duration five-fold by adapting strategies used by animals to endure freezing temperatures in winter.

An Alzheimer’s-defying Brain Offer Clues to Treatment and Prevention of Dementia
Featuring Yakeel T. Quiroz, PhD

The brain of a woman with a family history of early-onset Alzheimer’s disease who lived dementia-free into her 70s is providing researchers with important information about the pathobiology of Alzheimer’s dementia and possible ways to prevent or treat it.

Discrimination Took A Toll on the Mental Health of Racial and Ethnic Minority Groups During the COVID-19 Pandemic
Featuring Jordan Smoller, MD, ScD, and Younga “Heather” Lee, PhD

People who reported experiencing discrimination more than once a week early in the pandemic had 17-fold increased odds of moderate to severe depressive symptoms, and 10-fold increased odds of suicidal ideation, compared to those who reported no discrimination.

New Technology Developed by Mass General Researchers Creates a Multi-Color Molecular Movie

The process allows researchers to see many different molecules at the same time in their natural state without destroying them.

Blog Posts

Congratulations to the 2022 Claflin Distinguished Scholars (Part 1)

Congratulations to the 2022 Claflin Distinguished Scholars (Part 2)

The Claflin Distinguished Scholar Awards were established to support women and their careers during their child-rearing years.

Humans of MGRI: Julian Gonzalez

Julian Gonzalez, originally from Colombia, is a summer intern on the Harris Orthopedics Lab microbiology team, and a first-generation medical student.

Researchers Call for New Studies to Learn How Our Brains Change When We’re Awake After Midnight

More research is needed to understand the neurophysiological changes in the brain that occur when we’re awake during the circadian night.

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Snapshot of Science for July 2022