Snapshot of Science for August 2021

Welcome to our Snapshot of Science for August 2021

Here's a quick look at some recent publications, press releases and stories about the Mass General Research Institute community.

In this issue we highlight:

31 new studies published in high impact journals, along with 23 summaries submitted by the research teams
15 new research-related press releases from the Mass General Public Affairs office
6 posts from the Mass General Research Institute blog

Publications

RACIAL AND ETHNIC DISPARITIES IN HEALTH CARE
Changes in Racial and Ethnic Disparities in Access to Care and Health Among U.S. Adults at Age 65 Years
Wallace J, Jiang K, Goldsmith-Pinkham P, Song Z
Published in JAMA Internal Medicine on July 26, 2021

HOST PROTEIN REGULATES SUBSTRATE LEVEL AND IMPAIRS BACTERIAL EFFECTOR FUNCTION DURING XENOPHAGY
SAC1 Regulates Autophagosomal Phosphatidylinositol-4-phosphate for Xenophagy-directed Bacterial Clearance
Liu K, Kong L, Graham DB, Carey KL, Xavier RJ
Published in Cell Reports on July 27, 2021 | *Summary available

WEIGHT LOSS AND RISK OF BREAST CANCER-RELATED ARM LYMPHEDEMA
Weight Loss Does Not Decrease Risk of Breast Cancer-related Arm Lymphedema
Roberts SA, Gillespie TC, Shui AM, Brunelle CL, Daniell KM [et al.], Taighan AG
Published in Cancer on July 27, 2021 | *Summary available

A CELLULAR AND MOLECULAR CHECKPOINT THAT DETERMINES THE MAGNITUDE AND OUTCOME OF T CELL TUMOR RESPONSES
CXCR6 Positions Cytotoxic T Cells to Receive Critical Survival Signals in the Tumor Microenvironment
Di Pilato M, Kfuri-Rubens R, Pruessmann JN, Ozga AJ, Messemaker M [et al.], Mempel TR
Published in Cell on July 27, 2021 | Press Release

A NEW APPROACH TO RESOLVING SCHIZOPHRENIA HETEROGENEITY
Resolving Heterogeneity in Schizophrenia Through a Novel Systems Approach to Brain Structure: Individualized Structural Covariance Network Analysis
Liu Z, Palaniyappan L, Wu X, Zhang K, Du J [et al.], Feng J
Published in Molecular Psychiatry on July 28, 2021

DEFINING EFFECTIVE SENIOR SURGICAL RESIDENTS
Effective Senior Surgical Residents as Defined by Their Peers: A Qualitative Content Analysis of Nontechnical Skills Development
Coe TM, Jogerst KM, Petrusa E, Phitayakorn R, Lipman J
Published in Annals of Surgery on July 29, 2021 | *Summary available

NEOADJUVANT FOLFIRINOX FOLLOWED BY CRT FOR LOCALLY ADVANCED GASTROESOPHAGEAL CANCER
Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas
Wo JY, Clark JW, Eyler CE, Mino-Kenudson M, Klempner SJ [et al.], Hong TS
Published in Clinical Cancer Research on July 30, 2021 | *Summary available

EARLY LIFE SYSTEMS-CHANGE INTERVENTION WITH COACHING IMPROVES INFANT WEIGHT STATUS AND MATERNAL POSTPARTUM CARE
Twelve-Month Outcomes of the First 1,000 Days Program on Infant Weight Status
Taveras EM, Perkins ME, Boudreau AA, Blake-Lamb T, Matathia S [et al.], Cheng ER
Published in Pediatrics on August 1, 2021 | *Summary available

REVERSING T CELL EXHAUSTION MAY REQUIRE NEW APPROACHES TO INCREASE EPIGENETIC PLASTICITY
Epigenetic Scars of CD8+ T Cell Exhaustion Persist After Cure of Chronic Infection in Humans
Yates KB, Tonnerre P, Martin GE, Gerdemann U, Al Abosy R [et al.], Sen DR
Published in Nature Immunology on August 2, 2021

DURATION OF T CELL STIMULATION IMPACTS EXHAUSTION RECOVERY
Differentiation of Exhausted CD8+ T Cells After Termination of Chronic Antigen Stimulation Stops Short of Achieving Functional T Cell Memory
Tonnerre P, Wolski D, Subudhi S, Aljabban J, Hoogeveen RC [et al.], Lauer GM
Published in Nature Immunology on August 2, 2021 | *Summary available

RATES AND RISK FACTORS FOR THROMBOTIC EVENTS IN PATIENTS WITH HYPEREOSINOPHILIC SYNDROMES
Association of Thrombosis with Hypereosinophilic Syndrome in Patients with Genetic Alterations
Leiva O, Baker O, Jenkins A, Brunner AM, Al-Samkari H [et al.], Hobbs GS
Published in JAMA Network Open on August 2, 2021 | *Summary available

LIMITED FOOTBALL GAME ATTENDANCE DID NOT CAUSE COVID-19 SPIKES
Association of Limited In-Person Attendance in U.S. National Football League and National Collegiate Athletic Association Games with County-level COVID-19 Cases
Toumi A, Zhao H, Chhatwal J, Linas BP, Ayer T
Published in JAMA Network Open on August 2, 2021 | Press Release

LIFESTYLE AND ENVIRONMENTAL EFFECTS ON DIABETES PHENOTYPES
Molecular Aspects of Lifestyle and Environmental Effects in Patients with Diabetes
Nayor M, Shah SH, Murthy V, Shah RV
Published in J Am Coll Cardiol on August 3, 2021 | *Summary available

PREOPERATIVE BREAST MRI CAN ENHANCE DCIS TREATMENT
Preoperative Breast MRI for Newly Diagnosed Ductal Carcinoma In Situ: Imaging Features and Performance in a Multicenter Setting
Chou SS, Romanoff J, Lehman CD, Khan SA, Carlos R [et al.], Rahbar H
Published in Radiology on August 3, 2021 | *Summary available

NEW TARGET FOR TREATING ALZHEIMER'S DISEASE
Exercise Hormone Irisin is a Critical Regulator of Cognitive Function
Islam MR, Valaris S, Young MF, Haley EB, Luo R [et al.], Wrann CD
Published in Nature Metabolism on August 3, 2021 | *Summary available | Press Release

TRENDS IN PANCREATIC CYSTIC TUMORS
Evolving Trends in Pancreatic Cystic Tumors: A 3-Decade Single-Center Experience with 1,290 Resections
Roldán J, Harrison JM, Qadan M, Bolm L, Baba T [et al.], Castillo CF
Published in Annals of Surgery on August 4, 2021

PROTEOGENOMICS DATA RESOURCES MAY GUIDE RESEARCH INTO BIOLOGY AND TREATMENT OF LSCC
A Proteogenomic Portrait of Lung Squamous Cell Carcinoma
Satpathy S, Krug K, Jean Beltran PM, Savage SR, Petralia F [et al.], Gilette MA
Published in Cell on August 5, 2021 | *Summary available

LONG-RANGE GENE ACTIVATION USING CRISPR-BASED ATFS IN HUMAN CELLS
Augmenting and Directing Long-range CRISPR-mediated Activation in Human Cells
Tak YE, Horng JE, Perry NT, Schultz HT, Iyer S [et al.], Joung JK
Published in Nature Methods on August 5, 2021

INTERRUPTING CALCIUM ENTRY INTO THE SKIN MIGHT REDUCE HEAT HYPERSENSITIVITY
Heat but Not Mechanical Hypersensitivity Depends on Voltage-gated Ca V 2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin
DuBreuil DM, Lopez Soto EJ, Daste S, Meir R, Li D [et al.], Lipscombe D
Published in Journal of Neuroscience on August 5, 2021 | *Summary available

SENSORIMOTOR ORGANOIDS WITH PHYSIOLOGICALLY FUNCTIONAL NEUROMUSCULAR JUNCTIONS
Human Sensorimotor Organoids Derived from Healthy and Amyotrophic Lateral Sclerosis Stem Cells Form Neuromuscular Junctions
Pereira JD, DuBreuil DM, Devlin AC, Held A, Sapir Y [et al.], Wainger BJ
Published in Nature Communications on August 6, 2021 | *Summary available

CELL-FREE DNA ANALYSIS OF CSF TO DETECT LEPTOMENINGEAL DISEASE
Detection of Leptomeningeal Disease Using Cell-Free DNA From Cerebrospinal Fluid
White MD, Klein RH, Shaw B, Kim A, Subramanian M [et al.], Brastianos PK
Published in JAMA Network Open on August 9, 2021 | *Summary available

PRISON CROWDING AND COVID-19 RATES
Association Between Prison Crowding and COVID-19 Incidence Rates in Massachusetts Prisons, April 2020 - January 2021
Leibowitz AI, Siedner MJ, Tsai AC, Mohareb AM
Published in JAMA Internal Medicine on August 9, 2021 | *Summary available | Press Release

GLUCOCORTICOID USE AND ITS CORRELATION WITH MELANOMA PATIENT SURVIVAL OUTCOMES DURING ANTI PD-1 MONOTHERAPY
Early Use of High-dose-glucocorticoid for the Management of irAE is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy
Bai X, Hu J, Betof Warner A, Quach HT, Cann CG [et al.] Boland GM
Published in Clinical Cancer Research on August 10, 2021 | *Summary available

ADPRT TOXINS ARE NOT PATHOGEN RESTRICTED BUT WIDELY PREVALENT IN THE HUMAN GUT MICROBIOME
Gut Microbiome ADP-ribosyltransferases are Widespread Phage-encoded Fitness Factors
Brown EM, Arellano-Santoyo H, Temple ER, Costliow ZA, Pichaud M [et al.], Xavier RJ
Published in Cell Host Microbe on August 10, 2021 | *Summary available

INSIGHTS INTO GUT-MEDIATED METABOLISM EFFECTS ON IMMUNITY
Gut Microbiome-mediated Metabolism Effects on Immunity in Rural and Urban African Populations
Stražar M, Temba GS, Vlamakis H, Kullaya VI, Lyamuya F [et al.], Xavier RJ
Published in Nature Communications on August 11, 2021 | *Summary available

DISPARITIES IN CANCER TRIAL ENROLLMENT
Disparities in Phase 1 Cancer Clinical Trial Enrollment
Perni S, Moy B, Nipp RD
Published in Cancer on August 11, 2021 | *Summary available

CONVERSATIVE MANAGEMENT OF ASYMPTOMATIC PENETRATING AORTIC ULCERS
Prognostication of Asymptomatic Penetrating Aortic Ulcers: A Modern Approach
DeCarlo C, Latz CA, Boitano LT, Kim Y, Tanious A [et al.], Dua A
Published in Circulation on August 11, 2021 | *Summary available

WHY PARP INHIBITOR IS MORE EFFECTIVE IN TREATING BRCA1/2 DEFICIENT TUMORS
The Trans Cell Cycle Effects of PARP Inhibitors Underlie Their Selectivity Toward BRCA1/2-deficient Cells
Simoneau A , Xiong R , Zou L
Published in Genes & Development on August 12, 2021 | Press Release

A POTENTIAL STRATEGY TO ENHANCE MYCARDIAL COMPLEXITY AND MATURITY IN VITRO
Human iPS-derived Pre-Epicardial Cells Direct Cardiomyocyte Aggregation Expansion and Organization In Vitro
Tan JJ, Guyette JP, Miki K, Xiao L, Kaur G [et al.], Ott HC
Published in Nature Communications on August 17, 2021 | *Summary available | Press Release

THE ROLE OF MyoD in MYOGENIC REPROGRAMMING
Dissecting Dual Roles of MyoD During Lineage Conversion to Mature Myocytes and Myogenic Stem Cells
Yagi M, Ji F, Charlton J, Cristea S, Messemer K [et al.], Hochedlinger K
Published in Genes & Development on August 19, 2021 | *Summary available | Press Release

IMAGING CELL IMMUNOTHERAPY RESPONSES IN VIVO
Single-Cell Imaging of T Cell Immunotherapy Responses In Vivo
Yan C, Yang Q, Zhang S, Millar DG, Alpert EJ [et al.], Langenau DM
Published in Journal of Experimental Medicine on August 20, 2021 | *Summary available

Publication Summaries

Humans developed immune responses to prevent infection from pathogens including Salmonella, a cause of food-related illnesses. Pathogens, similarly, evolved strategies to evade these responses. We describe in new detail how human cells fight Salmonella infection and how the bacteria fight back. The composition of cellular membranes, specifically the amount of a lipid called PI(4)P, is important to prevent Salmonella from multiplying. The human protein SAC1 and Salmonella protein SteA work in opposing ways: SAC1 reduces membrane PI(4)P, protecting against infection, while SteA exploits excess PI(4)P to promote bacterial growth. These findings provide a potential target for therapeutics against bacterial infection.

(Summary submitted by Kimberly L. Carey, PhD, Broad Institute of MIT and Harvard)

Breast cancer-related lymphedema (BCRL) is a highly feared side effect of breast cancer treatment that is characterized by swelling of the upper extremity or trunk on the side of treatment. Though a high preoperative body mass index is a well-established risk factor for BCRL, our study demonstrated that in a cohort of 1,161 women, those who lost weight postoperatively did not have a decreased risk of developing BCRL compared to those who gained weight. Therefore, health care providers should focus on weight changes to meet the goal of overall health maintenance rather than to protect against BCRL.

(Summary submitted by Sacha A Roberts, Department of Radiation Oncology)

In this qualitative study, we conducted 15 focus groups to define an effective senior resident and describe the process of leadership and nontechnical skill development in the transition from a junior to senior surgery resident. We found that senior residents are responsible for managing the big picture of patient care and ideal traits of effective seniors, such as emotional intelligence and inherent personality traits, allow a resident to more naturally assume this role. Teachable skills, such as communication, expectation setting and clinical competence, can be taught to improve one's effectiveness. Temporal progression through residency allows nearly all juniors to become senior residents but personal engagement enhances the process. The actions of a senior resident impact the team and patient care, which underscores the importance of understanding this role.

(Summary submitted by Taylor Makena Coe, MD, Department of Surgery)

Folfirinox is an aggressive chemotherapy combination that has improved outcomes in pancreatic cancer and colorectal cancer. In this study, we applied this regimen as a preoperative treatment with Folfirinox followed by chemoradiation for locally advanced esophagogastric cancer. In this 25-patient study, we demonstrated that 1) completion rates are high; 2) the likelihood of eradication of the tumor (pathologic complete response) was 31%, which is higher than usually seen; and 3) ctDNA clearance was highly associated with improved survival. This promising study has led to a new study (PI Hong) being conducted by our team at Mass General, which will be a formal 40 patient phase II study to confirm the effectiveness of this regimen.

(Summary submitted by Theodore S. Hong, MD, Department of Radiation Oncology, Mass General Cancer Center)

EARLY LIFE SYSTEMS-CHANGE INTERVENTION WITH COACHING IMPROVES INFANT WEIGHT STATUS AND MATERNAL POSTPARTUM CARE
Twelve-Month Outcomes of the First 1000 Days Program on Infant Weight Status
Taveras EM, Perkins ME, Boudreau AA, Blake-Lamb T, Matathia S [et al.], Cheng ER
Published in Pediatrics on August 1, 2021

The First 1,000 Days program implements changes across early-life clinical and public health systems to reduce obesity risk factors among low-income families. Mothers enroll during their first trimester and are supported through their child's second birthday. At six and 12 months of age, the program was associated with lower infant weight-for-length z scores and lower odds of overweight, compared to infants in comparison sites. Additionally, mothers in the intervention sites had higher odds of completing their postpartum visit. These findings suggest that an early-life system-change intervention holds promise to improve the population health of women and children.

(Summary submitted by Meghan E. Perkins, Pediatric Medical Services, Mass General for Children)

We studied patients with chronic hepatitis C (HCV), the only chronic viral infection treatable with drugs completely eliminating the virus. The hypothesis was that virus removal would stop the molecular triggers that cause the exhaustion of T cells, leading to dysfunctional immunity in cancer and chronic infections. While characterizing the phenotype, function and molecular regulation of T cells targeting HCV, we observed phenotypic changes after termination of infection that seemed to indicate recovery of T cells. However, functionality of the cells remained poor and key regulatory molecules were stuck in the exhausted state. Furthermore, T cells in the same patients that had received HCV stimulation for a shorter time after infection looked more like HCV-specific T cells in spontaneously resolved infection. Overall, our data show that T cells with long term exhaustion from chronic infection are scarred and cannot recover after termination of infection, whereas early exhaustion might offer a window for T cell recovery. These findings were extended by a companion study conducted by Dr. Sen and colleagues analyzing the same patients, demonstrating that the scarring is manifest in the epigenetic state of cells, the earliest regulating mechanism turning genes on or off within a cell.

(Summary submitted by Georg Lauer, MD PhD, Division of Gastroenterology, Department of Medicine)

Hypereosinophilic syndromes (HES) are a rare group of blood disorders that lead to the overproduction of eosinophils, a kind of white blood cell. Researchers investigated the rates of blood clots and death in patients with HES and the role of genetic mutations found on peripheral blood genetic testing (that is sometimes done to identify other blood disorders) on these outcomes. They found that in our group of patients with HES, almost one in four had at least one blood clot. We also showed that the presence of genetic mutations increases the risk of blood clots. Our paper also suggested that patients who had blood clots had an increased risk of death.

(Summary submitted by Orly Leiva, MD, Bellevue Hospital Center )

We reviewed state-of-the-art research on the study of lifestyle and environmental effects in diabetes. Using technological advances in characterizing small circulating molecules in the blood (and in other biospecimens and organs, such as the intestines), progress has recently been made in being able to study the precise effects of lifestyle and behavioral factors on the development and progression of diabetes. This promising area of research has the potential to improve the personalization and effectiveness of efforts to prevent and treat diabetes and its cardiovascular complications.

(Summary submitted by Matthew G. Nayor, MD, Department of Medicine, Division of Cardiology)

Ductal carcinoma in situ (DCIS) is considered a very early non-invasive form of breast cancer when cancerous cells develop and proliferate in the lining of the milk ducts, and have not spread beyond the milk ducts into the surrounding breast tissue. Breast MRI is the most sensitive imaging tool in the diagnosis of breast cancer. In women already diagnosed with DCIS, researchers found that preoperative MRI could help with planning their surgery and detecting any additional cancer in 6.2% of cases, paving the way to help optimize and individualize the prognosis and treatment plan for patients with newly diagnosed DCIS.

(Summary submitted by Shinn-Huey S Chou, MD, Department of Radiology)

Exercise improves brain health, including cognitive function. Developing drugs that reproduce the exercise benefit is an exciting, innovative approach to treating cognitive decline in aging and Alzheimer's disease (AD). The team showed for the first time that the soluble irisin hormone, not its full-length parent protein FNDC5, can confer these cognitive exercise benefits. Mouse models genetically lacking irisin displayed impaired cognitive function during exercise, aging and AD. These changes were partly caused by altered newborn neurons in the hippocampus. Importantly, elevating irisin levels in the bloodstream improved cognitive function and neuroinflammation in multiple AD mouse models. This identifies irisin as a potential therapeutic for cognitive disorders, including AD.

(Summary submitted by Christiane Dorothea Wrann, PhD, DVM, Division of Cardiology, Department of Medicine)

Lung cancer remains the leading cause of cancer-associated death in the United States and worldwide. Unlike patients with the subtype called lung adenocarcinoma, who have benefited from the development of new targeted medicines, the search for effective new therapies for another subtype called lung squamous cell carcinoma (LSCC) has largely come up short. We brought proteomic, transcriptomic and genomic data together to develop a detailed "proteogenomic" view of LSCC, gaining new insights into its biology, identifying immune regulation pathways that might help the cancer evade immunotherapies, identifying potential new drug targets and even revealing a new molecular subtype of LSCC.

(Summary submitted by Michael Gillette, MD, PhD, Division of Pulmonary & Critical Care Medicine, Department of Medicine)

CaV2.2 voltage-gated calcium channels are important for detection of noxious stimuli and transmission of pain information. CaV2.2 channel inhibitors provide analgesia, but their use is limited due to severe side effects and invasive administration methods. In this study, the researchers discovered a new role for CaV2.2 channels in the peripheral nervous system where they are critical for pathological hypersensitivity related to inflammation. CaV2.2 channels are present in nerve fibers that innervate the skin and contribute to release of inflammatory signals that promote increased sensitivity to heat. These findings identify a new mechanism by which we may be able to interrupt inflammatory pain at its source.

(Summary submitted by Daniel M. Dubreuil, PhD, Department of Neurology)

Our study demonstrates how human stem cells can generate cell types and functional synapses that are important for sensory and motor nervous systems. The synapse between spinal motor neurons and skeletal muscle, the neuromuscular junction, is an early site of degeneration in amyotrophic lateral sclerosis (ALS). Using human stem cells from individuals with ALS, the authors show that the function and structure of the modeled neuromuscular junctions are impaired compared to those from healthy control stem cells. The strategy may be used in future studies to understand the roles of different cell types in sensorimotor diseases.

(Summary submitted by Brian Wainger, MD, PhD, Department of Anesthesia, Critical Care and Pain Medicine)

CELL-FREE DNA ANALYSIS TO DETECT LEPTOMENINGEAL DISEASE
Detection of Leptomeningeal Disease Using Cell-Free DNA From Cerebrospinal Fluid
White MD, Klein RH, Shaw B, Kim A, Subramanian M [et al.], Brastianos PK
Published in JAMA Network Open on August 9, 2021

Cell-free DNA consists of tumor genomic material released into the surrounding fluid that can be detected accurately by advanced DNA sequencing techniques. This study demonstrated that cell-free DNA can serve as a fingerprint for tumor DNA released into the cerebrospinal fluid by tumor in leptomeningeal carcinomatosis and confirmed the limited sensitivity of the "gold-standard-cytology." As the study was done retrospectively, prospective data will help solidify the hypothesis that cell-free DNA is more sensitive and specific to LMD than cytology and MRI, as well as give preliminary insight into whether earlier detection and clinical trial enrollment leads to better outcomes.

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

PRISON CROWDING AND COVID-19 RATES
Association Between Prison Crowding and COVID-19 Incidence Rates in Massachusetts Prisons, April 2020-January 2021
Leibowitz AI, Siedner MJ, Tsai AC, Mohareb AM
Published in JAMA Internal Medicine on August 9, 2021

People who are incarcerated in U.S. prisons are 5 to 7 times more likely to contract COVID-19 than the general population. Throughout the pandemic, public health experts have called for decarceration, or strategies to reduce the prison population through the release of inmates who are at low risk for re-offending. The research team investigated the association between prison crowding and COVID-19 incidence in Massachusetts state prisons. Using different measures of prison crowding, the team found that COVID-19 incidence was consistently higher in prisons that were overcrowded, particularly during periods of high community transmission. These findings support the implementation of decarceration and infection control measures to reduce the burden of COVID-19 among people who are incarcerated.

(Summary submitted by Amir Moheb Mohareb, MD, Infectious Disease Unit, Department of Medicine)

GLUCOCORTICOID USE AND ITS CORRELATION WITH MELANOMA PATIENT SURVIVAL OUTCOMES DURING ANTI PD-1 MONOTHERAPY
Early Use of High-dose-glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy
Bai X, Hu J, Betof Warner A, Quach HT, Cann CG [et al.] Boland GM
Published in Clinical Cancer Research on August 10, 2021

The use of immune checkpoint inhibitors (ICI), such as anti-PD-1, for metastatic melanoma is associated with side effects termed immune-related adverse events (irAE). Previous studies have shown that a subset of irAE correlate with better outcomes, suggesting there may be shared biology between response to ICI and irAE. Researchers performed a retrospective, multi-institutional, multi-national study that demonstrates that irAE treated with high dose steroids within the first eight weeks of starting ICI resulted in worse progression-free and overall survival. Therefore, clinicians should consider the judicious use of steroids for toxicity within the first two months of ICI initiation.

(Summary submitted by Genevieve Marie Boland, MD, PhD, Division of Gastrointestinal & Oncologic Surgery, Department of Surgery, Mass General Cancer Center)

Scientists have thought that bacterial ADP-ribosyltransferases (ADPRTs) are toxins involved in pathogenesis. But this study found that these proteins are common in commensal bacteria in the gut microbiome and often linked with phage elements. The team found that Bxa, an abundant ADPRT in Bacteroides, is secreted and can ADP-ribosylate non-muscle myosin II proteins. In epithelial cells, Bxa remodeled the actin cytoskeleton and caused secretion of inosine, which is used as a carbon source by a bxa-encoding Bacteroides to colonize the gut in high numbers. The results suggest that ADPRTs may act as bacterial fitness factors.

(Summary submitted by Ramnik Xavier, MD, PhD, Division of Gastroenterology, Department of Medicine)

The human gut microbiome is an important modulator of innate and adaptive immunity. Pinpointing causal mechanisms that impact immune responses requires exploring the full diversity of microbiome composition and function. From a Tanzanian cohort encompassing a range of environments, lifestyles and diets, researchers uncovered a gradient of microbial composition from rural through urban populations. They identified 34 microbes that modulate circulating cytokines and provide evidence supporting the involvement of histidine and arginine metabolism pathways in microbial modulation of host immunity. Gaining a better understanding of host-microbe communication will aid in development of more personalized therapeutic strategies or dietary interventions.

(Summary submitted by Heather Kang, PhD, Division of Gastroenterology, Department of Medicine)

DISPARITIES IN CANCER TRIAL ENROLLMENT
Disparities in Phase 1 Cancer Clinical Trial Enrollment
Perni S, Moy B, Nipp RD
Published in Cancer on August 11, 2021

Phase 1 trials are increasingly important in the molecularly driven era of oncology. Researchers conducted a study using serial samples of 2,657 patients enrolling on cancer trials, investigating factors associated with phase 1 versus phase 2/3 trial enrollment. Adjusting for age, sex, race, ethnicity, insurance status, marital status, income, cancer type, disease status, travel distance and trial year, we found that Black, and Hispanic/Latinx patients were significantly less likely to enroll on phase 1 trials versus phase 2/3 trials, suggesting a need for targeted interventions to improve access to and education about phase 1 trials for Black and Hispanic/Latinx patients.

(Summary submitted by Subha Perni, MD, Department of Radiation Oncology)

Penetrating aortic ulcer (PAU) is a rare condition where patients have small outpouchings from their aorta, which is the largest artery in the body. Occasionally, PAU can cause symptoms (most commonly chest, back or abdominal pain), however most do not and are found incidentally on imaging. The management and prognosis of asymptomatic PAU has mostly been unknown. In this study, we show that asymptomatic PAU generally have a benign course. They rarely enlarge in size and adverse events (such as symptoms, rupture or requiring an intervention) are rare, affecting 6% of patients at 10 years, postdiagnosis.

(Summary submitted by Charles Sylvester Decarlo, MD, Department of Surgery)

This study shows that we can direct the formation of pre-epicardial cells (cells that play a key role during cardiac development), and use these cells to enhance the maturation of stem cell derived cardiomyocytes in 3D. These findings aim to elevate directed differentiation of human induced pluripotent stem cells more towards the idea of directed morphogenesis, in engineering more complex and mature cardiac tissue. While there are many more steps still required to complete the puzzle of heart development, the present manuscript adds an important piece that will hopefully help us and others in recapitulating cardiac development to generate novel therapies for heart failure.

(Summary submitted by Harald Ott, MD, Department of Surgery, Division of Thoraic Surgery, Mass General Cancer Center)

Induction of the muscle regulatory gene MyoD converts skin cells to mature muscle cells, and additional modulation of signaling pathways facilitates reprogramming to more primitive induced myogenic progenitor cells (iMPCs). The researchers show that iMPCs are molecularly highly similar to muscle stem cells, and that removal of DNA-methylation is essential for acquiring a stem cell-like state. Importantly, iMPCs give rise to more stable and mature muscle cells than skin cells exposed to MyoD alone. These findings may facilitate the generation of other relevant stem cell types and lead to new strategies for the study and treatment of muscle-related diseases.

(Summary submitted by Masaki Yagi, PhD, Department of Genetics, Mass General Cancer Center)

IMAGING T CELL IMMUNOTHERAPY RESPONSES IN VIVO
Single-Cell Imaging of T Cell Immunotherapy Responses In Vivo
Yan C, Yang Q, Zhang S, Millar DG, Alpert EJ [et al.], Langenau DM
Published in Journal of Experimental Medicine on August 20, 2021

T cells and immunotherapies can coax the immune system to kill cancer cells. Yet, a major hurdle in T cell immunotherapies has been the lack of predictive preclinical animal models for use in large scale studies. We created zebrafish that grow human cancer and can be treated with a wide array of T cell immunotherapies. This new model imaged therapy responses at single cell resolution, capturing how T cell therapies engage with tumor cells to kill them. The work also identified an immunotherapy approach for the treatment of childhood muscle cancers, providing much needed rationale to move these therapies forward in the clinical setting.

(Summary submitted by Chuan Yan, PhD, Department of Pathology, Mass General Cancer Center)

Press Releases

The Hormone Irisin is Found to Confer Benefits of Exercise on Cognitive Function
Featuring Christiane Wrann, DVM, PhD

For the first time scientists have shown that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. This approach could lead to a therapeutic for patients with Alzheimer's disease and other neurodegenerative diseases.

New Insights on Mechanism That Could Help Treat Muscle-related Diseases
Featuring Konrad Hochedlinger, PhD, and Masaki Yagi, PhD

Investigators who previously developed a recipe for turning skin cells into primitive muscle-like cells that can be maintained indefinitely in the lab without losing the potential to become mature muscle have now uncovered how this recipe works and what molecular changes it triggers within cells. The study could allow clinicians to generate patient-matched muscle cells to help treat muscle injuries, aging-related muscle degeneration, or conditions such as muscular dystrophy.

Study Reveals Trends in Opioid Overdose Deaths in Nine States During the COVID-19 Pandemic
Featuring Mohammad S. Jalali, PhD, and Gian-Gabriel P. Garcia, PhD

During the COVID-19 pandemic, opioid overdose death rates increased in five of nine states examined. These increases reflect emergent trends that were not present in the previous two years. The demographic groups most affected by opioid overdose may be shifting.

New Research May Help Scientists Grow More Complex and Mature Heart Tissue in the Lab
Featuring Harald Ott, MD

Researchers have generated premature cells, called peri-epicardial cells, that support early heart development. The advance may help scientists recapitulate cardiac development to generate novel therapies for heart failure.

Researchers Identify Mechanisms of Resistance to Drug for Triple-Negative Breast Cancer
Featuring Aditya Bardia, MD, MPH, and Leif Ellisen, MD, PhD

Triple-negative breast cancer cells exposed to the antibody-drug conjugate sacituzumab govitecan may develop resistance to this powerful drug through alterations in both the target of the antibody and the target of the toxic payload. The findings illustrate how uncovering such mechanisms will critically inform strategies to overcome resistance to sacituzumab govitecan.

No Indication of COVID-19 Spread from Pro Football Events with Limited Attendance
Featuring Jagpreet Chhatwal, PhD

Investigators matched counties hosting NFL or NCAA games with in-person attendance in 2020 and 2021 with counties hosting games with no in-person attendance. Games with in-person attendance were not followed by spikes in COVID-19 cases in surrounding communities.

With Delta Variant Dominance, Simulator Predicts Surge in COVID-19 Deaths in Most of U.S.
Featuring Jagpreet Chhatwal, PhD

With the dominance of the COVID-19 Delta variant, the COVID-19 Simulator predicts that in several states, daily COVID-19 related deaths could exceed the peak daily deaths that occurred in early 2021.

Researchers Pinpoint How PARP Inhibitors Combat BRCA1 and BRCA2 Tumor Cells
Featuring Zou Lee, PhD

PARP inhibitors, used to treat patients with cancer of the breast, ovaries, prostate and pancreas, work by inducing persistent DNA gaps in tumor cells with BRCA1 and BRCA2 mutations. The discovery offers the potential to monitor tumors for the development of resistance to PARP inhibitor therapy, and to identify drug combinations that could improve the efficacy of cancer therapies.

CDC's Honor System Mask Guidance Threatened Vulnerable Communities
Featuring Simar Bajaj and Fatima Cody Stanford, MD, MPH, MPA, MBA

In a commentary, two Mass General researchers argue that this policy was premature and doomed to fail, with the Black community and other racial and ethnic minority groups most likely to suffer the consequences.

Scientists Discover How Immune Cells Survive Their Battle with Cancer
Featuring Thorsten Mempel, MD, PhD

New research uncovers some of the key factors that are needed for survival of immune cells in the battle against cancer. The findings point to potential therapeutic targets to tip the scales so that the immune system can effectively defeat aggressive cancers.

Crowding in Prisons Increases Inmates' Risk for COVID-19 Infections
Featuring Amir Mohareb, MD

Earlier research indicated that prison inmates have a significantly higher risk for COVID-19 infections compared to the general population. A new study offers powerful evidence that facility crowding is a major driver of this increased risk.

Preoperative Screening Urinalysis is Widely Used But Usually Unnecessary
Featuring Erica S. Shenoy, MD, PhD, Mia Giuriato, BBA, MA, and Zirui Song, MD, PhD

A new study finds that nearly nine out of 10 of preoperative urinalyses are unnecessary. Overuse of low-value screening tests wastes money, can harm patients and may contribute to the growing problem of antibiotic resistance.

Unsupervised AI Breaks New Ground by Predicting the Progression of COVID-19 and Survival of Patients Directly from Their Chest CT Images
Featuring Hiroyuki Yoshida, PhD

The study found that the prediction performance of the unsupervised AI model was significantly higher and the prediction error significantly lower than those of the previously established reference predictors.

Reducing Sugar in Packaged Foods Can Prevent Disease in Millions
Featuring Siyi Shangguan, MD, MPH

A new economic and health model estimates that cases of cardiovascular disease and diabetes in the U.S. would drop substantially if the food industry reformulates sugary products in 15 food categories.

Large Genetic Analysis Identifies Numerous Gene Variants Linked with Differences in Food Intake
Featuring Jordi Merino, RD, PhD, and Hassan Dashti, PhD

In a genome-wide association study, 26 genetic regions were associated with preferences for foods with increased protein, fat or carbohydrate. Two main clusters of genetic variants were differently associated with obesity and coronary artery disease.

Blog Posts

Conversations with Margarita: Suffering in Silence
Featuring Margarita Alegría, PhD

Dr. Alegría discusses why it is so hard for people to put their mental health first.

How Does Maternal Marijuana Use Affect the Developing Fetus? Researchers Call for New Studies to Find Out More
Featuring Nicole Zürcher Wimmer, PhD

With an increasing number of states approving marijuana for medical and recreational use, it's easy to think of the drug as relatively harmless. But despite its perceived safety, its use during pregnancy is questionable, with a growing recognition that maternal marijuana use can cause disruptions in placental function and fetal development.

Humans of MGRI: Nitasha Siddique

Nitasha Siddique, a clinical research coordinator in the Dunn Lab within the Center for Genomic Medicine, supports research exploring the biological mechanisms of childhood adversity and resilience.

Conversations with Margarita: Going Beyond the Numbers
Featuring Margarita Alegría, PhD

Dr. Alegría discusses two important pieces of our data infrastructure that need to be reexamined if we want to make our public health systems be more equitable: who should be involved in collecting data and what we should be measuring.

3D Printed Radioprotective Devices Could Reduce Painful GI Injuries in Cancer Patients
Featuring James Byrne, MD, PhD, and Carlo Giovanni Traverso, MB, BChir, PhD

Researchers from Massachusetts General Hospital, Brigham and Women's Hospital, Dana-Farber Cancer Institute and MIT are developing a new set of personalized, 3D printed, radioprotective devices that could vastly improve the protection of healthy tissues without compromising the effectiveness of cancer treatment.

Three Lessons from the Advancing Innovation in Dermatology Conference 2021

Doctors are ideally positioned to identify and solve challenges in patient care but need the support of industry to succeed.

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Snapshot of Science for August 2021