Snapshot of Science for July 2023

Welcome to our Snapshot of Science for July 2023.

 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: 

38 new studies published in high-impact journals, along with 31 summaries submitted by the research teams 
8 new research-related press releases
9 posts from the Mass General Research Institute blog
5 research spotlights

Publications

CRISPR-Cas13a: Advancing Cancer Diagnosis via Multiplexed EV Analysis
CRISPR/Cas13a-Based MicroRNA Detection in Tumor-Derived Extracellular Vesicles
Hong JS, Son T, Castro CM, Im H
Published in Advanced Science on 6/20/23 | *Summary available

Brain Injury Risk in Football Tied to Head Impact Severity and Frequency
Leveraging Football Accelerometer Data to Quantify Associations Between Repetitive Head Impacts and Chronic Traumatic Encephalopathy in Males
Daneshvar DH, Nair ES, Baucom ZH, Rasch A, Abdolmohammadi B [et al.], Mez J
Published in Nature Communications on 6/20/23 | *Summary available

Enhancing Care for Spanish-Speaking Patients with Down Syndrome and Caregivers
Healthcare Experiences of Patients with Down Syndrome from Primarily Spanish-speaking Households
Chung J, Krell K, Pless A Jr, Michael C, Torres A [et al.], Skotko BG
Published in American Journal of Medical Genetics on 6/20/23 | *Summary available | Press Release

Boosting Cancer Immunotherapies with the Power of B Lymphocytes
B-cell-specific Checkpoint Molecules That Regulate Anti-tumour Immunity
Bod L, Kye YC, Shi J, Torlai Triglia E, Schnell A [et al.], Kuchroo VK
Published in Nature on 6/21/23 | *Summary available

Unraveling Immune Suppression in Lymph Nodes
Cancer Cell Plasticity and MHC-II-mediated Immune Tolerance Promote Breast Cancer Metastasis to Lymph Nodes
Lei PJ, Pereira ER, Andersson P, Amoozgar Z, Van Wijnbergen JW [et al.], Padera TP
Published in Journal of Experimental Medicine on 6/21/23 | *Summary available

Understanding Tau Aggregation and Distinguishing Tauopathies in Alzheimer's Disease
Specific Post-translational Modifications of Soluble Tau Protein Distinguishes Alzheimer's Disease and Primary Tauopathies
Vanparys AAT, Huyghe NDG, Herinckx G, Johanns M, Boyer E [et al.], Hanseeuw BJ
Published in Nature Communications on 6/22/23 | *Summary available

Sex-Based Disparity in Liver Transplant Access and Outcomes
Sex-based Disparities in Access to Liver Transplantation for Waitlisted Patients With Model for End-stage Liver Disease Score of 40
Cron DC, Braun HJ, Ascher NL, Yeh H, Chang DC, Adler JT
Published in Annals of Surgery on 6/27/23 | *Summary available

Implication of Emerging Trends in Cancer Mortality Among the US Hispanic Population
US Cancer Mortality Trends Among Hispanic Populations From 1999 to 2020
Pompa IR, Ghosh A, Bhat S, Ragala S, Nwiloh A [et al.], Kamran SC
Published in JAMA Oncology on 6/29/23 | *Summary available

Enhancing Autophagy Reduces Inflammation and Identifies New Regulators
Constitutively Active Autophagy in Macrophages Dampens Inflammation Through Metabolic and Post-transcriptional Regulation of Cytokine Production
Xu J, Kong L, Oliver BA, Li B, Creasey EA [et al.], Xavier RJ
Published in Cell Reports on 6/30/23

Exploring Genomic Adaptation in Pathogenic Bacteria with Phase Variants in MTBC
Phase Variation as a Major Mechanism of Adaptation in Mycobacterium Tuberculosis Complex
Vargas R Jr, Luna MJ, Freschi L, Marin M, Froom R [et al.], Farhat MR
Published in PNAS on 7/3/23

Discordant Estimated Glomerular Filtration Rates in Cancer Patients
Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer
Hanna PE, Wang Q, Strohbehn IA, Moreno D, Harden D [et al.], Sise ME
Published in JAMA Network Open on 7/3/23 | *Summary available

Effective Management of Gastroesophageal Reflux Symptoms Improves Sleep Quality 
Assessment of Gastroesophageal Reflux Symptoms and Sleep Quality Among Women in the Nurses' Health Study II
Ha J, Mehta RS, Cao Y, Huang T, Staller K, Chan AT
Published in JAMA Network Open on 7/3/23 | *Summary available

Exercise-Induced Microvascular Benefits in Aging Brains
Aerobic Exercise Reverses Aging-induced Depth-dependent Decline in Cerebral Microcirculation
Shin P, Pian Q, Ishikawa H, Hamanaka G, Mandeville ET [et al.], Sakadžić S
Published in eLife on 7/4/23 | *Summary available

Researchers Pinpoint Protein Tied to Drug Resistance in Patients with Lung Cancer
Therapy-induced APOBEC3A Drives Evolution of Persistent Cancer Cells
Isozaki H, Sakhtemani R, Abbasi A, Nikpour N, Stanzione M [et al.], Hata AN
Published in Nature on 7/5/23 | *Summary available | Press Release

Long-Term Outcomes and Reassurance of Clonal Hematopoiesis in Young Breast Cancer Survivors
Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Gibson CJ, Fell G, Sella T, Sperling AS, Snow C [et al.], Miller PG
Published in American Association for Cancer Research on 7/5/23 | *Summary available

Positive Impact of a Multi-ancestry Polygenic Risk Score for Coronary Artery Disease Prediction
A Multi-ancestry Polygenic Risk Score Improves Risk Prediction for Coronary Artery Disease
Patel AP, Wang M, Ruan Y, Koyama S, Clarke SL [et al.], Khera AV
Published in Nature Medicine on 7/6/23 | *Summary available

An Analysis of Dialysis Patients and Facilities with Insurance Coverage and Access to Kidney Transplantation
The Association of Dialysis Facility Payer Mix With Access to Kidney Transplantation
Cron DC, Tsai TC, Patzer RE, Husain SA, Xiang L, Adler JT
Published in JAMA Network Open on 7/11/23 | *Summary available

Using Cytisinicline as a Promising Treatment for Smoking Cessation
Cytisinicline for Smoking Cessation: A Randomized Clinical Trial
Rigotti NA, Benowitz NL, Prochaska J, Leischow S, Nides M [et al.], Jacobs C
Published in JAMA Network Open on 7/11/23 | *Summary available | Press Release

Role of Heteroaromatic Small Molecules in Origin-of-life Research
Small-Molecule Organocatalysis Facilitates In Situ Nucleotide Activation and RNA Copying
Aitken HRM, Wright TH, Radakovic A, Szostak JW
Published in Journal of the American Chemical Society on 7/11/23

Antigen Prediction and Immune Response Analysis
HLA-II Immunopeptidome Profiling and Deep Learning Reveal Features of Antigenicity to Inform Antigen Discovery
Stražar M, Park J, Abelin JG, Taylor HB, Pedersen TK [et al.], Graham DB
Published in Immunity on 7/11/23 | *Summary available

The Importance of Macrophages in Atrial Fibrillation Pathogenesis
Recruited Macrophages Elicit Atrial Fibrillation
Hulsmans M, Schloss MJ, Lee IH, Bapat A, Iwamoto Y [et al.], Nahrendorf M
Published in Science on 7/13/23 | *Summary available | Press Release

Unraveling Platelet Shape-shifts for Drug Development and Function
Cryo-EM Structures of Full-length Integrin αIIbβ3 in Native Lipids
Adair BD, Xiong JP, Yeager M, Arnaout MA
Published in Nature Communications on 7/13/23 | *Summary available

Improving Gene Prioritization in GWAS with Polygenic Priority Score
Leveraging Polygenic Enrichments of Gene Features to Predict Genes Underlying Complex Traits and Diseases
Weeks EM, Ulirsch JC, Cheng NY, Trippe BL, Fine RS [et al.], Finucane HK
Published in Nature Genetics on 7/13/23

Advancing Precision Medicine with Urinary Genomic Profiling for Bladder Cancer Diagnosis and Surveillance
Development and Multicenter Case-control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk Prediction
Salari K, Sundi D, Lee JJ, Wu S, Wu CL [et al.], Feldman AS
Published in American Association for Cancer Research on 7/13/23 | *Summary available

Rare Brain Tumor Responds to Targeted Tumor Treatment
BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas
Brastianos PK, Twohy E, Geyer S, Gerstner ER, Kaufmann TJ [et al.], Galanis E
Published in New England Journal of Medicine on 7/13/23 | *Summary available | Press Release

Applying Cancer-associated Mesothelial Cells for Ovarian Cancer Treatment
Cancer-associated Mesothelial Cells Are Regulated by the Anti-Müllerian Hormone Axis
Chauvin M, Meinsohn MC, Dasari S, May P, Iyer S [et al.], Pépin D
Published in Cell Reports on 7/14/23 | *Summary available

Role of ZFHX3 in Atrial Fibrillation Development
Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias
Jameson HS, Hanley A, Hill MC, Xiao L, Ye J [et al.], Ellinor PT
Published in American Heart Association on 7/14/23 | *Summary available

Role of H3K36 Methylation in Cell Identity 
H3K36 Methylation Maintains Cell Identity by Regulating Opposing Lineage Programmes
Hoetker MS, Yagi M, Di Stefano B, Langerman J, Cristea S [et al.], Hochedlinger K
Published in Nature Cell Biology on 7/17/23

Analysis of Disparities in Acute Heart Attack Care
Race-Based Differences in ST-Segment-Elevation Myocardial Infarction Process Metrics and Mortality From 2015 Through 2021: An Analysis of 178 062 Patients From the American Heart Association Get With The Guidelines-Coronary Artery Disease Registry
Osho A, Fernandes MF, Poudel R, de Lemos J, Hong H [et al.], Goyal A
Published in Circulation on 7/17/23 | *Summary available

Phase 3 Trial of Solanezumab and Early-Stage Alzheimer's Disease
Trial of Solanezumab in Preclinical Alzheimer's Disease
Sperling RA, Donohue MC, Raman R, Rafii MS, Johnson K [et al.], Aisen PS
Published in New England Journal of Medicine on 7/17/23 | *Summary available

"Weekend Warrior" Physical Activity Patterns Improves Heart Health 
Accelerometer-Derived "Weekend Warrior" Physical Activity and Incident Cardiovascular Disease
Khurshid S, Al-Alusi MA, Churchill TW, Guseh JS, Ellinor PT
Published in JAMA on 7/18/23 | *Summary available | Press Release

Regulation and Regulatory Function of Self-antigen-specific CD4+ T Cells for Lung Injury
Lung Injury Induces a Polarized Immune Response by Self-antigen-specific CD4+ Foxp3+ Regulatory T Cells
Shin DS, Ratnapriya S, Cashin CN, Kuhn LF, Rahimi RA, Anthony RM, Moon JJ
Published in Cell Reports on 7/19/23 | *Summary available

New Discovery of Autoimmune Response in Post-Infectious Lyme Arthritis
Autoimmunity to Synovial Extracellular Matrix Proteins in Patients with Post-infectious Lyme Arthritis
Kanjana K, Strle K, Lochhead RB, Pianta A, Mateyka LM [et al.], Steere AC
Published in Journal of Clinical Investigation on 7/20/23 | *Summary available

Functional Role of BMP5 in Hepcidin and Iron Homeostasis Regulation
BMP5 Contributes to Hepcidin Regulation and Systemic Iron Homeostasis in Mice
Xiao X, Xu Y, Moschetta GA, Yu Y, Fisher AL [et al.], Babitt JL
Published in Blood on 7/21/23

Role of NLRP11 in Human Macrophages in Sensing Bacterial Infection
NLRP11 is a Pattern Recognition Receptor for Bacterial Lipopolysaccharide in the Cytosol of Human Macrophages
Rojas-Lopez M, Gil-Marqués ML, Kharbanda V, Zajac AS, Miller KA [et al.], Goldberg MB
Published in Science Immunology on 7/21/23 | *Summary available | Press Release

The Early Ovarian Cancer Biomarkers and Detectors
Inaugurating High-Throughput Profiling of Extracellular Vesicles for Earlier Ovarian Cancer Detection
Jo A, Green A, Medina JE, Iyer S, Ohman AW [et al.], Lee H
Published in Advanced Science on 7/23/23 | *Summary available

REPRIEVE: Mitigating Heart Disease Risks in People Living with HIV Through Statin Therapy
Pitavastatin to Prevent Cardiovascular Disease in HIV Infection
Grinspoon SK, Fitch KV, Zanni MV, Fichtenbaum CJ [et al.], Douglas PS; REPRIEVE Investigators
Published in New England Journal of Medicine on 7/23/23 | *Summary available | Press Release

Role of ATR in Protecting DNA Replication Forks
ATR Protects Ongoing and Newly Assembled DNA Replication Forks Through Distinct Mechanisms
Leung W, Simoneau A, Saxena S, Jackson J, Patel PS [et al.], Zou L
Published in Cell Reports on 7/25/23

Publication Summaries 

Extracellular vesicles (EVs) are emerging circulating biomarkers for early cancer detection and post-treatment monitoring through blood tests. EVs carry protein and RNA markers reflecting the molecular status of their cellular origins. However, existing methods analyze either markers (protein or RNA), not fully harnessing their troves. Here, we developed a new sensing technology that enables multiplexed analysis of EV protein and RNA markers based on CRISPR-Cas13a technology. We demonstrate accurate quantification of tumor-derived EVs and significantly improved detection accuracy of ovarian cancer from the multiplexed EV analysis. This approach has the potential to further improve cancer diagnosis accuracy from liquid biopsies.

(Summary submitted by Hyungsoon Im, PhD, Center for Systems Biology)

In a new study of 631 deceased football players, the largest CTE study to date, scientists found that the number of diagnosed concussions alone was not associated with CTE pathology. Instead, football players’ odds of developing CTE were related to both how many head impacts they received and how hard the head impacts were. The study used an innovative new tool called a positional exposure matrix (PEM) that synthesized data from 34 independent studies to estimate the number and severity of football players’ head impacts over their careers.

(Summary submitted by Daniel H. Daneshvar, MD, PhD, Department of Physical Medicine and Rehabilitation)

A study of Spanish-speaking caregivers and primary care providers found that limited English proficiency, a lack of health information translated into Spanish, and systemic racism often undermine the care of patients with Down syndrome. The research team identified strategies for providers to bolster trust with families, including using on-site interpreters, offering patients with greater needs more time, and being open to cultural differences.

(Summary submitted by Brian Skotko, MD, MPP, Down Syndrome Program, Department of Pediatrics)

Over the past decade, novel therapies to treat cancer are focusing on boosting our own immune system, especially our “T lymphocytes”, to attack and remember any potential cancer cell. While these therapies dramatically change cancer care, they remain limited and about only 1 patient out 5 respond to these treatments. In this study, we harnessed another angle, exploiting another cell type called “B lymphocytes”, where we identified a molecular switch, allowing us to improve their anti-cancer function and consequently help T lymphocytes. This discovery increases the arsenal of immunotherapies, opening new avenues for cancer patients.

(Summary submitted by Lloyd Bod, PhD, Center for Cancer Research, Department of Medicine)

In breast cancer, adjacent lymph nodes play a crucial role in generating anti-cancer immune cells and often serve as the primary site of cancer metastasis. Subsequently, cancer cells can disseminate from the lymph nodes to other parts of the body. Our research has shed light on how cancer cells suppress anti-cancer immune responses within the lymph nodes, thereby facilitating their own survival and promoting metastatic spread. These significant findings could lead to novel strategies to prevent this immune suppression and unleash the immune system to fight cancer.

(Summary submitted by Pinji Lei, PhD, Department of Radiation Oncology)

Alzheimer’s disease and primary tauopathies are neurodegenerative disorders, which have in common the aggregation of tau protein in the brain. They differ by the type of tau isoform aggregating in the brain (either 4R or 3R-tau). Previous research has been unsuccessful to distinguish primary tauopathies using tau isoforms measures in fluid samples collected in-vivo. We demonstrated in human brain samples that the production of soluble tau isoforms is equivalent between tauopathies. However, specific modifications of the soluble tau protein (hence potentially detectable in-vivo) are associated with the aggregation of specific tau isoforms (i.e. specific diseases). Better understanding the process of tau aggregation is important for developing appropriate therapies in these different neurological disorders.

(Summary submitted by Hanseeuw Bernard, MD, PhD, Gordon Center for Medical Imaging, Department of Neurology)

In this national study of adult patients waitlisted for liver transplant, we document a sex-based disparity in access to liver transplant and waitlist outcomes among the sickest patients with the same disease severity-based allocation scores (i.e. patients with the same “MELD” score). Among patients with a MELD score of 40—the highest possible score—women were less likely to have a deceased donor liver offer accepted on their behalf, less likely to be transplanted, and more likely to die or be removed from the waiting list for being too sick. Solutions to this disparity may need to look beyond adjustments to the MELD calculation alone.

(Summary submitted by David Cron, MD, MS, Center for Surgery and Public Health, Department of Surgery)

Cancer is the leading cause of death among the US Hispanic population, despite Hispanic individuals generally having lower cancer incidence. Cancer death rates among Hispanic individuals have declined in general over the past two decades. However, our study found increasing rates of liver cancer deaths among both Hispanic men and women and increasing pancreas and uterine cancer deaths among Hispanic women. We found worrisome increasing cancer mortality rates among Hispanic men aged 25-34, likely due to increasing cancer mortality rates from colorectal and testicular cancers. Strategies such as improving access, screening, and education are needed to address these concerning trends.

(Summary submitted by Sophia Kamran, MD, Department of Radiation Oncology)

An analysis of 1869 patients with cancer within Mass General Brigham who had a simultaneous measurement of creatinine and cystatin C-based estimated glomerular filtration rate (eGFR) found that having a cystatin C based eGFR more than 30% lower than creatinine based eGFR was common (affecting 29% of the cohort), and was associated with medication-related adverse events including elevated vancomycin trough, trimethoprim/sulfamethoxazole-associated hyperkalemia, elevated digoxin levels, baclofen neurotoxicity, and an increased risk of death within 30 days. The work suggests that a subset of patients with cancer who have discordant eGFR may be receiving medications that are overdosed for their true eGFR.

(Summary submitted by Meghan E. Sise, MD, Department of Nephrology)

We report that having gastroesophageal reflux symptoms (i.e., heartburn and reflux) more frequently and for a longer duration is associated with an increased risk of having poor sleep quality in the future. Compared with individuals with gastroesophageal reflux symptoms less than once a month, those with symptoms more than once a week have around 1.5 times higher chance of having poor sleep quality after 4 years. The findings suggest that effective management of reflux symptoms may be important not only for the improvement of symptoms but also for the reduction of comorbidities associated with poor sleep quality.

(Summary submitted by Jane Ha, MD, Clinical & Translational Epidemiology Unit, Department of Medicine)

This study reveals for the first time that the age-related reductions in cerebral microvascular perfusion and oxygenation exhibit strong depth dependency, being significantly more pronounced in the deeper cortical layers and subcortical white matter than in the superficial cortical layers. Five months of voluntary exercise in old age not only ameliorated these changes but beneficially impacted deeper cortical layers and subcortical white matter significantly more than superficial cortical layers. Our work demonstrates the vulnerability of the deep cortex and white matter to aging-induced decline in microcirculation, as well as the responsiveness of these regions to exercise.

(Summary submitted by Paul Shin, PhD, Department of Radiology)

Humankind has encountered threats from viruses and evolved to survive, acquiring complex viral defense systems over time. Cancer cells also evolve when exposed to therapy, but less is known about the detailed mechanisms. We found that APOBEC (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like), a key restricter of viral infection, is responsible for the survival of drug-tolerant "persister" cells during targeted therapy in non-small-cell lung cancer. Targeted therapy can induce APOBEC3A, whose catalytic activity generates somatic mutations across the genome and increases genomic instability. Over 70% of patients exhibited APOBEC mutagenesis after targeted therapy. Genetic deletion of APOBEC3A delayed the acquired resistance in vitro. Thus, APOBEC3A drives the evolution of persister cancer cells, and inhibition of APOBEC3A is a potential new therapeutic strategy to prevent acquired resistance.

(Summary submitted by Hideko Isozaki, PhD, Mass General Cancer Center)

Patients who are treated with chemotherapy and radiation for cancer are more likely to have acquired mutations in their blood cells, termed clonal hematopoiesis of indeterminate potential (CHIP). Since CHIP has been associated with an increased risk of developing blood cancers and elevated mortality in aging populations, understanding factors that contribute to its development is important for our patient populations. We studied a group of women under 40 years old who were treated for breast cancer and found a low rate of CHIP one year after the completion of treatment, that the level of CHIP did not significantly change over a four-year interval, and that after nine years of follow up, individuals with CHIP did not have an increased risk of breast cancer relapse or mortality. These results should be reassuring to young women with breast cancer who are incidentally found to have CHIP, and to oncologists who use genomic assessments of peripheral blood in the care of their breast cancer patients.

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

Polygenic scores, which estimate an individual’s genetic risk for disease, have the potential to identify people at high risk to guide prevention strategies. Building on previous scores, researchers developed a new polygenic score for coronary artery disease (CAD) using data from genetic studies of CAD and related traits involving more than 1.2 million people from 5 ancestry groups. This new score outperforms previously published scores among participants of African, European, Hispanic, and South Asian ancestry. It can better identify individuals in the extremes of the genetic risk spectrum, including the top 3% of unaffected individuals who have risk for a future CAD event as high as people who’ve already been diagnosed with the disease.

(Summary submitted by Aniruddh Patel, MD, Cardiology Division, Department of Medicine)

In this national study of the relationship of insurance with access to kidney transplantation for dialysis patients and facilities, we found that patients with commercial insurance were more likely to be waitlisted for kidney transplant. However, for facilities with higher proportions of commercially insured patients, despite having presumably more resources due to higher revenue, access to transplant was no different compared to facilities with less commercially- (and more publicly-) insured patients. As the landscape of insurance coverage for dialysis continues to change, the potential impact on access to kidney transplantation must be monitored.

(Summary submitted by David Cron, MD, MS, Center for Surgery and Public Health, Department of Surgery)

Cigarette smoking remains the leading preventable cause of death worldwide, and new treatment options are needed. Cytisinicline, a plant-based alkaloid that binds to brain nicotine receptors, is a potential new medication to help smokers quit. This multi-site randomized clinical trial tested the drug’s efficacy and safety. It compared two durations of cytisinicline treatment (6 or 12 weeks) to placebo, with follow-up to 24 weeks, among 810 adult cigarette smoker who wanted to quit. Both cytisinicline treatment schedules were superior to placebo for producing continuous tobacco abstinence, and both were very well tolerated by participants. The findings suggest that cytisinicline may be a new smoking cessation treatment option.

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

Adaptive immunity relies on interactions between T cells and peptide antigens displayed by human leukocyte antigen class II (HLA-II). The principles underlying antigen presentation and recognition, however, remain incompletely understood. Using mass spectrometry, we profiled 358,024 peptides presented by 42 unique HLA-II molecules, generating a comprehensive dataset of HLA-II binding features. This data informed development of CAPTAn, a machine learning model for antigen prediction that incorporates HLA-II affinity and full protein sequence from which antigens are derived. CAPTAn accurately predicted antigens from SARS-CoV-2 and bacteria in the human microbiome, highlighting its capacity to facilitate discovery of disease-associated antigens and functional characterization of antigen-specific immune responses.

(Summary submitted by Heather Kang, PhD, Broad Institute)

Atrial fibrillation is the most common arrhythmia and a serious clinical problem. In our study, we compared atrial tissues from afib patients to controls. Macrophages were the most dynamically expanding cell population, and these cells became more inflammatory in character. To perturb macrophages, we created a new atrial fibrillation mouse model. Deletion of the pro-inflammatory and pro-fibrotic gene osteopontin drastically reduced atrial fibrillation burden in these mice, alongside atrial fibrosis and inflammation. The study indicates that macrophages and atrial inflammation are a major driver of atrial fibrillation, and could be targeted in future immunomodulatory therapeutics for arrhythmia.

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

Platelets are blood cells that rapidly react to bleeding from an injured blood vessel by inducing an activating shape-shift in the major platelet receptor αIIbβ3 allowing it to bridge platelets together, forming a clot to stop bleeding. Current αIIbβ3 inhibitory drugs reduce excessive blood clot formation that causes acute coronary syndromes and stroke, but inadvertently activate αIIbβ3 and lead to serious bleeding and paradoxical formation of additional blood clots. The 3-dimensional structure of the activating shape-shifts in membrane-bound αIIbβ3 has eluded scientists for decades. The present work provides the first atomic structures of native membrane-bound αIIbβ3 and the drug-induced shapeshifts leading to severe and potentially life-threatening side effects. The present studies are expected to enable the structure-guided development of new drugs to minimize these side effects while maintaining efficacy.

(Summary submitted by Brian Adair, PhD, Department of Nephrology)

The implementation of precision medicine in the management of urothelial carcinoma (bladder cancer) is a major challenge. New tools are needed for detecting both new diagnoses as well as recurrent disease for patients on surveillance. Quantification of genomic alterations in urine-derived DNA has notable promise to enhance risk stratification. Here, we validated a urinary comprehensive genomic profiling (uCGP) test that predicts the presence and pathologic grade of urothelial carcinoma. For initial diagnosis, uCGP had a validated sensitivity and specificity of 95% and 90%. For surveillance, uCGP significantly predicted future recurrence and pathologic grade. These findings demonstrate the utility of genomic medicine to support risk-adapted care for urothelial carcinoma.

(Summary submitted by Keyan Salari, MD, PhD, Department of Urology)

Papillary craniopharyngiomas are brain tumors that can be associated with significant symptoms, including visual deficits, hydrocephalus and endocrine abnormalities. We previously discovered that 95% of papillary craniopharyngiomas harbor BRAF V600E mutations. Our team translated these data to a national multicenter cooperative trial (Alliance A071601) and evaluated the efficacy of targeted therapy in this patient population. We reported that all patients who received one or more cycles of vemurafenib/cobimetinib had dramatic responses to therapy. Given that these types of responses are unprecedented for patients with brain tumors, this likely will lead to a paradigm in the clinical management of patients with papillary craniopharyngioma.

(Summary submitted by Priscilla Brastianos, MD, Central Nervous System Metastasis Center, Mass General Cancer Center)

During metastasis, invading ovarian cancer cells can alter the surrounding normal cells to promote tumor growth and immune evasion. The mesothelium lining covering abdominal organs represents the first point of contact for these cells during this process. In this study, we show how cancer cells reprogram mesothelial cells into pro-tumoral cancer-associated-mesothelium. We identify a hormone called Anti-Müllerian hormone, which is used by cancer cells to control the secretion of growth factors and immunosuppressive cytokines by cancer-associated mesothelial cells. Thus, targeting the mesothelial cells or disrupting the AMH paracrine axis may represent novel therapeutic opportunities for ovarian cancer.

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

Atrial fibrillation (AF) is the most common irregular heart rhythm and can lead to increased risk of stroke and death. More than a decade ago, genetic variants near the gene, ZFHX3, we found to be strongly associated with AF. In the current study, we found that these AF-related genetic variants altered expression of ZFHX3. We then found that deletion of Zfhx3 in the mouse heart resulted in the development of AF, increased size of the atria, and ultimately dilated cardiomyopathy. Our results reveal an important role for Zfhx3 in the development of AF and identified potential therapeutic targets for AF.

(Summary submitted by Heather Jameson, PhD, Cardiology Division, Department of Medicine)

Systems of care have been developed across the US to improve outcomes in patients with acute heart attacks. In this study, data from >175,000 patients enrolled in an American Heart Association registry were analyzed to investigate race-ethnicity based disparities in treatment and outcomes. Results demonstrated that Hispanic and Black/African American patients presenting with heart attacks were less likely than non-Hispanic White patients to receive a prehospital ECG or receive treatment within established target times (including time to reopen blocked coronary vessels). Future research will necessarily focus on defining strategies to eliminate disparities in care provided after heart attacks.

(Summary submitted by Asishana Avo Osho, MD, MPH, Division of Cardiac Surgery, Department of Surgery)

The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study ’s the first of its kind Phase 3 trial in preclinical AD, that is in cognitively normal older individuals with amyloid plaque build up in their brains at high risk for memory loss. The A4 Study tested solanezumab, an antibody aimed at soluble forms of amyloid, in 1168 individuals across four countries over 4 and 1/2 years. Unfortunately, there was no evidence that treatment with solanezumab slowed cognitive decline or decreased the likelihood of progression to mild cognitive impairment or dementia due to Alzheimer’s disease. Higher baseline levels of amyloid were strongly associated with risk of decline across both placebo and solanezumab treated groups. Solanezumab slightly slowed the rate of further amyloid accumulation but did not lower amyloid below baseline levels. These findings, as well as results from recent trials at later stages of Alzheimer’s disease, suggest that aggressive amyloid removal may be needed even at this very early stage of Alzheimer’s disease.

(Summary submitted by Reisa Sperling, MD, Center for Alzheimer Research and Treatment, Department of Neurology)

Physical activity is good for overall health. But it is unclear whether it is better to spread activity out, versus getting most activity in 1 or 2 days each week. Using wearable activity sensors in nearly 90,000 people, we compared three groups: those who spread their activity out, those who concentrated their activity in 1-2 days, and those who were not active. We found that both concentrated and more regular activity patterns were associated with very similar improvements in risk for bad health outcomes including atrial fibrillation (an abnormal heart rhythm), heart failure, heart attack, and stroke when compared to inactive people.

(Summary submitted by Shaan Khurshid, MD, MPH, Cardiology Division, Department of Medicine)

T cells can recognize virtually any foreign protein, which gives them the ability to establish adaptive immunity against pathogens. However, T cells can also recognize self proteins, creating a risk for autoimmunity if they become activated during inflammatory events. Using a mouse model of acute lung injury, we tracked a single self-reactive T cell population and found that only regulatory T cells within this population expand in response to inflammation. This polarized response requires IL-2 and limits harmful immune activity in the lungs. These findings highlight the predisposition of self-reactive T cells to maintaining immune tolerance during inflammation.

(Summary submitted by James Moon, PhD, Center for Immunology and Inflammatory Diseases, Department of Medicine)

In some patients, Lyme arthritis (LA), which is caused by a tick-borne infection, persists after appropriate oral and intravenous antibiotic therapy, called post-infectious Lyme arthritis. In the current study, we developed a novel approach to identify self-antigens which may trigger an infection-induced autoimmune response. We identified a subset of patients with post-infectious LA who developed T and B cell immune responses to 1 or more of 3 extracellular matrix proteins, fibronectin, laminin, and collagen. Clinical correlations suggested that these autoimmune responses are an important component of disease pathogenesis. This work has important implications for diagnosis and treatment of post-infectious LA

(Summary submitted by Allen Steere, MD, Rheumatology Unit, Department of Medicine)

Infection with bacteria triggers specific responses from the human immune system that help clear the infection. We discovered a protein (NLRP11) that is key to this response in human macrophages. We found that NLRP11 is critical to activation of a specific immune pathway that serves both to alert the host that an infection is occurring and to initiate an effective immune response designed to eradicate the infection. Because NLRP11 is present in humans but absent in mice, which are the most common laboratory model for human infection, including for the life-threatening syndrome sepsis, this discovery has the potential to aide in the development of improved humanized mouse models of sepsis and other infections and inflammatory diseases.

(Summary submitted by Marcia Goldberg, MD, Infectious Disease Unit, Department of Medicine)

Ovarian cancer often presents with advanced disease due to non-specific symptoms and poor biomarkers. This study is the first to explore extracellular vesicles (EVs) as a potential early biomarker in high-grade serous ovarian carcinoma (HGSOC). Leveraging the growing understanding that HGSOC originates in the fallopian tube, the researchers examined EVs derived from murine fallopian tube cells with oncogenic mutations and identified markers specific to this tissue. In a pilot study using human patient plasma, an EV biomarker signature was highly accurate in differentiating HGSOC, across all stages, from non-cancer cases. This innovative approach could be used to monitor women at risk of ovarian cancer, helping with early intervention management.

(Summary submitted by Cesar Castro, MD, MMSc, Division of Gynecologic Oncology, Mass General Cancer Center)

People living with HIV have up to a two-fold increased risk of heart disease, including strokes and heart attacks, which often happen even in young patients without symptoms. Until REPRIEVE, no treatments had been tested on a large scale to prevent the heart disease in this population. Critically, people living with HIV were not ordinarily offered standard treatments given their low traditional risk scores for heart disease. In REPRIEVE, we tested a once-a-day statin strategy, a pill known to simultaneously lower cholesterol and importantly reduce inflammation thought to contribute to heart disease in this population. We enrolled a diverse group of participants across the globe from 12 countries and showed a 35% reduction in heart attacks and strokes. No unexpected safety effects were seen.

(Summary submitted by Steven Grinspoon, MD, Metabolism Unit, Department of Medicine)

Press Releases

Study Analysis of Cancer Mortality Trends Reveals Disparities for Hispanic Populations 
Featuring Sophia C. Kamran, MD 

In multi-year study, Mass General Cancer Center researchers found increase in rates for liver cancer deaths among Hispanic men and rates for liver, pancreatic, and uterine cancer deaths among Hispanic women. An increase in cancer deaths among 25-34-year-old men also considered ‘striking’. 

First large U.S. clinical trial of cytisinicline finds the smoking cessation medication effective and well tolerated 
Featuring Nancy Rigotti, MD 

A Phase 3 clinical trial has demonstrated the safety and effectiveness of cytisinicline, a smoking cessation medication which, if approved by regulatory authorities, would become the first such product approved in this country in nearly 20 years. The multi-site randomized placebo-controlled study of 810 adult cigarette smokers showed a statistically significant increase in biochemically confirmed continuous abstinence for six months. There were no reports of drug-related serious adverse side effects. 

Rare Brain Tumor Responds to Targeted Tumor Treatment with ‘Unprecedented’ Success 
Featuring Priscilla Brastianos, MD 

Mass General Cancer Center’s precision medicine approach resulted in 91 percent reduction in tumor size, with all 15 patients who received one or more cycles of therapy responding to treatment. 

Mass General Cancer Center Researchers Pinpoint Protein Tied to Drug Resistance in Patients with Lung Cancer 
Featuring Aaron Hata, MD, PhD and Michael Lawrence, PhD 

Targeted therapies induced tumor expression of the APOBEC3A protein, which was shown to directly cause new mutations and accelerate the development of drug resistance. Discovery could help in development of new solutions for tumor drug resistance. 

Mass General Researchers Find Targeting Immune Cells May Help Treat Atrial Fibrillation 
Featuring Matthias Nahrendorf, MD, PhD 

Analyses of atrial heart tissue collected from patients with and without atrial fibrillation indicate that immune cells called macrophages expand more than any other cell type in diseased tissue. In a mouse model of atrial fibrillation, macrophages support inflammation and scarring of the atria, which hinder electrical conduction between heart cells. The SPP1 gene is highly overexpressed in macrophages during atrial fibrillation, and its expressed protein promotes tissue scarring. 

“Weekend Warrior” Physical Activity Provides Similar Heart-Related Benefits As More Regular Exercise 
Featuring Patrick Ellinor, MD, PhD and Shaan Khurshid, MD, MPH 

A weekend warrior pattern of exercise—concentrating moderate-to-vigorous physical activity to 1–2 days during the week—is common among adults. Compared with inactivity, both the weekend warrior or a more evenly distributed physical activity pattern were associated with similarly lower risks of heart attack, heart failure, atrial fibrillation (an abnormal heart rhythm), and stroke. 

Many Spanish-Speaking Families Encounter Language Barriers, Racism, and Discrimination in Obtaining Medical Care For Loved Ones With Down Syndrome 
Featuring Brian Skotko, MD, MPP 

In a study of Spanish-speaking caregivers and primary care providers, researchers found that limited English proficiency, a lack of health information translated into Spanish, and systemic racism often undermines care of patients with Down syndrome. The researchers identify strategies for providers to bolster trust with families, including using on-site interpreters, offering patients with greater needs more time, and being open to cultural differences. 

Daily Statin Medication Reduces Risk of Major Cardiovascular Events by More Than One-Third in People Living with HIV 
Featuring Steven K. Grinspoon MD 

Adults living with HIV have an increased risk of cardiovascular disease that is roughly two times that of the general population. A recent study found that adults with HIV who took a daily statin reduced their risk of major cardiovascular events (MACE) by 35% and their risk of MACE or premature death by 21%. The findings of the trial, which was halted early for efficacy, could change current clinical guidelines for this at-risk population. 

Blog Posts

Meet Our Newest MGRI Intern, Rachel! 
Meet our newest MGRI intern, Rachel! Learn more about her educational background, outlook on healthcare, and other areas of interest. 

Benchmarks: Mass General Research News and Notes for July 7, 2023 
Getting answers on chronic pain, a study on alcohol use disorder, and the tiniest patients at Mass General for Children celebrate the Fourth. 

Footnotes in Science: Q&A with Kathryn Himmelstein, MD, MSEd 
Children in immigrant families often face mental health challenges that are exacerbated by social determinants of health. 

How Building Resiliency in Young Adults Could Help Address a Mental Health Crisis 
Featuring Daphne Holt, MD, PhD 

Daphne Holt, MD, PhD, discusses the modern issues in psychiatric diagnosis, and the prevention of disease through resiliency training. 

How a Doctor with Mass General Roots Found a Cure for Pernicious Anemia and Shared the 1934 Nobel Prize 
This lifesaving treatment would not have happened without scientific collaboration, persistence, and serendipity. 

Benchmarks: Mass General Research News and Notes for July 14, 2023 
Promising results for a new smoking cessation medicine, the role of macrophages in atrial fibrillation, the tweets of the week and more. 

Benchmarks: Mass General Research News and Notes for July 21, 2023 

Weekend warriors reap similar cardiovascular benefits to more regular exercisers, getting a handle on the environmental toll of hospital waste and more. 

DreAMLand App Seeks to Help Patients Cope with the Trauma of an Acute Myeloid Leukemia Diagnosis 
Featuring Areej El-Jawahri, MD 

A Mass General oncologist has designed an iPad app to help patients navigate the challenges of acute myeloid leukemia treatment. 

Benchmarks: Mass General Research News and Notes for July 28, 2023 
What’s next in imaging research at the Martinos Center, Williams syndrome researcher to be recognized, the tweets of the week and more. 

Research Spotlights

Vulvovaginal Discomfort Symptoms in Women Enrolled in a Randomized Trial Evaluating Treatment for Genitourinary Syndrome of Menopause 
Caroline Mitchell, MD, MPH, a physician-investigator in the Department of Obstetrics and Gynecology at Massachusetts General Hospital and an associate professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School, is the lead author of a new Paper in the journal Menopause: The complexity of genitourinary syndrome of menopause: number, severity, and frequency of vulvovaginal discomfort symptoms in women enrolled in a randomized trial evaluating treatment for genitourinary syndrome of menopause 

Signaling Between Cancer and Mesothelial Cells Promotes Ovarian Cancer Tumorigenesis and Immune Evasion 
David Pépin, PhD, an investigator in the Pediatric Surgical Research Laboratories at Massachusetts General Hospital and an associate professor of Surgery at Harvard Medical School, is the senior author of a new study published in Cell Reports, Cancer-Associated Mesothelial Cells are Regulated by the Anti-Müllerian Hormone Axis. 

Leveraging Self-Supervised Learning and Physics Inspired Augmentations for Enhanced Liver Segmentation in Ultrasound Imaging 
Abder-Rahman Ali, PhD, a Research Fellow in the Center for Ultrasound Research & Translation (CURT) at Massachusetts General Hospital, is the first author of a new study published in the 36th Canadian Conference on Artificial Intelligence (CANAI), Liver Segmentation in Ultrasound Images Using Self-Supervised Learning with Physics-inspired Augmentation and Global-Local Refinement. 

Establishment of a Consensus Protocol to Explore the Brain Pathobiome 
William Eimer, PhD, and Rudolph Tanzi, PhD, from the Department of Neurology at Massachusetts General Hospital, are among the authors of a recently published paper in Alzheimer’s & Dementia, Establishment of a Consensus Protocol to Explore the Brain Pathobiome in Patients With Mild Cognitive Impairment and Alzheimer’s Disease 

Lab on a Chip Technologies to Improve the Assessment of Stored Red Blood Cells 
Ziya Isiksacan, PhD, a research fellow in the Center for Engineering in Medicine and Surgery (CEMS) is the lead author, and Osman Berk Usta, PhD, an investigator in the CEMS at Massachusetts General Hospital and an associate professor of Surgery at Harvard Medical School, is the senior author of a new study published in PNAS, Assessment of Stored Red Blood Cells Through Lab-on-a-Chip Technologies for Precision Transfusion Medicine. The article is a collaboration between multiple international institutes and disciplines, and seeks to create discussion and change towards better assessment of stored blood. 

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