Snapshot of Science for August 2023

Welcome to our Snapshot of Science for August 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: 

26 new studies published in high-impact journals, along with 24 summaries submitted by the research teams 
7 new research-related press releases
10 posts from the Mass General Research Institute blog
5 research spotlights

Publications

Analysis of National Survey on Firearm-Related Violence and Behavioral Health Issues
Where Are the Questions About Firearms?: An Analysis of US Federal Public Health Survey Data Infrastructure
Donelan K, Guzikowski S, Buonomo G, Galls A, Sacks CA, Masiakos PT
Published in Annals of Surgery on 8/1/2023 | *Summary available

Shorter Leukocyte Telomere Length Partially Explains Heightened Risk of CAD
Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women
Schuermans A, Nakao T, Uddin MM, Hornsby W, Ganesh S [et al.], Honigberg MC
Published in Circulation Research on 7/25/2023 | *Summary available

SGLT2is May Reduce Recurrent Gout Flares, ED Visits and Hospitalizations
Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations : A General Population Cohort Study
McCormick N, Yokose C, Wei J, Lu N, Wexler DJ [et al.], Choi HK
Published in Annals of Internal Medicine on 7/25/2023 | *Summary available

Identification of Genetic Drivers for Esophageal Cancer Creates New Opportunity for Screening, Treatment
Germline Determinants of Esophageal Adenocarcinoma
Lee M, Eng G, Handte-Reinecker A; MGH-MIT Gastrointestinal Cohorts Working Group [et al.], Gala MK
Published in Gastroenterology on 7/26/2023 | *Summary available | Press Release

Role of Inflammasomes in CHIP-associated Cardiovascular Diseases
Genetic Modification of Inflammation and Clonal Hematopoiesis-associated Cardiovascular Risk
Yu Z, Filder TP, Ruan Y, Vlasschaert C, Nakao T [et al.], Natarajan P
Published in Journal of Clinical Investigation on 7/27/2023 | *Summary available

Ethanol Toxicity in Perinatal Animal Model
A Dynamic Balance Between Neuronal Death and Clearance in an in Vitro Model of Acute Brain Injury
Balena T, Lillis K, Rahmati N, Bahari F, Dzhala V, Berdichevsky E, Staley K
Published in Journal of Neuroscience on 8/1/2023 | *Summary available

Genetic Association Study Attempts to Identify Novel Drug Treatments for Comorbid Psychiatric Disorders
Transcriptome-Wide Structural Equation Modeling of 13 Major Psychiatric Disorders for Cross-Disorder Risk and Drug Repurposing
Grotzinger AD, Singh K, Miller-Fleming TW, Lam M, Mallard TT [et al.], Smoller JW
Published in JAMA Psychiatry on 8/1/2023 | *Summary available

Promising New Treatment for Breast Cancer
An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer
Chandarlapaty S, Dickler MN, Perez Fidalgo JA, Villanueva-Vázquez R, Giltnane J [et al.], Bardia A
Published in Clinical Cancer Research on 8/1/2023

Study Reveals Unexpected Importance of the Thymus in Adults
Health Consequences of Thymus Removal in Adults
Kooshesh KA, Foy BH, Sykes DB, Gustafsson K, Scadden DT
Published in New England Journal of Medicine on 8/3/2023 | *Summary available | Press Release

New Software to Study Gene Regulatory Networks
Dictys: Dynamic Gene Regulatory Network Dissects Developmental Continuum with Single-cell Multiomics
Wang L, Trasanidis N, Wu T, Dong G, Hu M, Bauer DE, Pinello L
Published in Nature Methods on 8/3/2023 | *Summary available

Insight into Stimulator of Interferon Genes 
Human STING is a Proton Channel
Liu B, Carlson RJ, Pires IS, Gentili M, Feng E [et al.], Hacohen N
Published in Science on 8/4/2023

New Blood-Pressure Related Measure Predicts Health Outcomes in Patients in Intensive Care
Tissue Perfusion Pressure Enables Continuous Hemodynamic Evaluation and Risk Prediction in the Intensive Care Unit
Chandrasekhar A, Padrós-Valls R, Pallarès-López R, Palanques-Tost E, Houstis N [et al.], Aguirre AD
Published in Nature Medicine on 8/7/2023 | *Summary available | Press Release

Regulation of Chromatin Structure by CBX2 Critical for Stem Cell Maintenance
Cell Type-specific Role of CBX2 and its Disordered Region in Spermatogenesis
Kim JJ, Steinson ER, Lau MS, de Rooij DG, Page DC, Kingston RE
Published in Genes & Development on 8/8/2023 | *Summary available

Atorvastatin Lowers Rate of Cardiac Dysfunction in Lymphoma Patients with Treated with Anthracyclines
Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial
Neilan TG, Quinaglia T, Onoue T, Mahmood SS, Drobni ZD [et al.], Scherrer-Crosbie M
Published in JAMA on 8/8/2023 | *Summary available

Transplant Recipients Experience Limited Protection With Primary COVID-19 Vaccination Series, but Third Dose Boosts Response
Delayed and Attenuated Antibody Responses to Coronavirus Disease 2019 Vaccination With Poor Cross-Variant Neutralization in Solid-Organ Transplant Recipients-A Prospective Longitudinal Study
Liew MY, Mathews JI, Li A, Singh R, Jaramillo SA [et al.], Goldberg MB
Published in Open Forum Infectious Diseases on 8/10/2023 | *Summary available | Press Release

Patterns of Protein Regulation Across Nearly a Dozen Tumor Types
Pan-cancer Analysis of Post-translational Modifications Reveals Shared Patterns of Protein Regulation
Geffen Y, Anand S, Akiyama Y, Yaron TM [et al.], Getz G; Clinical Proteomic Tumor Analysis Consortium
Published in Cell on 8/14/2023 | *Summary available

New Approach to Transportation of Donor Organs
Impact of Portable Normothermic Machine Perfusion for Liver Transplantation From Adult Deceased Donors
Yamamoto T, Atthota S, Agarwal D, Crisalli K, MacConmara M [et al.], Markmann JF
Published in Annals of Surgery on 8/15/2023 | *Summary available

Genome Sequencing Shown to be an Improved Prenatal Diagnostic Test
Systematic Evaluation of Genome Sequencing for the Diagnostic Assessment of Autism Spectrum Disorder and Fetal Structural Anomalies
Lowther C, Valkanas E, Giordano JL, Wang HZ, Currall BB [et al.], Talkowski ME
Published in American Journal of Human Genetics on 8/16/2023 | *Summary available

How mtDNA Changes as We Age
Nuclear Genetic Control of mtDNA Copy Number and Heteroplasmy in Humans
Gupta R, Kanai M, Durham TJ, Tsuo K, McCoy JG [et al.], Mootha VK
Published in Nature on 8/16/2023 | *Summary available

Groundbreaking New Noninvasive Elastography Technique
Ultra-wideband Optical Coherence Elastography from Acoustic to Ultrasonic Frequencies
Feng X, Li GY, Yun SH
Published in Nature Communications on 8/16/2023 | *Summary available

New Noninvasive Probes for Imagining of Fibrotic Disease Activity
Tailored Chemical Reactivity Probes for Systemic Imaging of Aldehydes in Fibroproliferative Diseases
Ma H, Zhou IY, Chen YI, Rotile NJ, Ay I [et al.], Caravan P
Published in Journal of the American Chemical Society on 8/17/2023 | *Summary available

Blocking PPM1D Made Leukemia Cells More Sensitive to Chemotherapies 
PPM1D Modulates Hematopoietic Cell Fitness and Response to DNA Damage and is a Therapeutic Target in Myeloid Malignancy
Miller PG, Sperling AS, Mayerhofer C, McConkey M, Ellegast JM [et al.], Ebert BL
Published in Blood on 8/18/2023 | *Summary available

Potential Transfer of AD-associated Gut Microbiota between Non-AD to AD Individuals
Transmission of Alzheimer's Disease-Associated Microbiota Dysbiosis and its Impact on Cognitive Function: Evidence from Mouse Models and Human Patients
Zhang Y, Shen Y, Liufu N, Liu L, Li W [et al.], Xie Z
Published in Molecular Psychiatry on 8/21/2023 | *Summary available

Study Reveals How Diabetes Drug Extends Lifespan in Lab Models
Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms in Caenorhabditis elegans
Cedillo L, Ahsan FM, Li S, Stuhr NL, Zhou Y [et al.], Soukas AA
Published in eLife on 8/22/2023 | *Summary available | Press Release

New Human Cell-based 3D Model Reveals Insights into How Immune Cells Contribute to Alzheimer’s Disease
Infiltrating CD8+ T Cells Exacerbate Alzheimer's Disease Pathology in a 3D Human Neuroimmune Axis Model
Jorfi M, Park J, Hall CK, Lin CJ [et al.], Kim DY, Tanzi RE
Published in Nature Neuroscience on 8/24/2023 | *Summary available | Press Release

Publication Summaries 

Clinical Trial Shows Promise in Treatment of New Adenocarcinomas Biomarker
ILUSTRO: Phase 2 Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma
Klempner SJ, Lee KW, Shitara K, Metges JP, Lonardi S [et al.], Shah MA
Published in Clinical Cancer Research on 7/25/2023

The treatment of gastric (GC) and gastroesophageal junction (GEJ) adenocarcinomas is increasingly being driven by the presence or absence of specific molecular features often called biomarkers. The tight junction protein Claudin18.2 (CLDN18.2) is overexpressed in ~38% of all GC/GEJ cancers and represents a new biomarker in this tumor type. In this phase II multicohort trial we explored the safety and clinical activity of chemotherapy and/or immunotherapy with the anti-CLDN18.2 antibody Zolbetuximab in CLDN18.2 positive GC/GEJ patients. The combination with standard FOLFOX chemotherapy demonstrated significant clinical activity and supports the two recently reported phase III trials demonstrating improved outcomes when Zolbetuximab is added to standard chemotherapy in CLDN18.2+ GC/GEJ.

(Summary submitted by Samuel J. Klempner, MD, Center for Hematology Oncology, Mass General Cancer Center)

Women with a history of premature natural menopause (i.e., <40 years) are at an increased risk of coronary artery disease (CAD) through partially unknown mechanisms. In the present study, we found that leukocyte telomere length (LTL)—a marker of cellular aging—was shorter among women with earlier age at menopause. Shorter LTL partially explained the heightened risk of CAD in women with vs. without a history of premature natural menopause. Our findings highlight the role of genomic instability and aging-related processes in cardiovascular diseases in women with premature natural menopause and support intensive prevention strategies in this population.

(Summary submitted by Art Schuermans, Cardiology Division, Department of Medicine)

SGLT2is May Reduce Recurrent Gout Flares, ED Visits and Hospitalizations 
Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations : A General Population Cohort Study 
McCormick N, Yokose C, Wei J, Lu N, Wexler DJ [et al.], Choi HK 
Published in Annals of Internal Medicine on 7/25/2023

Gout affects > 12 million Americans, who experience episodes of painful joint flares which impact quality-of-life and may temporarily increase risk of heart attack or stroke, potentially due to increased inflammation. We studied patients with gout and diabetes who started using sodium-glucose cotransporter-2 inhibitors (SGLT2i), a newer g
lucose-lowering medication also used for heart and kidney disease. SGLT2i were associated with lower rates of gout flares, and lower risk of heart attack. This is important because many people with gout also have diabetes or heart or kidney disease, but conventional gout medications (‘urate-lowering therapies’) do not seem to help with those comorbidities.

(Summary submitted by Natalie McCormick, PhD, Division of Rheumatology, Allergy, and Immunology, Mongan Institute, Department of Medicine)

Barrett's esophagus has been identified as a precursor lesion to esophageal adenocarcinoma. Despite up to 7% of middle-aged adults having the condition, only a very select few individuals will progress to develop cancer. While ascribed to "bad luck" for those who progress, through genetic analyses of 742 individuals of such individuals, we identified that 9% of such individuals have an occult cancer-predisposing syndrome. Furthermore, we determined that such germline mutations shape tumor evolution. Thie findings should lead to universal genetic testing for such individuals, and novel precision treatments.

(Summary submitted by Manish K. Gala, MD, Division of Gastroenterology, Department of Medicine)

By leveraging human genetic data and murine models, this study investigates the links between clonal hematopoiesis—acquired mutations in blood-forming systems—and cardiovascular disease (CVD) risk. By analyzing genetic information from over 400,000 individuals, the study demonstrates that clonal hematopoiesis is associated with CVD risk, and the expression levels of specific inflammatory genes can modify this association. The findings are substantiated using mouse models, corroborating the human data. Critically, the study pinpoints AIM2 and IL1RAP as molecular candidates for new targeted therapies. The research promises transformative advancements in personalized prevention and treatment strategies for clonal hematopoiesis-related CVD.

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

The practices of public health and medicine rely extensively on data collected by the federal government to understand and manage health risks from injury and disease. Our team in the MGH Gun Violence Prevention Center recently reviewed 25 years of national surveys on health issues conducted by the federal government. Among 22 surveys of adults and children conducted annually or biannually between 1995 and 2020 (more than 150 waves of survey data collection), only 9 surveys included questions on firearm violence and firearm related injury. Among those, 20% measured firearm ownership, use, and exposure to violence. We suggest that our nation needs more robust data infrastructure if we are to develop and test effective approaches to prevent the loss of life and the traumatic experience associated with firearms.

(Summary submitted by Karen Donelan, ScD, EdM, Health Policy Research Center, The Mongan Institute)

Ethanol has been widely reported to increase cell death in the perinatal rat brain. However, recent findings from our team showed that ethanol does not affect the healthy neurons; it just increases the permeability of the membrane of dying neurons, meaning they absorb damage indicators like propidium iodide more avidly. This does not mean that ethanol is not toxic to the developing fetus, but that toxicity is not manifested in the third trimester (which is the developmental stage that the perinatal rats model). This same model has been used to show the neurotoxicity of anticonvulsants and anesthetics, which are widely used in the medical practice. Our team is now investigating the robustness of these latter findings in vitro and in vivo.

(Summary submitted by Kevin Staley, MD, Department of Neurology)

In this genetic association study, we examined gene expression patterns that reflect genetic overlap or divergence across 13 psychiatric disorders. A new method, transcriptome-wide structural equation modeling, was used to identify 466 genes associated with psychiatric genomic factors that index shared risk across subsets of disorders. Analyses also revealed 35 drug-gene pairs that may target shared risk pathways across bipolar disorder and schizophrenia and 5 drug-gene pairs with potential transdiagnostic effects across all disorders. This approach has the potential to identify novel drug treatments for increasingly common, comorbid psychiatric disorders.

(Summary submitted by Jordan W. Smoller, MD, ScD, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine)

The thymus is an organ in the chest that makes critical cells for the immune system called T cells. This organ ages very early in life becoming atrophic progressively after puberty. Whether it has a critical role in adults has not been known. By studying people who had their thymus removed, we discovered that the thymus is absolutely required for health. If it isn't there, people's risk of dying and risk of cancer approximately doubles.

(Summary submitted by David Scadden, MD, Center for Regenerative Medicine, Mass General Cancer Center)

Gene regulatory networks (GRNs) are like cellular control systems that decide how cells work and who they are. These networks can change their connections as cells grow or get sick. To understand these cellular circuits, we made a computer software called Dictys. Dictys helps us reconstruct GRNs and analyze how they change over time in healthy development and disease. It uses data from individual cells to figure out which genes are active and how they interact. This tool improves our ability to reconstruct these networks accurately, which is important for studying how cells develop and change.

(Summary submitted by Luca Pinello, PhD, Molecular Pathology Unit, Center for Cancer Research, Mass General Cancer Center)

Patients with conditions such as advanced heart failure or circulatory shock require close monitoring and treatment in an intensive care unit (ICU). One of the primary goals of treatment is maintenance of adequate blood pressure to prevent injury to important organs. This study developed a new metric for monitoring patients in the ICU called tissue perfusion pressure (TPP) that may allow improved management of blood pressure and heart function, which could reduce the risk of death and other negative outcomes.

(Summary submitted by Aaron Aguirre, MD, PhD, Cardiology Division, Department of Medicine)

Gene silencing is at the core of cell fate regulation. If cells fail to repress genes that need to be silent, the misexpression can lead to developmental disorders and cancers. We investigated a critical factor for that silencing called CBX2 in adult tissue homeostasis. During spermatogenesis, CBX2 function is needed to repress the stem cell program for proper differentiation. We further showed its charged, disordered region is critical for the maintenance of stem cells during aging. Our work reveals that the regulation of chromatin structure by CBX2 at a specific stage of spermatogenesis is critical for stem cell maintenance.

(Summary submitted by Jongmin J Kim, PhD, Department of Molecular Biology)

Anthracyclines are a key component of some chemotherapy regimens among patients with breast cancer, leukemia, lymphoma, and sarcoma. However, anthracyclines can lead to a decline in cardiac function and the development of heart failure. There was preliminary evidence to support our hypothesis that atorvastatin may protect the heart during anthracycline-based chemotherapy. STOP-CA was a clinical trial among adult patients with newly diagnosed lymphoma where half were prescribed atorvastatin and half placebo. We found that among the atorvastatin group there was a 3-fold lower rate of cardiac dysfunction after anthracyclines and the use of atorvastatin was safe. These finding support the use of atorvastatin in patients with lymphoma at higher risk of cardiac dysfunction with anthracyclines.

(Summary submitted by Tomas G. Neilan, MD, MPH, Cardiology Division, Department of Medicine)

Transplant recipients must take life-long immunosuppressive medications to prevent rejection, but these drugs can compromise the effectiveness of vaccines. Moreover, immunity induced by vaccination decreases over time. To better understand protection conferred by COVID-19 vaccination and to inform optimal vaccination strategies, our team examined antibody responses among lung and heart transplant recipients over more than a year following vaccination. We found that lung and heart transplant recipients experienced diminished and delayed antibody responses to the first two COVID-19 mRNA vaccine doses, but most developed stronger responses following a third dose. A third dose also boosted cross-protection against recent variants. Vaccine doses beyond the third dose are likely extremely important for maintaining immunity.

(Summary submitted by Marcia B. Goldberg, MD, Center for Bacterial Pathogenesis, Department of Medicine)

As part of a suite of papers published simultaneously from the NCI’s Clinical Proteomic Tumor Analysis Consortium (CPTAC), our study focused on how pan-cancer analysis of post-translational modifications (PTMs), including phosphorylation and acetylation, reveals shared patterns of protein regulation across nearly a dozen tumor types. These shared patterns include: changes in protein acetylation and phosphorylation involved in hallmark cancer processes; dysregulated DNA repair driven by phosphorylation; altered metabolic regulation associated with immune response driven by acetylation; affected kinase specificity by crosstalk between acetylation and phosphorylation; and modified histone regulation. Overall, this rich resource highlights PTM-governed biology in cancer and exposes potential new therapeutic avenues.

(Summary submitted by Mendy Miller, PhD, Broad Institute)

A compelling case can be made that there have been few disruptive advances in the field of transplantation over the last 2 decades. This has recently changed with move from storing recovered organs on ice to placement on sophisticated perfusion devices. A recent large US randomized trial (Protect Trial) found that donor livers preserved on ice had significantly poorer outcomes post-transplant compared to organs placed on the Transmedics Organ Care System that delivers oxygenated blood and nutrients at physiological temperatures. The approach also permits organ functional assessment of questionable organs, allowing identification of organs appropriate for transplant thereby increasing the number of lives saved.

(Summary submitted by James F. Markmann, MD, PhD, Department of Surgery)

Prenatal genetic testing generally relies on three approaches — karyotyping, chromosomal microarrays, and exome sequencing — to detect a variety of genetic abnormalities, from chromosomal rearrangements to single nucleotide changes. We evaluated if genome sequencing (GS) could equal, and perhaps surpass, the sensitivity and diagnostic yield of the combination of the three standard-of-care technologies routinely used for the assessment of fetal structural anomalies (FSAs). We report that GS sensitivity and diagnostic yield does indeed exceed the other three tests, suggesting that GS should be considered as a first-tier diagnostic test for FSAs.

(Summary submitted by Elise Valkanas, Center for Genomic Medicine)

We have two types of DNA: the nuclear DNA (which is the bulk of our DNA and is passed down equally from both parents) and the mitochondrial DNA (mtDNA), which is much smaller, and passed down exclusively from mother to offspring. By analyzing DNA from >250,000 individuals, we have discovered how mtDNA changes as we age. Importantly, we also discovered that once inherited from mother, mtDNA quantity and quality are under the influence of variation in the nuclear genome. Our work provides new insights into how these two genomes are coordinated.

(Summary submitted by Vamsi K Mootha, MD, Department of Molecular Biology )

Understanding the mechanical properties of materials is critical in scientific and engineering fields, encompassing a wide range from soft hydrogels to biological tissues. However, current measurement methods lack the necessary spatial and time resolution to accurately characterize samples with complex structures. In this study, a groundbreaking noninvasive elastography technique is introduced, offering significant advancements in resolution, sensitivity, and measurement frequencies. This innovative technique unveils previously unknown viscoelastic moduli spanning from kHz to MHz and reveal depth-dependent stiffness in cartilages and human skins. This research presents a valuable noninvasive tool for the fields of material sciences, tissue engineering, and medical diagnostics.

(Summary submitted by Xu Feng,PhD, Department of Dermatology)

Fibroproliferative diseases occur in most organs, and examples include heart failure, cirrhosis, chronic kidney disease, and pulmonary fibrosis. These diseases share a common feature of oxidized collagen deposition in the extracellular matrix, where collagen side chains contain aldehyde units. In this work, three aldehyde-targeting probes based on chelated manganese are reported for noninvasive detection and quantification of oxidized collagen using MRI. We show how judicious molecular design can enable the imaging of fibrotic disease activity in the lungs, liver, and kidneys in different mouse models of disease.

(Summary submitted by Peter Caravan, PhD, Martinos Center, Department of Radiology)

In our study, we investigated how PPM1D, a gene that is commonly mutated in blood cancers, alters the biology of normal and leukemic blood cells. We found that cells with PPM1D activation (as occurs in human disease) have an advantage compared to normal cells, which explains why PPM1D mutations occur in the blood system. We further found that blocking PPM1D genetically or with a pharmacologic agent made leukemia cells more sensitive to chemotherapies commonly used in the clinic. These data support further drug discovery efforts to target PPM1D in leukemia and other malignancies to improve outcomes for patients with cancer.

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

The present study showed the potential transfer of gut microbiota from mice with Alzheimer's Disease (AD) pathogenesis (AD transgenic mice) to those without it. Researchers co-housed wild-type mice with AD transgenic mice and observed the emergence of AD-associated gut microbiota dysbiosis, AD pathogenesis, e.g., Tau phosphorylation, and cognitive impairment in the co-housed wild-type mice. The similar transfer of gut microbiota was also observed between AD patients and their partners. These findings highlight the association between gut microbiota and cognitive function and demonstrate the potential transfer of AD-associated gut microbiota dysbiosis, and pathogenesis between non-AD to AD individuals.

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

Metformin, the world’s most commonly used drug to treat type 2 diabetes, may also promote healthy aging. We found that metformin, and its sister drug phenformin, extend lifespan by promoting the body's production of ether lipids. Promoting the production of ether lipids alone extends lifespan, suggesting that if we can prompt higher production of ether lipids in humans, we may be able to promote healthy aging and reduce the impact of not one, but many aging-related diseases.

(Summary submitted by Alexander Soukas, MD, PhD, Center for Genomic Medicine)

Nerve cells in brain of Alzheimer’s disease (AD) patients progressively deteriorate and eventually die, a process known as neurodegeneration. Historically, studies primarily focused on uncovering the cause of AD neurodegeneration within the brain. However, recent studies have unveiled a surprising revelation: immune cells outside the brain, particularly T cells, can infiltrate the brain and exacerbate AD neuropathology. This discovery has raised numerous questions, including the mechanisms underlying the entry of these peripheral immune cells into the brain and their interactions with resident brain cells. To address these crucial questions, our team has engineered a cutting-edge 3D human cellular microfluidic model replicating the intricate interactions between brain cells and these invading immune cells. Using this model, we have demonstrated that as Alzheimer's pathology accumulates, specific types of human T cells, specifically CD8+ T cells, infiltrate the brain and intensify the damage by activating brain-resident immune cells, known as microglia. Furthermore, we have shown that blocking the axis between brain-secreted chemokine, CXCL10, and its T-cell receptor, CXCR3, selectively reduces T-cell infiltration and prevents AD neurodegeneration. This exciting discovery has unveiled a new target for drug intervention, situated on T cells outside the brain, which is more accessible to novel treatments, particularly considering the traditional challenges associated with delivering drugs into the brain. This novel human cellular model of AD holds significant promise for advancing our understanding of how immune cells outside the brain contribute to AD pathology and identifying new therapeutic targets.

(Summary submitted by Mehdi Jorfi, PhD, Doo Yeon Kim, PhD, and Rudolph E. Tanzi, PhD, Department of Neurology)

Press Releases

Identification of Genetic Drivers for Esophageal Cancer Creates New Opportunity for Screening, Treatment
Featuring Manish Gala, MD

Universal genetic testing may improve risk stratification and treatment for rare, lethal cancer previously attributed to ‘bad luck’

Study Reveals Unexpected Importance of the Thymus in Adults
Featuring David T. Scadden, MD

The thymus gland is often thought of as nonfunctional in adults and is sometimes removed during cardiac surgery—a process known as thymectomy. Compared with adults who did not have their thymus removed, adults who underwent thymectomy had a nearly three-times higher risk of dying over five years and a two-times higher risk of developing cancer during that time. Thymectomy was also linked to a higher risk of autoimmune disease in adults without prior infection, cancer, or autoimmune disease.

New Blood-Pressure Related Measure Predicts Health Outcomes in Patients in Intensive Care
Featuring Aaron Aguirre, MD, PhD

A new method derived from standard blood pressure assessments can improve monitoring of critically ill patients with circulatory shock. The method accurately predicts risk of death, length of hospital stay, and blood lactate levels (an indicator of tissue perfusion and oxygenation).

Transplant Recipients Experience Limited Protection With Primary COVID-19 Vaccination Series, but Third Dose Boosts Response
Featuring Marcia Goldberg, MD

Lung and heart transplant recipients experienced diminished and delayed antibody responses to the first two COVID-19 mRNA vaccine doses, but most developed stronger responses following a third dose. A third dose also boosted cross-protection against SARS-CoV-2 viral variants. For lung and heart transplant recipients, vaccine doses beyond the third dose are likely important for maintaining immunity.

Symptoms Previously Considered “Defective” in Patients with Language Disorder are Actually Adaptive
Featuring Neguine Rezaii, MD

In a new study, analyses revealed that the speech patterns of patients with nonfluent aphasia augmented the information content of sentences to the level of speakers without the condition. Identifying this feature as adaptive rather than defective indicates that treatment strategies for nonfluent aphasia should be revised.

Study Reveals How Diabetes Drug Extends Lifespan in Lab Models
Featuring Alexander Soukas, MD, PhD

In worms, genes that increase production of ether lipids are required for metformin-mediated lifespan extension. Increasing ether lipid synthesis by overexpressing an enzyme extends worms’ lifespan by favorably altering metabolism. The team’s findings suggest that alterations to the ether lipid landscape could promote healthy aging.

New Human Cell-based 3D Model Reveals Insights into How Immune Cells Contribute to Alzheimer’s Disease
Featuring Mehdi Jorfi, PhD, Doo Yeon Kim, PhD, Joseph Park, PhD, and Rudolph Tanzi, PhD

Researchers developed a new 3D model of Alzheimer’s Disease that allows them to study the role of immune cells in the disease. They found that infiltration of immune cells significantly increases in brains with AD pathology and contributes to neurodegeneration and neuroinflammation. The team also identified potential strategies to halt this process, which could lead to the development of new therapies.

Blog Posts

Mass General for Children Research Team is Working to Avoid the Need for Surgery in Patients with Hirschsprung Disease
Featuring Allan Goldstein, MD

Allan Goldstein, MD, and team are developing new treatment strategies for Hirschprung disease that can reduce the need for invasive surgery.

Benchmarks: Mass General Research News and Notes for August 4, 2023
Frequent naps might improve brain health, women are leaving academic medicine at higher rates then men, and a prior history of infertility may lead to worse menopause symptoms.

Introducing the 2023 Mass General Research Institute Image Awards
Our annual contest is a chance for the Mass General research community to share their best science images and the stories behind them.

Your Summer Reading List Powered by Authors from Massachusetts General Hospital
From self-care guidance to children’s literature, close out your summer reading by adding these books written by Massachusetts General Hospital clinicians and researchers to your list.

Snapshot of Science: Mass General’s High Impact Research Publications for July 2023
A promising clinical trial for a smoking cessation medication, targeting immune cells may help treat atrial fibrillation , “weekend warrior” physical activity provides similar heart-related benefits as more regular exercise, and much more

Benchmarks: Mass General Research News and Notes for August 21, 2023
Better care for patients in circulatory shock, tips for a good night’s sleep, the importance of the thymus in adults and lots more.

The Next Generation of Medical Innovators: Meet the MGRI Summer Students!
Each year 1,200+ summer students come to Mass General to train in our research labs and centers during their time off from school. These are their stories.

Humans of MGRI: Yirong Zhou, MD, PhD
Yirong Zhou, MD, PhD, is a cardiology researcher who enjoys Game of Thrones and socializing with International Medical Graduates.

The Voices of Summer Research Students: Meet Katya Tjahaja
Learn more about the experiences and adventures of a summer research student!

Benchmarks: Mass General Research News and Notes for August 25, 2023
Congrats to two pioneering pain researchers, a blood test to predict future CV risk for diabetes patients and lots more.

Research Spotlights

Crowd-Sourced Fundraising to Help Cover Exorbitant Costs Associated with Neurological Diseases
Featuring Altaf Saadi, MD, MSc

Altaf Saadi, MD, MSc, principal investigator of the Neurodisparities & Health Justice Lab in the Department of Neurology at Mass General and an assistant professor of Neurology at Harvard Medical School, is corresponding author of a new research letter in JAMA Neurology, Evaluation of Crowd-Sourced Fundraising to Cover Health Care Costs for Neurological Conditions in the US. Christopher Galvin, MD, MS, a neurology resident at Mass General Brigham, is the first author.

Comparing the Attrition Rates for Male and Female Doctors in Academic Medicine
Featuring Cassandra Kelleher, MD and Ya-Wen Chen, MD, MPH

Cassandra Kelleher, MD, and Ya-Wen Chen, MD, MPH, physician-scientists in the Department of Surgery at Massachusetts General Hospital, and an Associate Professor (CK) and an Instructor (YWC) of Surgery at Harvard Medical School, are the senior author and first author of a new study published in JAMA Network Open, Workforce Attrition Among Male and Female Physicians Working in US Academic Hospitals, 2014-2019

Social Support and Depression During a Global Crisis 
Featuring Karmel Choi, PhD

Karmel Choi, PhD, and Jordan Smoller, MD, ScD, from the Mass General Department of Psychiatry and colleagues recently published an article in Nature Mental Health, titled Social Support and Depression During a Global Crisis.

An Alternative Approach to the Lichtenstein Repair for Hernia Results in Improved Patient Quality of Life and Less Opioid Use Post Surgery
Featuring Divyansh Agarwal, MD and Michael Reinhorn, MD

Divyansh Agarwal, MD, a physician-scientist in the Department of Surgery at Massachusetts General Hospital and Michael Reinhorn, MD, a physician-scientist in the Department of Surgery at Newton-Wellesley Hospital are co-authors of a new study published in the journal Hernia, Improved patient-reported outcomes after open preperitoneal inguinal hernia repair compared to anterior Lichtenstein repair: 10-year ACHQC analysis

Alcohol Use Disorder Treatment in Sexually and Gender Diverse Patients
Featuring Alex Keuroghlian, MD, MPH

Alex Keuroghlian, MD, MPH, and Michal McDowell, MD, MPH, from the Department of Psychiatry at Mass General, authored a new study in the Journal of Clinical Psychiatry, Alcohol Use Disorder Treatment in Sexually and Gender Diverse Patients: A Retrospective Cohort Study.

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