Snapshot of Science for September 2023

Welcome to our Snapshot of Science for September 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: 

35 new studies published in high-impact journals, along with 27 summaries submitted by the research teams
2 new research-related press releases
5 posts from the Mass General Research Institute blog
3 research spotlights

Publications

Canagliflozin Modestly Reduced Rise Biomarkers for Diabetic Kidney Disease
Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial
Januzzi JL, Mohebi R, Liu Y, Sattar N, Heerspink HJL [et al.], Hansen MK
Published in Circulation on 8/22/2023

SGLT2i May Reduce the Burden of Recurrent Gout Flares
Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes
Wei J, Choi HK, Dalbeth N, Li X, Li C [et al.], Zhang Y
Published in JAMA Network Open on 8/25/2023

K. pneumoniae as Opportunistic Pathogen and Invasive Antimicrobial-resistant Infection
Clinical and Genomic Characterization of a Cohort of Patients with Klebsiella pneumoniae Bloodstream Infection
Roach DJ, Sridhar S, Oliver E, Rao SR, Slater DM [et al.], Harris JB
Published in Clinical Infectious Diseases on 8/26/2023

In-situ Applicable Hydrogels Promising for Extending Local Efficacy of Pain Medication
Hydrogel Device for Analgesic Drugs with In-situ Loading and Polymerization
Grindy S, Gil D, Suhardi J, Fan Y, Moore K [et al.], Oral E
Published in Journal of Controlled Release on 9/1/2023

The Automatic Process of GABA Regulation
Post-synaptic GABAA Receptors Potentiate Transmission by Recruiting CaV2 Channels to their Inputs
Zhao J, Gao L, Nurrish S, Kaplan JM
Published in Cell Reports on 9/23/2023

Genetic Link to T Cell Response in Pancreatic Cancer
PD-1 Blockade Induces Reactivation of Non-productive T Cell Responses Characterized by NF-kB Signaling in Patients with Pancreatic Cancer
Ali LR, Lenehan PJ, Cardot-Ruffino V, Dias Costa A, Katz MHG [et al.], Dougan SK
Published in Clinical Cancer Research on 9/21/2023 | *Summary available

Deep Learning Risk Assessment Model Showed Higher Cancer Detection Rate than Traditional Risk Models
Comparison of the Diagnostic Accuracy of Mammogram-based Deep Learning and Traditional Breast Cancer Risk Models in Patients Who Underwent Supplemental Screening with MRI
Lamb LR, Mercaldo SF, Ghaderi K, Carney A, Lehman CD
Published in Radiology on 9/19/2023

Solanezumab Did Not Slow Cognitive Decline in Persons with Preclinical Alzheimer’s Disease
Trial of Solanezumab in Preclinical Alzheimer's Disease
Sperling RA, Donohue MC, Raman R, Rafii MS [et al.], Aisen PS; A4 Study Team
Published in New England Journal of Medicine on 9/21/2023

Modelling Analysis Supports Scale Up of Program for Community-based HIV Treatment
Population Health Impact, Cost-effectiveness, and Affordability of Community-based HIV Treatment and Monitoring in South Africa: A Health Economics Modelling Study
Sahu M, Bayer CJ, Roberts DA, van Rooyen H, van Heerden A [et al.], Barnabas RV
Published in PLOS Global Public Health on 9/5/2023

Publication Summaries

Objective Measurement of ALS Progression with Wearable Sensors
At-home Wearables and Machine Learning Sensitively Capture Disease Progression in Amyotrophic Lateral Sclerosis
Gupta AS, Patel S, Premasiri A, Vieira F
Published in Nature Communications on 8/21/2023
In clinical trials in ALS and other neurodegenerative diseases, the effectiveness of the therapy is often determined by subjective patient or clinician reports. In this article, we develop a new approach for measuring motor function at home during natural, everyday behavior. Using wearable sensors and machine learning, we demonstrate that the sensor-based measurement is highly reliable, captures information about fine motor and gross motor function, and is more sensitive than the gold standard measurement. This approach has potential to help catalyze drug development in ALS by reducing the size, duration, and cost of clinical trials.
(Summary submitted by Anoopum S. Gupta, MD, PhD, Department of Neurology)

Educational Attainment May Have a Protective Effect Against Cognitive Impairment
Effect of Apolipoprotein Genotype and Educational Attainment on Cognitive Function in Autosomal Dominant Alzheimer's Disease
Langella S, Barksdale NG, Vasquez D, Aguillon D, Chen Y [et al.], Quiroz YT
Published in Nature Communications on 8/23/2023
Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. We investigated the influence of genetics and educational attainment on cognitive impairment in 675 carriers of the Presenilin-1 E280A mutation that predisposes them to early-onset ADAD. Cognitive impairment was accelerated in Presenilin-1 mutation carriers who also have an APOE e4 allele, the major genetic risk factor for late-onset AD, and delayed in those who also have an APOE e2 allele. Further, more years of education was associated with preserved cognitive ability particularly for those at highest genetic risk. Our findings suggest that educational attainment may have a protective effect against cognitive impairment, even in the presence of strong genetic risk factors.
(Summary submitted by Stephanie Langella, PhD, Multicultural Alzheimer's Prevention Program, Department of Psychiatry)

Combined Treatment a Promising Therapeutic Approach for Brain Metastases
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Nayyar N, de Sauvage MA, Chuprin J, Sullivan EM, Singh M [et al.], Brastianos PK
Published in Clinical Cancer Research on 8/23/2023
Patients with brain metastatic cancer have limited treatment options. Metastatic brain tumors frequently fail cancer immunotherapy treatment since immune responses within the brain are tightly regulated. We found that pharmacologically blocking CDK4 and CDK6, which drive cell growth and division, can boost cancer immunity within the brain by reducing immune suppression and improving T cell function. When combined with immunotherapy targeting PD-1, CDK4/6 inhibitor abemaciclib reduced tumor growth both inside and outside the brain and improved survival in animal models of brain metastasis. Our findings suggest that combined treatment with CDK4/6 and PD-1 inhibitors is a promising therapeutic approach for patients with brain metastases.
(Summary submitted by Naema Nayyar, Center for Cancer Research)

Targeting Diet and/or Gut Microbial Byproducts May Alleviate Impact of CSVD on Brain Health
Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients with Acute Ischemic Stroke
Kijpaisalratana N, Ament Z, Bevers MB, Bhave VM, Garcia Guarniz AL [et al.], Kimberly WT
Published in JAMA Network Open on 8/23/2023
Cerebral small vessel disease (CSVD) can impact long term brain health by leading to lacunar stroke and contributing to cognitive decline. The risk factors that lead to CSVD are incompletely understood, but mounting evidence suggests that dietary patterns and the gut microbiome may play a role. In this study, we evaluated whether plasma metabolites produced by the gut microbiome (e.g., TMAO) were linked to CSVD outcomes. We found that plasma TMAO measured in 351 stroke patients was associated with brain imaging markers of CSVD and lacunar stroke. This research suggests that targeting diet and/or gut microbial byproducts may alleviate the impact of CSVD on brain health.
(Summary submitted by W Taylor Kimberly, MD, PhD, Center for Genomic Medicine)

Randomized Study Comparing Pulsed Field Ablation to Conventional Thermal Ablation
Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation
Reddy VY, Gerstenfeld EP, Natale A, Whang W [et al.], Mansour M; ADVENT Investigators
Published in New England Journal of Medicine on 8/27/2023
Pulsed field ablation for atrial fibrillation (AF) is a novel nonthermal energy approach that involves the use of brief electrical pulses to cause irreversible electroporation of cell membranes. It is very specific and allows myocardial tissue to be preferentially ablated without effects on adjacent tissues such as the esophagus, phrenic nerve, and pulmonary vein tissue, which are occasionally affected by the conventional thermal ablation. ADVENT is the first randomized study comparing pulsed field ablation to conventional thermal ablation for the ablation of paroxysmal AF. It enrolled patients from 30 centers in the US. The study met both its primary safety and effectiveness endpoints, and as such will likely mark the beginning of a new era in the field of AF ablation.
(Summary submitted by Moussa Mansour, MD, Division of Cardiology, Department of Medicine)

Permissive B Cell Selection Enables the Discovery of Antibody Epitopes for HIV
Engaging an HIV Vaccine Target Through the Acquisition of Low B Cell Affinity
Ronsard L, Yousif AS, Nait Mohamed FA, Feldman J, Okonkwo V [et al.], Lingwood D
Published in Nature Communications on 8/28/2023
Broadly neutralizing antibodies (bnAbs) against HIV are difficult to elicit by vaccination. One roadblock is the weak B cell affinity used to initiate their development. Here we use a transgenic mouse bearing human-like antibody repertoires to uncover a natural window in which low affinity B cells persist and enable vaccine-expansion of antibodies that engage the CD4 binding site, a conserved target of HIV bnAbs.
(Summary submitted by Daniel Lingwood, PhD, Ragon Institute)

Anesthesia Not Simply a “Deep Sleep” State
Differential Cortical Network Engagement During States of Un/Consciousness in Humans
Zelmann R, Paulk AC, Tian F, Balanza Villegas GA, Dezha Peralta J [et al.], Cash SS
Published in Neuron on 8/29/2023
What happens in the human brain when we are unconscious? and what when we cannot be awakened? In the present study, we compared the response to stimulation from inside the human brain when participants were awake, asleep, and under general anesthesia. We found that the unconscious brain has less complex, more variable, and less connected responses. These changes were uniformly distributed across the brain during sleep, but there was substantial disruption of prefrontal regions during propofol-induced general anesthesia. These findings suggest that anesthesia is not simply a “deep sleep” state, but rather that different brain regions are responsible for unconsciousness and arousability.
(Summary submitted by Rina Zelmann, PhD, Center for Neurotechnology and Neurorecovery, Department of Neurology)

Stem Cell-based Disease Modeling Can Capture Components of Cell-type Specificity in ALS
iPSC Motor Neurons, but Not Other Derived Cell Types, Capture Gene Expression Changes in Postmortem Sporadic ALS Motor Neurons
Held A, Adler M, Marques C, Reyes CJ, Kavuturu AS [et al.], Wainger BJ
Published in Cell Reports on 8/30/2023
In amyotrophic lateral sclerosis (ALS), motor neurons degenerate while most other neurons remain intact. To determine why motor neurons are more vulnerable, we made motor neurons, sensory neurons, astrocytes, and cortical neurons from induced pluripotent stem cells harboring mutations that cause ALS. We then performed RNA-sequencing and identified misregulated genes caused by ALS mutations in each cell type. We observed dramatically different misregulated genes across the different cell types, which suggests that ALS mutations affect different cellular processes depending upon their cellular context. Furthermore, only the changes in stem cell-derived motor neurons correlated with changes in postmortem ALS motor neurons. Thus, stem cell-based disease modeling can capture components of cell-type specificity in ALS.
(Summary submitted by Aaron Held, PhD, Department of Neurology)

Interventions to Reduce Mortality Disparities among People Experiencing Homelessness Should Consider the Unique Health Needs Across Sociodemographic Groups
Mortality by Age, Gender, and Race and Ethnicity in People Experiencing Homelessness in Boston, Massachusetts
Fine DR, Dickins KA, Adams LD, Horick NK, Critchley N [et al.], Baggett TP
Published in JAMA Network Open on 8/31/2023
In this large mortality study of more than 60,000 people experiencing homelessness in Boston, MA, all-cause mortality rates differed by age, gender, and race and ethnicity. Within the cohort, all-cause mortality was highest among older White men. When compared to the general population, the disparity in all-cause mortality was highest among young White women. Drug overdose was a leading cause of death across all demographic subgroups. Suicide uniquely impacted young individuals and HIV infection and homicide uniquely affected Black and Hispanic/Latinx individuals. These findings suggest that interventions to reduce mortality disparities among people experiencing homelessness should consider the unique health needs across sociodemographic groups.
(Summary submitted by Danielle R Fine, MD, MSc, Department of Medicine)

Methods to Enhance Cross-cohort GWAS Studies
Demonstrating Paths for Unlocking the Value of Cloud Genomics Through Cross Cohort Analysis
Deflaux N, Selvaraj MS, Condon HR, Mayo K, Haidermota S [et al.], Bick AG
Published in Nature Communications on 9/5/2023
The surge in the size of genomic data necessitates a shift in research, with data centralized in secure cloud platforms like the All of Us research workbench and the UK Biobank research analysis platform. In this study, we investigate two GWAS approaches for lipid genetic analysis in both cohorts. The first method conducts separate analyses and then combines the results (meta-analysis), while the second merges data before analysis (pooled analysis). Both yield similar outcomes but differ in scope. Pooled analysis offers more genetic variants, especially rare ones, which are advantageous for studying rare diseases but identifies fewer trait-associated variants in certain populations. Through this study, we demonstrate that technical complexity and costs increase with the addition of cohorts. Therefore, centralized data, robust support, scalable infrastructure, and harmonized policies can enhance cross-cohort analysis in the future.
(Summary submitted by Margaret Sunitha Selvaraj, PhD, Cardiovascular Research Center, Department of Medicine)

New Goals-of-Care Video Decision Aid Help Patient-Centered Care
Video Intervention and Goals-of-Care Documentation in Hospitalized Older Adults: The VIDEO-PCE Randomized Clinical Trial
Volandes AE, Zupanc SN, Lakin JR, Cabral HJ, Burns EA [et al.], Paasche-Orlow MK
Published in JAMA Network Open on 9/5/2023
Despite the known benefits of serious illness conversations, many hospitalized individuals never communicate their goals and wishes to their medical teams. In this randomized trial of over 10,000 patients, a goals-of-care video decision aid that was available in 29 languages significantly increased discussions surrounding patient wishes and documentation of their goals of care. The video intervention was also associated with increased discussions and documentation for Black or African American individuals, Hispanic or Latino individuals, non-English speakers, and patients living with dementia. This represents one of the first rapidly adoptable paradigms to empower patients and deliver more goal-aligned and patient-centered care.
(Summary submitted by Angelo E Volandes, MD, MPH, Department of Medicine)

Pathobiology Underlying Bronchiolitis Severity
Epigenome-wide Association Analysis of Infant Bronchiolitis Severity: A Multicenter Prospective Cohort Study
Zhu Z, Li Y, Freishtat RJ, Celedón JC, Espinola JA [et al.], Hasegawa K
Published in Nature Communications on 9/7/2023
Bronchiolitis is the most common lower respiratory infection among infants, with its severity ranges from a minor nuisance to a fatal infection. Furthermore, the pathobiology underlying bronchiolitis severity remains unclear. In this study, we identify 33 differentially methylated CpGs (DMCs) associated with bronchiolitis severity. These DMCs are differentially methylated in blood immune cells, enriched in multiple tissues (e.g., lung) and cells (e.g., small airway epithelial cells), and biological pathways (e.g., interleukin-1-mediated signaling). Additionally, these DMCs are associated with respiratory and immune traits (e.g., asthma, IgE levels). Our findings should advance the development of targeted therapeutic measures (e.g., modification of DNA methylation-related immune response) and help clinicians manage this population with a large morbidity burden.
(Summary submitted by Zhaozhong Zhu, ScD, Department of Emergency Medicine)

Regulatory T Cells Keep the Inflammatory State under Control in the Male Reproductive Tract
Regulatory T Cells Play a Crucial Role in Maintaining Sperm Tolerance and Male Fertility
Barrachina F, Ottino K, Elizagaray ML, Gervasi MG, Tu LJ [et al.], Battistone MA
Published in PNAS on 9/7/2023
Regulatory T cells (Tregs) preserve the organism's health by preventing autoimmune disease that occurs when the immune system overreacts against healthy cells. Using an autoimmunity-induced model, we discovered that Tregs keep the inflammatory state under control in the male reproductive tract. The loss of this state induced uncontrolled inflammation and the development of antibodies that bind to spermatozoa causing their removal and a severe reduction in fertility. By identifying these mechanisms, our study may lead to the development of infertility therapies and the generation of male contraception methods. These studies shed light on an area that still remains relatively unexplored.
(Summary submitted by Maria Augustina Battistone, PhD, Nephrology Division, Department of Medicine)

Exercise-Induced Hormone Irisin May Reduce Alzheimer’s Disease Plaque and Tangle Pathology in the Brain
Irisin Reduces Amyloid-β by Inducing the Release of Neprilysin from Astrocytes Following Downregulation of ERK-STAT3 Signaling
Kim E, Kim H, Jedrychowski MP, Bakiasi G, Park J [et al.], Choi SH
Published in Neuron on 9/8/2023 | Press Release
Alzheimer’s Disease (AD) has become an increasing health burden. Exercise has been shown to be neuroprotective in animal models and human clinical studies of AD. The mechanisms by which exercise protects the brain should be diverse and complex. Particularly, exercise increases a hormone called irisin. We found that irisin treatment reduced amyloid-β (Aβ) peptide, a protein that causes AD, level in our three-dimensional (3D) AD cell culture systems, by increasing an Aβ-degrading enzyme called neprilysin secreted from astrocytes, key regulators of neuroinflammation. This led to decreased neuroinflammation, another AD hallmark. Our findings strongly support considering and developing irisin for AD.
(Summary submitted by Eunhee Kim, PhD, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease (MIND), Department of Neurology)

Detailed Protocol for Using the High Resolution Neuropixels Probe
Modified Neuropixels Probes for Recording Human Neurophysiology in the Operating Room
Coughlin B, Muñoz W, Kfir Y, Young MJ, Meszéna D [et al.], Paulk AC
Published in Nature Protocols on 9/11/2023
Moving new neurotechnologies into the clinical space to better understand the human brain takes a considerable amount of effort, time, and a team of neuroscientists, clinicians, researchers, engineers, and clinical staff. It also requires substantial attention to regulatory pathways and neuroethical considerations. In a major step forward, our team shares a detailed protocol for using the powerful and revolutionary high resolution Neuropixels probe in the human operating room with patient participants. This provides a framework for safe application and use of Neuropixels to record human brain activity at unprecedented resolution.
(Summary submitted by Yangling Chou, PhD, Center for Neurotechnology and Neurorecovery, Department of Neurology)

Identification of New Biomarker for Poor Outcome in Acute Gastrointestinal GVHD
Spatial Transcriptomics Reveals Distinct Tissue Niches Linked with Steroid Responsiveness in Acute Gastrointestinal GVHD
Patel BK, Raabe MJ, Lang ER, Song Y, Lu C [et al.], DeFilipp Z
Published in Blood on 9/12/2023
Acute graft-versus-host disease (GVHD) is a condition characterized by inflammation and tissue damage that can occur in patients who receive stem cell transplantation from a donor. When acute GVHD occurs in the lower intestines, it can be particularly challenging to treat. We analyzed colon tissue from patients with new GVHD using a novel technique called spatial transcriptomics, which allowed us to characterize the expression of genes in different cell types and their spatial relationship to each other. We identified two distinct patterns of gene expression that were associated with future response to initial treatment with steroids. We also identified high expression of USPL17 family of proteins in immune cells as a potential biomarker that predicts poor outcomes.
(Summary submitted by Zachariah DeFilipp, MD, Mass General Cancer Center, Department of Hematology Oncology)

Role of Mast Cells in Alzheimer's Disease
Mast Cell Deficiency Improves Cognition and Enhances Disease-associated Microglia in 5XFAD Mice
Lin CJ, Herisson F, Le H, Jaafar N, Chetal K [et al.], Tanzi RE
Published in Cell Reports on 9/13/2023
In this study, we are aiming to investigate the role of mast cells in Alzheimer's disease. To find answers, we bred Alzheimer's mice that didn't have mast cells. We discovered that removing mast cells in Alzheimer's mice improved their memory. Depleting mast cells also had an impact on a type of brain cell called microglia, which may help protect against Alzheimer's, and it reduced the activity of another type of brain cell called astrocytes, which can become problematic in Alzheimer's. These findings suggest that we might be able to change the course of Alzheimer's by targeting mast cells.
(Summary submitted by Chih-Chung "Jerry" Lin, PhD, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease (MIND), Department of Neurology)

Shared Genetic Influences on Sleep and Health Across Diverse Ethnic Backgrounds
Multi-ancestry Genome-wide Analysis Identifies Shared Genetic Effects and Common Genetic Variants for Self-reported Sleep Duration
Scammell BH, Tchio C, Song Y, Nishiyama T, Louie TL [et al.], Saxena R
Published in Human Molecular Genetics on 9/15/2023
Our study looked at genetics and sleep's impact on health. Too little (≤6 hours) or too much sleep (≥9 hours) can increase disease risks. We used genetic markers from mainly European populations to create a sleep-related genetic score. It was linked to sleep duration in African, East Asian, and South Asian groups but not in Hispanic/Latino individuals. In a large analysis, we identified 73 genetic locations related to habitual sleep duration, some affecting brain gene expression and relating to heart and mental health. This suggests shared genetic influences on sleep and health across diverse ethnic backgrounds.
(Summary submitted by Cynthia Tchio, MS, PhD, Center for Genomic Medicine)

Potential New Use for Alcohol Dependence Drug to Treat Solid Tumors Using CAR T
Stressed Target Cancer Cells Drive Nongenetic Reprogramming of CAR T Cells and Solid Tumor Microenvironment
Wang Y, Drum DL, Sun R, Zhang Y, Chen F [et al.], Wang X
Published in Nature Communications on 9/15/2023
Clinical trials highlight the pivotal role of a stem cell-like memory phenotype in ensuring lasting responses to chimeric antigen receptor T-cell therapy (CAR T) cell therapy in cancer patients. However, the immunosuppressive tumor microenvironment poses a substantial barrier to CAR T therapy in solid tumors. Our study demonstrates that cancer cells stressed by disulfiram (DSF), an FDA-approved drug treating alcohol dependence, and copper (Cu) complexes (DSF/Cu) and ionizing radiation promote profound reprogramming of the immunosuppressive tumor microenvironment and CAR T cells that acquire early memory-like characteristics, enabling enhanced and durable antitumor response in multiple preclinical solid tumor models.
(Summary submitted by Xinhui Wang, MD, PhD, Gastrointestinal & Oncologic Surgery, Department of Surgery)

Novel Strategy to Harness Bioluminescence Imaging for Alzheimer's
Bioluminescence Imaging with Functional Amyloid Reservoirs in Alzheimer's Disease Models
Yang J, Ding W, Zhu B, Zhen S, Kuang S [et al.], Ran C
Published in Analytical Chemistry on 9/15/2023
To accelerate the pace of drug development for Alzheimer’s disease, reliable and easy-to-use imaging technologies for reporting the in vivo levels of amyloid beta species are desperately needed. Bioluminescence imaging has been used in thousands of biomedical laboratories for preclinical cancer research, due to its high robustness, excellent signal-to-noise ratio and easy-to-use. By contrast, this imaging technology has rarely been used in preclinical research of Alzheimer’s disease. Based on our insight from our previous studies, we have devised a novel strategy to harness bioluminescence imaging with amyloid reservoir (BLIAR) to report the levels of amyloid beta species and monitor the disease progression and therapeutic effectiveness. We believe that our method could be widely applied to accelerate drug development for Alzheimer’s disease.
(Summary submitted by Chongzhao Ran, PhD, Martinos Center for Biomedical Imaging)

Genetic Link to T Cell Reponse in Pancreatic Cancer
PD-1 Blockade Induces Reactivation of Non-productive T Cell Responses Characterized by NF-kB Signaling in Patients with Pancreatic Cancer
Ali LR, Lenehan PJ, Cardot-Ruffino V, Dias Costa A, Katz MHG [et al.], Dougan SK
Published in Clinical Cancer Research on 9/21/2023
The treatment of several cancers has been revolutionized by the introduction of immunotherapy, such as PD-1 blockade, which activates the immune system’s powerful cell-killing agents, known as T cells, against cancer cells. Disappointingly, pancreatic cancer has proven refractory to treatment with immunotherapy. In this study, we analyzed the blood and tumors of pancreatic cancer patients before and after treatment with PD-1 blockade. We employed an advanced technique called “single-cell RNA sequencing” that allows us to identify the specific genes being used by the patients’ T cells. This gave us extensive information about what those T cells were doing over the treatment course. Our results revealed a set of genes associated with poor activity in the patients’ T cells. Subsequent studies could potentially focus on targeting those counterproductive genes to promote effective T cell responses against pancreatic cancer.
(Summary submitted by Lestat Ali, MD, Department of Medicine)

Role of Brain Endothelial Cells in Psychotic Disorders
Brain Microvascular Endothelial Cells and Blood-brain Barrier Dysfunction in Psychotic Disorders
Lizano P, Pong S, Santarriaga S, Bannai D, Karmacharya R
Published in Molecular Psychiatry on 9/20/2023
We generated stem cells from patients with schizophrenia and bipolar disorder to examine how vascular abnormalities contribute to disease biology in psychotic disorders. Brain endothelial cells generated from the stem cells showed that a subset of patients had intrinsic deficits that affected barrier function properties necessary for an intact blood-brain barrier. Brain endothelial cells from these patients showed increased activity of the enzyme matrix metallopeptidase 1; inhibiting this enzyme in the endothelial cells led to improved barrier function. Our findings show how brain endothelial cells play an important role in psychotic disorders and point to new targets for therapeutic intervention.
(Summary submitted by Rakesh Karmacharya, MD, PhD, Center for Genomic Medicine)

Promising Result for New Sickle Cell Gene Therapy
Genetic Reversal of the Globin Switch Concurrently Modulates Both Fetal and Sickle Hemoglobin and Reduces Red Cell Sickling
De Souza DC, Hebert N, Esrick EB, Ciuculescu MF, Archer NM [et al.], Higgins JM
Published in Nature Communications on 9/20/2023
Sickle cell disease is an inherited hematological disorder that produces an abnormal sickle hemoglobin molecule. Sickle hemoglobin polymerizes upon deoxygenation and causes red blood cells to deform often into a sickle-like shape. This distortion can cause several complications including painful vaso-occlusive episodes, organ damage, and reduced lifespan. Fetal hemoglobin induction is an effective treatment for sickle cell disease as it impedes hemoglobin polymerization within individual red cells. A sickle cell gene therapy designed to induce the production of fetal hemoglobin was associated with red cells with greater resistance to deoxygenation-induced polymerization compared to red cells from patients highly responsive to hydroxyurea.
(Summary submitted by John M Higgins, MD, Department of Pathology)

Ability of Small Protein D2D3 to Injure Pancreas and Kidney May Explain Occurrence of Both Diseases in Some People
The D2D3 Form of uPAR Acts as an Immunotoxin and May Cause Diabetes and Kidney Disease
Zhu K, Mukherjee K, Wei C, Hayek SS, Collins A [et al.], Sever S
Published in Science Translational Medicine on 9/20/2023
The Centers for Disease Control and Prevention estimated that in 2022 37.3 million Americans had been diagnosed with diabetes. Researchers have never truly understood why some people with diabetes get kidney diseases and others do not. This paper may have uncovered why some people with diabetes also get a kidney disease, reason being a small protein present in their circulation. Researchers found that a small protein termed D2D3 that is found in circulation of some people binds to beta cells of the pancreas thereby inhibiting insulin production. The same small protein also binds and injures kidney cells causing kidney diseases. Ability of this small protein to injure two different organs in the same time, pancreas and kidney, may explain occurrence of both diseases in some people.
(Summary submitted by Sanja Sever, PhD, Nephrology Division, Department of Medicine)

New Phototherapy Strategy for Alzheimer’s Disease
A Photolabile Curcumin-Diazirine Analogue Enables Phototherapy with Physically and Molecularly Produced Light for Alzheimer's Disease Treatment
Kuang S, Zhu B, Zhang J, Yang F, Wu B [et al.], Ran C
Published in Angewandte Chemie International Edition English on 9/18/2023
In this article, we present a new phototherapy strategy for Alzheimer’s disease using molecularly generated light (dubbed as “molecular light”) from chemiluminescent compounds. We showed that the combination of “molecular light” and photosensitizers could lead to changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aβ) species in vitro. This study presents the first example of Aβs regulation approach using molecular light.
(Summary submitted by Chongzhao Ran, PhD, Martinos Center for Biomedical Imaging)

Manipulation of FAM3D Holds Promise for the Development of Novel Therapies after Heart Attack
Cardioprotective and Anti-Inflammatory Effects of FAM3D in Myocardial Ischemia-Reperfusion Injury
Rhee J, Freeman R, Roh K, Lyons M, Xiao C [et al.], Rosenzweig A
Published in Circulation Research on 9/15/2023
Diverse biological processes underlie cardiac remodeling after heart attack, or myocardial infarction (MI). We looked for proteins whose levels were most different in blood collected from “favorable remodelers” (i.e., patients who experienced partial recovery of heart function after MI) versus “adverse remodelers” (i.e., patients who suffered further decline of heart function). The cytokine FAM3D was the most differentially abundant protein in the former group, suggesting a role in limiting injury and/or promoting recovery. Animals that received FAM3D showed reduced infarct size and improved cardiac function after surgically-induced MI. In immune cells, administration of FAM3D downregulated key pro-inflammatory genes. Thus, manipulation of FAM3D and its receptors holds promise for the development of novel therapies after heart attack.
(Summary submitted by James Rhee, MD, PhD, Department of Anesthesia, Critical Care and Pain Medicine)

More Depression in Communities Where People Rarely Left Home During the COVID-19 Pandemic
Community Mobility and Depressive Symptoms During the COVID-19 Pandemic in the United States
Perlis RH, Lunz Trujillo K, Safarpour A, Quintana A, Simonson MD [et al.], Lazer D
Published in JAMA Network Open on 9/27/2023 | Press Release
In a survey-based study of US adults, those living in communities in which most people seldom left home at certain times during the COVID-19 pandemic were more likely to report symptoms of depression. The link remained strong even after considering COVID-19 activity, weather, and county-level economics. Accounting for state-level pandemic restrictions only modestly attenuated the association.
(Summary submitted by Roy Perlis, MD, Center for Quantitative Health, Department of Psychiatry)

Press Releases

Exercise-Induced Hormone Irisin May Reduce Alzheimer’s Disease Plaque and Tangle Pathology in the Brain
Featuring Se Hoon Choi, PhD
Researchers have used a 3D human neural cell culture model to show that the exercise-induced muscle hormone, irisin, reduces the level of amyloid beta associated with Alzheimer’s disease. Irisin had this effect by triggering brain cells called astrocytes to increase production of the amyloid beta–degrading enzyme neprilysin. The findings could lead to new therapeutic strategies for the treatment of Alzheimer’s disease.

Study Reveals More Depression in Communities Where People Rarely Left Home During the COVID-19 Pandemic
Featuring Roy Perlis, MD
In a survey-based study of US adults, those living in communities in which most people seldom left home at certain times during the COVID-19 pandemic were more likely to report symptoms of depression. The link remained strong even after considering COVID-19 activity, weather, and county-level economics. Accounting for state-level pandemic restrictions only modestly attenuated the association.

Blog Posts

Benchmarks: Mass General Research News and Notes for Sept. 8, 2023
The future of cardiac care at Mass General, promising news about a potential Alzheimer’s treatment and much more.

Symposium Highlights the Legacy of Warren M. Zapol, MD, Mass General’s “Dr. Adventure”
Zapol pioneered the use of nitric oxide for patients in respiratory distress, a discovery that saved countless lives worldwide.

Remembering Norton Folsom, MD, a Civil War Veteran, Compassionate Clinician and Early Mass General Leader
Norton Folsom, MD, superintendent of Massachusetts General Hospital from 1872 to 1877, is remembered as a man of “good temper and invariable kindness.”

How A New Grant Will Support the Quest for a More Complete Map of the Brain
A more detailed understanding of the connections between brain networks could improve treatments for neurological and psychiatric disorders.

In New Role as Chair of Medicine, Florez Hopes to Empower Mass General’s Best Asset: The People
Featuring Jose C. Florez, MD, PhD
Florez will support the hospital’s culture of collaboration and compassion while staying true to its four-part mission.

Research Spotlights

History of Adverse Childhood Events Linked to Increased Risk of Head or Neck Injury and Concussion
Featuring Altaf Saadi, MD
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 lead author of a new study in the Journal of Head Trauma and Rehabilitation, Examining the Association Between Adverse Childhood Experiences and Lifetime History of Head or Neck Injury or Concussion in Children From the United States.

Population Health Impact, Cost-Effectiveness, and Affordability of Community-Based HIV Treatment and Monitoring in South Africa: A Health Economics Modelling Study
Featuring Ruanne Barnabas, MD
Ruanne Barnabas, MD, chief of the Division of Infectious Diseases at Massachusetts General Hospital and a professor of Medicine at Harvard Medical School, is the senior author of a new study published in PLOS, Population Health Impact, Cost-Effectiveness, and Affordability of Community-Based HIV Treatment and Monitoring in South Africa: A Health Economics Modelling Study.

Association of Food Insecurity on Body Mass Index Change in a Pediatric Weight Management Intervention
Featuring Lauren Fiechtner, MD and Alicia Persaud, MPH
Alicia Persaud, MPH, a graduate research assistant in the Division of Pediatrics at Massachusetts General Hospital is the lead author; and Lauren Fiechtner, MD, director of the Center for Pediatric Nutrition at Mass General for Children, Assistant Professor of Medicine at Harvard Medical School and Senior Health and Research Advisor at the Greater Boston Food Bank, is the senior author of a recent study published in Pediatric Obesity, The Association of Food Insecurity on Body Mass Index Change in a Pediatric Weight Management Intervention.

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Snapshot of Science for September 2023