Snapshot of Science for May 2023

Welcome to our Snapshot of Science for May 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:

32 new studies published in high-impact journals, along with 30 summaries submitted by the research teams
9 new research-related press releases
8 posts from the Mass General Research Institute blog
3 research spotlights

Publications

Unawareness of Memory Function Strongly Associated with Future Clinical Progression
Measurement of Dimensions of Self-awareness of Memory Function and Their Association With Clinical Progression in Cognitively Normal Older Adults
Mimmack KJ, Gagliardi GP, Marshall GA, Vannini P; Alzheimer’s Disease Neuroimaging Initiative
Published in JAMA Network Open on 4/25/2023

Limited Efficacy of Sodium Thiosulphate in Treating Calciphylaxis
Intravenous Sodium Thiosulphate for Calciphylaxis of Chronic Kidney Disease: A Systematic Review and Meta-analysis
Wen W, Portales-Castillo I, Seethapathy R, Durant O, Mengesha B [et al.], Nigwekar SU
Published in JAMA Network Open on 4/26/2023 | *Summary available

Fluorescent Guide Can Help Detect Tumor Left Behind After Breast Cancer Surgery
Intraoperative Fluorescence Guidance for Breast Cancer Lumpectomy Surgery
Smith BL, Hunt KK, Carr D, Blumencranz PW, Hwang ES [et al.], Wapnir IL for INSITE Study Team
Published in NEJM Evidence on 4/27/2023 | Press Release

Poop, Perfume, and Brain Health
Indole-3-Propionic acid, A Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium
Zhou X, Wu X, Wu Y, Yang L, Shi E [et al.], Shen S
Published in Annals of Surgery on 4/27/2023 | *Summary available

Where Patients Treated May Affect Access to Recommended Testing and Therapies
Practice-Level Variation in Molecular Testing and Use of Targeted Therapy for Patients With Non-Small Cell Lung Cancer and Colorectal Cancer
Roberts TJ, Kehl KL, Brooks GA, Sholl L, Wright AA, Landrum MB, Keating NL
Published in JAMA Network Open on 4/28/2023 | *Summary available

Patients with CHIP Without Increased Risk of Breast Cancer Relapse or Mortality
Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Gibson CJ, Fell GG, Sella T, Sperling AS, Snow C [et al.], Miller PG
Published in Clinical Cancer Research on 4/28/2023 | *Summary available

Learning from the Gut Microbiome to Identify New Cancer Immunotherapies
Targeting PD-L2-RGMb Overcomes Microbiome-related Immunotherapy Resistance
Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J [et al.], Sharpe AH
Published in Nature on 5/3/2023 | *Summary available

Chat GPT Able to Provide Easy-to-understand, Scientifically Adequate Answers about Colonoscopy
ChatGPT Answers Common Patient Questions About Colonoscopy
Lee TC, Staller K, Botoman V, Pathipati MP, Varma S, Kuo B
Published in Gastroenterology on 5/5/2023 | *Summary available

Health Inequities in Heart Transplantation and Failure to Rescue
Does Failure to Rescue Drive Race/Ethnicity-based Disparities in Survival After Heart Transplantation?
Abrahim O, Premkumar A, Kubi B, Wolfe SB, Paneitz DC [et al.], Osho AA
Published in Annals of Surgery on 5/5/2023 | *Summary available

Differences in the Airway Response to Allergens Between People With Allergic Asthma and Those With Allergies but No Asthma
A Human Model of Asthma Exacerbation Reveals Transcriptional Programs and Cell Circuits Specific to Allergic Asthma
Alladina J, Smith NP, Kooistra T, Slowikowski K, Kernin IJ [et al.], Medoff BD
Published in Science Immunology on 5/5/2023 | *Summary available | Press Release

Extensive IBD Genetic Investigation Conducted in East Asian Populations
Genetic Architecture of the Inflammatory Bowel Diseases Across East Asian and European Ancestries
Liu Z, Liu R, Gao H, Jung S, Gao X [et al.], Huang H
Published in Nature Genetics on 5/8/2023 | *Summary available

Majority of Rare Disease Experts Support Expanding Standard Newborn Genetic Testing
Perspectives of Rare Disease Experts on Newborn Genome Sequencing
Gold NB, Adelson SM, Shah N, Williams S, Bick SL [et al.], Green RC
Published in JAMA Network Open on 5/8/2023 | *Summary available

Elevated Lipoprotein(a) May Cause Heart Blockages and Heart Attacks
Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes
Gilliland TC, Liu Y, Mohebi R, Miksenas H, Haidermota S [et al.], Natarajan P
Published in Journal of the American College of Cardiology on 5/9/2023 | *Summary available

Gut Microbiota Affect Delirium Patients
The Association Between Gut Microbiota and Postoperative Delirium in Patients
Zhang Y, Baldyga K, Dong Y, Song W, Villanueva M [et al.], Xie Z
Published in Translational Psychiatry on 5/9/2023 | *Summary available | Press Release

Novel Tool to Study Trigeminal Neuralgia in Rodents
Foramen Lacerum Impingement of Trigeminal Nerve Root (FLIT) as a Rodent Model for Trigeminal Neuralgia
Ding W, Yang L, Chen Q, Hu K, Liu Y [et al.], Shen S
Published in JCI Insight on 5/9/2023 | *Summary available

Gut Microbiome Changes Linked to Precancerous Colon Polyps
Association of Distinct Microbial Signatures with Premalignant Colorectal Adenomas
Lee JWJ, Plichta DR, Asher S, Delsignore M, Jeong T [et al.], Chung DC
Published in Cell Host & Microbe on 5/10/2023 | *Summary available | Press Release

Don't Remove Bladder for Localized Muscle-Invasive Cancer
Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis
Zlotta AR, Ballas LK, Niemierko A, Lajkosz K, Kuk C [et al.], Efstathiou JA
Published in The Lancet Oncology on 5/12/2023 | *Summary available

New Drug Pathway Mediate Resistance in Ovarian Cancers
Systematic Identification of Anticancer Drug Targets Reveals a Nucleus-to-mitochondria ROS-sensing Pathway
Zhang J, Simpson CM, Berner J, Chong HB, Fang J [et al.], Bar-Peled L
Published in Cell on 5/15/2023 | *Summary available

Case Study Unlocks Clues to Rare Resilience to Alzheimer’s Disease
Resilience to Autosomal Dominant Alzheimer's Disease in a Reelin-COLBOS Heterozygous Man
Lopera F, Marino C, Chandrahas AS, O'Hare M, Villalba-Moreno ND [et al.], Quiroz YT
Published in Nature Medicine on 5/15/2023 | *Summary available

Connection of Narcolepsy with Autoimmunity, Immunization, and Infection with H1N1
Narcolepsy Risk Loci Outline Role of T Cell Autoimmunity and Infectious Triggers in Narcolepsy
Ollila HM, Sharon E, Lin L, Sinnott-Armstrong N, Ambati A [et al.], Mignot EJ
Published in Nature Communications on 5/15/2023 | *Summary available

New Family-centered Agenda for Quality Improvement in Children with Advanced Cancer
Parent Priorities in End-of-Life Care for Children With Cancer
Ananth P, Lindsay M, Mun S, McCollum S, Shabanova V [et al.], Wolfe J
Published in JAMA Network Open on 5/15/2023 | *Summary available

AI Tool Accurately Predict Lung Disease Mortality Beyond Age, Smoking, and Other Known Risk Factors
Deep Learning to Estimate Lung Disease Mortality from Chest Radiographs
Weiss J, Raghu VK, Bontempi D, Christiani DC, Mak RH, Lu MT, Aerts HJWL
Published in Nature Communications on 5/16/2023 | *Summary available

Genes Expressed in the Brain Before Birth May Affect Risk of Childhood Mental Illness
Genetic Patterning for Child Psychopathology Is Distinct from That for Adults and Implicates Fetal Cerebellar Development
Hughes DE, Kunitoki K, Elyounssi S, Luo M, Bazer OM [et al.], Roffman JL
Published in Nature Neuroscience on 5/18/2023 | *Summary available | Press Release

Novel Approach That Stimulates Cells’ DNA Repair Mechanisms May Combat a Leading Cause of Autism Spectrum Disorders
Site-specific R-loops Induce CGG Repeat Contraction and Fragile X Gene Reactivation
Lee HG, Imaichi S, Kraeutler E, Aguilar R, Lee YW, Sheridan SD, Lee JT
Published in Cell on 5/19/2023 | *Summary available | Press Release

Vascular Functions Non-uniformly Disrupted Across Brain Regions in Alzheimer’s
Endothelial Cells are Heterogeneous in Different Brain Regions and are Dramatically Altered in Alzheimer's Disease
Bryant A, Li Z, Jayakumar R, Serrano-Pozo A, Woost B [et al.], Bennett R
Published in Journal of Neuroscience on 5/19/2023 | *Summary available

BCG Vaccine Could Have a Protective Effect Against Alzheimer's Disease
Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non-Muscle-Invasive Bladder Cancer
Weinberg MS, Zafar A, Magdamo C, Chung SY, Chou WH [et al.], Vakulenko-Lagun B, Das S
Published in JAMA Network Open on 5/19/2023 | *Summary available | Press Release

Study Challenges the Transmission Model of Cluster Emergence in Mycobacterium Abscessus
Mutation Rates and Adaptive Variation among the Clinically Dominant Clusters of Mycobacterium Abscessus
Commins N, Sullivan MR, McGowen K, Koch EM, Rubin EJ, Farhat M
Published in PNAS on 5/22/2023 | *Summary available

No Difference in Kidney Outcomes over 5 Years When Next-step Glucose Lowering Medications Added to Metformin for Glycemic Control
Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial
Wexler DJ, de Boer IH, Ghosh A, Younes N, Bebu I, Inzucchi SE, McGill JB, Mudaliar S, Schade D, Steffes MW, Tamborlane WV, Tan MH, Ismail-Beigi F; GRADE Research Group
Published in JAMA Internal Medicine on 5/22/2023 | *Summary available

Atherosclerotic Cardiovascular Disease Patients with CHIP Face Higher Risk of New ASCVD Events or Death
Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease
Gumuser ED, Schuermans A, Cho SMJ, Sporn ZA, Uddin MM [et al.], Honigberg MC
Published in Journal of the American College of Cardiology on 5/23/2023 | *Summary available

Specific Genetic Susceptibilities Concerning Nutrient Preferences Can Shape Long-term Food Choices
Genetic Predisposition to Macronutrient Preference and Workplace Food Choices
Merino J, Dashti HS, Levy DE, Del Rocío Sevilla-González M, Hivert MF, Porneala BC, Saxena R, Thorndike AN
Published in Molecular Psychiatry on 5/23/2023 | *Summary available

Patients with HIV or Hepatitis C Less Likely to Receive Emergency Surgery
HIV and Hepatitis C Virus-Related Disparities in Undergoing Emergency General Surgical Procedures in the United States, 2016-2019
Himmelstein KEW, Afif IN, Beard JH, Tsai AC
Published in Annals of Surgery on 5/25/2023 | *Summary available

Role for Astrocytic Calcium Pathophysiology in Soluble-Abeta Mediated Neurodegenerative Processes in Alzheimer’s
Neuronally-derived Soluble Abeta Evokes Cell-wide Astrocytic Calcium Dysregulation in Absence of Amyloid Plaques In Vivo
Kelly P, Sanchez-Mico MV, Hou SS, Whiteman S, Russ A, Hudry E, Arbel-Ornath M, Greenberg SM, Bacskai BJ
Published in Journal of Neuroscience on 5/26/2023 | *Summary available

Publication Summaries

Calciphylaxis is a rare and fatal disease that mainly occurs in patients with chronic kidney disease (CKD) and there is no approved medication to treat it. Sodium thiosulphate (STS) has been used as an off-label therapeutic in calciphylaxis to improve pain and accelerate the healing of skin lesions. However, there are no data from clinical trials to demonstrate the effectiveness of STS in calciphylaxis. We performed a meta-analysis of present cohort studies that provided data comparing outcomes among patients treated with and without STS to evaluate the efficacy of STS for calciphylaxis in CKD patients. We discovered that skin lesion improvement and survival rates were comparable between the STS and control groups. We also noted that there is a trend of reporting calciphylaxis refractory to STS in recent years discovered by meta-regression. Considering the sample size and other methodological limitations of studies included in our meta-analysis, a future large and well-designed randomized controlled trial is warranted to establish the effect of STS on calciphylaxis.

(Summary submitted by Wen Wen, MD, MMSc, Division of Nephrology, Department of Medicine)

Indoles are small molecules that are responsible for the unpleasant fecal smell. However, at low concentrations, indoles are widely used in perfumes! Many indoles are generated in the gut by the microorganisms residing in the gastrointestinal tract, the gut microbiome. In a recent collaborative study, we found that a gut microbiome derived indole family member, indole-3 propionic acid (IPA), has a neuroprotective role in patients who undergo surgeries. Patients that have lower blood IPA levels have a higher likelihood of developing delirium after surgeries, suggesting raising the blood IPA levels might be protective.

(Summary submitted by Shiqian Shen, MD, Department of Anesthesia, Critical Care and Pain Medicine)

This cross-sectional analysis of Medicare claims from 2015 to 2019 looked at patterns in use of molecular testing and targeted therapies among patients with metastatic lung and colorectal cancer. The results showed that rates of molecular testing increased substantially during the study period and use of molecular testing remained low. Rates of molecular testing and targeted therapy use were lower than expected, and rates varied by practice type with higher rates at NCI-designated cancer centers. These results suggest that where patients were treated may have affected access to recommended testing and therapies.

(Summary submitted by Thomas J. Roberts, MD, MBA, Hematology/Oncology Unit, Department of Medicine)

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, Department of Medicine)

The gut microbiota influences the efficacy of immune checkpoint blockade, yet probiotics and fecal transplants have variable effects in patients. We used microbiome-dependent mouse cancer models to discover that gut bacteria suppress PD-L2 expression on dendritic cells and RGMb expression on CD8+ T cells. Combining blocking antibodies to PD-L2 or RGMb with PD-1/PD-L1 blockade promotes a durable anti-tumor response in multiple tumor models that do not respond to PD-1/PD-L1 blockade alone. These studies identify a novel role for RGMb in CD8+ T cells and suggest that targeting RGMB/PD-L2 could promote anti-tumor immunity in patients whose microbiome is preventing a response to PD-1/PD-L1 blockade.

(Summary submitted by Francesca S. Gazzaniga, PhD, Department of Pathology and Center for Cancer Research)

This study examines the quality of ChatGPT-generated answers to common questions about colonoscopy. ChatGPT is a conversational AI program that was developed based on natural language processing NLP) technology. We retrieved eight common questions and answers about colonoscopy from the publicly available webpages of three nationally ranked hospitals and input them into Chat GPT. A team of four gastroenterologists then rated the answers provided by ChatGPT. The study is the first of its kind, to our knowledge, to demonstrate that a contemporary LLM-derived conversational AI program is able to provide easy-to-understand, scientifically adequate, and generally satisfactory answers to CQs about colonoscopy as determined by gastroenterologists.

(Summary submitted by Braden Kuo, MD, Division of Gastroenterology, Department of Medicine)

Outcomes after heart transplantation (HT) vary by patients’ race/ethnicity in the U.S. Failure to rescue (FTR), or the inability to prevent death after a post-operative complication, is an important factor associated with cardiac surgery outcomes. The relationship between FTR and race/ethnicity is unknown. We discovered that this relationship is unique among non-White patients. In our study, Black recipients had an increased risk of mortality after HT without a significant difference in FTR compared to White recipients; while, in contrast, Hispanic recipients had an increased likelihood of FTR without a significant mortality difference. We suggest tailored approaches to addressing these health inequities to improve overall HT outcomes.

(Summary submitted by Orit Z. Abrahim, MD, MPH, Department of Surgery)

Many people have asthma that is driven by an allergic response to an environmental trigger, but not everyone with allergies develops asthma. This study used a unique experimental model to identify key differences in the airway response to allergens in allergic participants with and without asthma, with the goal of identifying biological signals that are specific to asthma. We identified several cellular and molecular pathways that were unique to asthma. In particular, asthmatic airways were dominated by pathways involved in airway inflammation and abnormal remodeling, while the airways of allergic individuals without asthma demonstrated signs of resolving inflammation and promoting tissue repair.

(Summary submitted by Jehan Alladina, MD, Pulmonary Division, Department of Medicine)

Inflammatory bowel disease (IBD) is a chronic GI disorder prevalent in European populations, with a rising incidence in recently industrialized countries. Genetics plays a significant role in IBD. However, most genetic data on IBD have been generated from people of European descent. Our new study represents the most extensive IBD genetic investigation conducted in East Asian populations. We discovered 80 new genetic loci linked to IBD among East Asians, and an additional 240 when combined with Europeans. Additionally, we developed an improved polygenic score for assessing IBD risk, particularly for those of Asian heritage.

(Summary submitted by Hailiang Huang, PhD, Analytic and Translational Genetics Unit, Department of Medicine)

Babies born in US hospitals undergo newborn screening, a laboratory test to identify their risk of up to 60 treatable conditions. But hundreds of genetic disorders that are not currently included in newborn screening now have targeted treatments, including a growing number of devastating childhood diseases for which gene and cell therapies can offer permanent cures. In this survey study of 238 rare disease experts, 87.9% agreed that genomic sequencing for treatable genetic conditions should be available to all newborns. Over 80% of participants agreed that a specific list of 25 genetic disorders should be added to newborn screening. This work may lay a roadmap for expanding newborn screening and identifying children at risk for rare disease.

(Summary submitted by Nina B. Gold, MD, Department of Pediatrics)

Lipoprotein(a) is a circulating cholesterol-rich particle that is hypothesized to contribute to atherosclerotic cardiovascular disease. In this study, we measured lipoprotein(a) levels in patients undergoing evaluation of the coronary arteries via invasive cardiac catheterization. We found that elevated lipoprotein(a) was associated with the number and severity of coronary artery blockages and with cardiovascular events – such as heart attack or cardiovascular death – in follow-up. This works adds to the evidence that elevated lipoprotein(a) may cause heart blockages and heart attacks. Clinical trials of new therapeutics aimed at lowering lipoprotein(a) are underway for patients with established cardiovascular disease.

(Summary submitted by Thomas C. Gilliland, Jr, MD, Division of Cardiology, Department of Medicine)

A new study has uncovered a potential association between gut bacteria and postoperative delirium, a common complication that affects patients after surgery. Through an analysis of fecal samples from surgical patients, researchers observed that higher levels of a specific bacterium called Parabacteroides distasonis in postoperative samples were potentially linked to the presence of delirium. These findings provide insights into the possible pathology of postoperative delirium and present the opportunity for targeted interventions. The study underscores the importance of investigating the relationship between gut bacteria and brain function, opening up exciting possibilities for improving postoperative care, particularly in elderly patients.

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

Trigeminal neuralgia is one of the most devastating pain conditions to humanity, also known as ‘suicidal disease’. Trigeminal neuralgia has yet to be successfully modeled in rodents. Our research team discovered that a natural skull base foramen, foramen of lacerum, provides direct access to the trigeminal nerve root in rodents. Impingement of the nerve at this location leads to drastic trigeminal neuralgia-like behavior in rodents, including lancinating pain attacks and dental pain. Using this model, the team discovered a unique brain cortical neural activity pattern that is likely a key substrate mediating pain. This novel tool provides a powerful platform to accelerate mechanistic exploration and therapeutics development.

(Summary submitted by Shiqian Shen, MD, Department of Anesthesia, Critical Care and Pain Medicine)

Using our GIDER registry of nearly 1000 healthy patients undergoing colonoscopy, we identified 2 different sets of gut bacteria that are linked to the 2 major types of pre-cancerous colon polyps, tubular adenomas and sessile serrated adenomas. These bacteria are influenced by diet and medications to regulate distinct metabolic pathways. These findings provide new insights into the ways that the micro-environment within the colon can lead to the formation of different types of pre-cancerous polyps and suggest new strategies for the diagnosis and even prevention of these polyps.

(Summary submitted by Daniel C Chung, MD, Gastrointestinal Unit, Department of Medicine)

Patients with muscle-invasive bladder cancers (MIBC) have a narrow window of cure that requires aggressive treatment. Radical cystectomy (RC) is the traditional standard of care, which involves removing the bladder and some surrounding organs. However, it is a major operation with significant morbidity. Bladder-sparing therapy using trimodality therapy (TMT) combines transurethral endoscopic resection of the bladder tumor (TURBT) with concurrent radiation and chemotherapy, and this alternative has emerged as an effective treatment for select patients with MIBC. In the absence of completed randomized control trials, we conducted a large multi-institutional study comparing cancer outcomes after RC and TMT in patients who were eligible for both approaches (e.g. single tumors less than 7 cm). We found no statistically significant differences in terms of rates of cancer specific survival. This paradigm-changing study provides the best available evidence to support that TMT should be offered to all suitable candidates with MIBC and not only to patients with significant comorbidities for whom surgery is not an option.

(Summary submitted by Jason A. Efstathiou, MD, DPhil, FASTRO, FACRO, Department of Radiation Oncology)

Multiple chemotherapy drugs can induce ROS production in cancer cells as a mechanism of their cytotoxic action. However, the specific targets of ROS following chemotherapy remain almost completely unknown. By integrating cysteine-based chemical proteomics and functional genomic CRISPR screening, we gain unprecedented insights into mechanisms of action of ROS-generating chemotherapies at protein- and organelle-level resolution. Importantly we identify CHK1 as a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway–required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

(Summary submitted by Junbing Zhang, PhD, MGH Cancer Center)

Researchers identified a man who despite carrying the Paisa mutation which causes individuals to develop dementia by their 50s, remained cognitively intact until 67. Through neuroimaging, his scans showed that his brain had extensive amyloid plaques and tau tangles. But one brain region called the entorhinal cortex, a known hub for memory, navigation and the perception of time, had a very minimal amount of tau tangles. Genetic analyses of this patient revealed that he was a carrier of a rare variant in the Reelin gene (Reelin-COLBOS), a variant that offers protection by diminishing the pathological modifications of tau. Together, the findings demonstrate that Reelin-COLBOS signaling pathways influencing tau play an important role in the protection against Alzheimer’s disease.

(Summary submitted by Yakeel T Quiroz, PhD, Departments of Psychiatry and Neurology)

Narcolepsy is a severe sleep disorder, where a subset of neurons controlling sleep are lost. Previous studies have described association with H1N1 infection and immunization. However, what are the risk factors that affect neuronal loss in narcolepsy has been the most important unanswered question in the field. In our study, we discovered genetic variants that mediate immunity through the human leukocyte antigen as well as variants affecting interferon signaling or infection. Our findings highlight the role of T-cells and antigen presentation, and connect narcolepsy with autoimmunity, immunization, and infection with H1N1.

(Summary submitted by Hanna M. Ollila, PhD, Center for Genomic Medicine)

Recent research from our group led to the creation of quality measures to evaluate care for children with advanced cancer. However, we did not know which of these measures were of highest priority to key stakeholders. In the current study, we engaged parents who lost a child to cancer in a discrete choice experiment to understand their priorities. Bereaved parents prioritized measures focused on managing symptoms and meeting families’ goals and wishes. In contrast, quality measures assessing their child’s hospital resource use were substantially less important. Findings help set a family-centered agenda for quality improvement in children with advanced cancer.

(Summary submitted by Joanne Wolfe, MD MPH, Department of Pediatrics)

Prevention and management of chronic lung disease (e.g., COPD, lung cancer) require tools to accurately predict which individuals will have severe disease. In this study, we developed an AI tool to identify those at highest risk for severe lung disease based on chest x-ray images from 40k individuals. We found that the AI tool could accurately predict lung disease mortality beyond age, smoking, and other known risk factors.

(Summary submitted by Vineet Raghu, PhD, Cardiology Division, Department of Medicine)

Our study focused on genetic risk for childhood psychiatric symptoms that occur during adolescence, and related differences in brain development. We found that a new, neurodevelopmental polygenic score (PGS) that reflects shared features of attention deficit hyperactivity disorder, autism, depression, and Tourette syndrome, predicted a wide range of symptoms in early adolescence. Using transcriptomic data, we found that expression of implicated neurodevelopmental genes peaks in prenatal life, within the cerebellum. In turn, smaller cerebellar volumes are associated with increased symptom severity. These findings suggest that the genetic basis of childhood psychiatric symptoms differs from that for adults, and implicate altered fetal cerebellar development in emergence of symptoms a decade after birth.

(Summary submitted by Joshua L. Roffman, MD, Department of Psychiatry)

Here we describe an approach to correct the genetic defect in Fragile X syndrome (FXS) by using the cell's own genetic repair machinery. A leading cause of autism spectrum disorders, FXS results from inactivation of FMR1 gene due to a congenital trinucleotide (CGG) repeat that expands to hundreds. By investigating conditions favorable to FMR1 reactivation, we discover conditions that induce a strong repeat contraction and full FMR1 reactivation in cellular models. We trace the mechanism to a special nucleic acid structure called "R-loops" formed between DNA and RNA, which cells see as DNA damage and instigate cells to bring repair mechanisms to fix the problem. The native repair mechanism drives excision of the long CGG repeat to more normal copies and enable cells to re-express the crucial FMR1 gene. Our study, therefore, identifies a potential method of treating or even "curing" FXS in the future.

(Summary submitted by Jeannie T Lee, MD, PhD, Department of Pathology, Department of Molecular Biology)

Our understanding of how the endothelial cells that make up blood vessels are impacted by Alzheimer’s disease is far from complete. To gain insight, we examined tissues from 32 Alzheimer’s disease and healthy donor brains and performed a detailed gene expression analysis using a technique called single-nucleus RNA sequencing. This generated a large dataset representing 51,586 individual endothelial cells, revealing new findings about this often-overlooked cell type. For example, comparisons of gene expression show these cells are surprisingly different across five brain regions even in healthy aging. In disease, cells in each brain region react differently to the development of pathology, with amyloid plaques being associated with the greatest changes. These findings help explain how important vascular functions are non-uniformly disrupted across brain regions in Alzheimer’s and point towards novel gene targets to reverse dysfunction. Our data can be further explored through the interactive website: https://ad-progression-atlas.partners.org

(Summary submitted by Rachel Bennett, PhD, Alzheimer's Disease Research Unit, Department of Neurology)

This manuscript reports a favorable association of older adults receiving the tuberculosis vaccine BCG with and reduced later incidence of Alzheimer’s disease and related dementias. BCG has a fascinating century-long history and has been linked with several beneficial off-target effects, including decreased death in newborns, decreased risk of several types of cancers, improvements in glucose metabolism in type-1 diabetes, and decreased respiratory infections. Currently, the only US FDA-approved use of the BCG vaccine is for treating certain superficial bladder cancers. In analyzing medical records from Mass General Brigham databases, our team identified a 20% decrease in the 15-year incidence of Alzheimer’s disease and related dementias in bladder cancer patients receiving BCG treatment compared with individuals receiving an alternative treatment for a similar disease. We also found a 25% decrease in the incidence of death in these individuals. Our results support further study of BCG in preventing and treating Alzheimer’s disease and related neurodegenerative diseases, as well as more broadly and improving geriatric health in a globally cost-effective way.

(Summary submitted by Marc Weinberg, MD, PhD, Departments of Neurology and Psychiatry)

Mycobacterium abscessus (Mab) is an emerging public health threat that causes severe lung disease in affected individuals. Recent genomic studies have revealed that the Mab evolutionary tree is characterized by extremely dense clusters of isolates sampled from diverse geographies. While Mab was historically thought to be acquired by patients independently from the environment, these results raise the possibility of patient-to-patient transmission. In this study we provide evidence that the emergence of Mab clusters has coincided with a slowing of the mutation rate, resulting in the appearance of dense clusters. We propose that changes in the mutation rate result from beneficial mutations in DNA repair machinery. These results challenge the transmission model of cluster emergence in Mab.

(Summary submitted by Maha R. Farhat, MD, MDCM, Pulmonary and Critical Care Medicine Unit, Department of Medicine)

Among people with type 2 diabetes for less than 10 years, we observed no difference in kidney outcomes over 5 years when the next-step glucose lowering medications sitagliptin (a DPP-4 inhibitor), glimepiride (a sulfonylurea), liraglutide (a GLP-1 receptor agonist), or glargine, (a basal insulin) was added to metformin for glycemic control.

(Summary submitted by Deborah J. Wexler, MD MSc, MGH Diabetes Center, Department of Medicine)

Over 10% of people aged >70 have clonal hematopoiesis of indeterminate potential (CHIP), an aging-related condition caused by cancer-causing mutations in blood stem cells in apparently healthy people. Recent studies suggest that CHIP accelerates development of atherosclerotic cardiovascular disease (ASCVD) in healthy persons. To evaluate CHIP's impact in a higher-risk population, we examined 13,000 patients previously diagnosed with ASCVD. Our study revealed that ASCVD patients with CHIP, particularly those with mutations in high-risk genes, faced a higher risk of new ASCVD events or death. These results pave the way for future clinical trials targeting CHIP for ASCVD risk reduction.

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

Decisions about what, when, why, and how much to eat occur repeatedly throughout the day. Although prior research has demonstrated multiple social, environmental, cultural, and molecular factors that influence food choices, the impact of genetic variation on food choice behavior remains largely unexplored. In a secondary analysis of the ChooseWell 365 study, the relationship between genetic variation linked to nutrient preferences (i.e., preference for carbohydrate, fat, or protein-rich foods) and workplace food purchases was examined among 397 MGH employees. The results suggested that individuals with a stronger genetic predisposition towards carbohydrate-rich foods tended to make more purchases overall and to select healthier food options. While these findings are preliminary, they provide valuable insights into how specific genetic susceptibilities concerning nutrient preferences can shape long-term food choices. This knowledge can guide future experiments to enhance understanding of food choice behavior.

(Summary submitted by Anne N. Thorndike, MD, Metabolic Syndrome Clinic, MGH Cardiovascular Disease Prevention Center, Department of Medicine)

This study used data on hospitalized patients from across the US to examine what happens to people living with HIV and hepatitis C when they got to the hospital with conditions requiring emergency surgery -- things like appendicitis or blockage in the intestines. We found that, relative to other patients, those living with HIV or hepatitis C are less likely to receive surgery, even though surgery is often the best treatment. This suggests that doctors and healthcare systems need to do more to combat discrimination, and to work directly with people living with HIV and hepatitis C to make sure that they are accountable to providing the best possible care to all of their patients.

(Summary submitted by Kathryn E. Himmelstein, MD, MSEd, Infectious Diseases Division, Department of Medicine)

Role for Astrocytic Calcium Pathophysiology in Soluble-Abeta Mediated Neurodegenerative Processes in Alzheimer’s
Neuronally-derived Soluble Abeta Evokes Cell-wide Astrocytic Calcium Dysregulation in Absence of Amyloid Plaques In Vivo
Kelly P, Sanchez-Mico MV, Hou SS, Whiteman S, Russ A, Hudry E, Arbel-Ornath M, Greenberg SM, Bacskai BJ
Published in Journal of Neuroscience on 5/26/2023

Astrocytes play an essential role to maintain the homeostasis in the brain, but its impairment could be a key mechanism of neurodegeneration affecting Alzheimer’s disease (AD) progression. Specifically, astrocytic calcium signaling is implicated in many functions such as regulating synaptic transmission, vascular dynamics and neurovascular coupling, among others. Here, we have used high-resolution multiphoton imaging to analyze calcium signaling in vivo in awake mice with AD pathology. We have observed a cell-wide astrocytic calcium dysregulation due mainly to neuronally-derived soluble Abeta, with calcium hypoactivity in the astrocyte structure in close contact with blood vessels (endfeet) and hyperactivity of spontaneous calcium signaling throughout the rest of the astrocyte. Our findings highlight a role for astrocytic calcium pathophysiology in soluble-Abeta mediated neurodegenerative processes in AD.

(Summary submitted by Brian Bacskai, PhD, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology)

Press Releases

New Insights on How Ketamine Can Lessen Symptoms of Depression But Also Cause Dissociative Side Effects
Featuring Fangyun Tian, PhD

Ketamine can lessen the effects of depression but can also trigger dissociative symptoms—such as detachment and out-of-body experiences. EEG tests revealed that ketamine produces antidepressant and dissociative effects in individuals by activating different structures in the brain via distinct circuits. The findings could help scientists design new therapies for depression with fewer side effects.

Study Reveals Differences in the Airway Response to Allergens Between People With Allergic Asthma and Those With Allergies but No Asthma
Featuring Jehan Alladina, MD and Benjamin Medoff, MD

The airways of individuals with asthma had higher expression of genes that amplify inflammation and promote abnormal structural changes to the airway. The airways of participants without asthma had higher expression of genes involved in tissue repair and antioxidant signaling. The types of immune cells in samples from participants with and without asthma also differed.

Gut Bacteria May Contribute to Delirium in Elderly Patients After Surgery
Featuring Zhongcong Xie, MD, PhD

The study suggests that changes of a specific gut bacterium, Parabacteroides distasonis, potentially link to postoperative delirium in elderly patients. Targeting the gut microbiota could be a potential strategy for preventing and treating postoperative delirium in elderly patients.

Study Finds Fluorescent Guide Can Help Detect Tumor Left Behind After Breast Cancer Surgery
Featuring Barbara Smith, MD, PhD

A new technique designed to allow surgeons to identify and remove residual tumor tissue during breast-conserving surgery showed promising results in a multi-center trial led by investigators from the Mass General Cancer Center.

Genes Expressed in the Brain Before Birth May Affect Risk of Childhood Mental Illness
Featuring Joshua Roffman, MD and Phil H. Lee, PhD

When expressed in the brain’s cerebellum before birth, certain genes in a “neurodevelopmental gene set” may affect a child’s risk of developing various psychiatric conditions. The genetic causes of these conditions differ from those of adult illness.

Early Data from Mass General Researchers Suggests the BCG Vaccine Could Have a Protective Effect Against Alzheimer's disease
Featuring Marc Weinberg, MD, PhD, Colin Magdamo, BS, Affan Zafar, MD, and Sudeshna Das, PhD

In a new study, treatment with the Bacillus Calmette-Guérin (BCG) vaccine—which prevents tuberculosis and is used to treat non–muscle-invasive bladder cancer—was associated with a reduced risk of Alzheimer’s disease and related dementias. Treatment with the vaccine was also linked to a lower risk of death during the study. Clinical trials of BCG vaccination in Alzheimer’s disease are underway at MGH, led by Drs. Weinberg, Arnold, and Faustman.

Novel Approach That Stimulates Cells’ DNA Repair Mechanisms May Combat a Leading Cause of Autism Spectrum Disorders
Featuring Jeannie T. Lee, MD, PhD and Hun-Goo Lee, PhD

Researchers have discovered that stimulating cells’ DNA repair mechanisms may correct the inherited genetic defect that defines fragile X syndrome, a leading cause of autism spectrum disorders. The method involves enhanced production of special nucleic acid structures called “R-loops” that cells see as DNA damage.

Gut Microbiome Changes Linked to Precancerous Colon Polyps
Featuring Daniel C. Chung, MD

Understanding the link between the gut microbiome and polyp growth opens the door to potential screenings and treatments.

Researchers Call for Changes to State Law Requiring Child Protective Services to Be Notified When Medications for Opioid Use Disorder Are Used During Pregnancy
Featuring Davida Schiff, MD

Massachusetts is one of several states that mandates reporting to child protective services (CPS) when a child is exposed to medications for opioid use disorder during pregnancy. A recent study found that this policy creates feelings of stigma and shame among those seeking treatment for substance use disorder, and negatively impacts medical decision making. The findings suggest that treatment decisions must be uncoupled from CPS reporting to ensure the safety and improved health outcomes for mothers and their infants.

Blog Posts

Humans of MGRI: Preeti Kumari, PhD
Preeti Kumari's research is focused on discovering new biomarkers for Myotonic dystrophy and Duchene muscular dystrophy.

Simulation Study Shows Unexpected Changes in Spaceflight Performance Over Time
Featuring Aleksandra Stankovic, PhD

The findings from the Mass General-led research team could help NASA in planning for long term space travel to Mars.

Benchmarks for May 5, 2023
Deaths from alcohol-related liver disease soar during the COVID-19 pandemic, plus tweets of the week and more.

The Psychology of Sports Injuries
Featuring Miho J. Tanaka, MD, PhD and Kyle Banker

Learn about the psychological and physical impacts of sports injuries from the perspectives of a Mass General researcher and a college athlete.

Footnotes in Science: Q&A with Emiliano Santarnecchi , PhD
In a recent research review, Dr. Santarnecchi and team found that brain aging is a process that begins way earlier than one’s later years.

Remembering Henry Bowditch, MD, a Trailblazer for Equality at Mass General and Beyond
Henry Ingersoll Bowditch, MD, a longtime Mass General physician, abolitionist and public health pioneer, was no stranger to controversy.

How much do you know about celiac disease? Experts debunk common myths
Featuring Alessio Fasano, MD and Maureen Leonard, MD, MMSc

Mass General researchers take on several common myths about celiac disease and share what the science actually tells us.

Conversations on Mental Health: Katherine Koh, MD, & Homeless Population Mental Health
Improving Mental Health Care for the Homeless: Insights from Mass General Research Institute Investigator, Dr. Katherine Koh

Research Spotlights

Down syndrome screening and diagnosis practices in Europe, United States, Australia, and New Zealand from 1990–2021
Featuring Brian Skotko, MD, MPP

Brian Skotko, MD, MPP, from the Mass General Down Syndrome Program and colleagues recently published a literature review in the European Journal of Human Genetics, titled Down syndrome screening and diagnosis practices in Europe, United States, Australia, and New Zealand from 1990–2021.

A Call to Action to Create Compassionate and Comprehensive Care for Patients Experiencing Homelessness and Mental Illness
Featuring Katherine Koh, MD, MSc

Katherine Koh, MD, MSc, physician-scientist in the Department of Psychiatry, is the first author of a recent viewpoint published in JAMA, Reimagining Institutionalization and a Continuum of Care for People Experiencing Homelessness and Mental Illness.

A Conversational Artificial Intelligence Program Can Generate Credible Medical Information in Response to Common Patient Questions
Featuring Braden Kuo, MD

Braden Kuo, MD, a neurogastroenterologist and the director of the Center for Neurointestinal Health at MGH and an associate professor of Medicine at Harvard Medical School and Tsung-Chun Lee, MD, PhD, of Taipei Medical University Shuang Ho Hospital, in Taiwan are co-authors of a recent research letter published in Gastroenterology, ChatGPT Answers Common Patient Questions About Colonoscopy.

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Snapshot of Science for May 2023