Snapshot of Science for June 2023

Welcome to our Snapshot of Science for June 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 24 summaries submitted by the research teams
10 new research-related press releases from the Mass General Public Affairs office
9 posts from the Mass General Research Institute blog
3 research spotlights

Publications

Defining the Symptoms Long COVID-19
Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection
Thaweethai T, Jolley SE, Karlson EW, Levitan EB, Levy B [et al.], Foulkes AS
Published in JAMA on May 25, 2023 | *Summary available

Genetic Variation and Response to Diabetes Medications
Genome-wide Association Analysis Identifies Ancestry-specific Genetic Variation Associated with Acute Response to Metformin and Glipizide in SUGAR-MGH
Li JH, Brenner LN, Kaur V, Figueroa K, Schroeder P [et al.], Florez JC
Published in Diabetologia on May 26, 2023 | *Summary available | Press Release

Loss of DNA Methylation Occurs Early in Prostate Cancer and Helps Avoid Immune Detection
DNA Hypomethylation Silences Anti-tumor Immune Genes in Early Prostate Cancer and CTCs
Guo H, Vuille JA, Wittner BS, Lachtara EM, Hou Y [et al.], Haber DA
Published in Cell Press on May 28, 2023 | *Summary available

A New Graph That Jointly Embeds Single Cells with Their Defining Features
SIMBA: Single-cell Embedding Along with Features
Chen H, Ryu J, Vinyard ME, Lerer A, Pinello L
Published in Nature Methods on May 29, 2023 | *Summary available

Predicting Preeclampsia and Gestational Hypertension
Polygenic Prediction of Preeclampsia and Gestational Hypertension
Honigberg MC, Truong B, Khan RR, Xiao B, Bhatta L [et al.], Natarajan P
Published in Nature Medicine on May 29, 2023 | *Summary available

A Clinically Approved Antibiotic As A Hypoxia-Sensing Molecular Probe
Development of Dissolution Dynamic Nuclear Polarization of [15N3]Metronidazole: a Clinical Approved Antibiotic
Guarin DO, Joshi SM, Samoilenko A, Kabir MSH, Hardy EE [et al.], Yen YF
Published in Angewandte Chemie International Edition on May 29, 2023 | *Summary available

Medications for Alcohol Rarely Given to Adolescents and Young Adults
Medications for Alcohol Use Disorder and Retention in Care in Medicaid-Enrolled Youth, 2014-2019
Earlywine JJ, Bagley SM, Rodean J, Zima BT, Chadi N, Leslie DL, Hadland SE
Published in Journal of Adolescent Health on May 29, 2023 | *Summary available | Press Release

The Phenomenon of Discordant Genotype Calls
Discordant Calls Across Genotype Discovery Approaches Elucidate Variants with Systematic Errors
Atkinson EG, Artomov M, Loboda AA, Rehm HL, MacArthur DG [et al.], Daly MJ
Published in Genome Research on May 30, 2023 | *Summary available

Identifying a B Cell Subset That Participates in Tissue Inflammation and Fibrosis
Extrafollicular IgD-CD27-CXCR5-CD11c- DN3 B Cells Infiltrate Inflamed Tissues in Autoimmune Fibrosis and in Severe COVID-19
Allard-Chamard H, Kaneko N, Bertocchi A, Sun N, Boucau J [et al.], Pillai S
Published in Cell Reports on May 30, 2023 | *Summary available

Acute Increases in Blood Tau May Contribute to Brain Dysfunction and Postoperative Delirium
Blood Tau-PT217 Contributes to the Anesthesia/Surgery-induced Delirium-like Behavior in Aged Mice
Lu J, Liang F, Bai P, Liu C, Xu M [et al.], Xie Z
Published in Alzheimer's and Dementia on May 30, 2023 | *Summary available | Press Release

Geneformer: A Pretrained Deep Learning Model for Transcriptomics
Transfer Learning Enables Predictions in Network Biology
Theodoris CV, Xiao L, Chopra A, Chaffin MD, Al Sayed ZR [et al.], Ellinor PT
Published in Nature on May 31, 2023

A New Selective Estrogen Receptor Degrader for Treating 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 June 1, 2023

Exploring Hypoxia-Related Therapies for Friedreich’s Ataxia
Continuous, but Not Intermittent, Regimens of Hypoxia Prevent and Reverse Ataxia in a Murine Model of Friedreich's Ataxia
Ast T, Wang H, Marutani E, Nagashima F, Malhotra R, Ichinose F, Mootha VK
Published in Human Molecular Genetics on June 1, 2023

The Role of MMGT1-GPR156-Lipid Droplets in Tuberculosis Persistence
Identification of Host Regulators of Mycobacterium tuberculosis
Phenotypes Uncovers a Role for the MMGT1-GPR156 Lipid Droplet Axis in Persistence
Kalam H, Chou CH, Kadoki M, Graham DB, Deguine J, Hung DT, Xavier RJ
Published in Cell Host Microbe on June 2, 2023 | *Summary available

Prebrolizumab in Patients with Untreated Brain Metastases
Pembrolizumab in Brain Metastases of Diverse Histologies: Phase 2 Trial Results
Brastianos PK, Kim AE, Giobbie-Hurder A, Lee EQ, Lin NU [et al.], Sullivan RJ
Published in Nature Medicine on June 2, 2023 | *Summary available

Identifying Four Functional Subtypes of Monocytes
Limited Plasticity of Monocyte Fate and Function Associated with Epigenetic Scripting at the Level of Progenitors
Rhee C, Scadden EW, Wong LP, Schiroli G, Mazzola MC [et al.], Scadden DT
Published in Blood on June 2, 2023 | *Summary available

Initial Implementation Challenges for Organization Participating in Massachusetts Flexible Care Services Program
Assessment of the Massachusetts Flexible Services Program to Address Food and Housing Insecurity in a Medicaid Accountable Care Organization
McCurley JL, Fung V, Levy DE, McGovern S, Vogeli C [et al.], Thorndike AN
Published in JAMA Health Forum on June 2, 2023 | *Summary available

A Safe, Durable and Non-Surgical Approach to Feline Contraception
Durable Contraception in the Female Domestic Cat Using Viral-vectored Delivery of a Feline Anti-Müllerian Hormone Transgene
Vansandt LM, Meinsohn MC, Godin P, Nagykery N, Sicher N [et al.], Pépin D
Published in Nature Communication on June 6, 2023 | *Summary available | Press Release

Potential New Therapeutic Strategy to Treat Thyroid Cancers
Thyroid Cancers Exhibit Oncogene-enhanced Macropinocytosis that is Restrained by IGF1R and Promotes Albumin-drug-conjugate Response
Hu H, Ng TSC, Kang M, Scott E, Li R [et al.], Miller MA
Published in Clinical Cancer Research on June 8, 2023 | *Summary available

Transplant Success for Donor Hearts After Circulatory Death Comparable to Traditional Cold Storage
Transplantation Outcomes with Donor Hearts after Circulatory Death
Schroder JN, Patel CB, DeVore AD, Bryner BS, Casalinova S [et al.], D'Alessandro DA
Published in New England Journal of Medicine on June 8, 2023

Public Health Interventions and the Reduction of Opioid Overdose Deaths
Estimated Reductions in Opioid Overdose Deaths With Sustainment of Public Health Interventions in 4 US States
Chhatwal J, Mueller PP, Chen Q, Kulkarni N, Adee M [et al.], Barbosa C
Published in JAMA Network Open on June 9, 2023 | *Summary available

Proton Pump Inhibitor Use Not Associated with Dementia or Cognitive Decline
Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study
Mehta R, Kochar B, Zhou Z, Broder JC, Chung P [et al.], Chan AT
Published in Gastroenterology on June 12, 2023

Impact of New Staging Criteria for Heart Failure
Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort
Mohebi R, Wang D, Lau ES, Parekh JK, Allen N [et al.], Ho JE
Published in Journal of the American College of Cardiology on June 13, 2023

The Time-Varying Effects of Childhood Adversity
Association Between the Timing of Childhood Adversity and Epigenetic Patterns Across Childhood and Adolescence: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) Prospective Cohort
Lussier, AA, Zhu Y, Smith BJ, Cerutti J, Fisher J [et al.], Dunn EC
Published in Lancet Child & Adolescent Health on May 3, 2023 | *Summary available | Press Release

Insights into Porcine-Kidney Xenotransplantation
Clinical and Molecular Correlation Defines Activity of Physiological Pathways in Life-sustaining Kidney Xenotransplantation
﷟HYPERLINK "https://pubmed.ncbi.nlm.nih.gov/35501382/"Firl DJ, Lassiter G, Hirose T, Policastro R, D'Attilio A [et al.], Hall KC Published in Nature Communications on June 13, 2023 | *Summary available

Gastric Bypass Surgery Reduces Bone Strength and Density in Adolescents
Two-year Skeletal Effects of Sleeve Gastrectomy in Adolescents with Obesity Assessed with Quantitative CT and MR Spectroscopy
Huber FA, Singhal V, Tuli S, Becetti I, López López AP [et al.], Bredella MA
Published in Radiological Society of North America on June 13, 2023 | *Summary available

Limiting Opioid Administration During Surgery May Paradoxically Increase Postsurgical Opioid Use
Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use
Santa Cruz Mercado LA, Liu R, Bharadwaj KM, Johnson JJ, Gutierrez R [et al.], Purdon PL
Published in JAMA Surgery on June 14, 2023 | *Summary available | Press Release

Immunological Mediators of Vaccine-Induced Protection from SARS-CoV-2
ChAdOx1 nCoV-19 (AZD1222) Vaccine-induced Fc Receptor Binding Tracks with Differential Susceptibility to COVID-19
Kaplonek P, Cizmeci D, Kwatra G, Izu A, Lee JS [et al.], Alter G
Published in Nature Immunology on June 15, 2023 | *Summary available

Bavituximab Has Activity in Newly Diagnosed Glioblastoma Patients
Bavituximab Decreases Immunosuppressive Myeloid-derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients
Ly KI, Richardson LG, Liu M, Muzikansky A, Cardona J [et al.], Gerstner ER
Published in Clinical Cancer Research on June 16, 2023 | *Summary available

Outcomes of Supraclavicular Thoracic Outlet Decompression Treatment
Efficacy and Safety of Supraclavicular Thoracic Outlet Decompression
Panda N, Hurd J, Madsen J, Anderson JN, Yang ME [et al.], Donahue DM
Published in Annals of Surgery on June 19, 2023 | *Summary available

Alcohol Lowers Activity in Stress-Related Brain Network
Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk
Mezue K, Osborne MT, Abohashem S, Zureigat H, Gharios C [et al.], Tawakol A
Published in Journal of the American College of Cardiology on June 20, 2023 | *Summary available | Press Release

How Breast Cancer Cells Evade Immune Surveillance in Lymph Nodes
Cancer Cell Plasticity and MHC-II-mediated Immune Tolerance Promote Breast Cancer Metastasis to Lymph Nodes
Lei PJ, Pereira ER, Andersson P, Amoozgar Z, Van Wijnbergen JW [et al.], Padera TP
Published in Journal of Experimental Medicine on April 27, 2023 | *Summary available | Press Release

Publication Summaries

Millions worldwide experience long COVID, which includes symptoms and conditions that persist long after acute COVID infection. However, no generally accepted definition for long COVID exists. We presented results from the NIH-funded Researching COVID to Enhance Recovery (RECOVER) Initiative and identified 12 symptoms that best set apart individuals with and without a history of infection. These include post-exertional malaise, loss of smell or taste, brain fog, and others. We developed a definition of long COVID based on these symptoms, which is an important launching point for studying risk factors, understanding mechanistic pathways, and ultimately, developing treatments for long COVID.

(Summary submitted by Tanayott Thaweethai, PhD, MGH Biostatistics, Department of Medicine)

In SUGAR-MGH, 1000 individuals who are at risk of developing type 2 diabetes received a short course of two different medications that are typically used to treat type 2 diabetes. Genetic data was collected on participants and used to find variations in the genetic code (genetic variants) that might make an individual respond better or worse to one of the medications. We found several genetic variants that impacted drug response; many of these were more commonly found in people of African descent and have the potential to help tailor medications to this population.

(Summary submitted by Josephine Li, MD, Diabetes Unit, Department of Medicine)

Cancer cells have long stretches of DNA with low methylation levels associated with silencing of genes, but it is unknown whether these changes are a cause or consequence of cancer. We used single cell analyses of prostate tumors and circulating tumor cells to show that certain genomic regions consistently lose DNA methylation even at the earliest stages. Strikingly, many genes silenced by loss of DNA methylation normally activate the immune system, and those genes spared from silencing help the cancer grow. Together, these findings indicate that loss of DNA methylation occurs early in prostate cancers and plays an important role in enabling cancers to escape detection by the immune system.

(Summary submitted by David T. Miyamoto, MD, PhD, Investigator, Center for Cancer Research, Department of Radiation Oncology)

To address shortcomings of single-cell analysis pipelines, researchers created a versatile method called SIngle-cell eMBedding Along with features (SIMBA). SIMBA has the ability to co-embed cells and features, including genes, chromatin-accessible regions, and DNA sequences, into a shared latent space, paving the way for the identification of marker features without the need for clustering, and facilitating the discovery of gene regulatory circuits that drive biological processes within single-cell data. SIMBA allows for exploring and comparing cell state-specific regulatory circuits and unearthing novel cell subpopulations, and also simplifies the execution of various single-cell analysis tasks and facilitates the development of analyses.

(Summary submitted by Luca Pinello, PhD, Molecular Pathology Unit)

The hypertensive disorders of pregnancy (e.g., preeclampsia/eclampsia, gestational hypertension) impose a large global burden of maternal and infant morbidity. To gain insights into the incompletely understood biology of these conditions, we performed an expanded genome-wide association study (GWAS) of preeclampsia/eclampsia and the first distinct GWAS of gestational hypertension. We found 18 genomic loci associated with preeclampsia/eclampsia and/or with gestational hypertension, 12 of which are novel. Polygenic risk scores derived from these GWAS results improved prediction of preeclampsia/eclampsia in independent cohorts and reclassified eligibility for low-dose aspirin to prevent preeclampsia. These findings provide new insights into the disease mechanisms and have the potential to improve pregnancy risk stratification.

(Summary submitted by Michael C Honigberg, MD, MPP, Division of Cardiology, Department of Medicine)

A Clinically Approved Antibiotic as a Hypoxia-Sensing Molecular Probe
Development of Dissolution Dynamic Nuclear Polarization of [15N3]Metronidazole: a Clinical Approved Antibiotic
Guarin DO, Joshi SM, Samoilenko A, Kabir MSH, Hardy EE [et al.], Yen YF
Published in Angewandte Chemie International Edition English on May 29, 2023

Hypoxia is a condition of insufficient oxygen to support metabolism. Hypoxia doubles the risk of early deterioration after stroke, increases the risk of dementia, and causes therapeutic resistance. Currently, clinicians have no accessible assay for hypoxic burden. We are developing a novel MRI contrast agent for hypoxia-sensing by using a clinically approved antibiotic, metronidazole. By labeling metronidazole with 15N isotopes, we can boost its signal 30,000-fold using a dynamic nuclear polarization technique. We reported several unusual MR properties of hyperpolarized 15N-metronidazole and demonstrated its feasibility for imaging, paving the way for the development of a new hypoxia-sensing MRI contrast agent.

(Summary submitted by Yi-Fen Yen, PhD, Martinos Center for Biomedical Imaging)

Medications for Alcohol Use Disorder Rarely Given to Youths
Medications for Alcohol Use Disorder and Retention in Care in Medicaid-Enrolled Youth, 2014-2019
Earlywine JJ, Bagley SM, Rodean J, Zima BT, Chadi N, Leslie DL, Hadland SE
Published in Journal of Adolescent Health on May 29, 2023

Addiction most commonly starts during adolescence. About 1 in 30 teens aged 12-17 has an alcohol use disorder, and about 1 in 6 young adults aged 18-25 has one. Treating addiction as early as possible is critical to prevent lifetime problems, and medications (including naltrexone, acamprosate, and disulfiram) are an effective form of treatment and recommended nationally. In a sample of nearly 5 million youth, we identified how often youth aged 13-22 across the US received a medication, and found that only 1 in 48 received one, likely representing a missed opportunity.

(Summary submitted by Scott E. Hadland, MD, MPH, MS, Division of Adolescent and Young Adult Medicine, Department of Pediatrics)

In many diseases including many cancers, a process of tissue scarring (called fibrosis) can damage organs. In some diseases drugs that remove B lymphocytes (a type of immune cell) can reduce the progression of fibrosis and reverse organ damage. In this study, a particular type of B cell (called a DN3 B cell) was found to accumulate at sites of inflammation and fibrosis in an autoimmune disease and in severe COVID-19. This knowledge may one day lead to therapies specifically targeting DN3 B cells for inhibition or removal and may provide a new approach to treat fibrosis while preserving essential immunity

(Summary submitted by Shiv Pillai, PhD, Ragon Institute of MGH, Harvard and MIT)

Preoperative plasma levels of phosphorylated Tau at threonine 217 (Tau-PT217) serve as a biomarker of postoperative delirium in patients. Plasma Tau-PT217 increases following anesthesia and surgery in patients. A new animal study demonstrated that anesthesia/surgery increased blood Tau-PT217 amounts potentially by promoting its generation in lungs and releasing its binding from B cells, which may enter brain and increase anterior cingulate cortex neuron excitability, resulting in delirium-like behavior in aged mice. B cells or mitochondrial function enhancer WS635 mitigated these changes. These findings provide insights into acute Tau metabolism in blood and the understanding and potential management of postoperative delirium.

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

Most tuberculosis infections result in latent infection, but the host factors enabling latency are unclear, hindering the development of effective interventions. We uncovered one mechanism that induces persistence of Mycobacterium tuberculosis (Mtb), by characterizing transcriptional signatures of host cells that harbor different phenotypic states of Mtb. A genome-wide CRISPR screen highlighted membrane magnesium transporter 1 (MMGT1). The team showed that MMGT1 regulates Mtb persistence in macrophages through interaction with the G protein-coupled receptor GPR156, which alters lipid droplet accumulation during infection.

(Summary submitted by Ramnik Xavier, MD, PhD, Center for the Study of Inflammatory Bowel Disease, Department of Medicine)

Brain metastases (BM) are an emerging challenge in oncology due to increasing incidence and limited treatments. We conducted a phase 2 trial evaluating intracranial efficacy of pembrolizumab for BM of diverse tumor types. Our study met its primary endpoint, demonstrating a 42.1% intracranial benefit rate and improved outcomes compared to historical controls. A subset (12.3%) of our cohort, many possessing tumor types that do not traditionally respond to checkpoint inhibition, derived durable intracranial efficacy (>2 years) from pembrolizumab. These results suggest that pembrolizumab benefits a select group of BM patients, and support further studies to identify biomarkers and mechanisms of resistance.

(Summary submitted by Albert E. Kim, MD, Department of Neurology)

Blood cells, known as monocytes, were seen as simple scavengers that protect against bacteria. However, they are now known to have diverse activities and be involved in diseases, such as atherosclerosis and cancer, and in healing. Initially considered generic, this paper shows that the cells possess predetermined capabilities dictated by the 'epigenome'—heritable traits beyond their DNA—present in their parental cells. Four distinct cell groups were identified, each with unique abilities. The response to challenges depends on the specific group present, likening the cells to chess pieces with specific capabilities. This implies that individuals may exhibit varying resilience or susceptibility to diseases based on the presence of different cell groups.

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

The Massachusetts Flexible Services program (Flex) is a 3-year pilot program to address food and housing insecurity by connecting Medicaid accountable care organization (ACO) enrollees to community resources. We investigated the initial Flex implementation challenges and solutions at MGB, and found that among all 67,098 ACO enrollees, 1.6% adults and 0.7% children enrolled in Flex; of these, 74% were female, 53% were Hispanic/Latinx, and 21% were Black. Flex enrollees who received nutrition services reported increased healthy eating and food security. Results of this implementation study suggested that future Medicaid food and housing resource programs should provide administrative funding, bidirectional data-sharing platforms, and nutrition supports tailored to patient preferences.

(Summary submitted by Anne Thorndike, MD, MPH, Department of Medicine)

The standard of care in feline population control is surgical sterilization. This approach cannot scale to the hundreds of millions of unowned free-roaming cats worldwide. In this study we tested a gene therapy approach that uses a viral vector to deliver a feline anti-Müllerian hormone (AMH) transgene as a non-surgical permanent contraceptive. The normal function of this hormone in the ovary is to inhibit the growth and maturation of follicles. Following a single intramuscular injection, treated females maintained elevated AMH levels resulting in prevention of ovulation and complete sterility in mating studies over the course of two years.

(Summary submitted by David Pépin, PhD, Department of Surgery)

Oncogenic signaling can promote the non-specific scavenging of extracellular nutrients in some cancer types via a process termed macropinocytosis, which is thought to promote disease progression and drug resistance. However, the degree to which macropinocytosis occurs in thyroid cancers with PI3K and MAPK-ERK pathway mutations has remained unclear. Using a combination of genetically engineered mouse model imaging, analysis of patient-derived datasets, and in vitro microscopy, we identified high levels of macropinocytosis in follicular and aggressive anaplastic thyroid cancers. Macropinocytosis in the latter depended on MAPK/ERK activity downstream of BRAFV600E and was regulated by AMPK and insulin-like growth factor 1 receptor (IGF1R). A synthesized albumin-drug-conjugate selectively delivered a chemotherapeutic payload via macropinocytosis and blocked tumor growth in mice. These results thus uncover oncogene-driven macropinocytosis in thyroid cancers and offer a new therapeutic strategy to treat them.

(Summary submitted by Miles Miller, PhD, Center for Systems Biology)

Surgeons and investigators lead a national US clinical trial examining the safety of using donation after circulatory death (DCD) hearts in patients and compared the outcomes with those achieved using standard criteria brain-dead donor hearts. The results of this trial were recently published in the New England Journal of Medicine and show for the first time in a randomized trial, that use of DCD hearts achieves outcomes similar to those using standard criteria hearts. The results of this trial will undoubtedly change clinical practice and make more donor hearts available for patients with advanced clinical heart failure.

(Summary submitted by David A D'Alessandro, MD, Transplant Center, Department of Surgery)

In 2017, the opioid epidemic was declared a US public health emergency. Despite ongoing efforts, opioid overdose deaths continue to rise. To address the ongoing crisis, a multipronged approach consisting of interventions across prevention, harm reduction, and treatment is needed. The study found that substantial scaling-up of interventions is needed to see a meaningful reduction in overdose deaths. Increasing initiation (by 2-5 fold) and retention of medications for opioid use disorder (to the levels seen under ideal conditions) along with increased supply of naloxone could reduce OOD by 13–17% in Kentucky, 17–27% in Massachusetts, 15–22% in New York, and 15–22% in Ohio after two years, compared with the status quo. The longer the interventions are sustained, the better the outcomes; however, these positive gains would be washed out if interventions are not sustained.

(Summary submitted by Jagpreet Chhatwal, PhD, Institute for Technology Assessment, Department of Radiology)

Proton pump inhibitors (PPIs) are among the most commonly used medications worldwide, but there have been well-publicized studies that have linked chronic use of these medications with long-term health complications. However, these studies had substantial limitations, including an inability to account for factors such as medical comorbidities that are more commonly seen in individuals taking PPIs. We conducted a study of nearly 19,000 adults over the age of 65 to 70 years in Australia and the U.S. and did not find any association between PPI use and risk of dementia or cognitive impairment.

(Summary submitted by Andrew Chan, MD, MPH, Clinical and Translational Epidemiology Unit and Mass General Cancer Center)

The Time-Varying Effects of Childhood Adversity
Association Between the Timing of Childhood Adversity and Epigenetic Patterns Across Childhood and Adolescence: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) Prospective Cohort
Lussier, AA, Zhu Y, Smith BJ, Cerutti J, Fisher J {et al.], Dunn EC
Published in Lancet Child & Adolescent Health on May 3, 2023

Childhood adversities (e.g., abuse, one-adult households, financial hardship) can considerably influence one’s future health, but the biological mechanisms underlying these effects remain unclear. Using data from multiple longitudinal studies, we examined how adversity relates to changes in DNA, or epigenetic mechanisms, during childhood and adolescence. Most of the differences in adolescent epigenetic patterns were linked to adversities experienced between ages 3-5. Surprisingly, epigenetic differences were specific to the age when they were measured. These findings reveal the dynamic influence of childhood adversity on biological mechanisms and provide insights into its connection to adverse health outcomes in children and adolescents.

(Summary submitted by Alexandre A Lussier, PhD, Center for Genomic Medicine)

Insights into Porcine-Kidney Xenotransplantation
Clinical and Molecular Correlation Defines Activity of Physiological Pathways in Life-sustaining Kidney Xenotransplantation
Firl DJ, Lassiter G, Hirose T, Policastro R, D'Attilio A [et al.], Hall KC
Published in Nature Communications on June 13, 2023

The combination of gene edited porcine donors and next generation immunosuppression has improved outcomes in pig to non-human-primate kidney xenotransplantation. As survival outcomes improve (>500days of life-sustaining-renal-function) and barriers to translation to humans decrease, it is important to appreciate safety signals that may affect patients in clinical trials. While a principal function of kidneys is the filtration of nitrogenous waste, endocrine functions are also important to maintain health. In this study of 17 NHPs that survived a minimum of 60 days after life-sustaining-porcine-kidney-transplant, there was no efficient initiation of the NHP renin-angiotensin-aldosterone-system by porcine renin and only partial participation in the calcium-vitamin D-parathyroid hormone system. High levels of calcium and low levels of phosphorus were frequently observed in these NHPs. These findings might warrant changes to routine post-kidney transplant monitoring and care in potential clinical trials of gene edited pig to human kidney xenotransplantation.

(Summary submitted by Daniel J. Firl, MD, Department of Surgery)

Childhood obesity is on the rise and weight-loss surgery, specifically sleeve gastrectomy, is the most effective and common way to reduce weight and improve cardiometabolic comorbidities. It removes 75% to 80% of the stomach to restrict food intake and induce weight loss, but the long-term impact of this procedure on bone strength was unknown. Here, researchers found that it decreases bone strength, and that patients had a significant increase in bone marrow fat and a decrease in bone density and strength in the lumbar spine. These deficits in bone accrual during adolescence could have a long-term impact on bone health and fracture risk later in life.

(Summary submitted by Miriam Bredella, MD, MBA, Department of Radiology)

The opioid crisis has led to a reduction in opioid administration for pain management, including during anesthesia for surgery. However, the relationship between intraoperative opioid usage and postoperative outcomes is not sufficiently understood. We found in an analysis of 61,249 surgical cases that intraoperative opioid exposure has lasting effects on postoperative outcomes. In particular, increased intraoperative fentanyl exposure led to lower total postoperative opioid usage, fewer cases of uncontrolled pain, fewer new chronic pain diagnoses at 3 months, fewer opioid prescriptions at 30, 90, and 180 days, and decreased new persistent opioid use, without significant increases in adverse effects.

(Summary submitted by Ran Liu, PhD, Department of Anesthesia, Critical Care, and Pain Medicine)

Individuals infected with SARS-CoV-2 can develop COVID-19 with various degrees of severity. Vaccines have been instrumental in preventing the onset of severe COVID-19, but mechanisms of this protection have been difficult to pinpoint. Using a systems serology approach to deeply profile antibody responses elicited in ChAdOx.1 vaccinated individuals, we identified that individuals who resisted developing COVID-19 had unique antibody signatures. Notably, COVID-19 resisters had higher levels of Fc-gamma receptor 3B binding antibodies towards SARS-CoV-2 Spike. Our results point toward non-neutralizing leveraged antibodies as mediators of protection against COVID-19, especially for SARS-CoV-2 variants.

(Summary submitted by Ryan McNamara, PhD, Ragon Institute of Mass General, MIT and Harvard)

In this Phase 2 trial, we added bavituximab, an antibody with anti-angiogenic and immunomodulatory properties, to standard radiation and temozolomide in newly diagnosed glioblastoma patients. Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival and post-treatment tumor specimens contained fewer myeloid-derived suppressor cells (which promote the immunosuppressive glioblastoma microenvironment), suggesting an on-target effect of bavituximab. Seventy-three percent of patients were alive at 12 months, suggesting some efficacy of bavituximab and warranting further study.

(Summary submitted by Elizabeth Gerstner, MD, Mass General Cancer Center, Department of Neurology)

We evaluated the relationship between light/moderate alcohol consumption and heart disease in approximately 50,000 MGB Biobank subjects. After accounting for genetic, clinical, lifestyle, and socioeconomic factors, we found that light/moderate alcohol consumption was associated with a substantial reduction in the risk of cardiovascular disease events. However, we also found that cancer risk increased. Next, using brain imaging (in several hundred individuals), we found that light/moderate alcohol consumption was associated with chronic reductions in stress-related neural activity… and that this impact on stress systems appeared to play a significant role in decreasing heart disease events. In support of that mechanism, we found that alcohol-related reductions in heart disease risk were twice as large (40% reductions) in individuals with (vs. without) a history of anxiety. New interventions are needed that have similar benefits on the biology of stress and on heart health but without alcohol’s negative effects.

(Summary submitted by Ahmed Tawakol, MD, MGH Heart Center, Department of Cardiology)

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

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

Press Releases

Alzheimer’s Disease Plasma Biomarker and Pathogenesis Contribute to Postoperative Delirium-like Behavior in Rodents
Zhongcong Xie, MD, PhD

Reducing plasma Tau-PT217 may help to mitigate postoperative delirium-like behaviors and associated changes in brain tissues and neuronal activity in mice.

Genetic variants may affect treatment response to commonly prescribed type 2 diabetes medication
Josephine Li, MD, and Jose C. Florez, MD, PhD

In a study of individuals at risk for developing type 2 diabetes, researchers identified genetic variants linked with participants’ responses to two different blood sugar–lowering drugs.

Gene Therapy Produces Long-term Contraception in Female Domestic Cats
David Pépin, PhD, and Patricia K. Donahoe, MD

A single dose of a viral vector containing anti-Müllerian hormone prevented ovulation and conception in female cats for at least two years.

Mass General Hospital Researchers Uncover Why Light-to-Moderate Drinking Is Tied to Better Heart Health
Featuring Ahmed Tawakol, MD

Alcohol, in light to moderate quantities, was associated with long-term reductions in stress signaling in the brain. This impact on the brain’s stress systems appeared to significantly account for the reductions in cardiovascular events seen in light to moderate drinkers participating in the study. 

Timing of childhood adversity is associated with unique epigenetic patterns in adolescents
Alexandre A. Lussier, PhD, and Erin C. Dunn, ScD, MPH

Researchers found that ages 3 through 5 is a potentially critical period for the biological embedding of childhood adversity that manifests in adolescence.

Study finds that proven medications for alcohol use disorder are rarely given to adolescents and young adults on public insurance
Featuring Scott Hadland, MD, MPH

A review of claims data from 4.7M publicly insured youths in 15 states found that only 2% of those with alcohol use disorder (AUD) were prescribed medication.

Limiting Opioids During Surgery May Lead to More Postoperative Pain and Opioid Use for Patients
Ran Liu, PhD, Laura A. Santa Cruz Mercado, MD, and Patrick L. Purdon, PhD

Patients administered more of the opioids fentanyl and hydromorphone during surgery were less likely to experience pain and used lower total dosages of opioids in the hospital after waking up from anesthesia.

Immunotherapy for Brain Cancer Metastases Shows Clinical Benefit
Priscilla K. Brastianos, MD

Immune checkpoint inhibitors have shown promise in patients with brain metastases that have originated from melanoma or non-small cell lung cancer.

Mass General Cancer Center Researchers Share Insights on the Evolution of Proton Radiotherapy
Featuring Susu Yan, PhD, and Thomas Bortfeld, PhD

Investigators describe the evolution of proton therapy and its benefits to patients and society.

Study Sheds Light on How Breast Cancer Cells Evade Immune Surveillance and Survive in Lymph Nodes
Featuring Pin-Ji Lei, PhD, and Timothy P. Padera, PhD

Study reveals how cancer cells suppress anti-cancer immune responses in the lymph nodes to survive and spread, or metastasize.

Blog Posts

Humans of MGRI: Maryam Azimi Mohammadabadi, PhD
Featuring Maryam Azimi Mohammadabadi, PhD

Maryam Azimi Mohammadabadi's research is focused on molecules involved in the development of ovarian cancer

Neurosurgery Researcher Working to Identify New Treatments for Children with Traumatic Brain Injuries
Beth Costine-Bartell, PhD

There are currently no therapeutics to treat children with traumatic brain injuries. How one Mass General researcher is working to change that.

Benchmarks: Mass General Research News and Notes for June 17, 2023

How noise has a negative effect on cardiovascular health, new treatment for restless legs syndrome, tweets of the week and more.

Meet Our Newest MGRI Intern, Sakura!
Featuring Sakura Chen

Realizing the hardship low health literacy populations encounter when accessing health information, Sakura started her academic training in converting medical jargon into plain language for the broader audience.

Benchmarks: Mass General Research News and Notes for June 23, 2023
How breast cancer cells evade immune cells in the lymph nodes, limiting opioids during surgery may lead to higher use post-surgery and more.

Footnotes in Science: Q&A with Margarita Alegría, PhD
Featuring Margarita Alegría, PhD

Children in immigrant families often face mental health challenges that are exacerbated by social determinants of health.

Through the Magnifying Glass: The Myhre Syndrome Clinic and Lindsay Lab
Featuring Mark Lindsay, MD, PhD and Angela Lin, MD

A close-up look at the Myhre Clinic and their research lab, the Lindsay Lab, which is working to understand more about the disease.

Research Spotlights

Estimated Reductions in Opioid Overdose Deaths with Sustainment of Public Health Interventions in Four US States
Featuring Jagpreet Chhatwal, PhD

Jagpreet Chhatwal, PhD, Director of the Institute for Technology Assessment at Massachusetts General Hospital and an associate professor of Radiology at Harvard Medical School, is the lead author of a new paper in JAMA Network Open, Estimated Reductions in Opioid Overdose Deaths with Sustainment of Public Health Interventions in Four US States.

Enhancing communication in healthcare with Emoji
Featuring Shuhan He, MD

Shuhan He, MD, a physician-scientist in the Department of Emergency Medicine at Massachusetts General Hospital and instructor of Medicine at Harvard Medical School, as well as the program director for the Masters in Science in Data Analytics offered at the Mass General Institute of Health Professions. He is the lead author of a new commentary published in JAMA Network Open, Interpreting Emoji: A Language for Enhancing Communication in Healthcare

Providing patients with food and housing resources through Medicaid
Featuring Anne Thorndike, MD, MPH

Anne Thorndike, MD, MPH, a physician-investigator in the division of General Internal Medicine at Massachusetts General Hospital and an associate professor of Medicine at Harvard Medical School, is the senior author of a recent study published in Jama Health Forum, Assessment of the Massachusetts Flexible Services Program to Address Food and Housing Insecurity in a Medicaid Accountable Care Organization.

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Snapshot of Science for June 2023