Snapshot of Science for October 2023

Welcome to our Snapshot of Science for October 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  26 summaries submitted by the research teams
8 new research-related press releases
8 posts from the Mass General Research Institute blog
10 research spotlights

Publications

iPSC Motor Neurons Help Explain Gene Expression 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 9/26/2023

Screen and Detection of SARS-CoV-2 mRNA Vaccine Persistence in Autopsy Tissues
Duration of SARS-CoV-2 mRNA Vaccine Persistence and Factors Associated with Cardiac Involvement in Recently Vaccinated Patients
Krauson AJ, Casimero FVC, Siddiquee Z, Stone JR
Published in NPJ Vaccines on 9/27/2023 | *Summary available

Gene Discoveries Open Door to Preventing Deadly Coronary Artery Disease
Multi-ancestry Genome-wide Study Identifies Effector Genes and Druggable Pathways for Coronary Artery Calcification
Kavousi M, Bos MM, Barnes HJ, Lino Cardenas CL, Wong D [et al.], Miller CL
Published in Nature Genetics on 9/28/2023 | *Summary available

An Organizing Framework for Targeting Circuit Dysfunction, Neuroinflammation and Amyloid Production Early in AD Pathogenesis
Early Alzheimer's Disease Pathology in Human Cortex Involves Transient Cell States
Gazestani V, Kamath T, Nadaf NM, Dougalis A, Burris SJ [et al.], Macosko EZ
Published in Cell on 9/28/2023

Genetic Testing Practices, Indications and Results in Patients with Down Syndrome
Beyond Chromosome Analysis: Additional Genetic Testing Practice in a Down Syndrome Clinic
Harisinghani A, Raffaele G, Zawatsky CB, Santoro SL
Published in American Journal of Medical Genetics on 9/29/2023 | *Summary available | Research Spotlight

Benefits of Inhaled Nitric Oxide for Patients with Respiratory Failure Due to COVID-19 Pneumonia
High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure due to COVID-19: A Multicenter Phase 2 Trial
Di Fenza R, Shetty NS, Gianni S, Parcha V, Giammatteo V [et al.], Berra L
Published in American Journal of Respiratory and Critical Care Medicine on 9/29/2023 | *Summary available | Press Release

New Effective Strategy to Exploit Genomic Instability in Cancer Therapy
The RNA m5C Modification in R-loops as an Off Switch of Alt-NHEJ
Yang H, Lachtara EM, Ran X, Hopkins J, Patel PS, Zhu X, Xiao Y, Phoon L, Gao B, Zou L, Lawrence MS, Lan L
Published in Nature Communications on 9/30/2023

A Need for Tailored Vaping Cessation Approaches for Youth
Adoption of Vaping Cessation Methods by US Adolescent E-Cigarette Users
Dai HD, Hanh P, Guenzel N, Morgan M, Kerns E, Winickoff JP
Published in Pediatrics on 10/2/2023 | *Summary available

Synaptic and Circuit Mechanism Identified Contributes to Social Cognition in Autism
An Inhibitory Circuit-based Enhancer of DYRK1A Function Reverses Dyrk1a-associated Impairment in Social Recognition
Shih YT, Alipio JB, Sahay A
Published in Neuron on 10/4/2023 | *Summary available

New Potential Immunotherapy Treatment for Advanced Solid Tumors
The PTPN2/PTPN1 Inhibitor ABBV-CLS-484 Unleashes Potent Anti-tumour Immunity
Baumgartner CK, Ebrahimi-Nik H, Iracheta-Vellve A, Hamel KM, Olander KE [et al.], Manguso RT
Published in Nature on 10/4/2023 | *Summary available

How a Single Gene Can Cause Two Completely Different Diseases: the Case of PLS3
PLS3 Missense Variants Affecting the Actin-binding Domains Cause X-linked Congenital Diaphragmatic Hernia and Body-wall Defects
Petit F, Longoni M, Wells J, Maser RS, Bogenschutz EL [et al.], High FA
Published in American Journal of Human Genetics on 10/5/2023 | *Summary available

Increased Smoking Cessation Support Needed in Cancer Care for Patients From Highly Disadvantaged Neighborhoods
The Effect of Neighborhood Socioeconomic Disadvantage on Smoking Status, Quit Attempts, and Receipt of Cessation Support among Adults with Cancer: Results from Nine ECOG-ACRIN Cancer Research Group (EA) Trials
Walter AW, Lee JW, Streck JM, Gareen IF, Herman BA [et al.], Park ER
Published in Cancer on 10/5/2023 | *Summary available

Younger, Female or Primary Care Physicians With Higher Rates of Burnout
Patterns in Physician Burnout in a Stable-Linked Cohort
Ortega MV, Hidrue MK, Lehrhoff SR, Ellis DB, Sisodia RC [et al.], Wasfy JH
Published in JAMA Network Open on 10/6/2023 | *Summary available

Benefits of Solriamfetol for Adults with ADHD
Solriamfetol for Attention-Deficit/Hyperactivity Disorder in Adults: A Double-Blind Placebo-Controlled Pilot Study
Surman CBH, Walsh DM, Horick N, DiSalvo M, Vater CH, Kaufman D
Published in Journal of Clinical Psychiatry on 10/9/2023 | *Summary available | Press Release

Activating Anti-Tumor Immunity Through Nanoparticles
Hybrid LNP Prime Dendritic Cells for Nucleotide Delivery
Das R, Halabi EA, Fredrich IR, Oh J, Peterson HM [et al.], Weissleder R
Published in Advanced Science on 10/9/2023 | *Summary available

Primary Care Reminder Plus Patient Outreach Intervention Improved Rates of Follow-up After Abnormal Cancer Test Results
A Multilevel Primary Care Intervention to Improve Follow-Up of Overdue Abnormal Cancer Screening Test Results: A Cluster Randomized Clinical Trial
Atlas SJ, Tosteson ANA, Wright A, Orav EJ, Burdick TE [et al.], Haas JS
Published in JAMA on 10/10/2023 | *Summary available | Press Release

Xenotransplantation as a Potential Solution for Organ Shortage
Design and Testing of a Humanized Porcine Donor for Xenotransplantation
Anand RP, Layer JV, Heja D, Hirose T, Lassiter G [et al.], Qin W
Published in Nature on 10/11/2023 | *Summary available

Researchers Develop Technology to Tabulate and Characterize Every Cell in the Human Brain
A Cellular Resolution Atlas of Broca's Area
Costantini I, Morgan L, Yang J, Balbastre Y, Varadarajan D [et al.], Hof PR
Published in Science Advances on 10/12/2023 | *Summary available | Press Release

Generic Daily HIV Prevention Pill for Young Men Who Have Sex with Men Could Save Lives and Money
Daily Oral Human Immunodeficiency Virus (HIV) Pre-exposure Prophylaxis Among Young Men Who Have Sex With Men in the United States: Cost-saving at Generic Drug Price
Amick AK, Eskibozkurt GE, Hosek SG, Flanagan CF, Landovitz RJ [et al.], Neilan AM
Published in Clinical Infectious Diseases on 10/12/2023 | *Summary available | Research Spotlight

Recently Developed Approach in Immunotherapy Leads to Durable Responses in Murine Cancer Models
Highly Active Myeloid Therapy for Cancer
Fredrich IF, Halabi EA, Kohler RH, Ge X, Garris CS, Weissleder R
Published in ACS Nano on 10/12/2023 | *Summary available

Recurrence Prediction Value Can Identify Stage II Colon Cancer Patients with High Risk of Cancer Recurrence Worldwide
Stratification of Stage II Colon Cancer Using Recurrence Prediction Value: A Multi-institutional International Retrospective Study
Mizuno S, Shigeta K, Kato Y, Okui J, Morita S [et al.], Kunitake H
Published in Annals of Surgery on 10/12/2023

Administration of NAT Followed by Surgical Resection Appears to be Safe and Effective among Patients ≥ 75 years of Age
Feasibility, Safety, and Efficacy of Aggressive Multimodal Management of Elderly Patients with Pancreatic Ductal Adenocarcinoma
Qiao G, Fong ZV, Bolm L, Fernandez Del-Castillo C, Ferrone CR [et al.], Qadan M
Published in Annals of Surgery on 10/13/2023 | *Summary available

Blocking Androgen Receptors Could Overcome Drug Resistance and Enhance the Immune System's Ability to Fight Melanoma
Androgen Receptor Is a Determinant of Melanoma Targeted Drug Resistance
Samarkina A, Youssef MK, Ostano P, Ghosh S, Ma M [et al.], Dotto GP
Published in Nature Communications on 10/14/2023 | *Summary available

Understanding How Cholangiocarcinoma Tumors Develop Drug Resistance
Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma
Wu Q, Ellis H, Siravegna G, Michel AG, Norden BL [et al.], Bardeesy N
Published in Clinical Cancer Research on 10/16/2023 | *Summary available

Carcinogen Exposure Makes Cancer Cells More Susceptible to Immune Attack
Carcinogen Exposure Enhances Cancer Immunogenicity by Blocking the Development of an Immunosuppressive Tumor Microenvironment
Huang M, Xia Y, Li K, Shao F, Feng Z [et al.], Demehri S
Published in Journal of Clinical Investigation on 10/16/2023 | *Summary available | Press Release

Polygenic Risk Scores for Cardiometabolic Disease in Arabs
Clinical Utility of Polygenic Scores for Cardiometabolic Disease in Arabs
Shim I, Kuwahara H, Chen N, Hashem MO, AlAbdi L [et al.], Fahed AC
Published in Nature Communications on 10/18/2023 | *Summary available | Research Spotlight

Validating an MRI Biomarker for Early Onset Alzheimer’s Disease
The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort
Touroutoglou A, Katsumi Y, Brickhouse M, Zaitsev A [et al.], Dickerson BC; LEADS Consortium
Published in Alzheimer's & Dementia on 10/18/2023 | *Summary available | Research Spotlight

Genomic Correlations to Clinical Outcomes in Bladder Cancer Cases
Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer
Kamran SC, Zhou Y, Otani K, Drumm M, Otani Y [et al.], Miyamoto DT
Published in Clinical Cancer Research on 10/19/2023

Heated Yoga May Reduce Depression Symptoms
A Randomized Controlled Trial of Community-Delivered Heated Hatha Yoga for Moderate-to-Severe Depression
Nyer MB, Hopkins LB, Nagaswami M, Norton R, Streeter CC, [et al.], Mischoulon D
Published in Journal of Clinical Psychiatry on 10/23/2023 | *Summary available | Press Release

Vast Majority of Patients with Type 2 Myocardial Infarction Had Some Plaque in Their Heart Arteries but No Severe Narrowing
Coronary Computed Tomographic Angiography With Fractional Flow Reserve in Patients With Type 2 Myocardial Infarction
McCarthy CP, Murphy SP, Amponsah DK, Rambarat PK, Lin C [et al.], Januzzi JL Jr
Published in Journal of the American College of Cardiology on 10/24/2023 | *Summary available

How Sleep Disruption Can Exacerbate Pain
The Endocannabinoid N-arachidonoyl Dopamine Is Critical for Hyperalgesia Induced by Chronic Sleep Disruption
Ding W, Yang L, Shi E, Kim B, Low S [et al.], Shen S
Published in Nature Communications on 10/25/2023 | *Summary available | Press Release

How Age, BMI, Race and Tumor Subtype Impact Breast Cancer Survival
Age, Body Mass Index, Tumor Subtype, and Racial and Ethnic Disparities in Breast Cancer Survival
Lipsyc-Sharf M, Ballman KV, Campbell JD, Muss HB, Perez EA [et al.], Warner ET
Published in JAMA Network Open on 10/25/2023

Publication Summaries

In response to the COVID-19 pandemic, SARS-CoV-2 mRNA vaccines BNT162b2 and mRNA-1273 were expediently designed, mass-produced, and administered worldwide for gain of immunity and greatly reduced hospital burden and morbidity. However, distribution and duration of SARS-CoV-2 mRNA vaccine persistence in human tissues is unclear. To gain a better understanding, we developed two specific assays and screened the presence of these mRNA vaccines in proximal and distal lymph nodes, heart, liver and spleen tissues of patients dying after vaccination. Interestingly, mRNA vaccine was detected in cardiac ventricles of three patients, all with healing myocardial injury and associated macrophage infiltration. This study shows that mRNA vaccine can distribute to damaged tissue. Our team is now investigating additional autopsies of patients dying post vaccination to understand the relationships between pathologic changes and vaccine distribution.

(Summary submitted by Aram J. Krauson, PhD, Department of Pathology)

Even before people develop clinical coronary disease, doctors can detect calcium buildup inside the walls of the coronary arteries. They do so by using non-invasive computed tomography (CT) scans. Such scans strongly predict future cardiovascular events such as heart attacks or strokes, which are the leading causes of death and morbidity around the world. Calcium accumulation is also associated with other age-related diseases, such as dementia, cancer, chronic kidney disease and hip fractures. Coronary calcification can lead to life-threatening coronary artery disease, a condition responsible for over 375,000 deaths in the United States each year. Doctors may be able to target these newly-identified genes with medications – or possibly even nutritional supplements – to slow or halt disease progression.

(Summary submitted by Rajeev Malhotra, MD, Cardiology Division, Department of Medicine)

People with Down syndrome have an extra chromosome 21, called trisomy 21. But, individuals with Down syndrome can have genetic diagnoses in addition to trisomy 21. It is reasonable to consider additional genetic testing in some clinical situations.

(Summary submitted by Stephanie L. Santoro, MD, Down Syndrome Program, MassGeneral Hospital for Children)

Researchers have posted the results of a multisystem phase II clinical trial of patients with COVID-19 and respiratory failure. Patients who received inhaled nitric oxide had improved blood oxygen levels and fewer risks of long-term sensory and motor neurologic symptoms. They also experienced a faster reduction of viral load in sputum and blood.

(Summary submitted by Lorenzo Berra, MD, Department of Anesthesia, Critical Care and Pain Medicine)

Need for Tailored Vaping Cessation Approaches for Youth
Adoption of Vaping Cessation Methods by US Adolescent E-Cigarette Users
Dai HD, Hanh P, Guenzel N, Morgan M, Kerns E, Winickoff JP
Published in Pediatrics on 10/2/2023

This is the first national study to provide timely evidence on the cessation methods used by youth e-cigarette users. Overall, a majority of adolescent vapers reported unassisted quit attempts. Fewer than 4% of adolescent vapers got support on their quit attempt from a doctor. Assisted tobacco cessation is generally considered more effective than unassisted tobacco cessation for youth because it provides additional resources and support to help youth quit. For adolescents who did seek assistance, they used peer and parental support more than doctors or health care providers. Adoption of different vaping cessation methods was associated with demographic factors and vaping behaviors, highlighting the need for tailored vaping cessation approaches for youth.

(Summary submitted by Jonathan Winickoff, MD, MPH, MassGeneral Hospital for Children)

Synaptic and Circuit Mechanism Identified Which Contributes to Social Cognition in Autism
An Inhibitory Circuit-based Enhancer of DYRK1A Function Reverses Dyrk1a-associated Impairment in Social Recognition
Shih YT, Alipio JB, Sahay A
Published in Neuron on 10/4/2023

We identified a synaptic and circuit mechanism by which the high risk Autism Spectrum Disorder gene Dyrk1a contributes to social cognition. Using genetic epistasis logic, we show that viral targeting of a synaptic substrate of DYRK1A, the cytoskeletal protein ABLIM3, in adulthood is sufficient to reverse impairments in GABAergic inhibition and social recognition associated with Dyrk1a haploinsufficiency. This study motivates optimization of AAV shRNA and siRNA/ASO based approaches to target ABLIM3 for restoration of GABAergic inhibition and social cognition in syndromic Autism Spectrum Disorder defined by Dyrk1a haploinsufficiency.

(Summary submitted by Amar Sahay, PhD, Department of Psychiatry)

Immunotherapy is effective for some patients with cancer, but many patients do not respond or go on to develop resistance. Thus, new immunotherapy options are needed to improve responses and overcome resistance. PTPN2 is an enzyme that inhibits several important immune-related signaling pathways. Previous genetic data suggested that targeting the PTPN2 protein could enhance immunotherapy, but inhibitors for this enzyme had not been described. Here, we describe the development of ABBV-CLS-484, the first orally-available inhibitor of PTPN2 and a closely related protein, PTPN1. We show that AC484 is a safe and highly effective immunotherapy, which acts by enhancing the functions of immune cells called T cells and NK cells. On the basis of these discoveries, AC484 is currently being evaluated in patients with advanced solid tumours.

(Summary submitted by Robert T Manguso, PhD, Krantz Family Center for Cancer Research, Mass General Cancer Center)

How a Single Gene Can Cause Two Completely Different Diseases: The Case of PLS3
PLS3 Missense Variants Affecting the Actin-binding Domains Cause X-linked Congenital Diaphragmatic Hernia and Body-wall Defects
Petit F, Longoni M, Wells J, Maser RS, Bogenschutz EL [et al.], High FA
Published in American Journal of Human Genetics on 10/5/2023

Mendelian conditions classically follow a model where a single gene causes a single disease. However, biology is not always so simple. We described 8 families where males are affected with birth defects, including diaphragmatic and abdominal wall hernias. Affected individuals were found to carry deleterious variants in PLS3, a gene on the X chromosome. However, PLS3 had previously been implicated in an entirely different disease, an X-linked form of severe osteoporosis. Using in silico protein modeling and a mouse model, we showed how different molecular mechanisms explain how these disparate disease phenotypes are associated with the same gene.

(Summary submitted by Frances A High, MD, PhD, MassGeneral Hospital for Children)

Increased Smoking Cessation Support Needed in Cancer Care for Patients From High Disadvantage Neighborhoods
The Effect of Neighborhood Socioeconomic Disadvantage on Smoking Status, Quit Attempts, and Receipt of Cessation Support among Adults with Cancer: Results from Nine ECOG-ACRIN Cancer Research Group (EA) Trials
Walter AW, Lee JW, Streck JM, Gareen IF, Herman BA [et al.], Park ER
Published in Cancer on 10/5/2023

Tobacco use can contribute to poor health outcomes among patients diagnosed with cancer. Socioeconomic status, characterized by education, income, employment, housing, and household characteristics, influences health and health outcomes. This study examined the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients enrolled in nine cancer clinical trials nationally. Findings demonstrate that patients with a cancer diagnosis in high disadvantaged neighborhoods are more likely to report current smoking and be asked about smoking, but less likely to report receiving counseling. Increased cessation support is needed in cancer care for patients from high disadvantaged neighborhoods.

(Summary submitted by Angela Walter, PhD, MPH, MSW, University of Massachusetts, Lowell)

Younger, Female, or Primary Care Physicians With Higher Rates of Burnout
Patterns in Physician Burnout in a Stable-Linked Cohort
Ortega MV, Hidrue MK, Lehrhoff SR, Ellis DB, Sisodia RC [et al.], Wasfy JH
Published in JAMA Network Open on 10/6/2023

While earlier studies indicate a national increase in physician burnout, they have notable shortcomings. Our longitudinal study evaluated physician survey data from 2017 to 2021. Throughout this time, female physicians experienced burnout at a higher rate than male physicians, primary care physicians faced higher burnout levels than those in other specialties, and less experienced physicians reported more burnout than their seasoned peers. This growing trend poses a potential risk to the U.S. health care system's capacity to serve patients and urgently requires solutions.

(Summary submitted by Marcus V. Ortega, MD, FACOG, Department of Obstetrics and Gynecology)

Young adult women received stimulant treatment at an increased rate in 2021, in the context of surging telehealth access and peri-pandemic challenges. In a small clinical trial, solriamfetol—which is currently approved for treating excessive daytime sleepiness caused by narcolepsy or obstructive sleep apnea—was an effective therapy for attention-deficit/hyperactivity disorder in adults. Larger trials could confirm whether solriamfetol is a promising alternative to current medications.

(Summary submitted by Craig B H Surman, MD, Department of Psychiatry)

Lipid nanoparticles (LNP) have advanced to the forefront of medicine following the pandemic. LNPs have a tremendous capacity to treat cancer through their ability to stimulate immune response-controlling cells known as dendritic cells (DC), gatekeepers of anti-tumor immunity. However, encapsulating traditional small-molecule drugs in LNP has been difficult. To address this, we developed a nanoparticle-in-nanoparticle platform that could simultaneously deliver nucleic acids and small molecule immune stimulants to DCs—this potentiated anti-tumor immunity in mouse cancer models and eradicated tumors long-term. We plan to enhance LNP-based immune therapeutics as they emerge as a critical, effective means to activate anti-tumor immunity.

(Summary submitted by Christopher Garris, PhD, Center for Systems Biology)

Primary Care Reminder Plus Patient Outreach Intervention Improved Rates of Follow-up after Abnormal Cancer Test Results
A Multilevel Primary Care Intervention to Improve Follow-Up of Overdue Abnormal Cancer Screening Test Results: A Cluster Randomized Clinical Trial
Atlas SJ, Tosteson ANA, Wright A, Orav EJ, Burdick TE [et al.], Haas JS
Published in JAMA on 10/10/2023 | Press Release

There is considerable interest in cancer prevention. Maximizing the benefits of screening for cancer requires efforts to ensure everyone is screened and those with abnormal results are followed up. However, timely follow-up of abnormal cancer screening results is not always achieved. In a study of almost 12,000 patients with an overdue abnormal screening test result for breast, cervical, colon and lung cancer in three large primary care networks, an intervention that included reminders in the patient’s electronic health record and outreach efforts significantly improved follow-up rates. This supports the need for population-based systems to ensure the timely follow-up of abnormal cancer screen test results.

(Summary submitted by Steven J. Atlas, MD, MPH, Division of General Internal Medicine, Department of Medicine)

Xenotransplantation as Potential Solution for Organ Shortage
Design and Testing of a Humanized Porcine Donor for Xenotransplantation
Anand RP, Layer JV, Heja D, Hirose T, Lassiter G [et al.], Qin W
Published in Nature on 10/11/2023

Organ shortage is a serious problem for transplantation. In the US, more than 100,000 patients need organ transplants and over 6,000 die every year while waiting. Human organ donors are not enough to meet the demand, so one possible solution is to use organs from other animals. This is called xenotransplantation. The current study showed that kidney xenografts from genetically modified pigs can replace kidney function for a long time in nonhuman primates. This is a major breakthrough for solving organ shortage with xenotransplantation.

(Summary submitted by Tatsuo Kawai, MD, PhD, Department of Surgery)

We built the technology needed to integrate information across many orders of magnitude in spatial scale from images in which pixels are a few microns to those that image the entire brain. By combining non-invasive imaging techniques, we have created a comprehensive cellular atlas of a region of the human brain known as Broca’s area. The methods could be used to create 3D models of not just particular brain areas, but of an entire human brain.

(Summary submitted by Bruce Fischl, PhD, Department of Radiology)

Compared to annual HIV screening alone, generic daily oral HIV pre-exposure prophylaxis (PrEP) with HIV screening every three months would result in fewer HIV acquisitions, longer life expectancy, and fewer HIV-associated costs among young men who have sex with men in the United States. These projections which come from a simulation modeling study supported by the National Institutes of Health, illustrate the value of promoting PrEP use in this population.

(Summary submitted by Anne M Neilan, MD, MPH, Infectious Disease Unit, Department of Medicine)

Recently Developed Approach in Immunotherapy which Leads to Durable Responses in Murine Cancer Models
Highly Active Myeloid Therapy for Cancer
Fredrich IF, Halabi EA, Kohler RH, Ge X, Garris CS, Weissleder R
Published in ACS Nano on 10/12/2023

Immunotherapy, which coordinates elements of the immune system to attack tumors, is a rapidly growing and effective method to treat cancer. However, not all tumors respond to immunotherapy, and certain resistant cell types, such as myeloid cells, can prevent immunotherapy's antitumor function against tumors. We designed a novel therapeutic approach we call Highly Active Myeloid Therapy (HAMT), which re-programs myeloid cells in tumors to promote immune rejection of cancers. HAMT testing in pre-clinical mouse cancer models showed robust, long-term, and safe treatment of animals. We hope to develop further HAMT and other myeloid-targeted therapies to boost immunotherapy responses to cancer.

(Summary submitted by Christopher Garris, PhD, Center for Systems Biology)

In this study, we aimed to evaluate the safety and efficacy of neoadjuvant therapy (chemotherapy and radiation before surgery) followed by surgical resection in patients with pancreatic cancer aged ≥75 years. Whether administration of neoadjuvant therapy (NAT) followed by surgical resection in elderly patients with pancreatic ductal adenocarcinoma (PDAC) is safe and effective was unknown. The present study was a three-part comparison of older (≥ 75 years) versus younger (< 75 years) patients in different settings throughout the continuum of PDAC care. The first analysis was a comparison of older versus younger consecutive patients with non-metastatic PDAC who were initiated on FOLFIRINOX. The second was a comparison of older vs. younger patients who underwent NAT followed by surgical resection, and the third and final analysis was a comparison of older patients who underwent either NAT followed by surgical resection vs. upfront surgical resection. We examined complications, survival, and recurrence of cancer and showed that administration of NAT followed by surgical resection appears to be safe and effective among patients ≥ 75 years of age. Thus, an aggressive approach should be offered to older adults.

(Summary submitted by Motaz Qadan, MD, PhD, Division of Gastrointestinal & Oncologic Surgery, Department of Surgery)

Blocking Androgen Receptor Could Overcome Drug Resistance and Enhance the Immune System's Ability to Fight Melanoma
Androgen Receptor Is a Determinant of Melanoma Targeted Drug Resistance
Samarkina A, Youssef MK, Ostano P, Ghosh S, Ma M [et al.], Dotto GP
Published in Nature Communications on 10/14/2023

Melanoma, a main form of skin cancer with greater aggressivity in the male than female populations, can respond well to targeted therapy with drugs known as BRAF/MEK inhibitors, but eventually it becomes resistant to these drugs. The receptor for male sex hormones, called Androgen Receptor (AR), is also active in female cells. We uncovered that increased expression of AR makes melanoma cells drug-resistant, while inhibiting AR reverses the changes in gene expression associated with drug resistance and suppresses tumorigenesis enhancing cancer cell death by infiltrating immune cells. This suggests that blocking AR could not only overcome drug resistance but also enhance the immune system's ability to fight melanoma, making it a promising possibility to use AR inhibitors alongside existing therapies in melanoma.

(Summary submitted by An Buckinx, PhD, International Cancer Prevention Institute)

Cholangiocarcinoma is a rare liver cancer with a poor prognosis. A subset of these tumors has an alteration in FGFR2, for which there are now FDA approved targeted therapies. However, clinical benefit of these drugs is limited by the cancer developing resistance. Our work highlights the landscape of resistance mechanisms seen in patients treated with FGFR targeted therapies, most commonly mutations in FGFR2 itself and rarely in a site where the drug binds. Understanding how tumors acquire resistance to treatments can help in designing better drugs and combination strategies to improve patient outcomes.

(Summary submitted by Haley Ellis, MD, Mass General Cancer Center)

Our research has revealed that carcinogen exposure (example: smoking) cause cancer cells to change how they regulate their environment leading to their increased susceptibility to immune attack. Surprisingly, this enhanced immune response against cancer is not associated with increased DNA mutations. Instead, it is related to loss of immune suppressing factors in the cancer environment. Thus, targeting these immune factors highlights a promising and actionable treatment strategy to effectively treat many cancers with cancer immunotherapy.

(Summary submitted by Shawn Demehri, MD, PhD, Center for Cancer Immunology, Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center)

Arabs constitute 5% of the world population and have high burden of cardiometabolic disease, yet very little has been done to understand the clinical utility of polygenic risk scores in Arabs. We partnered with collaborators in Saudi Arabia to study a unique cohort of >6000 participants and developed new Arab-specific polygenic scores for 10 cardiometabolic traits, demonstrating clinical utility.

(Summary submitted by Akl C Fahed, MD, MPH, Division of Cardiology, Department of Medicine)

Too young: Early-onset Alzheimer's disease (EOAD) is a particularly devastating form of Alzheimer's affecting individuals often in their 40s, 50s, or early 60s, at the peak of their productive lives. This variant of the disease needs its own biomarker to facilitate accurate diagnosis. Across two well-characterized EOAD cohorts, our team identified and validated the disease signature MRI biomarker that can accurately differentiate EOAD patients from healthy individuals and patients with other types of dementia. The EOAD Signature MRI biomarker demonstrated clinical validity by showing a clear correlation with the severity of symptoms associated with the disease. We plan to share our EOAD Signature biomarker as a tool for the scientific community.

(Summary submitted by Alexandra Touroutoglou, PhD, Department of Neurology)

This study examined a form of heated yoga for treatment of depression. Patients were adults with moderate-to-severe depression who were randomly assigned to either 8 weeks of heated yoga or a waitlist control group. The yoga group was encouraged to attend at least two weekly yoga classes in any of two Boston area studios. After 8 weeks, the yoga group experienced a much greater reduction in their depression symptoms compared the waitlist group. Even more encouraging, patients who could attend only one yoga session per week also benefited, which may make heated yoga more acceptable to the general public.

(Summary submitted by Maren Nyer, PhD, Department of Psychiatry)

Heart attacks can occur through several mechanisms. One type of heart attack, called type 2 myocardial infarction, occurs when a patient experiences another medical illness or undergoes a surgery or procedure that reduces the oxygen supply to the heart or increases the demands of the heart beyond its capabilities. We performed a new research study and found that the vast majority of patients with this type of heart attack had some plaque in their heart arteries but most did not have a severe narrowing or a focal narrowing that is impairing the blood flow in their heart. These results will help to inform testing and treatment strategies for these patients in the future.

(Summary submitted by Cian McCarthy, MB, BCh, BAO, Division of Cardiology, Department of Medicine)

After missing a night of sleep, you might experience headaches and body aches. Even though this phenomenon is well known, the mechanisms behind it are unclear. A collaborative effort between scientists at the MIT and MGH found that an endocannabinoid, cannabinoid-like molecules made by our body, is the missing link between sleep loss and generalized pain feeling. Sleep loss decreases brain levels of this endocannabinoid whereas administration of this endocannabinoid alleviates pain induced by sleep loss.

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

Press Releases

Clinical Trial Reveals Benefits of Inhaled Nitric Oxide for Patients with Respiratory Failure Due to COVID-19 Pneumonia
Featuring Lorenzo Berra, MD

Clinical trial demonstrates benefits of solriamfetol for adults with ADHD
Featuring Craig B.H. Surman, MD

In a small clinical trial, solriamfetol—which is currently approved for treating excessive daytime sleepiness caused by narcolepsy or obstructive sleep apnea—was an effective therapy for attention-deficit/hyperactivity disorder in adults. Larger trials could confirm whether solriamfetol is a promising alternative to current medications.

Three Researchers from Massachusetts General Hospital Elected to the National Academy of Medicine
Featuring Jeannie T. Lee, MD, PhD, Maurizio Fava, MD, and Rudolph Tanzi, PhD

Massachusetts General Hospital researchers Jeannie T. Lee, MD, PhD, Maurizio Fava, MD, and Rudolph Tanzi, PhD, have been elected as members of the National Academy of Medicine (NAM) for their ongoing contributions to health and medicine and their sought-after expertise and leadership.

Primary Care Reminder Plus Patient Outreach Intervention Improved Rates of Follow-up after Abnormal Cancer Test Results
Featuring Steven J. Atlas, MD, MPH

In a randomized clinical trial, reminders and outreach interventions for primary care patients and clinicians improved rates of follow-up for abnormal cancer screening results. Despite these interventions, many patients still did not receive recommended and timely follow-up care.

Researchers Develop Technology to Tabulate and Characterize Every Cell in the Human Brain
Featuring Bruce Fischl, PhD

By combining non-invasive imaging techniques, investigators have created a comprehensive cellular atlas of a region of the human brain known as Broca’s area. The methods could be used to create 3D models of not just particular brain areas, but of an entire human brain.

Study Finds Carcinogen Exposure Makes Cancer Cells More Susceptible to Immune Attack, with Implications for Treatment
Featuring Shawn Demehri, MD, PhD

While carcinogens are widely known to be perpetrators of cancer, a new study from researchers at the Mass General Cancer Center has shown that exposure to carcinogens can increase cancer cells’ susceptibility to immune attack.

Heated Yoga May Reduce Depression Symptoms, According to Recent Clinical Trial
Featuring Maren Nyer, PhD and David Mischoulon, MD, PhD

Heated yoga sessions led to reduced depressive symptoms in adults with moderate-to-severe depression. The trial findings suggest that the combination of yoga and heat should be considered as a potential treatment for individuals experiencing depression.

Research Reveals How Sleep Disruption Can Exacerbate Pain
Featuring Shiqian Shen, MD

A new study by led by Mass General researchers has identified a neurotransmitter that plays a major role in chronic pain associated with sleep loss. In lab models, this neurotransmitter—an endocannabinoid called N-arachidonoyl dopamine—decreased in a particular brain region after chronic sleep disruption. Administering this neurotransmitter to the brain reduced the pain caused by sleep loss.

Blog Posts

Snapshot of Science: Mass General’s High Impact Research Publications for September 2023

Exercise-induced hormone may reduce Alzheimer’s tangles in the brain, the role of brain endothelial cells in psychotic disorders and much more

World Mental Health Day: How Mass General Researchers are Working to Help

Today is World Mental Health Day, and we want to highlight some of our recent stories about mental health research happening at Mass General.

Humans of MGRI – Mengyao Xu, MD, PhD

Meet Mengyao Xu, a postdoctoral fellow whose work focuses on improving the efficacy of novel immunotherapeutic approaches for the management of gynecologic malignancies.

An Uncomfortable Truth: How Stigma and a Lack of Funding Has Set Back Research and Treatments for Vulvovaginal Disorders
Featuring Caroline Mitchell, MD, MPH

Mass General Researcher Caroline Mitchell, MD, MPH, discusses the barriers to studying women’s health topics.

Break It Down For Me: Jodi Gilman, PhD

In this episode, we challenge Dr. Gilman to break down the title of her recent paper about identifying functional brain impairment in marijuana users.

The Mass General Research Institute Has Fun at the Cambridge Science Festival
Featuring David Sykes, MD, PhD and Shannon Stott, PhD

The Mass General Research Institute Has Fun at the Cambridge Science Festival On October 1, the Mass General Research Institute participated in the Cambridge Science Festival’s annual Science Carnival and Robot Zoo.

How A Small Fish Could Lead to Better Strategies to Repair Tendon Tears
Featuring Jenna Galloway, PhD

Mass General researcher Jenna Galloway, PhD, is using zebrafish models to find new treatment strategies for tendon injuries.

Through the Magnifying Glass: The Demehri Lab
Featuring Shawn Demehri, MD, PhD

A close-up look at the Demehri Lab and how they are working to understand the immune system’s role in early cancer development.

Research Spotlights

Reported Risky Alcohol Use Among US Adults Prescribed Three Classes of Chronic Alcohol–Interactive Medications
Featuring Eden Bernstein, MD

Eden Bernstein, MD, a physician scientist in the Department of Medicine at Massachusetts General Hospital is the author of a recently published Research Letter in JAMA, Reported Risky Alcohol Use Among US Adults Prescribed 3 Classes of Chronic Alcohol–Interactive Medications

The Precision Medicine in Diabetes Initiative: 2nd International Consensus Report on Gaps & Opportunities for the Clinical Translation of Precision Diabetes Medicine

Several Massachusetts General Hospital investigators including Miriam Udler, MD, PhD, James Meigs, MD, Sara Cromer, MD, Magdalena Sevilla-Gonzalez, PhD, Aaron Deutsch, MD, Camille Powe, MD, Marie-France Hivert, MD and Jose Florez, MD, PhD, Chair of the Department of Medicine, are among the authors of a recent report published in Nature Medicine, The Precision Medicine in Diabetes Initiative: 2nd International Consensus Report on Gaps & Opportunities for the Clinical Translation of Precision Diabetes Medicine.

Addressing Crucial Concepts of Mucosal Immunology to Learn More About the Causes of Male Infertility
Featuring Maria Agustina Battistone, PhD

Maria Agustina Battistone, PhD, an Investigator in the Department of Nephrology at Massachusetts General Hospital and an Assistant Professor of Medicine at Harvard Medical School, is the senior author of a new study published in PNAS, Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility.

Generic Daily HIV Prevention Pill for Young Men who have Sex with Men Could Save Lives and Money
Featuring Anne Neilan, MD

Anne Neilan, MD, a physician-scientist in the division of Infectious Diseases at Massachusetts General Hospital is the senior author of a recently published paper in Clinical Infectious Diseases, Daily Oral HIV Pre-exposure Prophylaxis Among Young Men Who Have Sex With Men in the United States: Cost-Saving at Generic Drug Price.

Genetic Testing Practices, Indications and Results in Patients with Down Syndrome
Featuring Stephanie L. Santoro, MD

Stephanie L. Santoro, MD, director of Quality Improvement Research for the Down Syndrome Program at Mass General for Children is the senior author of a recent study published in the American Journal of Medical Genetics, Part C, Beyond Chromosome Analysis: Additional Genetic Testing Practice in a Down Syndrome Clinic.

Polygenic Risk Scores for Cardiometabolic Disease in Arabs
Featuring Akl Fahed, MD, MPH

Akl Fahed, MD, MPH, a physician investigator in the Cardiovascular Research Center at Massachusetts General Hospital, is co-senior author of a new study in Nature Communications, Clinical Utility of Polygenic Scores for Cardiometabolic Disease in Arabs.

Learning More About the Distribution and Persistence of mRNA Vaccines in the Body
Featuring Aram J. Krauson, PhD and James Stone, MD, PhD

Aram J. Krauson, PhD, of the Department of Pathology at Mass General, is the first author and James Stone, MD, PhD, is the senior author of a new study in NPJ Vaccines, Duration of SARS-CoV-2 mRNA Vaccine Persistence and Factors Associated with Cardiac Involvement in Recently Vaccinated Patients.

Principles for Health Information Collection, Sharing, and Use
Featuring Antonis A. Armoundas, PhD

Antonis A. Armoundas, PhD, a scientist in The Cardiovascular Research Center is an author of a recently published policy statement, published in Circulation, entitled “Principles for Health Information Collection, Sharing, and Use: A Policy Statement From the American Heart Association”

Validating an MRI Biomarker for Early Onset Alzheimer’s Disease
Featuring Alexandra Touroutoglou, PhD and Bradford Dickerson, MD

Alexandra Touroutoglou, PhD and Bradford Dickerson, MD, neuroscientists in the department of Neurology at Massachusetts General Hospital are the lead authors of a new study published in Alzheimer’s & Dementia, The Sporadic Early-onset Alzheimer’s Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer’s Disease Study (LEADS) Cohort.

Telehealth for Psychiatry and Mental Healthcare Can Improve Access and Patient Outcomes
Featuring Alex Keuroghlian, MD, MPH,

Alex Keuroghlian, MD, MPH, a physician investigator in the Department of Psychiatry at Massachusetts General Hospital, is the author of a new commentary in Nature Medicine, Telehealth for Psychiatry and Mental Healthcare can Improve Access and Patient Outcomes

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Snapshot of Science for October 2023