Snapshot of Science for March 2022

Welcome to our Snapshot of Science for March 2022.

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:

39 new studies published in high-impact journals, along with 32 summaries submitted by the research teams
22 new research-related press releases from the Mass General Public Affairs office
3 posts from the Mass General Research Institute blog

Publications

RNA Can Be Systematically Targeted by Drug-like Compounds
Targeting Xist With Compounds That Disrupt RNA Structure and X Inactivation
Aguilar R, Spencer KB, Kesner B, Rizvi NF, Badmalia MD [et al.], Lee JT
Published in Nature on Wednesday, March 30, 2022 | Press Release

B Lymphocytes are an Important Source of the Neurotransmitter Acetylcholine
B Lymphocyte-derived Acetylcholine Limits Steady-state and Emergency Hematopoiesis
Schloss MJ, Hulsmans M, Rohde D, Lee IH, Severe N [et al.], Nahrendorf M
Published in Nature Immunology on Monday, March 28, 2022 | *Summary available | Press Release

Challenging the Theory That Light Alcohol Consumption Benefits Heart Health
Association of Habitual Alcohol Intake With Risk of Cardiovascular Disease
Biddinger KJ, Emdin CA, Haas ME, Wang M, Hindy G [et al.], Aragam KG
Published in JAMA Network Open on Friday, March 25, 2022 | Press Release

A Role for the Warburg Effect Beyond Biomass Production in Tumors
A Non-dividing Cell Population With High Pyruvate Dehydrogenase Kinase Activity Regulates Metabolic Heterogeneity and Tumorigenesis in the Intestine
Sebastian C, Ferrer C, Serra M, Choi JE, Ducano N [et al.], Mostoslavsky R
Published in Nature Communications on Monday, March 21, 2022 | *Summary available | Press Release

Fluorescence Lifetime Imaging Can Provide Tumor Specificity at the Cellular Level
First Clinical Results of Fluorescence Lifetime-enhanced Tumor Imaging Using Receptor Targeted Fluorescent Probes
Pal R, Hom M, van den Berg NS, Lwin T, Lee YJ [et al.], Kumar ATN
Published in Clinical Cancer Research on Friday, March 18, 2022 | *Summary available

Discovery of Neurons that Drive Competition in Groups
Frontal Neurons Driving Competitive Behaviour and Ecology of Social Groups
Li SW, Zeliger O, Strahs L, Báez-Mendoza R, Johnson LM, Wojciechowski AM, Williams ZM
Published in Nature on Wednesday, March 16, 2022 | *Summary available | Press Release

A Fundamental Mechanism Restricting Direct NK Cell Cytotoxicity
Extracellular Matrix Proteins Regulate NK Cell Function in Peripheral Tissues
Bunting MD, Vyas M, Requesens M, Langenbucher A, Schiferle EB [et al.], Demehri S
Published in Science Advances on Wednesday, March 16, 2022 | Press Release

Healthy Lifestyle Lowers Risk of Heart Attack Even if Genetically Predisposed
Association of the Interaction Between Familial Hypercholesterolemia Variants and Adherence to a Healthy Lifestyle With Risk of Coronary Artery Disease
Fahed AC, Wang M, Patel AP, Ajufo E, Maamari DJ [et al.], Khera AV
Published in JAMA Network Open on Wednesday, March 16, 2022 | *Summary available

An Immediately Translatable Strategy for Liver Cancer Treatment
Increased CD8+ T-Cell Infiltration and Efficacy for Multikinase Inhibitors After PD-1 Blockade in Hepatocellular Carcinoma
Kikuchi H, Matsui A, Morita S, Amoozgar Z, Inoue K [et al.], Duda DG
Published in Journal of the National Cancer Institute on Tuesday, March 15, 2022 | *Summary available | Press Release

Protein That Attracts T Cells Can Signal Rejection in Limb Transplants
T Cell-attracting CCL18 Chemokine Is a Dominant Rejection Signal During Limb Transplantation
Borges TJ, Abarzua P, Gassen RB, Kollar B, Lima-Filho M, [et al.], Riella LV
Published in Cell Reports Medicine on Tuesday, March 15, 2022 | *Summary available

Regulation of RNA Modifications in R-Loop Dynamics During DNA Repair
FMRP Promotes Transcription-coupled Homologous Recombination via Facilitating TET1-mediated m5C RNA Modification Demethylation
Yang H, Wang Y, Xiang Y, Yadav T, Ouyang J [et al.], Lan L
Published in Proceedings of the National Academy of Sciences on Tuesday, March 15, 2022 | *Summary available

Vaccines Protect Against Severe Disease From COVID-19 Omicron Variant
Omicron Variant Spike-specific Antibody Binding and Fc Activity Is Preserved in Recipients of mRNA or Inactivated COVID-19 Vaccines
Bartsch YC, Tong X, Kang J, Avendaño MJ, Serrano EF [et al.], Alter G
Published in Science Translational Medicine on Tuesday, March 15, 2022 | *Summary available

Metastasized Cancers Evolve Differently in Different Locations
Differential Kinase Activity Across Prostate Tumor Compartments Defines Sensitivity to Target Inhibition
Karabacak NM, Zheng Y, Dubash TD, Burr R, Micalizzi DS [et al.], Maheswaran S
Published in Cancer Research on Tuesday, March 15, 2022 | *Summary available | Press Release

Mindfulness and Guided Imagery Therapy Can Reduce Depression and Anxiety in Caregivers of Dementia Patients
Four-Week Mentalizing Imagery Therapy for Family Dementia Caregivers: A Randomized Controlled Trial With Neural Circuit Changes
Jain FA, Chernyak SV, Nickerson LD, Morgan S, Schafer R [et al.], Yeung A
Published in Psychotherapy and Psychosomatics on Monday, March 14, 2022 | *Summary available | Press Release

Drug Slows Growth of Meningioma Tumors
Phase 2 Study of Pembrolizumab in Patients with Recurrent and Residual High-grade Meningiomas
Brastianos PK, Kim AE, Giobbie-Hurder A, Lee EQ, Wang N [et al.], Santagata S
Published in Nature Communications on Monday, March 14, 2022 | *Summary available | Press Release

SHN-1/Shank Promotes CaV1 Coupling to Calcium Activated Potassium Channels
Shank Promotes Action Potential Repolarization by Recruiting BK Channels to Calcium Microdomains
Gao L, Zhao J, Ardiel EL, Hall Q, Nurrish S, Kaplan JM
Published in eLife on Thursday, March 10, 2022

Severe Aortic Stenosis Remains Undertreated Despite Rise in Valve Replacements
Trends in Utilization of Aortic Valve Replacement for Severe Aortic Stenosis
Li SX, Patel NK, Flannery LD, Selberg A, Kandanelly RR [et al.], Elmariah S
Published in Journal of the American College of Cardiology on Tuesday, March 8, 2022 | *Summary available

Nanomedicine Can Improve Cancer Treatment by Normalizing the Tumor Microenvironment
Normalizing Tumor Microenvironment With Nanomedicine and Metronomic Therapy to Improve Immunotherapy
Mpekris F, Voutouri C, Panagi M, Baish JW, Jain RK, Stylianopoulos T
Published in Journal of Controlled Release on Tuesday, March 8, 2022 | *Summary available | Press Release

Connections in the Brain that Control Speech
Hyperdirect Connectivity of Opercular Speech Network to the Subthalamic Nucleus
Jorge A, Lipski WJ, Wang D, Crammond DJ, Turner RS, Richardson RM
Published in Cell Reports on Tuesday, March 8, 2022 | *Summary available

Furthering our Molecular Understanding of the Pathophysiology of Schizophrenia
The Schizophrenia-associated Variant in SLC39A8 Alters Protein Glycosylation in the Mouse Brain
Mealer RG, Williams SE, Noel M, Yang B, D'Souza AK [et al.], Cummings RD
Published in Molecular Psychiatry on Tuesday, March 8, 2022 | *Summary available

E-Visits for Overactive Bladder Help Patients Improve Symptoms
Asynchronous Telehealth Visits for the Treatment of Overactive Bladder
Ortega, MV, del Carmen, MG, Wakamatsu, M, Goldstein, SA, Siegal-Botti, E, Wasfy, JH
Published in Menopause on Monday, March 7, 2022 | *Summary available | Press Release

New Alzheimer's Disease Genes Discovered
Region-based Analysis of Rare Genomic Variants in Whole-Genome Sequencing Datasets Reveal Two Novel Alzheimer's Disease-associated Genes: DTNB and DLG2
Prokopenko D, Lee S, Hecker J, Mullin K, Morgan S [et al.], Tanzi RE
Published in Molecular Psychiatry on Friday, March 4, 2022 | *Summary available

Potential Treatment for Bacterial Vaginosis
Cysteine Dependence of Lactobacillus Iners Is a Potential Therapeutic Target for Vaginal Microbiota Modulation
Bloom SM, Mafunda NA, Woolston BM, Hayward MR, Frempong JF [et al.], Kwon DS
Published in Nature Microbiology on Thursday, March 3, 2022 | *Summary available | Press Release

Organoids Help in Identifying Pathologic Pathways and Potential Therapies for Kidney Injury
Modeling Injury and Repair in Kidney Organoids Reveals That Homologous Recombination Governs Tubular Intrinsic Repair
Gupta N, Matsumoto T, Hiratsuka K, Garcia Saiz E, Galichon P [et al.], Morizane R
Published in Science Translational Medicine on Wednesday, March 2, 2022

Gene Discovery in SCAD Patients Highlights the Role of Extracellular Matrix Dysfunction
Fibrillar Collagen Variants in Spontaneous Coronary Artery Dissection
Zekavat SM, Chou EL, Zekavat M, Pampana A, Paruchuri K [et al.], Lindsay ME
Published in JAMA Cardiology on Wednesday, March 2, 2022 | Press Release

Handheld Electrocardiograms Help Diagnose AFib
Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: the VITAL-AF Randomized Controlled Trial
Lubitz SA, Atlas SJ, Ashburner JM, Trisini Lipsanopoulos AT, Borowsky LH [et al.], Singer DE
Published in Circulation on Wednesday, March 2, 2022 | *Summary available | Press Release

Electrical Stimulation to Show Different Responses in the Brain
Local and Distant Cortical Responses to Single Pulse Intracranial Stimulation in the Human Brain Are Differentially Modulated by Specific Stimulation Parameters
Paulk AC, Zelmann R, Crocker B, Widge AS, Dougherty DD [et al.], Cash SS
Published in Brain Stimulation on Wednesday, March 2, 2022 | *Summary available

Surgeon Perception of Patient-Reported Outcome Measures
The Surgeon's Perceived Value of Patient-Reported Outcome Measures (PROMs): An Exploratory Qualitative Study of 5 Different Surgical Subspecialties
Mou D, Sisodia RC, Castillo-Angeles M, Ladin K, Bergmark RW [et al.], Heng M
Published in Annals of Surgery on Tuesday, March 1, 2022 | *Summary available

Maintenance Treatment Strategies After Allogenic HCT
How I Treat With Maintenance Therapy After Allogeneic HCT
DeFilipp Z, Chen YB
Published in Blood on Tuesday, March 1, 2022 | *Summary available

Unraveling the Connections Between Long COVID and Peripheral Neuropathy
Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID
Oaklander AL, Mills AJ, Kelley M, Toran LS, Smith B, Dalakas MC, Nath A
Published in Neurology: Neuroimmunology & Neuroinflammation on Tuesday, March 1, 2022 | *Summary available | Press Release

Molecular Signatures of Engraftment Potential in Fetal Liver HSCs
Multi-modal Profiling of Human Fetal Liver Hematopoietic Stem Cells Reveals the Molecular Signature of Engraftment
Vanuytsel K, Villacorta-Martin C, Lindstrom-Vautrin J, Wang Z [et al.], Balazs AB, Murphy GJ
Published in Nature Communications on Tuesday, March 1, 2022 | *Summary available | Press Release

Receiving a Medical Marijuana Card May Lead to Cannabis Use Disorder
Effect of Medical Marijuana Card Ownership on Pain, Insomnia, and Affective Disorder Symptoms in Adults: A Randomized Clinical Trial
Gilman JM, Schuster RM, Potter KW, Schmitt W, Wheeler G [et al.], Evins AE
Published in JAMA Network Open on Tuesday, March 1, 2022 | *Summary available | Press Release

Thalamus Plays an Active Role in Understanding Language While Reading Aloud
Lateralized and Region-specific Thalamic Processing of Lexical Status During Reading Aloud
Wang D, Lipski WJ, Bush A, Chrabaszcz A, Dastolfo-Hromack C [et al.], Richardson RM
Published in Journal of Neuroscience on Monday, February 28, 2022 | *Summary available

New Drug Treatment for Heart Failure
The SGLT2 Inhibitor Canagliflozin in Heart Failure: The CHIEF-HF Remote, Patient-centered Randomized Trial
Spertus JA, Birmingham MC, Nassif M, Damaraju CV, Abbate A [et al.], Januzzi JL
Published in Nature Medicine on Monday, February 28, 2022 | *Summary available

Mistreatment of Internal Medicine Residents
Prevalence and Sources of Mistreatment Experienced by Internal Medicine Residents
Finn KM, O'Connor AB, McGarry K, Harris L, Zaas A
Published in JAMA Internal Medicine on Monday, February 28, 2022

New Technology to Improve RNA Sequencing
Mitochondrial Variant Enrichment from High-throughput Single-cell RNA Sequencing Resolves Clonal Populations
Miller TE, Lareau CA, Verga JA, DePasquale EAK, Liu V [et al.], van Galen P
Published in Nature Biotechnology on Thursday, February 24, 2022 | *Summary available

Mechanisms of Enhanced Tissue Vulnerability to Ischemic Injury in CADASIL
CADASIL Mutations Sensitize the Brain to Ischemia via Spreading Depolarizations and Abnormal Extracellular Potassium Homeostasis
Oka F, Lee JH, Yuzawa I, Li M, von Bornstaedt D [et al.], Ayata C
Published in Journal of Clinical Investigation on Thursday, February 24, 2022 | *Summary available

The Role of Video Decision Aids in Advanced Care Planning
Association of an Advance Care Planning Video and Communication Intervention With Documentation of Advance Care Planning Among Older Adults: A Nonrandomized Controlled Trial
Volandes AE, Zupanc SN, Paasche-Orlow MK, Lakin JR, Chang Y [et al.], Lindvall C
Published in JAMA Network Open on Thursday, February 24, 2022 | *Summary available

Molecular Mechanisms of Memory Consolidation
A Dentate Gyrus-CA3 Inhibitory Circuit Promotes Evolution of Hippocampal-cortical Ensembles During Memory Consolidation
Twarkowski H, Steininger V, Kim MJ, Sahay A
Published in eLife on Tuesday, February 22, 2022 | *Summary available

Publication Summaries

In the bone marrow, B lymphocytes produce the neurotransmitter acetylcholine, and that this reduces white blood cell production and systemic inflammation. In psychosocial stress and after myocardial infarction (MI), sympathetic nerves influence leukocyte numbers via instructing the bone marrow niche. Looking for the parasympathetic counterbalance, we found acetylcholine as a major break on steady-state blood production. The pathway could be used to curb leukocyte supply and inflammation in disease, as indicated by reduced leukocytes in MI patients that took the Alzheimer’s drug donepezil during their MI. Acetylcholine depletion from B cells reduced cardiovascular disease in mice.

(Summary submitted by Matthias Nahrendorf, MD, PhD, Center for Systems Biology, Department of Radiology)

Normally, glucose—the main nutrient needed for cells to function—is sent to the cell’s mitochondria to be broken down for energy, a process that requires oxygen. In the 1920s, Otto Warburg discovered that cancer cells rapidly increase their glucose uptake and directly ferment it into lactate, even in the presence of oxygen and functional mitochondria. Warburg called the process aerobic glycolysis, but it is commonly known as the Warburg effect, and was believed to take place in all cancer cells. We developed a fluorescent reporter that stains for glycolysis in cells of colon cancer tumors. Using this and a mass spectrometry approach developed by Nathalie Agar, PhD, of Brigham and Women’s Hospital, we discovered that this process occurs in a heterogeneous population of cancer cells, and surprisingly, in cells that are not dividing. For the past 10-15 years, most researchers believed glycolysis was an adaptation to support the biomass needs of rapidly dividing cancer cells. Instead, we found the main reason the cells were doing this was to reduce reactive oxygen species, a byproduct of normal glucose breakdown that can damage cells. Our findings suggest a need to rethink cancer metabolism and the tools we use to study it.

(Summary submitted by Raul Mostoslavsky, MD, PhD, Mass General Cancer Center)

Surgery is the mainstay for cancer treatment. However, there are currently limited tools to accurately identify and distinguish tumors from healthy/normal tissue intraoperatively, which is essential to remove tumors completely while minimizing loss of functionality and appearance. We demonstrated a novel clinical application of fluorescence lifetime imaging, with fluorescent agents that specifically target the endothelial growth factor receptor, to achieve unprecedented accuracy for delineating oral cancers at a microscopic level in human tissue. Besides application to intraoperative imaging, the technique can also be extended to non-invasive imaging to monitor cancer progression and treatment response.

(Summary submitted by Anand Kumar, PhD, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology)

Social interactions in humans and animals occur most commonly in large groups and play a prominent role in sociology, psychology and political science. By wirelessly recording neuronal activity in mice under naturalistic group settings, this study discovers neurons in the brain that drive competitive interactions and play a critical role in shaping the social behavior of groups. It also shows that it is possible to control competitive behavior by artificially changing the activities of these neurons and thus affect the interaction between individuals. As we utilize more genetic models of disease and advanced techniques for wireless recordings, these findings could have broad implications to the treatment of conditions such as autism spectrum disorder and schizophrenia.

(Summary submitted by Ziv Williams, MD, Department of Neurology)

A balanced diet, regular exercise and other elements of a healthy lifestyle reduce the risk of heart attack. We explored whether this holds true for individuals who inherit a familial hypercholesterolemia variant predisposing to high LDL cholesterol and heart disease. Using a large sequencing and lifestyle dataset from the UK Biobank, we found that among individuals who inherit those variants, an unfavorable lifestyle led to 66.2% estimated risk of heart attack by age 75 years whereas a favorable lifestyle led to 34.5% estimated risk. This work suggests that even for those who are most genetically predisposed to heart attack, a healthy lifestyle can significantly lower their risk.

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

This study shows that treatment with an immune checkpoint inhibitor could prime the tumor environment prior to a multikinase inhibitor drug and enhance the effectiveness of these existing therapeutics for hepatocellular carcinoma. This new approach led to greater infiltration within the cancer tissues by the immune system’s cytotoxic T cells, amplifying the effectiveness of the multikinase inhibitor drug, in part by maintaining a normalized/stable vasculature. This new treatment strategy could have applicability in other forms of liver cancer and shows great promise of reducing the doses needed for therapy as well as the toxicity of these medicines.

(Summary submitted by Dan G. Duda, DMD, PhD, E.L. Steele Laboratories, Department of Radiation Oncology, Mass General Cancer Center)

We provide a comprehensive immune characterization of limb transplant recipients, demonstrating that chemokine CCL18 is a dominant signal during rejection. Local CCL18 mediates the recruitment of pathogenic allo-T cells into grafts, which is abrogated by CCR8 blockade. Targeting the CCL18:CCR8 pathway is a promising complementary immunosuppressive approach in transplantation.

(Summary submitted by Leonardo V. Riella, MD, PhD, Center for Transplantation Sciences, Division of Nephrology, Department of Medicine)

We found that mRNA methyl-5-cytosine (m5C) modification could serve as “damage code” to promote homologous recombination repair and contributes to tumor growth and drug resistance, while the regulation of mRNA m5C modification in cells remain elusive. In this work, we reveal a new reader of m5C, Fragile X mental retardation protein (FMRP), to regulate m5C dynamics and promote TET1-mediated demethylation. Loss of FMRP leads to defective repair in cells and increased radio-sensitivity in cancer patients. These findings significantly advanced our understanding of the regulation of RNA modifications and provided molecular basis to target mRNA modifying enzymes in cancer therapy.

(Summary submitted by Li Lan, PhD, Department of Radiation Oncology, Mass General Cancer Center)

With the emergence of the novel SARS-CoV-2 Omicron variant, vaccine breakthrough cases of COVID-19 surged. In an international collaboration, researchers at the Ragon Institute of MGH, MIT and Harvard and the Pontificia Universidad Católica de Chile recently showed that mRNA and inactivated particle vaccines can induce robust antibody responses against the full-length Omicron spike protein. These antibodies, despite substantial loss of neutralizing activity, these antibodies were readily able to induce additional Fc effector functions and might explain why vaccines are still protective against severe disease upon Omicron infection.

(Summary submitted by Yannic Bartsch, PhD, Department of Medicine, Ragon Institute of MGH, MIT and Harvard)

Cancer, originally confined to the primary site, metastasizes to distal organs and evolves differently depending on the environment. This work shows that prostate cancer metastases in the lung, liver and bone, despite originating from the same primary tumor, have different signaling networks that make them differentially sensitive to drugs. Bone metastases compared to lung and liver metastases harbored the highest PI3K and mTOR activity, making it exquisitely sensitive to PI3K/mTOR inhibitors. Further, cancer cells in the epithelial state compared to those in the mesenchymal state had higher PI3K and mTOR activity rendering the epithelial cells more responsive to PI3K/mTOR inhibitors. Such site-specific and cell-state specific kinase activities should be considered when evaluating responses to drugs targeting specific pathways.

(Summary submitted by Shyamala Maheswaran, PhD, Surgical Oncology, Department of Surgery, Mass General Cancer Center)

Mindfulness and Guided Imagery Therapy Can Reduce Depression and Anxiety in Caregivers
Four-Week Mentalizing Imagery Therapy for Family Dementia Caregivers: A Randomized Controlled Trial With Neural Circuit Changes
Jain FA, Chernyak SV, Nickerson LD, Morgan S, Schafer R [et al.], Yeung A
Published in Psychotherapy and Psychosomatics on Monday, March 14, 2022

Family caregivers of patients with chronic illness often suffer from elevated depression, anxiety and burnout. Mentalizing Imagery Therapy (MIT) is a novel mindfulness and guided imagery therapy that focuses on reducing stress and improving connections with others. Caregivers who received 4-week MIT showed longer-lasting reductions in depression and anxiety than a support group. MIT participants also reported greater improvements in happiness, well-being, and the ability to mindfully be in the present moment. Furthermore, MIT participants showed brain changes that correlated with outcome and that were not observed in the support group, including strengthening of brain networks involved in emotion control.

(Summary submitted by Felipe A. Jain, MD, Department of Psychiatry)

Drug Slows Growth of Meningioma Tumors
Phase 2 Study of Pembrolizumab in Patients With Recurrent and Residual High-grade Meningiomas
Brastianos PK, Kim AE, Giobbie-Hurder A, Lee EQ, Wang N [et al.], Santagata S
Published in Nature Communications on Monday, March 14, 2022

Meningiomas are the most common primary brain tumor with few medical treatment options once surgery and radiation fail. In this clinical trial, our multidisciplinary team investigated the role of pembrolizumab, a drug that blocks PD-1 and enables the immune system to identify and destroy tumor, in slowing the growth of aggressive meningiomas. The trial met its goal, with about half of the patients alive and without disease progression for at least 6 months. Given the promising results of this study, we plan to extend these investigations to larger clinical trials.

(Summary submitted by Priscilla K Brastianos, MD, Division of Hematology/Oncology, Mass General Cancer Center)

Narrowing of the aortic valve within the heart (i.e., aortic stenosis) is a dangerous disease that, when severe, can result in heart failure and death unless the aortic valve is replaced. We performed a large study spanning an 18-year period to determine the frequency with which aortic valve replacement, whether surgical or transcatheter, was performed in patients with symptomatic aortic stenosis. Despite significant growth in the number of aortic valve replacement procedures performed annually, we found that nearly half of patients in need of life-saving aortic valve replacement did not receive one and identified several factors that may contribute to the under treatment of aortic stenosis. Given the impact of aortic stenosis on health and well-being, our study establishes the urgent need to improve the management of aortic valve stenosis.

(Summary submitted by Sammy Elmariah, MD, MPH, Division of Cardiology, Department of Medicine)

Nanocarriers can reduce the toxicities associated with chemotherapy in cancer patients, but the resulting survival benefits are modest compared to conventional chemotherapy. Here we show that nanomedicine administered at lower, more frequent doses—called metronomic dosing—rather than the standard maximum tolerated dose of current treatments improves therapeutic efficacy. Moreover, we demonstrate that Doxil, an FDA-approved nanomedicine, when administered in a metronomic manner, can induce normalized tumor blood vessels resulting in improved tumor perfusion and oxygenation, and an immunostimulatory tumor microenvironment in breast cancer and sarcoma in mice. Moreover, pretreatment with metronomic Doxil can improve the efficacy of immune-checkpoint blockers.

(Summary submitted by Rakesh K. Jain, PhD, E.L. Steele Laboratories, Department of Radiation Oncology)

How the basal ganglia participate in the uniquely human behavior of speech is poorly understood, despite their known role in modulating critical aspects of cognitive and motor behavior. Using electrocorticography in patients undergoing awake deep brain stimulation surgery, evidence is reported for a left opercular hyperdirect pathway in humans via stimulating the subthalamic nucleus (STN) and examining antidromic-evoked activity. The data suggest hyperdirect connectivity not only between the inferior frontal gyrus (i.e., Broca’s area) and the STN, but also from areas of the opercular speech cortex that are primarily sensory, including the auditory cortex. These connections may be unique to humans, evolving alongside the ability for speech.

(Summary submitted by Mark Richardson, MD, PhD, Department of Neurosurgery)

A New Molecular Understanding of the Pathophysiology of Schizophrenia
The Schizophrenia-associated Variant in SLC39A8 Alters Protein Glycosylation in the Mouse Brain
Mealer RG, Williams SE, Noel M, Yang B, D'Souza AK [et al.], Cummings RD
Published in Molecular Psychiatry on Tuesday, March 8, 2022

Schizophrenia is severe mental illness for which diagnostic and treatment options are limited, but recent advances in genetics have provided researchers new clues to study the disorder. Our team followed one of these genetic clues and discovered changes in the brain’s biochemistry resulting from a genetic variant associated with schizophrenia. By studying the connections of sugar molecules to proteins in the brain, termed glycosylation, the results provide new insights into the disorder and could lead to novel treatment strategies for schizophrenia.

(Summary submitted by Robert G. Mealer, MD, Department of Psychiatry)

Overactive bladder affects 17% of women, and treatment adherence is notoriously low. Our exploratory pilot study concludes that women who received treatment for overactive bladder enhanced by asynchronous telehealth (e-visits) visits had significant improvement in their symptoms, and high satisfaction with their care. We found that more frequent engagement with their clinicians led to the patients’ better compliance in behavioral changes and medication use. E-visits may also accelerate the time for patients to receive advanced therapies. E-visits offer many other advantages, such as not requiring a camera, reducing unnecessary medical visits, and the convenience of receiving care at a distance, especially in areas where few specialists practice.

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

New Alzheimer's Disease Genes Discovered
Region-based Analysis of Rare Genomic Variants in Whole-genome Sequencing Datasets Reveal Two Novel Alzheimer's Disease-associated Genes: DTNB and DLG2
Prokopenko D, Lee S, Hecker J, Mullin K, Morgan S [et al.], Tanzi RE
Published in Molecular Psychiatry on Friday, March 4, 2022

In this study, we identified two previously unreported Alzheimer’s disease (AD) genes: DTNB and DLG2. Both genes are highly expressed in brain where they are involved with synaptic function and have been previously associated with schizophrenia and autism. To discover these new Alzheimer’s disease genes, we used whole genome sequencing. This allows for the testing of rare DNA variants associated with disease. We combined groups of rare genomic variants and systematically scanned the whole genome for clusters of rare variants showing association with AD. Two genomic regions around the dystobrevin beta (DTNB) and disc large homolog 2 (DLG2) genes exhibited consistent association with AD risk in both discovery and replication cohorts.

(Summary submitted by Dmitry Prokopenko, PhD, and Rudolph E. Tanzi, PhD, Department of Neurology)

Lactobacillus iners, the most common bacterial species in the vaginal microbiome, is linked to risk of bacterial vaginosis (BV) and other adverse health outcomes. However, this species has been difficult to study because of challenges growing it in the lab. We discovered a simple way to grow L. iners in culture and validated our findings using a collection of hundreds of L. iners strains and genomes from diverse populations around the world. This led to discovery of a potential treatment that selectively blocks L. iners growth in favor of Lactobacillus crispatus, a vaginal bacterial species associated with more beneficial health outcomes. These findings enable a better understanding of L. iners biology and suggest treatments to modulate the vaginal bacteria to improve reproductive health for women globally.

(Summary submitted by Seth M. Bloom, MD, PhD, Ragon Institute of MGH, MIT and Harvard, Division of Infectious Diseases, Department of Medicine)

The VITAL-AF trial randomized Mass General primary care practices to point-of-care screening for atrial fibrillation (AF) using single lead handheld electrocardiograms versus usual care in patients aged ≥ 65 years. AF screening was done during vital sign measurement at ambulatory visits. The study included > 35,000 patients and demonstrated that screening is widely feasible; > 90% of patients offered screening were screened. Screening all individuals aged ≥ 65 did not significantly increase diagnoses of AF at 1 year, but screening was associated with an increase in the rate of AF diagnosis in individuals aged ≥ 85 years. The majority of these oldest patients were treated with anticoagulants to reduce stroke risk.

(Summary submitted by Steven A Lubitz, MD, MPH, Division of Cardiology, Department of Medicine)

We examined brain responses to varying input parameters of single pulse direct electrical stimulation in the brains of individuals with intractable epilepsy undergoing intracranial brain recordings to localize seizure onset zones in the brain. We found significant nonlinear effects of altering duration, stimulating electrode orientation, and injected current amplitude on brain activity. The main finding was that stimulation in the white matter (which connects different brain regions) induced more widespread distant neural responses but stimulation at the boundary between the white matter and the grey matter (where the cell bodies of the neurons are located) in the cortex produced bigger local responses, with different effects in different brain regions. The work will lead to both a better understanding of the connectivity of the human brain as well as possibly tailor our use of stimulation in various therapies such as in deep brain stimulation.

(Summary submitted by Yangling Chou, PhD, Department of Neurology)

Surgeon Perception of Patient-Reported Outcome Measures
The Surgeon's Perceived Value of Patient-reported Outcome Measures (PROMs): An Exploratory Qualitative Study of 5 Different Surgical Subspecialties
Mou D, Sisodia RC, Castillo-Angeles M, Ladin K, Bergmark RW [et al.], Heng M
Published in Annals of Surgery on Tuesday, March 1, 2022

Patient-reported outcome measures (PROMs) are questionnaires that capture the symptoms, function, and quality of life purely from the patient's perspective. Though it may seem obvious that this is important to measure, it is rarely used by surgeons. To understand why, we interviewed 30 surgeons across five subspecialties. Surgeons use PROMs to guide their clinical decision-making, counsel patients before and after surgery, and obtain sensitive information from patients that otherwise may be missed. However, barriers to using PROMs include unhelpful data, difficulty collecting PROMs logistically, and inappropriate use of PROMs to track performance. A better understanding of the clinician’s perspective of PROMs will help with meaningfully implementing PROMs in clinical care.

(Summary submitted by Danny Mou, MD, MPH, General Surgery, PGY5 Brigham and Women’s Hospital)

Maintenance Treatment Strategies After Allogenic HCT
How I Treat With Maintenance Therapy After Allogeneic HCT
DeFilipp Z, Chen YB
Published in Blood on Tuesday, March 1, 2022

Disease relapse is the leading cause of failure for patients receiving allogeneic hematopoietic cell transplantation. Maintenance therapy administered after transplant is a promising strategy to reduce the incidence of relapse and enhance the curative potential of treatment. However, many questions and challenges remain regarding the feasibility and clinical impact of this approach. In this article, we present four common case scenarios addressing select therapeutic agents as a framework to review published data and ongoing studies in this rapidly evolving field.

(Summary submitted by Zachariah DeFilipp, MD, Division of Hematology/Oncology, Mass General Cancer Center)

10-30% of people notice prolonged illness after COVID-19 infections. Long-COVID causes difficulty completing usual activities and sometimes brain fog, abnormal heart rate/blood pressure, and odd sensations including pain. The NIH is eager to identify causes and targeted treatments. We explored the hypothesis that peripheral neuropathy contributes. In 17 long-COVID patients without earlier neuropathy undergoing neuropathy testing, we analyzed symptoms, examinations, neurodiagnostic test results, and outcomes. Sixteen reported mild COVID, without heart or lung damage. Overall 59% had abnormal test results confirming neuropathy. Ten were diagnosed with small-fiber neuropathy, and two with other types. Their neurologists thought COVID-triggered immune dysregulation was the cause and treated 65% with immunotherapies, often with benefit.

(Summary submitted by Anne Louise Oaklander, MD, PhD, Department of Neurology)

New Potential Treatment for Blood Disorders Using Stem Cells
Multi-modal Profiling of Human Fetal Liver Hematopoietic Stem Cells Reveals the Molecular Signature of Engraftment
Vanuytsel K, Villacorta-Martin C, Lindstrom-Vautrin J, Wang Z [et al.], Balazs AB, Murphy GJ
Published in Nature Communications on Tuesday, March 1, 2022

Blood stem cells are used to treat a variety of diseases, including blood disorders, leukemias and lymphomas. Our work has uncovered the underlying genetic program within stem cells that is responsible for the unique ability of these cells to engraft into a new donor. Taking advantage of new experimental techniques, we simultaneously measured the expression of both genes and proteins within individual stem cells to uncover their unique signature. With this advance, we are poised to improve treatments of numerous diseases and potentially create limitless numbers of these rare cells by growing them outside of the body.

(Summary submitted by Alejandro B. Balazs, PhD, Ragon Institute of MGH, MIT and Harvard, Department of Medicine)

Molecular Signatures of Engraftment Potential in Fetal Liver HSCs
Effect of Medical Marijuana Card Ownership on Pain, Insomnia, and Affective Disorder Symptoms in Adults: A Randomized Clinical Trial
Gilman JM, Schuster RM, Potter KW, Schmitt W, Wheeler G [et al.], Evins AE
Published in JAMA Network Open on Tuesday, March 1, 2022

This study used a randomized controlled design to test whether patients who received medical cannabis cards (MMC), compared to a waitlist control group (WLC), experienced outcomes such as new-onset symptoms of cannabis use disorder (CUD), health benefits on symptoms of pain, sleep, depression, or anxiety, or neurocognitive impairments. The results of the trial showed that obtaining an MMC was associated with significant risk for CUD symptoms over the brief 12-week intervention period. There was no significant benefit on symptoms of pain, depression, or anxiety. There was a modest but significant improvement in self-reported insomnia. These results warrant further investigation of benefits of cannabis products for insomnia and short-term risk for addiction.

(Summary submitted by Jodi Gilman, PhD, Center for Addiction Medicine, Department of Psychiatry)

Although most studies of speech and language focus on function of the cortex, subcortical structures also play an integral role in this uniquely human behavior. Using local field potential recordings in neurosurgical patients, this study demonstrated that the thalamus participates in processing whether a word or a non-word (lexical status) is being read aloud, in a lateralized and region-specific manner. The results provide rare direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.

(Summary submitted by Mark Richardson, MD, PhD, Department of Neurosurgery)

The CHIEF-HF Trial was a unique, completely virtual clinical trial, where eligible study participants with heart failure were identified, approached, enrolled, randomized and followed without a single study visit. They were randomized to receive either placebo or canagliflozin, an SGLT2 inhibitor, and followed for 12 weeks to evaluate change in health status (including quality of life) via recording of the Kansas City Cardiomyopathy Questionnaire. We found superior improvement in health status with canagliflozin treatment compared to placebo. Similar effects were observed in participants regardless of ejection fraction or presence of diabetes, demonstrating that canagliflozin significantly improves symptom burden in heart failure, regardless of these factors.

(Summary submitted by James L. Januzzi, MD, Cardiology Division, Department of Medicine)

Our collaboration developed new technologies to combine single-cell RNA-sequencing with "lineage tracing" in primary human tissue, using mitochondrial mutations as natural cell barcodes. This method, named MAESTER (for Mitochondrial Alteration Enrichment from Single-cell Transcriptomes to Establish Relatedness), can be applied to the most common single-cell RNA-sequencing methodologies and implemented on prior datasets. MAESTER will help researchers better associate changes in the transcriptional state of cells with clonal evolution, enabling insights into the fundamental biology of human development and disease, including cancer.

(Summary submitted by Tyler E. Miller, MD, PhD, Department of Pathology)

Cerebral autosomal dominant arteriopathy, subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes and dementia. Here, we show that two different human CADASIL mutations worsen ischemic stroke outcomes in transgenic mice. But, contrary to our expectations, CADASIL mutations did not affect residual brain perfusion, ruling out cerebrovascular dysfunction and collateral insufficiency to explain the larger infarcts. Instead, abnormal extracellular potassium homeostasis and susceptibility to ischemic depolarizations emerged as novel mechanisms of enhanced tissue vulnerability to ischemic injury in CADASIL.

(Summary submitted by Cenk Ayata, MD, Department of Neurology)

African American and Hispanic Patients Outpaced White Patients in Advanced Care Planning
Association of an Advance Care Planning Video and Communication Intervention With Documentation of Advance Care Planning Among Older Adults: A Nonrandomized Controlled Trial
Volandes AE, Zupanc SN, Paasche-Orlow MK, Lakin JR, Chang Y [et al.], Lindvall C
Published in JAMA Network Open on Thursday, February 24, 2022

Advance care planning (ACP)—by all races—grew dramatically from the pre-pandemic fall of 2019 through the middle of 2021. Most striking is that African American patients and their families and caregivers greatly outpaced white patients in making advance care plans with their clinicians. Hispanic patients and their families also improved to a greater degree than white patients. ACP effectively improves the opportunity for patients to receive care that reflects what matters most to them. ACP involves patients discussing medical choices with clinicians and their families and choosing a trusted person to make decisions in the event an individual can no longer do so.

(Summary submitted by Angelo E. Volandes, MD, MPH, Department of Medicine)

Understanding how memories are formed in the hippocampus and stored in the cortex may guide strategies to maintain the capacity to form memories in aging and in Alzheimer’s disease. We identify a molecular mechanism in the hippocampus by which memories retain specificity and are maintained in the cortex.

(Summary submitted by Amar Sahay, PhD, Department of Psychiatry, Center for Regenerative Medicine)

Press Releases

Does Nerve Damage Contribute to “Long-COVID” Symptoms?
Featuring Anne Louise Oaklander, MD, PhD

Almost all post-COVID neuropathy appears due to infection-triggered immune dysfunction that is potentially treatable.

Multi-center Clinical Trial Launched to Investigate New Treatment for Pediatric Type 1 Diabetes
Featuring Denise Faustman, MD, PhD

Researchers are investigating the potential for the BCG vaccine to reverse the disease.

New Research Findings Could Help Improve Bone Marrow and Stem Cell Transplantation for Patients With Blood-related Diseases
Featuring Alejandro B. Balazs, PhD

Scientists uncover the unique signature of genes expressed by hematopoietic stem cells capable of making healthy blood cells after being transplanted.

Common Cause of Heart Attacks in Younger Adults Linked to Gene Variants
Featuring Mark Lindsay, MD, PhD, Pradeep Natarajan, MD, MMSC, and Malissa Wood, MD

Disruptive variants in genes involved in the production of collagen are implicated in spontaneous coronary artery dissection, a major cause of heart attacks in women under 50.

Researchers Identify Potential Approaches to Modify the Vaginal Microbiome
Featuring Doug Kwon, MD, PhD

Insights may lead to more effective treatments for bacterial vaginosis and improve women’s health outcomes globally.

Handheld Devices for AFib Screening May Be Most Effective in the Oldest Adults During Primary Care Visits
Featuring Steven Lubitz, MD, MPH

Single-lead ECGs fail to show increased detection of atrial fibrillation in all patients over 65.

In Pilot Study, Asynchronous Telehealth Visits Effectively Treat Overactive Bladder
Featuring Marcus Ortega, MD

Women with overactive bladder are frequently frustrated with treatment and discontinue therapy. Asynchronous telehealth visits kept women engaged in follow-up care and led to improvement in symptoms.

Study Reveals How to Activate the Immune System’s Natural Killer Cells to Protect Against Cancer and Other Diseases
Featuring Shawn Demehri, MD, PhD

Scientists discover that certain proteins surrounding organs and tissues switch off natural killer cells’ “killer” function. Blocking these interactions could re-activate the cells.

Novel Therapy for Family Caregivers Reduces Depression and Boosts Wellbeing
Featuring Felipe Jain, MD

Family caregivers of loved ones with dementia often have high rates of depression and anxiety and physical problems related to chronic stress from their caretaking duties. A new study describes the first randomized controlled trial of a new therapeutic approach that seeks to build empathic imagination for caregivers.

Many Patients with Severe COVID-19 Recover Consciousness, but Recovery Can Take Days or Even Weeks
Featuring Emery Brown, MD, PhD, and Brian Edlow, MD

Researchers find that low blood oxygen levels are linked with a longer time to regain consciousness.

Lower, More Frequent Doses of Nanomedicines May Enhance Cancer Treatment
Featuring Rakesh K. Jain, PhD

The strategy may make tumors more vulnerable to anti-cancer therapies.

Sequencing of Drug Combinations Could Amplify the Anti-tumor Immune Response in Liver Cancer
Featuring Dan G. Duda, DMD, PhD

Researchers uncover a new effective treatment approach for hepatocellular cancer that could reduce drug exposure.

Study Identifies Key Barriers to Innovation Among Medical Trainees
Featuring Marc Succi, MD

Promoting innovation could encourage more to pursue and develop ideas for new medical treatments and tools.

Scientists Identify Neurons in the Brain That Drive Competition and Social Behavior Within Groups
Featuring Ziv M. Williams, MD

A study in mice may provide new insights into human interactions and advance research related to autism spectrum disorder and other neurocognitive conditions.

Marijuana for Medical Use May Result in Rapid Onset of Cannabis Use Disorder
Featuring Jodi Gilman, PhD

The hype over medical marijuana for treating health problems may be exaggerated, researchers find.

Immunotherapy Delays Disease Progression of High-grade Meningiomas
Featuring Priscilla K Brastianos, MD

The immune checkpoint inhibitor pembrolizumab showed activity against high-grade tumors of the membranes surrounding the brain and spinal column.

Cancer Cells That Spread to Different Sites in the Body Express Varying Levels of Targetable Proteins
Featuring Shyamala Maheswaran, PhD

Findings may help predict patient response to drugs that inhibit these proteins.

Fundamental Cancer Metabolism Dogma Revisited
Featuring Raul Mostoslavsky, MD, PhD

New research finds that non-dividing colon cancer cells use altered glucose metabolism to ward off accumulation of toxic reactive oxidative species.

Does Youth Tobacco Use Drop After Cities Ban Flavored Tobacco Sales?
Featuring Jonathan P. Winickoff, MD, MPH

Study examines data from Oakland and San Francisco, California.

Large Study Challenges the Theory That Light Alcohol Consumption Benefits Heart Health
Featuring Krishna G. Aragam, MD, MS

Any observed benefit likely results from other lifestyle factors common among light to moderate drinkers, say researchers.

Immune Cells Produce Chemical Messenger That Prevents Heart Disease–related Inflammation
Featuring Matthias Nahrendorf, MD, PhD

The messenger, called acetylcholine, blocks white blood cell production in the bone marrow.

Study Shows That RNA Can Be Targeted by Small Molecule Drugs, Creating New Possibilities for Disease Treatment
Featuring Jeannie Lee, MD, PhD

The discovery could lead to new therapies for many diseases.

Blog Posts

Sympathy Cards Help ICU Team Process the Depersonalization of Loss During the COVD-19 Pandemic
Featuring Helen D’Couto, MD

Sending handwritten cards to the families of patients who died in the ICU during the COVID-19 pandemic has been a way to remember their individual stories.

Synthetic Opioid Overdose Deaths on the Rise in Boston’s Homeless Population, Highlighting Need to Do More
Featuring Danielle Fine, MD, MSc, and Travis Baggett, MD, MPH

A study of individuals experiencing homelessness in Boston shows a worrying increase in the number of deaths due to synthetic opioids and the use of multiple substances.

Is Your Shampoo Secretly Harming You? Mass General Dermatologists Call for Better Regulation of Personal Care Products

A team of researchers from the Department of Dermatology at Mass General recently published a Legislative Update regarding the lack of PCP regulation, urging lawmakers to give the FDA more regulatory authority to oversee what goes into personal care products.

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Snapshot of Science for March 2022