Snapshot of Science for September 2022

Welcome to our Snapshot of Science for September 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 26 summaries submitted by the research teams
7 new research-related press releases from the Mass General Public Affairs office
5 posts from the Mass General Research Institute blog

Publications

Two Blood Biomarkers Help Distinguish Between Harmful and Helpful Inflammation
Human Acute Inflammatory Recovery Is Defined by Co-regulatory Dynamics of White Blood Cell and Platelet Populations
Foy BH, Sundt TM, Carlson JCT, Aguirre AD, Higgins JM
Published in Nature Communications on August 22, 2022 | *Summary available

Two New Probes Enable Noninvasive Detection of Early-onset Fibrosis
Dual Hydrazine-equipped Turn-On Manganese-based Probes for Magnetic Resonance Imaging of Liver Fibrogenesis
Ning Y, Zhou IY, Rotile NJ, Pantazopoulos P, Wang H [et al.], Caravan P
Published in Journal of the American Chemical Society on August 23, 2022 | *Summary available

Molecular MRI Quantification of Extracellular Aldehyde Pairs for Early Detection of Liver Fibrogenesis and Response to Treatment
Ning Y, Zhou IY, Roberts JD Jr, Rotile NJ, Akam E, Caravan P
Published in Science Translational Medicine on September 21, 2022

Overcoming a Key Challenge in the Quest for New Malaria Treatments
Elucidating the Path to Plasmodium Prolyl-tRNA Synthetase Inhibitors That Overcome Halofuginone Resistance
Tye MA, Payne NC, Johansson C, Singh K, Santos SA [et al.], Mazitschek R
Published in Nature Communications on August 25, 2022 | *Summary available

The Need for More Nationwide Data About Firearms
Where Are the Questions About Firearms? An Analysis of U.S. Federal Public Health Survey Data Infrastructure
Donelan K, Guzikowski S, Buonomo G, Galls A, Sacks CA, Masiakos PT
Published in Annals of Surgery on August 25, 2022

Association of HLA Genes With Greater Risk of Tuberculosis
Large Registry-based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA
Tervi A, Junna N, Broberg M, Jones SE, FinnGen F [et al.], Ollila HM
Published in Human Molecular Genetics on August 26, 2022 | *Summary available

Ten Genes Implicated in General Onset Crohn's Disease
Large-scale Sequencing Identifies Multiple Genes and Rare Variants Associated With Crohn's Disease Susceptibility
Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B [et al.], Daly MJ
Published in Nature Genetics on August 29, 2022

New Clinical Decision Support Systems for Monkeypox Infection
Development and Implementation of a Clinical Decision Support System Tool for the Evaluation of Suspected Monkeypox Infection
Albin JS, Lazarus JE, Hysell KM, Rubins DM, Germaine L [et al.], Shenoy ES
Published in Journal of the American Medical Informatics Association on August 29, 2022 | Press Release

Fentanyl Produces Unique Brain Signature
An EEG Biomarker of Fentanyl Drug Effects
Balanza GA, Bharadwaj KM, Mullen AC, Beck AM, Work EC [et al.], Purdon PL
Published in PNAS Nexus on August 30, 2022 | *Summary available | Press Release

Novel Anti-Bacterial Treatment for Drug Resistant Pseudomonas Aeruginosa Infections
Tackling Recalcitrant Pseudomonas Aeruginosa Infections in Critical Illness via Anti-virulence Monotherapy
Singh VK, Almpani M, Maura D, Kitao T, Ferrari L [et al], Rahme LG
Published in Nature Communications on August 30, 2022 | *Summary available

New Insights into Severe Bronchiolitis
Integrated Relationship of Nasopharyngeal Airway Host Response and Microbiome Associates With Bronchiolitis Severity
Fujiogi M, Raita Y, Pérez-Losada M, Freishtat RJ, Celedón JC [et al.], Hasegawa K
Published in Nature Communications on August 30, 2022 | *Summary available

New Paradigm for Population-based Genetic Association Testing for Monogenic Disease Endophenotypes
Endophenotype Effect Sizes Support Variant Pathogenicity in Monogenic Disease Susceptibility Genes
Halford JL, Morrill VN, Choi SH, Jurgens SJ, Melloni G [et al.], Lubitz SA
Published in Nature Communications on August 30, 2022 | *Summary available

Genetic Factors Associated With Suicide Attempt Risk Across the Life Span
Associations Between Genetic Risk for Adult Suicide Attempt and Suicidal Behaviors in Young Children in the U.S.
Lee PH, Doyle AE, Silberstein M, Jung JY, Liu R [et al.], Kessler RC
Published in JAMA Psychiatry on August 31, 2022

AI-aided Interpretation Associated With Improved Radiography Reader Performance
Association of Artificial Intelligence-aided Chest Radiograph Interpretation With Reader Performance and Efficiency
Ahn JS, Ebrahimian S, McDermott S, Lee S, Naccarato L [et al.], Kalra MK
Published in JAMA Network Open on August 31, 2022

Using Language to Understand the Spectrum of Genetic Diversity in Africa
Genetic Structure Correlates With Ethnolinguistic Diversity in Eastern and Southern Africa
Atkinson EG, Dalvie S, Pichkar Y, Kalungi A [et al.], Martin AR; NeuroGAP-Psychosis Study Team
Published in American Journal of Human Genetics on September 1, 2022 | *Summary available

DNA-based Score Could Enable Early Identification of Alzheimer’s Risk
Neurocognitive Trajectory and Proteomic Signature of Inherited Risk for Alzheimer's Disease
Paranjpe MD, Chaffin M, Zahid S, Ritchie S, Rotter JI [et al.], Khera AV
Published in PLoS Genetics on September 1, 2022 | *Summary available

Physicians' Tolerance for Uncertainty Associated With Differences in Resource Use and Patient Experience
Association of Self-reported Primary Care Physician Tolerance for Uncertainty With Variations in Resource Use and Patient Experience
Begin AS, Hidrue MK, Lehrhoff S, Lennes IT, Armstrong K [et al.], Wasfy JH
Published in JAMA Network Open on September 1, 2022

Laser Therapy Increased Effectiveness of Immunotherapy
Dual Near-Infrared II Laser Modulates the Cellular Redox State of T Cells and Augments the Efficacy of Cancer Immunotherapy
Katagiri W, Yokomizo S, Ishizuka T, Yamashita K, Kopp T [et al.], Kashiwagi S
Published in FASEB Journal on September 2, 2022 | *Summary available

Near-Infrared II Photobiomodulation Augments Nitric Oxide Bioavailability via Phosphorylation of Endothelial Nitric Oxide Synthase
Yokomizo S, Roessing M, Morita A, Kopp T, Ogawa E [et al.], Kashiwagi S
Published in FASEB Journal on August 5, 2022 | *Summary available

Unvaccinated Patients Had Higher True Positive COVID-19 Rates Than Vaccinated Patients
True-Positive Rate of RSNA Typical Chest CT Findings for COVID-19 Pneumonia in an Increasingly Vaccinated Population
Polyakov NJ, Som A, Mercaldo ND, Di Capua J, Little BP, Flores EJ
Published in Radiology on September 6, 2022 | *Summary available

Clinical Utility of Cell-Free DNA Analysis in Biliary Tract Cancer
The Clinical Landscape of Cell-Free DNA Alterations in 1,671 Patients With Advanced Biliary Tract Cancer
Berchuck JE, Facchinetti F, DiToro DF, Baiev I, Majeed U [et al.], Goyal L
Published in Annals of Oncology on September 8, 2022 | *Summary available

New Insights into How CAR T-Cells Work
Distinct Cellular Dynamics Associated With Response to CAR T Therapy for Refractory B Cell Lymphoma
Haradhvala NJ, Leick MB, Maurer K, Gohil SH, Larson RC [et al.], Maus MV
Published in Nature Medicine on September 12, 2022 | *Summary available

Two Leading CHIP Genes May Promote the Risk for CAD
Clonal Hematopoiesis of Indeterminate Potential, DNA Methylation, and Risk for Coronary Artery Disease
Uddin MDM, Nguyen NQH, Yu B, Brody JA, Pampana A [et al.], Conneely KN
Published in Nature Communications on September 12, 2022

Common Pathogenic Mechanism for Huntington’s Disease and McLeod Syndrome
Impaired XK Recycling for Importing Manganese Underlies Striatal Vulnerability in Huntington's Disease
Chhetri G, Ke Y, Wang P, Usman M, Li Y [et al.], Li X
Published in Journal of Cell Biology on September 13, 2022 | *Summary available

NAFLD Simulator Provides Stage-specific Outcomes
Analysis of a Simulation Model to Estimate Long-term Outcomes in Patients With Nonalcoholic Fatty Liver Disease
Chhatwal J, Dalgic OO, Chen W, Samur S, Bethea ED [et al.], Loomba R
Published in JAMA Network Open on September 13, 2022 | *Summary available

Sex-specific Mechanisms Contributing to Myocardial Infarction Risk Among People With HIV
Sex-Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation among People with HIV in the U.S.
Zanni MV, Foldyna B, McCallum S, Burdo TH, Looby SE [et al.], Grinspoon SK
Published in Clinical Infectious Diseases on September 14, 2022 | *Summary available

Fundamental Mechanism of Nutrient Signaling in Direct Epigenome Reprogramming
Glucose-driven TOR-FIE-PRC2 Signalling Controls Plant Development
Ye R, Wang M, Du H, Chhajed S, Koh J [et al.], Sheen J
Published in Nature on September 14, 2022 | *Summary available

The Role of SIRT6 in Muscle Wasting
Sirtuin 6 Inhibition Protects Against Glucocorticoid-induced Skeletal Muscle Atrophy by Regulating IGF/PI3K/AKT Signaling
Mishra S, Cosentino C, Tamta AK, Khan D, Srinivasan S [et al.], Sundaresan NR
Published in Nature Communications on September 15, 2022 | *Summary available

New Blocking Antibody Therapy for Medulloblastoma
A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma
Saulnier-Sholler G, Duda DG, Bergendahl G, Ebb D, Snuderl M [et al.], Jain RK
Published in Clinical Cancer Research on September 15, 2022 | *Summary available

Potential of Targeted Antigen Discovery Within the Microbiome for Treatment of Crohn's Disease
The CD4+ T Cell Response to a Commensal-derived Epitope Transitions From a Tolerant to an Inflammatory State in Crohn's Disease
Pedersen TK, Brown EM, Plichta DR, Johansen J, Twardus SW [et al.], Graham DB
Published in Immunity on September 16, 2022

Chromosome 16p11.2 Reciprocal Genomic Disorder Disrupts Multiple Biological Processes
Tissue- and Cell-type-specific Molecular and Functional Signatures of 16p11.2 Reciprocal Genomic Disorder Across Mouse Brain and Human Neuronal Models
Tai DJC, Razaz P, Erdin S, Gao D, Wang J [et al.], Gusella JF
Published in American Journal of Human Genetics on September 21, 2022 | *Summary available

Electrical Engineering to Boost Electrochemiluminescence
Electrochemiluminescence in Paired Signal Electrode (ECLipse) Enables Modular and Scalable Biosensing
Cho YK, Kim H, Bénard A, Woo HK, Czubayko F [et al.], Lee H
Published in Science Advances on September 21, 2022 | *Summary available

Three Drugs Slow Progression of Autosomal Recessive Polycystic Kidney Disease
Organoid-on-Chip Model of Human ARPKD Reveals Mechanosensing Pathomechanisms for Drug Discovery
Hiratsuka K, Miyoshi T, Kroll KT, Gupta NR, Valerius MT [et al.], Morizane R
Published in Science Advances on September 21, 2022 | *Summary available | Press Release

Two Popular Diabetes Drugs Outperformed Others in Large Clinical Trial
Glycemia Reduction in Type 2 Diabetes—Microvascular and Cardiovascular Outcomes
GRADE Study Research Group, Nathan DM, Lachin JM, Bebu I, Burch HB [et al.], Younes N
Published in New England Journal of Medicine on September 22, 2022 | *Summary available | Press Release

Glycemia Reduction in Type 2 Diabetes—Glycemic Outcomes
GRADE Study Research Group, Nathan DM, Lachin JM, Balasubramanyam A, Burch HB [et al.], Younes N
Published in New England Journal of Medicine on September 22, 2022

Researchers Identify Immune Evasion Mechanisms in Cancer
In Vivo CRISPR Screens Reveal the Landscape of Immune Evasion Pathways Across Cancer
Dubrot J, Du PP, Lane-Reticker SK, Kessler EA, Muscato AJ [et al.], Manguso RT
Published in Nature Immunology on September 23, 2022

Wearable Devices May Facilitate Identifying Individuals with Undiagnosed Atrial Fibrillation
Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study
Lubitz SA, Faranesh AZ, Selvaggi C, Atlas SJ, McManus DD [et al.], Foulkes AS
Published in Circulation on September 23, 2022

Nlp7 Represents a Nitrate Sensor in Land Plants
NIN-like Protein 7 Transcription Factor Is a Plant Nitrate Sensor
Liu KH, Liu M, Lin Z, Wang ZF, Chen B [et al.], Sheen J
Published in Science on September 23, 2022 | *Summary available

Simple, Rapid, and Cost-effective Method for Clinical Dressings and Burn Wound Healing
Supramolecular Hybrid Hydrogels as Rapidly On-Demand Dissoluble, Self-healing, and Biocompatible Burn Dressings
Gokaltun AA, Fan L, Mazzaferro L, Byrne D, Yarmush ML [et al.], Usta OB
Published in Bioactive Materials on September 27, 2022 | Press Release

Publication Summaries

Two Blood Biomarkers Help Distinguish Between Harmful and Helpful Inflammation
Human Acute Inflammatory Recovery Is Defined by Co-Regulatory Dynamics of White Blood Cell and Platelet Populations
Foy BH, Sundt TM, Carlson JCT, Aguirre AD, Higgins JM
Published in Nature Communications on August 22, 2022

Inflammation is a natural process that occurs as the immune system responds to an injury or infection in the body to restore health. Clinicians are good at identifying patients with signs of inflammation but have little guidance on whether the process is on track to recovery or going awry. It is thus tough to know whether to stand back and let the body repair itself, or to further intervene. Our study has identified a signature of recovery in the tempo of changes in two blood biomarkers, providing a near-universal frame of reference to recognize and guide successful healing.

(Summary submitted by John Higgins, MD, Center for Systems Biology)

Molecular MRI Quantification of Extracellular Aldehyde Pairs for Early Detection of Liver Fibrogenesis and Response to Treatment
Ning Y, Zhou IY, Roberts JD Jr, Rotile NJ, Akam E , Caravan P
Published in Science Translational Medicine on September 21, 2022

Liver fibrosis (scarring) can be present in most chronic liver diseases, and both the presence of fibrosis and its severity are associated with poor outcomes. Clinically, fibrosis and fibrogenesis are assessed by biopsy, while noninvasive methods are only sensitive to advanced disease and cannot report on disease activity. We hypothesized that extracellular allysine aldehyde pairs formed during fibrogenesis could be targeted with a molecular MRI probe for noninvasive quantification of disease activity. The first paper describes the design of a manganese-based probe with two hydrazine moieties for targeting allysine pairs that undergoes a turn-on in MRI signal in the presence of fibrogenesis. The second paper extends this work with a more potent probe that is highly selective for liver fibrogenesis but that does not enhance the healthy liver. The high sensitivity of that probe enabled the earliest detection of liver fibrosis in a mouse model of nonalcoholic steatohepatitis, as well as reporting on early response to therapy in which imaging changes could be seen prior to reductions in liver fibrosis. This technology was validated in three rodent models and in human liver tissue, pointing to its high potential for clinical translation.

(Summary submitted by Yingying Ning, PhD, Department of Radiology)

Malaria remains one of the deadliest infectious diseases and the spread of resistance to existing therapies threatens global eradication efforts. To address this critical public health need, next-generation antimalarials that exploit new targets are urgently needed. Here, the malaria parasites prolyl-tRNA synthetase (ProRS) represents a promising target. However, the lack of reliable assay systems to characterize ProRS inhibitors has greatly impeded drug discovery efforts. To overcome these challenges, we have developed a novel assay platform that overcomes the limitations of existing technologies, which has allowed us to identify and optimize new inhibitor classes with potent antimalarial activity.

(Summary submitted by Ralph Mazitschek, PhD, Center for Systems Biology)

Tuberculosis is a significant public health concern resulting in the yearly death of over one million individuals worldwide. While treatment options and vaccines exist, a substantial number of infections remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Infection risk is often moderated by our inheritance. With genetic analysis tools, we identified a statistically significant association with HLA II alleles and tuberculosis in the FinnGen cohort. The HLA genes are important players in our immune function. Additionally, our results support smoking as a risk factor for tuberculosis. Our findings indicate that specific HLA alleles associate with the risk of tuberculosis alongside with environmental factors such as smoking.

(Summary submitted by Anniina Tervi, Doctoral Researcher, Institute for Molecular Medicine, Finland)

Fentanyl is commonly given to patients during surgery and intensive care, but it has played a deadly role in the opioid epidemic. Our study revealed two major findings about Fentanyl: 1) We found that Fentanyl impairs people's breathing several minutes before they feel sedated, which may explain why Fentanyl is so dangerous; 2) Fentanyl produces a brain signature distinct from other anesthetic drugs. Currently, there is no way to directly monitor effects of opioids given to unconscious patients. This unique signature could be used to monitor and adjust the amount of opioids given to patients during surgery or intensive care.

(Summary submitted by Patrick L. Purdon, PhD, Department of Anesthesia, Critical Care, and Pain Medicine)

Novel Anti-Bacterial Treatment for Drug Resistant Pseudomonas Aeruginosa Infections
Tackling Recalcitrant Pseudomonas Aeruginosa Infections in Critical Illness via Anti-Virulence Monotherapy
Singh VK, Almpani M, Maura D, Kitao T, Ferrari L [et al], Rahme LG
Published in Nature Communications on August 30, 2022

Pseudomonas aeruginosa (PA) presents a serious threat to critically ill and immunocompromised patients due to the development of antimicrobial resistance. Infections by this pathogen in critically ill patients increases gut permeability and leads to gut-driven sepsis. Our strategy to target virulence functions with the use of novel anti-Pseudomonas compounds we developed provides for the development of crucial preventive/therapeutic monotherapy options against untreatable multidrug-resistant PA infections. This strategy is fundamentally different from current traditional therapies.

(Summary submitted by Laurence G. Rahme, PhD, Department of Surgery)

New Insights Into Severe Bronchiolitis
Integrated Relationship of Nasopharyngeal Airway Host Response and Microbiome Associates With Bronchiolitis Severity
Fujiogi M, Raita Y, Pérez-Losada M, Freishtat RJ, Celedón JC [et al.], Hasegawa K
Published in Nature Communications on August 30, 2022

Bronchiolitis—severe airway infection in infants—is the leading cause of infant hospitalizations in the U.S. However, its mechanisms remain uncertain, and no specific treatment is available to date. In this multicenter study, we applied integrated omics and network analysis approaches to the airway transcriptome and microbiome (metatranscriptome) data of infants with severe bronchiolitis. We demonstrated complex interplays between host and microbiome, and their contribution to disease severity. Our data advance the development of targeted therapeutic measures (e.g., modification of immune response, microbiome composition, and function) and help clinicians manage this population with a large morbidity burden.

(Summary submitted by Kohei Hasegawa, MD, MPH, PhD, Department of Emergency Medicine)

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care, but contemporary approaches are limited. The emergence of large-scale human genetic sequence and phenotype data in biorepositories provides an opportunity to develop tools to improve variant classification. In this study, we assessed whether population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (familial hypercholesterolemia, long QT syndrome, and maturity-onset diabetes of the young) could provide evidence supporting variant pathogenicity. Using data from three cohorts, we demonstrated that endophenotype-derived effect sizes are associated with pathogenic ClinVar assertions and discriminate pathogenic from non-pathogenic variants. An endophenotype-specific effect size threshold was applied to nominate rare variants with pathogenic potential. In conclusion, population-based genetic association testing for monogenic disease endophenotypes is a new paradigm that can provide evidence supporting variant pathogenicity.

(Summary submitted by Jennifer L. Halford, MD, Department of Medicine)

The NeuroGAP-Psychosis program is working to expand our understanding of the genetics of schizophrenia in African populations and is teaching us something about the continent's linguistic heritage as well. When we analyzed our early genetic and demographic data, we noted that many genetic features tracked with participants' self-reported language proficiencies. Our analysis reveals new insights into language transmission patterns across generations and aspects of genetic architecture that would be missed by considering geography alone.

(Summary submitted by Alicia Martin, PhD, Analytic & Translational Genetics Unit, Department of Medicine)

Alzheimer’s disease is the leading cause of dementia globally but identification of a medicine that meaningfully alters the disease process has proven challenging. One possible explanation for recent failed clinical trials is that intervention is too late in the disease process, when therapies are unlikely to be effective. In our study, we developed a genetic score to identify individuals at a high genetic risk for developing Alzheimer's disease prior to symptom onset and observe that these individuals have accelerated neurocognitive decline. We then studied the levels of over 3,000 proteins in the healthy blood donors with very high versus very low genetic risk, identifying 28 proteins whose levels were significantly different. These nominated biomarkers, which include several known drivers of disease as well as several newly discovered proteins, may prove useful in identifying new pathways or monitoring response to therapy.

(Summary submitted by Amit Khera, MD, MSc, Center for Genomic Medicine)

Immunotherapy revolutionized oncology care, but it works for only a minor fraction of patients. In response to this, investigators worldwide are racing to improve immunotherapeutic efficacy and find a way to cure cancer. In this study, we found that brief near-infrared II light exposures revitalized immune cells attacking cancer and increased the effectiveness of immunotherapy. Since the laser does not pose a risk of drug-to-drug interactions, it can be broadly combined with other therapies to treat cancer patients effectively. The laser-based technology is widely used in medicine already and represents a clinically translatable approach.

Near-Infrared II Photobiomodulation Augments Nitric Oxide Bioavailability via Phosphorylation of Endothelial Nitric Oxide Synthase
Yokomizo S, Roessing M, Morita A, Kopp T, Ogawa E [et al.], Kashiwagi S
Published in FASEB Journal on August 5, 2022

Various beneficial effects of low-power laser exposure, called “photobiomodulation,” have been established by Dr. Hamblin at Mass General and other investigators. We found a new function of photobiomodulation. The impaired production of a gaseous mediator, nitric oxide (NO), in blood vessels is well known to cause cardiovascular diseases. In this study, we found that brief exposures of endothelial cells to low-power near-infrared II light induced NO production. Since near-infrared II light reaches deep tissues, this study implicates that laser exposures could be used to treat diseases like heart attack and stroke. Furthermore, unlike chemical drugs, near-infrared II laser poses little chance of side effects and represents a clinically translatable approach.

(Summaries submitted by Dmitriy Atochin, MD, PhD, Cardiovascular Research Center, Department of Medicine, and Satoshi Kashiwagi, MD, PhD, Gordon Center for Medical Imaging, Department of Radiology)

During the COVID-19, chest CT scans have been used by many institutions to triage patients using the RSNA consensus guidelines, given the high false negative rate of COVID-19 PCR tests. Chest CT scans help to maintain a reasonable suspicion of COVID-19 infection in the event of a single negative PCR test result. This study compared the true positive rates of COVID-19 typical chest CT scans (patients with positive PCR test and Chest CT with typical findings for COVID-19 infection) in unvaccinated compared to vaccinated patients. The study found that overall, unvaccinated patients had higher true positive rates than vaccinated patients, particularly when the Alpha and Delta variants were dominant, but not when Omicron was dominant.

(Summary submitted by Efrén J. Flores, MD, Thoracic Division, Department of Radiology)

Efficient genomic profiling to identify actionable alterations is critical to maximizing survival for patients with advanced biliary tract cancer (BTC). We report the largest and most comprehensive study to date on the clinical utility of cell-free (cf)DNA analysis in BTC. We found that profiling cfDNA identifies similar frequencies of clinically actionable alterations compared to tissue profiling, provides insights into genomic drivers of BTC, uncovers novel mechanisms of resistance to targeted therapy not detected on tumor biopsy, and provides prognostic and predictive data to integrate into clinical decision-making. These findings have immediate clinical relevance for management of patients with advanced BTC.

(Summary submitted by Jacob Berchuck, MD, Dana-Farber Cancer Institute)

New Insights Into How CAR T-Cells Work
Distinct Cellular Dynamics Associated With Response to CAR T Therapy for Refractory B Cell Lymphoma
Haradhvala NJ, Leick MB, Maurer K, Gohil SH, Larson RC [et al.], Maus MV
Published in Nature Medicine on September 12, 2022

Chimeric antigen receptor modified T cells, or CAR T, is a form of immune-cell therapy that has transformed the treatment of large-cell lymphoma, a kind of blood cancer. About 40% of patients with lymphomas have long-term responses after treatment with CAR T, but not all patients respond. Our multidisciplinary, multi-institution team discovered that the presence of a certain kind of inhibitory T-cell that is associated with relapse. Using single-cell RNA sequencing and deep computational analyses, we also showed which kinds of T-cells are the most effective in patients who respond to two of the CAR T-cell products in clinical use. Our work sheds light on how CAR T-cells work and on what strategies could be implemented to make them work in more patients.

(Summary submitted by Marcela Maus, Md, PhD, Mass General Cancer Center, Department of Medicine)

Mutant huntingtin, which causes Huntington’s disease, presents in all cells but preferentially induces striatal neurons to die by unclear mechanisms. We have shown that Huntington’s disease progression involves improper function of Rab11. In profiling proteins regulated by Rab11, we came across XK, which causes McLeod Syndrome, a disorder resembling Huntington’s disease in neurologic presentations. We showed that XK deficiently trafficked in Huntington’s disease cells because of Rab11 functional decline. We further found that XK participated in transporting manganese, an essential trace metal reduced in Huntington’s disease brains. Our study identifies a common pathogenic mechanism for Huntington’s disease and McLeod syndrome.

(Summary submitted by Xueyi Li, PhD, Department of Neurology)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and leads to liver failure and liver cancer. Several treatments for NAFLD are under development, but none has yet been approved for use. Because NAFLD is a slowly progressive disease, ongoing clinical trials use surrogate markers as primary end points. It is important to understand the relationship between surrogate endpoints and long-term adverse outcomes. Therefore, we developed the NAFLD Simulator that provides stage-specific outcomes, including liver- and non-liver-related mortality. The Simulator can be used as an educational tool to increase awareness and consequences of NAFLD.

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

Sex-specific Mechanisms Contributing to Myocardial Infarction Risk Among People With HIV
Sex-differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With HIV in the U.S.
Zanni MV, Foldyna B, McCallum S, Burdo TH, Looby SE [et al.], Grinspoon SK
Published in Clinical Infectious Diseases on September 14, 2022

People with HIV (PWH) face an increased risk of myocardial infarction (MI), related to persistent systemic inflammation. We leveraged data from REPRIEVE (clintrials NCT02344290) to compare sex-differences in cardiovascular disease risk indices among PWH living in the United States. Females (vs. males) demonstrated a lower prevalence and burden of subclinical atherosclerosis despite higher levels of several inflammatory markers. While many immune-plaque relationships were consistent between groups, a relationship between higher levels of D-dimer and noncalcified/vulnerable plaque prevalence was apparent only among females. Our work advances understanding of sex-specific mechanisms contributing to MI risk among PWH, of relevance to the development of targeted preventive strategies.

(Summary submitted by Markella V. Zanni, MD, Metabolism Unit, Endocrine Division, Department of Medicine)

The evolutionarily conserved target-of-rapamycin (TOR) kinase is a master integrator of nutrient and energy signaling that controls growth. Little is known about how TOR shapes developmental transitions and differentiation. Our new study reveals that glucose-activated TOR phosphorylates FIE to promote its nuclear translocation, which activates polycomb repressive complex 2 and controls epigenomic reprogramming that regulates cell fates and development in plants and humans. This newly defined glucose-TOR-FIE-PRC2 signaling axis serves as a nutritional checkpoint leading to epigenetic silencing of key transcription factor genes that specify stem-cell destiny in meristems and control leaf, flower and silique patterning, branching, and vegetative-to-reproduction transition.

(Summary submitted by Jen Sheen, PhD, Department of Molecular Biology)

Chronic stress under disease conditions increases corticosteroid levels, resulting in muscle wasting. We identified SIRT6 as a major regulator of dexamethasone-induced muscle wasting in mice and in primary myotubes. We found that muscle-specific SIRT6 deficient mice, SIRT6 inhibitor-treated mice, and SIRT6 depleted primary myotubes were resistant to dexamethasone-induced muscle mass loss and reduction in myotube diameter respectively. On contrary, SIRT6 overexpression spontaneously reduced myotube diameter. Our mechanistic analysis suggested that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling via c-Jun-mediated increased IGF2 expression, thus suppressing FoxO, a known activator of muscle atrophy. Our findings suggest the role of SIRT6 in muscle wasting.

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

Effective and safe treatments are needed for medulloblastoma—the most common type of brain tumor in children—especially for patients whose cancer has spread to the spinal cord. Our recent phase I clinical trial has generated promising results for a new blocking antibody therapy (TB403) that targets placental growth factor (PlGF), a protein found to be critical in our laboratory for medulloblastoma cells to multiply and spread. TB403 treatment was well tolerated and induced stable disease in some medulloblastomas in a setting with no effective treatments, warranting further studies.

(Summary submitted by Dan G. Duda, DMD, PhD, Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology)

Recurrent and reciprocal copy number variations (CNVs) encompassing multiple genes can contribute to neurodevelopmental and neuropsychiatric disorders. For example, recurrent deletion and duplication in chromosome 16p11.2 is associated with intellectual disability, autism spectrum disorder, and multiple other neuropsychiatric disorders, but the responsible molecular mechanisms are not known. To systemically dissect disease mechanisms, we performed cellular, transcriptional, and single-cell analyses in 16p mouse tissues and human iPSC-derived NSCs, neurons, and cerebral organoids. Impacts of the reciprocal CNVs on genome-wide gene expression, cellular function and neurodevelopment were highly context-dependent, arguing against a single driver gene within the deleted or duplicated segment.

(Summary submitted by Derek J.C. Tai, PhD, Center for Genomic Medicine)

Electrochemiluminescence (ECL) is a powerful biosensing method with inherently low background and precise chemical reactions through electrical control. We extended ECL’s advantages by devising a new system termed ECLipse (ECL in paired signal electrode). The key innovation was to separate ECL generation from target detection. With this strategy, we could maximize the analytical signal without crosstalk and integrate multiple sensors in a compact chip. In a clinical study, the ECLipse system accurately detected septic conditions by measuring host factors (IL-3, IL-6, PCT) and revealed distinct IL-3 and IL-6 patterns in patients with SARS-CoV-2 infection.

(Summary submitted by Hyunho Kim, PhD, Center for Systems Biology)

Three Drugs Slow Progression of Autosomal Recessive Polycystic Kidney Disease
Organoid-on-a-Chip Model of Human ARPKD Reveals Mechanosensing Pathomechanisms for Drug Discovery
Hiratsuka K, Miyoshi T, Kroll KT, Gupta NR, Valerius MT [et al.], Morizane R
Published in Science Advances on September 21, 2022

Autosomal recessive polycystic kidney disease (ARPKD) is a pediatric disease that causes the progressive loss of kidney function, and there is currently no FDA-approved treatment. In this work, we created an innovative new model using human kidney organoids to replicate the unique disease process underlying ARPKD. We found that two FDA-approved drugs (R-Naproxen and R-Ketorolac) and one investigational new drug (T-5224) were effective to slow the progression of ARPKD in their new experimental model. This work may lead to new clinical trials to investigate these therapeutics in ARPKD patients.

(Summary submitted by Ryuji Morizane, MD, PhD, Division of Nephrology, Department of Medicine)

Glycemia Reduction in Type 2 Diabetes—Glycemic Outcomes
GRADE Study Research Group, Nathan DM, Lachin JM, Balasubramanyam A, Burch HB [et al.], Younes N
Published in New England Journal of Medicine on September 22, 2022

The study enrolled 5,047 people with type 2 diabetes from diverse racial and ethnic groups who were already taking metformin. Participants were randomly placed into one of four treatment groups. Three groups took metformin plus a medicine that increased insulin levels (sitagliptin, liraglutide, or glimepiride). The fourth group took metformin and insulin glargine U-100, a long-acting insulin. After an average of four years of follow-up, the study found that participants taking metformin plus liraglutide or insulin glargine achieved and maintained their target blood levels for the longest time compared to sitagliptin or glimepiride. This translated into approximately six months more time with blood glucose levels in the target range compared with sitagliptin, which was the least effective in maintaining target levels. Treatment effects did not differ based on age, sex, race, or ethnicity. However, none of the combinations overwhelmingly outperformed the others. Although average blood sugar levels decreased during the study, nearly three quarters of all participants were unable to maintain the blood glucose target over four years, underscoring the difficulty in maintaining recommended targets in many patients with type 2 diabetes.

(Summary submitted by Mary E. Larkin, MS, RN, CRN-BC, Diabetes Research Center, Department of Medicine)

Plants play a central role in bridging inorganic to organic nitrogen conversion in the global nitrogen cycle by assimilating nitrate to generate amino acids, nucleic acids, and organic nitrogen-carbon molecules essential to build and sustain lives from plants to humans. Transcription-activating nitrate sensors have now been discovered in flowering plants. The protein’s nitrate-binding pocket resembles that found in bacteria nitrate sensors controlling anerobic respiration and is evolutionarily conserved in agronomically important crops. Conformation change upon nitrate binding allows the protein to then function as a transcriptional activator, triggering the plant’s universal responses to nitrogen availability vital for growth and development.

(Summary submitted by Jen Sheen, PhD, Department of Molecular Biology)

Press Releases

Study Reveals Fentanyl’s Effects on the Brain
Featuring Patrick L. Purdon, PhD

Electroencephalogram (EEG) tests revealed fentanyl’s effects on the brain and indicated that the drug stops people’s breathing before other noticeable changes and before they lose consciousness. This explains why fentanyl has been so deadly during the opioid epidemic.

Study Finds Damage in the Lungs of Chronic E-Cigarette Users
Featuring Lida Hariri, MD, PhD

In a small cohort of individuals with a history of vaping and small airway fibrosis with constrictive bronchiolitis, researchers concluded that vaping was the most likely cause.

New Tool Guides Clinicians to Identify and Treat Patients at Risk for Monkeypox Virus
Featuring Erica S. Shenoy, MD, PhD

In the setting of the current global monkeypox outbreak, clinicians are on now alert to identify, isolate, and treat individuals infected with the virus that causes it. Investigators recently developed a clinical decision support system to help with this effort, and they tested its initial performance in a large integrated healthcare system.

A Hydrogel That Allows for Quick Burn Dressing Changes While Minimizing Pain Developed
Featuring O. Berk Usta, PhD

Bioengineers have developed a first-of-its-kind hydrogel for second-degree burns that can be dissolved quickly and easily for wound dressing changes using a solution that breaks apart the supramolecular structure of the hydrogel.

Fitness Trackers May Help Detect Potentially Dangerous Irregular Heartbeats
Featuring Steven A. Lubitz, MD, MPH

A recent clinical trial indicates that Fitbit wearable devices can help spot undiagnosed atrial fibrillation and therefore identify patients who would benefit from stroke prevention therapies.

3D Organoid Models Identify Potential Treatment Targets for a Devastating Pediatric Kidney Disease
Featuring Ken Hiratsuka, MD, PhD, and Ryuji Morizane, MD, PhD

A research team from Mass General, the Brigham, the Wyss Institute recently united organoids with organ-on-a-chip technology to replicate the unique disease process underlying autosomal recessive polycystic kidney disease.

Two Popular Diabetes Drugs Outperformed Others in Large Clinical Trial
Featuring Deborah Wexler, MD

Researchers found that insulin glargine and liraglutide performed the best of four medications approved by the U.S. Food and Drug Administration to maintain blood glucose levels in the recommended range.

Blog Posts

Improving Body Positivity During After Pregnancy Could Lead to Healthier Mothers and Children
Featuring Rachel Vanderkruik, PhD, MSc

Body dissatisfaction can increase the risk of postpartum depression and eating disorders, with health consequences for mother and child.

Summer Safety Awareness Campaign: The Three Golden Rules of Bike Safety
Featuring Michael Flaherty, DO

The Summer Safety Awareness Campaign is geared toward sharing science-based strategies to reduce the risk of preventable injuries to children this summer.

Clinical Trial Will Test a New Drug in E-Cigarette Users Who Are Trying to Quit
Featuring Nancy Rigotti, MD

A Mass General clinical research study is testing the effectiveness of a new medication, cytisinicline, as a treatment for e-cigarette cessation.

Remembering Susan Dimock, a Pioneering Boston Physician

Mass General played a small but pivotal role in the education of a pioneering female doctor who helped women physicians gain equal recognition in Massachusetts.

Humans of MGRI: Abigail Kane, MD
Abigail Kane, MD, is a postdoctoral research fellow at the Mucosal Immunology and Biology Research Center, working in Dr. Lael Yonker’s lab, studying immune responses to COVID-19 infection and vaccination in children.

The Mass General Difference

Conditions & Treatments

Patients & Visitors

Research & Innovation

Mass General
Research Institute

Snapshot of Science for September 2022