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

A Smart Window into Complex Biology
Perfusion Window Chambers Enable Interventional Analyses of Tumor Microenvironments
Korolj A, Kohler RH, Scott E, Halabi EA, Lucas K, Carlson JCT, Weissleder R
Published in Advanced Science on 10/23/2023 | *Summary available

Retention of Four Different Gadolinium-based Contrast Agents
Gadolinium-based Contrast Agent Biodistribution and Speciation in Rats
Le Fur M, Moon BF, Zhou IY, Zygmont S, Boice A [et al.], Caravan P
Published in Radiology on 10/24/2023 | *Summary available

Receiving Real-Time-Digital Air Device Feedback Improved Infant Ventilation Significantly
Real-Time Digital Feedback Device and Simulated Newborn Ventilation Quality
Data S, Nelson BD, Cedrone K, Mwebesa W, Engol S, Nsiimenta N, Olson KR
Published in Pediatrics on 10/24/2023 | *Summary available

Creating Microfluidic Transistors that Control the Movement of Fluids to Autonomously Execute Miniature Lab Operations
A Microfluidic Transistor for Automatic Control of Liquids
Gopinathan KA, Mishra A, Mutlu BR, Edd JF, Toner M
Published in Nature on 10/25/2023 | *Summary available | Research Spotlight

Genetics Sheds Light on a Wound Healing Pathway
Genetic Vulnerability to Crohn's Disease Reveals a Spatially Resolved Epithelial Restitution Program
Nakata T, Li C, Mayassi T, Lin H, Ghosh K [et al.], Xavier RJ
Published in Science Translational Medicine on 10/25/2023 | *Summary available

Trivalent Rare Earth Metal Ions as an Alternative Cofactor
Trivalent Rare Earth Metal Cofactors Confer Rapid NP-DNA Polymerase Activity
Lelyveld VS, Fang Z, Szostak JW
Published in Science on 10/26/2023 | *Summary available

Imaging System Enables Quantitative Characterization of Various Pathological Features in Aging Process
Multi-Scale Label-Free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy
Chang S, Yang J, Novoseltseva A, Abdelhakeem A, Hyman M [et al.], Wang H
Published in Advanced Science on 10/26/2023

Patient Attendance and Perceived Benefits of Lifestyle Medicine Virtual Group Visits
Lifestyle Medicine Virtual Group Visits: Patient Attendance and Perceived Benefits
Mirsky J, Brodney S, Boratyn V, Thorndike AN
Published in American Journal of Lifestyle Medicine on 10/26/2023 | *Summary available | Research Spotlight

Durable Remissions and Almost Certain Cures in Approximately 40% of Patients with Large B-cell Lymphomas Two Years Post Treatment
Two-year Follow-up of Lisocabtagene Maraleucel in Relapsed or Refractory Large B-cell Lymphoma in TRANSCEND NHL 001
Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang ML [et al.], Siddiqi T
Published in Blood on 10/27/2023 | *Summary available

Prescribing of Benzodiazepines in a Homeless Veteran Population
Benzodiazepine Prescriptions for Homeless Veterans Affairs Service Users With Mental Illness
Koh KA, Szymkowiak D, Tsai J
Published in Psychiatric Services on 10/31/2023 | *Summary available | Research Spotlight

Ultrasound Technology Designed to Enhance the Precision of Elasticity Imaging
Acoustic Diffraction-resistant Adaptive Profile Technology (ADAPT) for Elasticity Imaging
Gu Y, Kumar V, Dayavansha EGSK, Schoen S Jr, Feleppa E [et al.], Samir AE
Published in Science Advances on 11/1/2023 | *Summary available

Firearm Injuries Among Children and Adolescents Lead to Huge Mental and Behavioral Health Consequences
Firearm Injuries In Children And Adolescents: Health And Economic Consequences Among Survivors And Family Members
Song Z, Zubizarreta JR, Giuriato M, Koh KA, Sacks CA
Published in Health Affairs on 11/1/2023 | *Summary available | Press Release

Factors Identified for Increased Odds of Nonsuicidal Self-Injury in Preadolescents
Nonsuicidal Self-Injury in Preadolescents
Burke TA, Bettis AH, Walsh RFL, Levin RY, Lawrence HR [er al.], Liu RT
Published in Pediatrics on 11/2/2023 | *Summary available

Promising Strategy to Complement and Augment MMR Deficiency-guided Immunotherapy
ATR Inhibition Induces Synthetic Lethality in Mismatch Repair-deficient Cells and Augments Immunotherapy
Wang M, Ran X, Leung W, Kawale A, Saxena S [et al.], Zou L
Published in Genes & Development on 11/6/2023 | *Summary available

Advanced Form of Meditation Impacts the Brain and is Linked to Aspects of Well-Being
Intensive Whole-brain 7T MRI Case Study of Volitional Control of Brain Activity in Deep Absorptive Meditation States
Yang WFZ, Chowdhury A, Bianciardi M, van Lutterveld R, Sparby T, Sacchet MD
Published in Cerebral Cortex on 11/6/2023 | *Summary available | Press Release

Innovative Strategy to Preserve the Efficacy of Existing Antibiotics
Blue Light Potentiates Antibiotics in Bacteria via Parallel Pathways of Hydroxyl Radical Production and Enhanced Antibiotic Uptake
Leanse LG, Anjos CD, Kaler KR, Hui J, Boyd JM [et al.], Dai T
Published in Advanced Science on 11/9/2023 | *Summary available

Regulatory T-Cells as Potent Suppressors of Immune Inflammatory Response in Lungs
Regulatory T Cell-derived IL-1Ra Suppresses the Innate Response to Respiratory Viral Infection
Griffith JW, Faustino LD, Cottrell VI, Nepal K, Hariri LP [et al.], Luster AD
Published in Nature Immunology on 11/9/2023 | *Summary available

Potential of Radiation Therapy for Improved ICB Therapy
Transport Barriers Influence the Activation of Anti-Tumor Immunity: A Systems Biology Analysis
Nikmaneshi MR, Baish JW, Zhou H, Padera TP, Munn LL
Published in Advanced Science on 11/10/2023

Proline Biosynthesis a Previously Unrecognized Major Consumer of Glutamate
Inhibition of the Proline Metabolism Rate-limiting Enzyme P5CS Allows Proliferation of Glutamine-restricted Cancer Cells
Linder SJ, Bernasocchi T, Martínez-Pastor B, Sullivan KD, Galbraith MD [et al.], Mostoslavsky R
Published in Nature Metabolism on 11/13/2023 | *Summary available

Health Care Organizations’ Reliance on Police and Security Personnel Can Exert Harm on Patients and Staff
Police Violence in Health Care Settings in US Media Coverage
Saadi A, Ray VE
Published in JAMA Network Open on 11/13/2023

Artificial Intelligence Model Accurately Reads and Interprets Echocardiograms
Deep Learning-Enabled Assessment of Left Heart Structure and Function Predicts Cardiovascular Outcomes
Lau ES, Di Achille P, Kopparapu K, Andrews CT, Singh P [et al.], Ho JE
Published in Journal of the American College of Cardiology on 11/14/2023 | *Summary available

COVID Rebound More Common in People Taking Paxlovid Therapy
SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study
Edelstein GE, Boucau J, Uddin R, Marino C, Liew MY [et al.], Siedner MJ
Published in Annals of Internal Medicine on 11/14/2023 | *Summary available | Press Release

New Promising Thyroid Cancer Treatment
Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer
Hadoux J, Elisei R, Brose MS, Hoff AO, Robinson BG [et al.], Wirth LJ; LIBRETTO-531 Trial Investigators
Published in New England Journal of Medicine on 11/16/2023 | *Summary available

Epigenetic Regulation That Coordinates Lung Progenitor Cells’ Regenerative Responses Becomes Dysregulated in Aging
Age-associated H3K9me2 Loss Alters the Regenerative Equilibrium Between Murine Lung Alveolar and Bronchiolar Progenitors
Rowbotham SP, Pessina P, Garcia-de-Alba C, Jensen J, Nguyen Y [et al.], Kim CF
Published in Developmental Cell on 11/16/2023 | *Summary available

Drugs Affecting Ras Pathway given to Fetus May Stop the Development of VOGMs
Mutation of Key Signaling Regulators of Cerebrovascular Development in Vein of Galen Malformations
Zhao S, Mekbib KY, van der Ent MA, Allington G, Prendergast A [et al.], Kahle KT
Published in Nature Communications on 11/17/2023 | *Summary available

Patient-reported Outcomes Associated with Better Outcomes than Tumor Markers
Patient-Reported Outcomes, Tumor Markers, and Survival Outcomes in Advanced GI Cancer
Jarnagin JX, Saraf A, Baiev I, Chi G, van Seventer EE [et al.], Parikh AR
Published in JAMA Network Open on 11/17/2023| *Summary available

Preventing Toxicity in CAR-T Cell Treatment for Multiple Myeloma
Anti-TACI Single and Dual-targeting CAR T Cells Overcome BCMA Antigen Loss in Multiple Myeloma
Larson RC, Kann MC, Graham C, Mount CW, Castano AP [et al.], Maus MV
Published in Nature Communications on 11/18/2023

New Small Molecule Inhibitor for Use Against Alzheimer’s Disease
Structure-Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology
Mondal P, Bai P, Gomm A, Bakiasi G, Lin CJ [et al.], Zhang C
Published in Advanced Science on 11/21/2023 | *Summary available | Press Release

How a Protein Called IKAROS Organizes the Genome in Nuclear Space to Control Healthy B Cell Development
Lineage-specific 3D Genome Organization is Assembled at Multiple Scales by IKAROS
Hu Y, Salgado Figueroa D, Zhang Z, Veselits M, Bhattacharyya S [et al.], Georgopoulos K
Published in Cell on 11/22/2023 | *Summary available | Research Spotlight

A Smart Window into Complex Biology
Perfusion Window Chambers Enable Interventional Analyses of Tumor Microenvironments
Korolj A, Kohler RH, Scott E, Halabi EA, Lucas K, Carlson JCT, Weissleder R
Published in Advanced Science on 10/23/2023

We often don’t fully understand how and where cells move, interact with each other, or respond to drugs dynamically. Most current measurement techniques only give us a snapshot in time but rarely the real “movie of life.” To observe such cell movements, communications and drug actions, we created a “smart” window that can be implanted into mice. We first designed an implantable “window frame” complete with microfluidic ports and channels and 3D printed it with biocompatible polymers. This allowed us to perfuse liquids quickly and locally to mouse tissues such as tumors while imaging. The novel perfusion device was tested for different applications such as cancer drug monitoring, topical application of drugs, highly multiplexed staining, and sampling of interstitial fluid. The new device enables new spatiotemporal analyses and in situ labeling capabilities, which will be critical for drug testing.

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

Retention of Four Different Gadolinium-based Contrast Agents
Gadolinium-based Contrast Agent Biodistribution and Speciation in Rats
Le Fur M, Moon BF, Zhou IY, Zygmont S, Boice A [et al.], Caravan P
Published in Radiology on 10/24/2023

FDA issued a class warning that gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) results in the metal ion gadolinium remaining in patients' bodies and brain for months to years after receiving these drugs. Here, we compared the retention of 4 clinically used GBCAs in rats and found that: 1) the majority of retained gadolinium is in the kidneys as intact GBCA; 2) despite high gadolinium levels, retained kidney gadolinium is not detectable by MRI; 3) retention varied widely among GBCAs but was lowest for gadoteridol; 4) analysis of human kidney specimens confirmed retention of gadoterate for at least 77 days after administration.

(Summary submitted by Mariane Le Fur, PhD, Martinos Center for Biomedical Imaging, Department of Radiology)

Receiving Real-time-digital AIR Device Feedback Improved Infant Ventilation Significantly
Real-Time Digital Feedback Device and Simulated Newborn Ventilation Quality
Data S, Nelson BD, Cedrone K, Mwebesa W, Engol S, Nsiimenta N, Olson KR
Published in Pediatrics on 10/24/2023

Effective bag-valve-mask ventilation is critical for reducing perinatal asphyxia-related neonatal deaths; however, providers often fail to achieve and maintain effective ventilation skills following training. We evaluated the effect of this real-time digital feedback, based on information from The Augmented Infant Resuscitator, on ventilation quality and effective determination of airway integrity in a randomized controlled study of simulated births in Uganda and the US.

(Summary submitted by Kristian R Olson, MD, MPH, Mass General Global Health, Department of Medicine)

Creating Microfluidic Transistors that Control the Movement of Fluids to Autonomously Execute Miniature Lab Operations
A Microfluidic Transistor for Automatic Control of Liquids
Gopinathan KA, Mishra A, Mutlu BR, Edd JF, Toner M
Published in Nature on 10/25/2023 | Research Spotlight

We created a microfluidic element that mimics the electronic transistor but manipulates fluids instead of electricity. Thanks to this analogous behavior, we could directly translate classic circuit designs from the extensive electronics repertoire to now perform complex operations on liquids and single particles in suspension. Just as the electronic transistor enabled unprecedented control over the flow of electricity, we aim to improve the complexity and precision at which we can control drugs, cells, and droplets on a microfluidic chip. While there is still much to optimize and understand, we hope to see this technology used to automate and scale biological and chemical processing for high-throughput drug screening, molecular biology assays, and lab-on-a-chip applications.

(Summary submitted by Kaustav Gopinathan, Harvard Medical School)

Genetics Sheds Light on a Wound Healing Pathway
Genetic Vulnerability to Crohn's Disease Reveals a Spatially Resolved Epithelial Restitution Program
Nakata T, Li C, Mayassi T, Lin H, Ghosh K [et al.], Xavier RJ
Published in Science Translational Medicine on 10/25/2023

Wound healing requires cooperation between many types of cells and processes. Upon injury, the coagulation cascade is triggered to produce a blood clot. A branch of this intricate pathway, controlled by HGFAC, promotes tissue repair. Genetic studies associate HGFAC with risk of inflammatory bowel diseases, recently implicating the HGFAC R509H variant in particular in Crohn’s disease risk. By characterizing how the R509H variant disrupts the spatial orchestration of wound healing in the intestine, we detail a process by which HGFAC induces the production of wound-associated epithelia cells that generate a gradient of retinoic acid to recruit fibroblasts to the site of injury and facilitate healing.

(Summary submitted by Theresa Reimels, Department of Gastroenterology, Department of Molecular Biology)

Trivalent Rare Earth Metal Ions as an Alternative Cofactor
Trivalent Rare Earth Metal Cofactors Confer Rapid NP-DNA Polymerase Activity
Lelyveld VS, Fang Z, Szostak JW
Published in Science on 10/26/2023

Many nucleoside analogs used in antiviral and anticancer therapy work by interfering with polymerase activity. Polymerases are enzymes responsible for replicating genetic material by stepwise addition of nucleotides to growing nucleic acid chains. Polymerization can become blocked if an incorporated analog bears certain chemical modification that inhibit subsequent additions. The mechanism of polymerases is highly conserved in nature, relying on precisely aligned magnesium ions to catalyze the formation of each new nucleotide linkage. Here we reported an alternative activity that incorporates and extends a substrate previously considered chain terminating. Using a modified DNA polymerase in the presence of rare earth metal ions, we showed that strands of a highly nuclease-resistant nucleic acid analog can be produced rapidly in routine bench-top enzyme reactions.

(Summary submitted by Victor S. Lelyveld, PhD, Center for Computational and Integrative Biology, Department of Molecular Biology)

Patient Attendance and Perceived Benefits of Lifestyle Medicine Virtual Group Visits
Lifestyle Medicine Virtual Group Visits: Patient Attendance and Perceived Benefits
Mirsky J, Brodney S, Boratyn V, Thorndike AN
Published in American Journal of Lifestyle Medicine on 10/26/2023 | Research Spotlight

Lifestyle Medicine Virtual Group Visits (LMVGVs) can be implemented in health systems to address chronic disease care gaps. In LMVGVs, several patients with common medical conditions meet together with a clinician to learn about behavior changes that improve health. Primary care patients in this survey study endorsed a wide range of behavior changes after attending LMVGVs, and most respondents reported maintaining lifestyle changes “some” or “a lot.” Respondents who attended ≥5 LMVGVs were about twice as likely, compared to respondents who attended 1-4 LMVGVs, to report eating healthier, increasing physical activity, and losing weight. LMVGV-based programs may be a scalable strategy for promoting healthy behavior change for improved chronic disease care.

(Summary submitted by Jacob Mirsky, MD, Department of Medicine)

Durable Remissions and Almost Certain Cures in Approximately 40% of Patients with Large B-cell Lymphomas Two Years Post Treatment
Two-year Follow-up of Lisocabtagene Maraleucel in Relapsed or Refractory Large B-cell Lymphoma in TRANSCEND NHL 001
Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang ML [et al.], Siddiqi T
Published in Blood on 10/27/2023

This 2 year follow up of lisocabtagene maraleucel (liso-cel) shows durable remissions and almost certain cures in approximately 40% of patients with previously incurable multiply relapsed/refractory large B-cell lymphomas. This anti-CD19 CAR T-cell was associated with the lowest rates observed for cytokine release syndrome and neurologic toxicities among pivotal trials in this indication, and no new safety signals were identified in long term follow up.

(Summary submitted by Jeremy S Abramson, MD, Mass General Cancer Center, Division of Hematology/Oncology, Department of Medicine)

Prescribing of Benzodiazepines in a Homeless Veteran Population
Benzodiazepine Prescriptions for Homeless Veterans Affairs Service Users With Mental Illness
Koh KA, Szymkowiak D, Tsai J
Published in Psychiatric Services on 10/31/2023 | Research Spotlight

Patients experiencing homelessness are at high risk for substance use disorders, overdose, and death. Benzodiazepines are medications that are known to increase risk of overdose particularly when combined with other sedating medications. However, benzodiazepine prescribing patterns have not previously been examined for this population. Using national data from the VA, our study found that homeless veterans with mental illness were less likely to receive benzodiazepine prescriptions than housed veterans with mental illness but when prescribed benzodiazepines, homeless veterans were more likely to receive prescriptions considered risky and potentially inappropriate, including high rates of concurrent prescriptions of benzodiazepines and other sedating medications. These findings highlight the need for heightened attention to safe benzodiazepine prescribing practices for homeless veterans.

(Summary submitted by Katherine A Koh, MD, MSc, Department of Psychiatry)

Ultrasound Technology Designed to Enhance the Precision of Elasticity Imaging
Acoustic Diffraction-resistant Adaptive Profile Technology (ADAPT) for Elasticity Imaging
Gu Y, Kumar V, Dayavansha EGSK, Schoen S Jr, Feleppa E [et al.], Samir AE
Published in Science Advances on 11/1/2023

Elasticity imaging is crucial for diagnosing diseases by assessing tissue mechanical properties. However, current methods face challenges in accuracy and are limited to specific regions of interest. We have developed ADAPT (Acoustic Diffraction–Resistant Adaptive Profile Technology), an ultrasound technology designed to enhance the precision of elasticity imaging. ADAPT employs the superposition of Bessel beams to create tailored, propagation-invariant acoustic beams, thereby improving image clarity and depth. This technology allows for precise modulation of wave numbers and beam multiplexing, using a single ultrasound probe to create adaptive beam profiles. Moreover, ADAPT can maintain the beam profile in lossy materials by compensating for attenuation and is compatible with different ultrasound systems.

(Summary submitted by Yuyang Gu, PhD, Department of Radiology)

Firearm Injuries Among Children and Adolescents Lead to Huge Mental and Behavioral Health Consequences
Firearm Injuries In Children And Adolescents: Health And Economic Consequences Among Survivors And Family Members
Song Z, Zubizarreta JR, Giuriato M, Koh KA, Sacks CA
Published in Health Affairs on 11/1/2023 | Press Release

Among families with employer-sponsored health insurance, firearm injuries in children and adolescents have detrimental health impacts not only on survivors but on the whole family, leading to large increases in health care spending ultimately paid for by wages and limited societal resources.

(Summary submitted by Zirui Song, MD, PhD, Department of Medicine)

Factors Identified for Increased Odds of Nonsuicidal Self-Injury in Preadolescents
Nonsuicidal Self-Injury in Preadolescents
Burke TA, Bettis AH, Walsh RFL, Levin RY, Lawrence HR [er al.], Liu RT
Published in Pediatrics on 11/2/2023

There is a dearth of national studies on sociodemographic and diagnostic predictors of preadolescent nonsuicidal self-injury (NSSI). This gap is significant given that NSSI predicts poor psychological outcomes and that early onset NSSI may predict a more severe course of self-injury. To address this gap, this study drew data from the Adolescent Brain and Cognitive Development study of 11,875 youth ages 9-10. Findings suggest preadolescents who are male, White, identify as a sexual minority, have unmarried parents, and low family income had increased odds of NSSI. NSSI was associated with numerous internalizing and externalizing disorders, greater comorbidity, and suicidal ideation.

(Summary submitted by Taylor A Burke, PhD, Department of Psychiatry)

Promising Strategy to Complement and Augment MMR Deficiency-guided Immunotherapy
ATR Inhibition Induces Synthetic Lethality in Mismatch Repair-deficient Cells and Augments Immunotherapy
Wang M, Ran X, Leung W, Kawale A, Saxena S [et al.], Zou L
Published in Genes & Development on 11/6/2023

The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells by inducing DNA damage. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors and triggers an interferon response that enhances the immune system's ability to fight cancer. Combining ATRi with an anti-PD-1 antibody works better than either alone, suggesting the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.

(Summary submitted by Mingchao Wang, PhD, Mass General Cancer Center)

Advanced Form of Meditation Impacts the Brain and is Linked to Aspects of Well-Being
Intensive Whole-brain 7T MRI Case Study of Volitional Control of Brain Activity in Deep Absorptive Meditation States
Yang WFZ, Chowdhury A, Bianciardi M, van Lutterveld R, Sparby T, Sacchet MD
Published in Cerebral Cortex on 11/6/2023 | Press Release

This study looked at an advanced state of meditation called jhanas or what our team calls advanced concentrative absorption meditation (ACAM). We aimed to understand what happens in the brain during ACAM, how it differs from regular thinking, and how this relates to the meditator’s experience. We did this by studying very detailed brain activity using advanced brain scanning technology in a skilled meditator across 27 sessions in five days. Our findings indicate that ACAM and specific features of ACAM including focus, self-perception, and joy are associated with rich patterns of brain activity. This research opens exciting possibilities for innovative therapies merging ancient meditation practices with modern neuroscience to improve health and well-being.

(Summary submitted by Matthew D Sacchet, PhD, Martinos Center for Biomedical Imaging)

Innovative Strategy to Preserve the Efficacy of Existing Antibiotics
Blue Light Potentiates Antibiotics in Bacteria via Parallel Pathways of Hydroxyl Radical Production and Enhanced Antibiotic Uptake
Leanse LG, Anjos CD, Kaler KR, Hui J, Boyd JM [et al.], Dai T
Published in Advanced Science on 11/9/2023

With the rising incidence of antibiotic resistance and the steady decline in the discovery of new antibiotics, there is a critical need to develop strategies to preserve the efficacy of existing antibiotics. We investigated the combination of antimicrobial blue light, a nonpharmacological approach, with antibiotics for a synergistically improved antimicrobial activity and/or for the preservation/potentiation of the potency of current antibiotics. Through a series of in vitro and animal studies, we successfully demonstrated the effectiveness and safety of this strategy. This research addresses, at least partially, the serious problem of emerging antibiotic resistance by providing an innovative and much-needed strategy.

(Summary submitted by Tianhong Dai, PhD, Wellman Center for Photomedicine)

Regulatory T Cells Potent Suppressors of Immune Inflammatory Response in Lungs
Regulatory T Cell-derived IL-1Ra Suppresses the Innate Response to Respiratory Viral Infection
Griffith JW, Faustino LD, Cottrell VI, Nepal K, Hariri LP [et al.], Luster AD
Published in Nature Immunology on 11/9/2023

Lung injury and respiratory failure resulting from respiratory viruses remain a major global health threat. The innate immune response to respiratory viral infection acts as a ‘double-edged sword’ by providing critical early viral control, while also being strongly associated with severe disease and death in later stages of infection. While regulatory T cell (Treg) modulation of adaptive immunity is well described, much less is known about how Tregs regulate the innate immune response. This study found that the alarmin IL-33 released in the lung following influenza infection induced Tregs to produce the IL-1 receptor antagonist (IL-1Ra) that suppressed granulocyte influx into the lung and cytokine production by innate lymphoid cells. These findings demonstrate that Tregs are potent suppressors of the innate immune inflammatory response induced by respiratory viral infection.

(Summary submitted by Andrew Luster, MD, PhD, Division of Rheumatology, Allergy and Immunology, Department of Medicine)

Proline Biosynthesis a Previously Unrecognized Major Consumer of Glutamate
Inhibition of the Proline Metabolism Rate-limiting Enzyme P5CS Allows Proliferation of Glutamine-restricted Cancer Cells
Linder SJ, Bernasocchi T, Martínez-Pastor B, Sullivan KD, Galbraith MD [et al.], Mostoslavsky R
Published in Nature Metabolism on 11/13/2023

Glutamine, a major metabolite used for protein and nucleotide synthesis as well as energy metabolism, is considered an obligate nutrient in cells. Cancer cells in particular are highly addicted, and whether they can adapt to proliferate under glutamine restricted conditions remained virtually unknown. A new study identified a novel mechanism by which cancer cells inhibited the expression of a critical enzyme in the proline synthesis pathway, P5CS, allowing cells to rewire glutamate to sustain proliferation under glutamine deprived conditions. The study highlights a potential resistance mechanism that cancer cells could acquire under nutrient stress and identifies proline biosynthesis as a previously unrecognized major consumer of glutamate.

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

Artificial Intelligence Model Accurately Read and Interpret Echocardiograms
Deep Learning-Enabled Assessment of Left Heart Structure and Function Predicts Cardiovascular Outcomes
Lau ES, Di Achille P, Kopparapu K, Andrews CT, Singh P [et al.], Ho JE
Published in Journal of the American College of Cardiology on 11/14/2023

Transthoracic echocardiogram or cardiac ultrasound is a noninvasive test to assess heart structure and function. The interpretation of echocardiograms requires significant time, resources, and expertise. Artificial intelligence has the potential to make interpretation of cardiac ultrasounds more reproducible and more widely available. We developed an artificial intelligence model to read and interpret echocardiograms using data from the MGH Echo Database. This model was able to accurately produce standard measures of heart structure and function. Those measures were able to predict future clinical outcomes. This study highlights the power of artificial intelligence methods for making echocardiogram interpretation more automated and to help advance biological discovery.

(Summary submitted by Emily S Lau, MD, MPH, Cardiology Division, Department of Medicine)

COVID Rebound More Common in People Taking Paxlovid Therapy
SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study
Edelstein GE, Boucau J, Uddin R, Marino C, Liew MY [et al.], Siedner MJ
Published in Annals of Internal Medicine on 11/14/2023 | Press Release

Our team of investigators studying acute COVID-19 infection have found that virologic rebound was more common in people taking Paxlovid therapy (21%) than those who were untreated (2%). Rebound occurred in the young and old, those with and without immunodeficiency, and across vaccination statuses. Those who rebound shed virus for an average of 14 days, versus 3 days in those who did not. Importantly, Paxlovid substantially reduces the risk of hospitalization and death in high-risk individuals with early-stage disease. This data should not deter its use but will help people who take it be aware of the frequency of rebound, so they can prepare and consider prolonged isolation if it occurs.

(Summary submitted by Mark J Siedner, MD, MPH, Infectious Disease Unit, Department of Medicine)

New Promising Thyroid Cancer Treatment
Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer
Hadoux J, Elisei R, Brose MS, Hoff AO, Robinson BG [et al.], Wirth LJ; LIBRETTO-531 Trial Investigators
Published in New England Journal of Medicine on 11/16/2023

LIBRETTO-531 is an international randomized controlled trial that studied the drug selpercatinib, which targets RET, a specific gene that is frequently mutated in a rare and aggressive type of thyroid cancer called medullary thyroid cancer (MTC). This type of cancer is more dangerous compared to other thyroid cancers. The trial found that selpercatinib performed better than the other usual treatments for MTC, such as cabozantinib or vandetanib, on all fronts; progression-free survival (PFS) was significantly longer with selpercatinib, and a higher rate of positive response to the treatment and fewer side effects were seen with selpercatinib compared to those on the other medications.

(Summary submitted by Lori J Wirth, MD, Mass General Cancer Center)

Epigenetic Regulation That Coordinates Lung Progenitor Cells’ Regenerative Responses Becomes Dysregulated in Aging
Age-associated H3K9me2 Loss Alters the Regenerative Equilibrium Between Murine Lung Alveolar and Bronchiolar Progenitors
Rowbotham SP, Pessina P, Garcia-de-Alba C, Jensen J, Nguyen Y [et al.], Kim CF
Published in Developmental Cell on 11/16/2023 

How does the lung, which must constantly repair itself, control which types of cells to make? We report that one of the annotations to the genome that switches genes off is reduced in older lungs. This alters the balance of alveolar versus bronchiolar cells, so there is less regeneration of alveolar cells. We think this may explain age-related susceptibility to lung disease like COPD and idiopathic pulmonary fibrosis (IPF), and eventually hope to find a way to rejuvenate alveolar cells to help repair injured or diseased lungs. 

(Summary submitted by Samuel P. Rowbotham, PhD, Department of Surgery) 

Drugs Affecting Ras Pathway given to Fetus May Stop the Development of VOGMs
Mutation of Key Signaling Regulators of Cerebrovascular Development in Vein of Galen Malformations
Zhao S, Mekbib KY, van der Ent MA, Allington G, Prendergast A [et al.], Kahle KT
Published in Nature Communications on 11/17/2023

To better understand how vein of Galen malformations (VOGMs), the most common and severe inborn blood vessel disorder of the brain, develop we sequenced the DNA of 310 VOGM families and studied the mutated genes. We found a high number of mutations in genes RASA1 and EPHB4, both involved in a cellular process called the Ras signaling pathway, and upon testing in mice found a second mutation during fetus development of the cells lining blood vessels may cause VOGMs by impairing the normal development of complex arteries, veins, and capillaries. This suggests drugs affecting the Ras pathway given to the fetus may stop the development of VOGMs or other similar disorders.

(Summary submitted by Kedous Mekbib, Yale School of Medicine)

Patient-reported Outcomes Associated with Better Outcomes than Tumor Markers
Patient-Reported Outcomes, Tumor Markers, and Survival Outcomes in Advanced GI Cancer
Jarnagin JX, Saraf A, Baiev I, Chi G, van Seventer EE [et al.], Parikh AR
Published in JAMA Network Open on 11/17/2023| *Summary available

We prospectively investigated the connection between early changes in patient-reported outcomes (PROs) and clinical outcomes in 159 patients with advanced gastrointestinal cancer. We found 1-month changes in PROs (including change in physical symptoms from tumor, overall mood, and quality of life due to disease/treatment effect) were associated with treatment response, progression-free survival, and overall survival. Notably, traditional tumor markers showed inconsistent associations with these outcomes. These findings underscore the importance of monitoring and addressing patients' quality of life and symptoms early in their cancer treatment, offering potential avenues for improving overall outcomes.

(Summary submitted by Anurag Saraf, MD, Department of Radiation Oncology, Brigham and Women’s Hospital)

New Small Molecule Inhibitor for Use Against Alzheimer’s Disease
Structure-Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology
Mondal P, Bai P, Gomm A, Bakiasi G, Lin CJ [et al.], Zhang C
Published in Advanced Science on 11/21/2023 | Press Release

The study provides new insights of Alzheimer's etiology and suggests our new small molecule inhibitor of HDAC6 as a potential therapeutic against Alzheimer’ disease.

(Summary submitted by Can Zhang, MD, PhD, McCance Center for Brain Health, Department of Neurology)

How a Protein Called IKAROS Organizes the Genome in Nuclear Space to Control Healthy B Cell Development
Lineage-specific 3D Genome Organization is Assembled at Multiple Scales by IKAROS
Hu Y, Salgado Figueroa D, Zhang Z, Veselits M, Bhattacharyya S [et al.], Georgopoulos K
Published in Cell on 11/22/2023 | Research Spotlight

IKAROS (Ikzf1) is one of the earliest regulators of lymphoid lineage identity. It exerts its effects in part by organizing chromatin in the nuclear space. IKAROS overcomes the insulating effects of CTCF to assemble lymphoid-specific topological domains. It assembles enhancers across great distances and intervening regions of heterochromatin and pre-configures much of the genome in the hematopoietic stem cell to enable different branches of lymphoid development. At the immunoglobulin light chain gene that spans 3 megabases, hundreds of loops anchored by IKAROS enhancers pull distant regions together to support the generation of a full repertoire of antibodies during VDJ recombination.

(Summary submitted by Katia Georgopoulos, PhD, Cutaneous Biology Research Center, Department of Dermotology)

Researchers Identify the Mutations That Drive Resistance to PI3K Inhibitors in Breast Cancer That Can Be Overcome by Next Generation Agents
Featuring Andreas Varkaris, MD, PhD and Dejan Juric, MD

PI3Kα inhibitors are approved to treat certain cancers with PIK3CA mutations, but resistance often develops during treatment. Researchers have now identified additional cancer mutations that arise to compromise the drugs’ effectiveness. In patients with advanced breast cancers, the team showed that a new class of PI3Kα inhibitors can overcome these resistance-generating mutations

New Research Reveals an Advanced Form of Meditation Impacts the Brain and is Linked to Aspects of Well-Being
Featuring Matthew D. Sacchet, PhD

Neuroimaging in an adept meditator revealed rich patterns of brain activity in specific cortical, subcortical, brainstem, and cerebellar regions associated with an advanced practice of meditation called jhana. Investigators observed correlations between brain activity during jhana and qualities such as attention, joy, mental ease, equanimity, and formlessness.

Firearm Injuries Among Children and Adolescents Lead to Huge Mental and Behavioral Health Consequences
Featuring Zirui Song, MD, PhD and Chana Sacks, MD, MPH

Firearm injuries to children and adolescents in the United States have far-reaching and profound mental and behavioral health implications, according to the findings of a Mass General-led research team. For victims and their families, the impacts include large increases in psychiatric and substance use disorders. The economy is also impacted by a significant increase in health care spending to care for firearm injury survivors and their families, the study found.

Researchers Identify a New Small Molecule Inhibitor for Use Against Alzheimer’s Disease
Featuring Can (Martin) Zhang, MD, PhD and Changning Wang, PhD

Researchers have learned more about how increased levels of an enzymatic protein called HDAC6 connects to the onset of harmful brain changes in Alzheimer’s disease (AD). In modeling studies, they identified several pathways through which drugs designed to inhibit HDAC6 activity could help—by reducing the accumulation of harmful plaques and tau, lowering inflammation and more. The findings suggest further investigation of HDAC6 inhibitors—including one developed by the research team—as potential pharmacological treatment for AD patients.

Researchers Develop New Method for Prenatal Genetic Testing
Featuring Harrison Brand, PhD and Michael E. Talkowski, PhD

Massachusetts General Hospital researchers developed a non-invasive genetic test that can screen the blood of pregnant individuals to survey all genes from the fetal genome. The method was effective at discovering new mutations that only occurred in the fetal genome. The blood test approach is potentially scalable and could offer the same genetic information that currently requires an invasive procedure such as amniocentesis.

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

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

Vote for Your Favorite Science Photo in the 2023 MGRI Image Awards

Vote for your favorite science images in the 2023 MGRI Image Awards, an up-close look at research at Massachusetts General Hospital.

World Diabetes Day 2023: Research Updates from Massachusetts General Hospital
Featuring Elaine Yu, MD, MSSC

As part of World Diabetes Day, Dr. Elaine Yu, a distinguished researcher and endocrinologist in the Endocrine Unit and the Chen Institute MGH Research Scholar for 2023-2028, shares insights from her recently published review titled “Vascular deficits contributing to skeletal fragility in type 1 diabetes.”

Congrats to the 52 Mass General Investigators Named to Clarivate Analytics’ Highly Cited Researchers List for 2023

Clarivate Analytics’ Highly Cited Researchers List is an annual report of individuals who demonstrate broad and significant influence in their fields.

Creating Microfluidic Transistors that Control the Movement of Fluids to Autonomously Execute Miniature Lab Operations
Featuring Kaustav Gopinathan and Mehmet Toner, PhD

Researchers were able to build a self-contained microfluidic circuit block that could sense, process, and controllably dispense individual particles in an automated fashion, without the use of electronic computers.

Patient Attendance and Perceived Benefits of Lifestyle Medicine Virtual Group Visits
Featuring Jacob Mirsky, MD, MA, DipABLM

A survey-based study of participants suggests that regular attendance in virtual group visits focused on lifestyle medicine are a promising approach for promoting healthy behavior changes in primary care.

Stroke-Related Visceral Alterations
Featuring Hakan Ay, MD

Researchers demonstrate that there are discrete regions of brain infarcts associated with CSAs that the patient can later develop using a mapping approach that is free from the bias of an a priori hypothesis as to any specific location. Demonstration of the existence of such regions is a step towards better understanding of the link between the brain and internal organ system dysfunction.

Prescribing of Benzodiazepines in a Homeless Veteran Population
Featuring Katherine Koh, MD, MSC

Researchers found that although homeless veterans were less likely than their housed peers to receive a benzodiazepine prescription, they were more likely to receive risky and potentially in appropriate prescriptions.

How a Protein Called IKAROS Organizes the Genome in Nuclear Space to Control Healthy B Cell Development
Featuring Katia Georgopoulos, PhD

In a new study, scientists show how a protein called IKAROS helps "weave" the genome into the correct structure required for B cell differentiation and generation of a life-saving repertoire of antibodies.