Snapshot of Science for October 2020

Welcome to our Snapshot of Science for October 2020

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:

34 new studies published in high impact journals, along with 28 summaries submitted by the research teams
22 new research-related press releases from the Mass General Public Affairs office
7 posts from the Mass General Research Institute blog

Publications

BRAIN AGE AS A DEMENTIA BIOMARKER
Association of Sleep Electroencephalography-based Brain Age Index with Dementia
Ye E, Sun H, Leone MJ, Paixao L, Thomas RJ [et al.], Westover MB
Published in JAMA Network Open on September 28, 2020 | *Summary available | Press release

SUPPRESSING T CELL RESPONSES IN THE LUNG
Interleukin-33 Activates Regulatory T Cells to Suppress Innate γδ T Cell Responses in the Lung
Faustino LD, Griffith JW, Rahimi RA, Nepal K, Hamilos DL [et al.], Luster AD
Published in Nature Immunology on September 28, 2020 | *Summary available

OVERCOMING TREATMENT RESISTANCE IN RET FUSION-POSITIVE NSCLC
Mechanisms of Resistance to Selective RET Tyrosine Kinase Inhibitors in RET-Fusion-Positive Non-Small Cell Lung Cancer
Lin JJ, Liu SV, McCoach CE, Zhu VW, Tan AC [ et al.], Gainor JF
Published in Annals of Oncology on September 28, 2020 | *Summary available

NOVEL MODIFIERS OF HUNTINGTON'S PATHOGENESIS
Histone Deacetylase Knockouts Modify Transcription, CAG Instability and Nuclear Pathology in Huntington Disease Mice
Kovalenko M, Erdin S, Andrew MA, St Claire J, Shaughnessey M [et al.], Wheeler VC
Published in eLife on September 29, 2020 | *Summary available

TRIPLET THERAPY FOR ADVANCED BREAST CANCER
Phase 1b Dose Escalation/Expansion Trial of Ribociclib in Combination with Everolimus and Exemestane in Postmenopausal Women with HR+, HER2- Advanced Breast Cancer
Bardia A, Modi S, Oliveira M, Cortés J, Campone M [et al.], Chavez-MacGregor M
Published in Clinical Cancer Research on September 30, 2020 | *Summary available

BRAIN PENETRANT ACE INHIBITORS AND AT1R BLOCKERS MAY PROTECT AGAINST ALZHEIMER'S
Aβ-accelerated Neurodegeneration Caused by Alzheimer's-associated ACE Variant R1279Q is Rescued by Angiotensin System Inhibition in Mice
Cuddy LK, Prokopenko D, Cunningham EP, Brimberry R, Song P [et al.], Vassar R
Published in Science Translational Medicine on September 30, 2020

ALTERATIONS OF THE TUMOR MICROENVIRONMENT OF GLIOBLASTOMA
Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma
Li M, Kirtane AR, Kiyokawa J, Nagashima H, Lopes A [et al.], Cahill DP
Published in Cancer Research on September 30, 2020 | *Summary available

PROTECTIVE EFFICACY OF SIV VACCINE-ELICITED ANTIBODIES
Passive Transfer of Vaccine-Elicited Antibodies Protects Against SIV in Rhesus Macaques
Alter G, Yu WH, Chandrashekar A, Borducchi EN, Ghneim K [et al.], Barouch DH
Published in Cell on October 1, 2020 | *Summary available

CHARACTERIZING ELECTRODERMAL ACTIVITY
Point Process Temporal Structure Characterizes Electrodermal Activity
Subramanian S, Barbieri R, Brown EN
Published in PNAS on October 2, 2020 | *Summary available

IMMUNE CHECKPOINT INHIBITORS AND RISK OF CARDIOVASCULAR EVENTS
Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque
Drobni ZD, Alvi RM, Taron J, Zafar A, Murphy SP [et al.], Neilan TG
Published in Circulation on October 2, 2020 | *Summary available

HIGH RESOLUTION MAP FOR ORGANOID MODEL OF EMBRYOGENESIS
Parallel Single-Cell RNA-Seq and Genetic Recording Reveals Lineage Decisions in Developing Embryoid Bodies
Kim IS, Wu J, Rahme GJ, Battaglia S, Dixit A [et al.], Bernstein BE
Published in Cell Reports on October 6, 2020 | *Summary available

PEER COMPARISON COULD IMPROVE EHR DOCUMENTATION
Association of Peer Comparison Emails with Electronic Health Record Documentation of Cancer Stage by Oncologists
Sinaiko AD, Barnett ML, Gaye M, Soriano M, Mulvey T, Hochberg E
Published in JAMA Network Open on October 6, 2020 | *Summary available

LIPOPROTEIN(A) AND LPA GENETIC RISK SCORE FOR HEART DISEASE PREDICTION
Clinical Utility of Lipoprotein(a) and LPA Genetic Risk Score in Risk Prediction of Incident Atherosclerotic Cardiovascular Disease
Trinder M, Uddin MM, Finneran P, Aragam KG, Natarajan P
Published in JAMA Cardiology on October 6, 2020 | *Summary available | Press Release

DEEP MACHINE LEARNING TO RECONSTRUCT BOLD SIGNAL
Reconstructing Lost BOLD Signal in Individual Participants Using Deep Machine Learning
Yan Y, Dahmani L, Ren J, Shen L, Peng X [et al.], Liu H
Published in Nature Communications on October 7, 2020 | *Summary available

COPING SKILLS FOR CAREGIVERS OF STEM CELL TRANSPLANT RECIPIENTS
Enhanced Coping and Self-efficacy in Caregivers of Stem Cell Transplant Recipients: Identifying Mechanisms of a Multimodal Psychosocial Intervention
Jacobs JM, Nelson AM, Traeger L, Waldman L, Nicholson S [et al.], El-Jawahri A
Published in Cancer on October 7, 2020 | *Summary available

ASSESSING BARRIERS TO BEHAVIORAL HEALTH CARE
Assessment of Behavioral Health Services Use Among Low-Income Medicare Beneficiaries After Reductions in Coinsurance Fees
Fung V, Price M, Nierenberg AA, Hsu J, Newhouse JP, Cook BL
Published in JAMA Network Open on October 8, 2020 | *Summary available

CAUSE-SPECIFIC MORTALITY IN NAFLD
Mortality in Biopsy-confirmed Nonalcoholic Fatty Liver Disease: Results from a Nationwide Cohort
Simon TG, Roelstraete B, Khalili H, Hagström H, Ludvigsson JF
Published in Gut on October 9, 2020

NOTCH1 GENE AMPLIFICATION PROMOTES CANCER
NOTCH1 Gene Amplification Promotes Expansion of Cancer Associated Fibroblast Populations in Human Skin
Katarkar A, Bottoni G, Clocchiatti A, Goruppi S, Bordignon P [et al], Dotto GP.
Published in Nature Communications on October 12, 2020

SUSTAINED SMOKING CESSATION COUNSELING VS SHORTER TERM COUNSELING
Effect of Sustained Smoking Cessation Counseling and Provision of Medication vs Shorter-term Counseling and Medication Advice on Smoking Abstinence in Patients Recently Diagnosed with Cancer
Park ER, Perez GK, Regan S, Muzikansky A, Levy DE [et al], Ostroff JS
Published in JAMA on October 13, 2020 | *Summary available | Press Release

TERT ANALYSIS FOR DIAGNOSIS AND MONITORING OF GLIOMAS
TERT Promoter Mutation Analysis for Blood-based Diagnosis and Monitoring of Gliomas
Muralidharan K, Yekula A, Small JL, Rosh ZS Kang KM [et al], Carter BS.
Published in Clinical Cancer Research on October 13, 2020 | *Summary available

COVID-19 PATIENT OUTCOME PREDICTION
Integrative Analysis for COVID-19 Patient Outcome Prediction
Chao H, Fang X, Zhang J, Homayounieh F, Arru CD [et al.], Yan P.
Published in Medical Image Analysis on October 13, 2020

TRIALS SHOW NEOADJUVANT CHEMOTHERAPY WORKS TO STOP RECURRENT PANCREATIC CANCER
Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma
Chawla A, Qadan M, Castillo CF, Wo JY, Allen JN [et al], Ferrone CR.
Published in Annals of Surgery on October 19, 2020

PHENOTYPING REFINES CARDIOVASCULAR RISK IN YOUNG ADULTS
Comprehensive Metabolic Phenotyping Refines Cardiovascular Risk in Young Adults
Murthy VL, Reis JP, Pico AR, Kitchen R, Lima JAC [et al], Shah RV.
Published in Circulation on October 19, 2020 | *Summary available

SUBSTANCE P RELEASE TRIGGERS IMMUNE RESPONSE TO ALLERGENS
Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens
Perner C, Flayer CH, Zhu X, Aderhold PA, Dewan ZNA [et al], Sokol CL.
Published in Immunity on October 21, 2020 | *Summary available | Press release

IMAGING THE PATIENT-CLINICIAN INTERACTION
Dynamic Brain-to-brain Concordance and Behavioral Mirroring as a Mechanism of the Patient-clinician Interaction
Ellingsen DM, Isenburg K, Jung C, Lee J, Gerber J [et al], Napadow V.
Published in Science Advances on October 21, 2020 | *Summary available | Press Release

TOCILIZUMAB IN HOSPITALIZED COVID-19 PATIENTS
Efficacy of Tocilizumab in Patients Hospitalized with Covid-19
Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L [et al], Mansour MK.
Published in New England Journal of Medicine on October 21, 2020 | *Summary available | Press Release

WOUND DRESSING FOR TOPICAL DRUG ABSORPTION
A Simple, Inexpensive and Reproducible Wound Dressing to Optimize Topical Drug Absorption Following Ablative Fractional Laser-assisted Drug Delivery
Buta MR, Nathan NR, Bojovic B.
Published in Journal of the American Academy of Dermatology on October 21, 2020 | *Summary available

MYOCARDIAL INJURY IN PREGNANT PATIENTS WITH COVID-19
New-Onset Myocardial Injury in COVID-19 Pregnant Patients: A Case Series of 15 Patients
Mercedes BR, Serwat A, Naffaa L, Ramirez N, Khalid F [et al.] Karout L.
Published in American Journal of Obstetrics and Gynecology on October 21, 2020 | *Summary available

METHOD FOR WHOLE BRAIN AND LESION SEGMENTATION IN MS
A Contrast-Adaptive Method for Simultaneous Whole-Brain and Lesion Segmentation in Multiple Sclerosis
Cerri S, Puonti O, Meier DS, Wuerfel J, Mühlau M [et al.], Leemput KV.
Published in NeuroImage on October 22, 2020

LIVER FUCTION MARKERS AND COLORECTAL CANCER RISK
Circulating Liver Function Markers and Colorectal Cancer Risk: A Prospective Cohort Study in the UK Biobank
He MM, Fang Z, Hang D, Wang F, Polychronidis G [et al], Song M.
Published in International Journal of Cancer on October 22, 2020 | *Summary available

MIR-30D REGULATES CARDIAC REMODELING
Mir-30d Regulates Cardiac Remodeling by Intracellular And Paracrine Signaling
Li J, Salvador AM, Li G, Valkov N, Ziegler O, Yeri AS [et al], Das S.
Published in Circulation Research on October 22, 2020 | *Summary available

ATRIAL FIBRILLATION DUE TO INHIBITION OF CSK
Ibrutinib-Mediated Atrial Fibrillation Due to Inhibition of CSK
Xiao L, Salem JE, Clauss S, Hanley, Bapat A [et al], Milan DJ.
Published in Circulation on October 23, 2020 | *Summary available

AI-BASED RISK SCORE PREDICTS PROGNOSIS OF OUTPATIENTS WITH POSSIBLE COVID-19
CoVA: An Acuity Score for Outpatient Screening that Predicts COVID-19 Prognosis
Sun H, Jain A, Leone MJ, Alabsi HS, Brenner LN [et al], Westover MB.
Published in Journal of Infectious Diseases on October 24, 2020 | *Summary available

RADIOTHERAPY VS SURGERY FOR EARLY STAGE LUNG CANCER
Stereotactic Body Radiotherapy Versus Delayed Surgery for Early-stage Non-small-cell Lung Cancer
Mayne NR, Lin BK, Darling AJ, Raman V, Patel DC [et al.], Yang CJ.
Published in Annals of Surgery on October 14, 2020 | *Summary available

Publication Summaries

Dementia is a growing cause of disability and loss of independence in the elderly yet remains largely under-diagnosed. Identification of individuals at risk and early detection of dementia could help maximize the therapeutic benefits of medicines and other interventions. Our sleep EEG-based Brain Age Index (BAI), derived using a machine learning approach, shows promise as a biomarker of progressive brain processes which ultimately result in dementia. In the future, we expect that measuring the BAI will become a routine part of primary care to objectively assess whether one's sleep is healthy and normal for age. BAI has potential as a screening tool for the presence of underlying neurodegenerative disease and monitoring of disease progression.

(Summary submitted by Elissa Ye, MS, Department of Neurology)

Regulatory T cells are well known to suppress adaptive immune responses. We describe an unexpected function of regulatory T cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. We found that a subset of lung regulatory T cells is activated by the alarmin interleukin-33, which is released by the epithelium in response to injury. These activated regulatory T cells suppress the innate γδ T cell response, resulting in less eosinophil and neutrophil recruitment into the lung, which is beneficial to the host in reducing inflammation induced by allergens.

(Summary submitted by Andrew D. Luster, MD, PhD, Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Department of Medicine)

OVERCOMING RESISTANCE IN RET FUSION-POSITIVE NSCLC
Mechanisms of Resistance to Selective RET Tyrosine Kinase Inhibitors in RET-Fusion-Positive Non-Small Cell Lung Cancer
Lin JJ, Liu SV, McCoach CE, Zhu VW, Tan AC [ et al.], Gainor JF
Published in Annals of Oncology on September 28, 2020

Patients with advanced non-small cell lung cancer (NSCLC) harboring RET fusions can now be treated with a selective RET inhibitor (pralsetinib or selpercatinib). While these RET inhibitors have shown good efficacy, acquired resistance may emerge and result in disease progression in most patients. In this study, we elucidated mechanisms of resistance to RET-selective inhibitors in NSCLC by analyzing post-treatment tumor or plasma biopsies. We demonstrated that RET solvent front mutations, while recurrent, occurred at a low frequency, and that the majority of resistance to RET inhibitors may be caused by RET-independent mechanism such as MET amplification. These findings help inform the development of therapeutic strategies to overcome RET inhibitor resistance in patients.

(Summary submitted by Jessica Jiyeong Lin, MD, Mass General Cancer Center, Division of Hematology/Oncology, Department of Medicine)

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by inheriting a "CAG" repeat mutation in the HTT gene. CAG repeat lengthening over an individual's lifetime triggers toxic processes, ultimately destroying medium spiny neurons (MSNs) in the striatum, a brain area that controls movement. Using HD mice, this study shows that eliminating the Hdac2 gene in MSNs profoundly alters the genes that are expressed, reverses a subset of gene expression alterations that are due to the CAG mutation and moderately slows CAG lengthening. The results provide insight into gene regulation in neurons susceptible in HD and into ways in which steps in the HD pathogenic process can be modulated.

(Summary submitted by Vanessa Wheeler, MD, Department of Neurology, Center for Genomic Medicine)

Endocrine therapy plus CDK4/6 inhibitors have become a preferred treatment option for HR+, HER2- advanced breast cancer; However, endocrine resistance often develops. Preclinical work suggests that inhibiting CDK4/6 activity or the mTOR signaling pathway may delay the development of endocrine resistance. This hypothesis was tested in this dose escalation/expansion phase Ib trial of triplet therapy with ribociclib, everolimus, and exemestane. The study demonstrated that the triplet therapy was generally well tolerated. Preliminary evidence of antitumor activity of the triplet combination was observed, highlighting the role of combined CDK 4/6 and PI3K/mTOR blockade for patients with metastatic breast cancer.

(Summary submitted by Aditya Bardia, MD, MPH, Mass General Cancer Center, Division of Hematology/Oncology, Department of Medicine )

In lethal brain cancer glioblastoma, nicotinamide phosphoribosyltransferase (NAMPT) drives the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a co-factor critical in cellular metabolism. NAMPT inhibitors thus can inhibit glioblastoma, but how they impact the tumor microenvironment has been unknown. We show that injections of micro-particles loaded with NAMPT inhibitors release the drug at the tumor, which then increases the expression of immune checkpoint protein PD-L1 and recruits CD8+ T cells and macrophages in the tumor. Such modification allows immune checkpoint blockade to be effective in a mouse glioblastoma model, providing a new therapeutic approach that combines therapeutics directed at metabolism and immunity.

(Summary submitted by Hiroaki Wakimoto, MD, PhD, Department of Neurosurgery, Brain Tumor Stem Cell Lab)

While neutralizing antibodies have long been considered essential for protection against HIV, emerging data point to protection from infection in the absence of neutralization. To test this, we isolated plasma-antibodies from vaccinated non-human primates, which generated killer, non-neutralizing antibodies and asked if these antibodies could still provide protection against SIV, the monkey analogue of HIV. Passive transfer of purified immunoglobulin G (IgG) from the vaccinated animals with the most robust protective signatures provided significant protection against SIVmac251 challenges in naive recipient rhesus macaques. Thus, for the first time, we show that passive transfer of purified "functional," non-neutralizing antibodies from vaccinated macaques can protect naive animals against SIVmac251 challenges. This points to a broader role for antibodies in protection against HIV.

(Summary submitted by Summary submitted by Rachel Leeson, MS, Ragon Institute of MGH, MIT and Harvard)

CHARACTERIZING ELECTRODERMAL ACTIVITY
Point Process Temporal Structure Characterizes Electrodermal Activity
Subramanian S, Barbieri R, Brown EN
Published in PNAS on October 2, 2020

Electrodermal activity (EDA), a read-out of the body's "fight or flight" response, measures the skin's microscopic sweating activity. Interest has grown in using EDA to track conditions such as stress levels, sleep quality and emotional states. Based on 50 years of sweat gland research, we hypothesized that EDA should follow an inverse Gaussian statistical model. In an analysis of EDA recorded in 11 healthy volunteers during quiet wakefulness, our model accurately characterized sweat activity. Our findings can improve the accuracy and reliability of EDA analysis—essential requirements for use of EDA in medical and personalized health care settings.

(Summary submitted by Sandya Subramanian, PhD, Department of Anesthesia, Critical Care and Pain Medicine)

Immune checkpoint inhibitors are now one of the new pillars of cancer care. These drugs leverage the immune system to target cancer cells. However, these same checkpoints targeted for cancer are also key negative regulators of atherosclerosis in basic and animal studies. Prior to this report, there were no clinical data testing the effect of immune checkpoint inhibitors on atherosclerosis and atherosclerosis-related cardiovascular events. We found that immune checkpoint inhibitors were associated with a >3-fold higher rate of atherosclerotic plaque progression and a 3-fold higher risk for atherosclerotic cardiovascular events. These findings highlight the importance of increased awareness of atherosclerotic cardiovascular events with immune checkpoint inhibitors and cardiovascular risk factor optimization prior to, during and after treatment with immune checkpoint inhibitors.

(Summary submitted by Zsofia Dora Drobni, MD, PhD, Division of Cardiology, Department of Medicine)

The development of a multicellular organism from a single cell, the fertilized zygote, is a complex yet tightly controlled process. This process gives rise to many cell types with drastically different morphology and function. Understanding how all the different cell types in a multicellular organism arise throughout development is critical to further our understanding of how cellular identities are established. We designed and implemented a novel cellular "barcode" system, allowing us to trace the origin of cells. We used these cellular barcodes, along with single-cell RNA sequencing and computational analysis, to trace the trajectories of the different cell types present in the embryoid body: an in vitro model of mouse development. We confirmed previous lineage relationships, while also uncovering novel links specifically in the establishment of germ cells—the cells from which sperm and egg cells ultimately arise.

(Summary submitted by Gilbert Joseph Rahme, PhD, MSc, Department of Pathology)

Recently the Mass General Cancer Center sought to change how physicians documented cancer staging in the electronic health record (EHR) in order to improve patient access to clinical trials and to gather more accurate information. We used "peer comparisons," where physicians are presented with their performance relative to their colleagues in order to motivate behavior change. After six months, the documentation practice increased by 69%. This result persisted for six months after the last report, suggesting physicians incorporated the documentation into their regular practice. Peer comparisons are a promising strategy to help health systems leverage the EHR to improve clinical quality of care.

(Summary submitted by Anna Doar Sinaiko, PhD, Harvard T.H. Chan School of Public Health)

Lipoprotein(a) is similar to the low-density lipoprotein, which is more commonly known as “LDL.” Elevated blood levels of lipoprotein(a) and LDL are strongly associated with increased risk of heart attacks and strokes. However, lipoprotein(a) is more heritable and receives much less attention than LDL. Our study sought to understand whether genetics could refine the predicted risk of cardiovascular disease associated with directly measured lipoprotein(a). We found that direct measurement of lipoprotein(a) or a genetic test for lipoprotein(a) were able to predict an individual’s risk of a major cardiovascular event among white Europeans similarly. Our findings also suggest that testing for elevated lipoprotein(a) is most useful for individual's at borderline-to-intermediate risk of cardiovascular disease.

(Summary submitted by Mark Trinder, MSc, Centre for Heart Lung Innovation, The University of British Columbia)

The signal in functional magnetic resonance imaging (fMRI) is prone to interference from various sources. As a result can get distorted or suffer a signal loss in specific brain regions, especially in patients with metal implants. We developed a machine learning method to reconstruct the signal in compromised regions. This model learns the patterns of brain activity from a training dataset and applies these learned principles to recover fMRI signal in compromised data. This method can recover lost signals in patients implanted with deep brain stimulator. Such an approach is promising for fMRI studies of clinical cohorts, where signal distortion and signal loss are common.

(Summary submitted by Hesheng Liu, MD, Martinos Center for Biomedical Imaging, Department of Radiology)

Caregivers of patients undergoing bone marrow transplant (BMT) experience a lot of stress as they provide the primary source of support for patients with blood cancers while navigating the difficulty of the BMT course. Our team has developed a brief psychosocial intervention (BMT-CARE) to help caregivers prepare for the transplant process and promote their effective coping with the patient’s illness course and recovery period. In a randomized controlled trial, BMT-CARE was shown to be effective at improving the quality of life and reducing depression and anxiety symptoms for caregivers of patients undergoing BMT. We have shown in this study that improvement in caregivers’ coping skills and self-efficacy is the primary mechanism by which BMT-CARE improved caregiver outcomes.

(Summary submitted by Areej El-Jawahri, MD, Mass General Cancer Center, Division of Hematology/Oncology, Department of Medicine)

Medicare beneficiaries historically paid higher fees for behavioral health care (including mental health and substance use services) than other types of care. Between 2010-2014, in an effort to introduce parity, Medicare reduced coinsurance fees for behavioral health care to that of medical and surgical care. We studied the impact of this policy change on low-income beneficiaries with serious mental illness. We found that although out-of-pocket costs for behavioral health visits decreased significantly over this time period, only about half of beneficiaries had a behavioral health visit and the policy change was not associated with increases in use. Although the policy change improved affordability of care, other policy efforts are needed to reduce barriers to care.

(Summary submitted by Vicki C. Fung, PhD, Mongan Institute for Health Policy Center, Department of Medicine)

Smoking can diminish the effectiveness of cancer treatment, as well as quality of life, for people with all forms of cancer. But many cancer centers have not fully implemented evidence-based tobacco treatment into routine care. In our study, we found recently diagnosed cancer patients who smoke are significantly more likely to quit and remain tobacco-free if they receive sustained telephone counseling and medication support, compared to brief telephone counseling support. This is the first trial to find an effective tobacco treatment integrated into cancer care. However, the generalizability of the study findings is uncertain and requires further research.

(Summary submitted by Elyse R. Park, PhD, MPH, Mass General Tobacco Research & Treatment Center and Mass General Cancer Center)

Diagnosis of glioma typically requires neurosurgical biopsy. Liquid biopsy is the principle of sampling genetic information found in biofluids like the blood as a non-invasive alternative to tissue biopsy. We developed a blood-based test for the TERT promoter mutation, a prevalent driver in gliomas, and showed its utility in the diagnosis and monitoring of the disease in a cohort of 157 patient samples. Blood-based glioma detection has been challenging in the past and this advancement is a significant step forward for glioma diagnosis and monitoring of the clinical course.

(Summary submitted by Leonora Balaj, PhD, Department of Neurosurgery)

In this study we examined the relationship between circulating markers of metabolism (“metabolites”) and markers of cardiovascular risk in a young adult population (mean age around 32 years) in the CARDIA study. The results suggest that specific profiles of metabolism are related to long-term risk of cardiovascular disease over two decades, across sex and race. These same patterns replicate in a large group of individuals from the Framingham Heart Study, with greatest importance in the younger individuals within Framingham. These results emphasize that early alterations in metabolism are especially important in young adulthood, before traditional risk factors are used to assess risk. Apart from studies in younger individuals to clarify the underlying mechanisms of cardiovascular risk, these findings highlight the importance of cardiometabolic health early in adulthood.

(Summary submitted by Ravi Shah, MD, Cardiovascular Research Center, Department of Medicine)

Allergens induce robust immune responses, but how they are detected by the body has been a mystery. Unlike bacterial and viral pathogens, allergens do not appear to directly activate immune cells. In this study, we found that protease allergens directly activate sensory neurons to induce an itch response and release the neuropeptide Substance P. This Substance P interacts with neighboring dendritic cells through their expression of MRGPRA1 inducing the migration of allergic-skewing dendritic cells to the draining lymph node where they initiate T cell activation and the allergic immune response. Thus, sensory neurons connect allergen exposure with immune activation.

(Summary submitted by Caroline Sokol, MD, PhD, Allergy and Clinical Immunology Unit, Center for Immunology and Inflammatory Diseases, Department of Medicine)

IMAGING THE PATIENT-CLINICIAN INTERACTION
Dynamic Brain-to-brain Concordance and Behavioral Mirroring as a Mechanism of the Patient-Clinician Interaction
Ellingsen DM, Isenburg K, Jung C, Lee J, Gerber J [et al], Napadow V.
Published in Science Advances on October 21, 2020 | Press Release

The relationship created between a patient and their physician can powerfully impact clinical outcomes. This relationship, often considered an intangible “art-of-medicine”, has largely eluded scientific inquiry. To better understand the brain circuitry involved in the patient/clinician relationship, this study used hyperscanning fMRI—wherein two MRI scanners, one for the patient and another for the clinician, were synchronized and collected brain fMRI data while the clinician interacted with their patient via live video during a pain treatment. The authors found that reduced pain was linked with dynamic coupling in brain activity between patients and clinicians. These findings suggest a brain-behavioral mechanism for therapeutic alliance and pain reduction.

(Summary submitted by Vitaly Napadow, PhD, LicAc, Center for Integrative Pain NeuroImaging, Martinos Center for Biomedical Imaging)

COVID-19 patients are susceptible to respiratory failure caused by lung inflammation, leading to intubation, mechanical ventilation and often death. A hyperinflammatory state known as “cytokine storm” and a protein called interleukin-6 are postulated to contribute to this downward spiral. We led a seven-hospital randomized, double-blind, placebo-controlled trial in which patients received standard care plus treatment with either tocilizumab, a blocker of the interleukin-6 receptor, or placebo. Contrary to our original hypothesis, we found that the administration of tocilizumab had no impact on patients' risk of progressing to respiratory failure. Patients who received tocilizumab were just as likely to require intubation or to die as those who did not receive the drug. The findings raise important questions about the current understanding of COVID-19 and suggest new approaches to the design of therapies and clinical trials for this disease.

(Summary submitted by John Stone, MD, MPH, Rheumatology Unit, Department of Medicine)

Laser-assisted drug delivery (LADD) is a promising therapy for different skin conditions such as scarring and age-related changes. LADD utilizes an ablative fractional laser to create microchannels in skin that help remodel it and improve delivery of topical agents directly to targets in various skin layers. A dry gauze dressing placed on laser-treated skin has significant absorptive potential and may withdraw topical agents from the skin—a counterproductive effect. We describe a simple, affordable, and readily adoptable dressing that fosters maximum interaction between topicals and microchannels, facilitating even delivery and optimizing therapeutic effects during the 48-hour window when these channels are still patent.

(Summary submitted by Martin Buta, MD, MBA, Division of Plastic and Reconstructive Surgery, Department of Surgery)

MYOCARDIAL INJURY IN PREGNANT PATIENTS WITH COVID-19
New-Onset Myocardial Injury in COVID-19 Pregnant Patients: A Case Series of 15 Patients.
Mercedes BR, Serwat A, Naffaa L, Ramirez N, Khalid F [et al.] Karout L.
Published in American Journal of Obstetrics and Gynecology on October 21, 2020

Our team illustrated the clinical, laboratory and radiological findings, and outcome of fifteen pregnant women with COVID-19 who developed cardiac injury with decreased ventricular function. Overall, all patients were severely ill requiring intensive care at the hospital, and around 87% needed intubation. All patients had elevated blood levels of cardiac injury markers and low left heart pumping function. Furthermore, 60% of patients delivered their infants prematurely due to their unstable clinical statuses and 13.3% of mothers died due to arrhythmic complications. Half of the delivered infants were low for birth weight and 35.7% needed intensive neonatal care.

(Mohamad Kassab, MD, Cardiovascular Research Center, Department of Medicine)

Despite the close link between the liver and gut, how liver function may influence colorectal cancer (CRC) risk in the general population remains unclear. In this large prospective cohort of 375,693 participants in the UK Biobank, we found that circulating levels of alanine transaminase, aspartate transaminase, total bilirubin, gamma glutamyltransferase, total protein and albumin, largely within the normal range, were inversely associated with CRC risk. The associations appeared stronger for proximal colon cancer than distal colon cancer and rectal cancer, but consistent for early-, mid-, and late-onset CRC. Our findings support a potential link between liver function and CRC and may spur future research on the gut–microbiota–liver axis.

(Summary submitted by Mingyang Song, MD, ScD, Clinical and Translational Epidemiology Unit, Department of Medicine)

RNA molecules found in the blood have found use as markers of disease severity and outcomes. In this study, we show that microRNA-30d is acutely increased in heart muscle cells in response to stress signals, such as lack of blood flow in a heart attack, but decrease over time, correlating with worsening heart function and increased scarring. Maintaining high levels of mIR-30d in mice models protects the heart muscle cells from cell death and can signal other heart cells such as fibroblasts to reduce scar formation after the heart attack. This study demonstrates a functional role for blood RNAs in addition to their role as markers of disease, and treatments that target miR-30d and the signals it regulates may provide new therapies in heart failure patients.

(Saumya Das, MD, PhD, Division of Cardiology, Department of Medicine)

Ibrutinib, the first FDA approved Bruton’s tyrosine kinase (BTK) inhibitor, has revolutionized the treatment for B cell cancers, but is unexpectedly associated with a 10-fold increased rate of atrial fibrillation (AFib) that is the common reason for its discontinuation. In order to understand if ibrutinib causes AFib through its on-target effect on BTK or another target, we performed a combination of studies in mice and human, chemoproteomic analysis and pharmacovigilance database. Our studies demonstrated that c-terminal src kinase (CSK) is the likely AFib target for ibrutinib. Our discovery has important implications for future development of BTK inhibitors that avoid CSK inhibition may also avoid proarrhythmic side effects.

(Ling Xiao, PhD, Cardiovascular Research Center, Department of Medicine)

AI-BASED RISK SCOER PREDICTS PROGNOSIS OF OUTPATIENT WITH POSSIBLE COVID-19
CoVA: An Acuity Score for Outpatient Screening that Predicts COVID-19 Prognosis
Sun H, Jain A, Leone MJ, Alabsi HS, Brenner LN [et al], Westover MB.
Published in Journal of Infectious Diseases on October 24, 2020

Early during the pandemic, we recognized the need for a method to identify outpatients at greatest risk of hospitalization, critical illness or death. We and an interdisciplinary team designed the artificial intelligence-based COVID-19 Acuity Score (CoVA), using information on more than 9,000 adult outpatients seen in Mass General’s respiratory illness clinics and emergency department. In a subsequent prospective validation group of more than 2,000 outpatients, CoVA demonstrated excellent predictive performance. Among 30 predictors, the top five were age, diastolic blood pressure, blood oxygen saturation, COVID-19 testing status and respiratory rate. Our hope is that CoVA will be useful in the current and future surges, when rapid clinical assessments are critical.

(Summary submitted by Haoqi Sun, PhD, Department of Neurology and Clinical Data Animation Center)

During the COVID-19 pandemic, in areas with a high number of coronavirus cases, guidelines have recommended that patients with early-stage lung cancer consider delaying treatment with surgery by at least 3 months. Alternatively, prompt treatment with stereotactic body radiotherapy (SBRT), instead of surgery, has also been recommended. However, it is unknown which strategy is better. We evaluated the difference in survival between patients who underwent "early" SBRT (within 1 month of diagnosis) versus "delayed" surgery (surgery performed 3-4 months after diagnosis). We found that delayed surgery was associated with better survival when compared to early treatment with SBRT.

(Chi-Fu Jeffrey Yang, MD, Division of Thoracic Surgery, Department of Surgery)

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Snapshot of Science for October 2020