Snapshot of Science for September 2019

Here's a quick look at publications in high impact journals from investigators at the Massachusetts General Hospital Research Institute.

CREATING A LIBRARY FOR THE MICROBIOME
A Library of Human Gut Bacterial Isolates Paired with Longitudinal Multiomics Data Enables Mechanistic Microbiome Research
Poyet M, Groussin M, Gibbons SM, Avila-Pacheco J, Jiang X [et al.], Xavier RJ.
Published in Nature Medicine on September 2, 2019

STUDYING THE EFFECTS OF SACUBITRIL-VALSARTAN IN PATIENTS WITH HFrEF
Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment with Cardiac Structure and Function in Patients with Heart Failure with Reduced Ejection Fraction
Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS [et al.], Solomon SD.
Published in JAMA on September 2, 2019 | *Summary available below

MECHANISMS THAT CURB UNWANTED RNA EDITING
CRISPR DNA Base Editors with Reduced RNA Off-target and Self-editing Activities
Grünewald J, Zhou R, Iyer S, Lareau CA, Garcia SP [et al.], Joung JK.
Published in Nature Biotechnology on September 2, 2019

KEEPING NT-proPNB LOW TO REDUCE RISK OF HEART FAILURE
Natriuretic Peptide Response and Outcomes in Chronic Heart Failure with Reduced Ejection Fraction
Januzzi JL Jr, Ahmad T, Mulder H, Coles A, Anstrom KJ [et al.], O'Connor CM.
Published in Journal of the American College of Cardiology on September 3, 2019 | *Summary available below

FLUORESCENCE LIFETIME IMAGING COULD IMPROVE TUMOR DETECTION
Fluorescence Lifetime-based Tumor Contrast Enhancement Using an EGFR Antibody Labeled Near Infrared Fluorophore
Pal R, Kang H, Choi HS, Kumar ATN.
Published in Clinical Cancer Research on September 3, 2019

EXPLORING NEW TARGETS FOR ALZHEIMER'S THERAPEUTICS
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ [et al.] Tanzi RE.
Published in Neuron on September 4, 2019

NEW DONOR ORGAN PRESERVATION TECHNIQUE TRIPLES THE SHELF LIFE OF HUMAN LIVERS
Supercooling Extends Preservation Time of Human Livers
de Vries RJ, Tessier SN, Banik PD, Nagpal S, Cronin SEJ [et al.], Uygun K.
Published in Nature Biotechnology on September 9, 2019 | *Summary available below

BLOOD BIOPSIES COULD PROVIDE MORE INFORMATION THAN INVASIVE TUMOR BIOPSIES
Liquid Versus Tissue Biopsy for Detecting Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers
Parikh AR, Leshchiner I, Elagina L, Goyal L, Levovitz C [et al.], Corcoran RB.
Published in Nature Medicine on September 9, 2019 | *Summary available below

LACK OF SLEEP MAY INCREASE RISK OF A HEART ATTACK
Sleep Duration and Myocardial Infarction
Daghlas I, Dashti HS, Lane J, Aragam KG, Rutter MK [et al.], Vetter C.
Published in Journal of the American College of Cardiology on September 10, 2019 | *Summary available below

EXAMINING THE UNDERLYING MECHANISMS OF SYNAPTIC VESICLE RELEASE
A Hyperactive Form of unc-13 Enhances Ca2+ Sensitivity and Synaptic Vesicle Release Probability in C. Elegans
Li L, Liu H, Hall Q, Wang W, Yu Y [et al.], Kaplan JM.
Published in Cell Reports on September 10, 2019

GENDER IDENTITY CONVERSION THERAPY AND ADULT MENTAL HEALTH OUTCOMES
Association Between Recalled Exposure to Gender Identity Conversion Efforts and Psychological Distress and Suicide Attempts Among Transgender Adults
Turban JL, Beckwith N, Reisner SL, Keuroghlian AS.
Published in JAMA Psychiatry on September 11, 2019 | *Summary available below

IDENTIFYING PATIENTS THAT COULD BENEFIT FROM TAVR
Ventricular Stroke Work and Vascular Impedance Refine the Characterization of Patients with Aortic Stenosis
Ben-Assa E, Brown J, Keshavarz-Motamed Z, de la Torre Hernandez JM, Leiden B [et al.], Edelman ER.
Published in Science Translational Medicine on September 11, 2019 | *Summary available below

HOW WHITE MATTER IS AFFECTED IN SCHIZOPHRENIA
White Matter Abnormalities Across the Lifespan of Schizophrenia: a Harmonized Multi-site Diffusion MRI Study
Cetin-Karayumak S, Di Biase MA, Chunga N, Reid B, Somes N [et al.], Kubicki M.
Published in Molecular Psychiatry on September 11, 2019 | *Summary available below

INSIGHTS INTO CDKL5 DEFICIENCY DISORDER
Aberrant Mitochondrial Function in Patient-derived Neural Cells from CDKL5 Deficiency Disorder and Rett Syndrome
Jagtap S, Thanos JM, Fu T, Wang J, Lalonde J [et al.], Perlis RH.
Published in Human Molecular Genetics on September 13, 2019 | *Summary available below

EXAMINING CORRELATIONS BETWEEN SLEEP TIMING AND OBESITY RISK IN ADOLESCENTS
Chronotype, Social Jet Lag, and Cardiometabolic Risk Factors in Early Adolescence
Cespedes Feliciano EM, Rifas-Shiman SL, Quante M, Redline S, Oken E, Taveras EM.
Published in JAMA Pediatrics on September 16, 2019 | *Summary available below

THE EVOLUTION OF THE HUMAN HEART
Selection of Endurance Capabilities and the Trade-off Between Pressure and Volume in the Evolution of the Human Heart
Shave RE, Lieberman DE, Drane AL, Brown MG, Batterham AM [et al.], Baggish AL.
Published in PNAS on September 16, 2019 | *Summary available below

REDUCING FALSE POSITIVES THROUGH IDENTIFICATION OF HOTSPOTS IN CANCER
Passenger Hotspot Mutations in Cancer
Hess JM, Bernards A, Kim J, Miller M, Taylor-Weiner A [et al.], Getz G.
Published in Cancer Cell on September 16, 2019 | *Summary available below

HOW BRAIN TUMOR CELLS COMMUNICATE WITH NORMAL CELLS
Glioblastoma-associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21
Abels ER, Maas SLN, Nieland L, Wei Z, Cheah PS [et al.], Breakefield XO.
Published in Cell Reports on September 17, 2019 | *Summary available below

DETERMINING THE ROLE OF CTCF IN GENOMICS
Epigenome Editing Strategies for the Functional Annotation of CTCF Insulators
Tarjan DR, Flavahan WA, Bernstein BE.
Published in Nature Communications on September 18, 2019

DEFINING STAGES OF CELL GROWTH IN TENDONS
A Distinct Transition from Cell Growth to Physiological Homeostasis in the Tendon
Grinstein M, Dingwall HL, O'Connor LD, Zou K, Capellini TD, Galloway JL.
Published in eLife on September 19, 2019 | *Summary available below

THE STIGMA OF MENTAL ILLNESS IN UGANDA
Portrayals of Mental Illness, Treatment, and Relapse and their Effects on the Stigma of Mental Illness: Population-based, Randomized Survey Experiment in Rural Uganda
Rasmussen JD, Kakuhikire B, Baguma C, Ashaba S, Cooper-Vince CE [et al.], Tsai AC.
Published in PLOS Medicine on September 20, 2019 | *Summary available below

COMPARING TAVR AND SAVR IN LOW-RISK PATIENTS
Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients
Kolte D, Vlahakes GJ, Palacios IF, Sakhuja R, Passeri JJ [et al.], Elmariah S.
Published in Journal of the American College of Cardiology on September 24, 2019

SEX DIFFERENCES IN CARDIOVASCULAR DISEASE
Sex Differences in Circulating Biomarkers of Cardiovascular Disease
Lau ES, Paniagua SM, Guseh JS, Bhambhani V, Zanni MV [et al.], Ho JE.
Published in Journal of the American College of Cardiology on September 24, 2019 | *Summary available below

VACCINE AMPLIFICATION AGAINST INFLUENZA
Germline-encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response Against Influenza Virus
Sangesland M, Ronsard L, Kazer SW, Bals J, Boyoglu-Barnum S [et al.], Lingwood D.
Published in Immunity on September 25, 2019 | *Summary available below

ALTERNATE DOSING STRATEGIES FOR ANTIANGIOGENIC THERAPY
Bevacizumab Reduces Permeability and Concurrent Temozolomide Delivery in a Subset of Patients with Recurrent Glioblastoma
Gerstner E, Emblem KE, Chang K, Vakulenko-Lagun B, Yen YF [et al.], Batchelor T.
Published in Clinical Cancer Research on September 26, 2019 | *Summary available below

APALUTAMIDE COULD REDUCE RISK OF DEATH IN PROSTATE CANCER
Apalutamide and Overall Survival in Non-metastatic Castration-resistant Prostate Cancer
Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA [et al.], Smith MR.
Published in Annals of Oncology on September 27, 2019

Publication Summaries
STUDYING THE EFFECTS OF SACUBITRIL-VALSARTAN IN PATIENTS WITH HFrEF
Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment with Cardiac Structure and Function in Patients with Heart Failure with Reduced Ejection Fraction
Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS [et al.], Solomon SD.
Published in JAMA on September 2, 2019

Sacubitril/valsartan (also known as Entresto) is a popular drug for treatment of heart failure. Though associated with significant improvement in heart failure prognosis, the mechanism of benefit from the drug remained uncertain. After initiation of sacubitril/valsartan in patients with heart failure, significant improvement in heart size and function was observed, which continued to improve over 12 months. These results strongly suggest the reason why sacubitril/valsartan reduces heart failure risk so substantially is due to its ability to significantly improve heart function.

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

Publication Summaries

Data have shown that elevated concentrations of NT-proBNP are associated with a higher risk for complications from heart failure, which suggests that NT-proBNP might be used as a barometer for heart failure status during treatment. The GUIDE-IT trial reduction in NT-proBNP after heart failure treatment was associated with a 64% reduction in death, and a 76% reduction in risk for death or heart failure hospitalization. Patients with lower NT-proBNP concentrations after treatment also had better quality of life. These results all indicate the importance of getting the NT-proBNP value as low as possible after heart failure treatment.

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

The time a donor organ can stay alive outside the human body is very limited, which makes transplantation a race against the clock. Extending preservation would have many important benefits and can be achieved by lowering the storage temperature from the conventional four degrees Celsius. However, the water inside organs freezes at subzero temperatures which causes severe injury. We developed a technique called supercooling which completely prevents ice formation during storage. With this technique, we, for the first time, stored human donor organs below the freezing point and successfully rewarmed them, showing that this method can be used to triple the preservation duration of human donor livers.

(Summary submitted by Reinier J. de Vries, PhD, Department of Surgery, Center for Engineering in Medicine)

This is the largest study directly comparing liquid biopsies to standard tumor biopsies in gastrointestinal cancer patients developing drug resistance. A liquid biopsy is a novel method for sampling tumors with a blood draw. We demonstrated that in 80% of patients, liquid biopsies revealed alterations associated with drug resistance not identified through standard tissue biopsies. In the blood, they also found patients developed not just one, but many resistance mechanisms. No one tumor lesion captured all the resistance mechanisms found in the blood, highlighting the ability of the blood to provide a more complete picture than a single, invasive tissue biopsy.

(Summary submitted by Aparna Parikh, MD, Mass General Cancer Center and Division of Hematology/Oncology)

Researchers have long known that sleeping too little or too much is correlated with a higher risk for heart attack, but a cause-and-effect relationship has been unclear. Using data from over 600,000 research participants, we found the strongest evidence to date for a cause-and-effect relationship between sleeping less than 7 hours per night and increased risk for heart attack. Importantly, healthy sleep duration was beneficial regardless of your inherited genetic risk for heart attack. This work highlights the key role of sleep in heart health and adds further evidence to the importance of sleep in maintaining a healthy lifestyle.

(Summary submitted by Iyas Daghlas, MD, Department of Neurology)

Gender identity conversion efforts (GICE) refer to psychological attempts to change a person’s gender identity from transgender to cisgender. This study utilized the largest survey of transgender people to date to examine associations between exposure to GICE and mental health outcomes among transgender people in the U.S. We found that 19.6% of transgender individuals who had ever spoken to a professional about their gender identity had been exposed to GICE. Lifetime exposure to GICE was associated with severe psychological distress in the past month and lifetime suicide attempts. These results support policy statements from several professional organizations, including the American Medical Association, The American Psychiatric Association and The American Academy of Child & Adolescent Psychiatry, which have discouraged GICE.

(Summary submitted by Jack Turban, MD, Department of Psychiatry)

Transcatheter aortic valve replacement (TAVR) is a treatment for patients with aortic stenosis (narrow aortic valve), which reduces the transvalvular pressure gradient; however, only some patients experience improved quality of life after the procedure. To understand how valvular, ventricular and systemic vascular conditions contribute to improvements after TAVR, we studied 70 patients undergoing the procedure. Patients with lower preprocedural vascular impedance and higher left ventricular stroke work had greater improvements in quality of life after TAVR. This suggests that analyzing valve, ventricle, and arterial system hemodynamics could identify patients likely to benefit from TAVR and inform the timing of the intervention.

(Summary submitted by Eyal Ben-Assa, MD, Division of Cardiology within the Department of Medicine)

In this paper we analyzed large, retrospective diffusion MR datasets collected in 13 centers around the world, and across the lifespan of 1200 patients with schizophrenia and matched controls between 14 and 65 years of age. This study was made possible by the in-house development of unique, innovative methods of diffusion imaging data harmonization and an active collaboration between several institutions across the globe. The results are the most robust to date, demonstrating that white matter in schizophrenia is affected across all stages of the disease, and that patients’ brains undergo maturational and degenerative processes that differ from those seen in healthy populations.

(Summary submitted by Marek Kubicki, MD, PhD, Department of Psychiatry)

We developed a cellular model of CDKL5 deficiency disorder (CDD), a rare cause of intellectual disability often accompanied by epilepsy, using cells from a patient with the disease. We found abnormalities in mitochondria, the part of the cells responsible for generating energy. Understanding these abnormalities may ultimately allow researchers to find new treatments for children with this disease.

(Summary submitted by Roy H. Perlis, MD, Department of Psychiatry, Center for Quantitative Health and the Center for Genomic Medicine)

We conducted an observational study of 804 adolescents using data from wrist monitors, questionnaires and body measurements. We found that adolescent girls, but not boys, had bigger waistlines and greater fat mass associated with going to bed and waking up later and greater social jet lag, due to later sleep timing on weekends versus weekdays, independent of sleep duration and other lifestyle factors. The findings suggest that obesity prevention efforts should consider regular patterns of sleep and wake times, in addition to more and better-quality sleep.

(Summary submitted by Elsie M. Taveras, MD, MPH, Department of Pediatrics, Mass General Hospital for Children)

We wanted to know if the human heart adapted for endurance physical activity (EPA) like the hearts of chimpanzees and gorillas adapted for resistance physical activities (RPAs). We specifically tested if volume-adapted hearts are less able to cope with high pressures during RPAs, while pressure-adapted hearts are less able to cope with the high volumes that accompany EPAs. In aggregate, our data confirm that the human heart has evolved to facilitate EPA and that the type of stress the human heart experiences determines the way in which it remodels over relatively short periods of time.

(Summary submitted by Aaron L. Baggish, MD, Department of Cardiology, Department of Medicine)

Over time, humans acquire often-innocuous genetic mutations via ubiquitous mutational processes (i.e., sunlight exposure, or normal cellular aging), with some regions of the genome being more susceptible than others. Yet, computational models seeking to identify cancer-causing genes do not account for these background mutations and thus misidentify innocuous, or “passenger,” mutations as the cancer-causing “drivers.” In this paper we more precisely model the occurrence of these background mutations at the finest resolution––the base pair. This model reduced the number of misidentified genes by 97%, ensuring higher confidence that only true “driver” genes are identified and potentially reducing wasted resources on researching mutated genes that do not drive cancer.

(Summary submitted by Mendy Miller, PhD, Broad Institute)

We found that brain tumor cells communicate with surrounding normal brain cells by transfer of micro RNAs within a living brain. This type of RNA is involved in repression of messenger RNA, which forms proteins, leading to reduced levels of certain proteins and changes in cellular functions. The tumor cells use small membrane sacs (extracellular vesicles) to transfer miRNA-21 to microglia. Microglia are immune cells in the brain involved in sensing danger, defending the brain and maintaining brain homeostasis. By transferring miRNA-21 from tumor cells to microglia, tumor cells reprogram microglia cells so that they support growth of the tumor instead of fighting it.

(Summary submitted by Erik Abels, Department of Neurology)

Tendons grow into highly organized extracellular matrix structures that connect muscle to bone and facilitate movement. Previous research has focused on tendon matrix growth and maturation, but less is known about the cells that build and reside within the matrix. Using a mouse model, we identified a distinct shift from high to low cell division rates that coincides with matrix expansion and a loss of regenerative capacity. Surprisingly, we detected mitotic activity in adult and aged tendons, suggesting the presence of resident tendon progenitors. Together, this work highlights the importance in defining stages of cell growth and physiological maintenance and has implications for tendon repair treatments.

(Summary submitted by Jenna Galloway, PhD, Center for Regenerative Medicine, Department of Medicine)

Mental illness stigma is a fundamental barrier to improving mental health worldwide. The extent to which mental illness is perceived as treatable may have an important role in reducing the stigma associated with it. However, evidence to support this hypothesis has been derived exclusively from high-income countries. We conducted a survey experiment in rural Uganda using vignettes containing varying portrayals of successful mental health treatment. Contrary to findings in the U.S., this study found that portrayals of mental illness, regardless of symptom description or treatment efficacy, resulted in an overwhelmingly large proportion of stigmatizing responses. Engaging local etiologies, making treatment more accessible and understanding how mental illness shapes social relationships might be important avenues of research to explore.

(Summary submitted by Alexander Tsai, MD, PhD, Department of Psychiatry and Division of Global Psychiatry)

We sought to study why heart disease differs in men and women. Using data from 7,184 participants in the Framingham Heart Study (54% women), we examined differences in cardiovascular biomarkers (substances found in the bloodstream) between men and women. Of the biomarkers studied, 86% were significantly different between men and women. We further showed that hormone status explained some but not all of the differences. These findings may help us better understand the causes of heart disease that are unique to men and women.

(Summary submitted by Jennifer E. Ho, MD, Division of Cardiology within the Department of Medicine)

Effective vaccines elicit protective antibodies against incoming pathogens. However, influenza virus resists traditional vaccine approaches because the responding antibodies often engage non-conserved viral features, hence the need for seasonal vaccination. We found that the human antibody repertoire utilizes a specific antibody gene that naturally endows for targeting solutions against a conserved site of vulnerability on influenza. Using a mouse vaccine model engineered to recapitulate human antibody responses, we demonstrate that an influenza vaccine nanoparticle selectively amplifies this gene-endowed antibody response, providing vaccine-protection against divergent influenza strains. This vaccine principle could therefore enable the elicitation of broadly protective antibodies in humans.

(Summary submitted by Daniel Lingwood, PhD, Infectious Disease Unit and the Ragon Institute of MGH, MIT, and Harvard)

ALTERNATE DOSING STRATEGIES FOR ANTI-ANGIOGENIC THERAPY
Bevacizumab Reduces Permeability and Concurrent Temozolomide Delivery in a Subset of Patients with Recurrent Glioblastoma
Gerstner E, Emblem KE, Chang K, Vakulenko-Lagun B, Yen YF [et al.], Batchelor T.
Published in Clinical Cancer Research on September 26, 2019

Targeting tumor blood vessels is an attractive treatment strategy in glioblastoma (GBM) because these cancers are characterized by a very abnormal, inefficient blood supply. However, anti-angiogenic therapy has not lived up to expectation for unclear reasons so we sought to elucidate how bevacizumab, an anti-angiogenic agent, modulates GBM vasculature and the impact those vascular changes have on concomitant chemotherapy delivery in patients with recurrent GBM. We found that bevacizumab decreased tumor penetration of chemotherapy by decreasing vascular permeability, thus, decreasing the efficacy of combination anti-angiogenic therapy and chemotherapy. These results suggest we need to find alternate dosing strategies for anti-angiogenic therapy when used in combination with chemotherapy.

(Summary submitted by Elizabeth R. Gerstner, MD, Department of Neurology and Mass General Cancer Center)

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Snapshot of Science for September 2019

Publication Summaries