Snapshot of Science for May 2019

Welcome to our Snapshot of Science for May 2019

Welcome to the May 2019 edition of Snapshot of Science. 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:

26 new studies published in high impact journals, along with 18 summaries submitted by the research teams
8 posts from the Mass General Research Institute blog

Publications

A CONNECTION BETWEEN FRATAXIN AND OXYGEN
Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis
Ast T, Meisel JD, Patra S, Wang H, Grange RMH [et al.], Mootha VK.
Published in Cell on April 25, 2019 | *Summary available

IDENTIFYING A TARGET FOR ANTIBIOTIC RESISTANCE
Defining the Core Essential Genome of Pseudomonas Aeruginosa
Poulsen BE, Yang R, Clatworthy AE, White T, Osmulski SJ [et al.], Hung DT.
Published in PNAS on April 29, 2019 | *Summary available

UNDERSTANDING BROWN FAT ACTIVITY
Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics
Flicker D, Sancak Y, Mick E, Goldberger O, Mootha VK.
Published in Cell Reports on April 30, 2019 | *Summary available

CREATING SAFER ANGIOTENSIN RECEPTOR BLOCKERS
Reprogramming the Microenvironment with Tumor-selective Angiotensin Blockers Enhances Cancer Immunotherapy
Chauhan VP, Chen IX, Tong R, Ng MR, Martin JD [et al.], Jain RK.
Published in PNAS on April 30, 2019 | *Summary available

GENDER DIFFERENCES IN ALCOHOLISM
Alcoholism Gender Differences in Brain Responsivity to Emotional Stimuli
Sawyer KS, Maleki N, Urban T, Marinkovic K, Karson S [et al.], Oscar-Berman M.
Published in eLife on April 30, 2019 | *Summary available

ANTI-BCMA CAR-T CELL THERAPY FOR MULTIPLE MYELOMA
Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma
Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S [et al.], Kochenderfer JN.
Published in New England Journal of Medicine on May 2, 2019

IDENTIFYING CRITICAL REGIONS OF VIRAL PROTEINS IN HIV
Structural Topology Defines Protective CD8+ T Cell Epitopes in the HIV Proteome
Gaiha GD, Rossin EJ, Urbach J, Landeros C, Collins DR [et al.], Walker BD.
Published in Science on May 3, 2019 | *Summary available

ISOLATED SEVERE TRICUSPID REGURGITATION
Surgery is Not Associated with Improved Survival Compared to Medical Therapy in Isolated Severe Tricuspid Regurgitation
Axtell AL, Bhambhani V, Moonsamy P, Healy EW, Picard MH [et al.], Wasfy JH.
Published in Journal of the American College of Cardiology on May 3, 2019 | *Summary available

LIFE SATISFACTION IN CHILDREN WITH CHRONIC ILLNESS
General Health and Life Satisfaction in Children With Chronic Illness
Blackwell CK, Elliott AJ, Ganiban J, Herbstman J, Hunt K [et al.], Camargo CA Jr.
Published in Pediatrics on May 6, 2019 | *Summary available

DETERMINING THE ROLE OF STRA8 IN MEIOSIS
Meiotic Gatekeeper STRA8 Suppresses Autophagy by Repressing Nr1d1 Expression During Sermatogenesis in Mice
Ferder IC, Fung L, Ohguchi Y, Zhang X, Lassen KG [et al.], Wang N.
Published in PLOS Genetics on May 6, 2019

THE IMPORTANCE OF JOB SATISFACTION
Assessment of Job Satisfaction and Feeling Valued in Academic Medicine
Simpkin AL, Chang Y, Yu L, Campbell EG, Armstrong K [et al.], Walensky RP.
Published in JAMA Internal Medicine on May 6, 2019 | *Summary available

TARGETING THE CXCR3 CHEMOKINE SYSTEM
Intratumoral Activity of the CXCR3 Chemokine System is Required for the Efficacy of Anti-PD-1 Therapy
Chow MT, Ozga AJ, Servis RL, Frederick DT, Lo JA [et al.], Luster AD.
Published in Immunity on May 6, 2019

THE RELATIONSHIP BETWEEN PROTEINS AND CHOLESTEROL-CARRYING PARTICLES
Association of an HDL Apolipoproteomic Score with Coronary Atherosclerosis and Cardiovascular Death
Natarajan P, Collier TS, Jin Z, Lyass A, Li Y [et al.], Januzzi JL Jr.
Published in Journal of the American College of Cardiology on May 7, 2019 | *Summary available

INSIGHTS INTO GUT HEALTH FROM BACTERIAL METABOLITES
Bacteroides-Derived Sphingolipids are Critical for Maintaining Intestinal Homeostasis and Symbiosis
Brown EM, Ke X, Hitchcock D, Jeanfavre S, Avila-Pacheco J [et al.], Xavier RJ.
Published in Cell Host Microbe on May 8, 2019 | *Summary available

PINPOINTING RESISTANCE-RELATED MUTATIONS IN TB
GWAS for Quantitative Resistance Phenotypes in Mycobacterium Tuberculosis Reveals Resistance Genes and Regulatory Regions
Farhat MR, Freschi L, Calderon R, Ioerger T, Snyder M [et al.], Murray M.
Published in Nature Communications on May 13, 2019

THE IMPLICATIONS OF HEALED PLAQUES
Healed Culprit Plaques in Patients with Acute Coronary Syndromes
Fracassi F, Crea F, Sugiyama T, Yamamoto E, Uemura S [et al.], Jang IK.
Published in Journal of the American College of Cardiology on May 14, 2019 | *Summary available

HOW GLYCOSYLATION AFFECTS IMMUNODOMINANCE
Influenza Antigen Engineering Focuses Immune Responses to a Subdominant but Broadly Protective Viral Epitope
Bajic G, Maron MJ, Adachi Y, Onodera T, McCarthy KR [et al.], Schmidt AG.
Published in Cell Host Microbe on May 14, 2019

PRIMING THE TUMOR ENVIRONMENT FOR SUCCESSFUL IMMUNE CHECKPOINT THERAPY
Targeting the CBM Complex Causes Treg Cells to Prime Tumours for Immune Checkpoint Therapy
Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN [et al.], Mempel TR.
Published in Nature on May 15, 2019 | *Summary available

EVALUATING EFFICACY OF ALPELISIB FOR ADVANCED BREAST CANCER
Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S [et al.], Juric D.
Published in New England Journal of Medicine on May 16, 2019

UNDERSTANDING IMMUNE RESPONSES OF INDIVIDUALS NATURALLY IMMUNE TO TB
IFN-γ-independent Immune Markers of Mycobacterium Tuberculosis Exposure
Lu LL, Smith MT, Yu KKQ, Luedemann C, Suscovich TJ [et al.], Alter G.
Published in Nature Medicine on May 20, 2019 | *Summary available

LEVERAGING SIMILARITIES BETWEEN SIV AND HIV
The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template
Andrabi R, Pallesen J, Allen JD, Song G, Zhang J [et al.], Burton DR.
Published in Cell Reports on May 21, 2019

INSIGHTS INTO MULTI-MODAL TREATMENTS FOR LUNG CANCER
Patient-specific Tumor Growth Trajectories Determine Persistent and Resistant Cancer Cell Populations During Treatment with Targeted Therapies
Grassberger C, McClatchy DM, Geng C, Kamran SC, Fintelmann F [et al.], Paganetti H.
Published in Cancer Research on May 21, 2019 | *Summary available

BENEFITS OF EARLY HIV TREATMENT
Augmentation of HIV-specific T Cell Function by Immediate Treatment of Hyperacute HIV-1 Infection
Ndhlovu ZM, Kazer SW, Nkosi T, Ogunshola F, Muema DM [et al.], Walker BD.
Published in Science Translational Medicine on May 22, 2019 | *Summary available

GENETIC TRIGGERS FOR MITRAL VALVE PROLAPSE
Primary Cilia Defects Causing Mitral Valve Prolapse
Toomer KA, Yu M, Fulmer D, Guo L, Moore KS [et al.], Norris RA.
Published in Science Translational Medicine on May 22, 2019

THE ROLE OF NEUROINFLAMMATION IN NEGATIVE AFFECT
The Neuroinflammatory Component of Negative Affect in Patients with Chronic Pain
Albrecht DS, Kim M, Akeju O, Torrado-Carvajal A, Edwards RR [et al.], Loggia ML.
Published in Molecular Psychiatry on May 28, 2019 | *Summary available

UNDERSTANDING THE TIMING OF SEX-RELATED DIFFERENCES IN BRAIN AGING
When Does the Youthfulness of the Female Brain Emerge?
Tu Y, Fu Z, Maleki N.
Published in PNAS on May 28, 2019 | *Summary available

Summaries

Friedreich's ataxia (FRDA) is a devastating neurological disorder that results in ataxia- problems with movement and coordination- impaired speech, hearing, and vision as well as diabetes and heart muscle disease. The Mootha lab has recently discovered that frataxin, the gene whose depletion causes FRDA, is completely unnecessary in low oxygen tensions. Human cells, yeast, worms and mice that are depleted for frataxin and typically develop complications seen in FRDA thrive if they are kept in low oxygen tensions. While there is still a lot of work to be done before the results of this work can be translated into a therapy, this exciting basic research points to a profound and conserved connection between frataxin and oxygen.

(Summary submitted by Tslil Ast, PhD, Department of Molecular Biology)

The World Health Organization (WHO) has declared antibiotic resistance one of the greatest threats to human health. However, antibiotic discovery has been challenging, in part due to incomplete knowledge of the essential bacterial genes that could be targeted for antibiotic discovery. Mass General researchers and colleagues have presented a strategy for identifying these critical essential genes, focusing on the priority pathogen Pseudomonas aeruginosa, but generalizable to all pathogens. By performing genome-wide genetic selection studies on a diverse collection of clinically-isolated strains and infection-relevant growth conditions, they identified a set of core essential genes that constitute a high-priority list of candidate targets for drug discovery.

(Summary submitted by Brad Poulsen, PhD, Department of Molecular Biology)

The mitochondrial calcium uniporter is an ancient channel that mediates calcium signaling between the cytosol and mitochondria. The uniporter has been reported to have high activity in mitochondria isolated from brown fat, but the contribution of the channel to in vivo brown fat physiology has not been explored. Here, we show that complete genetic ablation of the uniporter in brown fat does not impair this tissue’s activity in vivo in mice. Unexpectedly, we also report that that cold exposure powerfully induces ATF4-dependent stress signaling in brown fat. This leads to increased circulation of the energy regulating hormones FGF21 and GDF15, suggesting a mechanism whereby brown fat activity supports systemic metabolic health.

(Summary submitted by Daniel Flicker, PhD, Department of Molecular Biology)

Cancer-associated fibroblasts (CAFs) can either inhibit or enable antitumor immunity, suggesting that they may be reprogrammed between these states. Angiotensin receptor blocker (ARB) drugs can reprogram CAFs to a quiescent state, but it is unknown whether ARBs can enhance antitumor immunity. Moreover, ARBs cause adverse effects that limit their use in cancer. We created safer ARBs by chemically linking them to a polymer that degrades selectively in the slightly acidic microenvironment of tumors but not in the neutral environment outside of tumors. This tumor selectivity makes ARBs more effective at reprogramming CAFs while eliminating their side effects. These enhanced ARBs reduce immunosuppression and improve cancer immunotherapy efficacy.

(Summary submitted by Vikash Pal Singh Chauhan, formerly of the Steele Laboratories of Tumor Biology, Department of Radiation Oncology)

In a neuroimaging study of brain activity, abstinent alcoholic men and women were compared to control groups of nonalcoholic men and women. Volunteers were shown emotionally charged images of happy, erotic, gruesome, and aversive scenes, along with neutral images, and the differences in brain responses to the emotionally charged images versus the neutral ones were then analyzed. Abstinent alcoholic men had more muted brain responses to the emotionally charged images than alcoholic women. This effect was seen in brain regions involved in memory and emotion. Consideration of such alcoholism-related gender differences offers opportunities to improve strategies for facilitating treatment.

(Summary submitted by Kayle Sawyer, PhD, Martinos Center)

Vaccine design for highly mutable pathogens is hindered by the absence of methods to reliably identify vulnerable sites for immune targeting. In this study, we utilized a new approach that applies network theory to HIV protein structure to identify regions critical to the structural integrity of viral proteins. Mutation of amino acids at important network positions disproportionately impaired viral replication. Moreover, targeting of networked amino acids by cytotoxic T cells was strongly associated with natural control of HIV infection. This approach reveals a mechanistic basis for successful immune control of HIV and a means to design rational T cell-based vaccines.

(Summary submitted by Gaurav Gaiha, MD, Department of Gastroenterology)

Tricuspid valve regurgitation is a disorder in which the valve between the two right heart chambers does not close properly, causing blood to flow backwards into the heart’s upper right chamber. Over time, this can lead to heart failure and patients with this condition have a high risk of death. When tricuspid valve regurgitation occurs alone (i.e. no other heart valves are abnormal), the role of surgical intervention to repair or replace the valve is unclear. In this study, researchers compare a matched sample of patients with isolated tricuspid regurgitation and demonstrate that there is no difference in long-term survival regardless of whether patients underwent surgery or medical therapy alone.

(Summary submitted by Andrea Axtell, MD, Department of Surgery, Division of Cardiac Surgery)

Dr Carlos Camargo (Mass General Emergency Medicine) and colleagues investigated children's general health and life satisfaction in the context of chronic illness. Briefly, more than 1,100 caregivers completed validated instruments to help assess their children’s health. As expected, children with chronic illness had worse general health than those without illness. By contrast, children with chronic illness had similar levels of life satisfaction. The authors concluded that “although children with chronic illness have lower parent-reported general health, their life satisfaction appears comparable with that of peers without chronic illness.” The study suggests that chronic illnesses do not preclude children from leading happy and satisfying lives.

(Summary submitted by Carlos Camargo, MD, DrPH, Department of Emergency Medicine)

With evidence suggesting faculty are increasingly dissatisfied and burnt-out in their current work environment, researchers at Mass General sought to determine some of the key variables that influence job satisfaction. They found significant association with feeling valued by leadership, feeling treated with respect, and feeling that the work environment was social and supportive. The good news is there is much that is amenable to change, which may not require large sums of money to fix. This study suggests wise investment would be in social capital—promoting a sense of value and respect in the work environment, identifying and eliminating sources of discrimination, and intentionally boosting collegiality.

(Summary submitted by Arabella Simpkin, MD, MMSc, Department of Medicine)

THE RELATIONSHIP BETWEEN PROTEINS AND CHOLESTEROL-CARRYING PARTICLES
Association of an HDL Apolipoproteomic Score With Coronary Atherosclerosis and Cardiovascular Death
Natarajan P, Collier TS, Jin Z, Lyass A, Li Y [et al.], Januzzi JL Jr.
Published in Journal of the American College of Cardiology on May 7, 2019

Cholesterol, packaged in complex particles, are importing predictors for heart attack risk and are drug targets for reducing heart attack risk. In addition to conveying cholesterol, these complex particles have diverse functions which may also influence heart attack risk. Drs. Natarajan, Januzzi, and colleagues profiled several proteins that determine the functions of cholesterol-carrying particles in nearly 1,000 patients who underwent cardiac catheterization at Mass General. They observed that these proteins independently influence the likelihood of developing plaque in heart arteries as well as future risk of cardiovascular death after plaque is present in the heart arteries. Whether novel therapies that alter these proteins can reduce cardiovascular risk requires future study.

(Summary submitted by Pradeep Natarajan, MD, MMSc, Deprtment of Caridology)

The human intestinal tract contains trillions of microorganisms and their metabolic products that are necessary for health. Changes in this microbial environment contribute to disorders such as inflammatory bowel diseases (IBD), but our understanding of how these changes influence disease is incomplete due to limited knowledge of the breadth of metabolites produced by microbes in the gut. Brown et al. discovered that the gut bacterial species Bacteroides produces a greater variety of metabolites known as sphingolipids than previously recognized. The authors demonstrated that an absence of these sphingolipids promotes intestinal inflammation in mice and is associated with IBD in humans, suggesting that bacterial sphingolipids are important for maintaining intestinal health.

(Summary submitted by Theresa Reimels, PhD, Center for Computational and Integrative Biology)

Healed plaques, the result of prior plaque destabilization and subclinical thrombosis, were frequently found in patients who suffered from sudden cardiac death. However, in vivo data are lacking. Using OCT, we found healed plaque in more than one quarter of culprit lesions in 376 acute coronary syndrome (ACS) patients. Healed plaques at the culprit lesion identify a subset of patients with greater systemic inflammation and plaque vulnerability. This group of patients with ACS may benefit from a more aggressive secondary prevention aiming at suppression of inflammation and platelet activity.

(Summary submitted by IK Jang, MD, PhD, Department of Caridology)

While therapies that harness the power of the immune system against cancer have made remarkable progress against certain types of tumors, they still remain ineffective in most cancer patients. This study from the Center for Immunology and Inflammatory Diseases describes a method of reprogramming the regulatory T cells that usually suppress immune responses into inflammatory cells that not only permit but also intensify an antitumor immune response.

(Summary submitted by Thorsten Mempel, MD, PhD, Center for Immunology and Inflammatory Diseases)

Once known as “consumption,” Mycobacterium tuberculosis (Mtb) was discovered in 1882, when 1 in 7 Americans were killed by this bacteria. While less common today in the US, Mtb is still a leading cause of deaths worldwide. When used together, diagnostics and antibiotics result in a marked reduction in disease. Emerging data now point to the presence of a population that resists infection despite heavy disease exposure. Here, the authors demonstrate the presence of a robust immune response to Mtb in these “resistors” that are otherwise invisible to traditional diagnostics. Understanding these individuals’ immune responses may be key to developing next-generation vaccines and eradicating this global killer.

(Summary submitted by Lenette Lu, MD, PhD, Division of Infectious Diseases)

Targeted therapies have significantly advanced the treatment of advanced stage lung cancer patients in the last decade, though the eventual development of tumor resistance remains a key obstacle. A multi-disciplinary team from the Mass General has investigated the dynamics of this process using mathematic models describing the observed tumor growth trajectories in lung cancer patients. The results give insight into the temporal evolution of resistance and the size of resistant cell populations throughout treatment. This can give important clues how to integrate these new therapies into multi-modality treatments, such as multi-agent schedules or combinations of targeted agents and radiotherapy.

(Summary submitted by Clemens Grassberger, PhD, Department of Radiation Oncology)

The World Health Organization (WHO) recommends starting HIV treatment as soon as possible after diagnosis because early treatment results in reduced morbidity, mortality and reduced risk of transmission. However, before this study, it was not known whether early treatment initiation could result in the generation of immune responses against HIV. The study found that early therapy gives rise to superior and more durable immune responses against HIV infection compared to when treatment is delayed. These findings open up the possibility of designing new therapeutic interventions that can boost pre-existing responses to levels adequate for achieving sustained HIV suppression in the absence of therapy.

(Summary submitted by Zaza Ndhlovu, PhD, Ragon Institute)

THE ROLE OF NEUROINFLAMMATION IN NEGATIVE AFFECT
The Neuroinflammatory Component of Negative Affect in Patients with Chronic Pain
Albrecht DS, Kim M, Akeju O, Torrado-Carvajal A, Edwards RR [et al.], Loggie ML.
Published in Molecular Psychiatry on May 28, 2019

Chronic pain patients who also suffer from depression report significantly higher pain severity and lower quality of life, and respond less to treatments. Thus, understanding the biological mechanisms of depression may ultimately help patients with chronic pain and related conditions. Studying patients with chronic back pain with advanced brain imaging techniques, Albrecht and colleagues observed that the more severe the depression, the higher the inflammation, as well as the changes in neural communication, in brain regions involved in emotion regulation. This study identifies neuroinflammation as a potential therapeutic target for depression, including in chronic pain patients.

(Summary submitted by Marco Loggia, PhD, Martinos Center)

UNDERSTANDING THE TIMING OF SEX-RELATED DIFFERENCES IN BRAIN AGING
When Does the Youthfulness of the Female Brain Emerge?
Tu Y, Fu Z, Maleki N.
Published in PNAS on May 28, 2019

The female adult brain has been shown to have a lower metabolic brain age compared with the male brain at the same chronological age. But when does the difference between men and women in brain aging emerge? This study aimed to determine whether slower aging in female vs. male brain traces back to differences in cortical development during childhood and adolescence and found an opposite pattern during brain development. Understanding the timing of the emergence of sex-related differences in brain aging may hold clues to the mechanisms involved that may eventually allude to means to boost brain’s youthfulness and protect against aging associated neurological disorders.

(Summary submitted by Nasim Maleki, PhD, Department of Psychiatry)

Blog Posts

How a Global Partnership Could Save the Lives of Women and Children in Africa
Featuring Salome Maswime, PhD, MBCHB

Young women and expecting mothers are one of the most-affected groups, and research has shown that HIV/AIDS can significantly increase the chances of both maternal deaths and still births. One Massachusetts General Hospital Discovery Foundation Fellow has witnessed the disease’s impact first-hand and is determined to help and give back to her community.

Ladies: If Your Moisturizers Seem Overpriced, It’s Because They Probably Are, Science Finds
Featuring Maryanne Senna, MD

There are day creams, night creams, eye creams, serums, scrubs, face masks and more all marketed toward women, and most come with a hefty price tag. But are the ingredients and packaging really that expensive?

How Changing Laws on Cannabis are Impacting Pediatric Patient Visits to the Emergency Room
Featuring Yih-Chieh Chen, MD, and Jean E. Klig, MD

Researchers from the Mass General for Children recently published a review paper taking a detailed look at cannabis-related emergency department (ED) visits by pediatric patients.

Could This Short Question Help Women at Risk for Intimate Partner Violence?
Featuring Anand K. Narayan, MD, PhD, and Constance D. Lehman, MD, PhD

Mass General researchers were able to identify women at risk for intimate partner violence by adding a screening question to mammography intake forms.

Why We Need More Diversity in Genetics Research
Featuring Alicia Martin, PhD, and Mark Daly, PhD

A team of Mass General researchers recently published a perspective piece that shed light on the fact that majority of publicly available genetic data belongs to people of European ancestry, meaning the medical advances made using European genetic data are less informative to non-Europeans.

Five Things to Know: Nature Article Advocates for Open Data Sharing in Science

The state of science today is divided: some believe all data should be publicly available to promote collaboration, while others believe it is safest to hold onto their findings to protect themselves from competitors who may use them as a foundation for a new, more exciting study. Nature recently published an article explaining the importance and benefits of openly sharing scientific data. Here are five things to know.

Mass General Research Roundup for May 2019

Experiencing adverse events at a young age may increase risk of mental health disorder, evaluating the price of skincare products for women and a new model for cancer treatments.

Study Finds A Connection Between What You Buy for Lunch at Work and Your Health
Featuring Anne Thorndike, MD, MPH

Sometimes making your lunch seems like a hassle, so buying a slice of pizza or a sandwich can be an easy solution. But those purchases can add up after a while and have the potential to affect not only your wallet, but your health as well.

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Snapshot of Science for May 2019