Snapshot of Science for February 2019

Welcome to our Snapshot of Science for February 2019

Welcome to the February 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 16 summaries submitted by the research teams
8 posts from the Mass General Research Institute blog

Publications

UNDERSTANDING THE MECHANISMS BEHIND TUMOR PROGRESSION
A Code of Mono-phosphorylation Modulates the Function of RB
Sanidas I, Morris R, Fella KA, Rumde PH, Boukhali M [et al.], Dyson NJ.
Published in Molecular Cell on January 30, 2019 | *Summary available

USING ANTI-FIBROTIC DRUGS TO TREAT PATIENTS WITH METASTATIC BREAST CANCER
Blocking CXCR4 Alleviates Desmoplasia, Increases T-Lymphocyte Infiltration, and Improves Immunotherapy in Metastatic Breast Cancer
Chen IX, Chauhan VP, Posada J, Ng MR, Wu MW [et al.], Jain RK.
Published in PNAS on January 30, 2019 | *Summary available

COMPARING OUTCOMES OF REPAIRED ABDOMINAL AORTIC ANEURYSMS
Open Versus Fenestrated Endovascular Repair of Complex Abdominal Aortic Aneurysms
O'Donnell TFX, Boitano LT, Deery SE, Schermerhorn ML, Schanzer A [et al.], Patel VI.
Published in Annals of Surgery on February 1, 2019 | *Summary available

USING URINE-BASED TUBERCULOSIS SCREENING TOOL FOR PATIENTS WITH HIV
Cost-effectiveness of Urine-based Tuberculosis Screening in Hospitalised Patients with HIV in Africa: A Microsimulation Modelling Study
Reddy KP, Gupta-Wright A, Fielding KL, Costantini S, Zheng A [et al.], Walensky RP.
Published in The Lancet Global Health on February 1, 2019 | *Summary available

INCREASED SYNAPTIC PRUNING LINKED TO SCHIZOPHRENIA
Increased Synapse Elimination by Microglia in Schizophrenia Patient-derived Models of Synaptic Pruning
Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM [et al.], Perlis RH.
Published in Nature Neuroscience on February 4, 2019 | *Summary available

NEW STUDY IDENTIFIES CELLS THAT REGULATE FEAR RESPONSES
Dorsolateral Septum Somatostatin Interneurons Gate Mobility to Calibrate Context-specific Behavioral Fear Responses
Besnard A, Gao Y, TaeWoo Kim M, Twarkowski H, Reed AK [et al.], Sahay A.
Published in Nature Neuroscience on February 4, 2019 | *Summary available

UNDERSTANDING THE RELATIONSHIP BETWEEN TB AND HIV
HIV-1 and SIV Infection Are Associated with Early Loss of Lung Interstitial CD4+ T Cells and Dissemination of Pulmonary Tuberculosis
Corleis B, Bucsan AN, Deruaz M, Vrbanac VD, Lisanti-Park AC [et al.], Kwon DS.
Published in Cell Reports on February 5, 2019 | *Summary available

TESTING POTENTIAL TREATMENTS FOR PROSTATE CANCER
Addition of Radium-223 to Abiraterone Acetate and Prednisone or Prednisolone in Patients with Castration-resistant Prostate Cancer and Bone Metastases (ERA 223): A Randomised, Double-blind, Placebo-controlled, Phase 3 Trial
Smith M, Parker C, Saad F, Miller K, Tombal B [et al.], Higano C.
Published in The Lancet Oncology on February 6, 2019

HOW GENETICS INFLUENCE ALZHEIMERS
Effects of Species-Specific Genetics on Alzheimer's Mouse Models
Hyman B, Tanzi RE.
Published in Neuron on February 6, 2019

NOVEL BIOPROBES FOR SEQUENTIAL CELL TRACKING
Lysosome-targeted Bioprobes for Sequential Cell Tracking from Macroscopic to Microscopic Scales
Park GK, Lee JH, Levitz A, El Fakhri G, Hwang NS [et al.], Choi HS.
Published in Advanced Materials on February 10, 2019 | *Summary available

IMPROVING THE FUNCTION OF CRISPR-CAS12A ENZYMES
Engineered CRISPR-Cas12a Variants with Increased Activities and Improved Targeting Ranges for Gene, Epigenetic and Base Editing
Kleinstiver BP, Sousa AA, Walton RT, Tak YE, Hsu JY [et al.], Joung JK.
Published in Nature Biotechnology on February 11, 2019 | *Summary available

USING BONE MARROW TO ENHANCE T CELL REGENERATION
An Injectable Bone Marrow-like Scaffold Enhances T Cell Immunity After Hematopoietic Stem Cell Transplantation
Shah NJ, Mao AS, Shih TY, Kerr MD, Sharda A [et al.], Scadden DT.
Published in Nature Biotechnology on February 11, 2019

INVESTIGATING THE MECHANISMS BEHIND HOMEOSTASIS
YAP1-LATS2 Feedback Loop Dictates Senescent or Malignant Cell Fate to Maintain Tissue Homeostasis
He C, Lv X, Huang C, Hua G, Ma B [et al.], Wang C.
Published in EMBO Reports on February 12, 2019 | *Summary available

A NEW APPROACH TO PREVENT CANCER IN CHRONIC INFLAMMATION
IL-33/Regulatory T Cell Axis Triggers the Development of a Tumor-promoting Immune Environment in Chronic Inflammation
Ameri AH, Moradi Tuchayi S, Zaalberg A, Park JH [et al.], Demehri S.
Published in PNAS on February 12, 2019 | *Summary available

MONITORING TUMOR EVOLUTION IN RESPONSE TO TREATMENT
Experimental and Computational Analyses Reveal Dynamics of Tumor Vessel Cooption and Optimal Treatment Strategies
Voutouri C, Kirkpatrick ND, Chung E, Mpekris F, Baish JW [et al.], Jain RK.
Published in PNAS on February 12, 2019

POOR SLEEP LINKED TO HIGHER RISK OF HEART DISEASE
Sleep Modulates Haematopoiesis and Protects Against Atherosclerosis
McAlpine CS, Kiss MG, Rattik S, He S, Vassalli A [et al.], Swirski FK.
Published in Nature on February 13, 2019 | *Summary available

EXPLORING TREATMENT STRATEGIES FOR COGNITIVE DEFICITS DUE TO CHEMOTHERAPY
Pharmacologic Management of Cognitive Impairment Induced by Cancer Therapy
Karschnia P, Parsons MW, Dietrich J.
Published in The Lancet Oncology on February 20, 2019

NEW AVENUES TO IMPROVE STROKE RECOVERY
Glucocorticoids Regulate Bone Marrow B Lymphopoiesis After Stroke
Courties G, Frodermann V, Honold L, Zheng Y, Herisson FE [et al.], Nahrendorf M.
Published in Circulation Research on February 20, 2019 | *Summary available

COMPARING THERAPIES FOR BODY DYSMORPHIC DISORDER
Efficacy and Posttreatment Effects of Therapist-delivered Cognitive Behavioral Therapy vs Supportive Psychotherapy for Adults with Body Dysmorphic Disorder: A Randomized Clinical Trial
Wilhelm S, Phillips KA, Greenberg JL, O'Keefe SM, Hoeppner SS [et al.], Schoenfeld DA.
Published in JAMA Psychiatry on February 20, 2019 | *Summary available

PROMISING TREATMENT FOR TRIPLE-NEGATIVE BREAST CANCER
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer
Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ [et al.], Kalinsky K.
Published in The New England Journal of Medicine on February 21, 2019 | *Summary available

EXPLORING TREATMENTS FOR PEANUT ALLERGIES
Effect of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Ingestion Among Children with Peanut Allergy: The PEPITES Randomized Clinical Trial
Fleischer DM, Greenhawt M, Sussman G, Bégin P, Nowak-Wegrzyn A [et al.], Shreffler W.
Published in JAMA on February 22, 2019

NEW INSIGHTS INTO THE MITOCHONDRIAL UNIPORTER
Crystal Structure of MICU2 and Comparison with MICU1 Reveal Insights into the Uniporter Gating Mechanism
Kamer KJ, Jiang W, Kaushik VK, Mootha VK, Grabarek Z.
Published in PNAS on February 26, 2019 | *Summary available

Summaries

Tumor suppressors protect us against cancer and the loss of these protective shields is a hallmark of tumor progression. Sanidas et al. investigated the mechanism of action of one of the best-known tumor suppressors, the retinoblastoma protein (RB), an inhibitor of cell proliferation. Cells contain many different forms of RB that have been tailored by phosphorylation to interact with different sets of proteins. This study specified which proteins associate with each form of RB and revealed that phosphorylation determines RB activity beyond the regulation of cell cycle. Overall, this study generated an essential framework of information that is needed to understand how RB works.

(Summary submitted by Ioannis Sanidas, PhD, Department of Medicine and Mass General Cancer Center)

Improving the survival of patients with metastatic breast cancer (mBC) remains a significant challenge. The dense mBC tumor tissue, known as fibrotic, can suppress the immune response to cancer, yet little is known about degrees of fibrosis and its role in immunosuppression in metastatic lesions. We found that blocking fibrosis and immunosuppression using CXCR4 inhibitors significantly reduced the spreading of mBC and improved response to immune checkpoint blockers in mouse models. Our results suggest that anti-fibrotic drugs, such as CXCR4 inhibitors, that are safe and already FDA-approved could be rapidly translated to the clinic and may benefit patients with mBC.

(Summary submitted by Ivy Chen, PhD, Mass General Cancer Center)

Although endovascular repair has supplanted open surgical repair as the procedure of choice for the majority of abdominal aortic aneurysms in the United States, complex aneurysms, which involve the visceral and renal vessels, present unique challenges. This study used a large, multinational registry to show that although endovascular repairs are associated with lower perioperative morbidity and mortality, open repair was associated with lower long-term mortality. More data are clearly needed to establish the long-term durability of complex endovascular repairs.

(Summary submitted by Tom FX O'Donnell, MD, Department of Surgery)

Tuberculosis is the leading killer of people with HIV, and many tuberculosis cases are missed by conventional sputum-based diagnostic strategies. In conjunction with a clinical trial in Malawi and South Africa, we used a mathematical model to project long-term clinical and economic outcomes of urine-based screening for tuberculosis among hospitalized patients with HIV. We found that adding the urine-based lipoarabinomannan and Xpert tests would decrease mortality, improve life expectancy and be cost-effective in both countries. Our findings make a compelling case for expanding urine-based tuberculosis screening to all hospitalized patients with HIV in areas of high HIV and tuberculosis prevalence.

(Summary submitted by Krishna Reddy, MD, Medical Practice Evaluation Center and Division of Pulmonary and Critical Care Medicine)

This study describes combining two types of cells derived from patient skin cells, microglia and neurons, to understand how microglia trim the connections between neurons. This process is called synaptic pruning. The study found that synaptic pruning is more active in cells from people with schizophrenia compared to people without a psychiatric illness. It also found that synaptic pruning can be reduced by the antibiotic minocycline, which is often used to treat acne.

(Summary submitted by Roy Perlis, MD, Department of Psychiatry and Center for Quantitative Health)

Motion is one of the fundamental readouts or reflections of higher order brain computations. Think about how you calibrate your motion (walk fast or slow or cautiously) when you approach something rewarding or fearful (an alleyway where you were robbed) or something that is ambiguous (a dim alley that looks like that alleyway). Besnard and colleagues in the Sahay lab identified how a class of brain cells act as threat sensors and gate motion to calibrate behavioral responses to threats in the environment. Their findings motivate targeting these threat sensors to rectify pathological behavioral responses to ambiguous threats in the environment such as that seen with the overgeneralization of fear in PTSD.

(Summary submitted by Amar Sahay, PhD, Department of Psychiatry and Center for Regenerative Medicine)

Tuberculosis (TB) is the leading cause of death globally among people living with HIV and HIV infection increases the risk of TB by 20-40-fold. Despite this, the impact of HIV on protective immune responses in the lung is not well understood. In this study, we show that lung tissue immune cells, called CD4+ T cells, are highly susceptible to killing by HIV and that this may contribute to the spread of TB from the lungs to other parts of the body. Our study helps to explain the high burden of disseminated TB in those who are co-infected with HIV and may help us find better way to leverage the lung immune system to protect people from TB.

(Summary submitted by Bjorn Corleis, PhD, Ragon Institute)

The ability to monitor behavior of administered cells in patients using high-resolution optical imaging techniques would provide useful information for cell-based therapies in the treatment of diseases. Currently, long-term live cell tracking is limited due to the lack of available bioprobes with stable optical and biological properties. We developed a novel fluorescent cell-labeling probe, CTNF126, in the near-infrared window, which can be permanently fixed within the cells using naturally occurring organic fixatives, while retaining high stability. In addition, CTNF126 is resistant to harsh chemical treatment, allowing continuous recording of the fate of administered cells from the body to histopathological analysis.

(Summary submitted by G. Kate Park, MS, Department of Radiology)

Genome-editing technologies, including the recently described CRISPR-Cas12a enzymes, allow researchers to permanently change DNA sequences in the genome. However, the naturally occurring properties of Cas12a nucleases are not optimal for biomedical research or experiments in primary human tissues. To improve the broad utility, activity, and safety of CRISPR-Cas12a enzymes, we utilized protein engineering strategies to develop enhanced Cas12a variants with superior gene-editing activities and targeting ranges, making Cas12a enzymes more widely useful to the research and therapeutic communities.

(Summary submitted by Benjamin Kleinstiver, PhD, Department of Pathology and Center for Genomic Medicine)

Like our body, cells also employ a multitude of molecular and cellular signaling events to maintain a stable, relatively constant internal environment. However, the machinery by which cells to maintain their homeostasis is largely unknown. We found that our cells, smart enough, employ a LATS2-YAP1 feedback loop to switch the fate of cells with high tumorigenic YAP1 signal from transformation (malignant growth) to senescence (permanent arrest of cell growth). The disruption of the YAP1-LATS2 feedback loop under pathological conditions could result in malignant cell growth and cancer development.

(Summary submitted by Cheng Wang, PhD, Vincent Center for Reproductive Biology)

Chronic inflammation accounts for almost 20% of all human cancer deaths worldwide. Chronic inflammation-associated cancers include: inflammatory bowel disease-associated colorectal cancer, hepatitis-associated liver cancer, gastritis-associated gastric cancer, and skin cancers associated with several skin inflammatory diseases. This study reveals a critical immunological axis that initiates the development of cancer-promoting chronic inflammation. IL-33/regulatory T cell axis is chronic inflammation’s Achilles’ heel and its blockade prevents inflammation-induced skin and colon cancer. This work promises to provide a therapeutic target to prevent inflammation-associated cancers and treat cancers that rely on immune cells in their environment for their growth.

(Summary submitted by Shawn Demehri, MD, PhD, Department of Dermatology and Mass General Cancer Center)

Sleep is an increasingly important public health issue as half of adults sleep fewer than the recommended 7-8 hours per day. A number of clinical studies have correlated poor sleep with an increased risk of developing cardiovascular disease. However, how sleep protects us from disease is unclear. In our study we found that mice with disturbed sleep produced more inflammatory white blood cells and developed exacerbated cardiovascular disease. We uncovered a mechanism linking the brain and the immune system that is disrupted by poor sleep.

(Summary submitted by Cameron McAlpine, PhD, Center for Systems Biology)

After stroke, the injury to the brain rapidly activates production of myeloid cells and adaptive immune cells become rare. This decline in lymphocytes compromises an organism's ability to resist post-stroke infections such as pneumonia and can influence the brain's recovery. We describe that post-stroke lymphopenia arises across the entire B cell lineage and includes B cell progenitor cells in the bone marrow. Our data demonstrate that the hypothalamic-pituitary-adrenal (or brain-bone marrow) axis mediates B lymphopoiesis defects after stroke via the hormone glucocorticoid. Such understanding of the hematopoietic response to stroke may provide new avenues to augment stroke recovery.

(Summary submitted by Matthias Nahrendorf, MD, PhD, Center for Systems Biology)

Body dysmorphic disorder (BDD) is a relatively common, severe disorder associated with substantial impairment and high rates of hospitalization and suicidality. Cognitive behavioral therapy (CBT), a skills-based treatment addressing disorder-specific symptoms, is the best-studied psychosocial treatment for BDD, but had never been tested against therapist-delivered supportive psychotherapy (SPT), the most commonly received psychotherapy for BDD. In the largest BDD treatment study to date, both treatments improved BDD symptoms; however, CBT-BDD improved BDD symptoms and quality of life more consistently across study sites. The results suggest that CBT-BDD can be delivered effectively and reliably, whereas SPT may be more variable.

(Summary submitted by Sabine Wilhelm, PhD, Department of Psychiatry)

Triple negative breast cancer is a subset of breast cancer associated with aggressive tumor biology that tends to affect younger patients and African Americans. The response rate with standard chemotherapy regimens is low (10-15%), and median progression-free survival is short (3-4 months). In this clinical trial, we evaluated efficacy and safety of sacituzumab govitecan and observed an overall response rate of 33.3 % with median duration of response of 7.7 months. The results suggest that sazituzumab govitecan is an active agent that is cross-resistant with other chemotherapy and immunotherapy agents with a manageable safety profile, thus representing an important therapy for patients with triple negative breast cancer.

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

Mitochondria are intracellular organelles responsible for generating energy. They have the capability to match their energy output to the rapidly changing energy requirements of the cell. An essential part of this process is the detection and rapid uptake of minute amounts of ionized calcium into the mitochondrion. Previous studies from our laboratory revealed the molecular identity of the protein complex responsible for the mitochondrial calcium uptake, the so-called calcium uniporter. In the present work the atomic resolution structure of MICU2, one of the components of the uniporter, provided important insights into the inner mechanisms of calcium sensing and gating of the uniporter. It is an important step towards understanding how inherited defects in calcium communication to mitochondria lead to neurological and muscle disease.

(Summary submitted by Zenon Grabarek, PhD, Department of Molecular Biology)

Blog Posts

Heart Health Month 2019: Spotlighting Mass General’s Heart Researchers (Part 1)
Featuring Matthias Nahrendorf, MD, PhD, Malissa Wood, MD, Anthony Rosenzweig, MD, and Ami Bhatt, MD

Since every February is dedicated to heart health awareness, we reached out to some of our cardiology researchers to learn more about what they’re working on.

Helping Mothers Recover When the Psychological Trauma of Giving Birth Lingers
Featuring Sharon Dekel, PhD

Sharon Dekel, PhD, an assistant professor of Harvard Medical School and a researcher and psychologist in the Department of Psychiatry at Massachusetts General Hospital, is studying childbirth-related posttraumatic stress disorder, a condition that may affect as many as 5-11% of postpartum women.

Heart Health Month 2019: Spotlighting Mass General’s Heart Researchers (Part 2)
Featuring Pradeep Natarajan, MD, MMSC, Nandita Scott, MD, James Januzzi, MD, and Hanna Kim Gaggin, MD, MPH

In the second installment of our Heart Month researcher spotlight series, we highlight investigators studying the genetics and prevention of heart disease, maintaining heart health during pregnancy, heart attacks, and precision medicine.

Mass General Researcher Uses PET Imaging to Shed Light on the Inner Workings of the Brain
Featuring Jacob Hooker, PhD

Researchers at Massachusetts General Hospital are using advanced brain imaging techniques to learn more about how brain disorders function at a molecular and genetic level.

Heart Health Month 2019: Spotlighting Mass General’s Heart Researchers (Part 3)
Featuring Jeffrey Huffman, MD, Amy Sarma, MD and Robert Levine, MD

In the third installment of our Heart Month researcher spotlight series, we highlight investigators working on how heart health relates to mental health, heart disease and pregnancy, and cardiovascular imaging.

Cardiac Psychiatry: Exploring Connections Between the Head and the Heart
Featuring Jeffrey Huffman, MD

Cardiac psychiatry, also called behavioral cardiology, is the study of psychiatry as it relates to patients with heart conditions. It explores the connections between mental health, behavior, and medical health in patients who have suffered from an acute cardiac event, heart disease, or other chronic conditions.

How a Dedicated Mass General Team Became the First to Discover Circulating Brain Tumor Cells in the Blood
Featuring Shannon Stott, PhD, and Brian Nahed, MD, MSc

Mass General researchers Shannon Stott and Brian Nahed have been working together for 10 years, and used their different backgrounds to their advantage to be the first to identify circulating brain tumor cells in the blood.

Rare Disease Day 2019: Neuromyelitis Optica
Featuring Farrah Mateen, MD, PhD

Rare diseases can be very complex to treat due to lack of understanding, little to no options for treatment and limited funding. But it is for these reasons that raising awareness and supporting research and funding for rare diseases is so important.

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Snapshot of Science for February 2019