Research at Mass General

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Snapshot of Science is a monthly digest of publication summaries, press releases and blog posts featuring researchers from Massachusetts General Hospital.

Welcome to the December 2017 edition of Snapshot of Science. Here's a quick look at some recent publications, press releases and stories about the Mass General research community.

In this issue we highlight:

  • 23 new studies published in high impact journals, along with 19 summaries submitted by the research teams
  • 14 new research-related press releases from the Mass General Public Affairs office
  • 17 posts from the Mass General Research Institute blog

Publications List

*Author-submitted summaries available when indicated

COMMUNICATION BETWEEN LUNG TUMORS AND BONES CONTRIBUTES TO TUMOR PROGRESSION
Osteoblasts Remotely Supply Lung Tumors with Cancer-Promoting SiglecFhigh Neutrophils
Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, [et al.] Scadden DT, Weissleder R, Pittet MJ
Published in Science on December 1, 2017 

EXPLORING FACTORS THAT DETERMINE PROLONGED HOSPITALIZATIONS AND READMISSIONS AMONG PATIENTS WITH ADVANCED CANCER
The Relationship Between Physical and Psychological Symptoms and Health Care Utilization in Hospitalized Patients with Advanced Cancer
Nipp RD, El-Jawahri A, Moran SM, D'Arpino SM, Johnson PC, Lage DE, [et al.] Jackson VA, Greer JA, Ryan DP, Hochberg EP, Temel JS
Published in Cancer on December 1, 2017 

A RISK SCORE FOR SEIZURES
Association of an Electroencephalography-Based Risk Score With Seizure Probability in Hospitalized Patients
Struck AF, Ustun B, Ruiz AR, Lee JW, LaRoche SM, Hirsch LJ, [et al.] Westover MB
Published in JAMA Neurology on December 1, 2017 

COMPUTATIONAL METHOD FOR IDENTIFYING NEW CANCER GENES
NetSig: Network-Based Discovery from Cancer Genomes
Horn H, Lawrence MS, Chouinard CR, Shrestha Y, Hu JX, Worstell E, [et al.] Boehm JS, Getz G, Lage K
Published in Nature Methods on December 4, 2017

ASSESSING QUALITY OF INPATIENT CARE PROVIDED BY TEMPORARY FILL-IN PHYSICIANS
Association Between Treatment by Locum Tenens Internal Medicine Physicians and 30-Day Mortality Among Hospitalized Medicare Beneficiaries
Blumenthal DM, Olenski AR, Tsugawa Y, Jena AB
Published in JAMA on December 5, 2017 

READMISSION RATES AFTER SURGERY FOR PERIPHERAL ARTERIAL DISEASE
Readmissions After Revascularization Procedures for Peripheral Arterial Disease: A Nationwide Cohort Study
Secemsky EA, Schermerhorn M, Carroll BJ, Kennedy KF, Shen C, Valsdottir LR, Landon B, Yeh RW
Published in Annals of Internal Medicine on December 5, 2017 

E2F/DP AND FAT BODY CELLS
E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression
Guarner A, Morris R, Korenjak M, Boukhali M, Zappia MP, Van Rechem C, [et al.] Dyson NJ
Published in Developmental Cell on December 7, 2017 

EXPLORING BRAIN CIRCUITS THAT REGULATE SOCIAL RECOGNITION
Hippocampal Oxytocin Receptors are Necessary for Discrimination of Social Stimuli
Raam T, McAvoy KM, Besnard A, Veenema A, Sahay A
Published in Nature Communication on December 8, 2017

DNA REPEAT EXPANSION DETERMINES ONSET OF A RARE MOVEMENT DISORDER
Disease Onset in X-Linked Dystonia-Parkinsonism Correlates with Expansion of a Hexameric Repeat Within an SVA Retrotransposon in TAF1
Bragg DC, Mangkalaphiban K, Vaine CA, Kulkarni NJ, Shin D, Yadav R, [et al.] Breakefield XO, Sharma N, Ozelius LJ
Published in PNAS on December 11, 2017

CONVERTING AUTOIMMUNE-CAUSING ANTIBODIES TO ANTI-INFLAMMATORY ANTIBODIES
Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease
Pagan JD, Kitaoka M, Anthony RM
Published in Cell on December 11, 2017 

A COMPLEMENT TO THE PERSONALIZED CANCER THERAPY APPROACH
Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care
Kodack DP, Farago AF, Dastur A, Held MA, Dardaei L, Friboulet L, [et al.] Benes CH
Published in Cell Reports on December 12, 2017

ASSOCIATION BETWEEN BLOOD CLOTTING, A RARE SKIN DISEASE, AND KIDNEY DISEASE
Association Between Hypercoagulable Conditions and Calciphylaxis in Patients With Renal Disease: A Case-Control Study
Dobry AS, Ko LN, St John J, Sloan JM, Nigwekar S, Kroshinsky D
Published in JAMA Dermatology on December 13, 2017

LINK BETWEEN RAINY WEATHER AND ACHY JOINTS
Association Between Rainfall and Diagnoses of Joint or Back Pain: Retrospective Claims Analysis
Jena AB, Olenski AR, Molitor D, Miller N
Published in BMJ on December 13, 2017 

DESTROYING THE CELLS THAT CAUSE LIFE-THREATENING ORGAN SCARRING
Targeted Apoptosis of Myofibroblasts with the BH3 Mimetic ABT-263 Reverses Established Fibrosis
Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA [et al.], Tager AM
Published in Science Translational Medicine on December 13, 2017

ATLAS OF HEAD AND NECK CANCER CELLS
Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer
Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, [et al.] Lin DT, Regev A, Bernstein BE
Published in Cell on December 14, 2017 

PROCESS FOR CHANGING CODE STATUS FROM FULL CODE TO DO NOT RESUSCITATE
Processes of Code Status Transitions in Hospitalized Patients with Advanced Cancer
El-Jawahri A, Lau-Min K, Nipp RD, Greer JA, Traeger LN, Moran SM, [et al.] Ryan DP, Temel JS
Published in Cancer on December 15, 2017

ASSOCIATION BETWEEN BRAIN LESIONS AND CRIMINAL BEHAVIOR
Lesion Network Localization of Criminal Behavior
Darby RR, Horn A, Cushman F, Fox MD
Published in PNAS on December 18, 2017 

NEW APPROACH TO GENETIC SCREENING USING CRISPR–CAS9
Orthologous CRISPR–Cas9 Enzymes for Combinatorial Genetic Screens
Najm FJ, Strand C, Donovan KF, Hegde M, Sanson KR, Vaimberg EW, [et al.] Bernstein BE, Root DE, Doench JG
Published in Nature Biotechnology on December 18, 2017 

EXPLORING NEW THERAPY FOR RECURRING BRAIN CANCER
Phase 2 and Biomarker Study of Trebananib, an Angiopoietin-Blocking Peptibody, With and Without Bevacizumab for Patients with Recurrent Glioblastoma
Reardon DA, Lassman AB, Schiff D, Yunus SA, Gerstner ER, Cloughesy TF, [et al.] Duda DG, Jain RK, Wen PY
Published in Cancer on December 19, 2017 

ZIKA VIRUS' EFFECT ON CELLS
Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication
Sun X, Hua S, Chen HR, Ouyang Z, Einkauf K, Tse S, [et al.] Yu XG
Published in Cell Reports on December 19, 2017

SHINGLES RISK AMONG PATIENTS WITH PSORIASIS
Herpes Zoster Rates in a Large Cohort of Patients With Systemically Treated Psoriasis
Levandoski KA, Quesenberry CP, Tsai AL, Asgari MM
Published in JAMA Dermatology on December 20, 2017

HYPOGLYCEMIA IN HOSPICE PATIENTS WITH TYPE 2 DIABETES
Hypoglycemia in Hospice Patients With Type 2 Diabetes in a National Sample of Nursing Homes
Petrillo LA, Gan S, Jing B, Lang-Brown S, Boscardin WJ, Lee SJ
Published in JAMA Internal Medicine on December 26, 2017

REACTIVATING DORMANT X CHROMOSOMES
A Mixed Modality Approach Towards Xi Reactivation for Rett Syndrome and Other X-Linked Disorders
Carrette LLG, Wang CY, Wei C, Press W, Ma W, Kelleher RJ 3rd, Lee JT
Published in PNAS on December 27, 2017 

Publication Summaries

1. COMMUNICATION BETWEEN LUNG TUMORS AND BONES CONTRIBUTES TO TUMOR PROGRESSION
Osteoblasts Remotely Supply Lung Tumors with Cancer-Promoting SiglecFhigh Neutrophils
Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, [et al.] Scadden DT, Weissleder R, Pittet MJ.
Published in Science on December 1, 2017

Tumors are often infiltrated by diverse immune cell types, some of which remain largely unexplored. In this study, we uncovered a new type of neutrophil that promotes lung cancer. The production of these neutrophils involves an unexpected remote crosstalk between tumors and bones: lung tumors remotely activate osteoblasts; in turn, those bone cells shape immunity by supplying distant tumors with cancer-promoting neutrophils. The findings open new avenues for cancer immunotherapy.

(Summary submitted by Mikael Pittet, PhD, of the Center for Systems Biology)

2. EXPLORING FACTORS THAT DETERMINE PROLONGED HOSPITALIZATIONS AND READMISSIONS AMONG PATIENTS WITH ADVANCED CANCER
The Relationship Between Physical and Psychological Symptoms and Health Care Utilization in Hospitalized Patients with Advanced Cancer
Nipp RD, El-Jawahri A, Moran SM, D'Arpino SM, Johnson PC, Lage DE, [et al.] Jackson VA, Greer JA, Ryan DP, Hochberg EP, Temel JS
Published in Cancer on December 1, 2017

We demonstrated that hospitalized patients with advanced cancer experience an immense physical and psychological symptom burden, with over half reporting moderate to severe physical symptoms such as fatigue, pain, and poor appetite. Notably, more than one quarter also reported clinically significant depression and anxiety symptoms. We also found novel results that hospitalized patients’ physical and psychological symptoms were associated with longer hospital stays and greater risk for unplanned hospital readmissions. These findings highlight the critical need to develop and test interventions to address patients’ symptom burden. Importantly, patients’ symptoms represent a potentially modifiable risk factor and studies have shown that targeted interventions aimed at improving symptom management can enhance patient outcomes.

(Summary submitted by Ryan Nipp, MD, MPH, of the Cancer Center)

3. A RISK SCORE FOR SEIZURES
Association of an Electroencephalography-Based Risk Score With Seizure Probability in Hospitalized Patients
Struck AF, Ustun B, Ruiz AR, Lee JW, LaRoche SM, Hirsch LJ, [et al.] Westover MB
Published in JAMA Neurology on December 1, 2017

Many ICU patients suffer from seizures - harmful “electrical storms” in the brain. It is important to identify patients at risk so monitoring and treatment can be provided. We used a new artificial intelligence method to discover which factors in a patient’s brain monitoring (EEG) data, and which medical factors, best predict an ICU patient’s risk for seizures. We developed a score, “2HELPS2B,” that assigns points to each risk factor. Adding these points accurately predicts the patient’s risk. The letters in 2HELPS2B remind doctors what the risk factors are and how many points each gets, making the method easy to use.

(Summary submitted by Brandon Westover, MD, PhD, of the Department of Neurology)

4. ASSESSING QUALITY OF INPATIENT CARE PROVIDED BY TEMPORARY FILL-IN PHYSICIANS
Association Between Treatment by Locum Tenens Internal Medicine Physicians and 30-Day Mortality Among Hospitalized Medicare Beneficiaries
Blumenthal DM, Olenski AR, Tsugawa Y, Jena AB
Published in JAMA on December 5, 2017

Hospitals commonly hire Locum Tenens, substitute physicians, to temporarily cover for doctors who are vacationing or on leave. However, little is known about locum tenens’ quality and costs of care. We used Medicare claims data to compare clinical outcomes and care spending for Medicare beneficiaries hospitalized with general medical conditions and treated by locum tenens versus non-locum tenens general internal medicine physicians (i.e. hospitalists and primary care physicians). Compared to non-locum tenens’ patients, patients treated by locum tenens had similar 30-day mortality rates, slightly higher costs, and slightly longer lengths of stay. Our findings suggest that care delivered by locum tenens is similar in quality to, but slightly less efficient than, care delivered by non-locum tenens.

(Summary submitted by Daniel Blumenthal, MD, of the Department of Medicine)

5. READMISSION RATES AFTER SURGERY FOR PERIPHERAL ARTERIAL DISEASE
Readmissions After Revascularization Procedures for Peripheral Arterial Disease: A Nationwide Cohort Study
Secemsky EA, Schermerhorn M, Carroll BJ, Kennedy KF, Shen C, Valsdottir LR, Landon B, Yeh RW
Published in Annals of Internal Medicine on December 5, 2017

Peripheral arterial disease (PAD) is a disorder that prevents blood flow to the extremities and vessels outside the heart. Revascularization procedures – including surgical bypass operations and procedures in which balloons and stents are placed in the arteries to open blockages – can significantly improve patients’ quality of life and disease outcomes. However, little is known regarding the need for readmission after these procedures and how rehospitalizations affect patient outcomes. Our study showed that more than 1 in 6 patients with PAD are readmitted within 30 days. Complications were the main reason for needing readmission, whereas differences in hospital quality may have had some impact as well. Of patients needing readmission, nearly 5% died and 20% underwent another procedure. We conclude that revascularization for PAD should be considered alongside the highest risk conditions for rehospitalization. New strategies are now needed to keep patients with PAD out of the hospital.

(Summary submitted by Eric Secemsky, MD, of the Department of Medicine)

6. E2F/DP AND FAT BODY CELLS
E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression
Guarner A, Morris R, Korenjak M, Boukhali M, Zappia MP, Van Rechem C, [et al.] Dyson NJ
Published in Developmental Cell on December 7, 2017

Deregulation of E2F/DP drives cancer-cell proliferation. However, the preclinical development of E2F/DP inhibitors requires information about the consequences of the complete elimination of E2F/DP activity in vivo. Here, we examined the consequences of eliminating E2F/DP during fly development. The results reveal that E2F/DP is important in the fat body and uncover a new mechanism by which E2F/DP maintains cell quiescence. In this tissue, highly differentiated polyploid cells grow via endocyces, a process that results in accumulation of DNA breaks. Here, E2F/DP promotes quiescence by repressing expression of ATM (a master regulator of cellular responses to DNA damage) and preventing the repair of DNA damage. Thus, unexpectedly, E2F/DP-dependent suppression of DNA damage signaling is important for normal animal development.

(Summary submitted by Nicholas Dyson, PhD, of the Cancer Center)

7. EXPLORING BRAIN CIRCUITS THAT REGULATE SOCIAL RECOGNITION
Hippocampal Oxytocin Receptors are Necessary for Discrimination of Social Stimuli
Raam T, McAvoy KM, Besnard A, Veenema A, Sahay A
Published in Nature Communication on December 8, 2017

The role of the hippocampus, often referred to as the brain’s librarian of memories, in social recognition is poorly understood. Our study illuminates how the hippocampus helps to guide social behavior when enabled by oxytocin, an ancient, evolutionary conserved neurochemical that plays a role in social bonding. Our findings demonstrate that oxytocin utilizes a basic memory processing circuit in the hippocampus to differentiate between social, but not non-social, memories. Alterations in hippocampal circuitry may underlie social memory deficits seen in autism spectrum disorders.

(Summary submitted by Amar Sahay, PhD, of the Center for Regenerative Medicine)

8. CONVERTING AUTOIMMUNE-CAUSING ANTIBODIES TO ANTI-INFLAMMATORY ANTIBODIES
Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease
Pagan JD, Kitaoka M, Anthony RM
Published in Cell on December 11, 2017

When Immunoglobin G (IgG) antibodies attack parts of our bodies, they contribute to the pathology of autoimmune diseases, including systemic lupus and rheumatoid arthritis. Somewhat paradoxically, IgG antibodies from healthy donors are also used to treat autoimmune and inflammatory diseases in the form of high-dose intravenous immunoglobulin (IVIG). Previous studies from our group and others have demonstrated that the anti-inflammatory properties of IgG are attributed to a small portion of IgG that carry sialic acid. We therefore sought to convert pathogenic autoimmune causing IgG to their anti-inflammatory counterparts through a process called glycoengineering. We engineered enzymes that attached sialic acid to disease-causing IgG, which successfully reduced autoimmune disease in animals. These results underscore the therapeutic potential of glycoengineering in vivo.

(Summary submitted by Robert Anthony, PhD, of the Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, and Department of Medicine)

9. A COMPLEMENT TO THE PERSONALIZED CANCER THERAPY APPROACH
Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care
Kodack DP, Farago AF, Dastur A, Held MA, Dardaei L, Friboulet L, [et al.] Benes CH
Published in Cell Reports on December 12, 2017

Deciding upon the best treatment course for a cancer patient is a careful and sometimes complex decision. In recent years, genetic analysis of tumors has helped guide treatment decision for some patients. However, our understanding of how tumors respond to drugs is still limited. In this study, working with clinicians and laboratory scientists, we aimed to develop an approach that allows us to directly test the effect of drugs on tumor cells. Together with genetic data, we hope that this will help improve treatment decision and outcome in the near future.

(Summary submitted by Cyril Benes, PhD, of the Cancer Center)

10. ASSOCIATION BETWEEN BLOOD CLOTTING, A RARE SKIN DISEASE, AND KIDNEY DISEASE
Association Between Hypercoagulable Conditions and Calciphylaxis in Patients With Renal Disease: A Case-Control Study
Dobry AS, Ko LN, St John J, Sloan JM, Nigwekar S, Kroshinsky D
Published in JAMA Dermatology on December 13, 2017

Our study focuses on better understanding risk factors for developing calciphylaxis, a highly fatal condition characterized by widespread vessel calcification with subsequent clotting and skin necrosis. To investigate whether there are associations between development of calciphylaxis and hypercoagulable conditions (conditions in which the blood clots too much), we compared the hypercoagulability status of patients with kidney disease who went on to develop calciphylaxis versus those who did not. Overall, results showed that the presence of an antibody called lupus anticoagulant was significantly associated with development of calciphylaxis in patients with the disease.

(Summary submitted by Allison Dobry, MD, of the Department of Medicine)

11. LINK BETWEEN RAINY WEATHER AND ACHY JOINTS
Association Between Rainfall and Diagnoses of Joint or Back Pain: Retrospective Claims Analysis
Jena AB, Olenski AR, Molitor D, Miller N
Published in BMJ on December 13, 2017

It’s frequently believed that joint aches abound on rainy days. In a new analysis of over 10 million Medicare physician office visits, linked to data on daily rainfall, we found no increase in the proportion of office visits that relate to joint pain on rainy versus non-rainy days. Moreover, during weeks with heavy rainfall versus weeks with little or no rainfall, there is no difference in the proportion of office visits that relate to joint pain. There is also no increase in joint pain visits in the week following heavy rainfall, an analysis which was conducted because people may be unable to schedule physician visits on such short notice. While this is the first large-scale analysis of this question, the findings do not preclude the possibility that a true relationship between joint pain and rainfall exists.

(Summary submitted by Anupam Jena, MD, PhD, of the Department of Medicine)

12. DESTROYING THE CELLS THAT CAUSE LIFE-THREATENING ORGAN SCARRING
Targeted Apoptosis of Myofibroblasts with the BH3 Mimetic ABT-263 Reverses Established Fibrosis
Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA [et al.], Tager AM
Published in Science Translational Medicine on December 13, 2017

Human organs can undergo self-repair following injury. However, severe or chronically injured organs develop fibrosis (dense scar tissue) at the expense of regeneration. A dramatic example of this is scleroderma, an autoimmune disease characterized by multiorgan fibrosis. In this study, we found that a drug known as ABT-263 selectively induces apoptosis (cell self-destruction) of scar-forming cells called myofibroblasts in patients with scleroderma. We found the drug also induces myofibroblast apoptosis and reverses fibrosis in a mouse model of scleroderma. Of clinical importance, we demonstrate that a functional assay called “BH3 profiling” can predict sensitivity of scleroderma myofibroblasts to apoptosis induced by ABT-263. This assessment may serve as a novel precision medicine tool that could help personalize treatment of patients with scleroderma.

(Summary submitted by David Lagares, PhD, of the Department of Medicine)

13. ATLAS OF HEAD AND NECK CANCER CELLS
Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer
Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, [et al.] Lin DT, Regev A, Bernstein BE
Published in Cell on December 14, 2017

Our team has completed a detailed single cell atlas of head and neck squamous cell carcinomas, defining the heterogeneous landscape of cancer cells, immune cells and stroma in primary tumors and metastases. We identified a subpopulation of malignant cells that express a partial epithelial-to-mesenchymal transition that appears to drive invasion and metastasis in this common form of skin cancer. This work suggests new diagnostic methods for predicting cancer spread based on biomarkers in the primary tumor, as well as new avenues for therapeutically targeting metastasis programs.

(Summary submitted by Bradley Bernstein, MD, PhD, Bernard and Mildred Kayden Endowed MGH Research Institute Chair, of the Department of Pathology)

14. PROCESS FOR CHANGING CODE STATUS FROM FULL CODE TO DO NOT RESUSCITATE
Processes of Code Status Transitions in Hospitalized Patients with Advanced Cancer
El-Jawahri A, Lau-Min K, Nipp RD, Greer JA, Traeger LN, Moran SM, [et al.] Ryan DP, Temel JS
Published in Cancer on December 15, 2017

Previous research has shown that hospitalized patients with advanced cancer have a low chance of surviving cardiopulmonary resuscitation (CPR) and mechanical ventilation, life-sustaining interventions that are collectively termed “code status.” Therefore, it is important for doctors to have honest conversations about whether a transition from these interventions to a “do not resuscitate” (DNR) code status is appropriate for their patients. Our study found that 53% of patients with advanced cancer did not have a code status discussion at the time of hospitalization. Educating patients and their families about the potential harms and futility of CPR ultimately emerged as an important process facilitating code status transitions to DNR.

(Summary submitted by Kelsey Lau-Min, MD, of the Department of Medicine)

15. ASSOCIATION BETWEEN BRAIN LESIONS AND CRIMINAL BEHAVIOR
Lesion Network Localization of Criminal Behavior
Darby RR, Horn A, Cushman F, Fox MD
Published in PNAS on December 18, 2017

Cases like that of Charles Whitman, who murdered 16 people after growth of a brain tumor, have sparked debate about why some brain lesions, but not others, might lead to criminal behavior. Here we systematically characterize such lesions and compare them with lesions that cause other symptoms. We find that lesions in multiple different brain areas are associated with criminal behavior. However, these lesions all fall within a unique functionally connected brain network involved in moral decision making. Furthermore, connectivity to competing brain networks predicts the abnormal moral decisions observed in these patients. These results provide insight into why some brain lesions, but not others, might predispose to criminal behavior, with potential neuroscience, medical, and legal implications.

(Summary submitted by Michael Fox, MD, PhD, of the Department of Neurology)

16. NEW APPROACH TO GENETIC SCREENING USING CRISPR–CAS9
Orthologous CRISPR–Cas9 Enzymes for Combinatorial Genetic Screens
Najm FJ, Strand C, Donovan KF, Hegde M, Sanson KR, Vaimberg EW, [et al.] Bernstein BE, Root DE, Doench JG
Published in Nature Biotechnology on December 18, 2017

Cancer vulnerabilities can be difficult to identify due to complex biological interactions involving two or more cooperative genes. We aimed to simplify this complexity. Using CRISPR-Cas9 gene editing, which acts like a molecular scissor, we developed a system named “Big Papi” that effectively disrupts two genes simultaneously so that the effects of their combination can be assessed. We found that two independently-directed molecular scissors are better than one scissor directed to two sites. With this system, hundreds of two-gene combinations can be screened to identify the most promising targets for combination therapy. Our results also show that “Big Papi” can be used to simultaneously cut in one genetic location and increase activity at another location, expanding the utility of the system. The “Big Papi” system will be widely used to identify complex interactions that could be used as therapeutic targets in cancer and other diseases.

(Summary submitted by Bradley Bernstein, MD, PhD, Bernard and Mildred Kayden Endowed MGH Research Institute Chair, of the Department of Pathology, and Fadi Najm, MD, PhD, of the Department of Pathology and Center for Cancer Research)

17. EXPLORING NEW THERAPY FOR RECURRING BRAIN CANCER
Phase 2 and Biomarker Study of Trebananib, an Angiopoietin-Blocking Peptibody, With and Without Bevacizumab for Patients with Recurrent Glioblastoma
Reardon DA, Lassman AB, Schiff D, Yunus SA, Gerstner ER, Cloughesy TF, [et al.] Duda DG, Jain RK, Wen PY
Published in Cancer on December 19, 2017

The current standard of care for recurrent glioblastoma is bevacizumab. This therapy blocks growth of new tumor blood vessels and improves the status of the patients but doesn’t extend survival. In this clinical study, we looked at a new therapy for recurrent glioblastoma called trebananib, an experimental agent that blocks angiopoietin 1 and angiopoietin 2 which both promote growth of new tumor blood vessels. The hypothesis was that these angiopoietins are important in the disease progression and blocking them would prevent bevacizumab treatment resistance. We found that trebananib was ineffective on its own and did not enhance bevacizumab’s ability to improve the outcomes of patients with recurrent glioblastoma. Correlative biomarker studies confirmed the biologic effects of these treatments and identified Interleukin 8, which promotes cell-to-cell interaction, as a potential biomarker of evasion.

(Summary submitted by Daniel Duda, PhD, DMD, of the Department of Radiation Oncology)

18. ZIKA VIRUS' EFFECT ON CELLS
Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication
Sun X, Hua S, Chen HR, Ouyang Z, Einkauf K, Tse S, [et al.] Yu XG
Published in Cell Reports on December 19, 2017

Zika virus infection has caused considerable disease during the recent epidemic in South and Central America. Paradoxically, our work showed that dendritic cells, highly specialized immune cells that act as the backbone of antiviral immune defense, are highly susceptible to Zika virus infection, and can act as mobile vehicles to disseminate the virus in infected humans. By analyzing blood samples from patients with Zika Virus infection diagnosed at MGH/BWH, this study demonstrates that Zika can reprogram these dendritic cells to a point that they effectively support the viral life cycle instead of defending patients against viral infection. Thus, Zika virus transforms its strongest adversaries in the human immune system into loyal friends.

(Summary submitted by Xu Yu, MD, of the Ragon Institute)

19. SHINGLES RISK AMONG PATIENTS WITH PSORIASIS
Herpes Zoster Rates in a Large Cohort of Patients With Systemically Treated Psoriasis
Levandoski KA, Quesenberry CP, Tsai AL, Asgari MM
Published in JAMA Dermatology on December 20, 2017

Many systemic medications used to treat psoriasis, including genetically engineered drugs called biologics, have been linked to increased shingles risk in other diseases, but few studies have focused on shingles risk among systemically-treated psoriasis patients. Using data from a large, community-based practice setting, we compared shingles rates among 5,889 psoriasis patients treated with biologics and non-biologic medications. We found no significant differences in shingles risk among those exposed to biologic versus non-biologic therapy after adjusting for patient age and sex. Our findings suggest that among psoriasis patients, treatment with a biologic or a non-biologic medication does not differentially impact shingles risk.

(Summary submitted by Maryam Asgari, MD, of the Department of Dermatology)

20. HYPOGLYCEMIA IN HOSPICE PATIENTS WITH TYPE 2 DIABETES
Hypoglycemia in Hospice Patients With Type 2 Diabetes in a National Sample of Nursing Homes
Petrillo LA, Gan S, Jing B, Lang-Brown S, Boscardin WJ, Lee SJ
Published in JAMA Internal Medicine on December 26, 2017

About a quarter of Americans die in nursing homes. In this study, we evaluated whether adults with type 2 diabetes experienced hypoglycemia (low blood sugar) while on hospice in veterans’ nursing homes, since hypoglycemia signals inappropriately aggressive diabetes treatment in patients close to death and contributes to unnecessary discomfort. We found that one in nine people experienced hypoglycemia at least once while receiving hospice care. Hypoglycemia was most common among patients receiving insulin. Our study indicates that clinicians in nursing homes may not fully switch from usual care to comfort-focused care when adults with type 2 diabetes are enrolled in hospice.

(Summary submitted by Laura Petrillo, MD, of the Department of Medicine)

21. REACTIVATING DORMANT X CHROMOSOMES
A Mixed Modality Approach Towards Xi Reactivation for Rett Syndrome and Other X-Linked Disorders
Carrette LLG, Wang CY, Wei C, Press W, Ma W, Kelleher RJ 3rd, Lee JT
Published in PNAS on December 27, 2017

The X-chromosome harbors hundreds of disease genes, a subset of which gives rise to neurodevelopmental disorders such as Rett syndrome (RTT). There is presently no disease-specific treatment. Here, we identified a pharmacologically relevant cocktail that is able to reactivate part of the second inactive X chromosome. While females have two X chromosomes, only one is active in order to have a similar gene expression as males who have only one X chromosome. The other is dormant but we reactivated part of it to express the protein (MECP2) that is mutated in Rett syndrome. Cells that were missing this protein on the active X chromosome were able to restore expression of some of the protein from the inactive X upon treatment. These findings provide proof of concept for a mixed modality approach to treating X-linked disorders, including RTT.

(Summary submitted by Jeannie Lee, MD, PhD, of the Department of Molecular Biology and Howard Hughes Medical Institute, and Lieselot Carrette, PhD, of the Department of Molecular Biology)

Press Releases

Study Finds More Than 1 in 6 Patients With Peripheral Arterial Disease Who Undergo Revascularization Readmitted Within 30 Days
Featuring Eric Secemsky, MD, MSc

A study of nearly 62,000 hospitalizations nationwide has found that more than one in six patients with peripheral arterial disease who undergo revascularization procedures to restore blood flow to blocked leg arteries and other arteries outside of the heart are readmitted to the hospital within 30 days.

Opioid Deaths Jump
Featuring Zirui Song, MD, PhD

People who end up in the hospital due to an opioid-related condition are four times more likely to die now than they were in 2000, according to research led by a Harvard Medical School/Massachusetts General Hospital investigator.

Targeting the Bone Marrow to Drive Brain Repair After Radiation Injury
Featuring David Scadden, MD, and Jorg Dietrich, MD, PhD

Researchers leverage a link between the bone marrow and brain regeneration, aiming to improve outcomes for brain tumor patients with radiation injury.

When the Doctor's Away
Featuring Anupam Jena, MD, PhD, and Daniel Blumenthal, MD

A study led by Massachusetts General Hospital/Harvard Medical School physicians finds that temporary, "locum tenens" physicians provide the same level of care as regular hospital staff.

Novel Harvesting Method Rapidly Produces Superior Stem Cells for Transplantation
Featuring Jonathan Hoggatt, PhD

A new method of harvesting stem cells for bone marrow transplantation – developed by a team of investigators from the Massachusetts General Hospital Cancer Center and the Harvard Stem Cell Institute – appears to accomplish two goals: making the donation process more convenient and less unpleasant for donors and providing cells that are superior to those acquired by current protocols.

Patient Satisfaction, Communication with Caregivers Can Reduce Risk of Hospital Readmission
Featuring Jocelyn Carter, MD

A survey of patients admitted to Massachusetts General Hospital has found that patients reporting greater levels of satisfaction with their care and good communication with their health care providers were significantly less like to readmitted to the hospital in the 30 days after discharge.

Mass General Team Identifies DNA Element that May Cause Rare Movement Disorder
Featuring Nutan Sharma, MD, PhD, Cristopher Bragg, PhD, and Laurie Ozelius, PhD

A team of Massachusetts General Hospital researchers has identified a specific genetic change that may be the cause of a rare but severe neurological disorder called X-linked dystonia parkinsonism, which occurs only among individuals with ancestry from the Philippines island of Panay.

Centralized Population Health Coordinators Help Improve Care for Patients with Chronic Disease
Featuring Jeffrey Ashburner, PhD, MPH

A centralized chronic disease management program produced significant improvements in the care of patients with diabetes, hypertension or cardiovascular disease treated at practices in the Massachusetts General Hospital primary care network.

That Feeling in Your Bones
Featuring Anupam Jena, MD, PhD

Rainy weather has long been blamed for achy joints. Unjustly so, according to new research from investigators at Massachusetts General Hospital and Harvard Medical School.

Underactive Thyroid Within Normal Range May Affect Woman's Ability to Conceive
Featuring Pouneh Fazeli, MD

New research suggests that a slightly underactive thyroid may affect a women's ability to become pregnant--even when the gland is functioning at the low end of the normal range.

Should Uninfected Patients Accept Hepatitis C-Infected Livers to Reduce Waiting Time?
Featuring Jagpreet Chhatwal, PhD, Raymond Chung, MD, Sumeyye Samur, PhD, and Emily Bethea, MD

A study by Massachusetts General Hospital investigators finds that the availability of directly-acting antiviral drugs to treat hepatitis C virus infection could allow the transplantation of livers from HCV-positive donors into HCV-negative recipients without posing undue risk.

New Evidence Supports HIV Screening in Young Adulthood
Featuring Anne Neilan, MD, MPH, and Andrea Ciaranello, MD, MPH

A new study led by Massachusetts General Hospital investigators suggests that the most beneficial age for a one-time screening HIV test of the general population would be age 25.

Many Brain Tumor Patients Do Not Receive Adequate End-of-Life Care
Featuring Justin Jordan, MD, MPH, and Deborah Forst, MD

While more than 60 percent of patients with the brain tumors called malignant gliomas enroll in hospice services, almost a quarter of them do so within a week of death, probably too late for patients and family members to benefit from hospice care.

MGH Team Engineers Anti-Inflammatory Antibodies that May Treat Autoimmune Disease
Featuring Robert Anthony, PhD

A team of Massachusetts General Hospital investigators has found a way to engineer antibodies within an organism, converting autoantibodies that attack “self” tissues into anti-inflammatory antibodies in animal models of two autoimmune diseases.

Blog Posts

World AIDS Day 2017
Featuring Sara Looby, PhD, ANP-BC, FAAN, Julie Levison, MD, MPH, MPhil, FACP, and Krishna Reddy, MD

Each year, December 1st marks World AIDS Day. Learn how Massachusetts General Hospital researchers are working to expand our knowledge of the HIV virus, reduce transmission rates, and advance treatment.

Four Mass General Investigators Recognized with Endowed Chairs
Featuring Marlene Freeman, MD, Moussa Mansour, MD, Patrick L. Purdon, PhD, and Van Wedeen, MD

Massachusetts General Hospital recently established four endowed chairs. Meet the four investigators whose contributions have been recognized through their appointment to these roles and join us in congratulating them!

Proteins Take Shape with New Technology
Featuring Luke Chao, PhD

A new technique called cryo-electron microscopy (cryo-EM) provides scientists with an opportunity to better see the shapes of molecules. Learn more about this exciting technology in our recap of a recent Proto Magazine podcast featuring Luke Chao from the Mass General department of molecular biology.

Study Predicts Alzheimer’s Cases to Double in US by 2060. How Mass General Researchers are Fighting Back
Featuring Doo Yeon Kim, PhD, Rudy Tanzi, PhD, Mark Albers, MD, PhD, Martin Reuter, PhD, Jorge Sepulcre, MD, PhD, Yakeel T. Quiroz, PhD, and Edmarie Guzman-Velez, PhD

A new report from the NIH estimates that there are 6 million Americans who currently have either Alzheimer’s disease or some form of cognitive impairment, and that number is expected to more than double to 15 million by 2060. Learn how researchers from Massachusetts General Hospital are fighting back with improved diagnoses and treatments.

Gatchel Untangles the Causes of Mood and Anxiety Symptoms and Loss of Brain Function in Aging Populations
Featuring Jennifer Gatchel, MD, PhD

Could there be a link between mental illnesses, like depression and anxiety, and Alzheimer's disease? Learn how Jennifer Gatchel, a Massachusetts General Hospital geriatric psychiatrist and researcher, is untangling the causes of these conditions and how her results could advance clinical care.

12 Days of Research at Mass General: She Watches Worms While They Sleep
Featuring Haley Mattison, PhD

How can the sleep habits of tiny worms tell us more about the brain chemistry behind a good night's sleep? Haley Mattison, PhD, a postdoctoral researcher in the laboratory of Joshua Kaplan, PhD, explains the connection.

12 Days of Research at Mass General: Autism and the Blood-Brain Barrier

A study from researchers at Mass General Hospital for Children found alterations in both the brain-blood barrier and intestinal permeability in individuals with autism. These alterations could be contributing to the inflammation of nervous system tissue and impacting behavior.

12 Days of Research at Mass General: Lack of Sleep Can Impact Childhood Behavior
Featuring Elsie Taveras, MD, MPH

Want to set your children up for success in school? You can start by establishing good sleep habits at an early age. Researchers at the Mass General Hospital for Children found that children ages 3 to 7 who don't get enough sleep are more likely to have behavioral problems later in childhood.

12 Days of Research at Mass General: Aspirin and Risk of Cancer Death
Featuring Yin Cao, MPH, ScD

In a large scale study of health outcomes from 86,000 women and 44,000 men over a 32 year period, researchers from Mass General found that long-term aspirin use was associated with a lower risk of dying from colorectal cancer, breast cancer and prostate cancer, among others.

12 Days of Research at Mass General: Do Alzheimer’s Patients Suffer Silent Seizures?
Featuring Andrew Cole, MD, and Alice Lam, MD, PhD

New research from Massachusetts General Hospital suggests a potential new connection between the devastating memory loss associated with Alzheimer's disease and "silent" seizures in the memory center of the brain.

12 Days of Research at Mass General: Why Autistic Individuals Avoid Eye Contact
Featuring Nouchine Hadjikhani, MD, PhD

A new research study finds that a region of the brain that responds to eye contact is overstimulated in autistic individuals, which could help to explain why they tend to avoid eye contact during conversations.

12 Days of Research at Mass General: A Strategy for Sneaking Drugs Into Tumor Cells
Featuring Miles Miller, PhD, and Ralph Weissleder, MD, PhD

At Massachusetts General Hospital, a real-life Trojan horse scenario that takes place on the nanoscale level could provide a way to sneak cancer drugs into fortified tumor cells so the drugs can attack from within.

12 Days of Research at Mass General: Predicting Painful Migraine Attacks
Featuring Tim Houle, PhD

At team of researchers at Massachusetts General Hospital has developed a new forecasting model that has the potential to pinpoint when a migraine will strike by tracking an individual's stress levels over time.

12 Days of Research at Mass General: Lady Gaga News Highlights Fibromyalgia Research
Featuring Marco Loggia, PhD

Lady Gaga has been remarkably honest and open about her struggles with fibromyalgia, a chronic pain disorder that has been challenging to diagnose and treat because there is no test for it. Researchers at Mass General are hoping to change that by using imaging techniques to identify the brain changes associated with fibromyalgia.

12 Days of Research at Mass General: Modeling Alzheimer’s Disease in 3D
Featuring Doo Yeon Kim, PhD, and Rudy Tanzi, PhD

Find out how an innovative new approach to modeling Alzheimer's disease in the lab—one that uses a three-dimensional gel that more accurately replicates how neurons interact in the brain—could help speed up research and treatment efforts.

12 Days of Research at Mass General: An On-the-Go Test For Food Allergies
Featuring Ralph Weissleder, MD, PhD, and Hakho Lee, PhD

What if you could quickly and accurately test the food at a restaurant for the presence of allergens such as gluten, milk, eggs or peanuts? A research team at Mass General has created a keychain-sized device to do just that, and it could soon be available for less than $50.

12 Days of Research at Mass General: Untangling the Connections Between Alzheimer's Disease and Mental Illness
Featuring Jennifer Gatchel, MD, PhD

How do psychological symptoms such as depression and anxiety intertwine with cognitive disorders such as Alzheimer's disease in senior citizens? Jennifer Gatchel, MD, PhD, is using brain imaging technology to untangle these complex connections.