Snapshot of Science for February 2020

Welcome to our Snapshot of Science for February 2020

Here's a quick look at some recent publications, press releases and stories about the Mass General Research Institute community.

In this issue we highlight:

25 new studies published in high impact journals, along with 19 summaries submitted by the research teams
8 new research-related press releases from the Mass General Public Affairs office

Publications

A NEW SUBGROUP OF NEUTRALIZING HIV-1 CONTROLLERS
Immunological Fingerprints of Controllers Developing Neutralizing HIV-1 Antibodies
Martin-Gayo E, Gao C, Chen YR, Ouyang Z, Kim D [et al.], Yu XG.
Published in Cell Reports on January 28, 2020

IDENTIFYING NEW HALLMARKS OF CANCER PREDISPOSITION
Aneuploidy and a Deregulated DNA Damage Response Suggest Haploinsufficiency in Breast Tissues of BRCA2 Mutation Carriers
Karaayvaz-Yildirim M, Silberman RE, Langenbucher A, Saladi SV [et al.], Ellisen LW.
Published in Science Advances on January 29, 2020 | *Summary available

ULTRA-FAST TECHNIQUE FOR SINGLE CELL ANALYSIS
Ultra-Fast Cycling for Multiplexed Cellular Fluorescence Imaging
Ko J, Oh J, Ahmed MS, Carlson JCT, Weissleder R.
Published in Angewandte Chemie on January 31, 2020

EVALUATING ACCESSIBILITY OF INFORMATION ON LUNG CANCER SCREENING WEBSITES
Evaluation of the Informational Content and Readability of US Lung Cancer Screening Program Websites
Gagne SM, Fintelmann FJ, Flores EJ, McDermott S, Mendoza DP [et al.], Little BP.
Published in JAMA Open Network on January 31, 2020 | *Summary available

EFFECTS OF REMOVING COHESIN ON GENE EXPRESSION
Cohesin Removal Reprograms Gene Expression upon Mitotic Entry
Perea-Resa C, Bury L, Cheeseman IM, Blower MD.
Published in Molecular Cell on February 7, 2020

SAVOLITINIB & OSIMERTINIB IN NON-SMALL CELL LUNG CANCER
Osimertinib Plus Savolitinib in Patients with EGFR Mutation-Positive, MET-Amplified, Non-Small-Cell Lung Cancer after Progression on EGFR Tyrosine Kinase Inhibitors: Interim Results from a Multicentre, Open-Label, Phase 1b Study
Sequist LV, Han JY, Ahn MJ, Cho BC, Yu H [et al.], Oxnard G.
Published in The Lancet Oncology on February 3, 2020

MICROENVIRONMENT REGULATION FOR CANCER IMMUNOTHERAPY
Combining Microenvironment Normalization Strategies to Improve Cancer Immunotherapy
Mpekris F, Voutouri C, Baish JW, Duda DG, Munn LL [et al.], Jain RK.
Published in PNAS on February 3, 2020 | *Summary available | Press Release

HIV THERAPY COSTS IN THE US
HIV Antiretroviral Therapy Costs in the United States, 2012-2018
McCann NC, Horn TH, Hyle EP, Walensky RP.
Published in JAMA Internal Medicine on February 3, 2020 | *Summary available

IDENTIFYING SIGNIFICANT DRIVER POINT MUTATIONS IN CANCER
Analyses of Non-Coding Somatic Drivers in 2,658 Cancer Whole Genomes
Rheinbay E, Nielsen MM, Abascal F, Wala JA, Shapira O [et al.], Getz G.
Published in Nature on February 5, 2020

COMPARING OPIOID USE DISORDER TREATMENTS
Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder
Wakeman SE, Larochelle MR, Ameli O, Chaisson CE, McPheeters JT [et al.], Sanghavi DM.
Published in JAMA Open Network on February 5, 2020 | *Summary available

EFFECTS OF KIDNEY TRANSPLANT ON CARDIOVASCULAR FUNCTION
Cardiovascular Functional Reserve Before and After Kidney Transplant
Lim K, Ting SMS, Hamborg T, McGregor G, Oxborough D [et al.], Hiemstra TF.
Published in JAMA Cardiology on February 5, 2020 | *Summary available

HIGH RIBOSOMAL PROTEIN CONCENTRATION LINKED TO CANCER METASTASIS
Deregulation of Ribosomal Protein Expression and Translation Promotes Breast Cancer Metastasis
Ebright RY, Lee S, Wittner BS, Niederhoffer KL, Nicholson BT [et al.], Micalizzi DS.
Published in Science on February 6, 2020 | *Summary available | Press Release

ROUTINE GENOTYPING UNCOVERS MUTATIONS IN CANCER PATIENTS
Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations Among Patients with Advanced Solid Tumors
Vidula N, Rich TA, Sartor O, Yen J, Hardin A [et al.], Cristofanilli M.
Published in Clinical Cancer Research on February 7, 2020 | *Summary available

EFFECTS OF REACTIVATING THE INACTIVE X CHROMOSOME
Widespread Organ Tolerance to Xist Loss and X Reactivation Except Under Chronic Stress in the Gut
Yang L, Yildirim E, Kirby JE, Press W, Lee JT.
Published in PNAS on February 10, 2020 | *Summary available

POTENTIAL "UNIVERSAL" TARGET FOR ANTIVIRAL TREATMENT
A Requirement for Argonaute 4 in Mammalian Antiviral Defense
Adiliaghdam F, Basavappa M, Saunder TL, Harjanto D, Prior JT [et al.], Jeffrey KL.
Published in Cell Reports on February 11, 2020 | *Summary available | Press Release

EFFECTS OF ADDITIONAL NEOADJUVANT CHEMOTHERAPY AFTER PCR
Pathological Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: a Comprehensive Meta-Analysis
Spring LM, Fell G, Arfe A, Sharma C, Greenup RA [et al.], Bardia A.
Published in Clinical Cancer Research on February 11, 2020 | *Summary Available

TRACKING MUMPS IN THE US
Combining Genomics and Epidemiology to Track Mumps Virus Transmission in the United States
Wohl S, Metsky HC, Schaffner SF, Piantadosi, Burns M [et al.], Sabeti PC.
Published in PLoS Biology on February 11, 2020

ROLE OF EARLY LIFE TRAUMA IN FUNCTIONAL NEUROLOGICAL DISORDER
Early-Life Trauma Endophenotypes and Brain Circuit-Gene Expression Relationships in Functional Neurological (Conversion) Disorder
Diez I, Larson AG, Nakhate V, Dunn EC, Fricchione GL [et al.], Perez DL.
Published in Molecular Psychiatry on February 12, 2020 | *Summary available | Press Release

RELATIONSHIP BETWEEN PCI, TAVR, AND TMVr
Association of Hospital Inpatient Percutaneous Coronary Intervention Volume with Clinical Outcomes After Transcatheter Aortic Valve Replacement and Transcatheter Mitral Valve Repair
Butala NM, Bucholz EM, Kolte D, Elmariah S.
Published in JAMA Cardiology on February 12, 2020 | *Summary available

POSTPARTUM COMPLICATIONS FOR NEWBORNS IN THE US
Patient and Hospital Factors Associated with Unexpected Newborn Complications Among Term Neonates in US Hospitals
Clapp MA, James KE, Bates SV, Kaimal AJ.
Published in JAMA Open Network on February 12, 2020 | *Summary available

MEDIATING FGF23 PRODUCTION TO MINIMIZE RISK OF ACUTE KIDNEY INJURY
Glycerol-3-Phosphate is a FGF23 Regulator Derived From the Injured Kidney
Simic P, Kim W, Zhou W, Pierce KA, Chang W [et al.], Rhee EP.
Published in Journal of Clinical Investigation on February 17, 2020

HIPPOCAMPAL PATHWAYS THAT PLAY A ROLE IN FEAR RESPONSES
Distinct Dorsal and Ventral Hippocampal CA3 Outputs Govern Contextual Fear Discrimination
Besnard A, Miller SM, Sahay A.
Published in Cell Reports on February 18, 2020 | *Summary available

KEY PROTEIN LEVELS IDENTIFIED IN YOUNG MEN WITH ASD
[11C]PBR28 MR-PET Imaging Reveals Lower Regional Brain Expression of Translocator Protein (TSPO) in Young Adult Males with Autism Spectrum Disorder
Zürcher NR, Loggia ML, Mullett JE, Tseng C, Bhanot A [et al.], Hooker JM.
Published in Molecular Psychiatry on February 19, 2020 | *Summary Available | Press Release

MET ALTERATIONS LINKED TO RESISTANCE TO LUNG CANCER
MET Alterations are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer
Dagogo-Jack I, Yoda S, Lennerz JK, Langenbucher A, Lin JJ [et al.], Hata AN.
Published in Clinical Cancer Research on February 21, 2020 | *Summary Available

NEW INSIGHTS INTO INFLUENZA VACCINES
Pulmonary Surfactant-Biomimetic Nanoparticles Potentiate Heterosubtypic Influenza Immunity
Wang J, Li P, Yu Y, Fu Y, Jiang H [et al.], Wu MX.
Published in Science on February 21, 2020

Summaries

Women who inherit BRCA1 and BRCA2 mutations have up to an 80% risk of developing breast cancer. To study the earliest steps in the development of these cancers, we analyzed normal breast tissues from preventive mastectomies of BRCA2 carriers. Using advanced molecular analyses, we found that nearly 30% of breast cells had major chromosomal damage, together with altered stress responses and cell survival, even in tissue that looked entirely normal microscopically. These findings suggest that that an early DNA damage response or repair defect may initiate these cancers. Understanding this defect may lead to more sensitive methods for breast cancer detection and prevention in this setting.

(Summary submitted by Leif Ellisen, MD, PhD, Division of Hematology Oncology, Mass General Cancer Center)

Annual CT lung screening has been shown to decrease deaths from lung cancer in high risk active and prior smokers. There are now hundreds of programs in the U.S. alone. These programs use websites as a key way to explain the process and to recruit patients for screening. Our group of chest radiologists analyzed almost 260 U.S. lung cancer screening program websites for reading level and content. Only four websites were written at the 6th grade level recommended by the American Medical Association. Only 3% of websites correctly mentioned the proper annual screening, and about half had information on smoking cessation. Only half reminded patients that Medicare and most private insurance plans cover the cost of screening.

(Summary submitted by Brent Little, MD, Department of Radiology)

Immunotherapy using immune checkpoint blockade has changed the standard of care in several cancers but an estimated 86% of patients currently do not derive long-term benefit. Therefore, new therapeutic strategies are needed to improve the durable response rates in patients who are resistant to this new treatment. We developed a mathematical framework to determine how strategies aimed at normalizing the tumor stromal compartment and the resulting increase in blood perfusion can improve immunotherapy efficacy. Our study incorporated complex interactions among various types of cancer cells, immune cells, stromal cells and the vasculature as well as physical mechanisms and derived guidelines for designing effective combinatorial therapeutic strategies.

(Summary submitted by Rakesh Jain, PhD, Department of Radiation Oncology, Mass General Cancer Center)

HIV THERAPY COSTS IN THE US
HIV Antiretroviral Therapy Costs in the United States, 2012-2018
McCann NC, Horn TH, Hyle EP, Walensky RP.
Published in JAMA Internal Medicine on February 3, 2020

Compared with other well-resourced countries, the US has the highest prices for antiretroviral therapy (ART), but one of the lowest rates of HIV viral suppression. We examined the increases in ART costs, as reported in the U.S. HIV guidelines from 2012-2018. We found first-line ART costs in 2018 range from $36,000-$48,000 per patient per year. Since 2012, the costs of first-line regimens have increased 34%, an average of 6% increase per year; this cost increase is 3.5-fold higher than the rate of inflation. As high drug costs are among the many structural barriers preventing sustained treatment access, slowing this trend of escalating costs is an essential to meet the national “End the HIV Epidemic” goals.

(Summary submitted by Rochelle Walensky, MD, MPH, Division of Infectious Diseases, Department of Medicine)

We studied nearly 41,000 adults with opioid use disorder and compared the effectiveness of six different treatment pathways—no treatment, outpatient counseling, intensive outpatient counseling, detox/residential, methadone/buprenorphine, or naltrexone—on overdose and opioid-related hospital or emergency room visits. When we compared the effectiveness of each treatment pathway to no treatment, only treatment with methadone or buprenorphine was associated with a reduction in overdose; a 76% reduction in overdose at three months and a 59% reduction in overdose at 12 months. Methadone and buprenorphine treatment were also associated with a reduction in opioid-related hospital or ER visits at three and 12 months.

(Summary submitted by Sarah Wakeman, MD, Department of Medicine, Primary Care)

It is unknown whether cardiovascular function alters after kidney transplantation. We assess changes in cardiovascular functional reserve before and after kidney transplantation by measuring maximum oxygen consumption (VO2Max) using state-of-the-art cardiopulmonary exercise testing (CPET) technology. We found that cardiovascular functional reserve significantly improved one year after kidney transplantation in the absence of substantial alterations in the structure of the heart. These findings tell us that kidney transplant can boost cardiovascular functional reserve and the potential mechanisms. The study also provides evidence that measuring cardiovascular function may be a better way to assess cardiovascular improvement or decline in kidney patients in future clinical trials.

(Summary submitted by Kenneth Lim, MD, PhD, Division of Nephrology, Department of Medicine)

Hormone receptor-positive breast cancer can shed tumor cells into the bloodstream facilitating their spread to distant metastatic sites. In this study, we have identified increased ribosome protein expression and protein translation as promoters of breast cancer metastasis. We have also identified a subset of circulating tumor cells in breast cancer patient blood samples that correlate with increased aggressiveness and poor clinical outcomes and exhibit higher levels of ribosome proteins. Importantly, we identified a combination of targeted therapies that disrupt ribosome function and slow cancer cell growth and are particularly effective against these aggressive breast cancer cells in a mouse model.

(Summary submitted by Douglas Micalizzi, MD, PhD, Division of Hematology Oncology, Mass General Cancer Center)

Poly ADP-ribose inhibitors (PARPi) are approved for the treatment of several malignancies with BRCA1/2 mutations, either germline (inherited) or somatic. In contrast, acquired reversion mutations in BRCA1/2 cause resistance to PARPi. We evaluated the utility of next-generation sequencing of cell-free DNA (liquid biopsies) to identify various types of BRCA1/2 mutations in individuals with advanced malignancies. We were able to identify a high rate of BRCA1/2 mutations including germline, somatic, and reversion mutations. Liquid biopsies may help to identify BRCA1/2 mutations that could influence clinical decision-making regarding PARPi for patients with advanced malignancies.

(Summary submitted by Neelima Vidula, MD, Division of Hematology Oncology, Mass General Cancer Center)

The inactive X chromosome (Xi) holds numerous good gene copies that are not normally used during a lifetime. There is growing interest in reactivating these genes as a method of treating X-linked disorders. Because Xi-reactivation would be expected to increase expression of some other X-linked genes, the safety of this approach must be investigated with care. Here, we use mouse models to investigate safety and observe a surprising tolerance to partial Xi-reactivation after ablating Xist RNA, the factor responsible for X-inactivation.

(Summary submitted by Jeannie Lee, MD, PhD, Department of Molecular Biology, Department of Pathology)

RNA interference (RNAi) is a gene silencing mechanism in humans and an antiviral strategy in lower organisms. The first RNAi-based therapy was approved by the FDA last year. At the core of RNAi are four Argonaute proteins: AGO1-4. Individual roles for AGOs has been elusive in any biological context. Here we found that AGO4 is essential for mammalian antiviral defense against influenza and other viruses. Thus, some aspects of antiviral RNAi have been maintained in mammals and AGO4 has a unique role in that process. Harnessing RNAi machinery, and particularly AGO4, may be a viable strategy for boosting host responses to virus infection.

(Summary submitted by Kate Jeffrey, PhD, Division of Gastroenterology, Department of Medicine)

The vast majority of patients who develop metastatic breast cancer first present with localized (stage I-III) disease. Among localized breast cancer patients, those undergoing neoadjuvant (pre-surgery) therapy represent an inherently high-risk population. In the largest individual patient-level meta-analysis to date on the topic, we demonstrated that achievement of a pathological complete response (i.e. no invasive cancer left at the time of surgery) was strongly associated with improved event free and overall survival. The receipt of additional cytotoxic chemotherapy following surgery did not further improve outcomes. The study results support the use of escalation/de-escalation strategies based on neoadjuvant response to personalize treatment. They also have broad implications for the drug approval process.

(Summary submitted by Laura Spring, MD, Division of Hematology Oncology, Mass General Cancer Center)

In this present resting-state functional MRI study, we performed two network (graph theory) analyses to evaluate how individual differences in the brain architecture related to the magnitude of previously experienced childhood maltreatment in 30 individuals with functional neurological disorder (FND). We identified that individual differences in the experience of physical abuse and to a lesser extent physical neglect correlated with heightened influence of limbic, cognitive and sensorimotor networks in the overall brain architecture. Furthermore, a greater degree of experienced physical abuse in childhood correlated with the connectivity strength between limbic and primary motor brain areas.

(Summary submitted by David Perez, MD, MMSc, Department of Psychiatry, Department of Neurology)

The Centers for Medicare and Medicaid Services (CMS) determines whether they will reimburse hospitals for aortic valve replacement (TAVR) and transcatheter mitral valve repair (TMVr) using a minimum threshold for the volume of percutaneous coronary intervention (PCI) operations performed by the hospital. However, the relationship between hospital PCI volume and TAVR and TMVr outcomes is unknown. We investigated whether hospital inpatient PCI volume is associated with in-hospital mortality and 30-day readmission after TAVR and TMVr and found no association between PCI volume and TAVR or TMVr outcomes. Further evidence is needed to support inclusion of PCI volume minimums in CMS requirements for hospital TAVR and TMVr programs.

(Summary submitted by Neel Butala, MD, MBA, Division of Cardiology, Department of Medicine)

Unexpected newborn complications are now being measured and reported as a marker of quality for obstetric care. We examined the individual and hospital-specific factors that are associated with these complications. Notably, we found that neonatal transfer was the most common complication for many hospitals and that transfer was more likely in hospitals that did not have neonatal intensive care units. These findings raise concerns that the metric may disproportionately penalize hospitals without higher levels of neonatal care if transfer is considered a severe newborn complication.

(Summary submitted by Mark Clapp, MD, MPH, Department of Obstetrics & Gynecology)

FGF23 is a key hormone that controls blood phosphate levels. Marked increases in FGF23 can occur with kidney disease and are associated with increased risk of cardiac toxicity, infection, and death. However, why FGF23 increases in acute kidney injury has been unknown. We measured several thousand molecules in blood obtained from the kidney vein of human volunteers and identified glycerol-3-phosphate as a kidney-derived molecule that stimulates bone and bone marrow production of FGF23. Further, animal and cellular studies identified several key proteins as potential treatment targets to lower FGF23 levels in kidney disease.

(Summary submitted by Eugene Rhee, MD, Division of Nephrology, Department of Medicine)

Safely navigating the world requires an assessment of contextual information pertaining to threat. Depending on the level of danger perceived in any given situation, our brains help choose the best possible response to survive: pausing, fight or flight. Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination, but the pathways that route contextual information to guide adaptive behavioral responses are poorly understood. These studies illuminate how distinct dCA3 and vCA3 outputs calibrate contextual fear discrimination.

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

Autism spectrum disorder (ASD) is a common brain disorder impacting social skills for which there is no biomarker. We conducted a combined positron emission tomography (PET)-magnetic resonance imaging study to investigate brain expression of mitochondrial translocator protein (TSPO), which is involved in immune and mitochondrial functions. PET scans showed lower levels of TSPO in males with ASD compared to matched controls in several brain areas. Our study suggests that neuroimmune processes and/or metabolic functions may be affected in ASD in certain brain regions. Our work adds to findings from previous research efforts that have suggested a role for this mitochondrial protein in psychiatric disorders.

(Summary submitted by Nicole Zürcher Wimmer, PhD, Department of Radiology, Martinos Center)

ALK tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of lung cancer patients whose tumors harbor ALK fusions. However, drug resistance eventually develops, leading to relapse. We found that approximately 15% of patients relapsing on next-generation ALK TKIs had new amplifications or rearrangements of the MET receptor tyrosine kinase gene. Experimental studies showed that these mutations activated ALK-independent survival pathways and were sufficient to cause drug resistance. Two ALK lung cancer patients with acquired MET alterations also responded to ALK/MET TKI combination therapy. These findings demonstrate that MET alterations are recurring and targetable mechanisms of resistance to ALK inhibitors, paving the way for future testing of ALK/MET TKI combinations in the clinic.

(Summary submitted by Aaron Hata, MD, PhD, Division of Hematology Oncology, Mass General Cancer Center)

Current influenza vaccines induce poor protection when the circulating virus mismatches the vaccine virus. We developed a novel strategy to encapsulate a potent interferon stimulator with pulmonary surfactant-biomimetic nanoparticles to greatly strengthen influenza vaccines. Nanoparticles-adjuvanted influenza vaccines could elicit immunity against all mismatched influenza viruses tested in two animal models as the vaccination stimulated both T cell and humoral immunity, in contrast to antibody induction only with the vaccines alone. This “Universal” influenza vaccines can well prepare us to battle various influenza viruses including pandemic ones if it is confirmed in humans.

(Summary submitted by Meixiong Wu, MD, PhD, Department of Dermatology, Wellman Center for Photomedicine)

Press Releases

Math Models Add Up to Improved Cancer Immunotherapy
Featuring Rakesh Jain, PhD

By creating mathematical models that represent the complex interactions within the tumor microenvironment, researchers at Mass General and Harvard Medical School can predict how tumors may respond to immunotherapy.

Mass General Hospital Researchers Identify New “Universal” Target for Antiviral Treatment
Featuring Kate Jeffrey, PhD

Researchers at Mass General have uncovered a novel potential antiviral drug target that could lead to treatments protecting against a host of infectious diseases – creating a pan, or universal, treatment. Their work suggests that the protein AGO4 is an “Achilles heel” for viruses.

Cancer Cells Alter Protein Production Machinery to Hasten Metastasis
Featuring Douglas Micalizzi, MD, PhD

An increase in ribosomes, the protein-making machinery found in every living cell, increases the potential for metastasis, report investigators from Mass General Cancer Center and Harvard Medical School.

Injury Prevention Experts and Advocates Call for Increased Funding for Gun Violence Research and Prevention Efforts
Featuring Peter Masiakos, MD, MD, FACS, FAAP

Led by Mass General physicians, injury prevention experts, including the 17th Surgeon General of the United States Richard Carmona, MD, MPH, FACS, call on legislators to address the gun violence epidemic and support public health-based approaches to research and prevention efforts.

New Study Offers the First Evidence of Brain Inflammation in Veterans with Gulf War Illness
Featuring Marco Loggia, PhD

In a new discovery, researchers at Mass General have detected widespread inflammation in the brains of veterans diagnosed with Gulf War illness.

‘Quit Vaping’ Searches Increased During Lung-Disease Outbreak
Featuring Sara Kalkhoran, MD, MAS

The series of serious vaping-related lung injuries that began emerging in 2019 led to a four fold increase in online searches for terms such as "quit vaping."

Study Provides Insights on How Early Life Trauma Can Contribute to Functional Neurological Disorder
Featuring David Perez, MD, MMSc

Researchers led by investigators at Mass General examined the brains of individuals who experienced early-life trauma, some with FND and others without the condition.

Imaging Study Detects Abnormally Low Levels of a Key Protein in Brains of Young Men with Autism Spectrum Disorder
Featuring Nicole Zürcher Wimmer, PhD

Using cutting-edge imaging technology, researchers at Mass General have shown that the brains of young men with autism spectrum disorder have low levels of a protein that appears to play a role in inflammation and metabolism.

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Snapshot of Science for February 2020