Snapshot of Science for July 2019

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

UNDERSTANDING HOW TUMORS BECOME RESISTANT TO RADIATION THERAPY
Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer
Kamran SC, Lennerz JK, Margolis CA, Liu D, Reardon B [et al.], Allen EM.
Published in Clinical Cancer Research on June 28, 2019 | *Summary available below

USING NON-FUNCTIONAL PANCREATIC TUMORS TO LEARN MORE ABOUT PANCERATIC CANCER
Enhancer Signatures Stratify and Predict Outcomes of Non-functional Pancreatic Neuroendocrine Tumors
Cejas P, Drier Y, Dreijerink KMA, Brosens LAA, Deshpande V [et al.], Shivdasani RA.
Published in Nature Medicine on July 1, 2019

OBSERVING FAMILIAL PRESCRIPTION PATTERNS OF OPIOID USERS
Prescription Patterns of Family Members After Discontinued Opioid or Benzodiazepine Therapy of Users
Barnett ML, Hicks TR, Jena AB.
Published in JAMA Internal Medicine on July 1, 2019

A NEW POTENTIAL COMBINATION THERAPY FOR GLIOBLASTOMA
Myc Targeted CDK18 Promotes ATR and Homologous Recombination to Mediate PARP Inhibitor Resistance in Glioblastoma
Ning JF, Stanciu M, Humphrey MR, Gorham J, Wakimoto H [et al.], Rabkin SD.
Published in Nature Communications on July 2, 2019 | *Summary available below

DEFINING THE MECHANISMS THAT CONTRIBUTE TO CELL REGENERATION
Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping
Severe N, Karabacak NM, Gustafsson K, Baryawno N, Courties G [et al.], Scadden DT.
Published in Cell Stem Cell on July 3, 2019 | *Summary available below

DEVELOPING AN ALGORITHM TO STREAMLINE LAPAROSCOPIC OBESITY SURGERY
Computer Vision Analysis of Intraoperative Video: Automated Recognition of Operative Steps in Laparoscopic Sleeve Gastrectomy
Hashimoto DA, Rosman G, Witkowski ER, Stafford C, Navarette-Welton AJ [et al.], Meireles OR.
Published in Annals of Surgery on July 3, 2019 | *Summary available below

DIFFERENTIATING BETWEEN HEALTHY AND PATHOLOGICAL AGING
Neuroepigenetic Signatures of Age and Sex in the Living Human Brain
Gilbert TM, Zürcher NR, Catanese MC, Tseng CJ, Di Biase MA [et al.], Hooker JM.
Published in Nature Communications on July 3, 2019 | *Summary available below

XIST, PRC1 AND SMCHD1 COLLABORATE IN AN OBLIGATORY, SEQUENTIAL MANNER
PRC1 Collaborates with SMCHD1 to Fold the X-Chromosome and Spread Xist RNA Between Chromosome Compartments
Wang CY, Colognori D, Sunwoo H, Wang D, Lee JT.
Published in Nature Communications on July 3, 2019

INTERPRETING INDIVIDUAL GENOMES
Analyzing and Reanalyzing the Genome: Findings from the MedSeq Project
Machini K, Ceyhan-Birsoy O, Azzariti DR, Sharma H, Rossetti P [et al.], Rehm HL.
Published in American Journal of Human Genetics on July 3, 2019 | *Summary available below

CREATING A UNIFIED MODEL OF CELLULAR STATES IN GLIOBLASTOMA
An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma
Neftel C, Laffy J, Filbin MG, Hara T, Shore ME [et al.], Suvà ML.
Published in Cell on July 9, 2019

OBSERVING ASSOCIATIONS BETWEEN PATERNAL AGE AND OFFSPRING RISK FOR PSYCHIATRIC DISORDERS
Paternal-age-related De Novo Mutations and Risk for Five Disorders
Taylor JL, Debost JPG, Morton SU, Wigdor EM, Heyne HO [et al.], Robinson EB.
Published in Nature Communications on July 10, 2019 | *Summary available below

ASSESSING RISK OF COLORECTAL CANCER AFTER POLYP REMOVAL
Long-term Risk of Colorectal Cancer After Removal of Conventional Adenomas and Serrated Polyps
He X, Hang D, Wu K, Nayor J, Drew DA [et al.], Song M.
Published in Gastroenterology on July 11, 2019 | *Summary available below

ENHANCING CAR T-CELL FUNCTION IN SOLID TUMORS
Enhanced CAR T-Cell Activity Against Solid Tumors by Vaccine Boosting through the Chimeric Receptor
Ma L, Dichwalkar T, Chang JYH, Cossette B, Garafola D [et al.], Irvine DJ.
Published in Science on July 12, 2019

EXAMINING OUTCOMES OF PATIENTS IN INTENSIVE CARE WITH ACUTE MYELOID LEUKEMIA
Outcomes for Older Adults with Acute Myeloid Leukemia After an Intensive Care Unit Admission
Slavin SD, Fenech A, Jankowski AL, Abel GA, Brunner AM [et al.], El-Jawahri A.
Published in Cancer on July 12, 2019 | *Summary available below

BLOOD FLOW AND OXYGEN DISTRIBUTION IN BRAIN TISSUE
More Homogeneous Capillary Flow and Oxygenation in Deeper Cortical Layers Correlate with Increased Oxygen Extraction
Li B, Esipova TV, Sencan I, Kılıç K, Fu B [et al.], Sakadžić S.
Published in eLife on July 15, 2019 | *Summary available below

DEVELOPING TARGETED THERAPIES FOR CRANIOPHARYNGIOMAS
Targeted Treatment of Papillary Craniopharyngiomas Harboring BRAF V600E Mutations
Juratli TA, Jones PS, Wang N, Subramanian M, Aylwin SJB [et al.], Brastianos PK.
Published in Cancer on July 17, 2019 | *Summary available below

COMPUTATIONAL MODEL PREDICTS PRODUCTS OF MICROBIAL COMMUNITIES
Predictive Metabolomic Profiling of Microbial Communities Using Amplicon or Metagenomic Sequences
Mallick H, Franzosa EA, Mclver LJ, Banerjee S, Sirota-Madi A [et al.], Huttenhower C.
Published in Nature Communications on July 17, 2019 | *Summary available below

TREATING LYMPHOMA THAT HAS SPREAD TO THE CENTRAL NERVOUS SYSTEM
Tisagenlecleucel CAR-T Cell Therapy in Secondary CNS Lymphoma
Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD [et al.], Maus M.
Published in Blood on July 18, 2019 | *Summary available below

POPULATION-BASED HEALTHCARE PAYMENT MODEL REDUCES MEDICAL SPENDING
Health Care Spending, Utilization, and Quality 8 Years into Global Payment
Song Z, Ji Y, Safran DG, Chernew ME.
Published in New England Journal of Medicine on July 18, 2019

A CAR T-CELL THERAPY FOR SOLID TUMORS
CAR T-Cells Secreting BiTEs Circumvent Antigen Escape Without Detectable Toxicity
Choi BD, Yu X, Castano AP, Bouffard AA, Schmidts A [et al.], Maus MV.
Published in Nature Biotechnology on July 22, 2019 | *Summary available below

COMPARING OPERATIVE AND NONOPERATIVE TREATMENT OF PNEUMOPERITONEUM
Management of Pneumoperitoneum: Role and Limits of Nonoperative Treatment
Udelsman B, Lee K, Qadan M, Lillemoe KD, Chang D [et al.], Cooper Z.
Published in Annals of Surgery on July 23, 2019

DISTINGUISHING SUBTYPES OF MEDULLOBLASTOMA
Resolving Medulloblastoma Cellular Architecture by Single-cell Genomics
Hovestadt V, Smith KS, Bihannic L, Filbin MG, Shaw ML [et al.], Northcott PA.
Published in Nature on July 24, 2019

INVESTIGATING ASSOCIATIONS BETWEEN KIDNEY DISEASE AND CARDIOVASCULAR DISEASE IN AFRICAN AMERICANS
Association of APOL1 Risk Alleles with Cardiovascular Disease in African Americans in the Million Veteran Program
Bick AG, Akwo E, Robinson-Cohen C, Lee K, Lynch J [et al.], Damrauer SM.
Published in Circulation on July 24, 2019

ULCERATIVE COLITIS REWIRES THE HUMAN GUT
Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis
Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G [et al.], Xavier RJ.
Published in Cell on July 25, 2019 | *Summary available below

Publication Summaries

Radiation therapy (RT) is generally very effective at killing cancer cells but why some tumor cells survive RT is unknown. To study this, we obtained tumor tissues from rectal cancer patients before/after chemotherapy and RT (CRT). We expected that RT may make tumors more vulnerable to attack by the immune system but found that this is not the case. To the contrary, tumors resistant to CRT showed signs of escaping from immune attack and a higher probability of spreading. This behavior was associated with mutation of KRAS and TP53 genes (=KP). Findings highlight the promise of molecular profiling to identify RT resistance mechanisms and inform novel treatments, especially in KP tumors.

(Summary submitted by Sophia Kamran, MD, Department of Radiation Oncology)

PARP inhibitors are a new class of cancer therapeutic, however their use has been limited to tumors with genetic deficiencies in DNA repair. Glioblastoma, a lethal brain tumor, is usually resistant to PARP inhibitors. We discovered that MYC amplification makes glioblastoma sensitive to PARP inhibitors due to repression of CDK18 expression. CDK18 promotes ATR activity, DNA repair and resistance to PARP inhibitors. Based on this, we examined the efficacy of ATR inhibitors combined with PARP inhibitors to treat mice with glioblastoma and found that it greatly extends survival, supporting clinical investigation of this combination therapy for patients with glioblastoma.

(Summary submitted by Samuel D. Rabkin, PhD, Department of Neurosurgery)

Bones are the foundry for blood. Bone marrow stromal cells guide blood production and play a key role in stem cell transplantation, but which cells do this and how remains poorly defined. In this paper, we analyzed stromal cell protein production one cell at a time and defined which cells are resistant to injury and foster regeneration of blood after stem cell transplant. A molecule not previously recognized as assisting regeneration was defined, thereby offering a potential approach to improve the process of stem cell transplantation.

(Summary submitted by Nicolas Severe, PhD, Department of Medicine)

Gathering objective data on what is happening during an operation is important to improve the quality of surgical care. This study describes the development of artificial intelligence algorithms for laparoscopic obesity surgery. We developed a deep learning model, SleeveNet, that has similar performance to experienced bariatric surgeons in identifying the steps of a laparoscopic sleeve gastrectomy from intraoperative video. This work provides the foundation for automating the identification of steps of an operation and could lead to the prevention of complications through the detection of deviations in expected performance during surgery.

(Summary submitted by Daniel Hashimoto, MD, Department of Surgery)

The aim of the study was to investigate whether histone deacetylases (HDACs), epigenetic enzymes that turn genes on or off, are altered in normal aging. Evidence from animal models suggests that those enzymes may be involved in tipping the balance from healthy to pathological aging and play a role in neurodegenerative diseases (e.g. Alzheimer’s disease). We discovered that they are increased in white matter areas in the brains of older individuals. Furthermore, the higher expression of HDAC enzymes was observed in areas that also exhibit structural changes in aging. Future studies may be able to target those enzymes for therapeutic intervention.

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

In this study, we describe results of the MedSeq Project aimed at finding clinically useful information in each person’s genome. We found that 15% of individuals were at risk for diseases such as cancer, heart disease and hearing loss. We also found that most people have variants suggesting non-standard reactions to medications and also carry variants that could put their future children or relatives at risk for giving birth to a baby with a serious disease. When we re-examined the genomes 1-2 years later, new risks were found in 22% based on new scientific discoveries.

(Summary submitted by Heidi Rehm, PhD, Center for Genomic Medicine)

Observed associations between advanced paternal age and offspring risk for psychiatric and developmental disorders are commonly attributed to genetic mutations that accumulate as men age. We used data from whole-exome sequenced parent-child trios in order to provide estimates of the magnitude of this risk for five disorders including autism spectrum disorder (ASD), and schizophrenia (SCZ). We also used Danish registry data to investigate whether observed associations between each disorder and older fatherhood are consistent with the effects of new mutations. We show that paternal-age-related mutations confer a small amount of risk for each disorder studied. For ASD and SCZ, epidemiologic associations with delayed paternity significantly exceed what could plausibly be explained by accumulating genetic changes.

(Summary submitted by Jacob Taylor, MD, Broad Institute)

Endoscopic screening reduces incidence and mortality of colorectal cancer by removal of precursor lesions (i.e., colorectal polyps). However, existing clinical guidelines for colonoscopy surveillance vary widely and are largely based on limited evidence. We examined the association between the first endoscopic findings and colorectal cancer risk and found that, compared to participants with no polyp on initial endoscopy, those with advanced adenomas and large serrated polyps are at higher subsequent risk of colorectal cancer. Our findings support the current guidelines which recommend repeat lower endoscopy within three years of a diagnosis of advanced adenoma and large serrated polyp. In contrast, nonadvanced adenoma or small serrated polyp may require less intensive surveillance than what the current guidelines recommend.

(Summary submitted by Mingyang Song, MD, ScD, Department of Medicine)

Older adults with acute myeloid leukemia (AML) face a difficult disease with a poor prognosis, including frequent admission to the intensive care unit (ICU). Our study examined ICU outcomes for this population. We found that although almost one third of older patients with AML are admitted to an ICU, nearly half survive to hospital discharge with good functional outcomes. Baseline performance status and the need for two or more life-sustaining therapies (such as intubation, vasopressors or renal replacement) predict in-hospital mortality. These data support the judicious use of ICU resources for older patients with AML.

(Summary submitted by Samuel Slavin, MD, Department of Medicine)

Our understanding of how capillary blood flow and oxygen distribute across cortical layers to meet the local metabolic demand is incomplete. We addressed this question by using two-photon imaging of resting-state microvascular oxygen partial pressure and flow in the whisker barrel cortex in awake mice. Our findings suggest that more homogeneous distribution of the physiological observables relevant to oxygen transport to tissue is an important part of the microvascular network adaptation to local brain metabolism. These results will inform the modeling of layer-specific cerebral oxygen delivery and consumption and improve our understanding of the diseases that affect cerebral microcirculation.

(Summary submitted by Baoqiang Li, PhD, Department of Radiology)

Craniopharyngiomas are brain tumors that can cause significant neurological and endocrinological complications. FDA-approved systemic treatments are not available for patients in whom craniopharyngiomas recur. In this study, we showed that a subgroup of craniopharyngiomas are characterized by the presence of a specific point mutation, BRAFV600E. Clinical case reports have now shown dramatic responses to targeted treatment with BRAF inhibitors. There is now an ongoing unique national clinical trial (Alliance A071601) to further investigate the role of targeted therapy in papillary craniopharyngiomas.

(Summary submitted by Priscilla Brastianos, MD, Mass General Cancer Center)

Microbial communities that inhabit the human body promote health and disease. Research to determine the mechanisms by which this functions is increasingly focused on metabolic products of these microbiomes. Alterations in metabolite pools can reveal pathological pathways, establish biologic markers and lead to unexpected hypotheses, but several hurdles to directly profile metabolites within a microbiome currently exist. We address this issue by developing a computational model that infers molecules produced by a given collection of microbial genomes. This approach allows researchers to expand the utility of existing microbiome data when metabolite profiling is unfeasible and is of interest to a broad set of microbial habitats.

(Summary submitted by Ramnik Xavier, MD, PhD, and Theresa Reimels, Department of Gastroenterology, Department of Molecular Biology)

TREATING LYMPHOMA THAT HAS SPREAD TO THE CENTRAL NERVOUS SYSTEM
Tisagenlecleucel CAR T-Cell Therapy in Secondary CNS Lymphoma
Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD [et al.], Maus M.
Published in Blood on July 18, 2019

CAR T-cell immunotherapy has been especially effective in blood cancers such as lymphoma, but the clinical trials that led to their approval specifically excluded patients with lymphoma involving the brain or central nervous system. In this study, we treated eight patients whose lymphoma had spread to the central nervous system with a CAR T-cell product called tisagenlecleucel, or Kymriah. We found that the patients tolerated the CAR T-cells without concerning side effects, and several patients had partial or even complete responses. This study represents the first systematic study of CAR T-cells in patients with lymphoma that has spread to the central nervous system and offers guidelines for physicians and hope for patients.

(Summary submitted by Marcela Maus, MD, PhD, Department of Hematology/Oncology, Mass General Cancer Center)

Chimeric antigen receptor (CAR) T-cell therapy is an exciting form of immunotherapy based on genetically modified human T-cells engineered to recognize and attack tumor cells. We described a new type of CAR T-cell therapy that could be significantly more effective against solid tumors, including the worst form of brain tumor, glioblastoma (GBM). These CAR T-cells could locally deliver a specialized molecule called a bispecific T-cell engager (BiTE), which could overcome several significant barriers in the treatment of solid tumors like GBM, including tumor heterogeneity, therapeutic access beyond the blood-brain barrier and tumor-associated immune suppression. The goal now will be to translate this novel therapy to a clinical trial in patients with glioblastoma.

(Summary submitted by Bryan Choi, MD, PhD, Department of Neurosurgery, and Marcela Maus, MD, PhD, Department of Hematology/Oncology, Mass General Cancer Center)

In this study we aimed to compare morbidity and mortality between nonoperative and operative treatment of pneumoperitoneum, also termed abdominal free air. We used novel techniques including natural language processing to identify a cohort of patients presenting with pneumoperitoneum. We found that in the absence of peritonitis, pneumoperitoneum can be safely treated with initial non-operative management with reduced morbidity and an expected operative conversion rate of 12%. This work can help clinicians triage patients and better individualize treatment.

(Summary submitted by Brooks Udelsman, MD, MHS, Department of Surgery)

African-American individuals with kidney disease have increased risk of cardiovascular disease. Mutations in APOL1 cause kidney disease in African-Americans. A number of recent studies have evaluated whether the APOL1 mutations also cause cardiovascular disease. In this study of 30,903 African American Veterans cared for in the US VA Health System, we found a modest increase in risk for coronary disease, stroke and peripheral artery disease in kidney disease-free individuals, however this association was attenuated when simultaneously modeling kidney disease. We conclude that the impact of APOL1 mutations on cardiovascular disease amongst African-Americans without kidney disease is modest.

(Summary submitted by Alexander Bick, MD, Department of Medicine)

The human gut represents a circuit, and disruptions in the circuit cause malfunctions or diseases such as ulcerative colitis (UC), a chronic inflammatory condition. Mapping the gut as a circuit holds diagnostic and therapeutic value; comparisons between healthy and disease states expose pathological disturbances and potential therapeutic entry points. We generated such maps by analyzing single cells from the colons of healthy individuals and UC patients. We classified new cell types, associating them with disease and resistance to treatment, and pinpointed populations in which susceptibility genes function. This work provides new insights into complex interactions underlying UC that will lead to a better understanding of gut health and inflammation.

(Summary submitted by Ramnik Xavier, MD, PhD, and Theresa Reimels, Department of Gastroenterology, Department of Molecular Biology)

The Mass General Difference

Conditions & Treatments

Patients & Visitors

Research & Innovation

Mass General
Research Institute

Snapshot of Science for July 2019

Publication Summaries