tbuckley/cabot-search huggingface dataset:
VA Efforts to Reduce Opioid Overdose Deaths in At-Risk Veterans
Authors: Rita Rubin
Journal: JAMA (2019)

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Abstract 13187: Does Supplementation to Higher Plasma Omega-3 Levels Predispose to Prostate Cancer? Results From the Intermountain INSPIRE Biobank Registry
Authors: Viet T Le, Kirk U Knowlton, Mohit Jain, Raymond O McCubrey, Stacey Knight, Mahan Najhawan, Khoi Dao, Jeramie Watrous, Tami L Bair, Benjamin D Horne, Joseph B Muhlestein, Donald L Lappe, John F Carlquist, Jeffrey L Anderson
Journal: Circulation (2019)

Introduction: Omega-3 supplements are widely used for cardiovascular (CV) prevention. However, Brasky et-al* reported that levels of long-chain fatty acids correlated positively with the developmen...
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma
Authors: Sangeeta Goswami, Thomas Walle, Andrew E. Cornish, Sreyashi Basu, Swetha Anandhan, Irina Fernandez, Luis Vence, Jorge Blando, Hao Zhao, Shalini Singh Yadav, Martina Ott, Ling Y. Kong, Amy B. Heimberger, John de Groot, Boris Sepesi, Michael Overman, Scott Kopetz, James P. Allison, Dana Pe’er, Padmanee Sharma
Journal: Nature Medicine (2019)
A comprehensive tumour immunogenomics platform for precision immunotherapy: Enabling simultaneous characterization of tumours and the TME from a single FFPE sample
Authors: R. Power, G. Bartha, J. Harris, S.M. Boyle, E. Levy, P. Milani, P. Tandon, R. Li, M. Chinnappa, A. Haddad, P. McNitt, R. McClory, M. Morra, S. Saldivar, M. Clark, C. Haudenschild, E. Newburn, C. Johnson, R. Chen, J. West
Journal: Annals of Oncology (2019)
Kidney residency of VISTA-positive macrophages accelerates repair from ischemic injury
Authors: Jun-Gyu Park, Cho-Rong Lee, Min-Gang Kim, Gwanghun Kim, Hyun Mu Shin, Yun-Hui Jeon, Seung Hee Yang, Dong Ki Kim, Kwon Wook Joo, Eun Young Choi, Hang-Rae Kim, Cheol Kwak, Yon Su Kim, Murim Choi, Dong-Sup Lee, Seung Seok Han
Journal: Kidney International (2019)
Reversal of acquired resistance to pazopanib in soft tissue sarcoma with addition of an mTOR inhibitor: A case report.
Authors: Daniela Katz, Aviad Zick, Jonathan E. Cohen, Amir Sonnenblick, Evgeniya Fridman, Dorith Shaham, Tamar Peretz
Journal: Journal of Clinical Oncology (2013)

e21508 Background: Pazopanib (P) is a multikinase inhibitor targeting the VEGF and PDGF receptors capable of controlling soft tissue sarcoma for several months. Acquired resistance to P usually leads to chemotherapy resumption. We present a case of reversal of acquired resistance to P by addition of an mTOR inhibitor. Methods: A 46 year old female, completed five cycles of adjuvant treatment with epirubicin and ifosfamide followed by radiotherapy for a fully resected gluteal pleomorphic undifferentiated sarcoma. Ten months later, a single lung metastasis was resected, followed by trabectedin, then switched to gemcitabine and docetaxel after five cycles due to progression. Seven cycles were given with stable disease as best response. Upon progression, P 800mg/d was initiated as part of a compassionate program and continued for six months with a partial response. When disease progressed, treatment was switched to doxorubicin, dacarbazine and cyclophosphamide with rapid progression after two cycles, both complicated by febrile neutropenia. Uncontrolled disease after stopping P, limited response to chemotherapy in the past and worsening myelosupression led us to reintroduce P at 400mg/d in combination with sirolimus 2mg/d with the intention of overcoming acquired resistance to P by inhibiting downstream intracellular mediators. Results: One week after P and sirolimus initiation, pain in a paracostal protruding lesion subsided with softening and a decrease in mass size. After six weeks a CT scan demonstrated a partial response by Choi criteria with an 18% tumor shrinkage and decreased enhancement. Most of the lesions were previously of mixed density and became predominantly necrotic. Treatment was very well tolerated. Conclusions: We report a renewed response to P with addition of an mTOR inhibitor in advanced pleomorphic undifferentiated sarcoma. Crosstalk between pathways, upregulation of PI3K/mTOR signaling along with a rebound effect stirred by cessation of VEGFR blockade may have all contributed to more aggressive disease at the time of progression and may explain reversal of resistance by the addition of a downstream inhibitor such as sirolimus. A study designed to prove this concept is underway.
Estimating the Natural History of Cervical Carcinogenesis Using Simulation Models: A CISNET Comparative Analysis
Authors: Emily A Burger, Inge M C M de Kok, Emily Groene, James Killen, Karen Canfell, Shalini Kulasingam, Karen M Kuntz, Suzette Matthijsse, Catherine Regan, Kate T Simms, Megan A Smith, Stephen Sy, Fernando Alarid-Escudero, Vivek Vaidyanathan, Marjolein van Ballegooijen, Jane J Kim
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background The natural history of human papillomavirus (HPV)-induced cervical cancer (CC) is not directly observable, yet the age of HPV acquisition and duration of preclinical disease (dwell time) influences the effectiveness of alternative preventive policies. We performed a Cancer Intervention and Surveillance Modeling Network (CISNET) comparative modeling analysis to characterize the age of acquisition of cancer-causing HPV infections and implied dwell times for distinct phases of cervical carcinogenesis. Methods Using four CISNET-cervical models with varying underlying structures but fit to common US epidemiological data, we estimated the age of acquisition of causal HPV infections and dwell times associated with three phases of cancer development: HPV, high-grade precancer, and cancer sojourn time. We stratified these estimates by HPV genotype under both natural history and CC screening scenarios, because screening prevents cancer development that affects the mix of detected cancers. Results The median time from HPV acquisition to cancer detection ranged from 17.5 to 26.0 years across the four models. Three models projected that 50% of unscreened women acquired their causal HPV infection between ages 19 and 23 years, whereas one model projected these infections occurred later (age 34 years). In the context of imperfect compliance with US screening guidelines, the median age of causal infection was 4.4–15.9 years later compared with model projections in the absence of screening. Conclusions These validated CISNET-CC models, which reflect some uncertainty in the development of CC, elucidate important drivers of HPV vaccination and CC screening policies and emphasize the value of comparative modeling when evaluating public health policies.
Contractile myosin rings and cofilin-mediated actin disassembly orchestrate ECM nanotopography sensing
Authors: Stefania Di Cio, Thomas Iskratsch, John T. Connelly, Julien E. Gautrot
Journal: Biomaterials (2019)

The nanotopography and nanoscale geometry of the extra-cellular matrix (ECM) are important regulators of cell adhesion, motility and fate decision. However, unlike the sensing of matrix mechanics and ECM density, the molecular processes regulating the direct sensing of the ECM nanotopography and nanoscale geometry are not well understood. Here, we use nanotopographical patterns generated via electrospun nanofibre lithography (ENL) to investigate the mechanisms of nanotopography sensing by cells. We observe the dysregulation of actin dynamics, resulting in the surprising formation of actin foci. This alteration of actin organisation is regulated by myosin contractility but independent of adapter proteins such as vinculin. This process is highly dependent on differential integrin expression as β3 integrin expressing cells, more sensitive to nanopattern dimensions than β1 integrin expressing cells, also display increased perturbation of actin assembly and actin foci formation. We propose that, in β3 integrin expressing cells, contractility results in the destabilisation of nanopatterned actin networks, collapsing into foci and sequestering regulators of actin dynamics such as cofilin that orchestrate disassembly. Therefore, in contrast to the sensing of substrate mechanics and ECM ligand density, which are directly orchestrated by focal adhesion assembly, we propose that nanotopography sensing is regulated by a long-range sensing mechanism, remote from focal adhesions and mediated by the actin architecture.
Desiderata for delivering NLP to accelerate healthcare AI advancement and a Mayo Clinic NLP-as-a-service implementation
Authors: Andrew Wen, Sunyang Fu, Sungrim Moon, Mohamed El Wazir, Andrew Rosenbaum, Vinod C. Kaggal, Sijia Liu, Sunghwan Sohn, Hongfang Liu, Jungwei Fan
Journal: npj Digital Medicine (2019)

Data is foundational to high-quality artificial intelligence (AI). Given that a substantial amount of clinically relevant information is embedded in unstructured data, natural language processing (NLP) plays an essential role in extracting valuable information that can benefit decision making, administration reporting, and research. Here, we share several desiderata pertaining to development and usage of NLP systems, derived from two decades of experience implementing clinical NLP at the Mayo Clinic, to inform the healthcare AI community. Using a framework, we developed as an example implementation, the desiderata emphasize the importance of a user-friendly platform, efficient collection of domain expert inputs, seamless integration with clinical data, and a highly scalable computing infrastructure.
Изменения пуринового метаболизма при раке желудка
Authors: O.V. Syniachenko, R.F. Aliiev, M.V. Iermolaieva, V.G. Bondar
Journal: GASTROENTEROLOGY (2019)

Актуальность. Рак желудка (РЖ) считается актуальной проблемой онкологии, что объяс­няется его высокой распространенностью и смертностью вследствие него, запоздалой диагностикой заболевания, анатомо-топографическими особенностями поражаемого опухолью органа и низкой результативностью существующих методов лечения. Роль дисметаболизма пуринов в процессах канцерогенеза остается недостаточно изученной, а его клиническая значимость требует уточнения. Увеличение содержания мочевой кислоты в крови является фактором риска развития и дальнейшего тяжелого течения РЖ. Считается, что пуриновые основания относятся к опухолевым биомаркерам, но их диагностическая и прогностическая значимость при РЖ остается неизученной. Цель: оценить состояние пуринового метаболизма у больных РЖ, установить клинико-патогенетическую значимость выявленных изменений. Материалы и методы. Под наблюдением находились 88 больных РЖ (все мужчины) в возрасте от 29 до 79 лет (в среднем 60 лет). Локализация опухолевого процесса в выходном отделе желудка имела место в 76 % случаев, в теле — в 16 %, в антральном отделе — в 3 %, а тотальное поражение отмечено у 2 % от числа обследованных пациентов. Аденокарцинома диагностирована в 72 % наблюдений, аденогенный недифференцированный РЖ — в 18 %, плоскоклеточный — в 8 %, перстневидноклеточный — в 2 %. Соотношение IА, IB, IIA, IIB, IIIA, IIIB и IV стадий РЖ составило 1 : 3 : 9 : 12 : 6 : 5 : 6. Прорастание опухоли в селезенку установлено в 15 % случаев, в поджелудочную железу — в 7 %, в печень — в 6 %, в пищевод — в 3 %, в диафрагму — в 2 %, в желчный пузырь — в 1 %. Метастазы в лимфатические узлы обнаружены в 60 % наблюдений РЖ, в отдаленные органы — в 14 %. В сыворотке крови изучали уровни продуктов пуринового метаболизма — мочевой кислоты, оксипуринола, аденина, гуанина, ксантина, гипоксантина, активностей ксантиноксидазы, ксантиндезаминазы, аденозиндезаминазы и 5-нуклеотидазы. Результаты. Изменения пуринового метаболизма установлены у всех больных РЖ, в том числе по сравнению с контрольной группой здоровых лиц уровень мочевой кислоты был выше в 2,0 раза, оксипуринола — в 4,5 раза, аденина – на 16 %, активности ксантиноксидазы — в 2,1 раза, ксантиндезаминазы — на 33 % и аденозиндезаминазы — в 7,1 раза, повышенные показатели которых констатированы соответственно в 99, 84, 39, 90, 53 и 100 % случаев, зависят от степени тяжести течения опухолевого процесса, тотального поражения желудка, прорастания опухоли в печень, поджелудочную железу и пищевод, наличия метастазов в парааортальные лимфатические узлы, печень, легкое, скелет и головной мозг, а нарушения обмена пуринов ухудшают трехлетнюю выживаемость пациентов на фоне выполненного хирургического, медикаментозного и лучевого лечения. Выводы. Изменения пуринового метаболизма участвуют в патогенетических построениях РЖ, отражают особенности течения опухолевого процесса, причем параметры мочевой кислоты и аденина имеют прогностическую значимость.
Patients with Sickle Cell Disease and Venous Thromboembolism Experience Increased Frequency of Vasoocclusive Events
Authors: Romy Carmen Lawrence, Sarah L Khan, Vishal Gupta, Brittany Scarpato, Rachel Strykowski, Julia Newman, John Mark Sloan, Robyn T. Cohen, Seyed Mehdi Nouraie, Elizabeth S Klings
Journal: Blood (2019)
Abstract 11896: An Optimal Primary Arterial Switch Operation Timing Reduces Postoperative Complication and Costs for Delayed Patients With Transposition of the Great Arteries: A Decade In-Hospital Data From China
Authors: Shijun Gao, Yu Nie
Journal: Circulation (2018)

Introduction: Primary arterial switch operation (ASO) is recommended to be performed in TGA patients preferably within neonatal period. The recommended primary ASO timing is delayed for many patien...
Abstract B37: The complex immune-microenvironment heterogeneity in pancreatic cancer
Authors: Frederieke Grevers, Diba Latifi, Willem de Koning, Casper H.J. van Eijck, Dana A. Mustafa
Journal: Cancer Research (2019)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, resulting in more than 3,000 deaths per year in The Netherlands. The tumor microenvironment (TME) contributes largely to the treatment failure of the disease. TME consists of the stromal compartment, extracellular matrix, and tumor-infiltrative lymphocytes (TILs). Types and numbers of TILs are associated with clinical outcome, i.e., highCD8+: FOXP3 ratio is linked to a favorable prognosis. However, the intratumor immune variation in pancreatic cancer has not been studied so far. This study aims at investigating the differences of the immune infiltration within various areas of the same pancreatic cancer samples (intratumor variation) and comparing to healthy controls (extratumor variation). Such differences may be used for microenvironment remodeling, which may open new therapeutic approaches for PDAC patients. Materials and Methods: Formalin-fixed, paraffin-embedded (FFPE) samples of 26 PDAC patients and 8 healthy controls were selected. RNA was isolated separately from the tumor core and from the adjacent normal-like pancreatic tissue of the same sample. Immune profiling was carried out using the PanCancer Immune Profiling Panel of Nanostring technology. Subsequently, the gene expression data were analyzed using nSolver basic software and the advanced module. Results: The immune infiltration in the core of PDAC samples was different from that in the adjacent normal-like areas of the same patients. Tumor samples exhibited the lowest CD8+, Th1, neutrophil, and Natural Killer cell infiltration as compared to normal-like areas. In addition, the normal-like areas of PDAC samples showed a different immune profile as compared to the healthy controls. B lymphocytes were significantly higher in healthy controls compared to normal-like PDAC samples. Discussion and Conclusion: Our results present the variation in the immune microenvironment between the normal-like pancreatic tissue and the healthy pancreas, indicating that changes at the immune levels precede morphologic changes, tumorigenesis, and tumor cell infiltration. Additionally, specific changes in TILs occur in a gradient fashion from adjacent normal-like tissue to the tumor core. Understanding the differences of the immune microenvironment in the same tissue samples will enable developing an accurate microenvironment remodeling therapeutic approaches to treat PCDA patients. Citation Format: Frederieke Grevers, Diba Latifi, Willem de Koning, Casper H.J. van Eijck, Dana A. Mustafa. The complex immune-microenvironment heterogeneity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B37.
The trifunctional antibodies catumaxomab and ertumaxomab demonstrate efficacy in co-cultures of human multicellular tumor spheroids (MCTS) and peripheral blood mononuclear cells (PBMC)
Authors: Tobias Leidig, Franziska Wawrsinek, Carsten Lindemann, Wolfgang Mueller-Klieser
Journal: Cancer Research (2008)

399  Catumaxomab and ertumaxomab are intact, trifunctional monoclonal antibodies consisting of heavy chains of mouse IgG2a and rat IgG2b. The antibodies possess three different binding sites: the mouse Fab fragment binds to the tumor associated antigens human EpCAM or HER-2/neu, respectively; the rat Fab fragment targets human CD3 on T-cells; and a third functional binding site within the hybrid Fc-region selectively binds to and activates Fcγ-receptor-positive accessory cells.  The mode of action is based on the formation of a postulated tricell complex. The simultaneous recruitment and activation of T-cells and accessory cells leads to physiological co-stimulation of T cells, improved tumor cell elimination by different killing mechanisms and phagocytosis as well as processing and presentation of tumor material by bound and activated accessory cells.  We have used a 3D tumor model well-established in our laboratory, i.e. multicellular tumor spheroids (MCTS). MCTS were cultured using the EpCAM and HER-2/neu expressing cell line FaDu (human HNSCC) under standardized conditions. Studies were done in miniaturized spinner flasks in suspension culture. We focused on dose response and immune effector cell functions. Spheroids were co-cultured in spinner flasks under constant conditions in 20 ml medium with PBMC (1x106/ml) and different concentrations of antibody (0-10 ng/ml). The effect of combined therapy was quantified by the reduction of spheroid volume and clonogenicity. In histological sections the infiltration of CD45+ cells and the proportions of proliferating and apoptotic cells within the spheroid were assessed by immunostaining (Ki-67 and FragEL, respectively). Furthermore, different cytokines were analyzed using cytokine bead arrays (CBA). In addition, PCR with different PBMC relevant molecules was done to distinguish subsets of infiltrating leukocytes.  Here, we demonstrate the feasibility of co-culturing MCTS, as an adequate model for micro-metastases, with PBMC in suspension under well-defined conditions. Furthermore, we show that therapeutic efficacy of trifunctional antibodies can be quantified by various endpoints.  Our studies revealed that both antibodies caused a significant reduction or rather destruction in spheroid volume. Tumor cell clonogenicity was reduced as well; clinically relevant concentrations decreased colony formation to non-detectable low levels. In this set of in vitro experiments apoptosis was one of the major causes of therapeutic spheroid shrinkage. Immunohistochemical staining suggests that apoptosis was caused by infiltrating leukocytes. Measurement of cytokine concentrations and PCR results suggest that these PBMC are mostly identified as NK and T cells.  Supported by Fresenius Biotech GmbH and TRION Pharma GmbH (Munich, Germany)
Immune Checkpoint Inhibitor-Related Adverse Cardiovascular Events in Patients With Lung Cancer
Authors: Kalyan R. Chitturi, Jiaqiong Xu, Raquel Araujo-Gutierrez, Arvind Bhimaraj, Ashrith Guha, Imad Hussain, Mahwash Kassi, Eric H. Bernicker, Barry H. Trachtenberg
Journal: JACC CardioOncology (2019)

The purpose of this study was to evaluate whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE) compared with non-ICI therapies in patients with lung cancer. ICIs activate the host immune system to target cancer cells. Though uncommon, cardiovascular immune-related adverse events can be life-threatening. A retrospective single-institution cohort study of 252 patients with pathologically confirmed lung cancer who received ICI or non-ICI therapy was analyzed. The primary endpoint was MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure. During a median follow-up of 6 months, MACE occurred in 13.3% of ICI-treated patients, with a median time to event of 51 days, compared with 10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66) in a univariable Fine-Gray regression analysis incorporating noncardiovascular death as a competing risk. Multivariable regression analyses determined that patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27; 95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100 pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE. Patients pre-treated or receiving combined immunotherapy with ICIs and vascular endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors (TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04). ICIs were not independently associated with an increased risk of MACE in patients with lung cancer, although power is an important limitation in these analyses. ICI-associated cardiotoxicity was associated with elevations in serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future studies are needed to further define the role of cardiac biomarkers as a monitoring strategy with ICI therapy.