tbuckley/cabot-search huggingface dataset:
転移性膵癌におけるゲムシタビン対ゲムシタビン+AGS-1C4D4(ASP6182)を比較する大規模無作為化第II相臨床試験における前立腺幹細胞抗原陽性腫瘍を有する患者の改良された6か月生存率
Authors: Hidalgo Manuel, O’Reilly Eileen Mary, KO Yoo Joung, Blaszkowksy Lawrence Scott, Rarick Mark Urban, Lima Caio Max S. Rocha, S Ritch Paul, Chan Emily, L Spratlin Jennifer, Macarulla Teresa, Mcwhirter Elaine, Pezet Denis, Lichinitser Mikhail, D Roman Laslo, Hartford Alan, Jackson Lynnae, Vincent Martha, Reyno Leonard, M Wolpin Brian
Journal: Annals of Oncology (2011)
Measuring renal tumor endophycity by tumor center rather than edge
Authors: J. Schoephoerster, K. Moore, N. Heller, R. Tejpaul, C. Hornung, B. Byun, B. Abernathy, S. Abdulkadir, G. Struyk, J. Spriggs, A. Austin, B. Simpson, M. Hagstrom, N. Venkatesh, E. Walczak, J. French, S. Mcsweeney, S. Peterson, S. Virnig, D. Wu, C. Hannah, A. Jacobsen, N. Papanikolopoulos, C. Weight
Journal: European Urology (2021)
Vitamin K3 (menadione) Induces Cytotoxicity in Chronic Myeloid Leukemia Stem Cells By Upregulating DYRK2 through the Inhibition of SIAH2 Ubiquitin Ligase
Authors: Chun Shik Park, Ye Shen, Andrew H Lewis, Koramit Suppipat, Monica Puppi, Julie Tomolonis, Taylor J Chen, Paul Pang, Toni-Ann Mistretta, Leyuan Ma, Michael R Green, Rachel E. Rau, H. Daniel Lacorazza
Journal: Blood (2017)
Cytoreductive nephrectomy in patients receiving TKI therapy versus immune checkpoint inhibitor therapy: Comparative outcome analysis of the REMARCC registry
Authors: M.F. Meagher, A. Minervini, M. Mir, G. Rebez, R. Autorino, R. Campi, M. Kriegmair, E. Linares, V. Hevia, M. Musquera, M. D’Anna, E. Rousel, M. Albersen, N. Pavan, F. Claps, A. Antonelli, M. Marchioni, S. Erdem, N. Paksoy, I. Derweesh
Journal: European Urology (2021)
Abstract 1164: Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs
Authors: Sylwia Ammoun, Emmanuel A. Maze, Bora Agit, Robert Belshaw, C Oliver Hanemann
Journal: Cancer Research (2021)

Abstract Deficiency of the tumor suppressor Merlin causes the development of schwannoma, meningioma and ependymoma tumors. These can occur spontaneously or in the hereditary disease Neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Currently available treatments are surgery or radiosurgery which are only partially effective, with tumors frequently reoccurring and in case of meningioma often as a higher grade. There is an urgent need for effective drug treatments.In this study, we investigated the role of Human Endogenous Retrovirus Type K (HERV-K) and its targetability in Merlin negative schwannoma and meningioma tumors by using tissues and primary cells isolated form patients employing immunohistochemistry, immunocytochemistry, western blotting and proliferation assays. We demonstrate that HERV-K proteins are overexpressed in Merlin negative schwannoma and all meningioma grades. Furthermore, we implicate CRL4DCAF1 and YAPT/EAD Hippo pathway in this overexpression and suggest that exosome transport of the HERV-K Envelope (Env) protein might contribute to schwannoma development. We also show that: (i) Ectopic overexpression of HERV-K Env in normal Schwann cells increased proliferation and upregulated the transcription factor c-Jun. Env overexpression also increased activity of the extracellular signal-regulated kinase 1/2 (pERK1/2), a known mitogenic pathway in schwannoma. (ii) An anti-Env monoclonal antibody decreased pERK1/2 and reduced proliferation of schwannoma cells. iii) FDA-approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir decreased pERK1/2 and cyclin D1 and reduced proliferation of schwannoma and grade I meningioma cells. We provide evidence for HERV-K Env contributing to the development of NF2-associated schwannomas and meningiomas. Considering the urgent need of drugs to treat NF2, we suggest the trialling of antiretroviral protease inhibitors, and consideration of anti-HERV-K Env immunotherapy, as well as TEAD-specific inhibitors in these patients. The above treatments would also be potentially beneficial for patients with other tumors caused by Merlin deficiency. Citation Format: Sylwia Ammoun, Emmanuel A. Maze, Bora Agit, Robert Belshaw, C Oliver Hanemann. Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1164.
Abstract LB174: Discovery and preclinical characterization of INCA00186, a humanized monoclonal antibody antagonist of CD73, as a cancer immunotherapy
Authors: Shaun Stewart, Rebecca Buonpane, Jing Zhou, Michael Hansbury, Michael Smith, Hui Wang, None Lu, Bin Su, Rahel Awdew, Cheng-Yen Huang, Ashwini Kulkarni, Shane Harvey, Arpita Mondal, Steve Wang, Christina Stevens, Michael Pratta, Elham Behshad, Alexandra Fanuka, Xiaodi Ren, Holly Koblish, Horacio Nastri, Patrick Mayes
Journal: Cancer Research (2021)

Abstract In the tumor microenvironment, dying cells release ATP which gets converted to AMP by CD39. AMP is subsequently converted to immunosuppressive adenosine by the extracellular 5'-nucleotidase CD73. CD73 is linked to the cell surface by a GPI-anchor and can be released into the plasma as soluble CD73. In order to lower extracellular levels and reverse the immunosuppressive activity of adenosine in the tumor microenvironment, an antibody was researched and discovered that antagonizes CD73 function. INCA00186 is a humanized monoclonal antibody that binds and inhibits CD73 function. INCA00186 binds human and cynomolgus CD73 with sub-nanomolar affinity, and inhibits CD73 enzymatic activity in a manner that is non-competitive for AMP binding. In functional studies, INCA00186 restored effector T cell proliferation in the presence of high concentrations of AMP. In the human A375 melanoma tumor model in CD34+ humanized NSG mice, INCA00186 decreased levels of cell surface CD73, displayed high receptor occupancy on tumor cells, and decreased CD73 activity in ex vivo assays of tumor homogenates. In the human MDA-MB-231 breast tumor model in CD34+ humanized NSG mice, INCA00186 decreased intratumoral adenosine concentrations. In combination with the novel A2A/A2B adenosine receptor antagonist INCB106385, INCA00186 synergistically restored effector T cell activity as measured by interferon gamma (IFNγ) production in the presence of high concentrations of AMP. In the human MDA-MB-231 breast tumor model in CD34+ humanized NSG mice, combination treatment with INCA00186 and INCB106385 controlled tumor growth significantly better than monotherapies. In summary, the data presented in this study demonstrates that INCA00186 is a potent CD73 antagonist and effectively attenuates adenosine induced immunosuppression in the tumor microenvironment. INCA00186 demonstrated anti-tumor immunity alone and, to a greater extent, in combination with the A2A/A2B adenosine receptor antagonist INCB106385. Citation Format: Shaun Stewart, Rebecca Buonpane, Jing Zhou, Michael Hansbury, Michael Smith, Hui Wang, Lu, Bin Su, Rahel Awdew, Cheng-Yen Huang, Ashwini Kulkarni, Shane Harvey, Arpita Mondal, Steve Wang, Christina Stevens, Michael Pratta, Elham Behshad, Alexandra Fanuka, Xiaodi Ren, Holly Koblish, Horacio Nastri, Patrick Mayes. Discovery and preclinical characterization of INCA00186, a humanized monoclonal antibody antagonist of CD73, as a cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB174.
Convalescent plasma for COVID-19 in hospitalised patients: an open-label, randomised clinical trial
Authors: Leo Sekine, Beatriz Arns, Bruna R. Fabro, Murillo M. Cipolatt, Rafael R.G. Machado, Edison L. Durigon, Edino Parolo, José Augusto S. Pellegrini, Marina V. Viana, Patrícia Schwarz, Thiago C. Lisboa, José Miguel S. Dora, Julia P. Portich, Alessandra A. Paz, Lucia Silla, Almeri M. Balsan, Felipe da-Silva Schirmer, Juliana P.M. Franz, Luciana M. da-Silveira, Raquel C. Breunig, Viviana Petersen, Monalisa Sosnoski, Nanci F. Mesquita, Fabiana Caroline Z. Volpato, Daniel Sganzerla, Maicon Falavigna, Regis G. Rosa, Alexandre P. Zavascki
Journal: European Respiratory Journal (2021)

Background The effects of convalescent plasma (CP) therapy in hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect of CP on clinical improvement in these patients. Methods This is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment. Results A total of 160 (80 in each arm) patients (66.3% critically ill, 33.7% severely ill) completed the trial. The median (interquartile range (IQR)) age was 60.5 (48–68) years; 58.1% were male and the median (IQR) time from symptom onset to randomisation was 10 (8–12) days. Neutralising antibody titres &gt;1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC group and 65.0% in the SOC group (difference −3.7%, 95% CI −18.8–11.3%). The results were similar in the severe and critically ill subgroups. There was no significant difference between CP+SOC and SOC groups in pre-specified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratory marker values on days 3, 7 and 14 were similar between groups. Conclusions CP+SOC did not result in a higher proportion of clinical improvement on day 28 in hospitalised patients with COVID-19 compared to SOC alone.
Abstract 2184: Gene characteristics of Chinese patients with small bowel cancer
Authors: Quan Zhao, Hushan Zhang, Zhuyun Lei, Jianing Sheng, Dun Xiong
Journal: Cancer Research (2021)

Abstract Background: Small bowel cancer is a rare malignancy which account for only 1-3% of all malignant gastrointestinal tumors. Herein, we aim to provide an overview of gene characteristics of Chinese patients with small bowel cancer based on the location of the tumor in the small bowel. Methods: Tumor samples of 324 Chinese patients with small bowel cancer were consecutively collected in China from February 2018 to May 2020, among them, 289 patients with cancer located in duodenum (group 1), 35 patients with cancer located in the other region of small bowel (group 2). Next generation sequencing (NGS) was performed to detect gene mutation, microsatellite instability (MSI), and tumor mutational burden (TMB) measured by a 733 gene panel by 3D Medicines, a laboratory accredited by College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA). Results: NGS results revealed that the main mutated genes were different between two groups, in detail, the top ten gene mutation in group 1 were TP53 (51.4%,18/35), KRAS (45.7%, 16/35), APC (34.3%, 12/35), POLE (20.0%,7/35), PIK3CA/POLD1/MSH2 (17.1%,6/35), mTOR/PRSS1/LPR1B/BRCA1/SMAD4 (14.3%,5/35). While top ten gene mutation in group 2 were TP53 (66.4%,192/289), KRAS (49.8%, 144/289), ERCC1 (38.8%, 112/289), UGT1A1 (31.5%, 91/289), APC (29.4%, 85/289), BRCA1 (28.7%,83/289), AKT2 (27.3%, 79/289).In addition, TMB level and percentage of MSI-H were also compared between the two groups. 12 patients were available for TMB analysis in group 1, 59 for group 2, the average TMB level in two groups were 23.84 mutants/Mb and 7.8 mutants/Mb, respectively. 50%(6/12) and 11.8%(7/59) were under 10 mutants/Mb in two groups. What's more, the percentage of MSI-H in two groups were 16.7% (5/30) and 3.2% (8/243). Conclusion: Patients with cancer located in duodenum patients with cancer located in the other region of small bowel displayed obvious difference in gene landscape, this imply that these patients should be treated differently. Citation Format: Quan Zhao, Hushan Zhang, Zhuyun Lei, Jianing Sheng, Dun Xiong. Gene characteristics of Chinese patients with small bowel cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2184.
Abstract 16073: Combined Biomechanical and Pharmacological Treatments Prime Pluripotency in Mouse Embryonic Fibroblasts
Authors: Andrew Sligar, Jason Lee, Miguel Ochoa, Pablo Maceda, Eun Yoon, Lara Samarneh, Mitchell Wong, Aaron Baker
Journal: Circulation (2019)

Introduction: Induced pluripotent stem cells (iPSC) have great promise for providing new models of disease and generating novel cell types from patient derived samples. However, studies on iPSC der...
Telomere-to-telomere assembly of a fish Y chromosome reveals the origin of a young sex chromosome pair
Authors: Lingzhan Xue, Yu Gao, Meiying Wu, Tian Tian, Haiping Fan, Yongji Huang, Zhen Huang, Dapeng Li, Luohao Xu
Journal: Genome biology (2021)

Abstract Background The origin of sex chromosomes requires the establishment of recombination suppression between the proto-sex chromosomes. In many fish species, the sex chromosome pair is homomorphic with a recent origin, providing species for studying how and why recombination suppression evolved in the initial stages of sex chromosome differentiation, but this requires accurate sequence assembly of the X and Y (or Z and W) chromosomes, which may be difficult if they are recently diverged. Results Here we produce a haplotype-resolved genome assembly of zig-zag eel ( Mastacembelus armatus ), an aquaculture fish, at the chromosomal scale. The diploid assembly is nearly gap-free, and in most chromosomes, we resolve the centromeric and subtelomeric heterochromatic sequences. In particular, the Y chromosome, including its highly repetitive short arm, has zero gaps. Using resequencing data, we identify a ~7 Mb fully sex-linked region (SLR), spanning the sex chromosome centromere and almost entirely embedded in the pericentromeric heterochromatin. The SLRs on the X and Y chromosomes are almost identical in sequence and gene content, but both are repetitive and heterochromatic, consistent with zero or low recombination. We further identify an HMG-domain containing gene HMGN6 in the SLR as a candidate sex-determining gene that is expressed at the onset of testis development. Conclusions Our study supports the idea that preexisting regions of low recombination, such as pericentromeric regions, can give rise to SLR in the absence of structural variations between the proto-sex chromosomes.
Association of fluid balance trajectories with clinical outcomes in patients with septic shock: a prospective multicenter cohort study
Authors: Mei-Ping Wang, Li Jiang, Bo Zhu, Bin Du, Wen Li, Yan He, Xiu-Ming Xi, Bin Du, Li Weng, Tong Li, Mei-Li Duan, Wen-Xiong Li, Bing Sun, Jian-Xin Zhou, Jian-Guo Jia, Xi Zhu, Qing-Yuan Zhan, Xiao-Chun Ma, Tie-He Qin, Shou-Hong Wang, Yu-Hang Ai, Yan Kang, Xue-Lian Liao, Xiang-Yuan Cao, Yu-Shan Wang, Du-Ming Zhu
Journal: Military Medical Research (2021)

Abstract Background Septic shock has a high incidence and mortality rate in Intensive Care Units (ICUs). Earlier intravenous fluid resuscitation can significantly improve outcomes in septic patients but easily leads to fluid overload (FO), which is associated with poor clinical outcomes. A single point value of fluid cannot provide enough fluid information. The aim of this study was to investigate the impact of fluid balance (FB) latent trajectories on clinical outcomes in septic patients. Methods Patients were diagnosed with septic shock during the first 48 h, and sequential fluid data for the first 3 days of ICU admission were included. A group-based trajectory model (GBTM) which is designed to identify groups of individuals following similar developmental trajectories was used to identify latent subgroups of individuals following a similar progression of FB. The primary outcomes were hospital mortality, organ dysfunction, major adverse kidney events (MAKE) and severe respiratory adverse events (SRAE). We used multivariable Cox or logistic regression analysis to assess the association between FB trajectories and clinical outcomes. Results Nine hundred eighty-six patients met the inclusion criteria and were assigned to GBTM analysis, and three latent FB trajectories were detected. 64 (6.5%), 841 (85.3%), and 81 (8.2%) patients were identified to have decreased, low, and high FB, respectively. Compared with low FB, high FB was associated with increased hospital mortality [hazard ratio ( HR ) 1.63, 95% confidence interval (CI) 1.22–2.17], organ dysfunction [odds ratio ( OR ) 2.18, 95% CI 1.22–3.42], MAKE ( OR 1.80, 95% CI 1.04–2.63) and SRAE ( OR 2.33, 95% CI 1.46–3.71), and decreasing FB was significantly associated with decreased MAKE ( OR 0.46, 95% CI 0.29–0.79) after adjustment for potential covariates. Conclusion Latent subgroups of septic patients followed a similar FB progression. These latent fluid trajectories were associated with clinical outcomes. The decreasing FB trajectory was associated with a decreased risk of hospital mortality and MAKE.
SLM2 Is a Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy
Authors: Jes-Niels Boeckel, Maximilian Möbius-Winkler, Marion Müller, Sabine Rebs, Nicole Eger, Laura Schoppe, Rewati Tappu, Karoline E. Kokot, Jasmin M. Kneuer, Susanne Gaul, Diana M. Bordalo, Alan Lai, Jan Haas, Mahsa Ghanbari, Philipp Drewe-Boss, Martin Liss, Hugo A. Katus, Uwe Ohler, Michael Gotthardt, Ulrich Laufs, Katrin Streckfuss-Bömeke, Benjamin Meder
Journal: Genomics Proteomics & Bioinformatics (2021)

Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analyses were performed, which identified up-regulated expression of Sam68-Like mammalian protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as those encoding myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin.
Erythropoietin Reduces Auto- and Alloantibodies by Inhibiting T Follicular Helper Cell Differentiation
Authors: Chiara Guglielmo, Sofia Bin, Chiara Cantarelli, Susan Hartzell, Andrea Angeletti, Chiara Donadei, Arun Cumpelik, Lisa Anderson, Evan Cody, Peter T. Sage, Gaetano La Manna, Enrico Fiaccadori, Peter S. Heeger, Paolo Cravedi
Journal: Journal of the American Society of Nephrology (2021)

Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown.We assessed the effect and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell-dependent and T-independent antibody formation using in vitro culture systems, murine models of organ transplantation and lupus nephritis, and mice conditionally deficient for the EPOR expressed on T cells or B cells.In wild-type mice, recombinant EPO inhibited primary, T cell-dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T-independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell, but not B cell, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helper cells (TFH). In vitro and in vivo experiments showed that EPO directly prevented TFH differentiation and function via a STAT5-dependent mechanism that reduces CD4+ T cell expression of Bcl6. In lupus models, EPO reduced TFH, GC B cells, and autoantibody production, and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. In vitro studies verified that EPO prevents differentiation of human TFH cells.Our findings newly demonstrate that EPO inhibits TFH-dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney.
Novel classification for upper tract urothelial carcinoma to better risk-stratify patients eligible for kidney sparing strategies: an international collaborative study
Authors: G. Marcq, B. Foerster, S.F. Matin, P. Spiess, T. Bivalacqua, W. Wu, M. Rouprêt, L.M. Krabbe, E. Xylinas, C. Mir, K. Hendricksen, A. Mari, S. Egawa, A. Briganti, M. Moschini, R. Mathieu, J.H. Ku, R. Autorino, A. Heidenreich, P. Chlosta, S. Joniau, A. Pycha, D. D’andrea, S.F. Shariat, W. Kassouf, Wen-Jeng Wu
Journal: European Urology (2021)
Expanding Germline Testing to All Patients With Esophagogastric Cancers—Easy to Do, Harder to Justify
Authors: Thomas L. Holden, Catherine Neumann, Michael J. Hall
Journal: JAMA Network Open (2021)

Geoffrey Y. Ku, MD; Yelena Kemel, MS; Steve B. Maron, MD; Joanne F. Chou, MPH; Vignesh Ravichandran, MS; Zarina Shameer, MS; Anna Maio, BS; Elizabeth S. Won, MD; David P. Kelsen, MD; David H. Ilson, MD; Marinela Capanu, PhD; Vivian E. Strong, MD; Daniela Molena, MD; Smita Sihag, MD, MPH; David R. Jones, MD; Daniel G. Coit, MD; Yaelle Tuvy, MPH; Kendall Cowie, BA; David B. Solit, MD; Nikolaus Schultz, PhD; Jaclyn F. Hechtman, MD; Kenneth Offit, MD, MPH; Vijai Joseph, PhD; Diana Mandelker, MD, PhD; Yelena Y. Janjigian, MD; Zsofia K. Stadler, MD