tbuckley/cabot-search huggingface dataset:
Outcomes Associated With Oral Anticoagulants Plus Antiplatelets in Patients With Newly Diagnosed Atrial Fibrillation
Authors: Keith A. A. Fox, Priscilla Velentgas, A. John Camm, Jean-Pierre Bassand, David A. Fitzmaurice, Bernard J. Gersh, Samuel Z. Goldhaber, Shinya Goto, Sylvia Haas, Frank Misselwitz, Karen S. Pieper, Alexander G. G. Turpie, Freek W. A. Verheugt, Elizabeth Dabrowski, Kaiyi Luo, Liza Gibbs, Ajay K. Kakkar
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy. <h3>Objective</h3> To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone. <h3>Design, Setting, and Participants</h3> Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019. <h3>Exposure</h3> Participants received either OAC plus AP or OAC alone. <h3>Main Outcomes and Measures</h3> Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications. <h3>Results</h3> A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months). <h3>Conclusions and Relevance</h3> This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation.
Selective modulation of immune transcripts in extracellular vesicles from plasma of renal cell carcinoma patients receiving nivolumab.
Authors: Elena Verzoni, Eriomina Shahaj, Simona Frigerio, Agata Cova, Paola Squarcina, Samantha Pesce, Elisabetta Vergani, Viviana Vallacchi, Luca Lalli, Filippo Pietrantonio, Massimo A. Di Nicola, Giuseppe Procopio, Filippo G. De Braud, Alessia Mennitto, Melanie Claps, Pierangela Sepe, Monica Rodolfo, Licia Rivoltini, Veronica Huber
Journal: Journal of Clinical Oncology (2020)

719 Background: Patients (pts) displaying a full-fledged immune response show high levels of circulating extracellular vesicles (EVs) containing immune transcripts that might be transferred to neighboring cells to amplify immune responses, as in autoimmunity and transplantation. We hypothesized EV immune transcripts could reflect immune activation in cancer pts receiving immunotherapy with immune checkpoint inhibitors (ICI). These RNA-containing EVs may surrogate immune functionality and represent a plasma transcriptional signature of adaptive immunity that can be readily detected by liquid biopsy. Methods: Blood samples from metastatic renal cell cancer pts,treated with ICI nivolumab (n=8) or tyrosine kinase inhibitor cabozantinib (n=9) were collected at baseline, week 4 and 12. EV-RNA was isolated from plasma with membrane affinity spin columns and evaluated for CD274(PD-L1), IFNG, PDCD1 (PD-1), CD3 and GZMB (granzyme B) transcripts by qRT-PCR. Results: All pts showed a statistically significant increase of CD3, IFNG, GZMB, PD-1 and PD-L1 immune transcripts in plasma EVs, evidenced at 4 and 12 weeks of therapy. Treatment subgroup analysis revealed an upregulation of CD3, IFNG, GZMB and PD-1 transcripts only in plasma EVs of patients receiving nivolumab that was more evident in those showing clinical benefit (4/8), while PD-L1 increased significantly during cabozantinib treatment. Upon comparing transcripts with soluble proteins, PD-L1 displayed similar kinetics, while PD-1 increased only as transcript but not as protein, given its potential sequestration by the anti-PD-1 antibody. This effect was detectable only in nivolumab but not in cabozantinib treated pts. Conclusions: Monitoring immune transcripts carried by plasma EVs holds promise as potential tool to assess the entity of the ongoing immune activation during immunotherapy. Plasma EVs may be exploited as indicators of immune response and help to predict clinical efficacy at early on-treatment time points. This approach based on plasma EVs might represent a starting point for the development of a novel strategy to study immune responses in clinical setting.
Global case studies for chronic kidney disease/end-stage kidney disease care
Authors: Chih-Wei Yang, David C.H. Harris, Valerie A. Luyckx, Masaomi Nangaku, Fan Fan Hou, Guillermo Garcia Garcia, Hasan Abu-Aisha, Abdou Niang, Laura Sola, Sakarn Bunnag, Somchai Eiam-Ong, Kriang Tungsanga, Marie Richards, Nick Richards, Bak Leong Goh, Gavin Dreyer, Rhys Evans, Henry Mzingajira, Ahmed Twahir, Mignon I. McCulloch, Curie Ahn, Charlotte Osafo, Hsiang-Hao Hsu, Lianne Barnieh, Jo-Ann Donner, Marcello Tonelli
Journal: Kidney International Supplements (2020)
Free-Floating Right Atrial Thrombus Removed by Aspiration Thrombectomy under Transesophageal Guidance
Authors: Alexander E. Sherman, John M. Moriarty, Eric H. Yang, Deepak Ravi, Steven Y. Chang, Richard N. Channick
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Author(s): Sherman, Alexander E; Moriarty, John M; Yang, Eric H; Ravi, Deepak; Chang, Steven Y; Channick, Richard N
Sites of metastasis and survival in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Shaan Dudani, Guillermo de Velasco, Connor Wells, Chun Loo Gan, Frede Donskov, Camillo Porta, Anna Fraccon, Felice Pasini, Aaron Richard Hansen, Georg A. Bjarnason, Benoit Beuselinck, Sumanta K. Pal, Sebastien J. Hotte, Aly-Khan A. Lalani, Takeshi Yuasa, Ravindran Kanesvaran, M. Neil Reaume, Christina M. Canil, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2020)

642 Background: Across a variety of malignancies, sites of metastatic involvement are known to be associated with differences in survival. We sought to characterize the frequency and survival of patients with different sites of metastases in mRCC. Methods: Patients with mRCC starting treatment between 2002-2019 were identified and sites of metastatic involvement at time of systemic therapy initiation were documented. The primary outcomes of interest were prevalence of metastatic site involvement and overall survival (OS). Multivariable Cox regression models were performed to adjust for imbalances in IMDC risk factors. Results: A total of 10,320 patients were included. Median age at diagnosis was 60, 73% were male, 87% had clear-cell histology and 80% underwent nephrectomy. The most common sites of metastases were: lung (71%), lymph nodes (49%), bone (36%), liver (21%), adrenal (9%), brain (9%), pancreas (5%), pleura (4%) and thyroid (0.6%). Survival by metastatic site and adjusted hazard ratios are presented in Table. Conclusions: Metastases to endocrine organs (pancreas, thyroid, adrenal) are infrequent but are associated with the longest median OS, whereas bone, liver, pleura and brain metastases are associated with median OS &lt; 18 months. These benchmark values are useful for patient counseling and study design. Sites of metastatic involvement may reflect differences in underlying disease biology, and further work to investigate differences in immune, molecular and genetic profiles between metastatic sites is encouraged.[Table: see text]
Circulating immune cell populations and cytokines in patients with metastatic variant histology renal cell carcinoma (vRCC) treated with atezolizumab plus bevacizumab (AB): Dynamic changes on therapy and association with outcomes from a phase II trial.
Authors: Ronan Flippot, Ziad Bakouny, Xiao X. Wei, David A. Braun, Bradley Alexander McGregor, John A. Steinharter, Lauren Christine Harshman, Ulka N. Vaishampayan, Mariano Severgnini, David F. McDermott, F. Stephen Hodi, Gwo-Shu Mary Lee, Eliezer Mendel Van Allen, Sabina Signoretti, Toni K. Choueiri, Rana R. McKay
Journal: Journal of Clinical Oncology (2020)

740 Background: Metastatic vRCC are aggressive tumors with poor prognosis. Our phase 2 trial of AB in vRCC showed a response rate of 33%. We investigated on-therapy changes in circulating immune cells and cytokines and their association with outcomes. Methods: Blood was collected at baseline (C1D1) and on-therapy (C3D1). Peripheral blood mononuclear cells were analyzed for cell type, expression of immune checkpoints, markers of activation, proliferation and function using flow cytometry; circulating cytokines by multiplex immunoassay. Relationship with progression-free (PFS) and overall survival (OS) was assessed by cox regression models. Results: Baseline and on-therapy samples were collected from all 60 patients. High baseline levels of immunosuppressive cytokines IL1α, IL6, CCL4 and IL13, as well as high baseline levels of CD4+ lymphocytes expressing CD69, were associated with inferior PFS and OS (Table). However, a decline in these markers on-therapy was not predictive of outcomes. On-therapy assessments showed an increase in the IFN-γ inducible cytokine CXCL10 (p&lt;0.0001) as well as an increase in VEGF-A (p&lt;0.0001) consistent with induction of antitumor immunity and inhibition of angiogenesis. A decrease in PD-L1 expression on circulating CD8+ lymphocytes was associated with shorter PFS and OS (Table), suggesting a potential resistance mechanism. Conclusions: High baseline levels of immunosuppressive cytokines and CD4+ CD69+ lymphocytes portended worse survival in patients treated with AB. Early changes in PD-L1 expression on circulating CD8+ lymphocytes may inform resistance to therapy. Correlation of circulating and tissue-based biomarkers is ongoing. Clinical trial information: NCT02724878. [Table: see text]
YB-1 interplays with ERα to regulate the stemness and differentiation of ER-positive breast cancer stem cells
Authors: Fan Yang, Siqi Chen, Shengnan He, Qin Huo, Ye Hu, Ni Xie
Journal: Theranostics (2020)

Background: Some stemness-associated transcription factors consistently play essential roles in the maintenance of pluripotency or induce the differentiation of cancer stem cells (CSCs).However, the regulatory mechanism of CSC stemness mediated by transcription factors has not been extensively explored.Here, we show that two transcription factors (YB-1 and ERα), which are simultaneously highly expressed in estrogen receptor (ER)-positive CSCs, interact with each other to regulate the stemness and differentiation of ER-positive CSCs.Methods: The expression of YB-1 was examined in ER-positive CSCs and patient specimens.Western blot, real-time PCR, cell viability analysis, tumorsphere formation assay and subcutaneous tumorigenesis assays were used to study the stemness functions of YB-1 and ERα in CSCs.The relationship between YB-1 and ERα in cells was studied by promoter activity analysis, the electrophoretic mobility shift assay (EMSA) and the Co-IP assay.The mechanisms and functional significance of YB-1 in the sensitivity of CSCs to tamoxifen were further investigated with both in vitro and in vivo models.Results: YB-1 was aberrantly upregulated in the cancerous tissue of ER-positive breast cancer patients and in CSCs.Knockdown of YB-1 in ER-positive CSCs significantly inhibited cell stemness and induced differentiation, and the expression of YB-1 could be regulated by estrogen signaling and ERα in ER-positive breast CSCs.The Co-IP results showed that YB-1 interacted directly with ERα specifically in ER-positive non-CSCs and that YB-1 induced ERα degradation by ubiquitination via direct interaction in differentiated cells.Cell differentiation induced by FBS could inhibit YB-1 phosphorylation and promote YB-1 protein transfer from the nucleus to the cytoplasm.Moreover, cell differentiation induced by targeting inhibited the expression of YB-1 in ER-positive CSCs, which increased the sensitivity of cells to tamoxifen in vitro and in vivo. Conclusion:The ERα/YB-1 axis has an important role in the regulation of ER-positive breast cancer stemness.The dephosphorylation of YB-1 and the interaction between YB-1 and ERα may be the switch that initiates the differentiation of ER-positive CSCs.Targeting YB-1 to sensitize ER-positive CSCs to antiestrogen therapy might represent a new therapeutic strategy that warrants further exploration.
Sensitive detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes.
Authors: Pier Vitale Nuzzo, Jacob E Berchuck, Sandor Spisak, Keegan Korthauer, Amin Nassar, Sarah Abou Alaiwi, Ankur Chakravarthy, Shu Yi Shen, Ziad Bakouny, Francesco Boccardo, Sylvan Baca, Gwo-Shu Mary Lee, Steven Lee Chang, Sushrut Waikar, Guru Sonpavde, Rafael A. Irizarry, Mark Pomerantz, Daniel De Carvalho, Matthew L. Freedman, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2020)

728 Background: Improving early cancer detection has the potential to significantly reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMedDIP-seq) is a highly sensitive, low-input, cost-efficient and bisulfite-free assay capable of detecting and classifying various tumor types. We tested the feasibility of cfMeDIP-seq to detect RCC in plasma samples and, for the first time, in urine cell-free DNA (cfDNA), with an emphasis on early-stage disease. Methods: We performed cfMeDIP-seq on 117 samples (72 plasma and 45 urine samples): 68 stage I-IV RCC cases pre-nephrectomy, 21 stage IV urothelial bladder cancer (UBC) plasma samples from 15 patients, and 28 healthy cancer-free controls. 60.5% of plasma samples and 66.7% of urine samples came from patients with TNM Stage I/II disease. cfDNA was immunoprecipitated and enriched using an antibody targeting 5-methylcytosine and amplified to create a sequence-ready library. The top differentially methylated regions (DMRs) which partitioned RCC and control samples or UBC were used to train a regularized binomial generalized linear model using 80% of the samples as a training set. The 20% of withheld test samples were then assigned a probability of being RCC or control. This process was repeated 100 times. This was performed using both plasma and urine cfDNA samples. Results: We identified 89,799 DMRs in plasma samples and 38,462 DMRs in urine samples. Iterative training and classification of held out samples, using the 300 DMRs which partitioned RCC and control samples, resulted in a mean AUROC of 0.990 (95% CI 0.984-0.997) in plasma samples and 0.791 (95% CI 0.759-0.823) in urine samples. Classification performance between tumor types was evaluated comparing plasma cfDNA from patients with RCC and UBC, resulting in a mean AUROC of 0.954 (95% CI 0.940-0.969). Conclusions: cfMeDIP-seq is a powerful tool for genome-wide discovery of non-invasive DNA methylation biomarkers. This is the first independent validation of plasma cfMeDIP-seq, demonstrating near-perfect classification of RCC in a cohort enriched for patients with early-stage disease and the potential of urine cfDNA methylome-based biomarkers for cancer detection.
Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study
Authors: Heshui Shi, Xiaoyu Han, Nanchuan Jiang, Yukun Cao, Osamah Alwalid, Jin Gu, Yanqing Fan, Chuansheng Zheng
Journal: The Lancet Infectious Diseases (2020)

A cluster of patients with coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were successively reported in Wuhan, China. We aimed to describe the CT findings across different timepoints throughout the disease course.
Transcriptome profiling of NRG Oncology/RTOG 9601: Validation of a prognostic genomic classifier in salvage radiotherapy prostate cancer patients from a prospective randomized trial.
Authors: Felix Y Feng, Howard M. Sandler, Huei-Chung Huang, Jeffry Simko, Elai Davicioni, Paul L. Nguyen, Jason A. Efstathiou, Adam P. Dicker, James J. Dignam, Wendy Seiferheld, Himanshu Lukka, Jean-Paul Bahary, Thomas Michael Pisansky, William Adrian Hall, Amit I. Shah, Stephanie L. Pugh, Alan Pollack, Daniel Eidelberg Spratt, William U. Shipley, Phuoc T. Tran
Journal: Journal of Clinical Oncology (2020)

276 Background: Decipher is a genomic classifier (GC) that estimates risk of prostate cancer (PCa) distant metastases (DM) post-radical prostatectomy (RP). Herein, we validate the GC within the context of a randomized phase 3 trial. Methods: RP specimens from patients on the NRG/RTOG 9601 phase 3 placebo-controlled randomized trial of salvage radiotherapy (sRT) +/- 2 years of bicalutamide (NCT00002874) were centrally reviewed and the highest-grade tumor underwent RNA extraction. Samples passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to assign the GC score (scale 0-1). Our NCTN-CCSC approved pre-specified statistical plan (NRG-GU-TS002 CSC0075) included the primary objective of validating the ability of the GC to independently prognosticate the cumulative incidence of DM, with secondary endpoints of prostate cancer-specific mortality (PCSM) and overall survival (OS). Results: Of patients with tissue available, 352 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 13 years. On multivariable analysis, the GC (continuous variable) was independently associated with DM (HR 1.19 [95%CI 1.06-1.35], p=0.003), PCSM (HR 1.37 [95%CI 1.18-1.61], p&lt;0.001), and OS (HR 1.16 [95%CI 1.06-1.28], p=0.002) after adjusting for age, race, Gleason score, T-stage, margin status, entry PSA, and treatment arm. The estimated absolute impact of bicalutamide on 12-year OS was less in patients with lower vs higher GC scores (2.4% vs 8.9%), further demonstrated in men receiving early sRT at PSA &lt;0.7 ng/mL (-2.0% vs 5.0%). Conclusions: This is the first validation of this GC in a prospective randomized trial cohort and demonstrates association of the GC with DM and PCSM independent of standard clinicopathologic variables. The GC may help personalize shared decision-making to weigh the absolute benefit from the addition of bicalutamide to sRT.
A pathway to keep all lifelong learners up to date: the ERS continuing professional development programme
Authors: Amy Farr, Stefano Aliberti, Stelios Loukides, Gilbert Massard, Robert Primhak, Gernot G.U. Rohde, Nathalie Tabin, Carine Pannetier, Daiana Stolz
Journal: European Respiratory Journal (2020)

Albert Einstein's philosophy on lifelong learning was that intellectual growth should commence at birth and cease only at death. Yet in reality, across the board, the foundations of our education systems encourage individual learners early in life to choose a particular path or specialty in a structured way, and then provide little guidance for ongoing development at a more mature stage of their careers. Accordingly, considerable efforts have been invested in identifying relevant content (syllabus) and defining in detail how knowledge and skills are expected to be transferred (curriculum), including: learning objectives, lessons, assignments and learning materials, as well as assessments and other methods, to evaluate learning for the training period up to specialisation in a certain discipline. ERS is committed to offering a lifelong learning pathway for respiratory professionals <http://bit.ly/36HghAs> The authors would like to the following experts that have contributed to the development of this project: Airway diseases: Fauzi Anshar, Dragos Bumbacea, Antonio Spanevello, Alexander Mathioudakis and Omar Usmani. Interstitial lung diseases: Tiago Alfaro, Katerina Antoniou, Venerino Poletti and Michael Kreuter. Paediatric respiratory diseases: Jonathan Grigg, Alexander Moller, Rakesh Mudgal, Raffaella Nenna and Marielle Pijnenburg. Pulmonary vascular diseases: Marion Delcroix, Marc Humbert, Sheila Ramjug and Anton Vonk Noordegraaf. Respiratory critical care: Lieuwe Bos, Leo M.A. Heunks, Ezgi Ozyilmaz and Raffaele Scala. Respiratory infections: Graham Bothamley, Cristina Calarasu, Pieter Goeminne and Eva Polverino. Sleep and breathing disorders: Andrea Aliverti, Marisa Bonsignore, Pierantonio Laveneziana, Winfried Randerath, Manuel Sánchez-de-la-Torre and Anita Simonds. Thoracic oncology: Torsten Gerriet Blum, Nina Bostantzoglou, Bogdan Dragos Grigoriu, Fernando Gamarra, Georgia Hardavella and Nick Maskell.
A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
Authors: Danhui Ma, Yutian Zou, Yunxiang Chu, Zhengsheng Liu, Gaochao Liu, Jun Chu, Mengdi Li, Jiayu Wang, Shi-yong Sun, Zhijie Chang
Journal: Theranostics (2020)

Cancers remain a threat to human health due to the lack of effective therapeutic strategies.Great effort has been devoted to the discovery of drug targets to treat cancers, but novel oncoproteins still need to be unveiled for efficient therapy.Methods: We show that CREPT is highly expressed in pancreatic cancer and is associated with poor disease-free survival.CREPT overexpression promotes but CREPT deletion blocks colony formation and proliferation of pancreatic cancer cells.To provide a proof of concept for CREPT as a new target for the inhibition of pancreatic cancer, we designed a cell-permeable peptide-based proteolysis targeting chimera (PROTAC), named PRTC, based on the homodimerized leucine-zipper-like motif in the C-terminus domain of CREPT to induce its degradation in vivo.Results: PRTC has high affinity for CREPT, with Kd = 0.34 +/-0.11µM and is able to permeate into cells because of the attached membrane-transportable peptide RRRRK.PRTC effectively induces CREPT degradation in a proteasome-dependent manner.Intriguingly, PRTC inhibits colony formation, cell proliferation, and motility in pancreatic cancer cells and ultimately impairs xenograft tumor growth, comparable to the effect of CREPT deletion.Conclusions: PRTC-induced degradation of CREPT leads to inhibition of tumor growth, which is promising for the development of new drugs against pancreatic cancer.In addition, using an interacting motif based on the dimerized structure of proteins may be a new way to design a PROTAC aiming at degrading any protein without known interacting small molecules or peptides.