tbuckley/cabot-search huggingface dataset:
Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer
Authors: M. Eileen Dolan, Omar El Charif, Heather E. Wheeler, Eric R. Gamazon, Shirin Ardeshir-Rouhani-Fard, Patrick Monahan, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Chunkit Fung, Jeri Kim, Sophie D. Fossa, Daniel L Hertz, Taisei Mushiroda, Michiaki Kubo, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs). Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial. Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 × 10−9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10−9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each &amp;lt; 5 × 10−6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089). Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757–68. ©2017 AACR.
Abstract P295: The Inflammasome Is Involved in Myocardial Ischemia-Reperfusion Injury
Authors: Masafumi Takahashi, Masanori Kawaguchi, Fumitake Usui, Hiroaki Kimura, Shun'ichiro Taniguchi, Uichi Ikeda
Journal: Circulation Research (2011)

Background: Accumulating evidence indicates that inflammation is involved in the pathophysiology of myocardial ischemia-reperfusion (I/R) injury. However, the mechanism of I/R-initiated inflammation remains to be determined. The inflammasome is a multiprotein complex consisting of nod-like receptor (NLR), apoptosis-associated speck-like adaptor protein (ASC), and caspase-1, and regulates caspase-1-dependent maturation of IL-1beta and IL-18. In the present study, we investigated the role of inflammasome in myocardial I/R injury. Methods and Results: Wild-type (WT), ASC−/−, and caspase-1−/− mice were subjected to 30 min LAD ligation, followed by reperfusion. ASC and caspase-1 were expressed at the site of myocardial I/R injury. Deficiency of ASC and caspase-1 reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and subsequent injuries such as infarct development, myocardial fibrosis, and dysfunction in myocardial I/R injury. To determine the contribution of inflammasome in bone marrow cells, we produced bone marrow transplant mice and found that inflammasome activation was critical not only in bone marrow cells but also in myocardial resident cells. Since myocardial damage was observed before the inflammatory cell infiltration after I/R, we hypothesized that myocardial resident cells are responsible for an initial activation of inflammasome. To test this hypothesis, we examined whether hypoxia/reoxygenation (H/R) stimuli could induce inflammasome activation in cardiac fibroblasts and cardiomyocytes in vitro. Interestingly, inflammasome activation was detected only in cardiac fibroblasts, but not in cardiomyocytes, and mediated through reactive oxygen species (ROS) and potassium efflux. Conclusion: These findings indicate that inflammasome activation in cardiac fibroblasts is essential for inflammation and injury after myocardial I/R, and suggest that the inflammasome is a potential novel therapeutic target for myocardial I/R injury.
HCV:CD81 Interactions Inhibit Il-2 Production by T Cells: A Novel HCV Immune Evasion Strategy
Authors: L Golden-Mason, AM Kelly, HR Rosen, JE Hegarty, C O'Farrelly, A Long
Journal: Endoscopy (2004)

Factors contributing to the high rate of HCV chronicity are not fully understood. Interleukin 2(IL-2) is critical for the generation of broad-range antigen-specific host T-cell responses, essential for HCV clearance. Many viruses target IL-2 as part of their immune-evasion strategy, however, specific inhibition of IL-2 by HCV has not been demonstrated. CD81, a widely expressed tetraspanin, binds HCV envelope and inhibits NK cells, but, also acts as a co-stimulatory signal for IL-2 production by T cells. Thus, CD81:HCV interactions appear to favour the host and their role in viral persistence is paradoxical. We aimed to determine the role of IL-2 in HCV chronicity. We show that pre-engagement of CD81, using recombinant HCV-envelope or anti-CD81 antibodies, in a manner that mimics in vivo infection, inhibits IL-2 production by T cells. In addition HCV infectious serum produces the same inhibitory effect. We also demonstrate that hepatic IL-2 is significantly reduced in HCV compared to cirrhotic controls. These data support our model of HCV persistence whereby, CD81:HCV engagement prior to T-cell activation compromises host T cell responses. We describe a novel immune evasion strategy employed by HCV. Low-dose IL-2 in combination with current treatment regimes may lead to successful elimination of HCV.
Abstract 265: Uroetensin II Protects Cardiomyocytes from Apoptosis Induced by Oxidative Stress through Cystathionine-γ-Lyase (CSE)/Hydrogen Sulfide Pathway
Authors: Hui Gong, Zhidan Chen, Xiaoyi Zhang, Jie Zhang, Yang Li, Yong Ye, Guoping Zhang, Chunjie Yang, Yunzeng Zou
Journal: Circulation Research (2014)

Plasma UII has been observed to be raised in patients with acute myocardial infarction, a lower UII response is associated with more severe injury of myocardium, suggesting a possible cardioprotective role for this peptide. In the present study, we studied plasma UII concentration of thirty patients admitted to the Cardiology Department with acute myocardial infartion.The results showed that plasma UII was sharply increased in patients compared to that in health control within one week after admission. We then explore whether UII could protect cardiomyocytes from injury induced by oxidative stress. Cultured cardiomyocyte were treated with H2O2 to induce oxidative stress, and the influence of UII on H2O2-induced apoptosis was observed. The results showed that UII pretreatment significantly reduced the number of TUNEL-positive cardiomyocytes induced by H2O2, and it partly abolished the upregulation of pro-apoptotic protein Bax and the down-regulation of anti-apoptotic protein Bcl-2. siRNA targeted to urotensin receptor (UT) greatly inhibited these effects. H2S has been reported to exert protective effect on cardiomyocytes, we detected the effect of UII on H2S production and CSE (Major H2S-producing enzyme) expressions in cardiomyocytes exposed to H2O2.The present data revealed that UII increased the H2S production by enhancing the expression of CSE by activating the ERK signaling in cardiomyocytes exposed to H2O2. Si-CSE or ERK inhibitor not only greatly inhibited the upregulation of CSE or the phosphorylation of ERK induced by UII but also reversed UII-induced-upregulation of H2S production and anti-apoptosis in cadiomyocytes exposed to H2O2. In conclusion, UII rapidly promoted the phosphorylation of ERK, increased CSE exression and induced H2S production, which in turn enhanced the p-ERK level to protect cardiomyocytes from apoptosis under ischemic or oxidative stress. The increased plasma UII level in patients may be critical for cardiac protection in patients at early-phase of acute myocardial infarction.
Multi-institutional comparison of breast cancer risk stratification by 70-gene signature and 21-gene assay.
Authors: David J. Dabbs, Charles E. Cox, Steven Shivers, Nathaniel Bouganim, Jamil Asselah, Ramy Saleh, Lisa Eileen Blumencranz, Alberto J. Montero, Benjamin C. Calhoun, Tina Treece, Erin Yoder, William Audeh
Journal: Journal of Clinical Oncology (2017)

522 Background: Breast cancer risk stratification with the 70-gene signature (70-GS) provides a binary low risk (LR) or high risk (HR) result; by contrast the 21-gene assay (21-GA) provides LR, intermediate (IR), and HR results. Results from these two assays were compared for 769 patients from 5 institutions. Methods: The study included patients from McGill University (n = 86), UPMC (n = 437), USF (n = 135), Morton Plant North Bay Hospital (n = 79), and Cleveland Clinic (n = 32, all 21-GA IR). Results: With the 70-GS, 487 (63%) patients had a LR and 282 (37%) patients had a HR result. Excluding 32 cases selected for 21-GA IR results (n = 737), the 21-GA gave 369 (50%), 250 (34%), and 118 (16%) patients with LR, IR, and HR scores, respectively. Using the TAILORx cutoff, there were 134 (18%), 432 (59%), and 171 (23%) patients with LR, IR, and HR scores, respectively. There were 329 (45%) and 486 (66%) patients who were not classified in the same risk category by both assays using the clinical and TAILORx cutoffs for IR, respectively. Conclusions: In a large multi-institutional study the 70-GS and 21-GA results were discordant in 45-66% of patients, and the proportion of patients with a 21-GA score in the IR range varied from 34-59%. The 70-GS provided clinically actionable results for all patients. [Table: see text]
The Hunt Continues for Early Ovarian Cancer Clues
Authors: Bridget M. Kuehn
Journal: JAMA (2017)

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Helicobacter Pylori Interacts with the Human Single Domain Trefoil Protein, TFF1
Authors: M Clyne, P Dilon, S Daly, R O'Kennedy, F May, B Westley, B Drumm
Journal: Endoscopy (2004)

Background & Aims: H. pylori is found in vivo in association with gastric mucus secreting cells, in the overlying gastric mucus but rarely if ever deep in gastric glands. This localization mirrors the expression of trefoil factor 1, TFF1. We tested the hypothesis that TFF1 is a receptor for H. pylori on the gastric mucosa possibly explaining why H. pylori only colonises the stomach.
Roundabout 1 (ROBO1)/SLIT2 Is a Novel Signaling Pathway in Multiple Myeloma Promoting Survival and Bone Marrow Niche Interaction
Authors: Giada Bianchi, Peter G. Czarnecki, Aldo M. Roccaro, Antonio Sacco, Yawara Kawano, Mehmet K. Samur, Annamaria Gulla, Yu-Tzu Tai, Irene M. Ghobrial, Ruben D. Carrasco, Kenneth C. Anderson
Journal: Blood (2016)
NGS-Based Minimal Residual Disease (MRD) after Stem Cell Transplantation (SCT) Is More Specific for Relapse Prediction Than qPCR and Suggests the Possibility of False-Positive qPCR Results
Authors: Michaela Kotrova, Vincent H.J. van der Velden, Jacques J.M. van Dongen, Renata Formankova, Petr Sedlacek, Monika Brüggemann, Jan Zuna, Jan Stary, Jan Trka, Eva Fronkova
Journal: Blood (2016)
In Planta Recapitulation of Isoprene Synthase Evolution from Ocimene Synthases
Authors: Mingai Li, Jia Xu, Alberto Algarra Alarcon, Silvia Carlin, Enrico Barbaro, Luca Cappellin, Violeta Velikova, Urska Vrhovsek, Francesco Loreto, Claudio Varotto
Journal: Molecular Biology and Evolution (2017)

Isoprene is the most abundant biogenic volatile hydrocarbon compound naturally emitted by plants and plays a major role in atmospheric chemistry. It has been proposed that isoprene synthases (IspS) may readily evolve from other terpene synthases, but this hypothesis has not been experimentally investigated. We isolated and functionally validated in Arabidopsis the first isoprene synthase gene, AdoIspS, from a monocotyledonous species (Arundo donax L., Poaceae). Phylogenetic reconstruction indicates that AdoIspS and dicots isoprene synthases most likely originated by parallel evolution from TPS-b monoterpene synthases. Site-directed mutagenesis demonstrated invivo the functional and evolutionary relevance of the residues considered diagnostic for IspS function. One of these positions was identified by saturating mutagenesis as a major determinant of substrate specificity in AdoIspS able to cause invivo a dramatic change in total volatile emission from hemi- to monoterpenes and supporting evolution of isoprene synthases from ocimene synthases. The mechanism responsible for IspS neofunctionalization by active site size modulation by a single amino acid mutation demonstrated in this study might be general, as the very same amino acidic position is implicated in the parallel evolution of different short-chain terpene synthases from both angiosperms and gymnosperms. Based on these results, we present a model reconciling in a unified conceptual framework the apparently contrasting patterns previously observed for isoprene synthase evolution in plants. These results indicate that parallel evolution may be driven by relatively simple biophysical constraints, and illustrate the intimate molecular evolutionary links between the structural and functional bases of traits with global relevance.
Predicting patient response to cancer immunotherapy using quantitative computed tomography based texture analysis.
Authors: Joshua Ian Gordon, Michael S. Gordon, Ronald Lee Korn
Journal: Journal of Clinical Oncology (2017)

e14536 Background: Immuno-Oncology (I-O) therapies such as PD-L1/PD-1 antibodies disrupt a protective mechanism for tumor cells to evade the host immune system. To minimize toxicity and cost of care, we aim to determine if quantitative texture analysis (QTA) can be used as a predictive biomarker for response to these new drugs. Methods: A pilot study consisting of 20 cancer patients with metastatic disease who received PD-L1/PD-1 antibodies was performed. The subject pool consisted of 10 subjects (NSCLC 3, Urothelial CA 3, TNBC 1, RCC 3) who achieved objective responses to I-O therapy compared to 10 subjects (NSCLC 5, Urothelial CA 2, Ovarian 1, Pancreatic 1, Cervical 1) with primary progression as their best response. Pre-treatment diagnostic CT scans of the chest, abdomen, and pelvis were analyzed using QTA. A minimum of 1 objectively measurable lesion ( &gt; 10 mm in diameter) per study was identified to undergo QTA. Histogram readouts of tumor texture based upon tissue densities per pixel were obtained. Output values from the QTA provided an estimate of tumor signal properties as expressed as the mean pixel density, standard deviation, entropy, kurtosis, skewness, and mean positive pixel value. Results: There was no identifiable signature when examining all of the lesions together. There was statistically significant correlation noted between QTA and RECIST response for lung lesions (n = 14) based on the mean pixel density. A mean pixel density cutoff of 11.91 at a spatial scale factor of 3 predicted response with a sensitivity of 75% and a specificity of 100%. This achieved a Mann-Whitney Z statistic of 2.6 (p = 0.0092). Conclusions: Despite the small number of patients in this pilot study, there were promising findings when examining the mean pixel density of lung lesions, suggesting that quantitative textural analysis can be used to predict response to PD-L1/PD-1 antibodies. Further investigation is warranted in a larger population that can be differentiated by tumor type to validate these results.
PD-L1 expression, Cancer Genome Atlas (TCGA) subtype, and mutational load as independent predictors of response to atezolizumab (atezo) in metastatic urothelial carcinoma (mUC; IMvigor210).
Authors: Jonathan E. Rosenberg, Daniel Peter Petrylak, Michiel Simon Van Der Heijden, Andrea Necchi, Peter H. O'Donnell, Yohann Loriot, Margitta Retz, Jose Luis Perez-Gracia, Joaquim Bellmunt, Petros Grivas, Richard Wayne Joseph, Lawrence Fong, Edward E. Kadel, Zachary Boyd, Dorothee Nickles, Garrett Michael Frampton, Richard Bourgon, Priti S. Hegde, Sanjeev Mariathasan, Thomas Powles
Journal: Journal of Clinical Oncology (2016)

104 Background: Biomarkers of clinical benefit of immunotherapies, such as non-synonymous mutations, mutational load, PD-L1 IHC and immune signatures, have not been systematically evaluated in mUC patients (pts) treated with anti–PD-L1 agents. Methods: Exploratory analyses of immune and genetic predictors of response to atezo were performed on archival tumor specimens from mUC pts (NCT02108652 cohort 2). PD-L1 expression in tumor samples was assessed by IHC (SP142 assay) and associated with response as determined by RECIST v1.1 (central review). Gene expression was quantified by RNA-seq (Illumina TruSeq RNA Access; n = 195); molecular subtypes were assigned as per TCGA. Mutations were detected by genomic profiling (FoundationOne 315-cancer gene panel; n = 150) to estimate overall load. Results: PD-L1 tumor-infiltrating immune cell (IC) status was associated with CD8+ T effector (Teff) gene expression levels (P < 0.0001). Notably, response to atezo was associated with high expression of CXCL9 (P = 0.0057) and CXCL10 (P = 0.0079). Evaluable samples were classified into luminal (n = 73) and basal (n = 122) TCGA subtypes. PD-L1 IC prevalence was enriched in basal (60%) vs luminal (23%) samples (P < 0.0001); elevated tumor cell PD-L1 was mostly restricted to the basal subtype (39% basal vs 4% luminal, P < 0.0001) and did not correlate with ORR. Teff expression was elevated in luminal cluster II and basal III/IV and not in luminal I. Responses occurred in all subtypes, but ORR was significantly higher in luminal II samples: 34% (P = 0.0017). While median mutational load was significantly increased in responders (12.4/Mb) vs non-responders (6.4/Mb; P < 0.0001) and correlated with both PFS (P = 0.003) and OS (P = 0.014), these associations were independent of TCGA subtype. Conclusions: PD-L1 expression on IC was associated with response to atezo. Intrinsic TCGA subtype and mutational load each added predictive value. Simultaneous classification by these characteristics in mUC pts treated with atezo further defines the drivers of immune responsiveness and may suggest potential combination strategies. Clinical trial information: NCT02108652.
Lenalidomide and Obinutuzumab with CHOP for Newly Diagnosed Diffuse Large B-Cell Lymphoma: Phase I Results
Authors: Jason R. Westin, Vishwanath Sathyanarayanan, Luis E. Fayad, Loretta J. Nastoupil, Francesco Turturro, Fredrick B. Hagemeister, Kristin A. Simar, Ken H. Young, Timothy J. McDonnell, Hubert H Chuang, Fazal Kamil, Lei Feng, Eric Richard Davis, Sattva S. Neelapu, Yasuhiro Oki
Journal: Blood (2016)
Pseudoprogression in cancer immunotherapy: Rates, time course and patient outcomes.
Authors: Vikram Kurra, Ryan J. Sullivan, Justin F. Gainor, F. Stephen Hodi, Leena Gandhi, Cheryl A Sadow, Gordon J Harris, Keith Flaherty, Susanna Lee
Journal: Journal of Clinical Oncology (2016)

6580 Background: Pseudoprogression (PP), tumor growth from treatment effect rather than true disease progression, has been described with immune checkpoint inhibitors. Our study measures rates and time course of PP and associated patient outcomes using RECIST 1.1 and irRC criteria. Methods: Cohort was retrospectively drawn from subjects enrolled in phase I and II trials from March 2008 to July 2015 at two hospitals within one cancer center network. Inclusion required followup with every 4-12 week scheduled torso CT or MRI for > 1 year or until death analyzed using RECIST 1.1 and irRC criteria by the imaging core lab. A single investigator blinded to patient outcome abstracted the core lab database; another blinded to imaging assessment abstracted patient survival from the medical record. Pattern of response during the first year of therapy assessed according to RECIST 1.1 and irRC criteria were categorized as stable (SD), partial response (PR), progressive disease (PD) or pseudoprogression (PP). PP was defined as progression from nadir followed by response from peak. Results: Cohort of 356 was comprised of 214 melanoma, 103 non-small and 6 small cell lung, 16 breast, and 17 other cancer patients. Therapeutic agents were anti-PD1 (203, 57%), anti-PD-L1 (82, 23%), CTLA-4 alone (57, 16%) or in combination with anti-VEGF (5, 1%) or BRAF(V600E) inhibitor (4, 1%). 193 (54%) were alive at 1 year. Number (% of cohort) classified as SD, PR, PD and PP respectively was 59 (17%), 98 (28%), 192 (54%) and 7 (2%) with RECIST and 66 (19%), 101 (28%), 168 (47%) and 21 (6%) with irRC. PP rates between the two criteria were different (p < 0.01). Number (% in category, 95% CI) alive at 1 year respectively was 38 (64%, 51-75), 81 (84%, 74-89), 67 (35%, 29-42) and 7 (100%, 65-100) with RECIST and 38 (58%, 46-69), 82 (82%, 72-88), 56 (33%, 27-41) and 17 (81%, 60-92) with irRC. In the PP group, mean days (range) from baseline to progression, to response and intervening time in between were 74 (29-108), 169 (57-277), and 94 (28-169) with RECIST and 88 (29-181), 187 (57-364) and 99 (28-276) days with irRC. Conclusions: Pseudoprogression is uncommon and indicates a high likelihood of > 1 year survival. Complete course of progression from nadir followed by response from peak can take up to 1 year.