tbuckley/cabot-search huggingface dataset:
THU0004 Association between hla-drb1 polymorphism and markers of severity of rheumatoid arthritis
Authors: JA Stanczyk, J Hilt, G Woszczek, ML Kowalski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> It is now well established that genetic variations in HLA-DRB1 region may influence susceptibility to rheumatoid arthritis (RA). However genetic component of the disease severity has not been fully elucidated. <h3>Objectives</h3> The goal of the study was to assess the association of the HLA-DRB1 gene with different markers of severity of the disease. <h3>Methods</h3> Seventy six patients with RA and one hundred fifty two healthy controls were typed for HLA-DRB1 gene by molecular method (PCR-SSO). Clinical, radiographic and immunological assessment of patients was carried out. In order to compare disease progression in patients with different disease duration we introduced joint destruction index (JDI) defined as the number of eroded joints (II-IV<sup>o</sup> Steinbrocker's stage) per years of the disease duration. <h3>Results</h3> DRB1*04 alleles were present in 47% of RA patients and in 25% healthy controls (OR = 2,7; p<sub>cor</sub> = 0,01). The frequency of DRB1*04 alleles was higher in patients with: 1) rheumatoid factor (RF) positive RA vs RF negative RA (OR = 14,9; p<sub>cor</sub> = 0,001); 2) primarily chronic course of disease vs acute course of disease (OR = 4,7; p<sub>cor</sub> = 0,03) and familial incidence of RA comparing to patients without familial history of RA (OR = 7,8; p<sub>cor</sub> = 0,02). DRB1*04 alleles were significantly more frequent in patients with more intensive joint destruction reflected by JDI equal or higher than 1 (OR = 12,2; p<sub>cor</sub> = 0,001). We did not observed differences in frequencies of DRB1*01 alleles neither between patients and controls nor between subgroups of RA patients. <h3>Conclusion</h3> Our study confirmed association of DRB1*04 alleles not only with susceptibility to RA but with clinical features of the disease as well.
Mechanism of ventricular premature beats elicited by left stellate ganglion stimulation during acute ischaemia of the anterior left ventricle
Authors: Bastiaan J D Boukens, Michael Dacey, Veronique M F Meijborg, Michiel J Janse, Joseph Hadaya, Peter Hanna, M Amer Swid, Tobias Opthof, Jeffrey L Ardell, Kalyanam Shivkumar, Ruben Coronel
Journal: Cardiovascular Research (2020)

Enhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the non-ischaemic myocardium. This 'injury' current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the 'injury' current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion.In nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization.LSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.
Abstract 2593: Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development
Authors: Tianshun Zhang, Qiushi Wang, Wei-Ya Ma, Keke Wang, Xiaoyu Chang, Michele L. Johnson, Ruihua Bai, Ann M. Bode, Nathan R. Foster, Gary W. Falk, Prasad G. Iyer, Zigang Dong
Journal: Cancer Research (2020)

Abstract Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. In this study, COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels in patient biopsy samples. Acetylsalicylic acid (ASA) suppressed BE and EAC growth by targeting the TXA2 pathway in a esophagoduodenostomy mouse model of reflux. Additionally, biopsies from patients showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation in a window opportunity clinical trial. Overall, this study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. ASA targets the TXA2 pathway and suppresses BE and EAC. Citation Format: Tianshun Zhang, Qiushi Wang, Wei-Ya Ma, Keke Wang, Xiaoyu Chang, Michele L. Johnson, Ruihua Bai, Ann M. Bode, Nathan R. Foster, Gary W. Falk, Prasad G. Iyer, Zigang Dong. Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2593.
pipeComp, a general framework for the evaluation of computational pipelines, reveals performant single cell RNA-seq preprocessing tools
Authors: Pierre-Luc Germain, Anthony Sonrel, Mark D. Robinson
Journal: Genome biology (2020)

Abstract We present pipeComp ( https://github.com/plger/pipeComp ), a flexible R framework for pipeline comparison handling interactions between analysis steps and relying on multi-level evaluation metrics. We apply it to the benchmark of single-cell RNA-sequencing analysis pipelines using simulated and real datasets with known cell identities, covering common methods of filtering, doublet detection, normalization, feature selection, denoising, dimensionality reduction, and clustering. pipeComp can easily integrate any other step, tool, or evaluation metric, allowing extensible benchmarks and easy applications to other fields, as we demonstrate through a study of the impact of removal of unwanted variation on differential expression analysis.
THU0143 Associations of walking ability to isokinetic knee extensor and flexor strength in women with rheumatoid arthritis (ra)
Authors: OR Madsen, C Egsmose
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> <h3>Methods</h3> Seventy-five women with RA according to the 1987 ACR criteria were examined. Mean age was 62 ± 13 years, median disease duration 11 (1–51) years. Sixty-three were or had been on steroids [median cumulative prednisolone dose 2.5 (0.05–66) g]. Sixty-seven age-, weight- and height-matched healthy women served as controls. Maximal voluntary knee extensor and flexor strength (Nm) was assessed at 30o/s by an isokinetic dynamometer. Walking ability was expressed as walking and stair climbing speed (m/s). Markers of disease activity included number of swollen and tender joints, pain as recorded by the patients on a visual analogue scale (VAS), and disability as scored by the Stanford Health Assessment Questionnaire (HAQ). Statistics: non-parametric. <h3>Results</h3> Muscle strength, walking speed and stair climbing speed were on average reduced by 30%, 28% and 54% (p &lt; 0.0001), respectively, compared to the controls. Significant correlations were found between knee extensor strength and walking speed (r = 0.79, p &lt; 0.0001) and stair climbing speed (r = 0.69, p &lt; 0.0001). Similar correlations were found for flexor strength. The correlations remained significant (Rpartial ranging from 0.64 to 0.69, p &lt; 0.0001) in multiple regression analyses adjusting for age, height, weight, disease duration, number of swollen and tender joints, VAS- and HAQ-score. <h3>Conclusion</h3> In conclusion, leg muscle strength is considerably reduced and is an important determinator of walking ability in RA.
Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma
Authors: Nizar M. Tannir, Sabina Signoretti, Toni K. Choueiri, David F. McDermott, Robert J. Motzer, Abdallah Flaifel, Jean-Christophe Pignon, Miriam Ficial, Osvaldo Arén Frontera, Saby George, Thomas Powles, Frede Donskov, Michael R. Harrison, Philippe Barthélémy, Scott S. Tykodi, Judit Kocsis, Alain Ravaud, Jeronimo R. Rodriguez-Cid, Sumanta K. Pal, Andre M. Murad, Yuko Ishii, Shruti Shally Saggi, M. Brent McHenry, Brian I. Rini
Journal: Clinical Cancer Research (2020)

Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC.Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5.
THU0177 Prognostic factors of remission in early rheumatoid arthritis (ra). a multiparameter prospective study
Authors: B Combe, P Goupille, A Cantagrel, MC Bozonnat, J Sibilia, JF Eliaou, O Meyer, J Sany, JP Daures, M Dougados
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine prognostic factors of remission in early RA. <h3>Methods</h3> A cohort of 191 patients with RA and disease duration shorter than 1 year were prospectively followed-up for 3 years. Numerous baseline clinical, laboratory, genetic and radiographic data (Sharp's method modified by van der Heijde) were obtained. Remission, defined by a Disease Activity Score (DAS) &lt; 1.6, was used as outcome measure.<sup>1</sup> <h3>Results</h3> Forty eight patients (25.1%) fulfilled the remission criteria at the 3-year follow-up visit. According to Fisher?s exact test, remission was closely related with baseline values of DAS, HAQ score, morning stiffness, tender joint count, C-reactive protein and radiologic scores. No statistically significant correlation was demonstrated for sex, age, extraarticular manifestations, IgM and IgA rheumatoid factors, anti-perinuclear Ab, anti-keratin Ab, anti-HSP 90, anti-calpastatin Ab, antinuclear Ab, YKL-40 and HLA-DRB1* genotypes. The logistic regression analysis revealed that the independent variables able to predict the 3-year remission were: DAS, HAQ score, morning stiffness and total radiographic score. <h3>Conclusion</h3> Pronostic factors of remission in early RA were mainly clinical markers of disease activity and radiological scores. <h3>Reference</h3> Prevoo, <i>et al</i>. Br J Rheumatol. 1996;35:1101
Different PEG‐PLGA Matrices Influence In Vivo Optical/Photoacoustic Imaging Performance and Biodistribution of NIR‐Emitting <i>π</i>‐Conjugated Polymer Contrast Agents
Authors: Paul Robert Neumann, Frank Erdmann, Joost Holthof, Gabriela Hädrich, Mark Green, Jianghong Rao, Lea Ann Dailey
Journal: Advanced Healthcare Materials (2020)

Abstract The π ‐conjugated polymer poly[2,6‐(4,4‐bis‐(2‐ethylhexyl)‐4H‐cyclopenta[2,1‐b;3,4‐b0]‐dithiophene)‐ alt ‐4,7‐(2,1,3‐benzothiadiazole)] (PCPDTBT) with deep‐red/near‐infrared (NIR) absorption and emission has been investigated as a contrast agent for in vivo optical and photoacoustic imaging. PCPDTBT is encapsulated within poly(ethylene glycol) methyl ether‐block‐poly(lactide‐ co ‐glycolide) (PEG 2kDa –PLGA 4kDa or PEG 5kDa –PLGA 55kDa ) micelles or enveloped by the phospholipid, 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphoethanolamine‐ N ‐[methoxy(polyethylene glycol)‐2000] (PEG 2kDa ‐DPPE), to investigate the formulation effect on imaging performance, biodistribution, and biocompatibility. Nanoparticles that meet the quality requirements for parenteral administration are generated with similar physicochemical properties. Optical phantom imaging reveals that both PEG‐PLGA systems exhibit a 30% higher signal‐to‐background ratio (SBR) than PEG 2kDa ‐DPPE. This trend cannot be observed in a murine HeLa xenograft model following intravenous administration since dramatic differences in biodistribution are observed. PEG 2kDa –PLGA 4kDa systems accumulate more rapidly in the liver compared to other formulations and PEG 2kDa ‐DPPE demonstrates a higher tumor localization. Protein content in the “hard” corona differs between formulations (PEG 2kDa ‐DPPE &lt; PEG 2kDa –PLGA 4kDa &lt; PEG 5kDa –PLGA 55kDa ), although this observation alone does not explain biodistribution patterns. PEG 2kDa ‐PLGA 4kDa systems show the highest photoacoustic amplitude in a phantom, but also a lower signal in the tumor due to differences in biodistribution. This study demonstrates that formulations for conjugated polymer contrast agents can have significant impact on both imaging performance and biodistribution.
CSS: cluster similarity spectrum integration of single-cell genomics data
Authors: Zhisong He, Agnieska Brazovskaja, Sebastian Ebert, J. Gray Camp, Barbara Treutlein
Journal: Genome biology (2020)

Abstract It is a major challenge to integrate single-cell sequencing data across experiments, conditions, batches, time points, and other technical considerations. New computational methods are required that can integrate samples while simultaneously preserving biological information. Here, we propose an unsupervised reference-free data representation, cluster similarity spectrum (CSS), where each cell is represented by its similarities to clusters independently identified across samples. We show that CSS can be used to assess cellular heterogeneity and enable reconstruction of differentiation trajectories from cerebral organoid and other single-cell transcriptomic data, and to integrate data across experimental conditions and human individuals.
Abstract 13056: Right Ventricular Size and Function in Healthy Adults: Geographical Differences From the World Alliance of Societies of Echocardiography (WASE) Normal Values Study
Authors: Tatsuya Miyoshi, Karima Addetia, Alexandra Blitz, Roberto M Lang, Federico M Asch
Journal: Circulation (2019)

Introduction: Assessment of Right Ventricular (RV) size and function is important due to its prognostic value in various cardiovascular conditions. Normal reference values from the American Society...
Abstract 4206: EUD-GK-001 is a novel kinase inhibitor with <i>in vitro</i> anti-lymphoma activity
Authors: Lorenzo Scalise, Chiara Tarantelli, Fabio Zuccotto, Filippo Spriano, Michele Mascia, Luciano Cascione, Eugenio Gaudio, Mauro Angiolini, Francesco Bertoni
Journal: Cancer Research (2020)

Abstract Introduction. EUD-GK compounds, and in particular EUD-GK-91, show selectivity for a restricted number of kinases (ALK, RET, TRK, DDR2, ROS1) and have shown anti-tumor activity in specific solid tumor models (Zuccotto et al, EORTC-NCI-AACR 2016). Here, we have assessed a novel derivative of this class of compounds, EUD-GK-001, in a panel of lymphoma models. Methods. Lymphoma cell lines, including both B- and T-cells lymphomas, were exposed to a large range of concentrations of EUD-GK-001 as single agent for 72h, followed by MTT proliferation assay and IC50 calculation. Cell cycle were assessed in four cell lines (FARAGE, DOHH2, TMD8, OCI-LY-10) treated with 500 nM of EUD-GK-001 for 72h. Baseline protein expression was assessed by mass spectrometry. Baseline gene expression was obtained by using the Illumina HumanHT 12 Expression BeadChips. Results. EUD-GK-001 presented a median IC50 of 1.65 μM and 3.75 μM across 14 B- and 4 T- cell lines, respectively. Five out of 14 DLBCL cells lines, including both ABC- and GCB- subtypes, presented IC50 values lower than 1 μM, A dose-depended increase of the cells in the sub-G0 phase (15-55%) was observed in two GCB-DLBCL and two ABC-DLBCL cell lines after EUD-GK-001 exposure for 72h. Taking advantage of available omics data for the tested cell lines (Cascione at al, AACR 2019), functional annotation of RNA and protein levels showed that TNF/NFKB, inflammation, IL6/JAK/STAT3, IL2/STAT5 signatures were enriched among the transcripts more expressed in the sensitive cell lines, while E2F, DNA repair, MYC signatures were enriched in the resistant cell lines. No genes coding for kinases were more expressed in both GCB (n.=2) and ABC (n=2) sensitive than in resistant DLBCL cell lines (GCB, n=2; ABC, n=3 R). However, three kinases, namely SRC, JAK2 and LCK, were significantly more expressed in EUD-GK-001 GCB-DLBCL sensitive cell lines (DOHH2, FARAGE) than in EUD-GK-001 resistant cells (SU-DHL-8, TOLEDO) and merging the top-50 mRNA and top-50 proteins identified by limma, SRC appeared as a central hub of the top genes associated with sensitivity to EUD-GK-001. The pattern of activity of EUD-GK-001 was however different from what reported for the SRC inhibitor dasatinib in the same lymphoma models (Scuoppo et al, PNAS 2019). Conclusion. EUD-GK-001 is a novel small molecule with in vitro anti-tumor activity in subsets of lymphoma models, which needs to be further explored. Citation Format: Lorenzo Scalise, Chiara Tarantelli, Fabio Zuccotto, Filippo Spriano, Michele Mascia, Luciano Cascione, Eugenio Gaudio, Mauro Angiolini, Francesco Bertoni. EUD-GK-001 is a novel kinase inhibitor with in vitro anti-lymphoma activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4206.
Abstract 17120: Mir-130a Modulates Vascular Patterning During Embryogenesis
Authors: Bhairab N Singh, Naoyuki Tahara, Satyabrata Das, Mary Garry, Wuming Gong, Yasuhiko Kawakami, Naoko Koyano-Nakagawa, Daniel Garry
Journal: Circulation (2016)

Remodeling of the pre-existing primitive vasculature is necessary for the formation of a complex branched vascular architecture; however the factors that modulate these processes are incompletely d...
Abstract CT074: Pre-existing ESR1 mutations in early-stage primary breast cancer predict failure of endocrine therapy and poor survival
Authors: Malin Dahlgren, Anthony M. George, Christian Brueffer, Sergii Gladchuk, Yilun Chen, Johan Vallon-Christersson, Cecilia Hegardt, Jari Häkkinen, Lisa Rydén, Martin Malmberg, Christer Larsson, Sofia K. Gruvberger-Saal, Anna Ehinger, Niklas Loman, Åke Borg, Lao H. Saal
Journal: Cancer Research (2020)

Abstract Background: More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy. Although mutation in ESR1 is known as an acquired mechanism of resistance to endocrine therapy (ET), found in 12-55% of metastatic breast cancers treated previously with ET, the impact of ESR1 mutation on therapy response in primary breast cancer is unclear. Patients and methods: In this study we analyzed 3217 real-world and population-based early-stage primary breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096). Tissues were sampled from initial diagnosis prior to any treatment and analyzed for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by SAGAsafe droplet digital PCR. Results: We identified ESR1 resistance mutations in 30 cases (0.9%), of which 29 were ER-positive (1.1%). In ER-positive disease, presence of ESR1 mutation was significantly associated to poor relapse-free survival (RFS) and overall survival (OS) (p=0.011 and p=0.019, respectively), and moreover predicted poor RFS and OS within the patient group that received ET (p=0.007 and p=0.010, respectively). Conclusions: These results indicate that ESR1 mutations at diagnosis of untreated primary breast cancer are rare, however we confirm for the first time that such early mutations predict eventual resistance to standard hormone therapy in the adjuvant setting. If replicated, tumor ESR1 screening may be considered in ER-positive primary breast cancer and, in mutated cases, ER-degraders such as fulvestrant or other therapeutic options may be considered as more appropriate. Citation Format: Malin Dahlgren, Anthony M. George, Christian Brueffer, Sergii Gladchuk, Yilun Chen, Johan Vallon-Christersson, Cecilia Hegardt, Jari Häkkinen, Lisa Rydén, Martin Malmberg, Christer Larsson, Sofia K. Gruvberger-Saal, Anna Ehinger, Niklas Loman, Åke Borg, Lao H. Saal. Pre-existing ESR1 mutations in early-stage primary breast cancer predict failure of endocrine therapy and poor survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT074.