tbuckley/cabot-search huggingface dataset:
Pharmacodynamic activity of the AKT inhibitor AZD5363 in patients with advanced solid tumors.
Authors: Paul Elvin, Amy Palmer, Chris Womack, Matthew Tall, Karen E Swales, Michelle D Garrett, Udai Banerji, Kenji Tamura, S Y Amy Cheung, Peter Lawrence, Justin Lindemann, Helen Ambrose, Christine Stephens, Barry Davies, Andrew Foxley, Martin Pass, Elizabeth A. Harrington, J. Carl Barrett
Journal: Journal of Clinical Oncology (2014)

2541 Background: AZD5363 is an ATP competitive small molecule inhibitor of AKT1, AKT2 and AKT3 and is currently in phase 1 and 2 clinical trials in breast, gynaecological and prostate cancer. In pre-clinical tumour xenograft models, AZD5363 inhibited the phosphorylation of AKT substrates PRAS40 and GSK3β in tumour tissue. Methods: Tumour biopsies were obtained from patients with advanced solid tumours in Western and Japanese phase 1 studies. Pharmacodynamic activity of AZD5363 in formalin fixed paraffin embedded tumour tissue was measured by immunohistochemistry (IHC) for total and phospho-AKT, phospho-PRAS40 and phospho-GSK3β using commercially available antibodies. IHC was quantified by H-score (sum of % tumour cells with 0=negative; 1=weak; 2=moderate; 3=strong staining) based on the results from 3 sections for each antibody. Inhibition of PRAS40 phosphorylation in hair follicles obtained 4 hours after dosing was measured by immunofluorescence and quantified by image analysis. Results: Paired tumour biopsies at baseline and after approximately 2 weeks dosing were obtained from patients on continuous and intermittent dosing schedules. Inhibition of GSK3β and PRAS40 phosphorylation of >30% or >50% respectively was seen in 4/7 (GSK3β) and 2/8 (PRAS40) tumours at tolerated doses of AZD5363. Phospho-AKT was increased in 4/7 (AKT-Thr308) and 4/5 (AKT-Ser473) tumours commensurate with the mechanism of action of AZD5363. Hair follicle PRAS40 phosphorylation was reduced by >50% in 22/71 patients and showed evidence of an exposure related response with an IC50 of 2μM total plasma concentration. Blood glucose also demonstrated an exposure response relationship with maximum glucose concentration correlating with drug plasma Cmax. Conclusions: Inhibition of AKT substrate phosphorylation in tumour biopsies from advanced cancer patients with a range of solid tumours was qualitatively comparable to that observed in preclinical models showing tumour growth inhibition at clinically achievable exposures. Clinical trial information: NCT01226316; NCT01353781.
Mantle cell lymphoma: Toll-like receptors (TLRs) and B-cell receptor (BCR) gene expression analysis for identification of a distinct BCR-activated subset, with germinal center signature and indolent biology.
Authors: Ariz Akhter, Fahad Farooq, Etienne Mahe, Meer-Taher Shabani-Rad, Lesley Street, Donald Morris, Douglas Allan Stewart, Adnan Mansoor
Journal: Journal of Clinical Oncology (2014)

8585 Background: Mantle cell lymphoma (MCL) is an aggressive disease with complex biology. Enhanced understanding of pathogenesis can result in better utilization of novel therapies. MCL is believed to arise from naïve B-lymphocytes; however, there are indications that at least a subset of MCL arises from antigen-experienced B cells; where Toll-like Receptors (TLRs) and B-cell receptor (BCR) play an intricate role. Methods: Here, we report Gene Expression Profile (GEP) data on TLRs/BCR related genes and associated down stream pathways (154 gene-set) in a cohort (n=81) of MCL patients (pts.). GEP was assessed by Nano string technology utilizing mRNA from diagnostic biopsy tissue. Results: Hierarchical clustering based on TLR/BCR genes (n= 18), revealed four distinct clusters (A, n=12; B, n=30; C, n=19 and D, n=20) with differential expression of CD79b, SYK, LYN; BTK (p<0.002) and TLRs (2,3,6,7,8,9,) (p<0.01). On further analysis, Cluster C revealed higher expression of Germinal Centre (GC) associated genes (GCET, LMO2 and HGAL) (p<0.001). This cluster (C) showed lower expression of PI3K/Akt pathway (p<0.005) and MAP/ERK pathway associated genes (p<0.009) as compared to cluster B. Patients in cluster C, had a trend toward better overall survival (OS), in comparison with cluster B &D (p=0.07)(Log Rank (Mantel-Cox). Conclusions: Our data suggest that MCL pts. can be stratified based on BCR activity and these pts. can benefit from array of BCR inhibitors as second line therapy. A subset of MCL shows exposure to GC microenvironment, low PI3K/Akt and MAP/ERK pathway activity and a trend towards a better overall survival.
Critical role for arginase II in osteoarthritis pathogenesis
Authors: Wan-Su Choi, Jeong-In Yang, Wihak Kim, Hyo-Eun Kim, Seul-Ki Kim, Yoonkyung Won, Young-Ok Son, Churl-Hong Chun, Jang-Soo Chun
Journal: Annals of the Rheumatic Diseases (2019)

Objective Osteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. Methods Expression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2 −/− mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II). Results The gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice ( Arg2 −/− ) abolished all manifestations of DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway. Conclusions Our results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.
Trypsin-like proteinases and tissue inhibitors in adenomyosis and endometrial cancer.
Authors: Larisa Kozlova, Elena Frantsiyants, Tatiyana Moiseyenko, Nataliya Chernikova, Anna Birukova
Journal: Journal of Clinical Oncology (2014)

e22215 Background: The activity of trypsin-like proteinases (ATP), kallikrein (K) and multipurpose inhibitors, plays an important part in development of neoplastic processes. The integrated study of parameters of tissue metabolism of endometrium in adenomyose (A) and endometrial cancer (EC) will allow supplementing the ideas about pathogenesis thereof. Methods: The tissue of endometrium of A (n=32, aged 49-59) and EC (n=46, aged 53-62, T2N0M0) was studied. The control was conventionally healthy endometrium – CHE. ATP, K, α-2M è α-1PI was determined in 10% cytosols using ethylic ether N-benzoyl-L-arginin as the substrate, and calculated in mkM/g for the crude tissue. Results: It has been determined that in A the total ATP was similar to the values in CHE, and it was 2 times as high in EC. The activity of K in A was 66.7% lower, while in EC the value was 1.3 times as high. The activity of α-2M and α-1PI was reduced in A 2.3 and 1.4 times, in EC – 9.1 and 1.2 times (r<0,05). ATP/K were higher in A and EC than in CHE, 1.6 and 1.5 times as high, respectively. It is essential that the percentages of active K in the total ATP in A and in EC were comparable, 17.2% and 18.4, respectively. So the activity of both inhibitors underwent unidirectional change. It is important to point out a significant excess (as compared to CHE level) of the Ê/α-2M ratio in EC. In A the parameter was higher than in CHE just 1.4 times, the ATP/α-1PI was higher in A and in EC – 1.3 and 2.3 times as high, respectively. Conclusions: Unidirectional change of the hydrolytic system components have been found in endometrial tissue in A and in EC that are manifested in significant reduction of activity of inhibitors and equal percentage of K in the total ATP. This allows considering them as an indicator of proliferative activity and expect similarity of proliferation mechanisms in both pathologic processes.
The nationwide screening project on plasma angiogenesis-related mediators for treatment selection of optimal antiangiogenic inhibitors in metastatic colorectal cancer: GI-SCREEN CRC-Ukit.
Authors: Satoshi Yuki, Kentaro Yamazaki, Hiroya Taniguchi, Yu Sunakawa, Akihito Kawazoe, Yoshinori Kagawa, Ken Kato, Hiroki Hara, Tadamichi Denda, Eiji Oki, Toshikazu Moriwaki, Manabu Shiozawa, Taroh Satoh, HIsato Kawakami, Taito Esaki, Junji Furuse, Yukiko Abe, Shogo Nomura, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2018)

TPS885 Background: Antiangiogenic treatments are a proven useful tool to improve clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC). Recently, higher levels of vascular endothelial growth factor-D (VEGF-D) are a potential predictive biomarker for ramucirumab efficacy on overall and progression-free survival in mCRC (Tabernero J, et al. ESMO 2017). However, there are limited data on mCRC associating the efficacy of antiangiogenic therapy with angiogenesis-related mediators, such as VEGF family members and their receptors, and with dynamic transition among these mediators during clinical courses. In addition, immune-related factors such as interferon gamma (IFNγ) and transforming growth factor β1 (TGFβ1) may be associated with the regulation of angiogenesis. Methods: This prospective longitudinal study aims to investigate the association between plasma angiogenesis-related mediators and clinical outcomes in mCRC. The key eligibility criteria include pts with mCRC who will receive one of the following regimens: first-line chemotherapy plus bevacizumab, first-line chemotherapy plus anti-EGFR antibody (either cetuximab or panitumumab), second-line FOLFIRI plus ramucirumab, second-line FOLFIRI plus aflibercept, or second-line chemotherapy plus bevacizumab. Plasma is collected twice in pairs from all pts pre- and post-treatment. Comprehensive measurements of plasma angiogenesis-related mediators, such as placental growth factor (PlGF), hepatocyte growth factor (HGF), IL-6, IL-8, angiopoietin-2, neuropillin-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), thrombospondin-2 (TSP-2), osteopontin (OPN), sVEGFR-1, sVEGFR-2, sVEGFR-3, VEGF-A, VEGF-D, as well as key targets associated with immunotherapy such as IFNγ and TGFβ1 are analyzed in parallel by the multiplex assay with Luminex® technology. The target sample size is 1,000. This study was initiated in September 2017. Clinical trial information: UMIN000028616.
SAT0677 Prevotella copri in individuals at risk for rheumatoid arthritis
Authors: D. Alpizar-Rodriguez, T.R. Lesker, A. Gronow, E. Raemy, C. Lamacchia, D. Courvoisier, C. Gabay, A. Finckh, T. Strowig
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> <i>Prevotella spp</i>. have been identified as highly enriched in the intestinal microbiota of patients newly diagnosed with rheumatoid arthritis (RA), suggesting a role in the development of the disease.<sup>1</sup> Sequence homology between RA-specific autoantigens and proteins of <i>Prevotella copri</i> have been reported.<sup>2</sup> However, the role of these bacteriae in the pathogenesis of the disease is not yet established. <h3>Objectives</h3> To determine the microbiome composition and prevalence of <i>Prevotella spp.</i> in different pre-clinical phases of RA, in a group of individuals at risk for RA, namely first degree relatives of patients with RA (RA-FDR). <h3>Methods</h3> In an ongoing cohort study of RA-FDR, enrolling individuals without clinical evidence of RA at inclusion, we categorised individuals in the following groups: 'healthy controls': asymptomatic RA-FDR without any autoantibodies or symptoms associated with possible RA; 'pre-clinical RA': individuals with 'systemic autoimmunity associated with RA' defined by the presence of anti-citrullinated peptide antibodies (ACPA) or rheumatoid factor (RF) and/or symptomatic individuals with clinically suspect arthralgias or unclassified arthritis. Participants provided stool samples for microbiome analysis. We excluded subjects who had undergone antibiotic therapy within the last 3 months, with known history of inflammatory bowel disease and/or gastrointestinal tract surgery ever. Stool samples processing and microbial diversity culture-independent analyses were performed. After DNA extraction, the V4 region of the 16S rRNA gene was amplified using barcoded primers and sequencing was done on an Illumina MiSeq. Statistical analyses of community structures were performed.<sup>3</sup> <h3>Results</h3> Of the 134 participants enrolled, 51 were categorised as 'healthy controls' and 83 as 'pre-clinical RA'. table 1 shows the general characteristics of the two groups. The microbiota of 'pre-clinical RA' individuals was significantly altered compared to 'healthy controls', with abundance of specific bacteria, particularly an enrichment of <i>Prevotella spp</i>. (figure 1). <h3>Conclusions</h3> Individuals at risk of RA who have developed systemic autoimmunity associated with RA and/or symptoms, have enrichment of <i>Prevotella spp</i> in comparison with healthy controls. Our findings support the hypothesis of a causal role of <i>Prevotella spp</i> in the development of RA, which could lead to future attempts to interfere with its intestinal colonisation during the preclinical stages of disease. <h3>References</h3> [1] Scher JU, et al. eLife2013;2:e01202. [2] Pianta A, et al. J Clin Invest2017;127(8):2946–56. [3] Segata N, et al. Genome Biology2011;12:R60. <h3>Disclosure of Interest</h3> None declared
Diverse Landscape of TET2 Variants in MDS and AML
Authors: Eran Tallis, Christopher B. Benton, Abir Khan, Rita Assi, Courtney D. DiNardo, Marisa J Hornbaker, Catherine Kendall Major, Prajwal Boddu, Rashmi Kanagal-Shamanna, Keyur P. Patel, Naval G. Daver, Koichi Takahashi, Guillermo Montalban-Bravo, Tapan M. Kadia, Marina Y. Konopleva, Michael Andreeff, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2018)
THU0344 Assessment of the psychometric properties of patient-reported outcomes of depression in SLE
Authors: A. Kwan, S. Marzouk, H. Ghanean, K. Ali, N. Anderson, J. Su, Z. Touma
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Mood disorders, including depression, are amongst the most common manifestations of neuro-psychiatric SLE. Currently, the screening and diagnosis for depression in ambulatory settings are delayed and often missed due to the lack of standardised valid questionnaires for assessing depression in patients with SLE. <h3>Objectives</h3> This study aims to: 1) Determine the prevalence of depression in SLE patients using the Centre for Epidemiological Studies-Depression Scale [CES-D] and Hospital Anxiety and Depression Scale [HADS] questionnaires. 2) Study the criterion validity and interpretability of CES-D and HADS, and 3) evaluate their diagnostic accuracy when compared to the assessment of an independent psychiatric assessment using the Mini-International Neuropsychiatric Interview (MINI), based on the DSM-5, as the gold standard. <h3>Methods</h3> A cross-sectional study of consecutive consenting SLE patients (n=227), aged 18–65 and attending the Toronto Lupus Clinic between June 2017–September 2017, was performed. Participants were screened for depression using the CES-D and HADS, and underwent the MINI on the same date of their clinic visit. Conventional cut-off scores were used to indicate the prevalence of depression: CES-D ≥16 and HADS-D ≥8. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were evaluated against the MINI. Receiver operator characteristic (ROC) curves and the Youden Index were utilised to determine the optimal cut-off scores for CES-D and HADS-D. <h3>Results</h3> Among 227 patients, the prevalence of depression ranged from 27.8% (HADS-D) to 46.3% (CES-D). ROC curves showed that the CES-D (AUC 0.86, 95% CI: 0.78–0.95) slightly outperformed HADS-D (AUC 0.84, 95% CI: 0.75–0.93), when compared to the MINI. The sensitivity, specificity, PPV, and NPV for CES-D at the optimal cut-off of 26 was 80%, 82%, 43%, and 96%, respectively. The Youden index exhibited optimal cut-offs for CES-D at 26 and HADS-D at 8 that optimised their sensitivity and specificity as screening metrics for depression in SLE patients. The performance of the CES-D and HADS-D at various cut-offs are displayed in table 1 below. <h3>Conclusions</h3> This study assessed the criterion validity and interpretability of patient-reported outcome tools HADS, and CES-D for depression screening in SLE patients. Compared to the gold standard, CES-D outperformed HADS-D. These results suggest that SLE-specific cut-offs may improve diagnostic accuracy of current screening metrics in lupus. <h3>Acknowledgements</h3> The University of Toronto Lupus Clinic is supported by the University Health Network, the Lou Rocca Family, and the Lupus Foundation of Ontario. This summer project is supported by the Canadian Rheumatology Association Summer Studentship Program. <h3>Disclosure of Interest</h3> None declared
Flotillin-2 role in nasopharyngeal carcinoma metastasis and correlation with poor survival outcomes.
Authors: Liang Zhao, Min Shi, Jiangman Duan, Huanrong Ma, Zhenzhen Wu, Xi Chen, Ting Yang, Wangjun Liao
Journal: Journal of Clinical Oncology (2014)

e17050 Background: Flotillin microdomains, essential part of plain lipid raft domains in cell membranes, have been demonstrated to participate in several intracellular signal pathways. Recent studies have reported that flotillin-2(Flot2) promotes several types cancer progression including breast cancer, melanoma and gastric cancer. Transforming growth factor-β (TGF-β) can promote cancer invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT) process. However the mechanisms causing this are not completely clear. Therefore we intended to investigate the role of Flot2 are playing and how it influences TGF-β intracellular signal pathway in nasopharyngeal carcinoma. Methods: We analyzed Flot2 expression level in nasopharyngeal carcinoma tissues by immunohistochemistry. Statistical analyses were performed to evaluate the association of Flot2 expression with the follow-up data. The regulation of TGF-β signal pathway by Flot2 was examined with Flot2 siRNA transient transfection nasopharyngeal carcinoma cell lines. Results: Our data suggests that Flot2 expression level in nasopharyngeal carcinoma tissues positively correlates with clinical stage, N classification, M classification, not correlates with T classification. Patients with higher expression level of Flot2 had a shorter overall survival duration than patients with lower expression level of Flot2. Multivariate analysis showed that expression level of Flot2 in tumor tissue is an independent prognostic marker for patients with nasopharyngeal carcinoma. TGF-β can promote nasopharyngeal cancer cells metastasis by inducing an EMT progress. SiRNA-mediated reduction of Flot2 protein expression level significantly reduce the activity of Src tyrosine kinase and thus inhibit the EMT process inducing by TGF-β in human nasopharyngeal carcinoma cell lines in vitro. Conclusions: Our results suggest that Flot2 is an important metastatic marker and an important regulator of EMT in nasopharyngeal carcinoma.
Parallel detections of multi-driver genes in plasma DNA for patients with advanced non-small cell lung cancer (NSCLC).
Authors: Jie Wang, Hua Bai, Jianchun Duan, Zhijie Wang, Shuhang Wang, Rui Chen
Journal: Journal of Clinical Oncology (2014)

e19113 Background: Existence of Intra-tumor heterogeneity in EGFR mutant NSCLC implies that it is important for accurate personalized therapy to establish a platform of parallel and multi-genes detections. Here,we detected multi- driver genes in plasma DNA in advanced-NSCLC patients. Methods: 196 advanced-NSCLC patients with naïve-treatment were analyzed concurrently for molecular aberrances in EGFR (exon19 and 21), K-RAS (coden 12 and 13) by Denatured High Performance Liquid Chromatagraphy (DHPLC), PIK3CA (exon9 and 20) by AmoyDX PIK3CA Five Mutations Detection Kit, BRAF (V600E) by AmoyDX BRAF Mutations Detection Kit, for CMET copy number by TaqMan Real-Time PCR, EML4-ALK fusion and ROS1 translocation by AmoyDX EML4-ALK fusion Detection Kit and AmoyDX ROS1 fusion Detection Kit. Results: Fifty-six tumors harbored EGFR mutation (28.6%), ten had T790M mutation (5.1%), sixteen carried harbored K-RAS mutation (8.2%), three had BRAF mutation (1.5%), fourteen harbored CMET amplification (7.1%), four harbored PIK3CA mutation (2.0%). EML4-ALK or ROS1 fusion genes wasn’t detected in plasma despite being positive in tissue specimen in 8 and 3 of 196 patients, respectively. 17 patients possessed two kinds of mutations which included 1 KRAS mutation /CMET amplification, 2 EGFR /PIK3CA mutation, 7 EGFR/T790M mutation, 4 EGFR mutation/CMET amplification, 1 EGFR/BRAF mutation,1 EGFR/KRAS mutation. 1 patient carried three-types of mutation (EGFR/KRAS/T790M). Totally, 88(45%) patients had at least one- type of mutation detected in plasma DNA. Consistence of genes aberrance between tissue and plasma and clinical significance are being analyzed. Conclusions: Although mutant frequency detected in plasma DNA was lower than in tissue, blood detection remains available specimen due to its noninvasive, dynamic and easy-obtained.
Muscle Depletion Is an Important and Clinically Relevant Predictor of Outcomes after Autologous Hematopoietic Cell Transplantation
Authors: Alex Iukuridze, Meisi Xiao, Lee Brandyn, Jennifer Berano Teh, Kristen Mascarenhas, Sandra Xu, Nicholas Rosen, Jeannine S McCune, Jasmine M. Zain, Robert W. Chen, Leslie Popplewell, Jessica Scott, Thomas Slavin, Lee Jones, Stephen J Forman, Ryotaro Nakamura, F. Lennie Wong, Saro H. Armenian
Journal: Blood (2018)