tbuckley/cabot-search huggingface dataset:
SAT0452 Direct and Indirect Costs of Osteoarthritis the Republic of Moldova
Authors: V. Salaru, L. Mazur-Nicorici, N. Revenco, O. Lozan, V. Sadovici, M. Mazur
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Osteoarthritis (OA) is associated with healthcare resource utilization and loss or worker productivity. The total direct and indirect costs of OA can differ substantially across systems. No data as yet are available on economic impact of OA in Republic of Moldova. <h3>Objectives</h3> To estimate the direct and indirect costs of knee osteoarthritis in Republic of Moldova. <h3>Methods</h3> A cross-sectional study was performed from January 2012 to January 2013. There were included 256 patients that fulfilled the ACR classification criteria for knee OA (1991). The direct medical costs comprised: medication, hospitalization, medical visits and investigations; the direct non-healthcare costs included informal care and patient out-of-pocket payments. Human capital approach was used to estimate indirect costs by multiplying: 1) days of absence from work because of OA, with average earnings per capita per day for working patients; or 2) productivity loss with the market price of housekeeping for retirees/homemakers. Mean annual per patient costs were calculated from an employer9s perspective. Correlations were also calculated between the costs and quality of life (QoL) that was assessed by KOOS- Knee injury and Osteoarthritis Outcome Score (100% high QoL). <h3>Results</h3> There were 256 patients integrated in the study including 196 females and 60 males, mean age (SD) 62.4 (9.5) years (range 37 to 85 years). The disease duration (SD) was 8.1 (6.7) years (range 1-51).The KOOS results showed that the QoL constituted 35.7%, qualified as low. The average total cost excluding joint replacement, accounted $685, and the direct costs represented 71.04% (mean $485) per person per year and indirect costs - 29% ($190), respectively. The direct costs represented 18.4% of annual incomes, the insurance cover just 50.7% from direct costs. The three major components of direct costs were hospitalization (48.3%), drug cost (26.4%) and informal care (13%). We established moderate correlation between direct costs and QoL (r=0.4, p&lt;0.05), therefore the indirect costs were strongly correlated with quality of life level (r=0.7, p&lt;0.05). <h3>Conclusions</h3> The direct costs of osteoarthritis in the Republic of Moldova population are high being comparable to those reported in European countries and the economic burden is important by relatively high out-of-pocket expenditures. The indirect costs are not a major component of the cost of illness; this is mainly due to the low monetary value of paid work. Both types of costs correlated with the quality of life. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2527
Identification and Significance of Platelet Antibodies
Authors: James L. Tullis
Journal: New England Journal of Medicine (1956)

BLEEDING tendencies secondary to thrombopenia are of increasing frequency in medical, surgical and obstetric disorders. This has been attributed to diverse causes: chemotherapeutic agents1 , 2; insecticides3; increased incidence of leukemia4; radioisotopes; cytotoxic agents in industry5; complete blood replacement by transfusion during pulmonary or cardiovascular surgery6; and the alarm reaction secondary to surgery and anesthesia.7 The clinical management of such thrombopenia necessitates a clear understanding of the etiologic mechanisms that produce a decrease in circulating platelets. Within recent years, it has become clear that many cases of purpura, especially idiopathic thrombocytopenic purpura and hypersplenism, are due to . . .
Abstract 3406: Evaluation of (E)-Styrylsulfonyl methylpyridine: A novel kinase inhibitor targeting mitotic pathways.
Authors: Tiangong Lu, Shudong Wang, Charles Laughton, Tracey Bradshaw
Journal: Cancer Research (2013)

Abstract ON01910.Na, a styryl benzylsulfone, is a Phase III stage, non-ATP competitive anti-cancer agent. It is multi-targeted, promoting selective mitotic arrest and apoptosis in cancer cells. Extensive Phase II/III trials conducted in patients with solid tumors and hematological cancers have proved its excellent efficacy and impressive safety profile. However, incomplete understanding of mechanisms of action and relatively low drug oral bioavailability remain obstacles to development. By modifying the structure of ON01910.Na, a novel class of (E)-Styrylsulfonyl methylpyridines was designed and synthesized. We report herein the evaluation of a selected compound, TL-77, (E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide, as a potent small molecule inhibitor targeting mitotic pathways. MTT assays were performed to assess in vitro anti-proliferative effects. In a panel of 10 tumor and 2 non-transformed human cell lines following 96 h exposure, TL-77 gave consistent GI50 values in the sub-micromolar range in tumor cells, whereas, it was non-toxic to non-transformed human mammary endothelial cells (HMECs). Cell cycle was analyzed by flow cytometry. TL-77 caused significant G2/M arrest ≥ 6 h, whereas ON01910.Na caused the same effect after longer exposure periods (≥ 12 h). An OD-based tubulin polymerization assay allowed us to explain obstruction of cell division caused by TL-77. TL-77 retarded tubulin polymerization between 1μM and 6μM, intriguingly, microtubules were stabilizes at TL-77 concentrations &amp;gt; 8μM. Western blot analyses of cell lysates following treatment of cells with TL-77 revealed dose-dependent reduction of phosphorylated Cdc25c, a known substrate of Plk1 and/or Chk1/2, indicating Plk1 and/or Chk1/2 inhibition. Finally, dose- and time-dependent apoptosis triggered by TL-77, detected by Annexin-V assays, was closely associated with induction of caspase 3/7 activity. Importantly, pharmacokinetics studies in mice revealed that the oral bioavailability of TL-77 was optimized to 56% compared with 9% for ON01910.Na. In summary, TL-77 is a potent anti-cancer agent. It disturbs tubulin during cell division, resulting in G2/M cell cycle arrest, followed by caspase-dependent apoptosis. TL-77 appears to share an analogous mechanism of action with ON01910.Na, but exhibits greater selectivity towards cancer cells and possesses superior oral bioavailability. Therefore, further evaluation of TL-77 as a promising anti-tumor agent is justified. Citation Format: Tiangong Lu, Shudong Wang, Charles Laughton, Tracey Bradshaw. Evaluation of (E)-Styrylsulfonyl methylpyridine: A novel kinase inhibitor targeting mitotic pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3406. doi:10.1158/1538-7445.AM2013-3406
Five interval colorectal cancers
Authors: J. Edakkanambeth Varayil, T. Smyrk, P. de Groen
Journal: Endoscopy (2011)

A 78-year-old man presented with anemia and melena in 2010. His past history included resection of a sigmoid carcinoma in 1997. Colonoscopies in 1999 and 2000 had shown polyps. A repeat colonoscopy for anemia in 2001 had shown two interval cancers in the ascending and transverse colon, and a right hemicolectomy had been performed. Surveillance colonoscopies in 2002, 2003, and 2005 showed only hyperplastic polyps in 2003.
Abstract P4-04-02: Isolation and Characterization of Adult Mammary Stem Cells from the Periphery of Breast Cancer
Authors: A Shi, N Xu, Z Fan, Y Jiang, S. Fu
Journal: Cancer Research (2010)

Abstract Background: Normal adult mammary stem cells (AMSCs) provide promising cell sources for breast reconstruction, especially after the resection of breast tumors. However, the potential targeting by carcinogenic events may convert normal AMSCs to cancer stem cells, posing a safety issue for applying the AMSCs for tissue regeneration in clinic. Objective: In the current study, we characterized a population of AMSCs isolated from the normal tissue at the periphery of human breast tumors and provided evidence that these AMSCs remain normal but not cancerous phenotypes and therefore, could be candidates for breast reconstruction. Methods: A population of AMSCs was isolated from the normal tissue surrounding primary breast tumors using immunomagnetic sorting. The stemness of these cells were examined by differentiation analysis and the gene expression profile compared to that of the cancer cells by microarray, with several differentially expressed candidate genes confirmed by both RT-PCR and Western blot assays. The in vivo tumorigenic capability of these cells were also investigated and compared to that of MCF-7 cell line. Results: The AMSCs were positive for stem cell markers, epithelial specific antigen (ESA) and keratin 19 (K19). When stimulated with the differentiation agent, basic fibroblast growth factor (bFGF), these AMSCs formed lobuloalveolar structure with myoepithelium that are positive for CALLA. The gene expression profiles revealed that compared to the cancer cells, see Table 1,2. AMSCs were low in oncogenes such as c-myc, Ras and c-erbB-2, but high in tumor suppressor genes including Rb1, Pten and CDKN2A, see table 1,2 and fig 1,2. When injected into nude mice, the AMSCs formed no tumors but regular mammary ductal structures. Conclusion: The AMSCs isolated from the normal tissue surrounding the primary breast cancers present features of normal mammary stem cells, therefore, are promising candidates for mammary reconstruction after breast tumor resection. Gene expression by western blot (sample 1, 2, 3 were breast cancer; sample 4,5 were mammary stem cells) CerbB2 rtranscription (sample 1, 2, 3 were breast cancer; sample 4,5 were mammary stem cells) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-04-02.
OP0035 Progress Report on the Development of New Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies
Authors: A. Tjärnlund, M. Bottai, L. G. Rider, V. P. Werth, C. Pilkington, M. de Visser, L. Alfredsson, A. A. Amato, R. J. Barohn, M. H. Liang, J. A. Singh, F. W. Miller, I. E. Lundberg
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Inadequate classification criteria for IIM are a fundamental limitation in clinical studies. An international, multidisciplinary collaboration, the International Myositis Classification Criteria Project (IMCCP), supported by ACR and EULAR, was established to address this problem. <h3>Objectives</h3> Develop and validate new classification criteria for adult and juvenile IIM and its major subgroups. <h3>Methods</h3> Candidate variables were selected from published criteria and inclusion criteria in controlled trials of myositis. Comparator conditions confused with IIM were defined. Clinical and laboratory data from IIM and comparator patients were collected from 47 rheumatology, dermatology, neurology and pediatrics clinics worldwide from 2008-2011. Crude pair-wise associations among all measured variables and between each variable and clinicians' diagnoses were assessed. The explored approaches were: Traditional: case defined by specified number of items from a set of variables Probability score: case assigned a probability score by summing score-points associated with a set of variables Classification tree: case defined by a decision tree Internal validation using bootstrap methods was performed. <h3>Results</h3> Data from 973 IIM patients (74% adults; 26% children), representing subgroups of IIM, and 629 comparators (81% adults; 19% children) were obtained. Two probability score models were developed: Model 1 comprised clinical variables on muscles, skin, and laboratory measures; Model 2 additionally comprised muscle biopsy variables. Model 1 performed nearly as well as Model 2 (specificity 87% vs. 88%, sensitivity 89% vs. 89%, and correctly classified 87% vs. 89%). Both models performed as well as, and often better than, the classification tree that was developed (sensitivity 88%, specificity 72%, and correctly classified 84%) and published criteria. <h3>Conclusions</h3> New classification criteria for IIM with readily clinically assessable measurements and symptoms have been developed. They generally show superior performance compared with existing criteria. External validation is in progress. <h3>Disclosure of Interest</h3> None Declared
Abstract 3147: Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers
Authors: Mathewos Tessema, Christin M. Yingling, Marcie J. Grimes, Cynthia L. Thomas, Yushi Liu, Shuguang Leng, Nancy Joste, Steven Belinsky
Journal: Cancer Research (2012)

Abstract Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p &amp;lt; 0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas TOX3 was frequently methylated in lung (58%) than breast (30%) tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3147. doi:1538-7445.AM2012-3147
FRI0057 Synovial angiogenesis is mediated through notch signaling pathways
Authors: W. Gao, C. Sweeney, C. Walsh, P. Rooney, J. McCormick, U. Fearon, D.J. Veale
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Angiogenesis plays a crucial role in the formation and maintenance of the pannus in inflammatory arthritis. The Notch signaling pathway is critical for vascular angiogenesis and endothelial cell (EC) fate; however the mechanisms involved in regulating these processes in the inflamed joint remain to be elucidated. <h3>Objectives</h3> To examine if Notch signaling pathways mediate Vascular Endothelial Growth Factor (VEGF) and Angiopoietin 2 (Ang2)-induced vascular function in the inflamed joint. <h3>Methods</h3> Whole tissue synovial biopsies obtained at arthroscopy and human microvascular endothelial cells (HMVEC) were utilized. Notch-1 IC (intracellular domain), Notch-4 IC, Notch ligand DLL-4, downstream target genes <i>Hrt-1</i> and <i>Hrt-2</i> mRNA and/or protein expression was measured by Real-time PCR and/or Western Blot. VEGF/Ang2 induced EC function was assessed using transwell invasion chambers, matrigel tube formation assays and wound repair scratch assays +/- Notch-1 siRNA or a γ-secretase inhibitor (DAPT). Pro-MMP-2/9 expression was measured by zymography. <h3>Results</h3> Notch-1 IC and 4 IC protein expression were demonstrated in RA and PsA synovial explants with undetectable level in OA patients. VEGF and Ang2 induced Notch-1 IC and 4 IC protein expression in RA synovial explants cultures <i>ex-vivo</i> and HMVEC, levels of which were further potentiated following stimulation with VEGF and Ang2 in combination (p&lt;0.05). mRNA expression of Notch-1, DLL-4 and <i>Hrt-1</i> and <i>Hrt-2</i> were significantly induced following stimulation with VEGF and Ang2 alone and in combination (p&lt;0.05). VEGF-induced Notch-1 IC protein expression was completely blocked in the presence of Notch-1 siRNA (p&lt;0.05). Furthermore VEGF/Ang2-induced EC invasion, tube formation, migration and pro-MMp-2/9 expression were inhibited in the presence of Notch-1 siRNA or DAPT (p&lt;0.05). <h3>Conclusions</h3> This study demonstrates Notch-1 IC and -4 IC expression in RA and PsA synovial explants. VEGF and Ang2 alone induce Notch-1 IC signaling pathways, with a synergistic increase in combination. VEGF/Ang2-indcued HMVEC function is inhibited in the presence of Notch-1 siRNA and DAPT. These results suggest that in inflammatory conditions, VEGF/Ang2-induced angiogenesis is mediated in part through Notch signaling pathways. <h3>Disclosure of Interest</h3> W. Gao: None Declared, C. Sweeney: None Declared, C. Walsh: None Declared, P. Rooney: None Declared, J. McCormick: None Declared, U. Fearon: None Declared, D. Veale Grant/Research support from: Wyeth, GSK, Abbott, Opsona, Consultant for: Wyeth, GSK, Abbott, Pfizer, Schering Plough, Centocor, Speakers Bureau: Wyeth, GSK, Abbott, Pfizer, Schering Plough, Centocor, Mundipharma
AB0612 The investigation of factors associated with efficacy of methotrexate in rheumatoid arthritis and seronegative spondyloarthropathies
Authors: V. Vardanyan, A. Ayvazyan, A. Beglaryan, T. Bayramyan, A. Simonyan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis and seronegative spondyloarthropathies have high prevalence and present as the major cause of early invalidity worldwide. DMARDs present as an essential part of the treatment of these diseases. Methotrexate (MTX) is a fast working and effective DMARD. It has proved to have the best efficacy-toxicity ratio. Nevertheless, up to 30% of patients discontinue MTX intake both because of inefficacy and toxicity. <h3>Objectives</h3> The main objective of the study is the determination of factors associated with MTX efficacy in patients with different arthritides. <h3>Methods</h3> 90 patients (65 female, 25 male, mean age 48,49±15,12 years, 79 with rheumatoid arthritis, 7 with ankylosing spondylitis, 4 with psoriatic arthritis) were investigated. The anamnestic and treatment data were obtained. Joint disease activity scores (DAS, BASDAI), indices of joint disability (HAQ-FI, BASFI) and presence of extra-articular manifestations were determined. The CBC, urinalysis, determination of serum concentrations of homocysteine, creatinine, bilirubin, transaminases, glucose, CRP and RF, X-ray examination of hands/feet were performed. Both univariate and multivariate analyses (logistic regression) were performed to determine the factors associated with MTX efficacy. <h3>Results</h3> Only 60 from observed 90 patients were taking MTX regularly. The mean duration of MTX treatment was 107.7±11.6 weeks, mean cumulative MTX dose was 996.1±110.4 mg. The complete remission on MTX treatment was observed in 12 patients (20% of patients on regular MTX treatment). According to the results of univariate analysis and multivariate logistic regression, MTX efficacy was significantly (p&lt;0,05) associated with absence of intraarticular corticosteroids in treatment scheme (OR (95% CI) = 5,6 (1,4-22,3), p&lt;0,05) and low functional articular indices HAQ-FI and BASFI (OR (95% CI) = 36,7 (4,4-303,6), p&lt;0,01). <h3>Conclusions</h3> The possible association of more than 20 routine clinical and laboratory factors with MTX efficacy is studied. We've found that positive response to MTX treatment is associated with peculiarities of concomitant treatment with corticosteroids and less degree of joint disability. No other clinical or laboratory factor was found predictive for positive response to MTX. Further studies are needed to investigate novel biological or other markers. <h3>References</h3> Hider S.L., Silman A.J., Thomson W. et al Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann Rheum Dis 2008;68:57–62. <h3>Disclosure of Interest</h3> None Declared
Clinical Application of Liquid Biopsies
Authors: P. Mickey Williams, Barbara A. Conley
Journal: JAMA Oncology (2016)

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<i>BRAF<sup>V600E</sup></i>-Mutant Melanoma Presenting With Cardiac Involvement
Authors: Douglas B. Johnson, Jeffrey A. Sosman
Journal: Journal of the National Comprehensive Cancer Network (2014)

Melanoma is an aggressive skin cancer with historically limited treatment options. Approximately 50% of melanomas harbor BRAFV600 mutations. This report describes a 32-year-old man with metastatic BRAFV600-mutant melanoma who presented with cardiac involvement. Recently developed treatment options for patients with BRAF-mutant melanoma include BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib), and immune-based therapeutics (interleukin-2 or ipilimumab), but the most effective strategy for first-line therapy is heavily debated. Opinions vary for treatment selection, but the general consensus recommends immune-based therapies initially for asymptomatic patients with low-volume disease, and BRAF inhibitors for those with highly symptomatic or rapidly progressing disease. In this case, melanoma with cardiac involvement, although clinically uncommon, presents challenging management decisions.
771 TLR3-DEPENDENT IMMUNOLOGICAL PROPERTIES OF LIVER CELLS ARE CONTROLLED BY ANTI-INFLAMMATORY CYTOKINES THROUGH MODULATION OF MIR-155 EXPRESSION
Authors: M. Jiang, M. Trippler, R. Broering, J. Wu, E. Zhang, X. Zhang, G. Gerken, M. Lu, J.F. Schlaak
Journal: Journal of Hepatology (2012)