tbuckley/cabot-search huggingface dataset:
Analysis of multidrug resistant transporter expression in tumor blood vessels of urothelial carcinoma during chemotherapy.
Authors: Hiroshi Kikuchi, Nako Maishi, Kosuke Akiyama, Masahiro Morimoto, Misa Yanagiya, Naoto Miyajima, Kunihiko Tsuchiya, Satoshi Maruyama, Takashige Abe, Yasuhiro Hida, Toru Harabayashi, Kaname Ameda, Ryuji Matsumoto, Akira Kashiwagi, Yoshihiro Matsuno, Nobuo Shinohara, Kyoko Hida
Journal: Journal of Clinical Oncology (2017)

e23004 Background: ABCB1, a multidrug transporter, is encoded by multidrug resistance (MDR) 1 gene and plays a major role in drug resistance. Recently, we have reported that not only tumor cells, tumor vascular endothelial cells (TECs) also confer cancer drug resistance. We isolated TECs and found that they have various abnormalities such as aneuploidy or stemness characteristics. TECs showed resistance to Paclitaxel (PTX) with ABCB1 up-regulation. Furthermore, their resistance to PTX was abrogated by ABCB1 inhibition of TECs in vivo. In clinical urology, gemcitabine / cisplatin (GC) is standard 1st line chemotherapy for metastatic urothelial carcinoma (mUC). PTX is often selected in 2nd line chemotherapy for GC resistant cases, however the therapeutic outcomes are limited. We hypothesized that ABCB1 inhibitor/PTX combination would be more effective strategy for mUC, if TEC ABCB1 expression is upregulated. In this study, we investigated ABCB1 expression in tumor blood vessels of UC during 1st line chemotherapy. Methods: Paraffin-embedded samples were corrected from 50 patients who were performed tumor resection before and after 1st line chemotherapy. ABCB1 expressions were analyzed by immunohistochemical staining and the ratio of ABCB1 positive (+) vessels in total vessels were quantified. In vitro assays were performed to address how endothelial cells (ECs) are affected by change of tumor microenvironment during chemotherapy. Results: The ABCB1 (+) vessels were 0.00 – 16.80% (Median 0.00%) and 0.00-58.94% (Median 4.49%), before and after chemotherapy, respectively. In 32 of 50 cases (64%), the ratio of ABCB1 (+) vessels increased after 1 st line chemotherapy. Additionally, gemcitabine induced MDR1 mRNA expression in ECs via NF-kB activation. Furthermore, gemcitabine and cisplatin induced IL-8 secretion from tumor cells, and MDR1 mRNA expression level was elevated in ECs. Conclusions: It was suggested that conventional chemotherapy may cause inflammatory change in tumor tissues, which causes in ABC transporter induction in tumor blood vessels. It was suggested that inhibition of ABC transporter in TECs is one of important new strategy to overcome cancer drug resistance.
AB0438 Rheumatoid arthritis drug therapy in the perioperative period of large joints arthroplasty, its impact on the long-term results of surgery
Authors: S Lapshina, I Akhtyamov, I Gilmutdinov, L Myasoutova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To analyze the results of large joints arthroplasty depending on the received rheumatoid arthritis (RA) drug therapy <h3>Methods</h3> Knee and hip joints arthroplasty was performed for 54 RA patients (48 women, 6 men), mean age 51,4±12,8 years. At the time of the operation disease duration was 11,8±3,8 years, high activity (DAS28) - in 26%, moderate - in 55.5%, the low - at 18.5% patients. At the time of surgery 39 (72.2%) pts continued to take basic anti-rheumatic drugs (DMARDs) (methotrexate at a dose of 10–20 mg per week - 32, leflunomide (20 mg daily) -5). Corticosteroids (prednisone at a dose of 5–15 mg, an average of 7.1 mg per day) - 25 (46.2%) patients, of which in combination with DMARDs - 10 (18.6%). Before the operation, and after the 6 months joint pain (VAS), disease activity - DAS28, functional ability HAQ index were evaluated. In 32 patients, these same indexes were estimated after 12 months. <h3>Results</h3> The reduction of pain intensity VAS was observed in the first month after a joint arthroplasty, after 6 months VAS fell almost to 31.8 mm (p&lt;0.05). Activity of the disease decreased (high - 11.2%, moderate - 44.4%, low - 44.4%), HAQ - from 1,61±0,41 to 1,09±0,26 (p&lt;0, 05). After 12 months HAQ - 1,01±0,28. The analysis showed that in patients not receiving corticosteroids (n=29) arthroplasty was conducted in 13,6±3,2 years after RA onset, and receiving long-term steroids (n=25) significantly earlier (p&lt;0,05) - through 9,9±3,5 years. The functional capacity of patients in the group receiving DMARDs without corticosteroids (n=29) (the HAQ 6 months - 0,9±0,24, 12 months - 0 81±0,16) was significantly (p&lt;0.05) higher compared with patients receiving corticosteroids (n=25) without the basic treatment (HAQ 6 months -1.13±0.21, over 12 months- 1,24±0,19) <h3>Conclusions</h3> Large joints arthroplasty is an effective method to improve the functional capacity of patients with RA. For patients receiving corticosteroids need of arthroplasty arises a few years earlier. The function of the joints after surgery and in the remote period is better when patients continuously receive DMARDs compared to steroid therapy, the dose should be reduced to a reasonable minimum for the time of surgical treatment. <h3>Disclosure of Interest</h3> None declared
Bernie Sanders’ single payer bill gains momentum among Democrats
Authors: Owen Dyer
Journal: BMJ (2017)

The US senator Bernie Sanders, who missed out on becoming the Democratic party’s candidate in the presidential election last year, has launched a single payer healthcare bill to deliver health services to the entire country.

Although it stands no chance of passing through Congress, whose two houses are controlled by Republicans, the idea of single payer healthcare has seized the middle ground of the Democratic party, to judge from the names co-sponsoring Sanders’ Medicare For All Act.

There are 15 co-sponsors to the bill, including five senators often named as potential 2020 presidential candidates: Cory Booker of New Jersey, Kamala Harris of California, Kirsten Gillibrand of New York, Al Franken of Minnesota, and Elizabeth Warren of Massachusetts.

Their collaboration with Sanders in calling for single …
The Bidirectional Regulation between MYL5 and HIF-1α Promotes Cervical Carcinoma Metastasis
Authors: Lan Zhang, Shu-Ting Huang, Yan-Ling Feng, Ting Wan, Hai-Feng Gu, Jing Xu, Lin-Jing Yuan, Yun Zhou, Xing-Juan Yu, Long Huang, Rong-Zhen Luo, Wei-Hua Jia, Min Zheng
Journal: Theranostics (2017)

Myosin light chains (MLC) serve important regulatory functions in a wide range of cellular and physiological processes. Recent research found that MLC are also chromatin-associated nuclear proteins which regulate gene transcription. In this study, the MLC member myosin regulatory light chain 5 (MYL5) expression was upregulated in late stage cervical cancer patients, positively correlated with pelvic lymph node metastasis, and identified as a poor survival indicator. MYL5 overexpression promoted metastasis in cervical cancer in vitro and in vivo models, whereas MYL5 silencing had the converse effect. We demonstrated a bidirectional regulation between MYL5 and hypoxia inducible factor-1α (HIF-1α). HIF-1α activates MYL5 via binding to the hypoxia response element (HRE) in the promoter of MYL5, and MYL5 could sustain HIF-1α expression by tethering to recognition sequence AGCTCC in the HIF-1α promoter region. Clinical data confirmed a positive correlation between MYL5 and HIF-1α. In summary, our data show that MYL5 may act as a prognosis predictive factor in cervical carcinoma, and strategies that inhibit the interaction of MYL5 and HIF-1α may benefit the cervical carcinoma patients with metastasis.
YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63–GPX2 Axis and ROS Accumulation
Authors: Hsinyi Huang, Wenjing Zhang, Yafang Pan, Yijun Gao, Lei Deng, Fuming Li, Fei Li, Xueyan Ma, Shenda Hou, Jing Xu, Peixue Li, Xiaoxun Li, Guohong Hu, Cheng Li, Haiquan Chen, Lei Zhang, Hongbin Ji
Journal: Cancer Research (2017)

Abstract Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non–small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. Cancer Res; 77(21); 5769–81. ©2017 AACR.
PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer
Authors: Benjamin A. Kansy, Fernando Concha-Benavente, Raghvendra M. Srivastava, Hyun-Bae Jie, Gulidanna Shayan, Yu Lei, Jessica Moskovitz, Jennifer Moy, Jing Li, Sven Brandau, Stephan Lang, Nicole C. Schmitt, Gordon J. Freeman, William E. Gooding, David A. Clump, Robert L. Ferris
Journal: Cancer Research (2017)

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TILs were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (P < 0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1-based immunotherapy. Cancer Res; 77(22); 6353-64. ©2017 AACR.
SP0165 Can musculoskeletal ultrasound inform health beliefs and play a role for medication adherence?
Authors: K Kumar
Journal: Annals of the Rheumatic Diseases (2017)

Rheumatoid Arthritis (RA) is a condition with no cure and can cause disability<sup>1</sup>. RA affects nearly 1 in 100 adults. Early disease is characterised by pain and other features of inflammation, such as heat, swelling of joints, and loss of function. RA is associated with increased costs of co-morbid conditions (such as cardiovascular (CVD) associated with RA<sup>2</sup>. Medication can ease symptoms and limit disease progression in RA<sup>3</sup>. Despite this, nonadherence to medication is common in RA<sup>4</sup>. In the UK, we found that showing patients their joint swelling via musculoskeletal ultrasound scan as an educational tool helped to increase beliefs about the necessity of treatment<sup>5</sup>. Our study provided a deeper understanding of adherence to disease modifying anti-rheumatic drugs (DMARDs) in patients with RA. Improving adherence is likely to be facilitated by incorporating visual representations of the disease process and better explanations of the consequences of poorly controlled RA into the consultation. This session will uncover some suggestions around the use of musculoskeletal ultrasound in improving adherence to DMARDs. <h3>References</h3> Emery P. Evidence supporting the benefit of early intervention in rheumatoid arthritis. J Rheumatol, 2002;29 (2):3–8. John H, Kitas G, Toms T, Goodson N. Cardiovascular co-morbidity in early rheumatoid arthritis. Best Pract Res Clin Rheumatol 2009; 23(1):71–82. Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69(6):964–975. Pasma A, Schenk CV, Timman R, Busschbach J, van den bemt B, Molenaar E et al. Non-adherence to disease-modifying antirheumatic drugs is associated with higher disease activity in early arthritis patients in the first year of the disease. Arthritis Research &amp; Therapy 2015; 17:doi:10.1186/s13075-015-0801-4. Kumar K, Raza K, Gill P, Greenfield S. The impact of using musculoskeletal ultrasound imaging and other influencing factors on medication adherence in patients with rheumatoid arthritis: a qualitative study. Patient Prefer Adherence 2016; 10:1091–1100. <h3>Disclosure of Interest</h3> None declared
FRI0661 Capillaroscopy in patients with silica exposure. a case control study
Authors: M Freire, A Perez-Gonzalez, V Arnalich, D Boveda-Ruiz, A Salgado, JJ Blanco-Perez
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Exposure to silica dust has been associated with different autoimmune diseases and immunological abnormalities in which microvascular involvement is very common, as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis or dermatomyositis. <h3>Objectives</h3> To show capillaroscopic findings in patients exposed and not exposed to silica and to analyze the differences between both groups. <h3>Methods</h3> A case control design was made. Cases (Si+) were subjects exposed to silica (with and without silicosis). Controls (Si-) were healthy subjects not exposed to silica. Capillaroscopy was made with both Zuzi® Optical stereo microscope with Optikam® camera adapted and with USB Digital Microscope Video epiluminiscence Dino-Lite ® in each patient. The capillaroscopic alterations were evaluated according to a semiquantitative method. Background data on CVRF and variables related to capillaroscopy were collected. A comparative study was done. <h3>Results</h3> Capillaroscopy was performed on 61 Si+ and 12 Si- subjects. Mean age of Si+ was 52.6 years (SD: 7.3) and 54 years (SD: 6.6) in Si-. There were no significant differences in CVRF: hypertension (13.1% Si+ and 8.3% Si-), diabetes mellitus (3.3% Si+ and 8.3% Si-) and tobacco exposure (18.0% Si+ and 25.0% Si-). It was observed capillary dilation in 24 (33.9%) Si+ and only in 3 (25.0%) Si-. The dilation score was mild in all Si- while in Si+ was mild in 41.7%, moderate in 37.5% and extreme in 12.5%. 42.7% of Si + had a degree of tortuosity higher than 33% (score 2) whereas in all Si- the degree of tortuosity was &lt;33% (score 1). Capillaroscopic general pattern showed differences between both groups: it was normal in 24 (42.1%) Si+ and 9 (75%) Si-; slightly irregular in 30 (52.6%) Si+ and 3 (25%) Si- and unstructured in 3 Si+ (5.3%) and in none Si-. <h3>Conclusions</h3> The current study shows significant differences between the capillaroscopy of subjects exposed and not exposed to silica, with a trend in more frequency and severity of capillary dilatation, greater frequency of tortuosity in a severe degree and more frequent irregular capillaroscopic pattern in the exposed patients. <h3>References</h3> Blanc PD, Järvholm B, Torén K. Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers. Am J Med 2015;128(10):1094–101. <h3>Disclosure of Interest</h3> None declared
Efficacy of PD-1/PD-L1 inhibitors in the front-line setting as compared to previously treated patients.
Authors: Prantesh Jain, Monica Khunger, Vinay Pasupuleti, Adrian V Hernandez, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2017)

e20646 Background: Drugs targeting the PD-1/PD-L1 pathway show significant clinical activity in non-small cell lung carcinoma (NSCLC). Nivolumab, pembrolizumab and atezolizumab are currently approved for NSCLC patients who have progressed while on platinum-based chemotherapy. Recently, pembrolizumab received FDA approval for treatment naive NSCLC patients with tumor PD-L1 expression of ≥50%. However, there is relative lack of data on comparative efficacy of these drugs in the chemotherapy naive versus post-chemotherapy setting. In the current meta-analysis we compare the efficacy and toxicity of these drugs in chemotherapy naïve patients with those who receive them as subsequent therapy (after previous chemotherapy). Methods: A systematic search of electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings was done for all clinical trials using PD1/PD-L1 inhibitors. Objective response rates (ORR) for patients determined to have positive tumor PD-L1 expression (Tumor Proportion Score ≥1%) from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The ORR across trials was combined using DerSimonian-Laird random effects models. Higgins’ I2 statistic was used to assess heterogeneity. Results: 19 trials (7 with treatment naïve patients [n = 651]; 14 with chemotherapy treated patients [n = 2205]; 2 with separate treatment naïve and previously treated arms) were included. Treatment naïve patients were found to have statistically significant higher efficacy [ORR 28.27%(95% CI 20.70-36.52)] than those who received these drugs as subsequent therapy [ORR 20.13% (95%CI 17.53-22.85) (p = 0.02). Treatment naive patients had statistically significant higher rates of all grade pneumonitis as comapred to previously treated patients (4.9, 95%CI 3.4-6.7 vs 3.0 95% CI 2.0-4.1). Conclusions: PD1/PDL1 therapy for advanced NSCLC has a significantly improved efficacy (based on ORR) when used in treatment naïve patients as compared to its use in patients who have been previously treated with chemotherapy.
OP0262 Trends and costs for gout hospitalization in sweden
Authors: MI Dehlin, V Sigurdardottir, P Drivelegka, A Svärd, LT Jacobsson
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Gout is the most common arthritic disease in the world with increasing incidence and prevalence. There are differences in gout prevalence and course of disease due to cultural, ethnical and genetic factors stressing the need for data from different parts of the world. An increase in hospitalization for gout has been shown for the last two decades in North America. <h3>Objectives</h3> We evaluated the trend for hospitalization of gout in western Sweden 2000 – 2012 and the health care costs for this 2009 – 2012. <h3>Methods</h3> Hospitalization trends for gout were studied using data from the health care consumption register in the Western Swedish Health Care Region (WSHCR) from 2000–01–01 through 2012–12–31. This area is considered to be representative for the country as a whole. Patients aged 18 years and older who were hospitalized during the study period with a principal ICD-10 diagnosis of gout (M10) at discharge were included. We calculated annual population rates for hospitalization for gout. Inflation-adjusted health care costs for the gout hospitalizations were calculated using the Cost-Per-Patient register (CPP). Dispensation of urate lowering therapy (ULT), allopurinol (M04AA01) and probenecid (M04AB01), within 6 months prior to hospitalization was identified using The Swedish Prescribed Drug Register. <h3>Results</h3> There were 1873 hospitalizations for gout (mean age 75.0–77.6 years, 61–74% men) between 2000 and 2012. Demographic characteristics were similar over the study period. From 2000 to 2012, the annual hospitalization rate for gout increased from 12.2 to 16.7 per 100 000 adults (p=0.0038). The increase was most pronounced in males aged 65 and above and over the last three years of the study. From 2009 to 2012 the inflation-adjusted health care costs for gout hospitalizations increased from 5.21 to 8.15 10<sup>5</sup> USD. The duration of hospitalizations also increased from 3 to 5 days median 2000 and 2012 respectively (p=0.021). Only a minority of patients, 19 to 27%, received ULT the 6 months preceding their hospitalization, without any obvious secular trend. <h3>Conclusions</h3> Incidence of hospitalization for primary gout is increasing substantially in Sweden over the last decade and this is reflected in the health care costs. The main part of this increase consists of males aged 65 and above. Only a fourth of the patients were on ULT preceding the hospitalization. These findings are further emphasized by the fact that the total amount of days for somatic inpatient care in WSHCR decreased by 9% from 2002 (1 267 900 days, mean duration 5,7 days) to 2012 (1 151 630 days, mean duration 4,9 days). The findings in this study reflects increasing incidence of the gout disease and an ageing population but also a considerable lack of treatment. <h3>Disclosure of Interest</h3> None declared
SAT0025 MIR 106A, MIR 19A-B, MIR 20A and MIR21A regulate vγ9vδ2 functions participating in the inflammatory responses occurring in rheumatoid arthritis
Authors: G Guggino, F Ciccia, V Orlando, L SAieva, P Ruscitti, P Cipriani, I Chalcarz, R Alessandro, R Giacomelli, F Dieli, N Caccamo, G Triolo
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> miRNAs are non-coding RNAs which have significant roles in regulating gene expression. The miR17-92 cluster appears to be a key factor in the inflammatory pathways activated during RA. <h3>Objectives</h3> In this study we aimed to evaluate miR17–92 expression and functions in γδ T cell subsets in RA patients, γδ T cells, in fact produce proinflammatory cytokines such as IFN-g, IL-6 and IL-8 that may contribute to the inflammatory responses in RA. <h3>Methods</h3> Heparinized peripheral blood from 10 early RA untreated patients and 10 healthy donors was obtained for this study. Polyclonal Vγ9Vδ2 T cell lines were generated first by magnetic isolation followed by sorting (FACSAria) and further analysed by flow cytometry to define their phenotype and their pattern of cytokine production. Expression analysis of miRNA17–92 cluster was performerd by RT-PCR and after identification of relevant miRNA involved in RA, mRNA expression of miRNA target genes was studied. <h3>Results</h3> A remarkable change in the distribution of Vγ9Vδ2 T cell functional subsets with an expansion of effector subsets and a reduction of naïve cells, was observed in the peripheral blood of RA patients, as compared to healthy donors, which were accompanied by modifications in proinflammatory cytokine expression. Particularly, T<sub>EM (effector memory)</sub> and T<sub>EMRA (effector memory terminally differentiated)</sub> cells resulted the major souce of IL-6 and IL-8. A significant correlation between miRNA expression and levels of IL-6 and IL-8 was found. The comparative analysis of miRNA expression among Vγ9Vδ2 T cell subsets, between RA patients and healthy controls showed a downregulation of miR106a-5p and miR20a-5p and an upregulation of miR 21a-5p among Vγ9Vδ2 T<sub>EM</sub> cells; a downregulation of miR19–3p among Vγ9Vδ2 T<sub>EM</sub> and Tc<sub>M (central memory)</sub> cells was also found. This miRNA expression regulated IL-8 and IL-6 gene transcription contributing to the survival of the pro-inflammatory pool reducing the expression of the PDCD4 gene. <h3>Conclusions</h3> Our results provide evidence of a role of miR106a, miR19–3p, 20a and 21a in the regulation of Vγ9Vδ2 T cells function in RA patients and suggest the possibility that the miR17–92 family and γδ T cells participate to the pathogenesis of RA. <h3>Disclosure of Interest</h3> None declared