tbuckley/cabot-search huggingface dataset:
Benefit-risk evaluation of ziv-aflibercept in combination with irinotecan-fluoropyrimidine-based chemotherapy (FOLFIRI) from the VELOUR trial using multicriteria decision analysis (MCDA).
Authors: Teresa Macarulla, Jasmanda Wu, Larry Phillips, Sheikh Usman Iqbal, Chris Kripas, Zheng Gu, Amy Freedman, Pankaj Bhargava, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2013)

e14656 Background: In the VELOUR trial, in metastatic colorectal cancer (mCRC) patients, ziv-aflibercept (Afl) combined with FOLFIRI demonstrated significant improvements in median overall survival (OS) by 1.44 mos and median progression-free survival (PFS) by 2.23 mos when compared with FOLFIRI + placebo. We utilized a systematic approach to evaluate the benefit/risk profile of the regimen in the target disease population. Objectives: To evaluate favorable and unfavorable effects of Afl in combination with FOLFIRI in patients with mCRC previously treated with an oxaliplatin-based regimen using the MCDA method. Methods: Data from VELOUR were used to compare the 2 treatment arms (Afl + FOLFIRI vs placebo + FOLFIRI). An 8-step process based on the MCDA was used to construct a value tree that displayed evaluation criteria for favorable and unfavorable effects, determined score, assigned weight for each criteria, and then combined weights and scores for each treatment arm to derive an overall value. Sensitivity analysis was also conducted. Results: The final value tree comparing the 2 treatment arms had 2 branches representing favorable and unfavorable effects. Favorable effects criteria included survival probability at 12, 18, and 24 mos, median OS, median PFS, and overall response rate. Unfavorable effects criteria included 11 anti-VEGF- and FOLFIRI-associated adverse events (AEs), as well as deaths and treatment discontinuation due to AEs. The survival rate at 24 mos had the highest weight (100), followed by median OS (95). For unfavorable effects, diarrhea had the highest weight (15), followed by arterial thromboembolism (ATE) (12). AEs seen with Afl + FOLFIRI were generally manageable; their clinical impact did not outweigh the benefits. The overall value combining favorable and unfavorable effects for Afl + FOLFIRI was 53 vs 40 for placebo + FOLFIRI. Conclusions: Results from this quantitative benefit-risk analysis indicate that the benefit-risk balance for ziv-aflibercept in combination with FOLFIRI is favorable compared with FOLFIRI alone in adults with mCRC previously treated with an oxaliplatin-based regimen. Clinical trial information: NCT00561470.
FIELD HOCKEY INJURIES AMONG HIGH SCHOOL GIRLS IN THE UNITED STATES, 2008/09–2015/16
Authors: Lauren Pierpoint, Rae Dawn Comstock
Journal: British Journal of Sports Medicine (2017)

<h3>Background</h3> Although women9s field hockey is a popular sport world-wide, detailed epidemiological injury data on United States (US) high school players are sparse. Characterizations of injury rates and patterns in high school athletes is the first necessary step to drive targeted injury prevention efforts. <h3>Objective</h3> Describe rates and patterns of high school field hockey injuries. <h3>Design</h3> Retrospective descriptive epidemiology. <h3>Setting</h3> US High Schools. <h3>Patients(or Participants)</h3> Injured high school field hockey athletes. <h3>Interventions (or Assessment of Risk Factors)</h3> Athlete exposure (AE) and injury event data reported by athletic trainers to a large national high school sports-related injury surveillance system. <h3>Main Outcome Measurements</h3> Injury rates and patterns. <h3>Results</h3> From 2008/09–2015/16, 1,256 injuries were sustained during 723,026 AEs for a rate of 1.74/1,000 AE. Injury rates were significantly higher in competitions (2.64) than practices (1.32) (rate ratio=2.00, 95% CI=1.79–2.23). Neither practice nor competition injury rates changed significantly over time (p&gt;0.05). Overall, most injuries were due to contact with a playing apparatus (20.0% contact with ball; 15.9% contact with stick). The most common injury mechanism during practice was non-contact (32.2%) but during competition was contact with a playing apparatus (49.9%). The most common injuries were concussions (15.5%) and hip/thigh/upper leg strains (13.1%); eye injuries were uncommon (0.8%). Most concussions occurred during competition (77.1%) and were due to contact with a playing apparatus (50.0%) or contact with another player (39.5%). Most athletes returned to play within 3 weeks (81.8%); 3.8% of injuries resulted in medical disqualifications for the remainder of the season. Surgical repair was required in 4.1% of injuries; specifically, 16.7% of knee injuries and 12.8% of fractures. <h3>Conclusions</h3> Field hockey injury rates and patterns differ between competition and practice. Injury prevention efforts should focus on reducing contact with the ball and stick, especially during competitions, while preserving the integrity of the game.
CdSe・ZnS量子ドットは,NLRP3インフラマソーム活性化による肝細胞ピロトーシスと肝炎を誘発する
Authors: Lu Yonghui, Xu Shangcheng, Chen Haiyan, He Mindi, Deng Youcai, Cao Zhengwang, Pi Huifeng, Chen Chunhai, Li Min, Ma Qinlong, Gao Peng, Ji Yan, Zhang Lei, Yu Zhengping, Zhou Zhou
Journal: Biomaterials (2016)
THU0694 Effects of ANTI-TNF therapy on solubile urokinase plasminogen activator receptor (SUPAR) levels in arthritis
Authors: A Pusztai, E Végh, Ά Horváth, A Hamar, S Szántό, Z Szekanecz, G Szücs
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The urokinase plasminogen activator receptor (uPAR) is expressed mainly on immune cells, smooth muscle cells and endothelial cells, favoring extracellular matrix degradation, cell adhesion, cell proliferation and regulates cell migration. The suPAR is the soluble form of the cell membrane-bound protein uPAR, elevated levels may reflect increased activation of immune system which observed in the autoimmune diseases. <h3>Objectives</h3> The aim of this study was to assess the effects of anti-TNF therapy on uPAR production in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We also wished to correlate suPAR levels with various autoimmune-inflammatory biomarkers. <h3>Methods</h3> Altogether 33 arthritis patients including 22 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 11 AS patients treated with ETN were included in a 12- month follow-up study. Circulating suPAR levels were assessed by suPARnostic Quick Test Reader. In addition,disease activity (DAS28 or BASDAI), CRP, IgM rheumatoid factor, anti-CCP were also assessed. Assessment were performed at baseline, as well as 6 and 12 months after treatment initation. <h3>Results</h3> Anti-TNF treatment was highly effective in both disease, as the mean DAS28 decreased in RA, mean BASDAI decresead in AS. There were no significant change in the suPAR levels after 12 months of anti-TNF therapy, although resulted non-significant decrease (p&lt;0,18) in RA patients with critical suPAR levels (&gt;9ng/ml). Baseline suPAR levels positively correlated with anti-CCP (p&lt;0,001) and rheumatoid factor (p=0,024) in RA patients. Circulating suPAR levels did not correlate with DAS28, BASDAI or CRP. <h3>Conclusions</h3> In a mixed cohort of RA and AS patients, anti-TNF therapy did not affect the suPAR levels after 12 months. suPAR levels correlated with rheumatoid factor and anti-CCP. Based on these results suPAR may be a marker of autoimmunity rather than that of disease activity. <h3>Disclosure of Interest</h3> None declared
AB0217 The prognostic value of iga autoantibodies (rheumatoid factor and acpa) for prediction of therapeutic responses to anti-tnf therapy in patients with rheumatoid arthritis
Authors: G Steiner, D Sieghart, F Alasti, P Studenic, T Perkmann, T Horn, D Aletaha, JS Smolen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are important diagnostic markers in rheumatoid arthritis (RA). These antibodies are predominantly of the IgM (RF) or IgG (ACPA) isotype. The added diagnostic and prognostic value of IgA autoantibodies is being debated. <h3>Objectives</h3> To determine the prevalence of IgA-RF and IgA-ACPA in patients with RA and to investigate their potential predictive value regarding response to treatment with methotrexate (MTX) and TNF inhibitors. <h3>Methods</h3> A total of 255 patients were tested for the presence of IgA-RF, IgA-ACPA and IgG-ACPA by EliA® (Thermo Fisher Scientific); IgM-RF was measured by nephelometry. Therapeutic responses to MTX and TNF blocking biologicals were calculated in an inception cohort (n=104) who had started their DMARD therapy at our clinic. To define therapeutic responses simplified disease activity index (SDAI) 50 and American College of Rheumatology (ACR) 20 responses were calculated. <h3>Results</h3> Among the 255 patients tested 125 (49%) had at least one type of IgA autoantibody: 114 (44.7%) were found to be IgA-RF positive and of these 10.5% were negative for IgM-RF and 5.2% were double negative for both IgM-RF and IgG-ACPA; thus, in these patients IgA-RF was the only detectable antibody. IgA-ACPA were detected in 79 (31%) patients and apart from one exception all of them had also IgG-ACPA. Remarkably, the percentage of patients showing a SDAI50 response to TNF inhibitors was significantly lower in patients positive for IgA-RF and/or IgA-ACPA (p&lt;0.0001) compared to IgA negative patients. Thus, 58% of IgA negative (but IgM-RF and/or IgG ACPA positive) patients showed a SDAI50 response whereas only 25% of the IgA-RF and/or IgA-ACPA positive ones were responders. Interestingly, while the presence of both IgA specificities did not further change the percentage of responders, patients positive for IgA-ACPA but negative for IgA-RF showed the lowest response rate to anti-TNF treatment. Completely seronegative patients also showed a significantly lower SDAI50 response (p&lt;0.0001) to TNF inhibitors compared with the IgA negative (but IgM-RF and/or IgG-ACPA positive) patients. Similar results were obtained when ACR20 was used as response criteria. No differences between the various serological groups were seen with respect to treatment with MTX. <h3>Conclusions</h3> While the added diagnostic value of IgA antibody measurement was moderate, IgA-RF and particularly IgA-ACPA appear to be associated with poorer therapeutic responses to TNF inhibitory biological drugs and therefore may help in further stratification of RA patients and therapeutic decision making. <h3>Disclosure of Interest</h3> None declared
Parent-Reported and Self-Perceived Behavioral and Psychiatric Symptoms in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Wei Liu, Yin Ting Cheung, Tara M. Brinkman, Pia Banerjee, Deokumar Srivastava, Vikki G Nolan, Hongmei Zhang, James G Gurney, Ching-Hon Pui, Leslie L. Robison, Melissa M. Hudson, Kevin R. Krull
Journal: Blood (2016)
ニューロン標的ナノ粒子により仲介されるBDNF遺伝子送達は末梢神経損傷において神経保護作用を示す【Powered by NICT】
Authors: D F Lopes Catia, P Goncalves Nadia, P Gomes Carla, J Saraiva Maria, P Pego Ana
Journal: Biomaterials (2017)
08.16 Mir200B-5p expression in minor salivary glands (msg): a possible predictor of lymphoma development in sjögren's syndrome (ss)
Authors: Efstathia K. Kapsogeorgou, Aristea Papageorgiou, Michael Voulgarelis, Athanasios G. Tzioufas
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background-aim</h3> Our preliminary data suggested that miR200b-5p miRNA expression may be down-regulated in the MSG-tissues of SS patients with MALT-lymphoma (Gourzi <i>et al</i>., <i>Clin Exp Immunol</i>. 2015). Herein, we sought to investigate whether low miR200b-5p MSG-levels are associated with SS-related lymphomas and their possible prognostic value for lymphoma development. <h3>Methods</h3> miR200b-5p expression was analysed by quantitative real-time PCR in total RNA from MSG-tissues from 77 SS-patients and 9 patients with chronic sialadenitis associated with sarcoidosis, HCV (4-each) or HBV infection (1 who was also diagnosed with MALT-lymphoma). SS-patients included 28 that did not develop lymphoma during follow-up (without lymphoma; median follow-up time since biopsy performance, range: 6 years, 1–12.75 years), 17 that developed lymphoma in the future (prelymphoma; median follow-up time till lymphoma diagnosis, range: 3.59 years, 0.42–8.5 years, 15-MALT, 2-NMZL, 1-DLCBL) and 31 with SS-associated lymphoma at the time of biopsy (lymphoma; 24-MALT, 2-NMZL, 2-DLCBL,1-BALT, 1-LP and 1-SLL). In 15 cases, we had sequential MSG-samples from prelymphoma patients who transitioned to lymphoma (12-MALT, 2-NMZL, 1-DLCBL). <h3>Results</h3> Tukey's multiple comparison revealed that miR200b-5p levels were significantly down-regulated in MSG tissues of prelymphoma and lymphoma SS-patients (mean relative expression±SE: 0.37±0.10 and 0.26±0.06, respectively) compared to SS-patients without lymphoma (0.67±0.07; p≤0.05 and p≤0.0001 for pre- and lymphoma, respectively) or non-SS sialadenitis (0.85±0.28, p≤0.05 and p≤0.01, respectively). The expression of miR200b-5p was not found to differ between patients with SS without lymphoma and non-SS sialadenitis, or SS-associated pre-lymphoma and lymphoma. The miR200b-5p expression was not found to change significantly over transition to lymphoma. The miR200b-5p expression levels were negatively correlated with the biopsy focus score (r: −0.6550, p&lt;0.0001), whereas they were not associated with the site or the number of involved sites, the type or the stage of lymphoma. <h3>Conclusions</h3> The significantly lower expression of miR200b-5p in the MSG tissues of patients with SS-associated prelymphomas and lymphomas implicates it in SS-lymphomagenesis. In addition, the significantly lower levels of miR200b-5p in prelymphoma-MSGs suggests that it can serve as a prognostic marker for future lymphoma development. The prognostic value of miR200b-5p in SS-associated lymphomas, the expressing cell types and molecular pathways that regulates are under investigation.
A novel phosphatidylinositol 3-kinase inhibitor, ZSTK474 exerted antitumor activity against human tumor xenografts by oral administration
Authors: Shin-Ichi Yaguchi, Yasuhisa Fukui, Ichiro Koshimizu, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Goda, Shuichi Hirono, Kanami Yamazaki, Takao Yamori
Journal: Cancer Research (2005)

1691  Phosphatidylinositol 3-kinase (PI3K) is a promising molecular target of cancer therapy since it is a key enzyme playing important roles in various biological pathways such as cell survival, vesicle transport and cytoskeletal rearrangement and is also known to be involved in tumorigenesis. However, little anticancer agents targeting PI3K have been developed yet. We synthesized thousands of s-triazine derivatives and found by cell-based screening 2-(2-difluoromethylbenzoimidazol-1-yl)-4, 6-dimorpholino-1, 3, 5-triazine (ZSTK474) with potent antiproliferative activity. To predict the mode of action of ZSTK474, we exploited the COMPARE analysis based on the chemosensitivity database of a panel of 39 human cell lines. It revealed that ZSTK474 significantly correlated with LY294002 and wortmannin, suggesting that ZSTK474 inhibits PI3K. Then, we biochemically confirmed that ZSTK474 inhibited PI3K at concentrations of 10-100 nM. The inhibition was reversible as was the case of LY294002. Concerning the structure activity relationship, the difluoromethyl group of ZSTK474 was important for inhibiting both cell growth and PI3K. Furthermore, PI3K-inhibitory activities of several s-triazine derivatives significantly correlated with their growth-inhibitory activities. These results suggested that ZSTK474 inhibited cell proliferation through inhibiting PI3K activity. The computer-aided molecular modeling of PI3K-ZSTK474 complex revealed that ZSTK474 could bind to the ATP-binding site of PI3K, and that overall arrangement of ZSTK474 at the site was similar to that of ATP, but not of LY294002. We investigated the effects of ZSTK474 on the cellular signaling pathways and examined its anti tumor activity. ZSTK474 decreased the PDGF-dependent membrane ruffling of murine embryonic fibroblast cells, in which the PDGF-dependent generation of phosphatidylinositol-3,4,5-triphosphate was also reduced. ZSTK474 inhibited the phosphorylation of PI3K-downstream components, Akt and glycogen synthase kinase-3beta, and it decreased the cyclin D1 level. ZSTK474 showed potent antitumor activity by oral administration against murine solid tumors and human cancer xenografts. Severe body weight loss or serious bone marrow toxicity was not observed during the daily oral administrations for more than 10 days. The reduction of the Akt-phosphorylation and the cyclin D1 level in the tumor following ZSTK474 administration was confirmed. In conclusion, we found a novel PI3K inhibitor ZSTK474, and demonstrated its potent antitumor efficacy by oral administration without serious toxicity. ZSTK474 could be orally administered and showed favorable pharmacokinetic properties, which can be great advantages for clinical cancer treatment. ZSTK474 is a promising new anticancer agent for development toward clinical investigation.
05.05 Systematic profiling of mouse synovial fibroblasts during tnf-driven arthritogenesis and alignments to human rheumatoid arthritis
Authors: Evangelos Ntougkos, Panagiotis Chouvardas, Fani Roumelioti, Caroline Ospelt, Mojka Frank-Bertoncelj, Andrew Filer, Christopher D Buckley, Steffen Gay, Christoforos Nikolaou, George Kollias
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Aberrant activation of synovial fibroblasts (SFs) is a key determinant in the pathogenesis of rheumatoid arthritis (RA). We aimed to produce a systematic map of gene expression and epigenetic changes occurring in this cell type during disease progression in the human TNF-transgenic model of arthritis, as well as identify commonalities with the human disease. <h3>Materials and methods</h3> We used deep sequencing to probe the transcriptome, the methylome and the chromatin landscape of cultured mouse arthritogenic synovial fibroblasts at three stages of disease, as well as SFs stimulated with human TNF. We performed bioinformatics analyses at the gene, pathway and network levels, compared mouse and human data and validated selected genes in both species. <h3>Results</h3> SF arthritogenicity is reflected on distinct patterns of transcriptional deregulation and is enriched in pathways of the innate immune response and mesenchymal differentiation. A functionally-definable subset of these changes is associated with promoter methylation. The disease state involves highly active promoters, as marked by H3K4 trimethylation. We identified substantial overlap between mouse and human data, at the level of the gene and to an even higher degree at the level of pathways. <h3>Conclusions</h3> This work presents the first systematic examination of the pathogenic changes that occur in the mouse synovial fibroblast as TNF-driven arthritogenesis progresses. Comparisons with respective human RA data show significant correlations, further validating the human TNF-transgenic mouse as a reliable model of the human disease. The data generated may serve as a framework for the discovery of novel pathogenic mechanisms and biomarkers that will aid in translational efforts.
Do we need adjuvant therapy in rectal cancer with complete pathologic response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal excision?
Authors: Verónica Pereira, Aarón Sosa, Óscar Reig, Iván Victoria, Luis Roberto Féliz, Juan Ramón Ayuso, Josep Antoni Bombí, Antoni Castells, Carles Conill, Miriam Cuatrecasas, Salvadora Delgado, Gloria Fernández-Esparrach, Àngels Ginés, Antonio Lacy, Rosa Miquel, Mario Pagés, Estela Pineda, Xabier Garcia-Albeniz, Rosa Gallego, Juan Maurel
Journal: Journal of Clinical Oncology (2012)

3536 Background: Neoadjuvant chemo-radiotherapy (CRT) is the standard of care for patients (pts) with u&gt;T3 by endoscopic ultrasound (EUS) rectal cancer. Although pts with complete pathological response (ypT0N0) fare well in multiple series, there is uncertainty of whether it’s due to the induction (CRT), due to the adjuvant chemotherapy (ACT) or due to the combination of both therapies. We have evaluated long-term outcomes in CRT-treated pts. Those with ypT0N0, were not treated with ACT. Methods: Pts with u&gt;T3 rectal cancer, received neoadjuvant chemotherapy (225mg/m2/day 5-fluorouracil (FU)) in continuous infusion (CI) per 5 weeks (wks) and concomitant radiotherapy (45 Gy). Laparoscopic surgery (LAP) was planned after an interval of 5-8 wks. Pts achieving ypT0N0 were no treated with ACT. Pts with ypT&gt;1 or N1 were treated with 3 gr/m2 FU in 48 hour CI and LV 200 mg/m2 every 2 wks x 6 cycles. Results: From November 2000 to November 2008, a cohort of 173 pts were treated with induction CRT and 167 pts underwent total mesorectal excision (LAP, n=158, open surgery n=9). Complete pathological response was achieved in 26/167 pts (15.5%). After a median follow-up of 58.3 months, pts with ypT0N0 have a 5-year disease-free survival and overall survival rate of 96% (95% CI 76 to 99%) and 100% (95% CI not estimable) respectively. Conclusions: Using these results, a clinical trial comparing observation versus adjuvant therapy in ypT0N0 after standard CRT, would need to enroll 3088 pts to show a HR of 0.75 in favor of ACT after 5 years of follow-up (alpha=.05, beta=.2). In case that the true DFS lied in the lower bound of the 95% CI, 636 patients would be needed under the same assumptions. These results do not support the administration of ACT to ypT0N0 patients.
Abstract 17345: Particulate Matter and Risk of Incident Cardiovascular Disease in a Nationwide Cohort of Men
Authors: Jaime E Hart, Jarvis T Chen, Robin C Puett, Jeff D Yanosky, Eric B Rimm, Kathryn M Rexrode, Gregory A Wellenius, Francine Laden
Journal: Circulation (2015)

Introduction: Chronic exposures to particulate matter (PM) have been associated with cardiovascular disease (CVD) morbidity and mortality. We examined the impact of long-term exposures to PM on the risk of incident coronary heart disease (CHD) and stroke among members of the nationwide all-male Health Professionals Follow-Up Study (HPFS) prospective cohort. Methods: HPFS members were followed biennially between 1986-2006 to obtain information on incident disease and to update information on CVD risk factors. Time-varying ambient PM 10 , PM 2.5-10 , and PM 2.5 for the previous 12 months were calculated from monthly predictions at the address level. Multivariate adjusted Cox proportional hazards models were used to estimate [HR (95%CI)] for the association between each fraction of PM and each outcome among 43,371 CVD-free members of the HPFS, adjusting for risk factors and other potential confounders. We also assessed effect modification by region of the country, BMI, smoking status, and comorbidities (hypercholesterolemia, high blood pressure, and diabetes). Sensitivity analyses were conducted restricting the population to men who provided residential (N=15,395), as opposed to work, addresses. Results: The mean (SD) levels of 12-month average PM 10 , PM 2.5-10 , and PM 2.5 were 20.7 (6.2), 8.4 (4.7) and 12.3 (3.4) μg/m 3 . In the full population, there was only modest evidence of increased risks of incident CHD or stroke with increasing PM exposures. Associations with stroke were modified by region, hypercholesterolemia, high blood pressure, and diabetes, with larger effects among those with comorbid conditions and in the Northeast and South. CHD, but not stroke, dose-responses were stronger among those who provided residential as opposed to work addresses; each 10 μg/m 3 increase, was associated with increases in overall CHD [1.10 (95%CI: 1.01-1.20), 1.09 (0.97-1.23), and 1.14 (0.98-1.32) for PM 10 , PM 2.5-10 , and PM 2.5 , respectively]. Conclusions: In this cohort of US men, PM exposures were only modestly associated with elevated risks of CHD and stroke. Comorbidities and region modified the associations with stroke, and residential ambient exposures were more associated with CHD than work ambient exposure.