tbuckley/cabot-search huggingface dataset:
AB0191 Sdai as predictor of 1-year efficacy of the first tnf blocker in clinical practice.
Authors: R. Talotta, F. Atzeni, M. Battellino, M. C. Ditto, A. Batticciotto, S. Santandrea, P. Sarzi-Puttini
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic disabling autoimmune disease that affects the peripheral synovial joints. The new biological therapies have led to clinical improvements, but about 30% of patients discontinue treatment within the first year. Many studies (mainly based on national registries) have tried to identify variables to predict survival on biological therapy. High baseline HAQ or DAS 28 scores seem to be related to worse outcomes, but no definite variable can predict if or when a patient will be switched to another biological agent. <h3>Objectives</h3> To evaluate which of DAS28, CDAI and SDAI is more predictive of the discontinuation of a first TNF blocker within one year. <h3>Methods</h3> The variables considered were age at the start of therapy, gender, comorbidity, disease duration, RF positivity, DAS28, CDAI and SDAI scores, the number of previous DMARDs, the concurrent use of MTX and corticosteroids, the anti-TNF agents, the number of tender and swollen joints, functional class, the ESR, and C-RP levels. We compared the relative risk (OR) of switching to another biological agent within the first 12 months in patients in remission, and in those with low, medium or severe disease activity after three and six months. <h3>Results</h3> We collected information from the clinical records of 51 patients with RA according to the 1987 ACR criteria (41 F; mean age 56.5 ± 13.5 years, mean disease duration 15.3 + 8.5 years). Rheumatoid factor was positive in 36 patients and anti-CCP antibodies in 33 patients. Forty-one patients were concomitantly treated with MTX 5-20 mg/week, three with leflunomide 20 mg/day, five with hydroxychloroquine 200-400 mg/day, one with sulfasalazine 1500 mg/day, and 32 with prednisone 2.5-10 mg/day. Twelve subjects were treated with ETN 50 mg/week as the first biological agent, 20 with ADA 40 mg every other week, and 27 with IFN 3 mg/kg every eight weeks. Disease activity at the different times of evaluation is shown in Table I. Thirty-four patients switched to another biological agent. Twelve discontinued treatment within the first year. The reason for switching was an adverse event in only 4 cases. The SDAI assessment made after six months was the most accurate predictor of switching within 12 months (p=0.002, OR 16.1, 95% CI 1.5-200.7) compared to CDAI (p=0.04, OR 5.1, 95%CI 0.8-40) and DAS28 (p=0.01, OR 7.1, 95%CI 1.2-55). <h3>Conclusions</h3> The SDAI at 6 months seems to be most predictive factor when making therapeutic decisions. We suggest that periodic SDAI assessments should be used for RA follow-up in clinical practice. <h3>Disclosure of Interest</h3> None Declared
P648Myocardial protection by ischemic preconditioning is already evident during early index ischemia: analysis of ST-segment deviation during ischemia/reperfusion in pigs
Authors: A Skyschally, G Amanakis, G Heusch
Journal: Cardiovascular Research (2014)

Ischemic preconditioning (IPC), i.e. brief periods of ischemia/reperfusion (I/R) prior to prolonged ischemia, protects the myocardium from irreversible damage and reduces final infarct size. IPC is believed to act through reduction of reperfusion injury. We have now analyzed continuously recorded ECG-derived parameters, notably the time course of ST-segment deviation and the number of ventricular arrhythmias. Methods: Anesthetized open-chest pigs were subjected to 60 min LAD occlusion and 180 min reperfusion. IPC (n=8; 2 x 3 min LAD occlusion, separated by 2 min reperfusion) was induced 15 min before the sustained ischemia. Pigs without IPC served as controls (CON; n=8). Regional myocardial blood flow was measured by microspheres, area at risk was determined by Patent-Blue and infarct size by TTC-staining. ST-segment deviation was analyzed on ECG-lead II, defined as the voltage difference between a point 30 ms before the P-wave and 20 ms after the J-point. Ventricular arrhythmias were counted during ischemia and reperfusion. Results: Transmural blood flow at 5 min ischemia was not different between IPC (0.033±0.072 ml/min/g; mean±SEM) and CON (0.023±0.005; n.s., t-test) as was area at risk (IPC: 26±1% of the left ventricle; CON: 24±2%; n.s.). IPC reduced infarct size from 44±3% of the area at risk to 16±3% (p<0.05). The ST-segment deviation prior to ischemia was similar in both groups (IPC: 0.077±0.017 mV; CON: 0.041±0.017; n.s.; 2-way ANOVA) and increased with the onset of ischemia. However, the amplitude of ST-segment deviation was markedly smaller with IPC already at 5 min ischemia (IPC: 0.277±0.027 mV; CON: 0.374±0.067; p<0.05) and remained smaller throughout ischemia (55 min ischemia; IPC: 0.197±0.036; CON: 0.332±0.058; p<0.05) and up to 20 min reperfusion (IPC: 0.195±0.024 mV; CON: 0.303±0.045; p<0.05). The number of severe arrhythmias (ventricular fibrillation/sustained tachycardia) was not different between groups. With IPC, there were more ventricular extrasystoles (1-3 consecutive VES) during the first 30 min of reperfusion than with CON (IPC: 41(28-61) VES/30 min; median(IQR); CON: 21(18-22); p<0.05; Mann-Whitney-Test). Conclusion: Contrary to common notion, IPC impacts the myocardium already during early index ischemia. The increased number of VES during reperfusion with IPC might be related to the larger amount of viable, nevertheless still injured myocardium. It remains to be elucidated how the attenuation of ST-segment deviation during I/R is mechanistically related to the cardioprotective properties of IPC.
Studies Link Familial Breast, Prostate Cancers
Authors: J. Waalen
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Studies Link Familial Breast, Prostate Cancers Get access Jill Waalen Jill Waalen Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 10, 19 May 1993, Page 776, https://doi.org/10.1093/jnci/85.10.776 Published: 19 May 1993
Survey Shows M.D.s' Ambivalence About Maximum Androgen Blockade
Authors: J. Randal
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Survey Shows M.D.s' Ambivalence About Maximum Androgen Blockade Get access Judith Randal Judith Randal Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 24, 20 December 1995, Pages 1827–1829, https://doi.org/10.1093/jnci/87.24.1827 Published: 20 December 1995
Endoscopic Demonstration of Loss of Duodenal Folds in the Diagnosis of Celiac Disease
Authors: Emilio Brocchi, Gino Roberto Corazza, Giancarlo Caletti, Enrico A. Treggiari, Luigi Barbara, Giovanni Gasbarrini
Journal: New England Journal of Medicine (1988)

Among 873 patients undergoing upper gastrointestinal endoscopy for various reasons over a two-year period, four had a loss of Kerckring's folds in the descending duodenum. Endoscopic duodenal biopsy in all four patients revealed subtotal villous atrophy due to celiac disease. We undertook a prospective study to evaluate the extent to which this finding predicted celiac disease in 65 consecutive patients referred for intestinal biopsy. Duodenal folds were absent or markedly decreased in 15 of 17 patients with subtotal villous atrophy and in 8 of 48 patients with partial villous atrophy or normal duodenal mucosa, giving a sensitivity of 88 percent and a specificity of 83 percent for this endoscopic finding with respect to celiac disease. We recommend that all patients undergoing upper gastrointestinal endoscopy be examined for the loss or reduction of duodenal folds and, should this be found, that the examination include duodenal biopsy. The value of this procedure as an aid in the diagnosis of celiac disease should be particularly great in patients with minimal, transient, or unrelated symptoms. (N Engl J Med 1988; 319:741–4.)
CONTRAST MEDIA USE DURING ENDOVASCULAR THERAPY FOR INFRAINGUINAL PERIPHERAL ARTERIAL DISEASE: INSIGHTS FROM THE MULTI-CENTER XLPAD REGISTRY
Authors: Anand Prasad, Karan Sarode, Atif Mohammad, Emmanouil Brilakis, Osvaldo Gigliotti, Michael Luna, Tayo Addo, Mirza Baig, Nicolas Shammas, Mazen Abu-Fadel, Carolina Ortiz-Lopez, David Spelber, Maria Esparza, Shirling Tsai, Subhash Banerjee
Journal: Journal of the American College of Cardiology (2015)
Cancer Genes Pose New Dilemmas
Authors: E. Blume
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Cancer Genes Pose New Dilemmas Get access Elaine Blume Elaine Blume Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 11, 1 June 1994, Pages 818–820, https://doi.org/10.1093/jnci/86.11.818 Published: 01 June 1994
P133 Prediction equations for pulmonary function values in healthy Iranian children (aged 4-10 years)
Authors: M. H. Boskabady, S. Tababaei, S. Shahmohammadi, O. Mohammadi, P. Saremi, S. Amery, H. Esmaili, Z. Ghafari
Journal: Thorax (2010)

<h3></h3> Pulmonary function test variables (PFTs) are dependent on height, age, and gender and there is evidence of PFT variation in different ethnic groups. Therefore prediction equations for PFTs were derived from healthy, urban children in the city of Mashhad (northeast Iran). Predicted equations for normal PFT values have been derived from 414 healthy children including 192 boys and 222 females (aged 4–10 years). The subjects underwent measurement of following spirometric variables: forced vital capacity (FVC), forced expiratory volume in 1 s (FEV<sub>1</sub>), maximal mid-expiratory flow (MMEF), peak expiratory flow (PEF), maximal expiratory flow at 75%, 50% and 25% of the FVC (MEF<sub>75</sub>, MEF<sub>50</sub>, and MEF<sub>25</sub> respectively). Regression analysis using height and age as independent variables was applied to provide predicted values for both sexes. There were positive correlations between each pulmonary function variable with height and age. The largest positive correlations were found for FEV<sub>1</sub> with height and age in both sexes. Comparison of PFTs derived from the equations of the present study showed significant differences with those of several previous studies (p&lt;0.001 for most cases) (Abstract P133 Figure 1). A set of PFT reference values and prediction equations for both sexes has been derived using relatively large, healthy, Iranian children which has generated results that differ from several other prediction equations.
Abstract 2378: Upregulation of the ATR/CHK1 pathway and decreased therapeutic sensitivity in upper aerodigestive cancer cell lines with distal 11q loss.
Authors: Madhav Sankunny, Rahul A. Parikh, Susanne M. Gollin
Journal: Cancer Research (2013)

Abstract Gemcitabine, a pyrimidine analog/antimetabolite, is commonly used to treat breast, lung, head and neck, pancreatic, ovarian, biliary, urinary bladder, and cervical carcinomas. Gemcitabine inhibits DNA synthesis by direct inhibition of ribonucleotide reductase by its metabolite, gemcitabine diphosphate, and the incorporation of its active form, gemcitabine triphosphate into the elongating DNA strand, resulting in chain termination. Gemcitabine-induced DNA damage leads to activation of the ATR/CHK1 pathway and S-phase cell cycle arrest. Our previous studies showed that carcinoma cells with our biomarker (distal 11q loss) overexpress ATR and CHK1, resulting in decreased sensitivity to ionizing radiation in biomarker-positive head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) cell lines. Several studies in the literature have shown that inhibition of CHK1 increases the sensitivity of tumor cell lines to replication inhibitors, including gemcitabine. In pancreatic cancer cell lines, small molecule inhibitor (SMI)-mediated disruption of CHK1 signaling has been reported to potentiate the cytotoxic effect of gemcitabine. Based on the literature and our previous findings, we now report that biomarker-positive HNSCC and NSCLC cell lines also show ATR/CHK1 upregulation and decreased sensitivity to gemcitabine, Further, we observed that siRNA knockdown of the ATR/CHK1 pathway and SMI inhibition of CHK1 signaling in HNSCC and NSCLC cell lines increase their sensitivity to treatment with gemcitabine. Our previous results showed increased efficacy of ionizing radiation combined with CHK1 inhibition in biomarker-positive cell lines; our new results show increased efficacy of gemcitabine combined with CHK1 inhibition in biomarker-positive HNSCC and NSCLC cell lines. These results provide further support for combining CHK1-targeted therapy with standard therapy in conjunction with an appropriate companion diagnostic biomarker, like distal 11q loss. As is the case with other targeted therapies, biomarker-based selection of the right drug for the right patient appears to increase therapeutic efficacy. Citation Format: Madhav Sankunny, Rahul A. Parikh, Susanne M. Gollin. Upregulation of the ATR/CHK1 pathway and decreased therapeutic sensitivity in upper aerodigestive cancer cell lines with distal 11q loss. [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 2378. doi:10.1158/1538-7445.AM2013-2378
FRI0453 Patients with ankylosing spondylitis have elevated soluble biomarkers of cardiovascular disease compared to controls
Authors: I. J. Berg, A. G. Semb, D. van der Heijde, H. Dagfinrud, T. K. Kvien, I. Seljeflot, P. Aukrust, T. Ueland, S. A. Provan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patients with ankylosing spondylitis (AS) have higher risk of atherosclerotic cardiovascular disease (CVD) than the general population, but few have studied soluble biomarkers of CVD in AS. Asymmetric dimethylarginine (ADMA) and ratio of L-arginine/ADMA are markers of endothelial dysfunction where elevated ADMA and reduced L-arginine/ANDA indicates increased risk of CVD. Osteoprotegerin (OPG) is a marker and regulator of arterial calcification and a predictor of CVD and adverse outcome. N-terminal pro-natriuretic peptide (NT-pro-BNP) is a predictor of myocardial function and cardiac mortality. <h3>Objectives</h3> To compare levels of ADMA, L-arginine/ADMA, OPG and NT-pro-BNP in AS patient and controls. <h3>Methods</h3> A cross-sectional study of AS patient and controls. AS patients recruited from a hospital cohort of AS patients diagnosed according to the mod New York criteria, were stratified according to age gender and residential area. Controls were selected according to these criteria. Data collection took place 2008-2010. ADMA, L-arginine/ADMA and OPG were analyzed from frozen plasma samples. NT-pro-BNP was analyzed consecutively. Demographic data were analyzed using bivariate tests as appropriate using SPSS 20. Comparisons of the biomarkers between AS and controls were analyzed by linear regression models, adjusted for age and gender. OPG and NT-pro-BNP were log transformed to obtain normality. <h3>Results</h3> 151 patients and 143 controls were in the original cohorts, but due to missing data 145 patients and 125 controls were analyzed in this study. Demographic data showed no differences in male gender (AS vs. controls) 60.7% vs. 69.0%, p= 0.91 or smoking habits 13.9% vs. 23.2%, p=0.44. The AS patients were younger than the controls, mean (SD) 49 (11) vs. 53 (11) years, p=0.003. Both ADMA and OPG were significantly elevated and L-arginine/ADMA significantly reduced in AS compared to controls after adjustments of the demographic variables (table), but levels of NT-pro-BNP were similar. <h3>Conclusions</h3> AS patients have elevated ADMA and OPG and reduced L-arginine/ADMA, supporting that AS patients are at higher risk of CVD than the general population. Further validation in longitudinal settings should be performed. <h3>Disclosure of Interest</h3> None Declared
Reassessment of the Use of Desferrioxamine B in Iron Overload
Authors: Richard D. Propper, Susan B. Shurin, David G. Nathan
Journal: New England Journal of Medicine (1976)

Treatment of transfusion-induced iron overload by daily intramuscular injection of the chelator desferrioxamine has not produced impressive urinary iron excretion. We attempted to augment net iron excretion by altering both the route and quantity of chelator administered. Two ascorbic acid-replete patients excreted a mean of 14.5 mg of iron per 24 hours after a single intramuscular injection of 750 mg of desferrioxamine. Excretion increased to a mean of 44.9 mg when this dose was delivered by a continuous 24-hour intravenous infusion. When the intravenous dose of chelator was increased incrementally to as high as 16,000 mg per 24 hours, iron excretion increased up to 180 mg per day. At these high-dose levels, efficiency of binding of iron to chelator was compromised. Constant exposure of the labile iron pool to a chelating agent markedly enhances net iron excretion in splenectomized transfusion-dependent patients.
A1.22 NaÏve and memory CD4<sup>+</sup>T-cell DNA methylation profile in RA
Authors: F Ponchel, P Chambers, A Droop, R Parmar, J Halstead-Rastrick, P Emery
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Introduction</h3> Several abnormal features of T-cell responses are observed in RA. These range from MHC disease association, repertoire distortion, compromised thymic activity, accelerated ageing, abnormal signalling, formation of secondary ectopic lymphoid structure. More recently the RA genetic predisposition has been shown to reside mostly in T-cell related genes. We investigated DNA methylation profiles in naïve and memory T-cells isolated from healthy controls and RA patients to identify additional levels of regulation in T-cell functionalities. <h3>Methods</h3> 6 HC and 10 RA patients (5 ACPA+) were recruited. 30 ml of EDTA blood was collected and naïve and memory T-cells purified using cell sorting. DNA was extracted and treated for bi-sulfite conversion. A 450k micro-bead array (Illumina) was used to investigate genome-wide DNA methylation. QA/QC procedure included inspection of beta-value density plots generated using the "minfi" R package. <h3>Results</h3> 30/32 samples passed QA/QC procedure. Signal from methylated and un-methylated probes was normalised and converted in to M values using the "minfi" package. M values were analysed using t-tests in the "gene filter" R package. Multidimentional scaling analysis clearly separated naïve from memory cells suggesting that the phenotype of the cells (notably between two CD4<sup>+</sup> subsets) is essential for the detection of disease specific changes. Memory cell analysis revealed 37050 differentially methylated positions between health and RA and 36750 for naïve cells (P &lt; 0.05). We selected the top 1000 most significant differences for both subsets and compared them. Surprisingly only 180 positions were common to the 2 subsets but importantly included 5 positions for the IL-6 gene, 15 for histone deacethylation-4 (HDAC4), 26 in Wnt3/Frizzle8 and homeobox-1 pathway and 43 in various transcription factors (notably FoxP1) all suggestive of a strong disease effect. Memory cells showed additional differential methylation of positions near genes such SMAD 2/7, p21-CIP-1, FGFR-3, HSP70 and TNFR-member-13. Naïve cells showed similar differential methylation but for different members of these gene families (TNFR-I, TGFR-3, FGFR-1, HSP40) in addition to other specific genes such as interferon regulator 1, SUMO-1, several PAX transcription factors, P-selectin and importantly the IL-17R. <h3>Conclusion</h3> These pilot data demonstrate that there are important differences in the methylation of DNA between RA patients and HC that can be identified in relevant pathways provided cells are separated into the same phenotype (naïve vs. memory) even if from the same lineage (both CD4<sup>+</sup>T-cells).
Abstract 3946: Stem cell protein piwil2 enhances nucleotide excision repair through regulating chromatin remodeling following DNA damage
Authors: Qien Wang, Chunhua Han, De-Tao Yin, Li Chen, Keisha Milum, Qingtao Yan, Gulzar Wani, Alo Ray, Jianxin Gao, Altaf A. Wani
Journal: Cancer Research (2010)

Abstract The piwi family gene, which are defined by conserved PAZ and Piwi domains, play important roles in stem cell self-renewal, RNA silencing, and translational regulation in various organisms. Three piwi homologs have been identified in the mouse genome. Amongst these, mili (piwil2) protein expression appears to be associated with tumorigenesis as evidenced by the facts that piwil2 stably expresses in pre-cancerous stem cells and also appears at variable levels in different human and animal tumor cell lines. Based on our preliminary data showing that piwil2 is induced in normal cultured human fibroblasts in vitro by physical and chemical genotoxic agents, we hypothesized that piwil2 might function in DNA damage response. Here, we demonstrated that mammalian cells lacking piwil2 are hypersensitive to cisplatin and UV irradiation. In addition, nucleotide excision repair (NER) efficiency is significantly decreased in the absence of piwil2 as assessed by the removal of cisplatin-induced intra-strand cross-links (Pt-GG) and UV-induced cyclobutane pyrimidine dimers (CPDs) from genomic DNA. Although quantitative real-time PCR analysis indicated higher transcript levels of various NER proteins in piwil2 knockout mouse embryo fibroblasts (MEFs), the Western blotting did not show an obvious difference in the NER protein levels between mili+/+ and mili−/− MEFs. Since piwil2 is believed to orchestrate chromatin remodeling, we reasoned that low NER efficiency in mili−/− MEFs may result from disrupted chromatin remodeling in response to UV or cisplatin induced DNA damage. Thus, chromatin relaxation and histone acetylation was analyzed in these MEFs following treatment with UV or cisplatin. MEFs lacking piwil2 showed less sensitivity to micrococcal nuclease (MNase) digestion compared with piwil2-proficient MEFs, indicating a compact chromatin structure in these cells. Moreover, in contrast to mili+/+ MEFs, mili−/− MEFs exhibited decreased acetylated Histone H3 upon both UV and cisplatin treatment. This decrease could be blocked by histone deacetylase (HDAC) inhibition indicating that piwil2 may function in damage-induced chromatin remodeling via inhibiting the HDAC activity. In summary, our data suggests that piwli2 can participate in the NER through regulating chromatin relaxation which could be a pivotal factor in genotoxin-induced tumorigenesis as well as efficacy of cancer therapeutics. (Supported by NIH grants CA93413, ES2388 and ES12991 to AAW). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3946.