tbuckley/cabot-search huggingface dataset:
OP0120 Specific Identification of Anti-Citrullinated Glucose-6-Phospate Isomerase Peptide (CCG) Antibodies Associated with HLA-DRB1 SE and Disease Activity in Patients with RA
Authors: N. Umeda, I. Matsumoto, A. Inoue, Y. Tanaka, Y. Kondo, H. Tsuboi, T. Suzuki, N. Tsuchiya, T. Sumida
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Anti-citrullinated protein antibodies (Abs) (ACPA) are identified as a hallmark of diagnosis and disease progression in sera of patients with RA. Although several ACPA targeting citrullinated fibrinogen, collagen type II, a-enolase and vimentin have been confirmed, their pathogenic role are still mostly elusive due to the lack of association to disease activity. Anti-glucose-6-phosphate isomerase (GPI) Abs is confirmed as arthritogenic in mouse model, and only few patients with RA possessed them, however, anti-cyclic citrullinated GPI peptide (CCG) Abs have not been characterized. <h3>Objectives</h3> To identify and characterize anti-CCG Abs in patients with RA. <h3>Methods</h3> 1) Nine arginine-bearing peptide sequences in human GPI were selected and cyclic citrullinated GPI peptides (CCG-1∼-9) were constructed. Five unmodified GPI peptides were also synthesized (G-1, -2, -3, -4 and -7). Samples were obtained from patients with RA (n=208), SLE (n=101), Sjögren's syndrome (SS; n=101), and from healthy control subjects (n=174). Abs against CCG-1∼-9 and G-1, -2, -3, -4, -7 were measured by ELISA, and anti-citrullinated a-enolase-1 (CEP-1), and anti-CCP Abs were also examined. 2) Patients with RA were genotyped for HLA-DRB1. The numbers of shared epitope (SE) alleles were counted and compared with positivity of anti-CCG Abs. 3) The levels of auto-Abs were compared before and after six month treatment with TNF antagonists in 58 RA patients (infliximab, n=41, etanercept, n=15, adalimumab, n=2). <h3>Results</h3> 1) Anti-CCG-2, -4 and -7 Abs were detected in 25.5%, 33.2% and 37.0% patients with RA, respectively. These Abs were specific for RA (specificity, 98.1% ∼ 99.7%). Abs against five unmodified GPI peptides were detected only 0% ∼ 3.8% patients with RA. Altogether, 44.2% and 86.1% of RA sera were positive for anti-CEP-1 and -CCP Abs. The levels of anti-CCG-2, -4 and -7 Abs were correlated with that of anti-CCP and anti-CEP-1 Abs. 2) Anti-CCG-2, -4 and -7 Abs were significantly correlated with the presence of HLA-DRB1 SE alleles (P&lt;0.01, P&lt;0.05 and P&lt;0.001, respectively). 3) Treatment with TNF antagonists significantly reduced the levels of anti-CCG-2 and -7 Abs (P&lt;0.001, P&lt;0.05, respectively), but not of anti-CEP-1 Abs. <h3>Conclusions</h3> This is the first report documenting the presence of anti-CCG-1∼-9 Abs in patients with RA. Anti-CCG-2 and -7 Abs could be considered as markers for the diagnosis of RA and its disease activity. <h3>Disclosure of Interest</h3> None Declared
P1-12-01: Pregnancy during and Following Adjuvant Trastuzumab in Patients with HER2−Positive Breast Cancer: An Analysis from the HERA Trial (BIG 01-01).
Authors: HA Azim, O Metzger-Filho, Azambuja E de, S Loibl, F Focant, E Gresko, M Procter, M Piccart-Gebhart
Journal: Cancer Research (2011)

Abstract Background: 1-year of adjuvant trastuzumab (T) is the standard of care in managing patients (pts) with early HER2−positive breast cancer (BC). As T is not known to alter fertility, pts with childbearing potential could become pregnant during or following treatment with T. Cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus have been reported in women receiving T during pregnancy (preg). Here we report the outcome of preg in all pts enrolled in the HERA trial. Methods: Pregnancies in the HERA trial are reported on a distinct “pregnancy form” for up to 10 years following T completion. The form includes information on approximate date of conception, preg course &amp; outcome, fetal measurements at birth, and congenital anomalies. Any missing data were retrieved from the study site, if available. For this analysis, pts were grouped into 3 groups: 1) preg during and up to 3 months after T, 2) preg &amp;gt; 3 months of last T dose, and 3) preg with no prior exposure to T. Results: By March 2010, 70 preg were reported in 58 out of 5102 pts randomized. Five, 30 and 7 completed preg were reported in groups 1, 2 &amp; 3 respectively. As per protocol, all pts on T were required to use adequate contraceptive measures, yet 16 pts became pregnant during the course of T and up to 3 months thereafter. The percentage of completed preg was lowest in group 1, with 4 spontaneous and 7 induced abortions. In group 2, preg occurred at a mean of 29 months following completion of T, with 6 spontaneous and 4 induced abortions. In group 3, abortion was induced in 3 pts and no spontaneous abortions reported. Across all 3 groups, all but 1 spontaneous abortion occurred during the 1st trimester. Two congenital anomalies were reported; a Down's syndrome in a 43 year old pt &amp;gt;5 years after completing T for which abortion was induced, and one with partial fusion of the 2nd and 3rd toe born to a pt in group 3. Conclusions: Unintentional exposure to T during preg may be associated with spontaneous abortion, yet the numbers remain low to draw firm conclusions (spontaneous abortion rate in general population is up to 20%). No oligohydramnios or anomalies were observed in group 1. While an increased risk of oligohydramnios has been reported when T is administered after the 1st trimester, T administered to Cynomolgus monkeys during organogenesis did not cause fetal harm (Pentsuk et al; 2009). Nevertheless, women of childbearing potential should be advised to use effective contraception during and up to 6 months after treatment with T. On the other hand, prior exposure to T did not appear to affect the preg course or outcome. We are planning to collect information from the other T adjuvant trials to confirm our findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-01.
O127 STAGING EARLY HEPATOCELLULAR CARCINOMA WITH GADOXETIC ACID-ENHANCED MAGNETIC RESONANCE IMAGING AND IMPROVEMENT IN SURVIVAL
Authors: H.-D. Kim, Y.-S. Lim, S. Han, J. An, G.-A. Kim, S.J. Lee, S.Y. Kim, J.H. Byun, H.J. Won
Journal: Journal of Hepatology (2014)
P650Invasive surgery reduces infarct size in a porcine model of myocardial infarction
Authors: G P J Van Hout, MPJ Teuben, M Heeres, WW Solinge, L Koenderman, G Pasterkamp, IE Hoefer
Journal: Cardiovascular Research (2014)

Background: Successful translation of pre-clinical treatment strategies into clinical therapies depends on reproducible, conclusive models. To date, two distinctive procedures for the induction of myocardial ischemia-reperfusion to test novel therapies for myocardial infarction (MI) are commonly used. The first method applies coronary artery ligation via an open chest procedure, requiring invasive surgery. Alternatively, the coronary artery is occluded by balloon inflation via a transluminal, minimally invasive procedure. In the current study we hypothesized that invasive surgery as for open chest procedures reduces myocardial infarct size and preserves cardiac function post-MI.
Abstract 852: Apoptosis induction by ayurvedic medicine constituent withaferin A in human breast cancer cells is mediated by reactive oxygen species-dependent activation of Bak
Authors: Eun-Ryeong Hahm, Michelle B. Moura, Eric E. Kelley, Bennett van Houten, Shivendra V. Singh
Journal: Cancer Research (2011)

Abstract Withaferin A (WA) is a promising cancer chemopreventive constituent of Ayurvedic medicine plant Withania somnifera that has been used safely for thousands of years in India for treatment of different ailments. We have shown previously that WA treatment suppresses viability of cultured as well as xenografted human breast cancer cells by causing apoptosis but the mechanism of cell death is not fully understood. Here, we demonstrate that the WA-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species (ROS)-dependent activation of Bak. WA treatment caused ROS production in MDA-MB-231 (an estrogen-independent cell line with mutant p53) and MCF-7 cells (an estrogen-responsive cell line with wild-type p53) in a concentration- and time-dependent manner as judged by flow cytometry and fluorescence microscopy using a chemical probe (MitoSOX Red) and EPR spectroscopy using a cell permeable spin probe (1-hydroxy-3-methoxy-carbonyl-2,2,5,5-tetramethylpyrrolidine). WA-mediated ROS production, as well as, apoptosis [characterized by release of histone-associated DNA fragments into the cytosol, and cleavage of poly-(ADP-ribose) polymerase or procaspase-3], was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase (SOD) or Mn-SOD. Real-time measurements of oxygen consumption rate and extracellular acidification rate using a Seahorse Bioscience XF24 Extracellular Flux Analyzer revealed that the ROS production resulting from WA exposure was accompanied by inhibition of basal and reserve oxidative phosphorylation. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were significantly more resistant to WA-induced ROS production and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak, but only Bak activation was attenuated by Cu,Zn-SOD overexpression. Furthermore, RNA interference or genetic suppression of Bax and Bak expression conferred significant protection against WA-induced apoptosis. In conclusion, the present study provides novel insights into the molecular circuitry of WA-induced apoptosis involving ROS-dependent activation of Bak. This investigation was supported by the USPHS grant CA142604-01, awarded by the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 852. doi:10.1158/1538-7445.AM2011-852
P145Degradation of gap junction protein Cx43 by autophagy in ischemic heart is determined by the triggering signal: the role of AMPK Vs Beclin1
Authors: T Martins-Marques, P Pereira, H Girao
Journal: Cardiovascular Research (2014)

Several cardiomyopathies, including myocardial ischemia, have been associated with an impairment of gap junction intercellular communication (GJIC) between cardiomyocytes, due to an increased internalization and/or degradation of Connexin43 (Cx43). Recent data of our group, demonstrates that ischemia-induced activation of autophagy results in degradation of Cx43 in HL-1 cells. However, the molecular mechanisms underlying Cx43 degradation and the involvement of autophagy machinery remain unknown. It is broadly accepted that autophagy have a dichotomous role likely depending on the nature, extent and severity of the stimuli, as well as on the autophagy players involved. The emerging theory stands for a cardioprotective role of ischemia-induced autophagy via AMPK, being up-regulation of Beclin1 associated with exacerbated autophagy and cell death. Hence, it is conceivable to suggest that according to the stimuli (ischemia vs ischemia/reperfusion (I/R)), the triggering signals and mechanisms whereby autophagy is activated may differ and, consequently, determine the degradation levels of Cx43. To test this hypothesis, we used HL-1 cardiomyocytes subjected to different periods of ischemia and I/R, after which the levels and subcelullar distribution of Cx43 were determined by WB and confocal microscopy, respectively. Data show that Cx43 is degraded gradually during ischemia, and that reperfusion further increases its degradation. Furthermore, using chemical and genetic approaches to manipulate AMPK and Beclin-1 pathways, we showed that activation of AMPK occurs in the initial periods of ischemia, when an inhibition of AMPK protects Cx43 from degradation. On the other hand, for long periods of ischemia and during reperfusion, the protective effect regarding Cx43 degradation is mainly conferred by knockdown of Beclin 1. Concerning autophagy activation, we show that conversion of LC3-I in LC3-II occurs mainly during I/R, which is consistent with the increased degradation of Cx43 under these conditions. Interaction of Cx43 with autophagy adaptors during ischemia and I/R was also evaluated by immunoprecipitation assays and confocal microscopy. Increased interaction with autophagy players p62 and LC3 is mainly detected upon ischemia, which is likely required for the subsequent robust degradation of Cx43 observed during reperfusion. Altogether, our data led us to suggest a model in which differential activation of autophagy in ischemia and I/R, involving either AMPK or Beclin1, respectively, determines the final fate of Cx43.
SP0009 Case Presentation: Igg4 Related Disease
Authors: P. Reis
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> IgG4-related disease is a fibroinflammatory disorder of unknown etiology that can affect any organs. It is characterized by diffuse or localized infiltration of the involved tissue by IgG4- positive plasma cells associated with lymphoplasmacellular inflammation, storiform fibrosis and obliterative phlebitis. Elevated serum concentrations of IgG4 are present in many patients. Here we report the case of a patient with multi organ involvement due to IgG4-related disease. A 71-year-old Caucasian man presented with sialadenitis of the left submandibulary gland. Biopsy of the gland revealed distinct chronic sclerosis as well as lymphoplasmacytic infiltration with more than 100 IgG4-positive plasma cells per high power field. The patient developed progressive dyspnea and a chest CT scan showed thickening of the interlobular septum and alveolar walls as well as bilateral infiltrates and ground glass opacities. Serum concentration of IgG4 was 1050mg/dl (reference value 5 - 125mg/dl). The patient was initially treated with steroids with substantial clinical improvement and decrease of IgG4 serum levels. As the steroids were tapered, the patient developed cholangitis and pancreatitis. Another course of glucocorticoid therapy and adjunctive Rituximab therapy resulted in full clinical remission. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6187
Water exchange versus carbon dioxide insufflation in unsedated colonoscopy: a multicenter randomized controlled trial
Authors: Kjetil Garborg, Michal Kaminski, Wolfgang Lindenburger, Håvard Wiig, Audun Hasund, Ewa Wronska, Rolf Bie, Britta Kleist, Leif Løvdal, Øyvind Holme, Mette Kalager, Geir Hoff, Michael Bretthauer
Journal: Endoscopy (2014)

<b>Background and study aims:</b> Compared with air insufflation, water exchange and carbon dioxide (CO<sub>2</sub>) insufflation have been shown to reduce colonoscopy discomfort; however, head-to-head studies of the two methods are lacking. We aimed to compare water exchange and CO<sub>2</sub> insufflation directly with regard to pain during primary unsedated colonoscopy. <b>Methods:</b> Patients willing to undergo unsedated colonoscopy at three centers in Norway and Poland were randomized 1:1 to water exchange or CO<sub>2</sub> insufflation during colonoscope insertion. Patients were blinded to group allocation. The primary end point was the proportion of patients reporting moderate or severe procedural pain on a 4-point verbal rating scale (VRS-4) at discharge. Secondary outcomes included the proportion of patients reporting no pain on the VRS-4. <b>Results:</b> A total of 473 patients were randomized. A discharge pain questionnaire was completed by 226 of 234 patients (97 %) in the water exchange group versus 226 of 239 patients (95 %) in the CO<sub>2</sub> group (<i>P</i> = 0.37). Moderate or severe pain was reported by 47 of 226 patients (21 %) in the water exchange group versus 60 of 226 patients (27 %) in the CO<sub>2</sub> group (<i>P</i> = 0.15). No pain was reported by 100 of 226 patients (44 %) and 69 of 226 patients (31 %) in the water exchange and CO<sub>2</sub> groups, respectively (<i>P</i> = 0.003). On-demand sedation was used in 15 patients (6 %) in each group (<i>P</i> = 0.95). <b>Conclusions:</b> There was no significant reduction in moderate or severe pain in a comparison of water exchange with CO<sub>2</sub> insufflation. The secondary outcome of no pain was significantly more frequent in the water exchange group. Clinical trials registry number: NCT01633333.
Abstract 1349: Genetic variants in DNA repair pathway genes are associated with the risk of esophageal adenocarcinoma.
Authors: Yan Wang, Jaffer A. Ajani, Yuanqing Ye, Maosheng Huang, Xifeng Wu
Journal: Cancer Research (2013)

Abstract Esophageal Cancer (EC) is one of the leading causes of cancer death in the world. Over 90% of ECs are either esophageal squamous cell carcinomas (ESCC) or adenocarcinomas (EAC). EAC is the fastest growing malignancy in the US in the past three decades. In this large case/control study, we aim to assess genetic susceptibility to EAC by investigating single nucleotide polymorphisms (SNPs) in DNA repair related pathways, including nuclear excision repair (NER), base excision repair (BER) and double-strand-break repair (DSBR). The study population included 513 Caucasian EAC cases 1499 Caucasian controls. Genotyping was performed by candidate gene approach and obtained from genome-wide association study (GWAS). A total of 464 SNPs (254 SNPs in 26 NER genes, 173 SNPs in 22 BER genes and 37 SNPs in 26 DSBR genes) were included in the final analysis. Among the top significant SNPs, SNP rs10258834 in RPA3 from the NER pathway contributed to over 30% increased EAC risk (OR=1.30, 95% CI=1.12-1.51, P=5.26x10−4), SNP rs3827392 in SMC1B from the DSBR pathway was associated with a 25% increased EAC risk (OR=1.25, 95% CI=1.07-1.47, P=4.80x10−3); whereas rs3135998 in LIG3 from the BER pathway was associated with a decreased risk of EAC (OR=0.73, 95% CI=0.59-0.90, P=3.87x10−3). Unfavorable genotype analysis was performed among those SNPs showing significant association (P&amp;lt;0.05) in individual SNP analysis. We found a strong cumulative effect overall or stratified by DNA repair sub-pathway. For example, individuals carrying 10-13 unfavorable genotypes in BER pathway exhibited a nearly four-fold increased EAC risk compared to those in the reference group with fewer than 5 unfavorable genotypes. Our results suggest that genetic variants in DNA repair pathways significantly modify EAC risk individually and jointly. The results from this study, if validated in independent populations, could potentially categorize population into different risk groups and identify high-risk individuals for cost-effective screening and early detection of this deadly disease. Citation Format: Yan Wang, Jaffer A. Ajani, Yuanqing Ye, Maosheng Huang, Xifeng Wu. Genetic variants in DNA repair pathway genes are associated with the risk of esophageal adenocarcinoma. [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 1349. doi:10.1158/1538-7445.AM2013-1349
Abstract 5097: Genome-wide analysis of DNA copy number aberrations in gastric cancer
Authors: Yoshiyuki Tsukamoto, Tsuyoshi Noguchi, Tomohisa Uchida, Chisato Nakada, Tetsuya Aizawa, Naoki Hijiya, Keiko Matsuura, Masatsugu Moriyama
Journal: Cancer Research (2012)

Abstract Genomic copy number aberrations (CNAs) are believed to play a major role in the development and progression of human cancers. Although many CNAs have been reported in gastric cancer, their relevance to gastric carcinogenesis are poorly understood. In this study, we investigated CNAs of 30 advanced gastric cancers (AGC) and 20 gastric carcinoma in situ (CIS) by using array comparative genomic hybridization (array CGH). By comparing the frequencies of CNAs in CISs with those in AGCs, we identified several CNAs that were more frequent in AGCs than CISs. Among them, gain of 20q13 was detected in almost all cases of AGC (29/30). We further analyzed the expression of genes located on 20q13 and found that 8 genes were upregulated more than 2-fold on average compared with normal tissues, suggesting that these genes may play an important role in the progression of gastric cancer. Taken together, our data may provide useful information about the involvment of genomic CNAs in gastric carcinogenesis. References: 1. Tsukamoto et al, J Pathol. 2008;216(4):471-82. 2. Uchida et al, J Pathol. 2010;221(1):96-105. 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 5097. doi:1538-7445.AM2012-5097
Abstract 116: Targeting hypoxia for the identification of novel biomarkers for prostate cancer
Authors: Christian R. Gomez, Jan Marie Munz, Farhad Kosari, Jeffrey Karnes, John Cheville, Cristiane Ida, Thomas Sebo, George Vasmatzis, Stanimir Vuk-Pavlovic
Journal: Cancer Research (2012)

Abstract Tumor-associated hypoxia has been associated with malignant progression, metastasis, resistance to therapy, and poor clinical outcome in prostate cancer (CaP). Prompted by the evidence that hypoxia affects CaP, we studied global gene expression in 100 CaP tissues and 71 samples of adjacent benign tissues. RNA was extracted from cancer cells isolated by laser-capture microdissection (LCM) or without isolation (“bulk tissue”). We found 24 hypoxia-associated genes significantly overexpressed in CaP (p≤0.02), both in bulk tissue and LCM. Among hypoxia-associated genes, the disc large (drosophila) homolog-associated protein 5 (DLG7), hyaluronan-mediated motility receptor (HMMR) and cyclin B1 (CCNB1) were associated with Gleason score and systemic progression. Since the products of HMMR and CCNB1 have been recently identified as molecular markers of CaP progression, we postulated that DLG7 has prognostic value also. To test this hypothesis we measured transcript levels for DLG7 in a 150-pair case-control cohort. The cases (progression to systemic disease within five years of surgery) and controls (no progression within seven years) were matched for clinical and pathologic prognostic variables, including grade, stage, and preoperative serum levels of PSA. The overall prognostic ability of DLG7, as tested in receiver operating characteristic analysis was of 0.74 (95% CL, 0.68 to 0.8), independent of the for ERG status. Overall, our data indicate that DLG7, a hypoxia-controlled gene have a prognostic value in high-risk CaP. To better define the value of DLG7 as a molecular predictor of CaP progression, we are currently assessing DLG7 protein levels by immunohistochemistry. Then we will analyze the association of DLG7 levels with clinical parameters. Introduction of oxygen tension as a variable may constitute a tool for the identification of novel biomarkers for CaP. Present address CRG: University of Mississippi Cancer Institute, Jackson, MS, USA. Support: DOD PC094680 (CRG), PCF Creativity Award (CRG), Mayo Clinic Prostate SPORE 5P50CA091956 (SV-P); Mrs. Adelyn L. Luther, Singer Island, Florida and Mayo Clinic Cancer Center (SV-P). 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 116. doi:1538-7445.AM2012-116
Giant Postsurgical Pseudomeningocele by SPECT/CT Cisternography
Authors: Sébastien Dietemann, Mustapha Benmekhbi, Mohamed Amine Lahlou, Pierre Kehrli, Jean-Louis Dietemann, Izzie Jacques Namer
Journal: Clinical Nuclear Medicine (2014)

We describe a case of a 32-year-old man with a giant pseudomeningocele seen on MRI examination 6 months after spinal surgery. Radionuclide SPECT/CT cisternography performed after intrathecal suboccipital injection of In-DTPA identified the site of cerebral spinal fluid leak at the L4 level, and the patient underwent surgical correction of the dural defect. A repeat MRI examination 8 months later showed no signs of recurrence.