tbuckley/cabot-search huggingface dataset:
THU0066 Ankylosing Spondylitis and Non Radiographic Axial Spondyloarthitis: the Same Syndrome or Different Diseases? Results from Esperanza Cohort
Authors: A. Hernández-Sanz, V. Navarro-Compán, C. Fernández-Carballido, C. Montilla-Morales, J. Mulero-Mendoza, E. de Miguel
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The ASAS classification criteria for axial spondyloarthritis (axSpA) allow two possible entrances: the imaging arm (presence of sacroiliitis) and the clinical arm (presence of HLA B27). Additionally, patients from the imaging arm can be classified as non-radiolographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS). The concept of nr-axSpA as well as the use of the clinical arm to calssify patients with SpA are currently under discussion. Therefore, it is necesary to investigate whether or not these patients have similar characteristics compared to the classical AS. <h3>Objectives</h3> To describe and compare the characteristics of patients fulfilling the ASAS criteria for nr-axSpA versus patients with AS in an early disease cohort. Secondly, the characteristics of patients in the two axSpA arms (clinical and imaging) were compared too. <h3>Methods</h3> Baseline dataset from the EsPeranza cohort was used. This cohort included patients from 25 Spanish centers with the following referral criteria: age &lt;45 years, symptoms duration 3-24 months and with inflammatory back pain (IBP) or asymmetrical arthritis or spinal/joint pain plus ≥1 SpA features. Patients meeting ASAS axSpA criteria were included for this study. Demographic and clinical characteristics, activity indices (BASDAI and CRP), mobility (BASMI) and physical function (BASFI) were compared between groups. <h3>Results</h3> A total of 291 axSpA patients were included. From these, 194 (67%) fulfilled the imaging arm (44% axSpA-nr and 56% EA), and 97 (33%) the clinical arm. Significant differences between AS and nr-axSpA patients were just observed for the following variables: gender (higher frequency of males in AS), diarrhea/genitourinary symptoms (more frequent in nr-axSpA), physician9s VAS (higher in AS) and BASMI (lower in AS) (Table). No significant differences between both groups were found for the rest of variables. Moreover, patients in the clinical arm had significantly more diarrhea/genitourinary symptoms, peripheral arthritis, enthesitis, uveitis and family history of SpA compared with patients in the imaging arm. Physical function was more impaired in patients on imaging arm. <h3>Conclusions</h3> Overall, patients with nr-axSpA have similar clinical features than those observed in AS patients in the early stages of the disease. However, the mobility in AS patients is more restricted. Furthermore, patients with axSpA in the clinical arm present more often peripheral involvement, uveitis and family SpA history as well as better function than patients in the imaging arm. <h3>Acknowledgements</h3> The EsPeranza Program has been supported by Spanish Rheumatology Foundation and an unrestricted grant from Pfizer. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2865
Detection of the pufferfish toxin tetrodotoxin in European bivalves, England, 2013 to 2014
Authors: A D Turner, A Powell, A Schofield, D N Lees, C Baker-Austin
Journal: Eurosurveillance (2015)

We report the first detection of tetrodotoxins (TTX) in European bivalve shellfish. We demonstrate that TTX is present within the temperate waters of the United Kingdom, along the English Channel, and can accumulate in filter-feeding molluscs. The toxin is heat-stable and thus it cannot be eliminated during cooking. While quantified concentrations were low in comparison to published minimum lethal doses for humans, the results demonstrate that the risk to shellfish consumers should not be discarded.
A bridge too far: From basic exposure to understanding in artistic experience
Authors: Elisabeth Schellekens
Journal: Behavioral and Brain Sciences (2013)

Abstract In the context of a broad welcome to Bullot &amp; Reber's (B&amp;R's) proposals concerning the incorporation of contextual awareness into the study of the psychology of art appreciation, I raise two concerns. First, the proposal makes no allowance for degrees of relevance of contextual awareness to appreciation. Second, the authors assume that “basic exposure” and “artistic understanding” can be maintained as separate phases or modes, but this may be more problematic than anticipated.
Effects of Prenatal Meprobamate and Chlordiazepoxide Hydrochloride on Human Embryonic and Fetal Development
Authors: Lucille Milkovich, Bea J. van den Berg
Journal: New England Journal of Medicine (1974)

To examine the teratogenic potential of the minor tranquilizers, the incidence of severe congenital anomalies per 100 live births was studied in children of mothers who had received prescriptions for meprobamate, chlordiazepoxide, other drugs, or no drug for minor psychoneurotic complaints (anxiety) during pregnancy. These four populations were from a prospective longitudinal study of pregnancy and child health that included 19,044 live births. Rates of the anomalies after prescription of meprobamate or chlordiazepoxide in early pregnancy (the first 42 days) were higher 12.1 per 100 and 11.4 per 100 respectively than in children of the other-drug, 4.6 per 100, or no-drug cohorts, 2.6 per 100. When the reference date was later in pregnancy (43 days to termination), statistically insignificant differences in rates of the anomalies were observed among the four groups. These data suggest that meprobamate, and possibly chlordiazepoxide, may be teratogenic when taken during the first six weeks of gestation. (N Engl J Med 291:1268–1271, 1974)
Identification of NPM1 as a potential high-penetrance gene in hereditary breast cancer.
Authors: Z Ren, E Teugels, S De Brakeleer, E Sermijn, M Bonduelle, C Fontaine, J De Greve
Journal: Cancer Research (2009)

Abstract Abstract #1042 Background: In a major proportion of breast cancer patients with a strong familial cancer history no BRCA1 or BRCA2 mutations are detected which prompted us to explore other proteins on the BRCA1/2 pathway. Previously we have identified BARD1 (De Brakeleer et al, SABC 2006) as a rare high penetrance breast cancer predisposing gene. Nucleophosmin (NPM1) is a multifunctional protein that is ubiquitylated and stabilized by the BRCA1-BARD1 complex and thus is part of the BRCA1 pathway. Somatic protein truncating mutations in NPM1 are frequent events in acute myeloid leukemia (AML).&amp;#x2028; Aim: This study was aimed at determining whether NPM1 germline mutations may contribute to the breast cancer predisposition in families where no BRCA1 or BRCA2 mutation is found.&amp;#x2028; Methods: NPM1 mutation analysis was performed on genomic DNA extracted from blood of 198 breast cancer patients with strong indications for a hereditary form of the disease and 110 controls. All the 11 exons of the NPM1 gene were separately amplified by PCR. Since a high number of processed NPM1 pseudogenes are dispersed throughout the human genome, PCR primers had to be designed carefully. The PCR products were subsequently analyzed by denaturing gradient gel electrophoresis (DGGE) and when an abnormal migration pattern occurred, sequencing analysis was performed to determine the exact nucleotide-sequence alteration which was verified against the pseudogene sequences.&amp;#x2028; Results: Out of the six novel sequence variations, only one occurred in an exon: a duplication of thymidine located in the 3' non-coding sequence of exon 12 (c.1042dupT). The remaining 5 variants were located in intron sequences close to the exon borders. Two variants flanking exon7 (c.460-31G&amp;gt;A and c.524+42G&amp;gt;A) were always linked, and occurred at the same high frequency in breast cancer patients and controls. Two intron sequence variants were only found in one patient. One was a duplication of a sequence in intron 8 (c.582+52dupT) and the other a sequence deletion in intron 3 (c.139-9delT). One sequence variation located close to exon 11 (c.771-46C&amp;gt;A) was found in 7 familial breast cancer patients in 4 high incidence families but not in unaffected family members and in none of the control samples. This mutation leads to an alternative splicing of the NPM1 mRNA and is predicted to modify the carboxyterminal end of the protein, removing a nucleolar locating signal.&amp;#x2028; Discussion: A germline mutation in NPM1 was found only in familial breast cancer cases. This mutation may result in the synthesis of a C-terminal truncated NPM1 protein conferring high susceptibility to breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1042.
Abstract LB-28: A co-op of EGFR and EphA4 promotes the progression of NSCLC through EGF-Grb7-Stat3 mediated transcriptional regulation of EphA4 gene expression
Authors: Pei-Yu Chu, Tsai-Kun Li, Kai-Ming Chou, Tang-Long Shen
Journal: Cancer Research (2012)

Abstract Growth factor receptor bound protein-7 (Grb7) regulates diverse cellular functions as a result of its multi-domain functionality in protein-protein interactions. A number of reports have indicated that Grb7 is essential for EGFR-mediated tumorigenesis and cancer progression. However, it remains unclear how Grb7 potentiates tumor progression. To understand the underlying mechanisms by which Grb7 participates in EGFR-mediated tumorigenesis, we utilized microarray analyses and yeast two-hybrid screening to explore Grb7-mediated signaling. Of which, a migration related protein, EphA4, was markedly up-regulated in associated with Grb7 overexpression but down-regulated while knocking down Grb7. Eventually, in response to EGF stimulation, we found that Grb7 was trans-located into the nucleus from the cytoplasm, which in turn promoted STAT3 transcriptional activity on EphA4 gene expression. The significance of this finding is further highlighted by the co-upregulation of Grb7 and EphA4 is concurrent with the highly invasive capability of lung adenocarcinoma. Moreover, we found that EphA4 could also potentiate EGF-induced reorganization of cytoskeleton, ERK1/2 phosphorylation, and cancer cell functions such as proliferation, migration and anchorage-independent growth. Based on these findings, we hypothesize that EphA4 can act as an amplifier involved EGF-mediated cancer progression in an EGF/Grb7/Stat3-mediated transcriptional manner. This study reveals a novel mechanism by which Grb7 regulates tumor progression through the EGF- by triggering EphA4 expression and then prolonging EGFR signaling in regulation of diverse cellular functions involved in cancer progression, thereby highlighting the potential strategy to target Grb7 for anti-cancer therapy. 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 LB-28. doi:1538-7445.AM2012-LB-28
OC-024 Development and validation of a novel capture-fusion model for HCV replication
Authors: M E Cunningham, A Javaid, J A Waters, G R Foster
Journal: Gut (2012)

<h3>Introduction</h3> HCV replicates poorly in vitro, so testing of novel antiviral therapies currently relies on modified viral replicons, based on genotype (G)1, or the G2 JFH-1 virus. A model allowing patient virions to be cultured would facilitate drug discovery and allow direct sensitivity testing. Here we describe the development of a novel HCV replication assay, its validation using the antiviral agents alisporivir and telaprevir and its value in identifying responses to interferon and ribavirin. <h3>Methods</h3> CD14 (+) monocytes derived from patients with chronic HCV infection, or pre-stimulated THP-1 cells infected with serum from G1 and G3 HCV infected donors, were fused with HuH7 cells and treated with antiviral agents at various concentrations. The fused cells were maintained in tissue culture for up to 5 days, before extraction of HCV RNA and quantification by PCR. p Values were derived using the Mann–Whitney U test for comparison of non-parametric data. Results are expressed as mean±SEM. <h3>Results</h3> Replicating HCV from patients infected with diverse genotypes could be successfully transferred to HuH7 cells using the monocyte “capture-fusion” approach. RNA increased fivefold in fused cells and viral protein production as well as viral release could be demonstrated, confirming the presence of complete viral replication cycles in this new model. Treatment of G1 and G3 fused/infected Huh7 cells with escalating concentrations of alisporivir showed greater drug efficacy in cells infected with G3 than G1 (IC<sub>50</sub> 0.026±0.008 μM vs 0.109±0.02 μM, p=0.0286). Conversely, telaprevir showed greater efficacy in fused/infected cells with G1 than fused/infected cells with G3 HCV. Treatment with 0.1 μM telaprevir, which approximates its IC<sub>50</sub> in replicon cells, resulted in a reduction of HCV RNA by 66.15±10.43% in G1 cells vs 21.56±3.16% in G3 infected cells (p=0.016). We examined sensitivity to interferon and ribavirin in samples from patients who did (N=3), or did not (N=4), respond to therapy. We found no significant difference in the viral sensitivity, suggesting that for interferon based therapies host factors play a more important role than virological response. <h3>Conclusion</h3> These data confirm the value of a capture-fusion model for HCV replication in studying the replication of patient-derived HCV and demonstrate that for interferon and ribavirin based treatments, host factors dominate the response. However viral response determines the clinical response to direct acting anti-viral agents. This technique may be useful in identifying the most appropriate treatment strategies for patients with HCV planning therapy with the new direct acting antiviral agents. <h3>Competing interests</h3> M Cunningham: None declared, A Javaid: None declared, J Waters: None declared, G Foster grant/research support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.
Should Auscultation Be Rehabilitated?
Authors: Ernest Craige
Journal: New England Journal of Medicine (1988)

IN this issue of the Journal, Lembo et al. provide a convincing report on the efficacy of auscultation in the bedside diagnosis of systolic murmurs.1 A high degree of accuracy was achieved in a group of 50 patients with a variety of cardiac abnormalities. Reports on the value of auscultation have practically disappeared from the medical literature, as has interest in the subject among physicians in practice and in training. The studies of Lembo et al. suggest that we should reevaluate this time-honored technique. Should it be reserved for the occupational therapy of a dwindling coterie of antiquarians, or . . .
A7.2 Allograft Inflammatory Factor 1 (AIF1) Polymorphisms in French Caucasians with Rheumatoid Arthritis
Authors: Doua F Azzouz, Nathalie Balandraud, Sami B Kanaan, Isabelle Auger, Marielle Martin, Fanny Arnoux, Jean Roudier, Nathalie C Lambert
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Allograft inflammatory factor 1 (AIF1) is a cytoplasmic inflammatory protein encoded within the HLA class III genomic region on chromosome 6 (6p21.3). Although several risk loci for Rheumatoid Arthritis (RA) have been identified by Genome Wide Association Studies (GWAS), none of them involved AIF1 polymorphisms. However, two studies on small cohorts have shown that AIF1 single nucleotide polymorphism (SNP) Rs2269475 (C/T), causing a non-synonymous change of amino acid, is associated with RA (Harney, SM <i>et al</i>, 2008; Pawlik A <i>et al</i>, 2008). Moreover, AIF1 overexpression in inflammatory synovial tissues and macrophages isolated from synovial fluids of patients with RA, confirms its potential role in RA. <h3>Objective</h3> We propose to examine the association of the seven most described AIF1 SNPs in our French RA patients. <h3>Methods</h3> We have tested 99 Anti-Citrullinated Protein Antibody (ACPA) positive Caucasian RA patients who fulfilled ACR/EULAR criteria and 104 healthy Caucasians. We designed AIF1 primers to specifically amplify the AIF1 gene region containing the 7 SNPs: Rs2844475, Rs4711274, Rs2736182, Rs2736181, Rs2259571, Rs2269475 and Rs13195276. PCR products were sequenced (Cogenics Beckman Coulter) and chromatogram results analysed for the 7 SNPs positions in patients and controls. Patients and controls were genotyped for HLA-DRB1. <h3>Results</h3> Two SNPs out of the 7 were associated with RA: Rs4711274 (G/A) and Rs2269475 (C/T). Regarding Rs4711274, G/A and A/A genotypes were increased when compared with controls (p = 0.0005). The minor A allele was strongly associated with RA (p = 0.0005). Regarding Rs22699475, in linkage disequilibrium with the former, we found a similar pattern with increased T/T and C/T genotypes (p = 0.0009) and increased minor T allele frequency (p = 0.0008) in patients with RA. Interestingly, patients carrying the minor associated AIF1 allele expressed HLA-DRB*04 more often than the patient’s group carrying the C/C or G/G genotype (63.8% versus 44.4%), although the difference was marginal (p = 0.06). <h3>Conclusions</h3> In this study of French Caucasians with RA, we confirmed Rs2269475 association already described in British and Polish Caucasians. Additionally, we find an association with Rs4711274 in linkage disequilibrium with Rs2269475. Intriguingly, such associations have never been found in GWAS.
Abstract 3758: RIG-I plays a critical role in negatively regulating stemness properties in hepatoma cell lines.
Authors: Ping-Yu Chen, Chao-Kuen Lai, Min-Linag Kuo
Journal: Cancer Research (2013)

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide due to its high rate of recurrence. Cancer stem cells are considered to generate tumors through the stem cell processes including self-renewal and differentiation into multiple cell types. And these distinct populations of cells are suggested to cause relapse and metastasis by eliciting new tumors. Retinoic acid-inducible gene I (RIG-I) has been identified as a pattern recognition receptor in innate immune defense for sensing intracellular viral RNAs, like Hepatits C virus which is one of the major risks of HCC, and inducing type I interferons production. In previous studies, RIG-I-like receptors recognizing some potentially oncogenic agents may have functional consequences that can lead to association of such single nucleotide polymorphisms with risk of some diseases or even cancers. Thus these gene polymorphisms may affect cancer risk indirectly. On the other hand, a previous study have demonstrated that RIG-I is an essential regulator of physiological myelopoiesis suggesting RIG-I possesses the potential of modulating stem cell differentiation. In our present study, we examined Huh7 and its RIG-I-mutant cell line by sphere formation assay and found solely the mutated cells possessed the self-renewal ability. After transfection of dominant-negative mutant of RIG-I to Huh7, the self-renewal ability were rescued as expected. We also injected 1000 cells for each two cell lines into NOD/SCID mice subcutaneously and observed the mutated cells formed tumors whereas Huh7 didn't. Hence, our study reveals the potential of RIG-I to suppress the stemness properties in the HCC cell lines and provides a new possible remedy target of liver cancer. Citation Format: Ping-Yu Chen, Chao-Kuen Lai, Min-Linag Kuo. RIG-I plays a critical role in negatively regulating stemness properties in hepatoma cell lines. [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 3758. doi:10.1158/1538-7445.AM2013-3758
Abstract 3266: Repurposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints.
Authors: Neil Beeharry, Lauren Fink, Eugenia Banina, Vladimir Khazak, Natalia Skobeleva, Jeffrey R. Peterson, Igor Astsaturov, Timothy J. Yen
Journal: Cancer Research (2013)

Abstract Many conventional chemotherapies act as DNA damaging agents. Chemotherapy activates cell cycle checkpoint signaling to prevent cells from entering mitosis with either damaged or unreplicated DNA. Based on the observations that interference with the checkpoint mechanism (checkpoint override) results in cell death via mitotic catastrophe, the development of checkpoint inhibitors is actively being pursued as an anti-cancer therapy. In a cell-based screen of clinically relevant kinase inhibitors we identified three compounds that display checkpoint override properties: isomer of bosutinib, a recently FDA-approved Abl and Src inhibitor; BEZ235, a PI3K/mTOR inhibitor; and dovitinib, a multi-receptor tyrosine kinase inhibitor. Most interestingly, all compounds display off-target activity towards DNA damage checkpoint kinases including Chk1, ATR and Wee1. We determined these kinase inhibitors potently sensitized a panel of pancreatic cancer cell lines to S-phase acting (Gemcitabine, cisplatin) or G2-phase arresting (doxorubicin) DNA-damaging agents. Using a combination of live-cell videomicroscopy and immunofluorescence, we demonstrated that the inhibitors forced drug-treated cells to override the DNA damage induced checkpoint activation and aberrantly enter mitosis. The aberrant mitoses had characteristic chromatin fragmentation and that kinetochores and centromeres appeared to be detached from the chromatin mass, in a manner reminiscent of mitosis with unreplicated genomes (MUGs). As a result, cells died either in mitosis or due to mitotic catastrophe. The efficacy of pulsatile (24h and 48h after chemotherapy) administration of these previously unsuspected checkpoint inhibitors was further validated in tumor explants and cells isolated directly from a pancreatic cancer patient who is currently undergoing treatment. Tellingly, xenograft studies showed that gemcitabine and bosutinib isomer had significant activity as single agents but the combination significantly prevented tumor growth, even after drug removal. Our findings suggest that kinase inhibitors targeting cell cycle checkpoints, albeit in an off-target manner, may be fast-tracked into the clinic to enhance the efficacy of standard chemotherapies. Citation Format: Neil Beeharry, Lauren Fink, Eugenia Banina, Vladimir Khazak, Natalia Skobeleva, Jeffrey R. Peterson, Igor Astsaturov, Timothy J. Yen. Repurposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. [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 3266. doi:10.1158/1538-7445.AM2013-3266