tbuckley/cabot-search huggingface dataset:
THU0207 Acute serum amyloid a and TLR2 activation induces pro-inflammatory mechanisms in a novel EX vivo temporal artery explant culture/model of giant cell arteritis
Authors: D. Molloy, M. Connolly, J. McCormick, M. Haroon, D.J. Veale, C. Murphy, E. Molloy, U. Fearon
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Giant cell arteritis (GCA) is a common form of primary vasculitis characterised by dysfunctional vessels and inflammatory infiltration, however the underlying mechanisms involved in regulating these processes have yet to be elucidated. This study examines the role of acute serum amyloid A (A-SAA) and TLR2 activation in mediating pro-inflammatory pathways and angiogenesis using temporal artery (TA) whole tissue explants <i>ex-vivo.</i> <h3>Methods</h3> <i>Ex vivo</i> TA explant cultures were established from GCA patients direct from surgery and the effect of pro-inflammatory stimuli A-SAA (10μg/ml) and a TLR2 agonist Pam3CYSK4 (1μg/ml) on Ang2, MMP2, MMP9, IL-6 and IL-8 was quantified by ELISA and gelatin zymography. Furthermore, myofibroblast outgrowth from TA explants was assessed using matrigel assays over a time course of 1-15 days. <h3>Results</h3> <i>Ex vivo</i> TA explant cultures spontaneously released pro-inflammatory mediators, maintained cell viability and histological morphology, thus closely reflecting the <i>in vivo</i> microenvironment. A-SAA and Pam3CSK4 induced expression of instability growth factor Ang2 (p&lt;0.05) and MMP2 and MMP 9 which are involved in blood vessel invasion. A-SAA and Pam3CSK4 significantly induced IL-8 expression (p&lt;0.05), with no significant effect observed for IL-6. A-SAA and Pam3CSK4 induced myofibroblast outgrowths from TA explants embedded in matrigel over a time course of 1-15 days. In parallel, Ang2, MMP2/9 and pro-inflammatory chemokine IL-8 were induced in myofibroblast outgrowth cultures in response to A-SAA, and to a lesser extent Pam3CSK4. <h3>Conclusions</h3> Using a novel <i>ex vivo</i> TA explant culture we demonstrate for the first time that A-SAA and TLR2 activation induce angiogenic factors, chemokine expression and promote migrational/invasive processes as shown by their effect on myofibroblast outgrowths. Since TLR2 can mediate the effect of A-SAA, these results suggest that this pathway may represent a potential therapeutic target for GCA. <h3>Disclosure of Interest</h3> D. Molloy: None Declared, M. Connolly: None Declared, J. McCormick: None Declared, M. Haroon: None Declared, D. Veale Grant/Research support from: Wyeth, GSK, Abbott, Opsona, Consultant for: Wyeth, GSK, Abbott, Pfizer, Schering Plough, Centocor, Speakers Bureau: Wyeth, GSK, Abbott, Pfizer, Schering Plough, Centocor, Mundipharma, C. Murphy: None Declared, E. Molloy: None Declared, U. Fearon: None Declared
Abstract 3026: Increase in proliferation and migration of breast cancer cells via PKC activation-induced down-regulation of BKca channel
Authors: Eun Sil Park, Yun-Ja Mun, Kee Ryeon Kang, Jaehee Han, Dawon Kang
Journal: Cancer Research (2012)

Abstract Purpose: K+ channels are involved in tumorigenesis through the regulation of cell proliferation, apoptosis, migration, and invasion. However, the involvement of the large conductance Ca2+-activated K+ (BKCa) channels in the cancerous phenomenon is controversial. This study was performed to investigate whether and how BKCa channels are related to the cellular processes for tumorigenesis. Methods: Cell proliferation and migration assays were performed in non-invasive (MCF-7) and invasive (MDA-MB-231) breast cancer cells in the absence or presence of BKCa channel modulators or PKC modulators. Patch-clamp technique and reverse-transcriptase (RT)-polymerase chain reaction (PCR) were performed to study the expression of the BKCa channel in breast cancer cells. The relationship between BKCa channels and cell proliferation/migration was analyzed using gene overexpression and knock-down techniques. Results: Patch-clamp technique and RT-PCR data showed that BKCa channels were expressed in both MCF-7 and MDA-MB-231 cells. Inhibitors of BKCa channels increased cell proliferation and migration, whereas BKCa channel activators suppressed them. Overexpression of BKCa in breast cancer cells reduced proliferation and migration, whereas silencing of BKCa enhanced the proliferation and migration. BKCa inhibitors (paxilline, ChTx, and IbTx) induced PKC activation, and the PKC activation down-regulated the BKCa channel expression and activity. In addition, the treatment of PMA (a PKC activator) decreased BKCa channel expression, whereas combination of PKC inhibitors maintained the BKCa channel expression levels without reduction. Conclusion: These results show that a decrease in BKCa expression levels, which could be modulated by PKC activation, increases cell proliferation and migration in breast cancer cells and suggest that modulation of BKCa expression may regulate tumorigenesis of breast cancer cells. Key words: Breast cancer; Cell migration; K+ channels; Proliferation 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 3026. doi:1538-7445.AM2012-3026
1092 EFFECTS OF PRE-TREATMENT WITH BEZAFIBRATE FOLLOWED BY STANDARD OF CARE IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HEPATITIS C GENOTYPE 1 INFECTION AND ELEVATED GGT LEVELS
Authors: A. Bohlig, V. Weich, M. Biermer, R. Somasundaram, H. Hinrichsen, R. Heyne, B. Moller, B. Ruf, U. Spengler, R. Link, A. Herrmann, P. Malfertheiner, A.W. Lohse, E. Herrmann, S. Zeuzem, T. Berg
Journal: Journal of Hepatology (2012)
Abstract 3452: Molecular genetic analysis of the WTX gene in medulloblastoma
Authors: Eve-Kristin Wenzl, Maren Regehly, Katrin Guse, Gabriele Röhn, Roland Goldbrunner, Pablo Hernáiz-Driever, Ulrich Wilhelm Thomale, Ulrich Schüller, Frank Heppner, Arend Koch
Journal: Cancer Research (2011)

Abstract Medulloblastomas (MBs) represent the most frequent malignant brain tumors of childhood. Previous genetic studies in MBs have identified mutations in genes coding for beta-catenin, AXIN1 and Conductin (AXIN2), which cause activation of the Wnt signaling pathway in about 20% of this malignant tumors. The Wnt signaling pathway is negatively controlled by the Wilms tumor suppressor gene WTX, a component of this signaling complex. To investigate whether alterations in WTX may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the WTX gene in 76 MB biopsy samples and 5 MB cell lines using single-strand conformation polymorphism and sequencing analysis. Two rare WTX single nucleotide polymorphisms (SNPs) c.135C&amp;gt;T in exon 2 of two different MBs (Ser &amp;gt; Ser; TCC &amp;gt;TCT), both of them are not yet known, where identified. To investigate if the tumor suppressor WTX is regulated in MBs an mRNA expression analysis in 46 MBs and 5 MB cell lines revealed reduced expression of WTX mRNA compared to fetal cerebella tissues. Interestingly, when compared to adult cerebella tissue, WTX is up-regulated in fetal cerebella of different embryonic ages, which indicates a possible involvement of WTX during cerebella development. Moreover, wild-type WTX was found to be over-expressed in tumor cell lines in which the Wnt signaling pathway is activated by mutations in beta-catenin. Our findings indicate that the activation of the Wnt signaling pathway in MBs is not caused by alterations in WTX. However, the down-regulation of WTX could be a possible explanation for the Wnt activation in a subset of MBs. The up-regulation of WTX (related to adult controls) and in particular in Wnt-activated tumor cells suggests that WTX could be a potential target gene of the Wnt signaling pathway, which interacts in a negative feedback loop mechanism. 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 3452. doi:10.1158/1538-7445.AM2011-3452
<i>HER2</i> amplification does not alter outcome in small (≤1 cm) tumors.
Authors: P Ananthakrishnan, RJ Patrick, LA Rybicki, RR Tubbs, JP Crowe, GT Budd
Journal: Cancer Research (2009)

Abstract Abstract #6058 INTRODUCTION: Amplification of human epidermal growth factor receptor-2 (HER2) has been associated with an aggressive clinical phenotype, however the management of patients with small tumors (&amp;lt;1 cm) that amplify HER2 is controversial. The goals of this study were: 1) to describe characteristics of HER2 amplified tumors based on tumor size, and 2) compare outcomes among 4 groups based on tumor size (small tumors &amp;lt;1 cm or large tumors &amp;gt;1 cm) and HER2 amplification (+ or -.)&amp;#x2028; METHODS: Data were collected prospectively in our institutional review board approved breast center patient registry for patients with infiltrating ductal or infiltrating ductal-lobular mixed breast cancer. There were 770 patients with N0 tumors who were diagnosed between January 2001 and April 2005 (prior to treatment of HER2 amplified tumors with Trastuzumab). Categorical variables were compared using the Chi-squared test; outcomes were estimated using the Kaplan-Meier method and the log-rank test.&amp;#x2028; RESULTS: At 4 years, estimated disease free interval was 97% in small HER2- tumors, 92% in large HER2- tumors, 91% in small HER2+ tumors, and 86% in large HER2+ tumors.&amp;#x2028; &amp;#x2028; At 4 years, breast cancer specific survival was 97% in small HER2- tumors, 92% in large HER2- tumors, 91% in small HER2+ tumors, and 86% in large HER2+ tumors.&amp;#x2028; CONCLUSIONS: In our series, larger as opposed to smaller HER2+ tumors tended to be of higher histologic grade (SBR), and showed a trend toward more frequent lymphovascular invasion (LVI) and negative hormone receptor status. In small tumors, HER2 amplification did not predict recurrence-free survival or breast cancer disease specific survival at 4 years. The survival curves do show trends towards worsening outcomes for small tumors with HER2 amplification; these trends may show significance with additional follow-up. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6058.
The Association between Sleep Apnea and the Risk of Traffic Accidents
Authors: J. Terán-Santos, A. Jimenez-Gomez, J. Cordero-Guevara
Journal: New England Journal of Medicine (1999)

Drowsiness and lack of concentration may contribute to traffic accidents. We conducted a case–control study of the relation between sleep apnea and the risk of traffic accidents. The case patients were 102 drivers who received emergency treatment at hospitals in Burgos or Santander, Spain, after highway traffic accidents between April and December 1995. The controls were 152 patients randomly selected from primary care centers in the same cities and matched with the case patients for age and sex. Respiratory polygraphy was used to screen the patients for sleep apnea at home, and conventional polysomnography was used to confirm the diagnosis. The apnea–hypopnea index (the total number of episodes of apnea and hypopnea divided by the number of hours of sleep) was calculated for each participant.
Case 37-2014
Authors: Scott R. Beach, Daniela Kroshinsky, Nicholas Kontos
Journal: New England Journal of Medicine (2014)

A 35-year-old woman with a history of drug dependency was seen in the emergency department because of a rash that was thought to be due to mite infestation. She reported seeing bugs on her skin. Examination revealed excoriations on her skin, but the midback was spared.
PMO-137 Phenotypic and functional signature of CD4POSCD25HIGHCD127 low regulatory T-cells in autoimmune hepatitis
Authors: R Liberal, C Grant, G Mieli-Vergani, D Vergani, M Longhi
Journal: Gut (2012)

<h3>Introduction</h3> In autoimmune hepatitis (AIH) CD4<sup>pos</sup>CD25<sup>high</sup> regulatory T-cells (T-regs), a subset central to immune-tolerance, are numerically defective and impaired in their ability to control effector cell function. At variance with CD4 effectors, T-regs, classically known as CD25<sup>high</sup> and FOXP3<sup>pos</sup>, express low levels of the activation marker CD127. The aim of the current study was to provide a phenotypic and functional profile of CD4<sup>pos</sup>CD25<sup>high</sup>CD127<sup>low</sup>T-regs (CD127<sup>low</sup>T-regs) in AIH and to explore to what extent absence or low levels of CD127 impact on T-reg ability to suppress. <h3>Methods</h3> 20 ANA/SMA+ AIH patients and 12 healthy subjects (HS) were studied. T-reg phenotype was determined by flow cytometry using antibodies to CD4, CD25, CD127, CTLA-4 and Galectin-9, a molecule linked to T-reg ability to suppress. T-reg transcription factor and cytokine profile were assessed by intracellular staining. CD127<sup>low</sup>T-reg ability to suppress was evaluated in a proliferation assay following co-culture with CD25<sup>neg</sup> target cells. <h3>Results</h3> In AIH CD4<sup>pos</sup>CD25<sup>high</sup> cells contained fewer CD127<sup>low</sup> cells than in HS. Compared to conventional CD4<sup>pos</sup>CD25<sup>high</sup> (cT-regs), CD127<sup>low</sup>T-regs from both AIH and HS had a) higher numbers of FOXP3<sup>pos</sup>, CTLA-4<sup>pos</sup>, Galectin-9<sup>pos</sup> and IL-10<sup>pos</sup> cells; b) lower numbers of T-bet<sup>pos</sup>, RORC<sup>pos</sup>, IFNg<sup>pos</sup> and IL-17<sup>pos</sup> cells; and c) similar numbers of TGF-b<sup>pos</sup> cells. In AIH, CD127<sup>low</sup>T-regs contained fewer FOXP3<sup>pos</sup>, CTLA-4<sup>pos</sup>, Galectin-9<sup>pos</sup>, IL-10<sup>pos</sup> and TGF-b<sup>pos</sup> cells and higher frequencies of T-bet<sup>pos</sup>, RORC<sup>pos</sup>, IFNg<sup>pos</sup> and IL-17<sup>pos</sup> cells than in HS. CD127<sup>low</sup>T-regs inhibited CD25<sup>neg</sup> cell proliferation more effectively than cT-regs, though less markedly in AIH than in HS. In AIH, treatment with anti-IFNg and anti-IL-17 neutralising antibodies ameliorated the suppressive ability of cT-regs, while leaving unchanged that of CD127<sup>low</sup>T-regs; exposure to anti-IL-10 neutralising antibodies reduced cT-reg suppression in HS, but not in AIH. <h3>Conclusion</h3> CD127<sup>low</sup> T-regs bear the phenotypic and functional signature of “true T-regs”. Low numbers and reduced suppressive function of CD127<sup>low</sup>T-regs in AIH may contribute to breakdown of immune-tolerance by permitting effector cells to perpetrate hepatocyte damage. <h3>Competing interests</h3> None declared.
A Controlled Trial of Early versus Late Treatment with Zidovudine in Symptomatic Human Immunodeficiency Virus Infection
Authors: John D. Hamilton, Pamela M. Hartigan, Michael S. Simberkoff, Philip L. Day, Gigi R. Diamond, Gordon M. Dickinson, George L. Drusano, Merrill J. Egorin, W. Lance George, Fred M. Gordin, Clifton A. Hawkes, Peter C. Jensen, Nancy G. Klimas, Ann M. Labriola, Christopher J. Lahart, William A. O'Brien, Charles N. Oster, Kent J. Weinhold, Nelda P. Wray, Susan B. Zolla-Pazner
Journal: New England Journal of Medicine (1992)

Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established.
A6.40 Copy number increase of<i>TLR7</i>and<i>TLR8</i>genes in men with rheumatoid arthritis
Authors: GV Martin, SB Kanaan, DF Azzouz, N Balandraud, C Picard, I Auger, F Arnoux, M Martin, J Roudier, NC Lambert
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Men are less often affected by Rheumatoid arthritis (RA) than women. In mice studies, it was shown that a duplication in Toll-like receptor 7 (Tlr7) gene is sufficient to potentiate autoimmunity in males. We therefore propose to investigate whether an increase in copy number (CN) of TLR7, and its neighbouring paralog TLR8 on X chromosome, could contribute to the pathogenesis of RA in men. <h3>Materials and methods</h3> In a pilot analysis, we had first tested our hypothesis by real-time quantitative PCR assay to assess CN of <i>TLR7</i> gene and <i>TLR8 </i>compared to Beta-Globin gene <i> (HBB),</i> using the relative standard curve calculation method, on DNA from PBMCs of 49 men with RA and 42 healthy controls. TLR7/8 copy numbers significantly increased in PBMCs from men with RA when compared to healthy men. Nevertheless, because men with RA were significantly older than healthy donors, the increased TLR7/8 CN could be age-dependent. In the current study, we have tested whether TLR7/8 CN varies with age on a large number of controls from birth to 82 years old (160 men and 180 women). We also tested an additional autosomal RPP30 gene to further validate our results. DNA samples from peripheral blood of 49 men with RA <i>versus</i> 160 healthy men and 44 women with RA <i>versus</i> 180 healthy women were tested for TLR7/8 CN compared to mean CN values of HBB and RPP30. Similarly, DNA samples from PBMCs of 53 men with RA <i>versus</i> 42 healthy men and 40 women with RA <i>versus</i> 41 healthy women were analysed. <h3>Results</h3> TLR7 or TLR8 CN does not vary with age in healthy individuals (women or men). Similar findings were observed in patients with RA. Nevertheless, we confirmed that men with RA had an increased TLR7 and TLR8 CN in peripheral blood compared to healthy men (p &lt; 0.0001 and p = 0.002 respectively). A rather opposite trend was observed in women with RA. Similar results were observed in PBMCs. <h3>Conclusions</h3> We have presented evidence that copy number of X-linked <i>TLR7</i> and <i>TLR8</i> genes increases in men with RA. This increase is not only disease dependent but also sex-dependent. We are currently validating our results by digital droplet polymerase chain reaction to confirm this genetic heterogeneity between men and women with RA.
Age-Specific Reference Ranges for Serum Prostate-Specific Antigen in Black Men
Authors: Ted O. Morgan, Steven J. Jacobsen, William F. McCarthy, Debra J. Jacobson, David G. McLeod, Judd W. Moul
Journal: New England Journal of Medicine (1996)

The detection of prostate cancer by screening for prostate-specific antigen (PSA) in serum is improved when age-specific reference ranges are used, but these ranges have been derived from white populations. We determined the distribution of PSA and age-specific reference ranges in black men both with and without prostate cancer.From January 1991 through May 1995, we measured serum PSA in 3475 men with no clinical evidence of prostate cancer (1802 white and 1673 black) and 1783 men with prostate cancer (1372 white and 411 black). We studied the data as a function of age and race to determine the usefulness of measuring PSA in diagnosing prostate cancer.Serum PSA concentrations in black men (geometric mean in controls, 1.48 ng per milliliter; in patients, 7.46) were significantly higher than those in white men (geometric mean in controls, 1.33 ng per milliliter; in patients, 6.28). The values in the controls correlated directly with age. The area under the receiver-operating-characteristic curve was 0.91 for blacks and 0.94 for whites. If traditional age-specific reference ranges were used in screening black men, with the test specificity kept at 95 percent, 41 percent of cases of prostate cancer would be missed. For the test to have 95 percent sensitivity among black men, the following normal reference ranges should be used: for men in their 40s, 0 to 2.0 ng of PSA per milliliter (test specificity, 93 percent); for men in their 50s, 0 to 4.0 ng per milliliter (specificity, 88 percent); for men in their 60s, 0 to 4.5 ng per milliliter (specificity, 81 percent); and for men in their 70s, 0 to 5.5 ng per milliliter (specificity, 78 percent).Serum PSA concentrations can be used to discriminate between men with prostate cancer and those without it among both blacks and whites. Over 40 percent of cases of prostate cancer in black men would not be detected by tests using traditional age-specific reference ranges, which maintain specificity at 95 percent. In this high-risk population, the alternative approach--maintaining sensitivity at 95 percent--may be used with acceptable decrements in specificity.
The Key and the Lamppost
Authors: Samuel Hellman
Journal: Journal of Clinical Oncology (1999)

Article Tools EDITORIAL Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.10.3007 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10506593 The Key and the Lamppost Samuel HellmanxSamuel HellmanSearch for articles by this author Show More The University of Chicago, Center for Advanced Medicine, Chicago, IL https://doi.org/10.1200/JCO.1999.17.10.3007 Full Text PDF Figures and Tables "The Key and the Lamppost." Journal of Clinical Oncology, 17(10), pp. 3007–3008© 1999 by American Society of Clinical Oncology
AB0009 Gender-associated differences of dectin-2, dc-sign and mcp-1 polymorphisms in the susceptibility to rheumatoid arthritis
Authors: L. M. Canet, R. Cáliz, C. Lupiañez, A. Escudero, I. Filipescu, L. Romani, J. Segura-Catena, M. J. Soto-Pino, M. Expósito-Ruiz, M. A. Ferrer, A. García, A. González-Utrilla, T. Vallejo, K. Hemminki, A. Försti, E. Collantes, J. Sainz
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Hormonal, environmental and genetic factors interact in the development of rheumatoid arthritis (RA) but it is still not clear which factors are responsible for the observed gender associated differences in RA incidence and severity. Given that the invasion of RA synovial by macrophages (and subsequently by T-cells) is a critical step that requires the involvement of several immune molecules and given the role of genetic variants in determining the immune response, the present study was conducted to explore whether single nucleotide polymorphisms in immune-related genes might differentially influence the risk of RA in women and men. <h3>Methods</h3> Twenty-seven functional/tagging polymorphisms in <i>Dectin-1</i>, <i>Dectin-2</i>, <i>DC-SIGN, MCP-1</i> and <i>CCR2</i> genes were selected and genotyped in 970 individuals, 458 RA patients (359 women and 99 men) and 512 healthy controls (217 women and 295 men). <h3>Results</h3> We found that women carrying the <i>Dectin-2</i>rs4264222_T and <i>Dectin-2</i>rs7134303_G alleles had an increased risk of RA (OR=1.95, 95%CI 1.35-2.82 and OR=1.91, 95%CI 1.29-2.83) whereas women carrying the <i>MCP-1</i>rs1024611_G, and <i>MCP-1</i>rs13900_C alleles had a decreased risk of RA compared with those carrying the wild-type genotype (OR=0.60, 95%CI 0.42-0.86 and OR=0.65, 95%CI 0.46-0.93). In men, none of these associations were observed but we found that carriers of the <i>DC-SIGN</i>rs2287886_A allele had an increased risk of RA (OR=1.69, 95%CI 1.03-2.78) whereas carriers of the <i>DC-SIGN</i>rs4804803_G had a decreased risk of developing the disease (OR=0.54, 95%CI 0.32-0.91). SNP-SNP interaction analysis showed significant three- and four-locus interaction models in women that were not seen in men. Across all these models, the most accurate predictor was a model that consisted of <i>DC-SIGN</i>rs4804803, <i>Dectin-2</i>rs4264222 and <i>Dectin-2</i>rs7134303 polymorphisms and suggested a synergistic effect between <i>Dectin-2</i>rs7134303 and <i>Dectin-2</i>rs4264222. <h3>Conclusions</h3> These results suggest that <i>Dectin-2, MCP-1</i> and <i>DC-SIGN</i> polymorphisms may account for gender-associated differences in susceptibility to RA. Future studies in larger populations are needed to corroborate our findings. <h3>Disclosure of Interest</h3> None Declared