tbuckley/cabot-search huggingface dataset:
Abstract 1632: Paracrine Hedgehog as a mediator of stromal cell steroidogenesis that contributes to progression of prostate cancer to castration resistant disease.
Authors: Amy A. Lubik, Hans Adomat, Emma S. Guns, Ralph Buttyan
Journal: Cancer Research (2013)

Abstract Androgen deprivation therapy (ADT) is frontline treatment for metastatic prostate cancer (PCa). ADT initially blocks disease progression but eventually allows the outgrowth of castration resistant disease (CRPC) that is refractory to the diminished systemic androgen levels in ADT-treated patients. CRPC is associated with acquired intratumoral steroidogenesis (IS), a process that increases the androgen levels in the local microenvironment of prostate tumors and enables further tumor growth and progression. IS has mainly been attributed to a steroidogenic process linked to CRPC cells and here we present evidence that benign tumor-associated prostate stromal cells (PrSCs) can also contribute to IS through a paracrine Hedgehog (HH) tumor microenvironment associated with increased production and release ofHedgehog ligands (Hhs) from prostate cancer cells in response to ADT (Chen, et al., Mol Cancer, 9: 89, 2010). Primary human PrSCs upregulate expression of a large repertoire of steroidogenic genes upon treatment with HH chemical agonists, SAG (100 nM) or Hg 1.5 (1 nM). These effects are Gli2-dependent (Levina, et al., Prostate, 72: 817, 2012) and they can be inhibited by the HH antagonist, KAAD-cyclopamine. Previously we showed that this upregulation significantly increased output of testosterone (T) in PrSCs fed DHEA precursor. More comprehensive analysis (via LC/MS/MS) of androgen outputs from PrSCs fed 22 OH-cholesterol showed that Hg1.5 significantly increased the outputs of Progesterone, DHEA, androsterone, T and dihydrotestosterone (DHT) showing that HH signaling activity effects outputs throughout the androgen biosynthetic pathway. Upregulation of the RDH5 gene by Hg1.5 suggests that the effects on production of DHT from PrSCs might be generated by increased synthesis through both classical and back-door pathways. On a weight-to-weight basis, Hg1.5-stimulated PrSCs produce higher T and DHT outputs than LNCaP cells or an androgen growth-independent variant, LNCaP-AI. Finally, we found that treatment of Sonic Hh-producing LNCaP cells with simvastatin reduced the ability of conditioned medium from these cells to induce steroidogenic gene expression from PrSCs. In summary, this work provides evidence for a stromal cell contribution to IS in CRPC mediated by a paracrine-active HH signaling tumor microenvironment induced by ADT-treatment and identifies potential treatment strategies to interfere with this process. Citation Format: Amy A. Lubik, Hans Adomat, Emma S. Guns, Ralph Buttyan. Paracrine Hedgehog as a mediator of stromal cell steroidogenesis that contributes to progression of prostate cancer to castration resistant disease. [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 1632. doi:10.1158/1538-7445.AM2013-1632
Abstract 1621: Potent anti-cancer effect of crocin against hepatocellular carcinoma: A preclinical study
Authors: Amr Amin, Regine Schneider-Stock, Sayel Daoud
Journal: Cancer Research (2012)

Abstract Background: This is a follow up of our study published in September issue of Hepatology and featured in October issue of Science News that documented the antic-cancer potential of saffron. Here, we show the chemopreventive actions and mechanisms of saffron-based bioactive ingredient; crocin, against diethylnitrosamine (DEN)-induced liver cancer in rats. Methods: Administration of crocin at two doses of 100 and 200 mg/kg body wt per day was started two weeks prior to the DEN injection and was continued for 22 weeks. Result: Crocin decreased the number and the area of placental glutathione-S-transferase positive foci in livers of DEN-treated rats. Furthermore, crocin counteracted DEN-induced oxidative stress in rats as assessed by restoration of superoxide dismutase, catalase, and glutathione-S-transferase levels and diminishing of myeloperoxidase activity, malondialdehyde and protein carbonyl formation in liver. The results of immunohistochemical staining of rat liver showed that crocin inhibited the DEN-mediated elevations in numbers of cells positive for Ki-67, cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa Bp-65 and the phosphorylated tumor necrosis factor receptor. Crocin also blocked the depletion in the number of cells positive for TUNEL and M30 CytoDeath in liver tissues of DEN-treated rats. In vitro experiments carried out using HepG2 cells also confirmed these findings and showed inhibition of NFkB activation, increased cleavage of caspase-3, as well as DNA damage and cell cycle arrest upon saffron treatment. Conclusion: The present study provides evidence that crocin exerts a significant chemopreventive effect against liver cancer through inhibition of cell proliferation and induction of apoptosis. This report also shows some evidence that crocin protects rat liver from cancer via modulating oxidative damage and suppressing inflammatory response. This study is funded by Emirates Foundation. 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 1621. doi:1538-7445.AM2012-1621
Stat Bite: Cigarette Consumption Since 1900
Authors: D. Shopland
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Stat Bite: Cigarette Consumption Since 1900 Get access Don Shopland Don Shopland Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 11, 2 June 1993, Page 857, https://doi.org/10.1093/jnci/85.11.857 Published: 02 June 1993
A8.32 Tocilizumab contributes to the resolution of inflammation by affecting the migratory behaviour of monocytes in the synovial lining
Authors: RA Byrne, K von Dalwigk, G Steiner, JS Smolen, HP Kiener, C Scheinecker
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Monocytes (Mo) are among the first hematopoietic cells to migrate into the inflamed synovial tissue where they integrate into the synovial lining network of fibroblast-like synovial cells (FLS). Here we analyse the dependence of Mo – FLS interaction on proinflammatory cytokines and the effect of anti-IL-6 antibody (Ab) Tocilizumab using real time confocal/multiphoton microscopy of 3D micromass tissue cultures. <h3>Methods</h3> Human FLS were prepared from synovial tissues obtained as discarded specimens following joint arthroplasty. CD14<sup>+</sup> Mo were isolated from peripheral blood by magnetic bead sorting. For confocal imaging fluorescent labelled FLS and Mo were cultured in spherical extracellular matrix micromasses. Micromass cultures were set up in the presence of Tocilizumab or control Ab and stimulated with TNF-alpha. The resulting 4D live cell imaging movies were analysed with Imaris<sup>®</sup> Software. <h3>Results</h3> The highest migratory activity of Mo was observed on days 4–7 of culture, upon the formation of a FLS lining layer around a 3D micromass, The presence of Tocilizumab in TNF-alpha stimulated cultures i) increased the proportion of migrating Mo from 12% in control cultures to 22%, ii) increased the maximum track length of migrating monocytes and iii) stimulated a fast oscillating movement pattern of Mo. <h3>Conclusions</h3> The 3D synovial tissue culture system allows for monitoring and analyses of subtle migration patterns of Mo in relation to the organised synovial lining architecture that depends on the presence of proinflammatory cytokines. Tocilizumab causes significant changes in the migratory behaviour of Mo that might lead to the release of Mo from the inflamed synovial tissue and contribute to the dissolution of inflammation. Ongoing experiments will address the molecular mechanism (s) of Mo – FLS interaction as well as the cellular source and sequence of cytokine production in order to identify potential targets for future therapeutic interventions in arthritis.
PWE-107 Potential role of intravenous immunoglobulin treatment in the management of patients with severe and recurrent<i>Clostridium difficile</i>infection
Authors: T M Monaghan, M Wilson, K Teahon, Y R Mahida
Journal: Gut (2012)

<h3>Introduction</h3> Approximately 30% of patients with <i>Clostridium difficile</i> infection have recurrent disease, despite adequate treatment of the initial episode. Some patients with severe <i>C difficile</i>-associated disease (CDAD) fail to respond to standard treatment with oral vancomycin (125 mg three time a day). Intravenous immunoglobulin (IVIG) has been used in the management of these two groups of patients but no controlled trials have been reported and published clinical experience is mixed. We report our experience of the use of IVIG in these patients, including subsequent course of disease. <h3>Methods</h3> Clinical information was collected prospectively and/or retrospectively (via review of case notes and hospital information system) in seven patients [median age 77 yrs (range 52–91 yrs), six female] with recurrent CDAD and five patients [62 (21–75) yrs, four female] with severe <i>C difficile</i>-associated colitis. IVIG was used at a dose of 400 mg/kg, rifaximin was given for 2 weeks (200 mg twice daily) and <i>Saccharomyces boulardii</i> for 4 weeks (125 mg four times a day). <h3>Results</h3> Recurrent CDAD: median 5 (range 3–8) episodes of disease occurred over 9 (6–15) months. Two patients (4 and 7 episodes) were treated with courses of vancomycin and did not subsequently have a recurrence over the following 5 and 40 months (respectively). In addition to vancomycin courses, three patients received rifaximin (two also had <i>S boulardii</i>) and were free of recurrence over subsequent 15–27 months. One patient (8 episodes) failed to respond to the above treatment, but after IVIG, there has been no recurrence (20 months follow-up). By contrast, a patient with myeloma did not respond to three IVIG infusions. Severe CDAD: CT showed colitis in all, CRP—107 (58–366) mg/l, WBC—17.2 (4.8–39.7)×10<sup>9</sup>/l. In addition to IVIG, all also had high dose oral vancomycin (500 mg four times a day) and intravenous metronidazole. Four (out of five) responded and were subsequently discharged and one had recurrence (responded to oral vancomycin). One patient, whose IVIG was delayed by 48 h after it was recommended, required a colectomy. <h3>Conclusion</h3> (1) Some patients with multiple recurrences of CDAD may not require treatment in addition to courses of vancomycin but others may respond to IVIG. (2) There may be a role for IVIG in the management of patients with severe acute CDAD. (3) Our experience may facilitate identification of clinical characteristics to enable recruitment of suitable patients, with recurrent or severe CDAD, in multi-centre clinical trials of IVIG. <h3>Competing interests</h3> None declared.
1430 SAFETY AND EFFICACY OF BOCEPREVIR/PEGINTERFERON/ RIBAVIRIN (BOC/P/R) COMBINATION THERAPY FOR CHRONIC HCV G1 PATIENTS WITH COMPENSATED CIRRHOSIS: A META-ANALYSIS OF FIVE PHASE 3 CLINICAL TRIALS
Authors: J.M. Vierling, S. Zeuzem, F. Poordad, J.-P. Bronowicki, M.P. Manns, B.R. Bacon, R. Esteban, S.L. Flamm, P.Y. Kwo, L.D. Pedicone, W. Deng, F.J. Dutko, M.J. DiNubile, K.J. Koury, F.A. Helmond, J. Wahl, S. Bruno
Journal: Journal of Hepatology (2013)
The Public Interest: Overview
Authors: Samuel S. Epstein
Journal: Environmental Health Perspectives (1975)

I should like, first of all, to commend both EPA and NIEHS for having organized this conference which I regard as being truly in the public interest. This occasion has afforded many of us an unusual opportunity to exchange information and to interact on scientific and technological issues critical to the formulation of rational policies prior to the decision-making process, rather than following it as is customarily the case. I do, however, regret that a conflict between this conference and the rescheduled meeting of the President's Air Quality Advisory Board, prevented some key EPA decision-makers from being in attendance. I also regret that the EPA Office of Public Affairs decided not to issue a press release for this meeting. I suspect that the Office of Public Affairs considers that an open expression of differences in viewpoints and attitudes within the agency, such as those which perhaps it anticipated would emerge at this meeting, is a sign of weakness. I feel, on the contrary, that such differences, which fortunately exist within the various echelons of EPA, are an expression of strength and are clearly preferable to the more traditional monolithic image projected by most federal agencies. Further, I particularly regret the refusal of GM and Ford to make presentations or even participate in discussions at this meet-
Abstract 2397: SSX-2 vaccines with enhanced MHC class I binding epitopes elicit anti-prostate tumor CTL
Authors: Heath A. Smith, Douglas G. McNeel
Journal: Cancer Research (2010)

Abstract The tumor-associated antigen synovial sarcoma X breakpoint 2 (SSX-2) is classified as a cancer-testis antigen (CTA) based upon its tissue-restricted expression to germline cells and its frequent expression in a variety of malignancies. We have previously identified SSX-2 as a potential prostate cancer antigen that can be inducibly expressed in several prostate cancer cell lines. We have also previously identified two nonamer peptides from the amino acid sequence of SSX-2 that have significant affinity for HLA-A2 as assessed by in vitro T2 binding assay. These HLA-2-binding peptides were found to represent HLA-A2-restricted epitopes, able to induce peptide-specific immune responses in peptide- or DNA-immunized HHD-II (HLA-A2.1+/HLA-DR1+ transgenic) mice. Given these observations, the current study was conducted to determine if CTL generated in vaccinated HHD-II mice are capable of lysing HLA-A2+ prostate cancer cells and whether SSX-2 vaccine efficacy could be enhanced using an altered peptide ligand binding strategy. We found that peptides that were designed in silico to have increased or decreased HLA-A2+ affinity had enhanced and reduced HLA-A2 binding by in vitro T2 binding assay, respectively. Additionally, HHD-II mice immunized with modified SSX-2 vaccines developed increased or decreased frequencies of peptide-specific T cells in vivo, which could be detected by IFNγ ELISPOT assay and cytotoxicity assay. Animals immunized with enhancing modified SSX-2 vaccines generated CTL with cross-reactivity to the native SSX-2 epitopes. These CTL were capable of lysing target cells pulsed with both modified and native peptides and could also lyse an HLA-A2-expressing prostate cancer cell line. These results provide support for the further investigation of SSX-2 as an immunotherapeutic target for prostate cancer using vaccines modified to increase MHC class I binding. 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 2397.
1298 THE PROGRESSION OF NONALCOHOLIC STEATOHEPATITIS IS INFLUENCED BY SKELETAL MUSCLE FUNCTION AND MORPHOLOGY
Authors: Y. Kitajima, Y. Eguchi, R. Iwakiri, R. Shimoda, S. Fujii, S. Nonaka, M. Ono, S. Ono, T. Saibara, N. Ono, T. Eguchi, K. Fujimoto
Journal: Journal of Hepatology (2012)
A NEW AUTOMATIC PROGRAM FOR THE QUANTITATION OF LEFT VENTRICULAR FUNCTION FROM TC-99m GATED BLOOD POOL IMAGES.
Authors: Kenneth Nichols, Joseph Areeda, Kokila Shah, Alan Rozanski, Pierre Chouraqui, Hosen Kiat, Daniel Berman
Journal: Clinical Nuclear Medicine (1988)

Nichols, Kenneth; Areeda, Joseph; Shah, Kokila; Rozanski, Alan; Chouraqui, Pierre; Kiat, Hosen; Berman, Daniel Author Information
Abstract 3148: Frequent epigenetic inactivation of keap1 gene in non small cell lung cancer
Authors: Lucia Anna Muscarella, Paola Parrella, Annamaria la Torre, Vito D'Alessandro, Raffaela Barbano, Fabio Pellegrini, Antonio Tancredi, Vito Guarnieri, Michelina Coco, Teresa Balsamo, Gianluigi Vendemiale, Evaristo Maiello, Vito Michele Fazio
Journal: Cancer Research (2012)

Abstract The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 Non Small Cell Lung Cancer tissues and 12 normal lung specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumours (15%), and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumours had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR=3.62; 95% CI 1.24-10.65, p=0.02). This result was confirmed by Kaplan-Meier analysis which demonstrated an association between worst outcome and KEAP1 double alterations (p=0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients. 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 3148. doi:1538-7445.AM2012-3148
A phase I study with the agonistic TRAIL-R1 antibody, mapatumumab, in combination with gemcitabine and cisplatin
Authors: C. Oldenhuis, C. Mom, S. Sleijfer, J. A. Gietema, N. L. Fox, A. Corey, F. Eskens, W. Loos, E. G. de Vries, J. Verweij
Journal: Journal of Clinical Oncology (2008)

3540 Background: Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that binds and activates the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Mapatumumab combined with gemcitabine (gem) and cisplatin (cis) resulted in increased cytotoxicity in human cancer cell lines and mouse xenograft models. Administration of mapatumumab as a single agent appeared to be safe in prior phase I and II studies. In this phase 1 study we evaluated the safety, tolerability and pharmacokinetics (PK) of mapatumumab in combination with gem and cis. Methods: Gem 1,250 mg/m2 IV on days 1 and 8 and cis 80 mg/m2 IV on day 1 every 21 days was administered to patients (pts) with advanced solid malignancies for a maximum of 6 cycles. Escalating doses of mapatumumab were administered IV every 21 days. Planned dose levels were 1, 3, 10, 20 and 30 mg/kg. PK analysis of plasma mapatumumab, gem, dFdU, unbound and total platinum was performed in the first two cycles. Formation of antibodies was also tested. Results: Enrollment is completed with 49 pts treated at 1 mg/kg (n=4), 3 mg/kg (n=7), 10 mg/kg (n=12), 20 mg/kg (n=13) and 30 mg/kg (n=13) mapatumumab. The most frequently occurring tumor types were pancreatic cancer (35%), carcinoma of unknown primary (17%) and non-small cell lung cancer (13%). Pts received a median of 6 cycles. Dose Limiting Toxicity (DLTs) were experienced by 4/12 pts in the 10 mg/kg group, 2/13 pts in the 20 mg/kg group and 0/13 pts in the 30 mg/kg group (the DLT criteria early in the study included events considered related to gem and/or cis). The DLTs included elevations of transaminases, neutropenic fever, thrombocytopenia and fatigue. The most common adverse events were fatigue, nausea and vomiting. There is no apparent evidence that mapatumumab exacerbates adverse events associated with chemotherapy. No alterations in the PK profiles of the drugs were observed and in 1 pt antibodies were detected. 9/45 pts experienced a partial response and 13/45 pts achieved stable disease ≥ 6 cycles. Conclusions: Mapatumumab can be administered safely up to 30 mg/kg every 3 weeks in combination with gem and cis. Further evaluation of this combination in phase II studies is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Human Genome Sciences Human Genome Sciences
A8.21 Identification of geneexpression networks in different immunological states
Authors: M Bonin, J Kokatjuhha, K Mans, A Grützkau, B Smiljanovic, T Sörensen, T Häupl
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objective</h3> Knowledge about gene networks is of great importance for analysis of transcriptome data. However, current tools mainly rely on information about direct molecular interactions between proteins, which is not directly connected to expression levels. These differences between transcriptome based perception of biological information and tools for network analysis are the main reason for difficulties in functional interpretation. Therefore, we started to use transcriptome data of biologically well-defined states to define functional markers and signatures as tools for future analysis. <h3>Materials and Methods</h3> GeneChip HG-U133 Plus 2.0 transcriptomes from highly purified blood cell types (granulocytes, monocytes, CD4+ and CD8+ T-cell, B-cells, NK-cells) as well as from monocyte stimulation with LPS, TNF and type 1 IFN were selected from the BioRetis database (www.bioretis.de). Correlations of expression between all probesets were calculated to filter for co-regulation Correlation matrices were calculated, clustered and displayed in heat maps The web-platform was constructed based on Ruby on Rails to provide a framework for analysis and storage of data The database and the correlation-algorithm will be provided on our homepage http://www.charite-bioinformatik.de. <h3>Results</h3> Initially, correlation matrices were determined for each individual stimulation condition and its control. Stepwise combination of the three different conditions for calculation of correlation coefficients revealed a reduction of the correlation network and a reduction of overlap between the networks. This indicates increasing functional specificity of the identified candidates. All of the typical previously published IFN related genes were identified and thus confirmed our strategy. In a similar way, cell type specific co-expression networks were determined. Additional filtering for high signal intensity provides candidates for sensitive detection of the function related patterns even in highly diluted conditions. These marker panels are currently tested for detection and quantification of functional signatures in biopsies of inflamed tissue. <h3>Conclusions</h3> Correlating transcription between genes in well-defined biological states identifies function-related markers and signatures. Depending on the type of function, appropriate conditions have to be selected.