tbuckley/cabot-search huggingface dataset:
Abstract 4948: Uncovering microRNA and transcription factor-mediated regulatory network in glioblastoma
Authors: Zhongming Zhao, Jingchun Sun
Journal: Cancer Research (2012)

Abstract Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from that in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. In this study, we systematically explored the combinatory regulation of miRNAs and transcription factors (TFs) impacting GBM genes. We compiled GBM-related miRNAs, genes, and TFs and then identified 1,128 3-node feed-forward loops (FFLs) and 805 4-node FFLs with statistical significance. These FFLs were converged to construct a comprehensive GBM-specific miRNA-TF mediated regulatory network and, from which, an essential GBM-specific regulatory network. To further identify critical miRNA components in the GBM regulatory network, we specifically extracted a subnetwork for Notch signaling pathway. Our follow up network and functional association analyses revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some supported by previous studies. This study has generated the first comprehensive miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. Our findings of important miRNAs in the Notch signaling pathway, with partial verification by previous studies, demonstrates that our network-based approach is promising for identifying new and important miRNAs in GBM and, potentially, other cancers. 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 4948. doi:1538-7445.AM2012-4948
AB0915 Ankylosing spondylitis: The correlation between mobility limitation score (BASMI) and a new disease activity index (ASDAS)
Authors: W. Hamdi, M.M. Ghannouchi, I. Zouch, M.M. Kchir
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Ankylosing spondylitis disease activity score (ASDAS) is a new disease activity index with good metrological parameters. It includes the most relevant items of disease activity according to patient and doctors. Weighting of these parameters is the principal characteristic of the ASDAS when compared with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Correlation of ASDAS with mobility limitation parameters in patients hasn't be investigated previously. <h3>Objectives</h3> To investigate correlation between the ASDAS and the Bath Ankylosing Spondylitis Metrology Index (BASMI). <h3>Methods</h3> A cross sectional study was conducted in our department of Rheumatology that includes 56 patients (45 male/10 female) with ankylosing spondylitis according to the modified New York criteria. Clinical data used for calculation of ASDAS and BASMI were collected. ASDAS formula B was used (calculated with erythrocyte sedimentation rate) [1]. <h3>Results</h3> Patients mean age were 38,35±11 years [16-73]. The mean ASDAS was 4,5±2,3 [0,5-10,2]. The mean BASMI was 4,2±2,3 [0.5-10]. ASDAS was positively correlated to BASMI (r: 0.300, p: 0,029) [fig 1]. Figure 1: Distribution of ASDAS and BASMI in patient with ankylosing spondylitis. <h3>Conclusions</h3> ASDAS is a new activity index. It confirms that not only structural damage but also disease activity were responsible of mobility limitation in patients with ankylosing spondylitis. <h3>References</h3> C Lukas, R Landewe', J Sieper, et al. Development of an ASAS-endorsed disease activity (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68:18–2 <h3>Disclosure of Interest</h3> None Declared
Abstract 2457: Ex vivo analysis of novel isoflavanoids (ME-143 and ME-334) in patient derived triple negative breast cancer tumors.
Authors: Kesavan Nair Praveen, Thomas Broudy, Cyrus Mirsaidi, Ofir Moreno, Daniel Gold
Journal: Cancer Research (2013)

Abstract There is an unmet need for novel effective therapeutics to treat triple negative (ER, PR and Her2 negative) breast cancer in clinics. Phase I clinical studies of 2 novel isoflavonoid investigational drugs, ME-143 and ME-344 have been shown them to be generally well tolerated in patients with solid tumors. ME-143, a next analogue of the investigational anti-cancer drug Phenoxodiol binds at low nanomolar concentrations to a tumor-specific variant of cell surface associated NADH oxidase (tNOX), resulting in caspase activation and apoptotic tumor cell death. ME-344, a second investigational anti-cancer isoflavonoid, is structurally related to ME-143 but functionally distinct. ME-344 is a mitochondrial targeting agent that interferes with tumor cell energy generation resulting in cell death via mitochondrial membrane destabilization and autophagy induction through the disruption of both mTOR1 and mTOR2 upstream and downstream signal transduction pathways. Pre-clinical studies using in vitro cell lines showed significantly high potency for both compounds either when used as single agents or when combined with cytotoxic and targeted anti-cancer agents. The present study investigated the ex vivo efficacy of ME-143 and ME-344 using patient-derived tumor cells from triple negative breast cancer. Tumor tissue was disintegrated into single cell suspension and expanded in mouse as subcutaneous patient-derived xenograft before harvesting for the studies. Mouse tumor cells were disintegrated into single cells and were grown as spheroids to mimic the tumor micro-environment and single agent as well as combination treatments were performed. Using a high content imaging platform, various endpoints were evaluated to compare the efficacies of the drugs. Both ME-143 and ME-344 as single agents showed efficacy in inhibiting cell proliferation as well as colony formation in patient-derived triple negative breast cancer cells while combination of these agents with Cisplatin and Gemcitabine demonstrated additive or synergistic effects. Use of high content imaging has enabled the identification of patient population that has tumor cells resistant to very high doses of drugs. Follow-up studies are planned to characterize the sub-population of cells that are resistant to high dose of these drugs. Citation Format: Kesavan Nair Praveen, Thomas Broudy, Cyrus Mirsaidi, Ofir Moreno, Daniel Gold. Ex vivo analysis of novel isoflavanoids (ME-143 and ME-334) in patient derived triple negative breast cancer tumors. [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 2457. doi:10.1158/1538-7445.AM2013-2457
Abstract 1481: microRNA mediated reprograming of fibroblasts into cancer associated fibroblasts in ovarian cancer
Authors: Anirban K. Mitra, Marion Zillhardt, You-Jia Hua, Payal Tiwari, Andrea E. Murmann, Marcus E. Peter, Ernst Lengyel
Journal: Cancer Research (2012)

Abstract Cancer associated fibroblasts (CAFs) are a major constituent of the tumor stroma and promote the invasion and growth of cancer cells. However, the mechanism by which cancer cells transform normal fibroblasts into CAFs is unclear. While it is clearly established that microRNAs are deregulated in cancer and are involved in cellular reprograming, it is not known if they play a role in the transformation of normal fibroblasts into CAFs. Therefore, we investigated the novel possibility of microRNA mediated reprogramming of normal fibroblasts into CAFs. Primary CAFs extracted from the metastasis of patients with ovarian cancer and normal omental fibroblasts (NOFs) extracted from non-cancer patients were profiled for microRNA expression. The functional role of microRNAs in CAFs was established by assessing their ability to promote ovarian cancer co-invasion, colony formation and tumor growth in mice. The microRNA targets were identified using gene array analysis, validated by 3′UTR luciferase reporter assay, and functionally verified both in vitro and in mouse xenografts. Comparing CAFs and NOFs we found that, in ovarian cancer CAFs miR-31 and miR-214 were downregulated while miR-155 was upregulated as compared to normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting microRNAs and microRNA inhibitors induced a phenotypic and functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reprograming of CAFs into normal fibroblasts. The microRNA induced CAFs and patient-derived CAFs shared multiple upregulated genes highly enriched in chemokines important for CAF function. The most highly upregulated chemokine, CCL5/RANTES, was found to be a direct target of miR-214. CCL5 was functionally important for both CAFs and normal fibroblasts reprogrammed into CAFs, in vitro and in mouse xenografts. These results indicate that tumor cells can reprogram fibroblasts to become CAFs through the regulation of their microRNAs, suggesting that targeting microRNA in stromal cells, as well as in tumor cells, could be beneficial for cancer treatment. 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 1481. doi:1538-7445.AM2012-1481
FRI0526 The Infantile Gut Bacterial Colonization Pattern is Associated with Higher Cytokine Responses but not to the Proportions of Putative Regulatory T Cells in Childhood
Authors: A. Rudin, R. Hardis, S. Anna, A. Ljung, A.-C. Lundell, K. Andersson, A.E. Wold, I. Adlerberth
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Establishment of the gut microbiota commences directly after birth when the neonate is exposed to microbes. The gut microbiota is a major stimulus for the immune system and late acquisition or reduced complexity of the gut flora may delay adaptive immune maturation. However, it is still unknown whether the gut bacterial colonization pattern is related to the T cell development during early childhood. <h3>Objectives</h3> To explore whether the neonatal gut colonization pattern is related to the T cell development during the first 3 years of life. <h3>Methods</h3> We followed 65 Swedish children prospectively from birth up to 3 years of age. Fecal samples were cultured for major facultative and anaerobic bacteria and yeasts at several time points during the first 2 months of life. The production of IL-1β, TNF, IL-6, IL-5, IL-13 and IFN-γ by mononuclear cells stimulated with PHA was analyzd at 18 and 36 months of age. Furthermore, the proportions of CD4<sup>+</sup> T cells that were CD45RO<sup>+</sup>, FOXP3<sup>+</sup>CD25<sup>high</sup> or CTLA-4<sup>+</sup>CD25<sup>+</sup> at birth and at 1, 4, 18 and 36 months of age were examined by flow cytometry. The relation between colonization with different groups of gut bacteria and immune parameters was analyzed with the use of multivariate factor analysis. <h3>Results</h3> Early colonization by bifidobacteria and <i>Escherichia coli</i> was associated with mononuclear cells with higher capacity to produce TNF, IL-6, IL-5 and IL-13 at 18 or 36 months of age. In contrast, colonization by <i>Staphylococcus aureus</i>, clostridia and enterococci was inversely related to TNF, IL-5 and IL-13 responses and the proportion of CD45RO<sup>+</sup> T cells later in childhood. There was no association between the early gut bacterial colonization pattern and the proportions of the FOXP3<sup>+</sup>CD25<sup>high</sup> and CTLA-4<sup>+</sup>CD25<sup>+</sup> cells within the circulating CD4<sup>+</sup> T cell population, markers of putative regulatory T cells. <h3>Conclusions</h3> Colonization by an early gut microbiota containing bifidobacteria and <i>Escherichia coli</i> may enhance T cell activation in children, but does not appear to have any association with the proportions of circulating putative regulatory T cells later in life. If increased activation of the CD4<sup>+</sup> T cells may have any relation to the development of inflammatory disordes later in childhood remains to be examined. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5341
Abstract P5-21-04: Real-world use and effectiveness of adjuvant trastuzumab in 2665 consecutive breast cancer patients
Authors: VCG Tjan-Heijnen, SC Seferina, DJA Lobbezoo, AC Voogd, MW Dercksen, F van den Berkmortel, RJW van Kampen, AJ van de Wouw, MA Joore, GF Borm
Journal: Cancer Research (2012)

Abstract Background The impact of drug prescriptions in the real world as opposed to strict trial prescription is only rarely assessed even though it is well recognized that incorrect use may harm a patient and may have a huge impact on health care resources. We aimed to assess how and to whom trastuzumab was given since its introduction in September 2005 as adjuvant treatment, and to assess its efficacy in daily practice. Patient and methods We set up a registry of all patients diagnosed with stage I-III invasive breast cancer in 5 Dutch hospitals during the years 2005–2007. Patients were included irrespective of HER2 status and of treatment received. We present the main patient and tumor characteristics, treatment delivered and 5-year treatment outcomes. Results Of 2665 patients included, n=479 (18%) had a HER2 positive tumor. As of September 2005, adjuvant trastuzumab was given to 96% of patients with a HER2 positive tumor receiving adjuvant chemotherapy. The median age of these patients was 51 (27–72) years. Their median tumor size was 23 (5–65) mm, 55% had node-positive, 57% ER-positive and 47% PR-positive disease. In 83% of patients, trastuzumab was delivered in sequence after (taxane-based) chemotherapy, mainly in the first years after introduction, and in 91% in a 3-weekly regimen. Trastuzumab was delivered for a median of 49 (IQR 45–52) weeks. For patients with a HER2 positive tumor treated with adjuvant trastuzumab (n = 232), the five-year disease-free survival was 81%. For patients with a HER2 positive tumor who were not treated with trastuzumab (n = 247) the five-year disease-free survival was 75% (p = 0.13). Corresponding 5-year overall survival rates were 91% and 78%, respectively (p = 0.0002). Conclusion In the Netherlands, trastuzumab was rapidly implemented since its introduction in September 2005. Characteristics of patients treated with trastuzumab resembled those included in the HERA study. Similarly, outcomes were in agreement with reported phase III studies. More detailed and multivariate analyses will be shown at the meeting. Funding Netherlands Organization for Health Research and Development (ZonMw: 80–82500-98-9056) and Roche Netherlands. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-21-04.
Abstract 1518: Gene expression profiling reveals acidosis/GPR4-induced inflammatory responses in vascular endothelial cells
Authors: Lixue Dong, Reid D. Castellone, Jen-Tsan Chi, Li V. Yang
Journal: Cancer Research (2011)

Abstract Due to deficient blood perfusion, hypoxia, and glycolytic metabolism, acidic tissue microenvironments commonly exist in solid tumors, inflammation, and many other pathological conditions. However, the molecular mechanisms by which cells respond to acidic microenvironments are not well understood. GPR4 has recently been identified as a novel proton-sensing receptor expressed in endothelial cells, cancer cells, and other cell types. GPR4 is activated by acidic extracellular pH but has lower activation at the physiological pH 7.4 and minimal activation at more alkaline pH. To delineate the function and signaling pathways of GPR4 in endothelial cells under acidic conditions, we performed gene expression microarray analyses. Primary human umbilical vein endothelial cells (HUVEC) that express endogenous GPR4 were stably transduced with the MSCV-IRES-GFP control vector (designated as HUVEC/Vector cells) or the MSCV-GPR4-IRES-GFP construct (designated as HUVEC/GPR4 cells). HUVEC/Vector and HUVEC/GPR4 cells were treated with pH 6.4 (400 nM H+) for 5 hours to activate GPR4 or with pH 8.4 (4 nM H+) as a negative control. RNAs were isolated, labeled, and hybridized with the Agilent Whole Genome Microarray Chip to compare gene expression. The results demonstrated that the acidic pH treatment of HUVEC/Vector cells stimulated the expression of a number of inflammatory genes, which represent a predominant signature in the microarray dataset. The induction of most of the acid-responsive inflammatory genes were further enhanced by GPR4 overexpression in HUVEC/GPR4 cells at pH 6.4, suggesting these genes are responsive to varying levels of GPR4 signaling. The inflammatory genes with substantial up-regulation by acidosis/GPR4 include chemokines, cytokines, adhesion molecules, genes involved in the TNFα and NF-κB pathways, prostaglandin-endoperoxidase synthase, and EGR transcription factors. The up-regulation of the genes at pH 6.4, compared to pH 7.4 and pH 8.4, was further confirmed by real-time RT-PCR. Taken together, our results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Since the inflammatory response of endothelial cells is important for blood vessels to interact with immune cells and tumor cells in the microenvironment, the acidosis/GPR4 signaling may play a role in the processes such as tumor immunity and metastasis. 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 1518. doi:10.1158/1538-7445.AM2011-1518
Psychiatry in Europe: Directions and Developments
Authors: A. W Clare
Journal: BMJ (1995)

Ed Tom Sensky, Cornelius Katona, Stuart Montgomery Gaskell/Royal College of Psychiatrists, pounds sterling10, pp 201 ISBN 0 902241 71 0

Europe certainly has a strange effect on the mental health of the British. It provokes either apoplectic outbursts of Little Englander psychosis or overblown sentimental evocations of Britain's role as a sturdy cultural bridge linking the great continent to our American siblings across the Atlantic. Psychiatry in Europe exudes the latter spirit. The cover is a fetching Euroblue with twelve yellow stars (how time marches on!) and the title, like one of those grandiloquent European position papers that pour out of Brussels, promises a veritable grand tour …
Abstract 1492: FoxM1 expression and its association with matrix metalloproteinases in diffuse large B-cell lymphoma
Authors: Abdul K. Siraj, Azhar R. Hussain, Maqbool Ahmed, Saeeda O. Ahmed, Rong Bu, Fouad Al-Dayel, Prashant Bavi, Shahab Uddin, Khawla S. Al-Kuraya
Journal: Cancer Research (2011)

Abstract Forkhead Box M1 (FoxM1) has been shown to play a critical role in pathogenesis of various malignancies however its role in lymphoid malignancies is not fully elucidated. Therefore, in this study, we first investigated the role of FoxM1 in a large series of DLBCL tissues in a tissue micro array (TMA) format by Immunohistochemistry (IHC). We then followed this with in vitro studies on DLBCL cell lines using either pharmacological inhibitors of FoxM1 or siRNA knock down strategy. Using IHC, FoxM1 was detected in 84.6% of DLBCL tumors. FoxM1 expression was found to be significantly associated with early stage (p=0.0149), germinal centre phenotype (p=0.0126) and high proliferative tumor marker Ki67 (p&amp;lt;0.0001). In addition, FoxM1 expression was also significantly associated with expression of SKP2 (p&amp;lt;0.0001) and inversely associated with p27 expression (0.0215). Metalloproteinases, such as MMP-2 and MMP-9 play an important role in invasion and migration of cancer cells were also found to be significantly associated with expression of FoxM1 (p=0.0008 and p=0.0002) respectively. Our in vitro studies showed that treatment of DLBCL cell lines with thiostrepton, a specific inhibitor of FoxM1 inhibited cell proliferation, invasion and migration of DLBCL cells and induced apoptosis in a dose dependent manner. Inhibition of FoxM1 led to down-regulation of MMP-2, MMP-9 and SKP2 expression while the expression of p27 was up-regulated in DLBCL cells. Similar results were obtained using siRNA targeted against FoxM1. Furthermore, treatment of DLBCL cells with thiostrepton caused a dose dependent apoptosis in all DLBCL cell lines used in the study. On dissecting the apoptotic pathway, we found that thiostrepton induced its apoptotic effect via the mitochondrial pathway and activation of caspases. Finally, treatment of DLBCL cells with thiostrepton down-regulated the expression of XIAP, cIAP1 and Survivin. Altogether, these results suggest that FoxM1 signaling contribute in pathogenesis of germinal centre subtype of DLBCL and may serve as useful molecular biomarker and potential therapeutic target. 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 1492. doi:10.1158/1538-7445.AM2011-1492