tbuckley/cabot-search huggingface dataset:
Abstract LB-149: Identification of novel genes that cooperate with increased eIF4E expression to generate medulloblastoma using the Sleeping Beauty transposon system
Authors: Lori A. Mainwaring, Anna Kenney
Journal: Cancer Research (2010)

Abstract Medulloblastoma is a malignant brain tumor that arises in the cerebellum of young children and occasionally is observed in adults. Increasing evidence suggests that different cell populations represent distinct cells of origin for the various medulloblastoma subtypes, and that these subtypes can be associated with aberrant activation of specific signaling pathways. Current mouse models recapitulate the Shh pathway driven tumors however few models are available to study other medulloblastoma subtypes as genetic events that drive tumorigenesis remain unknown. To address this problem we used the Sleeping Beauty transposon system to uncover novel mutations that contribute to medulloblastoma. Based on earlier work in normal CGNPs, we found that the translation initiation factor eIF4E is critical for regulating CGNP proliferation and the mRNA translation machinery is uniformly upregulated across medulloblastoma subtypes. Using a mouse model wherein eIF4E is ubiquitously over-expressed under control of the -actin promoter (T-Eif4e) we investigated cerebellum development and found that the CGNPs have increased proliferation in vitro in the absence of Shh as well as an expanded proliferative zone in vivo; however these mice do not develop medulloblastoma. Because eIF4E is an oncogene and been shown to cooperate with other known oncogenes in different cell types to accelerate tumorigenesis, we investigated whether eIF4E can cooperate with other mutated genes to generate medulloblastoma. Using a CGNP-specific promoter to drive transposase expression (“Math1-SB”), we crossed these mice with two different lines that carry the Sleeping Beauty transposon (T2/Onc 68 or T2/Onc 76) on different chromosomes. The progeny were then crossed with the T-Eif4e mice and observed for medulloblastoma occurrence; no tumors arise as a result of Math1-SB-mediated transposase activity alone. However, compared to the latency of tumors generated in SmoA1 mice, which have constitutive activation of the Shh pathway, tumors in T-eIF4E/Math1-SB/T2Onc animals arose earlier and were highly proliferative based on Ki-67 staining. They also expressed Otx2, which is associated with a medulloblastoma subtype that does not contain Shh or Wnt pathway mutations. Sequencing of the tumors to identify the genes whose activity is induced (novel oncogenes) or repressed (novel tumor suppressors) by transposon insertion will reveal genes that cooperate with eIF4E to induce medulloblastoma, and may lead to development of new mouse models for medulloblastoma as well as increased insight into genetic events contributing to these tumors. 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 LB-149.
Abstract LB-89: Claudin-11 (CLDN11): A potential marker of gastric carcinogenesis
Authors: Rachana Agarwal, Yuriko Mori, Yulan Cheng, Zhe Jin, Alexandru Olaru, James P. Hamilton, Stefan David, Florin M. Selaru, Jian Yang, John Abraham, Mark Duncan, John Harmon, Elizabeth Montgomery, Patrice J. Morin, Stephen J. Meltzer
Journal: Cancer Research (2010)

Abstract Gastric cancer (GC) remains the second most-common cause of cancer deaths globally, with an overall 5-year survival rate below 20%. The poor prognosis of this cancer, due largely to delayed diagnosis, would be greatly improved by the identification of biomarkers to stratify risk and accelerate diagnosis. In search of such markers, a pilot microarray-based genome-wide search conducted by our group identified claudin-11 (CLDN11), a tight junction (TJ) protein, as a potential target of epigenetic inactivation in gastric cancers. Claudin-11 belongs to the family of claudin proteins, which contains more than 23 members. In recent years, it has been demonstrated by us and others that members of the claudin gene family are involved in various human cancers. Our data identified the CLDN11 promoter region as being heavily hypermethylated in GC tissues and cell lines. Moreover, CLDN11 mRNA was found to be expressed only in primary noncancerous gastric mucosal tissues, as well as in an immortalized normal gastric epithelial cell line, whereas it was silenced in all GC tissues and cell lines examined. Interestingly, siRNA-mediated downregulation of CLDN11 in CLDN11-expressing gastric cells was also associated with cancer-related phenotypic changes, specifically increased cell motility and invasiveness. Our recent data also demonstrates that CLDN11 methylation levels can differentiate GC from its corresponding non-cancerous normal gastric mucosae with 100% sensitivity and specificity. A deeper understanding of the timing of CLDN11 inactivation during the development and progression of gastric neoplasia will lead to the development of potential early detection and prognostic biomarkers. Further, large-scale prospective validation studies of this alteration as a predictive biomarker for GC development are warranted. 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 LB-89.
Correlation of clinical data and expression levels of six tumor supressor genes in breast cancer.
Authors: A Celebiler Cavusoglu, Y Kilic, S Saydam, T Canda, AI Sevinc, Z Baskan, M Sakizli
Journal: Cancer Research (2009)

Abstract Abstract #1058 As the scientists and physicians began to share more information for improving the personalization in medicine, we aimed to check the expression profiles for major tumor suppressor genes of 70 breast tumor samples obtained from the Dokuz Eylul Breast Tumor Biobank. We tried to figure out the levels of expressions of tumor suppressor genes by the quantity of the RNA which belongs to the examined gene in the tumor tissue samples. The expression level was measured by quantitative RT-PCR using total RNA extracted from the tissues. Fluorescence amplification plots were observed and the Ct values were used for comparing the expression levels. For quantification, we chose to normalize the Ct differences by using Genorm software with averaging four housekeeping genes (PUM1, RPL13A, ACTB, B2M). Correlation analysis is performed between genetic expression levels and the data obtained from the clinical records of the biobank.&amp;#x2028; Although further statistical analysis is still continuing, we observed direct significant correlations between ki67 level and BRCA1 expression and between intraductal component level and CDH1 expression. Also significant relations between tubuler formation and BRCA1 expression; between intraductal component and P16 expression were observed. Dermal infiltration had significant correlatios with both TIMP3 and P16 expressions. Significant inverse correlation between estrogen receptor level and BRCA1 expression were found as well as the inverse correlation between progesteron receptor level and TIMP3 and BRCA1 expression levels. Staging had only significant correlations with TIMP3 levels.&amp;#x2028; We also found out that expression status of BRCA1 and BRCA2; BRCA2 and CDH1; BRCA1 and GSTP1, and GSTP1 and TIMP3 shows significant correlations within themselves.&amp;#x2028; *This study is supported by TÜBITAK, The Scientific and Technological Research Council of Turkiye. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1058.
Abstract 1018: Analyzing αvβ8 integrin functions in mouse and human glioma cells
Authors: Jeremy H. Tchaicha, Joseph H. McCarty
Journal: Cancer Research (2010)

Abstract In this study we aim to determine the functional roles for αvβ8 integrin in glioblastoma multiforme (GBM)-induced angiogenesis. These studies originate from our analyses of αvβ8 integrin in developmental brain angiogenesis. αv and β8 knockout (KO) mice develop brain-specific vascular phenotypes that resemble vascular pathologies observed in GBM. Thus, we hypothesize that altered αvβ8 integrin expression and/or function in tumor cells leads to vascular pathologies like those in GBM. Indeed, a murine xenograft model of astrocytoma suggested a role for the integrin in glioma-induced angiogenesis. Primary mouse astrocytes were cultured from wild type (WT) and β8 KO neonates to be immortalized (HPV:E6/E7) and transformed (HRas:G12V). WT and β8 KO transformed astrocytes were intracranially injected into athymic mice. WT tumors displayed pathological features of grade III astrocytomas, whereas β8 KO tumors resembled grade IV GBMs. KO tumors contained widespread edema and hemorrhage as well as pathological angiogenesis, as assessed by quantitation of microvascular density. Interestingly, astrocyte transformation resulted in a significant reduction in αvβ8 integrin cell surface expression in WT cells. Additionally, WT mouse transformed astrocytes lost αvβ8 integrin expression after approximately eight passages in vitro. Exogenous expression of β8 integrin in β8 KO transformed astrocytes resolved the pathologies observed in KO tumors giving further credence to the idea that loss of αvβ8 integrin expression correlates with tumorigenic potential of oncogene-transformed astrocytes. To compliment our mouse model, several established human glioma cell lines were characterized for expression of αvβ8 integrin protein. Some of the cell lines displayed diminished expression of αvβ8 integrin, whereas others showed increased levels, as compared to non-malignant human astrocytes. Intracranial implantation of high and low β8 integrin-expressing human glioma cell lines resulted in tumors exhibiting similar phenotypes to those observed in the mouse model; low expressers were marked by vascular pathologies indicative of β8 KO mouse tumors. Upon overexpression of β8 integrin in a low β8 integrin-expressing human glioma cell line, angiogenic pathologies were largely resolved. Collectively, these data suggest an important functional role for αvβ8 interin in glioma angiogenesis. 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 1018.
1149 PREDICTIVE FACTORS FOR NONRESPONSE IN GENOTYPE 2/3 INFECTED CHRONIC HEPATITIS C (CHC) PATIENTS TREATED WITH PEGINTERFERON ALFA-2A (PEG) AND RIBAVIRIN (RBV) IN REAL LIFE SETTING
Authors: J. Petersen, T. Lutz, R. Link, G. Moog, A. Baumgarten, E. Schott, W. Schmidt, T. Witthoeft, E. Schnaitmann, M. Seidel, A. Rieke, K.G. Simon, A. Herrmann, C. Herold, D. Klass, U. Alshüth, P. Büggisch, S. Mauss, D. Hueppe
Journal: Journal of Hepatology (2012)
OP0198 Proliferative Lymphoid Nodules and not Germinal Centers are the Sites of Autoantigen Stimulation in Human Spleen
Authors: C. Daridon, C. Loddenkemper, S. Spieckermann, A. A. Kühl, A. Salama, G. R. Burmester, P. E. Lipsky, D. Thomas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> This study focused on understanding the cellular mechanisms involved in the breakdown of tolerance and resulting in the production of autoantibodies in human spleen. Therefore, spleens of patients with immune thrombocytopenia (ITP) were studied as a model of the breakdown of immune tolerance. <h3>Methods</h3> 31 spleens from ITP patients and 36 control spleens were analyzed by immunohistochemistry and immunofluorescence, including the detection of antiplatelet reactivity. <h3>Results</h3> Two different splenic structures accommodating proliferating B cells within the white pulp, classical germinal centers (GC) and proliferative lymphoid nodules (PLN) were clearly identified. The number of typical GCs was decreased in ITP spleens whereas PLN were prominent and comparable to the number found in normal spleens. Notably, PLN were observed in control and ITP spleens. PLN were characterized by proliferating Ki67<sup>+</sup> B cells in close contact with follicular dendritic cells lacking polarization into dark and light zones. As opposed to cells in GC, proliferating B cells in PLN lacked expression of Bcl6. Of note, the density of T cells was reduced in both GC and PLN in ITP in comparison to controls. T follicular helper cells were found within PLN as well as in GC, but the density of Foxp3<sup>+</sup> regulatory T cells (Treg) was reduced in both structures in ITP. Strikingly, FDC networks of PLN but not GCs from ITP spleens contained abundant platelet glycoproteinIIb/IIIa autoantigens in IgM containing immune complexes in close proximity to proliferating B cell. <h3>Conclusions</h3> This data is consistent with the conclusion that PLN and not GC are the site of the development and maintenance of autoimmunity in ITP, which could be accentuated by the reduced density of Treg in these structures. <h3>Disclosure of Interest</h3> None Declared
AB0473 Is Subcutaneous Methotrexate is Better than Oral Methotrexate in the Treatment of Rheumatoid Arthritis?: Table 1
Authors: P. Borman, G. Demir, M. Okumus
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Methotrexate (MTX) is an anchor drug in the treatment of patients with rheumatoid arthritis (RA) but gastrointestinal side effects of oral route may restrict its use in most of the patients (1). <h3>Objectives</h3> The aim of this study was to evaluate if subcutaneous MTX is more effective in a group of patients with RA, previously received oral methotrexate and switched to sc MTX, due to side effects and/or inefficacy of oral form. <h3>Methods</h3> Eigthy patients recruited from the Rheumatology unit of a tertier Education and Research Hospital, were included to the study. The patients were only on MTX therapy as disease modifying agent but some of them were on low dose steroid or NSAI drugs. Demographic data, including age, gender, disease duration, and disease activity parameters comprising DAS28, ESR, CRP, RF, pain by VAS, as well as number of patients with gastrointestinal (GIS) side effects due to MTX treatment were recorded. The parameters were determined for the last visit of oral MTX, and 1st and 3rd month visit after subcutaneous MTX (Table 1). <h3>Results</h3> Sixty-eight female and 12 male patients with a mean age of 54.06±1.4 years were recruited to the study. The mean disease duration and oral MTX duration were 122.5±96.8 months and 52.01±45.1 months respectively. There were 76 patients with GIS side effects. All of the disease activity parameters including DAS28, ESR, CRP, pain by VAS were decreased at 1st and 3th month visits after the subcutaneous therapy (Table 1). The number of patients with GIS side effects, were also decreased in the first (n=30, p&lt;0.05) and third month visits (n=27, p&lt;0.05). No statistically significant difference was observed in RF levels before and after subcutaneous MTX therapy (p&gt;0.05). At 3rd month visit, there was no drop out with subcutaneous MTX. <h3>Conclusions</h3> In conclusion subcutaneous MTX has better efficacy in regard to disease activity and better tolerability than in oral forms, if there is inefficacy or intolerability due to GIS side effects. <h3>References</h3> Yazici Y, Bata Y. Bull Hosp Jt Dis 2013;71(Suppl 1):46-8. <h3>Acknowledgements</h3> none <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1690
Abstract 4356: Combination use of anti-CD133 antibody and SSA lectin can effectively enrich cells with high tumorigenicity
Authors: Kumiko Okudo, Kenta Moriwaki, Naotsugu Haraguchi, Shunsaku Takeishi, Masahiro Tanemura, Masaki Mori, Eiji Miyoshi
Journal: Cancer Research (2011)

Abstract A growing body of evidence has suggested that tumors are frequently composed of heterogeneous cell types, and that tumor initiation and growth are driven by a small subset of cells, termed cancer stem cells (CSCs) or tumor-initiating cells. CSCs can self-renew and also give rise to more differentiated progeny that comprise the bulk of a tumor. Glycans exhibit characteristic changes in their structures during development and thus have been used as markers for stem/progenitor cells. However, the glycan structures unique to CSCs have remained unknown. In this study, we examined glycan structures in CD133+CD13+ CSCs, which were recently found to have a high CSC ability, by means of lectin microarray. Seven sialylated glycan-recognizing lectins, MAL-I, SNA, SSA, TJA-I, ACG, ABA, and MAH, showed higher affinity to CD133+CD13+ CSCs than CD133+ cells with a lower CSC ability. In addition, we demonstrated that CD133+SSA+ cells isolated from Huh7 cells had a significantly higher ability to form tumors in NOD/SCID mice and spheres under serum-free conditions than CD133+SSA- cells. These results suggest that hepatic CSCs highly express sialylated glycans and that SSA lectin can be used as a tool for isolating CSCs. This study is the first report to demonstrate the characteristic glycan structures in CSCs and to indicate a new methodology involving lectins for isolating CSCs. 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 4356. doi:10.1158/1538-7445.AM2011-4356
P772Plakoglobin immune analysis as a diagnostic test for arrhythmogenic cardiomyopathy: a comparison of immunoperoxidase and immunofluorescence methods in heart and endomyocardial biopsy samples
Authors: K Pilichou, M Cason, E Lazzarini, E Carturan, S Rizzo, G Thiene, C Basso
Journal: Cardiovascular Research (2014)

Background: Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disorder characterized by a progressive fibro-fatty replacement of cardiomyocytes, accounting for life-threatening arrhythmias and sudden cardiac death. In vivo AC diagnosis is a challenge particularly in concealed forms and the recent proposed immune-analysis test of plakoglobin (JUP) remains controversial.
Activating FCγ RECEPTORS mediate immune complex-induced inhibition of osteoclastogenesis
Authors: LC Grevers, PLEM van Lent, T J de Vries, V Everts, W B van den Berg
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Rheumatoid arthritis is characterised by osteoclast-mediated bone loss. Co-stimulatory signalling via ITAM- and ITIM-coupled receptors is essential for osteoclast formation and function. The ITAM- and ITIM-coupled Fcγ receptors (FcγR) play a crucial role in mediating inflammation and cartilage destruction in experimental arthritis, but their role in osteoclast-mediated bone loss is unknown. <h3>Objectives</h3> To investigate the role of FcγRs in osteoclastogenesis and osteoclast function. <h3>Materials and methods</h3> Bone destruction was analysed in arthritic knee joints of FcγRIIB-deficient, FcRγ-chain<sup>−/−</sup> (lacking expression of activating FcγRs), and wild type mice. Bone marrow-derived osteoclast precursors were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with or without TNFα or LPS. Additionally, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption, and the expression of FcγRs and osteoclast markers. <h3>Results</h3> Bone erosions and cathepsin K-positive osteoclast numbers were significantly increased during antigen-induced arthritis in the knee joints of FcγRIIB-deficient mice. All FcγR classes were highly expressed on bone marrow-derived osteoclast progenitors. On mature osteoclasts, as compared to macrophages, expression of the inhibitory FcγRIIB was similar, whereas expression of activating FcγRs was significantly lower. IC stimulation of mature osteoclasts neither affected their number nor their bone resorptive capacity. Differentiation of bone marrow-derived precursors in the presence of ICs significantly inhibited osteoclast formation, bone resorption, and expression of the osteoclast markers cathepsin K, CTR, DC-STAMP and NFATc1. In the presence of ICs, osteoclastogenesis of FcγRIIB<sup>−/−</sup> precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcRγ-chain<sup>−/−</sup> precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFα or LPS, the inhibitory effects of ICs were overruled. <h3>Conclusions</h3> Activating FcγRs, but not the inhibitory FcγRIIB, mediate IC-induced inhibition of osteoclastogenesis. In the presence of pro-inflammatory mediators like TNFα and LPS the inhibitory effect might be overruled. This suggests that the balance of FcγR-mediated induction of inflammation, through pro-inflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.
Abstract 4771: Regulatory role of an orphan nuclear receptor LRH-1 in castration-resistant growth of prostate cancer cells.
Authors: Lijia Xiao, Shan Yu, Wendy W.L. Hsiao, Franky Leung Chan
Journal: Cancer Research (2013)

Abstract The advanced development of castration-resistant prostate cancer (CRPC) in patients upon androgen-deprivation therapy is generally believed to be mostly mediated by reactivation of androgen receptor (AR) signaling or its bypass with mechanisms involved, including clonal selection of androgen-independent or stem cell-like cell populations, AR hypersensitivity due to AR overexpression, and ligand promiscuity or independence by AR mutations, intratumoral conversion of adrenal androgens to high affinity AR ligands. Besides, the de novo steroid synthesis from cholesterol in CRPC has also been proposed. In this study, we found that the nuclear receptor liver receptor homolog-1 (LRH-1) might contribute to the CRPC growth or de novo steroid synthesis in prostate cancer cells through its positive regulation on expression of several critical enzymes in steroidogenesis, including CYP17A1, HSD3B1, HSD3B2 and StAR. Functional analyses showed that overexpression of LRH-1 could induce higher resistance to antiandrogen bicalutamide and steroid-depleted culture condition in AR-positive androgen-sensitive (LNCaP) but not in AR-negative androgen-insensitive (DU145) prostate cancer cells. In vivo tumorigenicity study showed that LNCaP-LRH-1 cells grew more aggressively in castrated or intact SCID mice, contrary to LNCaP-vector control cells that did not grow in castrated mice. Importantly, liquid chromatography-tandem mass spectrometry showed that intratumoral androgen concentrations (testosterone and DHT) were significantly higher in tumors formed by LNCaP-LRH-1 cells than those by LNCaP-vector control cells. Treatment of LNCaP-LRH-1 cells with a CYP17A1 inhibitor abiraterone could restore their sensitivity to bicalutamide and steroid-depleted culture condition. Gene knockdown of endogenous LRH-1 in AR-positive VCaP prostate cancer cells could not only suppress the mRNA expression of steroidogenic enzymes but also enhance their sensitivity to antiandrogen. Together, our results indicated that LRH-1 might play a regulatory role in advanced castration-resistant growth of prostate cancer via positive control on de novo steroid synthesis in prostate cancer cells. (This work was supported by a Direct Grant for Research 2011/2012 and a RGC-GRF grant 2009/2010) Citation Format: Lijia Xiao, Shan Yu, Wendy W.L. Hsiao, Franky Leung Chan. Regulatory role of an orphan nuclear receptor LRH-1 in castration-resistant growth of prostate cancer cells. [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 4771. doi:10.1158/1538-7445.AM2013-4771