tbuckley/cabot-search huggingface dataset:
1413 A FREQUENT PNPLA3 VARIANT PREDICTS DISEASE COURSE IN PRIMARY SCLEROSING CHOLANGITIS
Authors: D. Gotthardt, K. Friedrich, C. Rupp, N. Steinebrunner, P. Sauer, K.H. Weiss, A. Stiehl, P. Schirmacher, W. Stremmel, H. Runz
Journal: Journal of Hepatology (2012)
Abstract P6-05-07: Amplified in breast cancer 1 and ankyrin repeat containing cofactor 1 mediate estrogen induced repression of the ErbB2 oncogene
Authors: JP Garee, AT Riegel
Journal: Cancer Research (2012)

Abstract The oncogene amplified in breast cancer 1 (AIB1/SRC3) is a nuclear receptor coactivator and plays an important role in the regulation of gene transcription. Additionally, AIB1 is important in malignant progression as AIB1 has been shown to be a gene amplified in breast cancer and is also over-expressed in a variety of cancer types. Previous work from our laboratory has identified a splice variant of AIB1 termed AIB1-Δ4. This splice variant arises from the splicing of exon 4 from the mature mRNA. This leads to the formation of an N terminally truncated form of the AIB1 protein, which is a more potent coactivator of steroid dependent transcription compared to the full length AIB1. This suggests that the N-terminal fragment of AIB1, which is not present in AIB1-Δ4, may act to dampen AIB1 mediated transcriptional activation. The presence of this N terminal region suggests this region may be a site of interaction with a repressive protein, which could interact with AIB1 and not AIB1-Δ4. We have identified ANCO1 as an N terminal AIB1 binding protein that acts to repress AIB1 mediated transcriptional activity. Co-immunoprecipitation experiments have indicated interaction between AIB1 and ANCO1 but not between AIB1-Δ4 and ANCO1 indicating ANCO1 binds in the N terminal region of AIB1. AIB1 has a clinical implications and association with the oncogene ErbB2, which is an estrogen repressed gene with hormone effect acting through an estrogen response element (ERE) in intron 1 of the ErbB2 gene. We wanted to determine if the AIB1/ANCO1 complex played a role in hormone regulation of ErbB2. Silencing of AIB1 and ANCO1 by shRNA led to a reversal of estrogen-induced repression of ErbB2 indicating this protein complex may play a role in mediating this repression. Examining binding of these proteins to the intronic ERE of ErbB2 we determined that AIB1 and ANCO1 are recruited in the presence of estrogen. Additionally, repressive proteins such as HDAC3, HDAC4 and N-CoR are recruited along with the AIB1/ANCO1 complex. While AIB1-Δ4 can still be recruited to the intronic ERE no additional repressive proteins are recruited. This suggests a mechanism by which the AIB1/ANCO1 complex can recruit repressive proteins to repress ErbB2 gene transcription, while AIB1-Δ4 can escape this repressive mechanism. This may potentially have interesting clinical implications, as high levels of AIB1-Δ4 may be responsible for increasing the expression levels of the ErbB2 oncogene. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-07.
Abstract B75: TWISTing Stemness, Inflammation, and Proliferation of Epithelial Ovarian Cancer Cells through MIR199A2/214
Authors: Gang Yin, Rui Chen, Han-Hsuan Fu, Ayesha Alvero, Carlotta Glackin, Gil Mor
Journal: Cancer Research (2009)

Abstract Introduction: Twist1, a basic helix-loop-helix (bHLH) transcription factor, has an important role in tumor biology by regulating epithelial-mesenchymal transition. It also functions as a transcription repressor in NFκB-dependent cytokine expression. Recently, we reported the identification and characterization of epithelial ovarian cancer (EOC) cells with stem-like properties (Type I EOC cells). At the microRNA level, Type I EOC cells are characterized by low levels of hsa-miR-199a2 and hsa-miR-214. We also demonstrated the capacity of Type I EOC cells to differentiate into mature ovarian cancer cells (Type II EOC cells), which has lost stemness potential and express high levels of both hsa-miR-199a2 and hsa-miR-214. We also showed previously that hsa-miR-199a2 is able to regulate the levels of IKKβ and therefore have a direct effect on the NFκB pathway. Still, another group reported the regulatory control of hsa-miR-214 on the Akt pathway. In this study, we show that Twist1 is able to regulate the miR-199a2/214 cluster in EOC cells and can therefore control both NFκB and Akt pathways. Methods: 5′-RACE and 3′-RACE was used to clone the full length pre-miR-199a gene. Real-time PCR was used to determine the levels of Twist1 and miR-199a2/214. Twist1 was knocked-down in Type II EOC cells using siRNA. The effect of Twist1 knockdown on levels of IKKβ was determined by Western blot analysis. Cytokines were quantified using Luminex technology. Results: Characterization of full length of pre-miR-199a2 transcript reveals that the MIR199A2 gene contains a human microRNA cluster, miR-199a2/214, and pre-miR-199a2 within the human Dnm3os gene (NCBI GeneID 474332). PCR analysis showed low levels of Twist1 and miR-199a2/214 in Type I EOC cells but high levels of expression in Type II EOC cells. Knockdown of Twist1 in Type II cells induce a significant decrease in the levels both hsa-miR-199a2 and hsa-miR-214, and significant increase in IKKβ expression. Ectopic expression of hsa-miR-199a2 partially reverse the effect of Twist-1 knockdown on the levels of IKKβ. The combination of knockdown Twist1 and TNFα stimulation in Type II EOC cells significantly increase Rantes, an NFκB-dependent cytokine. Conclusion: We demonstrate for the first time that Twist1 plays a feedback role for the NFkB pathway by repressing IKKβ expression through hsa-miR-199a2. Twist1 inhibition of IKKβ expression through regulating hsa-miR-199a2, represents a novel negative feedback loop for the NFκB pathway. The demonstration that Twist1 can regulate the miR-199a2/214 cluster and therefore both the IKKβ and Akt survival pathways, suggests the potential role of Twist1 in EOC differentiation. Furthermore it opens the opportunity to develop new approaches for targeting the ovarian cancer stem cells. Citation Information: Cancer Res 2009;69(23 Suppl):B75.
PMO-015 What is the clinical relevance of a mildly elevated faecal calprotectin detected in new referrals to the gastroenterology clinic?: Abstract PMO-015 Table 1
Authors: F Moroni, J W Winter, A J Morris, D R Gaya
Journal: Gut (2012)

<h3>Introduction</h3> Analysis of faecal calprotectin (FC) is a non-invasive method for differentiating IBS from IBD. As a screening test, a normal FC has been employed to support a diagnosis of IBS, thereby avoiding invasive endoscopy in the patient cohort. We sought to investigate the diagnostic yield on subsequent colonoscopy in patients with mildly elevated FC and lower GI symptoms. <h3>Methods</h3> Between November 2009 and November 2010, all patients with a FC value of 50–100 μg/g of stool (normal &lt;50) were identified from our FC database. All of the stool samples were prepared and analysed according to the manufacturer9s instructions (Bühlmann calprotectin ELISA kit). Patients were excluded from analysis if they were outwith the age range 16–50, had previous faecal calprotectin levels &gt;100 ug/g stool, were known cases of IBD, had a history of NSAID intake, positive stool cultures, or any "alarm" GI symptoms. A similar cohort was identified with age &amp; sex matched controls with FC values &lt;50 μg/g. All the patients who did not go on to have a complete colonoscopy were removed from further analysis. Patients9 records were analysed electronically using the NHS Great Glasgow &amp; Clyde Clinical Portal. <h3>Results</h3> 216 patients were identified with a FC of 50–100 μg/g. After exclusion criteria, 158 patients remained. Of these 82 underwent complete colonoscopy (mean age 36.7, M:F 1:2.2) which was abnormal in only six cases (three cases of a single adenoma&lt;10 mm, one diverticulosis, one helminth infection &amp; one non-specific acute inflammation). 280 patients were identified with a FC&lt;50 μg/g. After exclusion criteria, 176 patients remained. Of these 65 underwent complete colonoscopy (mean age 36.6, M:F 1:2.3) which was abnormal in only eight cases (six cases of non-specific acute inflammation, one adenoma &lt;10 mm &amp; one diverticulosis). The colonoscopy outcome data, as expected, demonstrated that the pathology rate was very low in both groups. There was no difference in the rate of pathology detection between to two groups (p=0.3) and an FC&lt;100 μg/g has an NPV of 88% to exclude any pathology or 100% for significant pathology (IBD, advanced adenoma or colonic carcinoma). <h3>Conclusion</h3> In our population, the diagnostic yield of colonoscopy in patients below the age of fifty with new lower GI symptoms and a mildly elevated FC is very low. If our data can be replicated in a prospective manner, we suggest that invasive colonoscopy can be safely avoided in this cohort and interval FC analysis may be more appropriate. <h3>Competing interests</h3> None declared.
Abstract 1848: Expression of an androgen transporter, organic anion transporting polypeptide 1B3, impacts progression and treatment of prostate cancer
Authors: Heather M. Pressler, Tristan M. Sissung, Douglas K. Price, William D. Figg
Journal: Cancer Research (2012)

Abstract Organic anion transporting polypeptides (OATPs) are membrane transporters that facilitate the movement of large substrates into cells. One family member, organic anion transporting polypeptide 1B3 (OATP1B3) is aberrantly overexpressed in prostate cancer and has been shown to influx both endogenous small molecules and chemotherapy reagents. Our hypothesis is that the OATP1B3 affects tumor growth by influxing testosterone. However, little is known about the cause of OATP1B3 expression in cancer and the impact of OATP1B3 transport on tumor growth. Therefore, we completed a study investigating putative hypoxia elements in the OATP1B3 promoter region, characterizing the impact of OATP1B3 androgen transport on prostate cancer growth, and examining the effect of OATP1B3 on the efficacy of standard prostate cancer treatments. The results showed that OATP1B3 co-localized with HIF 1-alpha in prostate cancer tissues from patients, correlated significantly to HIF1A in xenograft tumors under castration (P=0.005), and confirmed HIF-1alpha elements in the SLCO1B3 promoter region. In addition, radioactive transport assays with Xenopus oocytes showed that OATP1B3 transports testosterone and dihydrotestosterone 50- to 250-fold over passive diffusion at low physiological concentrations. A prostate cancer cell line expressing OATP1B3 grew faster than untransfected in response to androgens at all concentrations. Finally, OATP1B3 increased cell sensitivity to docetaxel treatment. In summary, these data show that hypoxia and castration increases OATP1B3 expression in cancer, OATP1B3-mediated androgen transport significantly impacts prostate cancer growth and OATP1B3 impacts the efficacy of docetaxel. These data provides evidence that OATP1B3 impacts prostate cancer growth and treatment. Future studies could screen for specific inhibitors of OATP1B3-mediated androgen transport. 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 1848. doi:1538-7445.AM2012-1848
Abstract 633: Target therapy of glioblastoma by gene transfer of a monovalent antibody against the MET oncogene
Authors: Giovanni Pacchiana, Cristina Chiriaco, Lara Fontani, Paolo M. Comoglio, Elisa Vigna
Journal: Cancer Research (2011)

Abstract Glioblastoma multiforme is a severe brain tumor refractory to conventional radio-and chemotherapy. The tumor often relies on an autocrine-loop between HGF and its receptor, the product of the met oncogene. Recently we demonstrated that the monovalent form of the DN-30 anti-Met monoclonal antibody (MvDN-30), acting trough a mechanism of receptor shedding, is a potent Met inhibitor (Pacchiana et al., J Biol Chem. 2010; 285:36149-57). We now report its therapeutic effect on glioblastoma, delivering the MvDN-30 to U-87MG cells by mean of gene transfer through a Tet inducible lentiviral vector. Upon doxycicline (Dox) treatment U-87MG correctly express and secret MvDN-30, inhibiting Met receptor expression. Antibody gene transfer results in impairment of U-87MG invasive growth in vitro and tumorigenic properties in vivo. In a preclinical model of “prevention trial” nude mice transplanted with U87-MG were treated with Dox from the day of tumor cell injection. MvDN30 severely impaired tumor onset as, after 16 weeks of treatment, 80% of the mice were still tumor free. Dox treatment was then removed and after 12 weeks mice didn't develop tumors, indicating that MvDN-30 treatment was curative. In a preclinical model of “regression trial” mice bearing tumors of 50 mm3 were treated with Dox. 55% of the mice showed strong slow down of tumor growth or tumor regression that, in the 22% of the cases, took to complete tumor remission. This data highlights MvDN-30 as a candidate for glioblastoma target therapy. 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 633. doi:10.1158/1538-7445.AM2011-633
Airway Involvement of Relapsing Polychondritis Revealed by 18F-Fluoride PET/CT
Authors: Wei Zhang, Zhaohui Zhu
Journal: Clinical Nuclear Medicine (2015)

A 48-year-old man with progressive respiratory symptoms was suspected of having relapsing polychondritis (RPC). A 99mTc-MDP bone scintigraphy showed only mild activity in the bilateral costal cartilage. In contrast, 18F-fluoride PET/CT revealed intense radioactivity accumulation in the tracheal cartilages. Biopsy results from tracheal cartilage were consistent with a diagnosis of RPC. The patient received therapy toward RPC, and his symptoms was gradually alleviated.
Antibiotic Concentrations in Septic Joint Effusions
Authors: John D. Nelson
Journal: New England Journal of Medicine (1971)

Fifty specimens from 27 infants and children with septic joint disease were assayed for ampicillin (18 specimens), methicillin (14 specimens), penicillin (14 specimens) or cephalothin (four specimens). The ranges of observed values varied depending upon the dose and the interval after administration. The joint-fluid level was the same as or higher than the serum level in eight of nine paired specimens tested for ampicillin and in seven of 11 paired specimens assayed for methicillin. Comparable serum and joint-fluid levels of penicillin were found in 11 of 12 paired specimens. The four antibiotics studied enter joint fluid in concentrations greatly in excess of in vitro inhibitory levels of the usual bacteria that cause septic arthritis. There is no need for intra-articular administration. Intramuscular therapy appears as effective as the intravenous route with ampicillin and probably with methicillin and penicillin.
Abstract 5212: Loss of G-protein coupled calcium sensing receptor augments malignancy and bestows cancer stem cell-like properties in human colon carcinoma cells
Authors: Navneet Singh, Guangming Liu, Subhas Chakrabarty
Journal: Cancer Research (2011)

Abstract The G-protein coupled calcium sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells. Loss of CaSR expression allows cancer cells to escape from CaSR control. Loss of CaSR expression augments the malignant phenotype in vitro and is associated with undifferentiated and invasive colon carcinomas in vivo (Cancer Res. 63: 67, 2003; 65: 493, 2005; Int. J. Cancer 121: 1455, 2007;126: 631, 2010; Mol. Carcinogenesis 48: 202, 2009). Interestingly, human colon carcinoma cell lines contain small subpopulations (10-20%) that do not express CaSR (termed CaSR null cells). Here, we report the isolation and characterization of CaSR null cells from the CBS and HCT116 human colon carcinoma cell lines. We isolated CaSR null cells by magnetic cell sorting using monoclonal anti-CaSR antibody. CaSR null cells were cultured and maintained in stem cell culture medium. Biologic characterization of CaSR null cells showed that these cells were non-adherent and grew as three-dimensional spherical clusters with an increase in propensity for anchorage independent growth. CaSR null cells were highly invasive in matrigel invasion assays and resistant to treatment with cytotoxic drugs. Western analysis showed that CaSR null cells expressed a high level of thymidylate synthase and survivin which have been reported to be an underlying basis of drug resistance in colon cancer. Western analysis also showed that CaSR null cells expressed a high level of the previously reported cancer stem cell markers CD133, CD44 and Nanog. Molecular profiling by quantitative RT-PCR revealed a significant increase in the expression of epithelial-mesenchymal transition associated mRNAs in CaSR null cells. These mRNAs were N-cadherin, β-catenin, vimentin, fibronectin, FSP1, Snail1, Snail2, Twist, FOXC2 and SIP1. Interestingly, CaSR null cells re-expressed CaSR, over time, when placed in culture medium used to propagate the parental CBS and HCT116 cells. Re-expression of CaSR in CaSR null cells attenuated the expression of markers associated with the malignant phenotype. We conclude that CaSR null cells represent a highly malignant subpopulation of colon cancer cells and that these cells may possess cancer stem cell-like properties. 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 5212. doi:10.1158/1538-7445.AM2011-5212
Abstract 1571: Tumor cell panels: New tools in genomic era.
Authors: Chris White, Lysa-Anne Volpe, Luping Chen, Anupreet Bal, Michael Jackson, John Foulke, Fang Tian
Journal: Cancer Research (2013)

Abstract Increased understanding of cancer genome is affecting every corner of cancer research. Although human tumor cell lines have been used as essential tools for decades, there are only a few cell line panels have been developed for drug screening. The most widely used NCI60 human tumor cell line panel was composed by selecting cell lines to represent nine subtypes of cancer. The rising of targeted therapeutics has led to new generation anticancer agents. However, it's difficult to predict clinical response to these agents because of the genetic diversity and genomic heterogeneity in human cancers. Therefore, there is a gap between the new knowledge of cancer genome and the cell line based platforms for both basic and translational research. Here, we show that new generation tumor cell panels are filling the gap. The panels were generated by selecting authenticated cell lines derived from variant cancer types, and annotated with genetic alteration information generated by large scale sequencing projects such as the Catalog of Somatic Mutations in Cancer (COSMIC) and the Cancer Cell Line Encyclopedia (CCLE). There are more than 25 tumor cell line panels, which include hundreds of cell lines, have been developed in this initiative. They cover 18 most common cancer types, such as lung, breast, colon, pancreatic cancer and so on. To capture the genetic diversity of cancer, each panel includes cell lines with varying gene mutation complexity. To further facilitate targeted drug discovery, the molecular signature tumor cell line panels focus on individual driver genes, critical protein kinases, transcription factors and cell signaling pathways. Those panels have been analyzed to verify gene mutation, gene expression, protein expression and bio-functions. Therefore, the new generation tumor cell panels provide powerful tools to accelerate the discoveries in basic cancer research, compound screening, biomarker selection, pathway analysis, and targeted therapeutic development. Citation Format: Chris White, Lysa-Anne Volpe, Luping Chen, Anupreet Bal, Michael Jackson, John Foulke, Fang Tian. Tumor cell panels: New tools in genomic era. [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 1571. doi:10.1158/1538-7445.AM2013-1571
FRI0349 Results of a multinational survey regarding the definition of remission in juvenile idiopathic arthritis related uveitis
Authors: I. Foeldvari
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Currently new treatments appears to be more effective for the control of the disease in juvenile idiopathic arthritis (JIA) associated uveitis, that remission of JIA associated uveitis is a realistic aim. It would be nice to have a composite index to define remission of uveitis currently. <h3>Objectives</h3> to survey paediatric rheumatologist how they define remission of JIA associated uveitis. <h3>Methods</h3> Paediatric rheumatologic colleagues were asked to fill out a survey with 12 items regarding the definition of remission. The survey was distributed over the Paediatric Rheumatology E-Mail board. <h3>Results</h3> 34 centres responded to the survey till end of January 2012. The response reflects a multinational participation with 19 north American centres, 8 European centres, 4 South American centres, 2 centres from Israel and 1 centre from Australia. 30 of the 34 centres defined as part of remission less than 1 steroid eyedrop per day. Regarding the use of systemic steroids 16 centres defined remission as less than 0.05 mg/kg/day of applied systemic steroids and 14 as no use of systemic steroids at all. 28 of the centres defined remission as less than 1 cell per field in the anterior chamber on slit lamp exam and as the grading of chamber flare as none. 33 centres defined the absence of macular edema as a requirement for remission. 29 defined the absence of new or progressing synechia as part of remission. 23 centres defined the absence of decreased or increased ocular pressure as part of remission. 27 centres defined the absence of occurrence of new cataracts as part of remission. 29 centres defined the absence of new band keratopathy as part of remission. 23 defined the absence for need for surgery on the eye as part of remission. <h3>Conclusions</h3> The results of the survey are a start to define remission of JIA associated uveitis with a composition of items. Some of the items overlap reflect active disease and/or damage of the disease or side effects of medication. A planned consensus meeting will define a preliminary set of items to define remission. This new definition has to be tested prospectively regarding validity. <h3>Disclosure of Interest</h3> None Declared