tbuckley/cabot-search huggingface dataset:
Abstract 4284: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by v-Src.
Authors: Stephanie Guy, Mulu Geletu, Rozanne Arulanandam, Leda Raptis
Journal: Cancer Research (2013)

Abstract The signal transducer and activator of transcription-3 (Stat3) is an important signal transducer with a role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherin-11 (cad11), a cell to cell adhesion protein, known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to Stat3 activation. Stat3 in turn, downregulates the p53 antioncogene and upregulates anti-apoptotic genes, thus offering a potent survival signal. A large number of oncogenes such as vSrc activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for anti-apoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of downregulation of cad11 upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. However, intermediate Src levels, which are physiologically relevant, did allow cad11 expression, albeit at lower levels. Cad11 knockdown in these cells through shRNA expression with a retroviral vector caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, is actually also necessary for full neoplastic transformation by the Src oncogene. Citation Format: Stephanie Guy, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by v-Src. [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 4284. doi:10.1158/1538-7445.AM2013-4284
Abstract 2215: Use of peptide nucleic acid(PNA)-mediated PCR clamping method for detection EGFR mutation in patients with non-small cell lung cancer
Authors: Hee Joung Kim, Young-Chul Kim, Kyu-Sik Kim, Sung Yong Lee, Tae Won Jang, Min Ki Lee, Kyeong-Cheol Shin, Gwan Ho Lee, Hye Ryun Kim, Jae Chol Lee, Jeong Eun Lee, Sun Young Kim, Kye Young Lee
Journal: Cancer Research (2011)

Abstract Introduction : Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with nonsmall cell lung cancer (NSCLC). Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated Real-Time PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability. Methods : Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA extracted from paraffin-embedded tissue specimens, both PNA-mediated Real-Time PCR clamping and direct sequencing were performed. The results and clinical response to EGFR-TKIs were compared. Results : Sequencing revealed a total of 63(26.3%) mutations and PNA-mediated RT PCR clamping detected EGFR kinase mutation in 83(34.6%) samples. 61 mutations were consistent by both of direct sequencing and PNA-mediated RT PCR, however PNA-mediated RT PCR detected additional 22 mutations; 10 in exon 19, 9 in exon 21 and 3 in both of them. Furthermore, patients whose tumors expressed EGFR mutations exhibited an excellent response to EGFR-TKIs by more than 88%. Conclusion : PNA-mediated Real-Time PCR clamping is a simple and rapid, as well as a more sensitive method for screening of genomic alterations in EGFR gene compared to direct sequencing. This data suggests that PNA-mediated Real-Time PCR clamping should be implemented as a useful screening tool for detection of EGFR mutations in clinical setting. 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 2215. doi:10.1158/1538-7445.AM2011-2215
376 STATINS INDUCE SENESCENCE OF ACTIVATED HSC BY INHIBITION OF THE HEDGEHOG PATHWAY
Authors: S. Klein, M. Granzow, R. Schierwagen, P. Van der Ven, E. Raskopf, U. Pieper-Fürst, D. Fürst, F. Lammert, S. Choi, A.M. Diehl, V. Shah, T. Sauerbruch, J. Trebicka
Journal: Journal of Hepatology (2012)
Abstract 4810: Multiplexed immunoprecipitation-liquid chromatography-multiple reaction monitoring mass spectrometry quantification of protein expression and phosphorylation for breast cancer biomarkers
Authors: Yi Chen, David J. Britton, Elizabeth R. Wood, Ian Pike, John M. Koomen
Journal: Cancer Research (2012)

Abstract Introduction: Estrogen receptor alpha (ER alpha), progesterone receptor B (PR B), and the receptor tyrosine kinase, Her2, are tumor markers classified by the American Society of Clinical Oncology (ASCO) as level of evidence I in breast cancer. The quantitative evaluation of protein expression and phosphorylation status of these targets in tumor tissues will enable subtype classification and support clinical decision-making and selection of targeted therapy in breast cancer. Experimental Procedures: Breast cancer cell lines were used to develop peptide-based quantitative assays for protein expression and phosphorylation using immunoprecipitation (IP) and liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM). Stable isotope-labeled standard peptides were synthesized and developed as internal standards. Multiplexed IP for ER alpha, PR B, and HER2 will be developed to enable the enrichment of the proteins to enable quantification of the expression and phosphorylation of these biomarkers in the same sample. The sensitivity of each assay will be tested using serial dilutions of cell lysate to evaluate requirements for analysis of clinical specimens. Data Summary: LC-MRM assays for both unmodified and phosphorylated peptides have been developed and characterized for each protein. Recovery using multiplexed IP for these proteins is similar to recovery of individual IP. Data have been generated for cell line models of stimulation and treatment. For example, LC-MRM quantification of HER2 in cell line models stimulated with EGF or Heregulin shows that protein expression is unchanged, but phosphorylation increases; on the other hand, LC-MRM shows clearly that phosphorylation of Her2 is inhibited with Lapatinib. Conclusions: The ability to examine the protein expression as well as the phosphorylation status in these biomarkers with quantitative mass spectrometry will produce improved understanding of their role in the development and progression of breast cancer and has the potential to improve the selection of targeted therapeutics. 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 4810. doi:1538-7445.AM2012-4810
Abstract 1957: Loss of TGFβ1 alters host-microbial interactions, predisposing the colonic epithelium to inflammation
Authors: Corbie Ball, Mohamad Azhar, Constance Gard, Dora Chen, Thomas Mast, Bruce Aronow, David Besselsen, Thomas Doetschman
Journal: Cancer Research (2010)

Abstract Introduction: The TGFB pathway is mutated in up to 30% of human colon cancers. Genetically Engineered Mouse Models (GEMs) with deficient TGFβ signaling model several characteristics of IBD associated human colon cancers. Introduction of Helicobacter sp. into the Tgfb1−/−Rag2−/− mouse model is necessary for the development of inflammatory lesions which progress to adenoma and carcinoma. The exact role of TGFβ1 and bacterial-associated inflammation has yet to be elucidated and offers a potential target for the prevention of colon cancer. Methods: To determine the function of TGFβ1 on colonic bacterial composition we used GEM models, Tgfb1−/−Rag2−/− and Tgfb1+/+Rag2−/−. The cecal microflora of 10 Tgfb1−/−Rag2−/− and 10 Tgfb1+/+Rag2−/− mice were isolated and serially diluted onto brucella (BRU), bacteroides bile esculin (BBE), and laked kanomycin-vancomycin (LKV) media under anaerobic conditions. Colony forming units (CFUs) were enumerated. Individual colony types were then streaked onto trypitcase soy agar with 5% sheep blood and grown anaerobically and aerobically. The bacteria were then gram-stained and biotyped utilizing a Dade Berhing MicroScan instrument. To further examine the bacterial composition we designed primers specific to the 16s rRNA subunit of different Bacteroides species, and using the Roche LightCycler preformed quantitative Real Time-PCR (qRT-PCR) on fecal DNA. Results: The Dade Berhing Instrument showed that Tgfb1−/−Rag2−/− mice had a 4 fold increase in bacterial load and a 28 fold increase in Bacteroides species when compared with Tgfb1+/+Rag2−/− mice. The qRT-PCR results showed an increase in Bacteroides fragilis and Bacteroides distasonis and a significant decrease in Bacteroides thetaiotaomicron in the Tgfb1−/−Rag2−/− mice. These data suggest that loss of TGFβ1 alters the colonic microflora. Previous studies illustrated the importance of bacterial nutrient sources on bacterial composition. To examine if TGFβ1 is altering nutrient availability in the colon a previous micro-array was analyzed for candidate genes associated with glycoprotein metabolism. This showed changes in fucose metabolizing enzymes with the loss of TGFβ1. Conclusion: These findings suggest that TGFβ1 plays a role in bacterial load maintenance, possibly by altering available nutrient sources and when disrupted, can cause abnormalities in pathobionts (commensal bacterial with pathogenic potential) which could then lead to increased inflammation. 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 1957.
Postcolonic polypectomy pancreatitis
Authors: J. Fortea, I. Marín Jimenez, O. Nogales Rincon, V. Flores Fernandez, T. Savescu, A. Madrid Vallenilla, P. Menchen Fernandez-Pacheco
Journal: Endoscopy (2010)

A 71-year-old man, who was following a colonoscopy surveillance program for previous colonic polyps, attended our endoscopy unit for routine colonoscopy. He had undergone his last endoscopic procedure in February 2007, during which a total of five polyps were resected (size range 7 – 15 mm). Histological examination revealed adenomatous polyps with low-grade dysplasia.
Modeling justice as a natural phenomenon
Authors: Ken Binmore
Journal: Behavioral and Brain Sciences (2013)

Among other things, Baumard et al.’s “A Mutualistic Approach to Morality” considers the enforcement and establishment of moral norms, the interpersonal comparison of welfare, and the structure of fairness norms. This commentary draws attention to the relevance of the game theory literature to the first and second topic, and the social psychology literature to the third topic.
Abstract 2369: Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung.
Authors: Minkyu Jung, Chul Ho Lee, Hyung Soon Park, Ji Hyun Lee, Dae Joon Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho
Journal: Cancer Research (2013)

Abstract Purpose: The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed. Materials and Methods: We assessed polymorphisms at 8 sites in 4 genes (thymidylate synthase (TS), dihydrofolate reductase (DHFR) [1610, 680, 317, intron 1], methylenetetrahydrofolate reductase (MTHFR) [677, 1298], glycinamide ribonucleotide formyl transferase (GARFT) [2255]) associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung. Results: Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes with of pemetrexed. Conclusions: The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung. Citation Format: Minkyu Jung, Chul Ho Lee, Hyung Soon Park, Ji Hyun Lee, Dae Joon Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho. Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung. [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 2369. doi:10.1158/1538-7445.AM2013-2369 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
CT Nonuniform Attenuation and TEW Scatter Corrections in Brain Tc-99m ECD SPECT
Authors: Karim Farid, Marie-Odile Habert, Antoine Martineau, Nadine Caillat-Vigneron, Igor Sibon
Journal: Clinical Nuclear Medicine (2011)

Perfusion brain single photon emission computed tomography (SPECT) is currently used to evaluate patients with cognitive impairments. Although widely available, it has been reported to be significantly less sensitive than F-18 FDG positron emission tomography. Optimization of SPECT parameters using nonuniform attenuation correction (NUAC) and scatter correction (SC) might improve the accuracy of the method. This study assessed the effect of x-ray CT-based NUAC and triple-energy window (TEW-SC) on brain SPECT compared with Chang-uniform (UAC). A total of 31 patients with memory complaints underwent Tc-99m ECD SPECT/CT. CT-NUAC+TEW-SC and Chang-UAC were applied and compared. The images were spatially normalized to a default SPECT template supplied with Statistical Parametric Mapping software (SPM2). A paired t test image was then reconstructed. Regional cerebral blood flow measurements were apparently reduced in the frontal white-matter and in the frontotemporal cortex when CT-NUAC+TEW-SC were used. These findings need to be considered when interpreting Tc-99m ECD SPECT after applying CT-AC+TEW-SC. Further prospective studies with clinical correlations are needed.
DEVELOPMENT OF NOVEL SMALL MOLECULES THAT TARGET GLIOBLASTOMA STEM CELLS
Authors: S. Kesari, I. F. Tsigelny, R. Mukthavaram, V. L. Kouznetsova, Y. Chao, S. Pastorino, P. Jiang, S. C. Pingle, W. Wrasidlo, M. Makale
Journal: Neuro-Oncology (2014)

BACKGROUND: Transcription factors (TFs) are a major class of protein signaling molecules that play a critical role in most cancers. OLIG2 is a bHLH TF essential for survival and expansion of the highly aggressive brain cancer, glioblastoma (GBM), and represents an attractive therapeutic target. TFs including OLIG2 are typically activated by dimerization, and TF inhibition has proved problematic owing to expansive protein–protein interfaces and the absence of hydrophobic pockets. In silico modeling is increasingly being used in attempts to design TF dimerization inhibitors, but these efforts have met with very limited success. METHODS: evious in silico based drug design approaches for TFs focused on single residues or small foci, called binding hotspots, on TF dimerization surfaces. This approach has largely failed because hotspots do not adequately represent the total active TF dimerization interface. In our modeling approach, which we used to identify candidate small molecule scaffolds for OLIG2 inhibition, we represent the dimerization surface as a comparatively extensive parental pharmacophore. This active surface is comprised of multiple, specific subregions we term daughter pharmacophores or subpharmacophores. We hypothesized that a small molecule capable of binding each subpharmacophore would sufficiently populate the active dimerization surface to interfere with OLIG2 dimerization, thereby suppressing pathway activation. RESULTS: Computational screens, guided by parameters defined by our multiple pharmacophore algorithm, identified potential OLIG2 inhibitors from comprehensive in silico compound libraries. A subset of these candidates convincingly demonstrated OLIG2 pathway inhibition and anti-GBM activity in an array of biochemical, cell-based, and reporter assays. Further, when we tested in mice a leading representative from a chemically tractable structural class we found, (1) attenuation of GBM xenograft growth, and (2) a favorable CNS pharmacokinetic profile. Both observations prompted us to nominate and pursue the representative for further structural optimization in the context of in vivo efficacy and pharmacokinetics. CONCLUSIONS: We have developed a novel computational modeling approach for designing TF inhibitors, using the concept of multiple pharmacophores. We have identified a small molecule compound with significant in vitro/vivo anti-GBM activity and favorable pharmacokinetics. The initial compound is now being pursued as a development candidate for GBM, and if successful its final derivative may ultimately represent the first truly GBM-specific drug. Moreover, our study in a broader context presents a new pharmacologic paradigm and may pave the way for the development of TF-targeted therapeutics in general. SECONDARY CATEGORY: n/a.
Abstract 3147: Cancer-specific mutations in adult soft tissue sarcomas.
Authors: Ogan D. Abaan, Princy Francis, Marbin Pineda, Robert L. Walker, Yuelin J. Zhu, Sven Bilke, Sean R. Davis, Paul S. Meltzer
Journal: Cancer Research (2013)

Abstract Understanding of how cancer initiates and progresses is a fundamental goal of cancer research. Identification of cancer mutations is of profound importance for both understanding of the disease and for developing novel therapies. Soft-tissue sarcomas include multiple uncommon histotypes with features of diverse connective tissue lineages. Although some of their underlying genetic changes have been elucidated, for example in those types which contain etiologic chromosome translocations, in general, the genetic basis of these tumors is incompletely described. To investigate mutations in 8 subtypes of adult soft tissue sarcomas, we resequenced coding exons from about 1300 cancer relevant genes in 66 tumor samples. Data was analyzed for somatic variants in samples with matched normals while samples without normal were analyzed individually. The most frequent events were TP53 mutations (26%) followed by RB1 (9%) and APC (8%) mutations. Even though, well-defined oncogene activating mutations were present, they were very rare. Given the prevalence of tumor suppressor mutations in these samples we are currently integrating CGH results to look for chromosomal deletions to support loss of tumor suppressor genes. In addition, we are investigating low-frequency mutations in lesser-known genes that may be of potential interest. Our preliminary results suggest that these subtypes of soft-tissue sarcomas depend on tumor-suppressor loss predominantly, and may have gained multiple complex sets of mutations in a number of other pathways. In conclusion, our work will be important in cataloging novel cancer mutations in rare types of adult sarcomas, with potential implications for understanding their biology and the development of new therapies. Citation Format: Ogan D. Abaan, Princy Francis, Marbin Pineda, Robert L. Walker, Yuelin J. Zhu, Sven Bilke, Sean R. Davis, Paul S. Meltzer. Cancer-specific mutations in adult soft tissue sarcomas. [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 3147. doi:10.1158/1538-7445.AM2013-3147
AB0511 Does the Advanced AGE Influence on the Type of Renal Injury and the Prognosis of Lupus Nephritis?
Authors: E. Armengol, J. Narvaez, H. Borrell, S. Heredia, M. Ricse, E. Benavent, A. Roset, C. Gomez Vaquero, J. Torras, F. Mitjavila, J.M. Nolla
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To analyze if the advanced age influence on the type of renal injury and the prognosis of lupus nephritis (LN). <h3>Methods</h3> We evaluated 243 patients with systemic lupus erythematosus (SLE) followed in our department from 1980 until 2013 that were registered in a specific data basis (register AQUILES). Patients with biopsy-proven LN and 2 years of time tracking (n=79) were selected as the study population. We realize a comparative study between patients older (n=30) and younger (n=49) than 50 years old. In the evaluation of the response, we considered "responders" those patients who were in remission (partial or complete) after complete the induction treatment and "non responders" those who did not showed improvement in the analytics, as well as in those who we proved transformation of histologyc class and those who died by nephritis-related reasons. To compare between groups with continuous variables we had used the <i>Student9s t</i> test and <i>Mann</i>–<i>Whitney U</i> test (on non-normal distributions). To compare categorical variables we used c<i>hi</i>-square test and <i>Fisher9s</i> exact <i>test</i> when sample sizes were small than 5. The significance level was established for p value under 0.05. <h3>Results</h3> The cohort included 79 patients (64 females) with a mean age at LN diagnosis of 45±14 (rank, 17-80) years and mean LN disease duration of 15.9 months (rank, 0 - 456). 81% (64/79) of patients presented renal disease at LN diagnosis or during the first year of tracing. The mean SLEDAI score was 15±7.6. The comparative study results between age groups are showed at table 1. We did not note significant differences between groups in evolution course neither in the prognosis of SLE. About the treatment, we did not detect significant differences in the percentage of patients who get hydroxychloroquine, glucocorticoids or immunosuppressant drugs, but we found differences in a higher use of statins (p=0.038) and ACE inhibitors (p=0.033) in the elderly group of patients. <h3>Conclusions</h3> The advanced age does not determine the type of renal injury and the prognosis of lupus nephritis. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5048