tbuckley/cabot-search huggingface dataset:
Abstract 1712: Intestinal stem cell integrity is preserved through modulation of endoplasmic reticulum stress by guanylyl cyclase C
Authors: Crystal Kraft, Jieru Lin, Adam Snook, Gilbert Kim, Scott Waldman
Journal: Cancer Research (2016)

Abstract Intestinal stem cells (ISCs) are a long-lived, dynamic cell population at the base of intestinal crypts that adjust their molecular phenotypes as necessary to meet the maintenance and regenerative needs of the epithelium. The long-life, plasticity and proliferative potential of ISCs underlie the necessity for tight regulation, as these cells have been implicated as initiators of colorectal tumorigenesis. In that context, guanylyl cyclase C (GCC) and its effector, cGMP, regulate intestinal epithelial proliferation, differentiation, and susceptibility to intestinal insult and tumor formation. However, the specific role of this signaling axis in ISCs remains undefined. Here, utilizing transgenic mouse models and immunodetection techniques, we reveal that GCC mediates ligand-dependent cGMP signal transduction in ISCs. Further, the absence of GCC alters expression of key ISC markers, decreasing the active ISC marker Lgr5 and increasing the reserve ISC marker Bmi1. Endoplasmic reticulum (ER) stress, which is typically absent from ISCs and has been associated with inflammation and tumorigenesis, is elevated throughout the crypt base in the absence of GCC. Conversely, administration of cGMP or the chemical chaperone taurourdeoxycholic acid eliminates ER stress and restores the normal crypt ISC phenotype. Finally, ISCs exhibit an impaired regeneration response following irradiation in the absence of GCC, highlighting the importance of this signaling pathway in ISC survival and epithelial repair. Together, these observations suggest that GCC signaling modulates ER stress as part of the essential machinery defending the integrity of the ISC niche. Citation Format: Crystal Kraft, Jieru Lin, Adam Snook, Gilbert Kim, Scott Waldman. Intestinal stem cell integrity is preserved through modulation of endoplasmic reticulum stress by guanylyl cyclase C. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1712.
Abstract 4288: Association between tumor necrosis factor alpha -308 G/A polymorphism and risk of bladder cancer in Asian population: a meta-analysis
Authors: Wei-Tang Kao, Min-Che Tung, Kuan-Chun Hsueh, Yuan-Hung Wang, Chia-Chang Wu
Journal: Cancer Research (2016)

Abstract Previous studies have investigated the association between TNF-α-308 G/A polymorphism and bladder cancer risk in various populations. However, these findings remain inconclusive. Therefore, we performed a meta-analysis to explore the relationship between TNF-α-308 G/A polymorphism and bladder cancer risk. A literature search in PubMed was performed to select eligible studies regarding the association between TNF-α-308 G/A polymorphism and bladder cancer risk. The strength of risk under fixed- and random- effects models were estimated using the odds ratios (ORs) with 95% confidence intervals (CIs). We identified 7 case-control studies including 1153 cases and 1587 controls were included in the present meta-analysis. Compared with subjects carrying the G/G genotype of TNF-α-308 G/A polymorphism, those with the A/A and G/A genotypes had non-significant bladder cancer risks under the fixed effects model (OR = 1.037) and the random effects model (OR = 1.012). In the recessive model, subjects with the A/A genotype had an increased bladder cancer risk (OR = 1.875) compared with those carrying the G/A and G/G genotypes of TNF-α-308 G/A polymorphism. The major finding of this meta-analysis suggest that TNF-α-308 G/A polymorphism is correlated with the risk of bladder cancer in Asian population under the recessive model. We should further investigate the joint effects of environmental risk factors and TNF-α-308 G/A polymorphism on bladder cancer risk. Citation Format: Wei-Tang Kao, Min-Che Tung, Kuan-Chun Hsueh, Yuan-Hung Wang, Chia-Chang Wu. Association between tumor necrosis factor alpha -308 G/A polymorphism and risk of bladder cancer in Asian population: a meta-analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4288.
Obinutuzumab (GA101) in Combination with CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) or Bendamustine for the First-Line Treatment of Follicular Non-Hodgkin Lymphoma: Final Results from the Maintenance Phase of the Phase Ib GAUDI Study
Authors: Martin JS Dyer, Andrew P Grigg, Marcos González Díaz, Martin Dreyling, Simon Rule, Guiyuan Lei, Elisabeth Wassner-Fritsch, Günter Fingerle-Rowson, Paula V Marlton
Journal: Blood (2014)
Abstract 1159: Downregulation of TMPRSS11B in squamous cell carcinoma
Authors: Suburu Amano, Takeshi Iwaya, Satoshi Nishizuka, Kohei Kume, Chie Ito, Yuji Akiyama, Yoshihiro Shioi, Fumitaka Endo, Akira Sasaki
Journal: Cancer Research (2016)

Abstract [Background] Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers. The molecular mechanism of ESCC development has not been fully elucidated. [Aim] The aim of this study is to identify responsible genes for ESCC development. [Materials and Methods] Firstly, we performed transcriptome sequence (RNA-seq) analysis of surgically resected tumor and corresponding normal tissues form 3 ESCC patients with different tumor locus, histrogical differentiation, and TNM stage.by RNA-seq analysis: (Case 1) upper thoracic esophagus, well differentiated SCC, TNM, Stage I; (Case 2) middle thoracic esophagus, poorly differentiated SCC, T3N0M0, Stage II; and (Case 3) lower thoracic esophagus, moderately differentiated SCC, T3N1M0, Stage III. Next, we validated the expression status of the candidate gene in 64 clinical samples and 10 ESCC cell lines (KYSE150, KYSE270, KYSE410, KYSE450, KYSE510, TE1, TE6, TE8, TE9, and TE10) using quantitative real-time PCR (qRT-PCR). [Results] In RNA-seq analysis, 34 genes showed more than 30-fold decrease in tumor samples compared to normal tissues, and the most downregulated gene was transmembrane protease serine 11B (TMPRSS11B). Amon these 34 genes, other 5 genes of TMPRSS11 family (TMPRSS11A, TMPRSS11BNL, TMPRSS11D, TMPRSS11E, and TMPRSS11F) were included. qRT-PCR analysis revealed that TMPRSS11B expression in ESCC samples were lower than those in normal samples (p &amp;lt; 0.001). Downregulation of TMPRSS11B in tumor samples compared to corresponding normal samples were observed in 51 cases out of 64 (79.7%). Patients with expression levels of TMPRSS11B that were below the median value were assigned to the low expression group (n = 32), whereas those with expression values above the median were assigned to the high expression group (n = 32). Significant difference was not observed between two groups regarding clinicopathological data, including age, gender, TNM stage, and lymphatic/venous invasion. TMPRSS11B expression was not detected in all of ESCC cell lines and noncancerous esophageal epithelial cell line, HET1A. [Conclusion] Our results suggest that downreguration of TMPRSS11B expression occurs in early stage of the ESCC oncogenesis and that TMPRSS11B has tumor suppressive roles in ESCC development. Citation Format: Suburu Amano, Takeshi Iwaya, Satoshi Nishizuka, Kohei Kume, Chie Ito, Yuji Akiyama, Yoshihiro Shioi, Fumitaka Endo, Akira Sasaki. Downregulation of TMPRSS11B in squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1159.
Retrospective phase II study of efficacy and safety of <sup>177</sup>Lu-DOTATOC peptide receptor radiotherapy in patients with advanced neuroendocrine tumours.
Authors: Richard P. Baum, Andreas Kluge, Harshad Kulkarni, Manal Sayeg, Ulrike Schorr-Neufing, Karin Niepsch, Norman Bitterlich, Cees J.A. van Echteld
Journal: Journal of Clinical Oncology (2016)

436 Background: Emerging evidence, that 177 Lu-DOTATOC has a particularly favorable therapeutic index compared to other PRRT agents, prompted us to further evaluate efficacy and safety of 177 Lu-DOTATOC. Methods: 56 patients with metastasized and progressive neuroendocrine tumors (NET) (50% gastroenteral, 26.8% pancreatic, 23.2% other primaries) were consecutively treated with 177 Lu-DOTATOC and analyzed retrospectively. Patients received on average 2.1 (range 1 – 4) cycles of 177 Lu-DOTATOC as 7.0 GBq (median) doses at 3-monthly intervals. Efficacy was analyzed based on RECIST and stratified for number of treatment cycles and primary tumor origin. Results: Median progression-free (PFS) and overall survival in the total population (A) were 17.4 and 34.2 months, respectively. Patients treated with &gt; 1 cycle had a PFS of 32.0 months for all NET (B), 34.5 months for gastroenteropancreatic NET (GEP-NET) (C), and 11.9 months for other NET (D). Objective response (OR) rates [complete (CR) or partial (PR)], were 34%, 41%, 54%, and 0% for A, B, C, and D, while disease control [CR, PR and stable disease, SD] rates (DCR) were 66%, 94%, 100%, and 75%, resp. CR was found in 16%, 19% and 25% of A, B and C, resp. In 68% of responders initial response occurred within 4 months from the 1 st cycle, whereas in 32% this took 4-8 months. In 47% of all OR it took &gt; 8 months to achieve OR. No renal toxicity was found, although 20% of patients had mild renal insufficiency at baseline. No SAE and only a single case of self-limiting grade 3 myelotoxicity was observed. Conclusions: 177 Lu-DOTATOC shows unparalleled potential to induce OR and long lasting DC in progressive NET, even when administered at moderate activity doses. In GEP-NET patients CR was 25%, which is the highest value ever reported. Efficacy was highest when the agent was administered in repetitive cycles. Overall DCR was 94%, compared to 80-85% reported for 177 Lu-DOTATATE. This difference in DCR is mainly accounted for by an approx. 10-fold higher rate of CR with 177 Lu-DOTATOC. This high efficacy together with the observed safety profile suggests a very high therapeutic index, reflecting a uniquely low systemic uptake of 177 Lu-DOTATOC.
Abstract 3733: Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation
Authors: Ming-Hsi Wu, Lie-Chwen Lin, Te-Chang Lee
Journal: Cancer Research (2016)

Abstract Lung cancer is the most common cancer worldwide. Platinum-based combination chemotherapy is one of first line treatments for patients with lung cancer. Most of the cytotoxic drugs are targeting DNA, interfere with DNA synthesis, and triggering DNA damage response (DDR). Since DDR usually activates important defensive pathways to repair damaged DNA, DDR is known as a key factor determining the outcome of chemotherapy. Among them, RAD51, playing a central role in homologous recombination (HR) DNA repair, has been shown to interfere with the prognosis of patients treated with chemoradiotherapy. Since we have demonstrated that inhibition of RAD51 nuclear focus formation synergistically enhances the anticancer activity of cisplatin, we further screened purified natural products in order to find products with activity to inhibit RAD51 nuclear focus formation. In the present study, we found that a green tea catechin derivative, the (-)-Gallocatechin gallate (GCG) has potent inhibitory activity against RAD51 nuclear focus formation in cisplatin-treated H460 cells. The in vitro cytotoxicity assay showed that the combination of cisplatin or irinotecan with GCG significantly increases the sensitivity of H460 cells to these DNA damage agents. We also evaluated the anti-tumor growth activity of cisplatin or irinotecan in combination with GCG using H460 xenografts. Our results showed that cisplatin and irinotecan suppresses tumor growth by 17.6% and 33.8%, while in combination with GCG suppresses tumor growth by 52.2% and 68.9%, respectively. We further demonstrated that GCG is able to inhibit cisplatin-induced ATM and Chk2 phosphorylation. Together, our results suggest that GCG may interfere with ATM-Chk2 pathway and hence suppress RAD51 nuclear focus formation and DNA repair activities. Citation Format: Ming-Hsi Wu, Lie-Chwen Lin, Te-Chang Lee. Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3733.
Abstract 1990: Unique <i>in vitro</i> transcriptional activities of oncogenic Myb fusions identified in salivary gland adenoid cystic carcinoma
Authors: Candace A. Frerich, Scott A. Ness
Journal: Cancer Research (2016)

Abstract Chromosomal translocations involving the MYB and NFIB (t(6;9)) genes are the sole recurrent cytogenetic aberration in Adenoid Cystic Carcinoma (ACC), a rare cancer that frequently manifests as salivary gland tumors. Since ACC has poor prognosis and treatment is accompanied by high morbidity, there is a need for additional investigation of this cancer with the goal of improving patient outcomes. Recurrent translocations create fusions involving the N-terminus of MYB, located on chromosome 6, and the C-terminus of NFIB, located on chromosome 9. Our lab also recently identified translocations involving the related MYBL1 gene fusing it to NFIB t(8;9) and RAD51B t(8;14) genes. Further, recent work in our lab demonstrated tumors with MYB or MYBL1 translocations have similar gene expression (1). The presence of recurrent translocations involving both the MYB proto-oncogene and the related MYBL1 gene suggests that the resulting novel fusion proteins are likely oncogenic drivers in these tumors. In order to directly address the transcriptional activities of the resulting fusion proteins MYB and MYBL1 fusion genes, identified in primary ACC tumors, were cloned and expressed in vitro. The fusion proteins transcriptional activities were examined using reporter gene assays and trancriptomics. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) was performed to interrogate promoters bound by these proteins. Reporter genes specific for normal vs. oncogenic MYB variants have been constructed. These data demonstrate that the proteins predicted to be produced by MYB fusion genes after chromosomal translocation are transcriptionally active. Further, Myb fusion proteins bind and activate gene sets distinct from their wild type c-Myb and A-Myb counterparts. These data indicate Myb fusion proteins have unique transcriptional activities, perhaps underlying their ability to drive tumorigensis in ACC. 1. Brayer et al. Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma. Cancer Discovery. In press. Citation Format: Candace A. Frerich, Scott A. Ness. Unique in vitro transcriptional activities of oncogenic Myb fusions identified in salivary gland adenoid cystic carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1990.
Abstract 1733: Inhibition of embryonic stem cells gene expression in pancreatic cancer: Effects of metformin and indole-3-carbinol
Authors: Beverly D. Lyn-Cook, Stancy Joseph, Beverly Word, George Hammons
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is among the top five deadliest cancers in developing countries and is rapidly increasing in minority populations, particularly African Americans. Understanding molecular mechanisms involved in the etiology and progression of this cancer can greatly improve patient prognosis. Cancer stem cells have been identified in pancreatic tumors and have been shown to contribute to its progression and resistance to standard treatments. Pancreatic cancer stem cells are subject to regulation by key embryonic stem cell transcription factors that are known to be aberrantly expressed in pancreatic cancer, such as SOX2, OCT4 and NANOG. Overexpression of OCT4, SOX2 and NANOG together or separately led to tumor transformation and tumor metastasis. These stem cell factors are known to promote self-renewal by interacting with other transcription factors. Using a human embryonic stem cell RT2 Profiler gene array, numerous stem cell genes were expressed in pancreatic cancer cell lines (MIAPaca2, Panc1). Both cell lines expressed high levels of SOX2, NANOG, CD44, GATA2, POU5F1 (OCT4) and other genes. Panc1 expressed high levels of SOX 17, while MIAPaCa2 expressed high levels of SOX 3,15 and 17. Treatment of cells with indole-3-carbinol alone at 100 and 200μM inhibited or decreased the expression of SOX2, NANOG, CD44, SOX15 and STAT3. However, treatment with metformin alone increased expression of SOX 15 and STAT3 in Panc1 cells but not in MIAPaCa2. Combination of metformin and indole-3-carbinol inhibited the expression of SOX2, NANOG, STAT3, and CD44. SOX2, POU5F1(OCT4) and NANOG are thought to be important players in various human cancers. OCT4 has been found to be expressed in 69% of PDAC and expression was shown too correlated to status and clinical state. High levels of OCT4 and NANOG has been found to correlate to worse prognosis and furthermore, contribute to multidrug-resistance and metastasis. This study have shown that the dietary agent, indole-3-carbinol alone and in combination with metformin down-regulate critical stem cell genes involved in maintenance of pluripotency and self-renewal of cancer stem cells. Citation Format: Beverly D. Lyn-Cook, Stancy Joseph, Beverly Word, George Hammons. Inhibition of embryonic stem cells gene expression in pancreatic cancer: Effects of metformin and indole-3-carbinol. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1733.
Allogeneic HCT in Patients with 17p-CLL: Results of a Non-Interventional Study of the EBMT &amp; Eric
Authors: Johannes Schetelig, Jennifer Hoek, Stephan Stilgenbauer, Martin Bornhäuser, Niels S. Andersen, Christopher P Fox, Stig Lenhoff, Donald W. Bunjes, Liisa Volin, Avichai Shimoni, Wilfried A Schroyens, Michel van Gelder, Anja van Biezen, Liesbeth de Wreede, Theo M de Witte, Nicolaus Kröger, Peter Dreger
Journal: Blood (2014)
Abstract LB-338: Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing
Authors: Edward J.P. Fox, Michael W. Schmitt, Kate S. Reid-Bayliss, Robert A. Beckman, Lawrence A. Loeb
Journal: Cancer Research (2016)

Abstract The accumulation of somatic mutations is a defining hallmark of cancer. The genomes of solid tumors contain thousands of mutations that are present in most or all of the malignant cells in that tumor. In addition to these clonal mutations, subclonal mutations - those occurring only in a fraction of malignant cells - likely contribute to the phenotypic and morphologic heterogeneity of cancer cells within a tumor. These sub-populations may be the source for the rapid emergence of therapeutic resistance. The extent of subclonal mutations in cancer, however, has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 5% of cells. Here, we apply the highly accurate Duplex Sequencing methodology to quantify the extent of subclonal mutations in 15 colorectal cancers (CRC) and paired normal mucosa. We also quantify the clonal somatic mutation load by exome sequencing. By sequencing known CRC driver and non-driver genes (depth &amp;gt;5,000X and accuracy &amp;gt;10-7), we find that colorectal cancers without known DNA repair deficits harbor an extensive complement of subclonal mutations, suggesting that mutational diversity of CRCs has been greatly underestimated. We show that normal colonic mucosa also accumulates substantial numbers of subclonal mutations, predominantly CG&amp;gt;TA transitions at CpG dinucleotides, in an age-dependent manner. However, the burden of tumor-associated subclonal mutations does not correlate with age and has a distinct spectrum (relative increase in TA&amp;gt;CG transitions) indicating different mechanisms of mutation accumulation are operative in normal and tumor tissue. The frequency of tumor cells harboring unique subclonal mutations is so high that it is likely that every possible neutral somatic point mutation is present by the time a tumor is clinically detectable This could account for the high frequency by which tumors become resistant to chemotherapeutic agents. Citation Format: Edward J.P. Fox, Michael W. Schmitt, Kate S. Reid-Bayliss, Robert A. Beckman, Lawrence A. Loeb. Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-338.
Abstract 2871: Dual role of EpCAM cleavage in adhesion attenuation and transcription enhancement for cell migration
Authors: Ya-Ting Hsu, Pawel A. Osmulski, Yao Wang, Yi-Wen Huang, Lu Liu, Jianhua Ruan, Victor X. Jin, Nameer B. Kirma, Maria E. Gaczynska, Tim H.M. Huang
Journal: Cancer Research (2016)

Abstract Epithelial cell adhesion molecule (EpCAM), a membrane protein known to modulate cell-cell adhesion, is also a regulatory molecule internalized into the nucleus for transcriptional control of gene expression. Here we demonstrate that activated EGF/EGFR is a signaling factor to drive the cleavage of the extracellular fragment EpEX culminating in removal of cell-surface EpCAM as monitored with recognition atomic force microscopy (AFM). As a result, internalization of the cytoplasmic domain EpICD leads to formation of transcription factor complexes with LEF1 that regulate gene transcription for enhancing mobility functions of cancer cells. Comprehensive probing with AFM further reveals increased elasticity and decreased adhesiveness of these cells, implicating acquisition of an epithelial-mesenchymal transition phenotype. While EpCAM cleavage contributes to the loss of cell-surface adhesiveness, its internalized EpICD additionally regulates targets for promoting cell migration. Thus, this EGF/EGFR-modulated action on structural EpCAM and regulatory EpICD can enhance invasion potential of transformed cells. Citation Format: Ya-Ting Hsu, Pawel A. Osmulski, Yao Wang, Yi-Wen Huang, Lu Liu, Jianhua Ruan, Victor X. Jin, Nameer B. Kirma, Maria E. Gaczynska, Tim H.M. Huang. Dual role of EpCAM cleavage in adhesion attenuation and transcription enhancement for cell migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2871.