bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4753: Ovarian cancer stem cell marker ALDH1A2 is a candidate biomarker for patient selection for intraperitoneal chemotherapy
Authors: Seagle Brandon-Luke L. , Dandapani Monica , Luo Chen Hui , Hoppenot Claire , Samuelson Robert , Eng Kevin H. , Odunsi Kunle , Shahabi Shohreh 
Published: July 2016

Abstract
Objective. To evaluate ovarian cancer stem cells as predictors of survival we analyzed associations of cancer stem cell markers ALDH1, CD117 and CD133 with survival outcomes among patients with high grade serous ovarian cancer (HGS OvCa).
Methods. Data from HGS OvCa patients who were surgically staged prior to treatment with IP (n = 90) or IV-only (n = 398) chemotherapy was obtained from The Cancer Genome Atlas. Multivariate Cox proportional-hazards regression tested associations of tumor mRNA expression of 5 cancer stem cell markers with progression free survival (PFS) and overall survival (OS). Expression was analyzed as a continuous variable by restricted mean survival (RMS) analysis. Mean PFS or OS were compared between IP and IV groups by permutation testing stratified by expression. P-values were two-tailed.
Results. Increased tumor ALDH1A2 expression was associated with decreased OS among patients treated with IP chemotherapy, HR 2.36 (1.16-4.80), p = 0.017. IP treated patients with upper 20th percentile ALDH1A2 expression had decreased OS compared to bottom 20th percentile expression (30.4 versus 51.1 months, -20.7 months difference, p = 0.017). RMS curves for PFS and OS of IP versus IV treated patients crossed at high ALDH1A2 expression, indicating that IP treated patients had decreased survival compared to IV-only treated patients. Patients with upper 20th percentile ALDH1A2 expression treated with IP versus IV-only chemotherapy had no difference in mean PFS (21.3 versus 21.6 months, -0.3 months difference, p = 0.67) and decreased OS (30.4 versus 35.3 months, -4.9 months difference, p &lt; 0.0001). Upper 10th percentile ALDH1A2 expression was associated with decreased PFS (19.5 versus 22.0 months, -2.5 months, p = 0.005) and OS (27.1 versus 35.2 months, -8.1 months, p &lt; 0.0001) comparing IP versus IV groups. Increased CD133 expression was associated with increased PFS among IV-only patients, HR 0.85 (0.74-0.97), p = 0.016. CD117 and the ALDH1 genes ALDH1A1/3 were not associated with survival.
Conclusions. High primary tumor ALDH1A2 expression was independently associated with significantly decreased OS among patients treated with IP chemotherapy. High ALDH1A2 was associated with lack of benefit or decreased survival among patients treated with IP compared to IV-only adjuvant chemotherapy.
Citation Format: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi. Ovarian cancer stem cell marker ALDH1A2 is a candidate biomarker for patient selection for intraperitoneal chemotherapy. [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 4753.
Abstract 4754: Overexpression of TSH and ERBB2 (HER2) receptors is associated with sharply decreased survival in high grade serous ovarian cancer
Authors: Seagle Brandon-Luke L. , Dandapani Monica , Luo Chen Hui , Hoppenot Claire , Samuelson Robert , Eng Kevin H. , Odunsi Kunle , Shahabi Shohreh 
Published: July 2016

Abstract
Objective. To test if hormone or growth factor receptor expression is associated with survival among patients with high grade serous ovarian cancer (HGS OvCa) we analyzed tumor mRNA expression microarray and clinical data from The Cancer Genome Atlas (TCGA).
Methods. HGS OvCa patients were surgically staged prior to treatment with IP (n = 90) or IV-only (n = 398) chemotherapy. Multivariate Cox proportional-hazards regression tested associations of expression of 9 hormone or growth factor receptors with progression free survival (PFS) and overall survival (OS). Hazard ratios are hazard per each one standard deviation increase in gene expression. Expression was analyzed as a continuous variable by restricted mean survival analysis. Mean PFS or OS were compared between IP and IV groups by permutation testing stratified by expression. P-values were two-tailed.
Results. Expression of ESR1, PGR, FSHR, LHCGR, MET, and EGFR were not associated with PFS or OS. TSHR expression was associated with decreased OS (HR 1.22 (1.06-1.41), p = 0.005) and PFS (HR 1.18 (1.05-1.33), p = 0.006) among IV-only treated patients. ERBB2 expression was associated with decreased OS (HR 1.48 (1.05-2.10), p = 0.027) among patients who received IP chemotherapy. Using multigene (ESR2, PGR, TSHR, and ERBB2) analysis, among the IP group, ERBB2 (HR 1.76 (1.11-2.79), p = 0.015) and ESR2 (HR 0.28 (0.08-0.93), p = 0.037) were associated with OS. Only TSHR expression was associated with decreased OS (HR 1.22 (1.06-1.41), p = 0.005) and decreased PFS (HR 1.18 (1.05-1.33), p = 0.007) on multigene analysis of IV-only treated patients. OS and PFS decreased steeply at high expression of TSHR and ERBB2. Among patients with upper 10th percentile TSHR expression, no significant difference in mean OS or PFS was observed between patients treated with IP versus IV-only chemotherapy. Patients with lower TSHR expression (&lt; 90% percentile) experienced a mean 13.7-month increased OS and 16.4-month increased PFS associated with IP chemotherapy (p &lt; 0.0001).
Conclusions. Among HGS OvCa patients treated with IV-only chemotherapy, increased tumor TSHR expression was associated with decreased OS and PFS. High TSHR expression characterized patients who did not benefit from IP chemotherapy.
Citation Format: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi. Overexpression of TSH and ERBB2 (HER2) receptors is associated with sharply decreased survival in high grade serous ovarian cancer. [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 4754.
Abstract 476: Differential prognostic value of MYC immunohistochemistry in papillary RCC subtypes
Authors: Bellut Julia , Bertz Simone , Nolte Elke , Stoehr Christine , Polifka Iris , Herrmann Edwin , Jung Rudolf , Hartmann Arndt , Wullich Bernd , Taubert Helge , Wach Sven 
Published: July 2016

Abstract
Introduction
The histomorphological classification of type 1 and type 2 papillary renal cell carcinomas (pRCCs) has substantially improved the prognostication of patients’ long-term outcome. We previously established microRNA (miRNA) expression profiles of type1 and type 2 pRCCs and, based upon the results, hypothesize a differential expression of the MYC proto-oncogene in pRCCs.
Material and methods
An multi-institutional tissue microarray with more than 200 histomorphological classified pRCCs was acquired from the PANZAR consortium. Immunohistochemistry for MYC, the MYC-induced nuclear antigen MINA53 and Ki67 was performed. The prognostic value for patients’ long-term survival was examined using uni- and multivariate survival models.
Results
As expected, a pRCC type 2 morphology was associated with reduced overall and cancer-specific survival. Interestingly, pRCCs with a mixed type 1/2 morphology showed an even worse clinical outcome. When combining the pRCC morphology and immunohistochemical staining, only the combination of morphology and MYC staining patterns was able to further sub-stratify the group of pRCC type 1 tumors in a good and worse prognosis group. None of the patients with pRCC1 tumors and the favorable MYC staining pattern (&gt;44% of all pRCC type 1 tumors) suffered a tumor-related death. Patients with pRCC type 1 tumors and the adverse MYC staining pattern had an 4.5-fold elevated risk of death (multivariate corrected for pathological tumor stage).
Conclusions
Although a pRCC type 1 histomorphology is regarded as a favorable prognostic factor, associated with good clinical outcome, still patients die of tumor-related causes. We conclude, that in particular for patients with pRCC type 1 tumors, MYC immunohistochemistry is able to provide additional prognostic information for a sub-stratification of this patient population. This knowledge could be used for the establishment of risk-stratified follow-up schemes for patients after surgical treatment.
Citation Format: Julia Bellut, Simone Bertz, Elke Nolte, Christine Stoehr, Iris Polifka, Edwin Herrmann, Rudolf Jung, Arndt Hartmann, Bernd Wullich, Helge Taubert, Sven Wach. Differential prognostic value of MYC immunohistochemistry in papillary RCC subtypes. [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 476.
Abstract 4761: Translational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer
Authors: Gong Chun , Mok Ka Chun , CHEUNG Yuen-Nei , Man Pui-Sum , Lam EWF , Khoo Ui-Soon 
Published: July 2016

Abstract
Breast cancer is one of the prevalent causes of cancer in women and its occurrence has been rising in the last few decades. Two thirds of breast cancer patients are ER-positive and can receive tamoxifen (TAM) treatment. Unfortunately, many of the patients eventually develop resistance to tamoxifen. Identifying a molecular marker associated with tamoxifen resistance would help in designing better therapeutic strategies to overcome this. In eukaryotes, translation initiation is the most regulated step. Abnormal translation machinery underlies a variety of human diseases including cancers. Eukaryotic translation initiation factor 4E (eIF4E) is the least abundant initiation factor and is believed to be the rate limiting step for translation initiation. Overexpression of eIF4E in cells selectively promotes translation of mRNAs involved in cell proliferation, apoptosis and tumor progression. Recently, eIF4E overexpression has been implicated in drug resistance in melanoma1. We hypothesized that eIF4E may also be involved in tamoxifen resistance. The aim of this study was to characterize the role of eIF4E in tamoxifen resistance and identify novel molecular targets that may be translationally regulated.
Immunohistochemistry (IHC) staining of eIF4E showed up-regulation in human breast cancer samples compared with non-tumor counterparts. In silico analysis predicted that ERá and FOXM1 have a long and highly structured 5’-UTR, which are sensitive to the expression level of eIF4E. Polysomal fractionation confirmed that ERá and FOXM1 mRNA were more actively translated in MCF7 than in MCF10A. The correlation between eIF4E and ERá/FOXM1 were further confirmed in tissue microarray (TMA). The role of eIF4E in conferring TAM resistance was studied by MTT assays. Overexpression of eIF4E induced TAM resistance while knockdown eIF4E sensitized cells to TAM. Additionally, overexpression of eIF4E upregulated ERá/FOXM1 expression at protein level while knockdown eIF4E downregulated their expression at protein level.
Our results show that eIF4E induced TAM resistance possibly through translational regulation of ERá/FOXM1. eIF4E is a promising biomarker for anti-estrogen drug responsiveness and a future therapeutic target for treating drug resistant breast cancer patients.
Reference:
1. Zhan Y, et al. The role of eIF4E in response and acquired resistance to vemurafenib in melanoma J Invest Dermatol. 2015 May;135(5):1368-76.
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Citation Format: Chun Gong, Ka Chun Mok, Yuen-Nei CHEUNG, Pui-Sum Man, EWF Lam, Ui-Soon Khoo. Translational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer. [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 4761.
Abstract 4763: Targeted therapy by MET inhibitors against small-cell lung cancer with aberrant activation of HGF/MET pathway
Authors: Taniguchi Hirokazu , Takeuchi Shinji , Fukuda Koji , Yamada Tadaaki , Sakamoto Shuichi , Kawada Manabu , Yano Seiji 
Published: July 2016

Abstract
Small-cell lung cancer (SCLC) is one of the most aggressive malignancy, characterized by rapid growth and metastatic spread to multiple organs. Approximately 70% of SCLC patients have distant metastases at the diagnosis. Recent studies reported some genomic aberrations in SCLC and several molecular target drugs have been evaluated in clinical trials. However, no molecular target agents have been approved yet for SCLC.
Hepatocyte growth factor (HGF), also known as scatter factor, is only one ligand for MET receptor. HGF/MET pathway plays the crucial role in the growth of various types of cancers. The purpose of this study is to examine the role of HGF/MET pathway activation in SCLC and to evaluate therapeutic potential of MET inhibitors, including crizotinib and golvatinib, against metastasized SCLC.
We used eight human SCLC cell lines. Expression of HGF and MET was evaluated by ELISA and western blot, respectively. Cell viability was examined by MTT assay. Four cell lines produced discernible levels of HGF and four cell lines expressed phosphorylated MET, respectively. MET inhibitors, crizotinib and golvatinib, remarkably inhibited the viability of three cell lines, SBC-5, DMS273 and DMS273B1. Knockdown of either MET or HGF by specific siRNA suppressed the growth of these cell lines, indicating that HGF/MET pathway activation is essential for survival of these SCLC cell lines. These observations suggest that MET-TKIs may be useful for a subset of SCLC with aberrant HGF/MET pathway activation.
We recently established in vivo imaging model of multiple organ metastasis (including liver and bone metastases) with SBC-5 cells. We are now evaluating the anti-metastatic effect of MET-TKIs, crizotinib and golvatinib, in the in vivo imaging model. At the annual meeting, we will present the results of MET-TKI treatment and discuss their potential against multiple-organ metastasis produced by SCLC with aberrant HGF/MET pathway activation.
Citation Format: Hirokazu Taniguchi, Shinji Takeuchi, Koji Fukuda, Tadaaki Yamada, Shuichi Sakamoto, Manabu Kawada, Seiji Yano. Targeted therapy by MET inhibitors against small-cell lung cancer with aberrant activation of HGF/MET pathway. [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 4763.
Abstract 4769: Inhibition of ribosomal protein L9 expression suppresses colorectal carcinoma cell growth in vitro and in vivo
Authors: Baik In Hye , Park Keon Uk , Hwang Ilseon , Ryoo Hun-Mo , Lee Yun-Han 
Published: July 2016

Abstract
Background: Ribosomal protein L9 (RPL9), a component of the 60S subunit, is upregulated in human colorectal cancer (CRC). We thus hypothesized if targeting of RPL9 with small interfering (si) RNA could inhibit CRC progression. We also investigated molecular mechanism to mediate CRC cell death caused by RPL9 silencing. Methods: HCT116 and HT29 human CRC cells were transfected with RPL9 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to RPL9 knockdown, global changes in gene expression were examined using RNA sequencing. Results: RPL9 silencing caused inhibition of CRC cell growth through induction of apoptotic cell death. RNA sequencing revealed that RPL9-specific knockdown led to dysregulation of 622 genes in HCT116 and 2882 genes in HT29 cells. Among those, 256 genes showed the same directional regulation (128 up- and 168 down-regulated genes), including up-regulation of tumor suppressors such as KLF6 and ATF3, and were considered as a common RPL9 knockdown signature. Western blotting proved that downregulation of RPL9 was accompanied with the decrease in the levels of PARP-1 and pro-caspase 3 delaying cell cycle progression and accelerating apoptotic signaling. Of importance, targeting RPL9 significantly inhibited CRC growth in a murine xenograft model. Conclusion: These results suggest that inhibition of RPL9 expression could be an attractive option for molecular targeted therapy of colorectal cancer.
Citation Format: In Hye Baik, Keon Uk Park, Ilseon Hwang, Hun-Mo Ryoo, Yun-Han Lee. Inhibition of ribosomal protein L9 expression suppresses colorectal carcinoma cell growth in vitro and in vivo. [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 4769.
Abstract 4770: The regulation of pre-ribosomal RNA synthesis by LKB1
Authors: Jin Rui , Liu Faken , Liu Xiuju , Huang Henry , Wilkinson Scott C. , Zhong Diansheng , Khuri Fadlo R. , Fu Haian , Marcus Adam I. , He Yulong , Zhou Wei 
Published: July 2016

Abstract
LKB1 is commonly thought of as a tumor suppressor gene, because its hereditary mutation is responsible for a cancer syndrome, and somatic inactivation of LKB1 is found in non-small cell lung cancer, melanoma, and cervical cancers. Unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death, one of the functions of LKB1 is to suppress cell proliferation in order to promote cell survival under energetic stress conditions. We recently discovered that LKB1 promotes pre-ribosomal RNA synthesis under uridine down-regulated condition. The mechanistic basis of this finding is that LKB1 activates TIF-IA-mediated pre-riobosomal RNA synthesis, partly through the control of its cellular localization. Immuno-coprecipitation study revealed that the interaction between TIF-IA and nuclear transportation machinery may be regulated by LKB1. Our finding also has important clinical implication because the suppression of de novo UTP synthesis preferentially promotes apoptosis in LKB1-inactivated cells. This unique, pro-survival function of LKB1 led us to exploit the vulnerability of LKB1-null cells in their defect in sensing intracellular UTP depletion. Such targeted agents represent a novel treatment strategy because they only induce cell killing when LKB1 is absent.
Citation Format: Rui Jin, Faken Liu, Xiuju Liu, Henry Huang, Scott C. Wilkinson, Diansheng Zhong, Fadlo R. Khuri, Haian Fu, Adam I. Marcus, Yulong He, Wei Zhou. The regulation of pre-ribosomal RNA synthesis by LKB1. [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 4770.
Abstract 4774: Hypoxic bio-reduction of novel NBQ48 in treated tumor cells and the activity of cytochrome P450 reductase
Authors: Zayas Beatriz , Lebron Vivian , Rivera Juan P. , Velez Christian , Cox Osvaldo 
Published: July 2016

Abstract
The main goal of this research was to evaluate the reduction activity of a novel Nitrobenzazolo[3,2-a]quinolinium (NBQ48) compound under hypoxic environment thru the formation of a fluorescent metabolite and further to evaluate the activity of the cytochrome P450 (CYP450) reducatase in the reduction of these compounds. To evaluate the reduction of NBQ48 and the formation of its fluorescent metabolite two (2) tumor cell lines in culture Toledo (lymphoma) and A431 (endothelial) where treated under nitrogen or argon saturated environments to create a hypoxic (low oxygen) environment. In a 15 ml conical tube 4×106 cells in RPMI 1640 media were treated with NBQ 48 (3mM) for a final volume of 5mL and incubated with argon or nitrogen saturated environment at 37ºC, 5%. Cells were exposed at different time periods (0 to 48 hours) to evaluate the effect of exposure time in the reduction of the NBQ48 by detecting the reduced fluorescent product, the amino-substituted ABQ48. In addition NBQ48 treated tumor cells were located inside a hypoxic chamber to evaluate the formation of the fluorescent metabolites indicative of a metabolically active cell. To determine if the CYP450 reductase enzyme is activated in the reduction of the NBQ towards the formation of the ABQ metabolite, an experiment containing the NBQs and the CYP reductases was designed. Four (4) samples were prepared: blank media hypoxic, NBQ experimental hypoxic, positive ABQ spiked and negative aerobic control NBQ. Samples with NBQ48 (0.4mM) were incubated for 24 hours. After the incubation period, fluorescence emissions indicating the reductive fluorescent product were measured using a Modulus fluorometer (blue filter). The results on tumor cells treated with NBQ48 under hypoxic conditions demonstrated reduction and the formation of a fluorescent product, amino-substituted ABQ48. The time dependent increase in fluorescence in comparison with non treated cells indicated that the reduction of the NBQ increased with time. Results on the determination of the activity of CYP450 in the reduction of the NBQ48 indicated that only samples containing the CYP450 showed the formation of a fluorescent species presumably, ABQ48. This study provides evidence of the reduction of NBQ48 and the formation of a fluorescent metabolite thru the activations of the CYP450 reductases. The implemented experimental design could also be used to determine activity of hypoxic tissues with clinical applications.
Citation Format: Beatriz Zayas, Vivian Lebron, Juan P. Rivera, Christian Velez, Osvaldo Cox. Hypoxic bio-reduction of novel NBQ48 in treated tumor cells and the activity of cytochrome P450 reductase. [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 4774.