bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disparities in the receipt of robot-assisted radical prostatectomy: between-hospital and within-hospital analysis using 2009–2011 California inpatient data
Authors: Kim Jungyoon , ElRayes Wael , Wilson Fernando , Su Dejun , Oleynikov Dmitry , Morien Marsha , Chen Li-Wu 
Published: May 2015

ObjectivesDespite the rapid proliferation of robot-assisted radical prostatectomy (RARP), little attention has been paid to patient utilisation of this newest surgical innovation and barriers that may result in disparities in access to RARP. The goal of this study is to identify demographic and economic factors that decrease the likelihood of patients with prostate cancer (PC) receiving RARP.Design, setting and participantsA retrospective, pooled, cross-sectional study was conducted using 2009–2011 California State Inpatient Data and American Hospital Association data. Patients who were diagnosed with PC and underwent radical prostatectomy (RP) from 225 hospitals in California were identified, using ICD-9-CM diagnosis and procedure codes.Primary outcome measuresPatients’ likelihood of receiving RARP was associated with patient and hospital characteristics using the two models: (1) between-hospital and (2) within-hospital models. Multivariate binomial logistic regression was used for both models. The first model predicted patient access to RARP-performing hospitals versus non-RARP-performing hospitals, after adjusting for patient and hospital-level covariates (between-hospital variation). The second model examined the likelihood of patients receiving RARP within RARP-performing hospitals (within-hospital variation).ResultsAmong 20 411 patients who received RP, 13 750 (67.4%) received RARP, while 6661 (32.6%) received non-RARP. This study found significant differences in access to RARP-performing hospitals when race/ethnicity, income and insurance status were compared, after controlling for selected confounding factors (all p<0.001). For example, Hispanic, Medicare and Medicaid patients were more likely to be treated at non-RARP-performing hospitals versus RARP-performing hospitals. Within RARP-performing hospitals, Medicaid patients had 58% lower odds of receiving RARP versus non-RARP (adjusted OR 0.42, p<0.001). However, there were no significant differences by race/ethnicity or income within RARP-performing hospitals.ConclusionsSignificant differences exist by race/ethnicity and payer status in accessing RARP-performing hospitals. Furthermore, payer status continues to be an important predictor of receiving RARP within RARP-performing hospitals.
Diagnosed diabetes and premature death among middle-aged Japanese: results from a large-scale population-based cohort study in Japan (JPHC study)
Authors: Kato Masayuki , Noda Mitsuhiko , Mizoue Tetsuya , Goto Atsushi , Takahashi Yoshihiko , Matsushita Yumi , Nanri Akiko , Iso Hiroyasu , Inoue Manami , Sawada Norie , Tsugane Shoichiro 
Published: May 2015

ObjectiveTo examine the association between diabetes and premature death for Japanese general people.DesignProspective cohort study.SettingThe Japan Public Health Center-based prospective study (JPHC study), data collected between 1990 and 2010.PopulationA total of 46 017 men and 53 567 women, aged 40–69 years at the beginning of baseline survey.Main outcome measuresOverall and cause specific mortality. Cox proportional hazards models were used to calculate the HRs of all cause and cause specific mortality associated with diabetes.ResultsThe median follow-up period was 17.8 years. During the follow-up period, 8223 men and 4640 women have died. Diabetes was associated with increased risk of death (856 men and 345 women; HR 1.60, (95% CI 1.49 to 1.71) for men and 1.98 (95% CI 1.77 to 2.21) for women). As for the cause of death, diabetes was associated with increased risk of death by circulatory diseases (HR 1.76 (95% CI 1.53 to 2.02) for men and 2.49 (95% CI 2.06 to 3.01) for women) while its association with the risk of cancer death was moderate (HR 1.25 (95% CI 1.11 to 1.42) for men and 1.04 (95% CI 0.82 to 1.32) for women). Diabetes was also associated with increased risk of death for ‘non-cancer, non-circulatory system disease’ (HR 1.91 (95% CI 1.71 to 2.14) for men and 2.67 (95% CI 2.25 to 3.17) for women).ConclusionsDiabetes was associated with increased risk of death, especially the risk of death by circulatory diseases.
Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma
Authors: Gordon Ira K. , Lu Jie , Graves Christian A. , Huntoon Kristin , Frerich Jason M. , Hanson Ryan H. , Wang Xiaoping , Hong Christopher S. , Ho Winson , Feldman Michael J. , Ikejiri Barbara , Bisht Kheem , Chen Xiaoyuan S. , Tandle Anita , Yang Chunzhang , Arscott W. Tristram , Ye Donald , Heiss John D. , Lonser Russell R. , Camphausen Kevin , Zhuang Zhengping 
Published: May 2015

Abstract
Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiotherapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiotherapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of postradiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiotherapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared with radiotherapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA-damage response pathway activity. Mol Cancer Ther; 14(7); 1540–7. ©2015 AACR.
MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma
Authors: Kong Li Ren , Chua Kian Ngiap , Sim Wen Jing , Ng Hsien Chun , Bi Chonglei , Ho Jingshan , Nga Min En , Pang Yin Huei , Ong Weijie Richard , Soo Ross Andrew , Huynh Hung , Chng Wee Joo , Thiery Jean-Paul , Goh Boon Cher 
Published: May 2015

Abstract
Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK–ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS–MAPK–ERK pathway may augment patient responses to cisplatin treatment. Mol Cancer Ther; 14(7); 1750–60. ©2015 AACR.
Abstract 3425: Whole-transcriptome analyses of EBV-associated nasopharyngeal carcinoma using next-generation transcriptome sequencing
Authors: Mak Cathy Ka-Yan , Chung Grace Tin-Yan , Yip Kevin Yuk-Lap , Tso Ken Kai-Yuen , Lee Sau-Dan , Cheung Siu-Tim , Tsao Sai-Wah , Busson Pierre , To Ka-Fai , Lo Kwok-Wai 
Published: May 2015

Abstract
Nasopharyngeal carcinoma (NPC) is unique among epithelial cancers arising from the head and neck regions. This specific cancer type is consistently associated with EBV infection. Using RNA-seq, we have conducted a comprehensive assessment of EBV and cellular gene expression in six NPC cell line and patient-derived xenografts (PDXs). In these tumor lines, expression of EBV latent genes including EBNA1, LMP1, LMP2A and BamH1 A transcripts was quantitated. Among the viral genes, the BamH1 A transcripts were detected as the major transcripts with various splicing variants. Expression of these transcripts in NPC was further validated by qRT-PCR analysis. Active lytic gene expression and lytic viral replication was not observed in these tumor lines. Analysis of the RNA-seq data has identified multiple fusion transcripts. A total of 18 candidate fusions were validated in these tumor lines. A novel fusion transcript, UBR5-ZNF423 was detected in C666-1 cells and 8.3% of primary tumors. The transcript produces a chimeric fusion protein which might alter the function of EBF transcription factor. A significant growth inhibitory effect was observed in UBR5-ZNF423 knockdown C666-1 cells. Constitutive expression of UBR5-ZNF423 fusion in NIH3T3 cells induced in vivo tumor formation in nude mice model. The findings strongly suggest that the fusion gene play a causative role in NPC tumorigenesis. Using the expression profile of immortalized nasopharyngeal epithelial cells as control, our study also revealed the differential expression of cellular genes and specific alternative spliced transcripts in NPC. Significant upregulation of genes involved in cytokine-cytokine receptor interaction (e.g. CCL5, CCL20, CXCL10, CXCR4, IL2RG) was consistently detected in the tumor lines. Most of them were targets of the NF-kappaB signaling pathways, which are constitutively activated in EBV-associated NPC. In addition, the analyses also discovered several potential druggable targets (e.g. CD74) and oncogenic non-coding RNAs (e.g. AFAP1-AS1) in NPC, which may contribute to the development of new therapeutic strategies for this cancer. The whole-transcriptome analyses greatly enhance our understanding of the molecular basis of EBV-infected NPC.
Citation Format: Cathy Ka-Yan Mak, Grace Tin-Yan Chung, Kevin Yuk-Lap Yip, Ken Kai-Yuen Tso, Sau-Dan Lee, Siu-Tim Cheung, Sai-Wah Tsao, Pierre Busson, Ka-Fai To, Kwok-Wai Lo. Whole-transcriptome analyses of EBV-associated nasopharyngeal carcinoma using next-generation transcriptome sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3425. doi:10.1158/1538-7445.AM2014-3425
Abstract 3443: Wnt-beta-catenin-Rac1 signaling axis regulates metastasis-associated phenotypes in TNBC
Authors: Dey Nandini , Carlson Jennifer , De Pradip , Leyland-Jones Brian 
Published: May 2015

Abstract
Background: RAC1-GTPase controls many cellular phenotypes including integrin-directed migration via its control over the actin-cytoskeleton. We and others have established the upregulation of Wnt-beta-catenin pathway (WP) in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer (Dey et al., 2013, BMC Cancer; Dey et al., 2013, PLOS ONE). Here we report for the first time that metastasis-associated phenotypes in TNBC are controlled by Wnt-beta-catenin-RAC1signaling axis. Methodology: The involvement of WP was tested using (1) WP modulators (CHIR99021, Wnt-C59, XAV939), (2) sulindac sulfide and (3) beta-catenin SiRNA. We studied metastasis-associated phenotypes including, (1) proliferation (CelltiterGLO) (2) clonogenic growth (3D On-TOP assay) (3) fibronectin-directed migration (4) matrigel invasion (5) vascular mimicry (6) actin dynamics (confocal-microscopy and podia-parameters) (7) protein expression (WB) (8) real-time imaging for migration and vascular mimicry and (9) adhesion in the context of RAC1 activation in a panel of 3-4 TNBC cell lines. Results: Sulindac sulfide as well as transient transfection of beta-catenin SiRNA (1) decreased cellular levels of beta-catenin, inhibited proliferation, attenuated metastasis-associated different phenotypes and blocked fibronectin-mediated RAC1 as well as Cdc42 activities and (2) altered actin dynamics and inhibited podia-parameters (lamellopodia and fillopodia). Both Wnt-antagonists and RAC1 inhibitor (NSC23766) blocked fibronectin-induced RAC1 activation and inhibited the metastasis-associated phenotypes, while Wnt-activator enhanced phenotypes like vascular mimicry. Conclusion: Results of our experiments show that upregulation of WP regulates metastasis-associated phenotypes in TNBC via activation of RAC1 GTP-ase. The functional link between WP, metastasis and the activation of RAC1 is being currently worked out using RAC1SiRNA and pharmacological inhibitor of RAC1 in brain metastasizing MDA-MB231BR cells to specifically address the role of Wnt-beta-catenin-RAC1 signaling axis in the context of distant metastasis, the results of which will be presented at the meeting.
Citation Format: Nandini Dey, Jennifer Carlson, Pradip De, Brian Leyland-Jones. Wnt-beta-catenin-Rac1 signaling axis regulates metastasis-associated phenotypes in TNBC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3443. doi:10.1158/1538-7445.AM2014-3443
Abstract 3446: Fibroblast growth factor 23 promotes prostate cancer cell proliferation and invasiveness in vitro
Authors: Feng Shu , Ittmann Michael 
Published: May 2015

Abstract
Prostate cancer is the most common malignancy among American men and remains the second leading cause of male cancer mortality. Since age is thought to be one of the crucial factors in prostate cancer development, fibroblast growth factor 23 (FGF23), which forms a complex with Klotho, the age-related gene product, could play a key role in prostate development and progression. FGF23 is a peptide hormone member of the endocrine FGF subfamily (FGF19, FGF21, and FGF23), which signals through FGF receptors (FGFRs) in the presence of the coreceptor α-Klotho. FGF-23 has a critical role in phosphate homeostasis and vitamin D metabolism. The regulation of 1,25-Dihydroxyvitamin D by FGF-23 could also have implications for cancers, given that vitamin D metabolites have been shown to have anticarcinogenic effects. It has been reported that higher concentrations of FGF-23 were found in patients with advanced ovarian cancer compared with those with early-stage cancer or control subjects; circulating FGF-23 is associated with an increased risk of colorectal adenoma; however, to date, no investigations of the role of FGF-23 in prostate cancer have been reported. In the present study we investigated the function of FGF23 on human prostate cancer progression. FGF23 gene expression was determined in the commonly used prostate cancer cell lines: PC3, LNCaP, DU145, VCaP, and an immortalized normal prostate cell line PNTIA. RT-PCR showed that both FGF23 and αKlotho (KLA) genes are expressed in all these cell lines. Quantitative real-time RT-PCR indicated that FGF23 gene expression is elevated in prostate cancer compared to normal prostate tissue; FGF23 expression frequency is significantly higher in prostate cancer in compare with normal tissue (prostate cancer: total case number 35, positive 23; normal prostate tissue: total number 33, positive 15; p=0.04841). Biological function assays demonstrated that exogenous FGF23 stimulates prostate cancer cell proliferation (LNCaP by 30%, PC3 20%), anchorage-independent growth (by 60% for both LNCaP and PC3 cells), and invasion (LNCaP by 50% and PC3 55%). Suppression of FGF23 expression by FGF23 short hairpin RNA (shRNA) significantly inhibits PC3 and LNCaP cell proliferation, soft agar colony formation, and invasiveness in vitro. These data suggest that FGF23 promotes human prostate cancer progression and targeting FGF23 signaling pathway could decrease prostate cancer growth and metastasis.
Citation Format: Shu Feng, Michael Ittmann. Fibroblast growth factor 23 promotes prostate cancer cell proliferation and invasiveness in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3446. doi:10.1158/1538-7445.AM2014-3446
Abstract 3458: Role of the EphB1 gene in mediating migration, proliferation, and radiosensitization of medulloblastoma cells
Authors: Baig* Nimrah A. , Timofeeva* Olga , Dritschilo Anatoly , Pasquale Elena , Kool Marcel , Rood Brian , Rodriguez Olga , Albanese^ Christopher , Karam^ Sana 
Published: May 2015

Abstract
Eph/ephrin signaling in a variety of cancers has been reported to promote aspects of tumorigenesis, including proliferation, migration, and angiogenesis. Medulloblastoma is an aggressive primitive neuroectodermal tumor originating in the cerebellum. Recently performed integrative genomic approach to a large cohort of medulloblastomas has identified four subtypes (A-D) based on clinical presentation, transcription profiles, genetic abnormalities, and clinical outcome. We show high levels of EphB1 expression in tumors derived from children with group D medulloblastomas, which are known to exhibit a poorer response to current therapies. The purpose of this study is to examine the effect knockdown of EphB1 has on cellular migration, proliferation, and radiosensitization of medulloblastoma tumors. Using a human-derived medulloblastoma cell line (DAOY) and small interfering RNA (siRNA) targeting EphB1, we compared cell migration in an electrical impedance-based transwell Boyden chamber assay (xCELLigence RTCA DP system). We show that siRNA knockdown of EphB1 results in significantly decreased migration. Assessment of proliferation by MTT assay indicates that knockdown of EphB1 affects cell cycle progression in DAOY. Results from cell cycle and sub-G1 analysis by flow cytometry demonstrate that knockdown of EphB1 results in G1 arrest. Our previous systems analysis investigation of global gene expression regulated by an intact ATM gene product also identified EphB1 as a downstream signaling molecule correlating with enhanced cellular radiation resistance. Our data strongly support EphB1 as an unequivocal target for radiation sensitization in human fibroblasts as well as in vitro medulloblastoma cell lines. siRNA knockdown of EphB1 expression in human medulloblastoma cell lines known to express high levels of EphB1 results in sensitization to ionizing radiation by clonogenic survival assays. Preliminary data from an in vivo xenograft medulloblastoma animal model suggest an enhanced response to radiation in tumors lacking the EphB1 gene. Our data indicate that EphB1 is a potential molecular target for medulloblastoma cancer treatment and radiosensitization. The mechanisms and downstream signaling cascades underlying EphB1's action on cell migration, proliferation, and cellular radiosensitization are currently under investigation.
Citation Format: Nimrah A. Baig*, Olga Timofeeva*, Anatoly Dritschilo, Elena Pasquale, Marcel Kool, Brian Rood, Olga Rodriguez, Christopher Albanese^, Sana Karam^. Role of the EphB1 gene in mediating migration, proliferation, and radiosensitization of medulloblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3458. doi:10.1158/1538-7445.AM2014-3458
Abstract 3493: An in-situ proximity assay using biotin ligase
Authors: Jiang Zeyu (David) , Hong Rui , Farrell Mike 
Published: May 2015

Abstract
Protein-protein interactions (PPIs) are fundamental to biological processes, from signaling pathways that modulate gene expression, cell proliferation, tumor invasion to cytoskeleton networks that maintain morphological integrity of cells and tissues. Activation of oncogenes and inactivation of tumor suppressor genes in the cell that lead to carcinogenesis are inevitably accompanied by disruption of normal or activation of aberrant PPIs, thus detection and understanding of PPIs may advance the diagnosis and treatment of cancer.
Although many methods have been developed to discover and detect PPIs in vivo and ex vivo, few are applicable to in situ detection of PPIs, particularly in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Here we report a sensitive in situ PPI detection method for FFPE tissues that utilizes biotin ligase (BirA), an enzyme that covalently labels its specific peptide target substrate (BTS) with biotin. We developed BirA and BTS conjugated antibodies, each of which binds specifically to one of the interacting protein pair and whose close proximity permits BirA to biotinylate the BTS for subsequent visualization.
Using both artificial system such as hapten-labeled proteins and known biological PPI models such as E-cadherin and beta-catenin and HER2/HER3 dimers in the context of FFPE tissues, we have demonstrated that the assay is both sensitive and robust. Moreover, the assay has been fully automated and is easily adaptable for detecting protein dimers, fusion proteins, or other novel binary interactions in tissue specimens. As understanding details of signaling pathways becomes increasingly important in cancer biology, in situ proximity assay may offer novel mechanistic and therapeutic insights and provide a powerful tool for cancer diagnostics.
Citation Format: Zeyu (David) Jiang, Rui Hong, Mike Farrell. An in-situ proximity assay using biotin ligase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3493. doi:10.1158/1538-7445.AM2014-3493