bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomere dysfunction in prostatic carcinogenesis
Authors: Joshua A. M. , Vukovic B. , Braude I. , Evans A. , Srigley J. , Squire J. A. 
Published: March 2020

10021 Background: Telomeres are composed of tandemly repeated DNA sequences (TTAGGG) and specific binding proteins located at the ends of eukaryotic chromosomes. They stabilize chromosomal ends; telomere shortening is an important mechanism of genomic instability and can lead to end-to-end chromosomal fusion, rearrangements and cell death. Here we evaluate the hypothesis that telomere shortening contributes to the development of prostate cancer (CaP). Methods: We used telomeric, centromeric and chromosome specific peptide-nucleic acid probes with z-stacked quantitative fluorescence in-situ hybridisation analysis to initially analyse 15 radical prostatectomy specimens and then subsequently sextant core biopsies from 80 men obtained in 1998–2001 containing high-grade prostate intraepithelial neoplasia (HPIN) only. The biopsy cohort outcome is blinded to prevent experimental bias and has a minimum follow-up of 2 years with 41 men diagnosed subsequently with CaP and 39 men without CaP on rebiopsy. Regions of interest were identifying with an overlying haematoxylin and eosin slide. Results: We found a significant decrease in telomere length in both HPIN and CaP in comparison to normal prostatic epithelium accompanied by elevated rates of aneusomy. Telomere erosion in HPIN was more common in regions of the prostate-containing CaP. We now have analyzed ∼4000 cells of matching HPIN and surrounding stroma. Preliminary analysis demonstrated that the median telomere length in HPIN is approximately 27% of the surrounding stroma with upper and lower quartiles being 16% and 38% respectively. Logistic regression analysis is in progress to determine whether the length of the shortest telomeres or the average telomeric length in a sample predicts for subsequent diagnosis of CaP. Secondary analyses are examining the effect of telomere length on the interval to the diagnosis of CaP, the effect of age on telomere length and the eventual Gleason score. Conclusions: Analysis of telomere length holds great promise for developing improved prognostic markers in prostatic carcinogenesis. This is a first of its kind study in the field. No significant financial relationships to disclose.
The gene coding for secreted phosphoprotein1/osteopontin is the most overexpressed gene in cholangiocarcinoma—detected by oligonucleotide arrays and LightCycler analysis
Authors: Hass H. G. , Jobst J. , Nehls O. , Frilling A. , Hartmann J. T. , Kaiser S. 
Published: March 2020

10036 Background: Cholangiocarcinomas (CCC) are the second most common primary hepatic malignancy with a still poor prognosis and arise from biliary epithelia or cholangiocytes. Until now, less is known about the molecular pathways leeding to CCC. Methods: Oligonucleotide arrays were used to analyze gene expression profiles of 8 intrahepatic CCCs. After isolation of tRNA and transcription into cDNA, biotin-labelled cRNA probes were hybridized to GeneArrays (Affymetrix U 133A) containing probes of more than 22.000 genes/ESTs. For two-dimensional cluster analysis we used special software programs (Genexplore, GeneSpring). Dysregulated genes were determined by presence in more than 70% and a 2-fold change in relation to the corresponding non-malignant liver tissue. Lightcycler analysis were performed to validate the expression datas of dysregulated genes. Results: A total of 694 dysregulated genes (330 up-/364 down-regulated, compared with corresponding non-malignant tissue) were detected. As the gene with the highest and most consistent upregulation we were able to identify osteopontin (OPN) with an average 5-fold overexpression in all CCC tissues. OPN is an acidic phosphoprotein that is secreted by osteoblasts, macrophages and many other cell types and binds to a variety of cell surface receptors (integrins/CD44). OPN is multifunctional, with activities in cell migration, regulation of bone metabolism, immune cell function and control of tumor cell phenotype. Elevated OPN levels were seen in different tumors but until now no data exist about the expression in CCCs. As one possible interaction in human carcinogenesis, OPN has recently been shown to be a novel substrate for some MMPs, which play an importand role in tumor invasion and metastasis. Conclusions: This is the first report about an overexpression of OPN in CCC and our data indicate an important role in cholangiocarcinogenesis. Further studies are needed to illucidate the moleculargenetic mechanisms of OPN interactions in CCC. No significant financial relationships to disclose.
Transcription factor NFkB a potential molecular marker for predicting and improving treatment efficacy in esophageal cancer
Authors: Izzo J. G. , Wu T. , Malhotra U. , Ensor J. , Luthra R. , Chao C. K. , Swisher S. G. , Liao Z. , Aggarwal B. B. , Hittelman W. N. , Ajani J. A. 
Published: March 2020

10065 Background: Esophageal/gastroesophageal junction adenocarcinoma (E/GEJAC) remains one of the most aggressive malignancies. Chemoradiotherapy (CTXRT) followed by surgery has been used for localized E/GEJAC. Patients (pts) achieving pathologic complete response (pathCR) have an improved survival, but ≈70% of pts exhibit at surgery resistant residual, highly aggressive tumors despite CTXRT. There is a need to identify this high-risk population and target molecular pathways associated with cancer resistance. We have shown that nuclear NFκB was associated with poor clinical outcome of E/GEJAC pts undergoing 5FU, Docetaxel and Cisplatinum therapy. To validate our findings, we examined the impact of nuclear NFκB on clinical outcome of pts undergoing diverse CTXRT regimens. Methods: Pre- treatment tumor biopsies and post-treatment resected residual tumors were analyzed from pts receiving neo-adjuvant CT or CTXRT. NFκB protein expression was assessed by immunochemistry and correlated to pathCR and clinical outcome. Tumors were considered NFκB positive (pos) when ≥5% of cells expressed nuclear NFκB. Results: 80 pts, clinically staged II, III and IVA, were studied. All pts received antifolates, and 80%, 65% & 31% received taxanes, topo-1 inhibitors and/or platinum analogues, respectively. Radiation therapy was 50.4 Gy at 1.8 Gy once a day to all pts. 75/80 pts had available pre-treatment biopsies, all 58 pts with <pathCR had available residual tumors. Pre-treatment NFκB was predictive for lack of response to CTXRT [NFκB pos: 2/22 pathCR vs 27/53 <pathCR; P=.006]. In multivariate analysis, including clinical stage, tumor histology, pathCR and lymph nodes metastasis, pre-treatment NFκB was an independent prognostic factor of progression-free (P=.0029, HR=2.90, 95%CI:1.44–5.86) and overall (P=.0073,HR=2.70, 95%CI:1.30–5.60) survivals. NFκB was associated with recurrent disease [pre-treatment NFκB pos 14/29 (48%) vs NFκB negative11/46 (24%), P=.04; pre- or post- NFκB pos 22/47 (47%) vs NFκB neg 4/33 (12%), P=.003]. Conclusions: our data suggest that NFκB defines cancer biology and patterns to therapy response irrespective of the type of chemoradiation used. NFκB may serve as potential molecular target to improve treatment efficacy. No significant financial relationships to disclose.
A preoperative model evaluating the tissue effects of chemopreventive agents in low-volume prostate cancer
Authors: Kim J. , Wang X. , Babaian R. , Pisters L. , Pettaway C. , Wood C. , Sabichi A. , McDonnell T. , Logothetis C. , Troncoso P. 
Published: March 2020

1007 Background: To identify and assess biomarkers modulated by prostate cancer chemopreventive agents, we created a model that, by exploiting the time between histologic diagnosis of prostate cancer and definitive therapy (prostatectomy), expedites tissue cross comparison and confronts the multifocality and multizonal heterogeneity of prostate cancer. Methods: Between February 2001 and April 2002, 48 presurgical patients were enrolled in a single-institution, randomized, double-blind trial of vitamin E (VE) and L-selenomethionine (SeMET) based on the framework of the ongoing Selenium and Vitamin E Cancer Prevention Trial. Patients were treated with 400 IU VE, 200 μg SeMET, a combination of VE and SeMET, or placebo for 3 to 6 weeks before prostatectomy. All patients also received a multivitamin and vitamin C 250 mg each day. Ex vivo simulated sextant biopsies on the radical prostatectomy specimen (RPS) were performed, and 36 of 39 evaluable patients had RPS sections that were suitable for pathologic evaluation. Blood components were collected at baseline and prior to prostatectomy. We derived an apoptotic index (AI) morphologically and a proliferation index (PI) by using immunohistochemistry and counting Ki-67-positive nuclei. Cells were counted and identified by cell type (normal and cancerous) and by zone (peripheral [PZ], transition [TZ], and central [CZ]). Results: In normal epithelial cells when the Wilcoxon rank sum test was used to compare AI and PI changes between groups, the AI was higher in the TZ than in the CZ, a difference independent of treatment effects (p = .01). Between the largest PZ and TZ tumor foci, a statistically significant difference in PI was observed (p = .006). Using a multiple linear regression model fitted for AI from the largest RPS PZ tumor focus, we found a statistically significant difference between the SeMET group and the placebo group (p = .02). Conclusions: Besides introducing new findings, the clinicopathologic model proved itself a platform for biomarker discovery by leveraging molecular technologies to full advantage, including serum protein profiling (Kim et al., CEBP 2005) and gene expression profiling of different cell types. Supported by NIH grant CA88761. No significant financial relationships to disclose.
Preclinical rationale for therapeutic targeting of mTOR by CC-I779 and rapamycin in Hodgkin lymphoma
Authors: Georgakis G. V. , Yazbeck V. Y. , Li Y. , Younes A. 
Published: March 2020

10070 Background: Although conventional chemotherapy has been the golden standard for the treatment of Hodgkin Lymphoma (HL), significant long-term toxicities necessitate the need for development of targeted therapy that is potentially less toxic to normal cells. We and others have recently reported that the PI3K/AKT pathway is aberrantly activated in primary and cultured HL cells, and its inhibition induces apoptosis and cell cycle arrest. Because only mTOR inhibitors are currently being evaluated in clinical trials, we examined the biologic and molecular activity of two mTOR inhibitors CCI-779 and rapamycin in HL cell lines, and determined the molecular mechanisms of their activity. Methods: Three HL-derived cell lines were used (HD-LM2, L-428, and KM-H2). Cell viability was determined by the MTS assay. Cell cycle arrest was determined by propidium iodide staining and FACS analysis. Autophagy was determined by staining of intracellular organelles with Acridine Orange and FACS analysis. Molecular changes were determined by western blot. Results: The antiproliferative effect of CCI-779 and rapamycin in all HL cell lines was evident as early as 24 hour and was time- and dose-dependent. CCI-779 induced cell cycle arrest in all cell lines at the G0/G1 phase. CCI-779 and rapamycin were equally effective in HL cell lines. Cell cycle arrest was not followed by apoptosis but rather by autophagy, as evident by the increase of acidic autophagic intracellular organelles. On the molecular level, mTOR inhibition by CCI-779 dephosphorylated the downstream ribosomal S6 in all HL cell lines, but had no significant effect on AKT or phospho AKT. Cell cycle arrest was attributed to the upregulation of p27, but cyclin D1 remained unchanged. CCI-779 also enhanced the antiproliferative effect of the PI3K inhibitor LY294002, but did not change the effect of doxorubicin chemotherapy. Conclusions: Inhibition of mTOR by CCI-779 or rapamycin in HL cell lines has antiproliferative effect, by inducing cell cycle arrest followed by autophagy. CCI-779 enhances the activity of PI3K inhibitor LY294002. These data suggest that CCI-779 may have a therapeutic value in patients with HL. No significant financial relationships to disclose.
Targeting bladder tumor cells in vivo and in the urine by a peptide identified using phage display
Authors: Kwon T. , Lee B. , Yoo E. , Chung S. , Park Y. , Kim B. 
Published: March 2020

10071 Background: Bladder cancer is one of the most common tumors of genitourinary tract. Selective delivery of drugs to tumor tissues is important for effective tumor therapy. Here we identified a peptide targeting bladder tumor cells using phage display. Methods: Phage peptide library containing CX7C (C-cysteine and X-any amino acid residue) was based on T7 415–1b phage vector (Novagen). Tumor xenografts were prepared by subcutaneously injecting BALB/c Nu/nu female nude mice with HT-1376 bladder tumor cells. For a carcinogen-induced tumor model, Fischer 344 female rats were supplied ad libitum with tap water containing 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 8 weeks. Results: A phage library containing CX7C random peptides was screened for selective binding to cells from human bladder tumor xenografts. Selected phage clones were individually evaluated for binding to cultured bladder tumor cells and for binding to cells from human tumor tissues of six patients. The peptide displayed by the most promising clone was synthesized and designated as Bld-1. Fluorescein-conjugated Bld-1 peptide showed selective binding to frozen sections of human bladder tumor tissues of three patients. In vivo tumor targeting was examined in a carcinogen-induced rat tumor model (n=20). When the fluorescent peptide was introduced into the bladder lumen, it selectively bound to tumor epithelium. Next, when the fluorescent peptide was intravenously injected into the tail vein, it homed to the bladder tumor, but was not detectable in normal bladder and control organs such as lung. Moreover, the fluorescent peptide bound to cells from urinary specimens of tumor patients (n=10), whereas little binding was observed in cells from healthy individuals (n=3). Conclusions: The Bld-1 peptide may be useful for targeting bladder tumor cells in vivo and in the urine. No significant financial relationships to disclose.
Validation of a five reagent immunohistochemistry assay for prognostication of estrogen-receptor expressing breast cancer
Authors: Ross D. T. , Frost A. R. , Beck R. , Seitz R. S. , Ring B. Z. 
Published: March 2020

10081 Background: We have previously reported the translation of gene expression data into a five reagent polyclonal antibody immunohistochemistry assay targeting p53, SLC7A5, NDRG1, HTF9C, and CEACAM5 whose staining results are combined using a Cox proportional hazard model for prognostication of estrogen receptor expressing breast cancer. Monoclonal antibodies targeting these genes have now been obtained and or produced. Methods: Paraffin blocks from 229 patients seen at the University of Alabama at Birmingham Clinical Cancer Center were assembled into tissue arrays and clinical follow-up data was collected by chart review. Immunohistochemical stains were performed and cases scored as positive or negative with the five monoclonal antibody assay. In order to further test the assays predictive value for assessing outcome, the prospectively defined Cox proportional hazard model and high, moderate, and low risk cutoffs were applied to the staining results on the estrogen receptor positive (ER+) patients for whom a assessment of death due to disease (DOD) and staining results for all five biomarkers were available. Results: The Kaplan-Meier estimates of outcome confirmed that the Cox model distinguished ER+ patients with poor outcomes. The five antisera algorithm identified high risk patients with a five year estimate of DOD of 41% compared to 20% for moderate and 9% for good (p=0.006) (79 patients total). In ER+ node negative patients the model identified high risk patients with a five year estimate of DOD of 50% compared to 18% for moderate and 5% for good (p=0.01) (40 patients total). The prognosticator was independent of age, pathological stage, and tumor size. Conclusions: A panel of five antibodies can significantly improve upon traditional prognosticators in predicting outcome for estrogen receptor positive breast cancer patients. This represents the third independent validation study performed on cohorts from different institutions. Retrospective studies on clinical trial cohorts and prospective studies should be performed to further establish the utility of this test in identifying early stage breast cancer patients at high risk for recurrence. [Table: see text]
Hierarchical clustering analysis of tissue microarray immunostaining data identifies prognostically significant subsets of stage IIIA N2 non-small cell lung cancer patients. An Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 014)
Authors: Grossi F. , Bordo D. , Spizzo R. , Consiglieri C. , Aita M. , Morelli A. , Di Terlizzi S. , Ceschia T. , Beltrami C. A. , Belvedere O. 
Published: March 2020

10085 Background: Based on gene expression profiling, prognostically relevant cluster groups of patients have been recently identified for breast cancer, lung cancer, and lymphoma. The development of tissue microarray (TMA) technology provides methodology for the concomitant analysis of multiple proteins on large numbers of tumor samples. Methods: Here, we report the hierarchical clustering analysis of TMA immunostaining data from 87 patients with stage IIIA pN2 non-small cell lung cancer (NSCLC), treated with surgery alone between 1985 and 1997. A panel of 10 markers was tested by immunohistochemistry: EGFR, ErbB-2, c-kit, COX-2, survivin, bcl-2, cyclin D1, cyclin B1, MMP-2 and MMP-9. Univariate, multivariate analyses and unsupervised hierarchical clustering analysis by using these 10 markers were performed. Results: Bcl-2 (p<0.0001) and cyclin D1 (p=0.0036) are more expressed in squamous cell carcinoma (SCC), while MMP-2 (p=0.0115), MMP-9 (p=0.0075) and survivin (p=0.02) show increased expression levels in other histological subtypes. In univariate analysis, only squamous cell histology, bcl-2 and cyclin D1 expression were favorable prognostic factors (p=0.0149, p=0.0013, p<0.0001, respectively), while MMP-2 expression showed a significant correlation with poor outcome (p=0.013). In multivariate analysis, cyclin D1 and MMP-2 were the only positive and negative prognostic factors, respectively (p<0.0001, p=0.06). Unsupervised hierarchical clustering analysis produced 5 distinct cluster groups and the deduced dendrogram identified 2 prognostically significant subsets of patients, with a median survival of 51 (groups 1–2) and 10 (groups 3–4-5) months, respectively (p<0.0001). Notably, groups 1–2 were mostly composed of SCC (80%). Conclusions: This study suggests that hierarchical clustering of TMA immunostaining data by using a limited set of markers might provide a useful tool for the identification of radically resected NSCLC patients at high risk of recurrence, likely to benefit from more aggressive treatment. No significant financial relationships to disclose.
Elevated plasma endoglin (CD105) predicts decreased response and survival in metastatic breast cancer patients
Authors: Vo M. N. , Leitzel K. , Ali S. M. , Demers L. , Wilson M. , Evans D. , Lipton A. 
Published: March 2020

10091 Background: Endoglin (CD105) is a proliferation-associated surface protein expressed by human vascular endothelial cells. It is a co-receptor for transforming growth factor (TGF) -β1 and TGF-β3, and plays a major role in angiogenesis. Upregulation of endoglin has been reported in endothelial cells of breast and colorectal cancers, and elevated levels of serum endoglin have been associated with tumor metastasis in breast cancer patients. Materials and Methods: Pretreatment EDTA plasma from 224 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial and 50 healthy post-menopausal female controls were assayed for soluble endoglin using a double-antibody sandwich ELISA from R&D Systems (Minneapolis, MN). Results: In the post-menopausal female control group (n=50), the mean ± SD for plasma endoglin levels were 5.00 ± 1.84 ng/ml, with a range of 2.38–9.83 ng/ml. The upper limit of normal was defined as the mean + 2 SD (8.7 ng/ml) for plasma endoglin. In the breast cancer patient group, the mean ± SD for plasma endoglin was 6.40 ± 2.23 ng/ml, with a range of 3.00–19.79 ng/ml. Elevated plasma endoglin levels were detected in 26 of 224 patients (11.6%). Patients with elevated vs. normal plasma endoglin levels had a reduced clinical benefit rate (CR +PR+Stable)(15% vs. 42%)(p=0.01) to hormone therapy. Time to progression (TTP) was shorter for patients with elevated vs. normal plasma endoglin levels, but did not reach statistical significance (p=0.2). Patients with elevated plasma endoglin had decreased overall survival (median 645 days vs. 947 days)(p=0.005). Another plasma angiogenic marker, soluble Tie-2 receptor, did not significantly correlate with clinical outcome. A weak correlation existed between plasma endoglin and Tie-2 (r =.54, p<0.00001). There was no correlation between plasma endoglin levels and the presence of bone metastasis vs. other sites of metastases. Conclusions: Elevated pretreatment plasma endoglin levels predicted for decreased clinical benefit rate to 2nd-line hormone therapy and a shorter overall survival in metastatic breast cancer patients. Circulating endoglin levels deserve further study for monitoring anti-angiogenic therapy. [Table: see text]
Clinical significance of HuR expression, an mRNA-binding protein in non-small cell lung cancer (NSCLC)
Authors: Tanaka F. , Ogawa E. , Wada H. , Shanker M. , Garcia-Soto A. E. , Branch C. D. , Wistuba I. , Roth J. A. , Ramesh R. 
Published: March 2020

10098 Background: HuR is a nucleo-cytoplasmic shuttling protein that specifically binds to mRNA that has AU rich (ARE) sites at the 3’end and transports the RNA to the cytoplasm for protein translation. In addition to mRNA transportation, HuR plays a role in mRNA stabilization and protein translation. Preclinical studies have shown mRNA’s of several growth factors, cell-cycle regulators, and transcription-regulating proteins have ARE’s at the 3’end and bound by HuR. However, there has been reported no clinical data on HuR expression in NSCLC. Thus, in the present study, we assessed clinical significance of HuR expression in NSCLC. Patients and Methods: A total of 236 patients with completely resected p-stage I-IIIA, NSCLC, were reviewed, and HuR expression was evaluated immunohistochemically. Results (Table): HuR expression was seen in the nucleus and cytoplasm of tumor cells. Cytoplasmic HuR expression was positively correlated with tumor progression (p-stage, P<0.01), especially nodal metastasis, microvessel density (MVD), and COX-2 expression. Enhanced nuclear HuR expression was also correlated with tumor progression and COX-2 expression, but not with MVD. Positive cytoplasmic HuR expression was a significant factor to predict a poor prognosis in all patients (5-year survival rates: 85% for HuR-negative and 43% for HuR-positive patients; P<0.01) and in any p-stage/histology subset patients. Nuclear HuR expression status was also a significant prognostic factor in all patients, but not in all subsets. A multivariate analysis confirmed that cytoplasmic HuR status was an independent prognostic factor (hazard ratio [95% CI], 4.261 [2.109–8.609]; P<0.001). Conclusions: Cytoplasmic HuR expression was correlated with tumor progression, and was a significant and independent prognostic factor in correlation with enhanced COX-2 expression and increased tumor angiogenesis. [Table: see text] No significant financial relationships to disclose.