bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4329: Expression of serpin B2, neuroserpin and L1CAM in association with metastasis and survival in non-small cell lung cancer
Authors: Ramnefjell Maria , Helgeland Lars , Akslen Lars A. 
Published: August 2015

Abstract
Background: Lung cancer is a leading cause of cancer related deaths worldwide, and finding new prognostic and predictive biomarkers are of utmost importance.
Previous studies have shown that different serpins and adhesion molecules have an impact on disease progression and development of metastasis, especially to the brain. Here, we examined whether expression of the anti-plasminogen activators Serpin B2 and Neuroserpin, and the adhesion molecule L1CAM was associated with patient prognosis, brain metastasis or other clinicopathologic characteristics, in non-small cell lung cancer (NSCLC).
Study design: The material consists of surgical specimens from 100 NSCLC patients treated during 1993-1999 at Haukeland University Hospital, Bergen, Norway. Sections from tumor blocks were stained with antibodies to Serpin B2, Neuroserpin, and L1CAM.
Results: There were 66 men and 34 women, with a mean age at diagnosis of 65.7 (41 adenocarcinomas, 38 squamous cell carcinomas, and 21 carcinomas of other types).
Observation time ranged from 0 to 254 months (mean 74 months). 12 patients were fully recovered, 46 died of lung cancer, and 34 died from other causes. 11 of 89 patients developed brain metastasis.
Low expression of Serpin B2 was associated with reduced overall survival (p&lt;0.05) in adenocarcinomas, and with a trend for all types combined (p = 0.10), whereas there was no significant difference in survival related to expression of Neuroserpin or L1CAM.
Expression of Neuroserpin was associated with adrenal metastasis (OR 13.3 (95%CI 1.5-119.7), p&lt;0.05), and there were trends for associations between expression of Serpin B2 and metastases to skin and bone (p = 0.072 and p = 0.068, respectively). There were no significant associations between these markers and presence of brain metastasis.
Conclusions: Low expression of Serpin B2 in lung adenocarcinoma was associated with reduced overall survival in our cohort. In contrast to previous findings by others, we did not find a relationship between L1CAM expression and overall survival or metastasis. Neither was there any association between expression of Neuroserpin and survival, although we found an increase in adrenal metastasis in this group. Low expression of Serpin B2 could be a biomarker for prognosis in lung adenocarcinomas and should be studied in other cohorts.
Citation Format: Maria Ramnefjell, Lars Helgeland, Lars A. Akslen. Expression of serpin B2, neuroserpin and L1CAM in association with metastasis and survival in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4329. doi:10.1158/1538-7445.AM2015-4329
Abstract 4342: Differential expression of novel PKD1 related biomarker panel in African American men with prostate cancer
Authors: Nickkholgh Bita , Fang Xiaolan , Winters Shira M. , Fino Nora , Balaji KC. 
Published: August 2015

Abstract
Background: Prostate Cancer (PCa) exhibits striking racial disparity and is presented more aggressively in African Americans (AAs) than Caucasians (CAs). We have previously reported that the dysregulation of PKD1-centered signaling in primary AA prostate cancer cell line E006AA is akin to more aggressive Caucasian cell line C4-2. As PKD1 plays a central role in several cellular mechanisms that contribute in aggressive malignant phenotype, we defined a PKD1 related biomarker panel consisting of 11 biomarkers and explored whether PKD1 centered signaling would be differentially regulated in AA compared to CA PCa. Methods: PKD1 related biomarker panel consisted of PKD1, AR, HSP27, N-Cadherin, Snail, Vimentin, MMP-2, MMP-9, MT-1, E-cadherin, beta-Catenin. The validity of the PKD1 related biomarker panel in PCa was evaluated on available microarray databases (cbioportal.org). The differential expression of the biomarker panel was quantified on PCa tissue samples from15 AA and 15 CA men with matching Gleason score obtained from tumor tissue bank of Comprehensive Cancer Center of Wake Forest University. Results: The cbioportal consisted of six different PCa databases with approximately 662 human PCa samples in total. In average, PKD1 related biomarker panel was altered 47.7% in available cases. Quantification of the PKD1 related biomarker panel regarding gene expression demonstrated a trend toward higher expression of majority of biomarkers in AA samples in compare to CAs. However, only variances in expression of MMP2 (P&lt;0.0001) and MT1A (P = 0.03) were significantly different between AAs and CAs. The results obtained from human PCa samples showed a moderate correlation with previously reported cell line data which showed significantly higher expression of EMT markers N-Cadherin, Vimentin and Snail in AA cell line in compare to CA cell lines. Conclusion: The differential expression of PKD1 related biomarker panel in AAs in compare to CAs suggests a biological basis for disparity in PCa. Besides, relatively high altered PKD1 related biomarker panel in available microarray databases suggests the potential of the panel as a tool in diagnosis of aggressive phenotype in PCa.
Citation Format: Bita Nickkholgh, Xiaolan Fang, Shira M. Winters, Nora Fino, KC. Balaji. Differential expression of novel PKD1 related biomarker panel in African American men with prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2015-4342
Abstract 4345: FGFR1, a new FISH biomarker, may predict recurrence of prostate cancer after prostatectomy
Authors: Zhang Ying , Pestova Katerina , Du Jing , Liu Ping , Buckingham Lela , Colpitts Tracey 
Published: August 2015

Abstract
Background: To identify prostate cancer (CaP) with high recurrence risk after Radical Prostatectomy (RP) is a challenge. FGFR1 (Fibroblast Growth Factor Receptor 1) plays a critical role in prostate development and tumorigenesis. In this study, we explored the possibility of using FGFR1 fluorescence in situ hybridization (FISH) to predict recurrence after RP in the Formalin fixed paraffin embedded (FFPE) tissue from CaP patients.
Methods: FFPE histological specimens from 52 RP cases were evaluated with FGFR1 (8p12) / CEP 8 probe mix. While 32 of the 52 patients recurred within 5 years (PSA progression or death of disease), and 20 remained disease-free with 8 to 15 years. Median age of patients was 62 with Gleason Score range from 4 to 9. Percent of FGFR1 gain and FGFR1 loss per specimen, as well as mean number of FGFR1 signals per specimen were calculated. CEP8 was used as a control to assess hybridization quality. Statistical analysis (Cox Proportional Hazards model) was conducted using SAS 9.2.
Results: Survival analysis demonstrated that percent FGFR1 loss in a specimen could identify recurrent CaP with the Harzard Ratio (HR) of 3.34 (p = 0.0011), which indicated that the risk of recurrence for FGFR1 loss-positive group is 3.34 times than that for FGFR1 loss-negative group. On the other hand, survival analysis of the percent FGFR1 gain showed that FGFR1 gain (amplification) is favorable for survival with HR of 0.36 (p = 0.0043), which indicated that the risk of recurrence for FGFR1 gain-positive group is 0.36 times than that for FGFR1 gain-negative group. By using mean FGFR1 signals per specimen in the Kaplan-Meier analysis, the patient specimens stratified into three distinct groups (overall logrank p = 0.0011): normal for FGFR1, FGFR1 gain (more favorable outcome), and FGFR1 loss (highest risk of recurrence).
Conclusions: This study shows the utility of FGFR1 copy number abnormalities in CaP. Our results indicate that gain and loss of FGFR1 may have a different effect on disease recurrence. Therefore, FGFR1 FISH may provide predictive value for CaP recurrence in post RP patients, either by itself, or as an adjunct to the currently clinical prognostic indicators.
Citation Format: Ying Zhang, Katerina Pestova, Jing Du, Ping Liu, Lela Buckingham, Tracey Colpitts. FGFR1, a new FISH biomarker, may predict recurrence of prostate cancer after prostatectomy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4345. doi:10.1158/1538-7445.AM2015-4345
Abstract 4350: Prognostic potential of epithelial to mesenchymal transition in prostate cancer at first presentation
Authors: Al-Sukaini Ahmad , Hart Claire , Robinson Richard , Brown Mick , Clarke Noel 
Published: August 2015

Abstract
Introduction and Objective: Metastatic progression of prostate cancer requires a change of state, epithelial to mesenchymal transition (EMT), reducing cell to cell adherence and contact, with associated cell motility and invasion. EMT is one of the hallmarks of cancer and characterisation of the EMT process has defined a panel of EMT biomarkers. Here we investigate the potential of an EMT panel of biomarkers in an unscreened population at first presentation with prostate cancer.
Methods: A prostate Tissue Micro Array (TMA) comprising 2,450 cores containing normal adjacent, prostatic intraepithelial neoplasia and malignant prostate tissue from 524 diagnostic biopsies, linked to an extensive clinical database with long-term outcome, was studied. Expression of a panel of EMT biomarkers, including E-cadherin and vimentin, was assessed using an automated, high throughput fluorescent staining (Leica BOND-MAX), image capture (Carl Zeiss Microimaging Mirax scanner) and quantitative image analysis (Definiens Tissue Studio) protocol. Definiens H-Score was converted to pathological scores prior to univariate and multivariate Cox proportional hazards regression analysis in SPSS.
Results: Expression of an EMT profile predicted a significant reduction in both overall and cancer specific survival. In univariate analysis, low or negative E-cadherin staining was associated with a reduction in median overall survival by 45 months (95% CI: 10.4-79.6; P&lt;0.0001) and a cancer specific mean survival of 80.1 months (95% CI: 45.7-114.5; P&lt;0.0001) when compared to high and intermediate E-cadherin staining. Similarly, high EMT expression, defined as loss of E-cadherin and presence of vimentin, was compared to low EMT expression, defined as preserved E-cadherin and the absence of vimentin. There was a greater reduction in overall median survival in high EMT tumours of 54 months (95% CI: 12.5-95.5; p&lt;0.0001) and cancer specific survival of 93.2 months (95% CI: 62.8-123.7; p&lt;0.0001) when compared to low EMT tumours. Stage, grade, PSA at diagnosis and EMT status was included in the multivariate analysis for cancer specific survival. Both Gleason grade (p = 0.017) and EMT status (p = 0.030) were found to be significant prognostic factors in predicting cancer specific survival.
Conclusions: Loss of E-cadherin and concomitant expression of the EMT marker vimentin are powerful predictors of prostate cancer outcome at first presentation.
Citation Format: Ahmad Al-Sukaini, Claire Hart, Richard Robinson, Mick Brown, Noel Clarke. Prognostic potential of epithelial to mesenchymal transition in prostate cancer at first presentation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4350. doi:10.1158/1538-7445.AM2015-4350
Abstract 4353: Improved prediction of prostate cancer prognosis by using a multiparametric molecular classifier
Authors: Tsourlakis Maria Christina , Kluth Martina , Schlomm Thorsten , Simon Ronald , Sauter Guido , Minner Sarah 
Published: August 2015

Abstract
Background: Because no single molecular marker have proven to be sufficiently powerful for routine estimation of prostate cancer prognosis as to yet, it is hoped that the combined analysis of multiple markers will allow for distinguishing between indolent and aggressive forms of prostate cancer. In fact, first generation commercial multiparametric test assays show promising results. We hypothesized that such tests may be further optimized.
Design: A tissue microarray (TMA) containing 0.6 mm tissue cores from more than 12,000 prostate cancer patients with long-term follow-up data was analyzed with more than 100 molecular markers by immunohistochemistry or FISH. Markers with strong and independent prognostic value in uni- and multivariate analyses were combined to obtain panels of markers that yield additional prognostic information beyond the standard parameters (including pre-operative PSA, Gleason grade, tumor stage, nodal stage) in ROC analysis. For this purpose, a simple score (0-10 points) was build based on the number and type of adverse features per tumor.
Results: Markers with strong independent prognostic relevance included deletions of 6q15 and PTEN, overexpression of EZH2, TUBB3, and nuclear accumulation of p53, indicating dominant-negative TP53 gene mutation. A total of 5,129 cancers harbored none of these alterations (score 0) and showed the best prognosis in a Kaplan-Meier plot using biochemical recurrence as the study endpoint. The worst prognosis was found for 610 tumors harboring ≥8 (score 8-10) of these alterations, while an intermediate prognosis with decreasing time to recurrence was found for cancers with scores 1-2 (n = 2,418), 3-4 (n = 1,367) and 5-7 (n = 1038). The differences between the groups were high significant (p&lt;0.0001). The 5 genes classifier provided prognostic information independent from PSA, Gleason, stage, and nodal stage (p&lt;0.0001).
Conclusion: Multiparametric classifiers have a high potential to improve the predictive accuracy of current models using established clinic-pathological models. Analyses of very large sets of patient tissues are instrumental to identify the best candidates for such molecular marker panels. It is likely, that continued analysis of our TMA will identify even better marker panels than the current 5 genes classifier.
Citation Format: Maria Christina Tsourlakis, Martina Kluth, Thorsten Schlomm, Ronald Simon, Guido Sauter, Sarah Minner. Improved prediction of prostate cancer prognosis by using a multiparametric molecular classifier. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4353. doi:10.1158/1538-7445.AM2015-4353
Abstract 4360: Validation of phosphodiesterase 10A as a cancer target
Authors: Lee Kevin , Li Nan , Chen Xi , Zhu Bing , Yet Larry , Madeira da Silva Luciana , Russo Suzanne , Keeton Adam B. , Boyd Michael R. , Piazza Gary A. 
Published: August 2015

Abstract
Phosphodiesterase 10A (PDE10) is a cAMP and cGMP degrading PDE isozyme that is highly expressed in the brain striatum where it plays an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, likely because of low expression levels in peripheral tissues. We recently reported high levels of PDE10 in tumors and that genetic silencing by siRNA inhibits tumor cell growth with a high degree of selectivity over normal cells (Li et al., Oncogene 2014). These observations suggest that PDE10 may have an unrecognized role in tumorigenesis and represents a novel cancer target. To further test this possibility, we studied the effects of a highly specific PDE10 inhibitor, Pf-2545920 (MP-10) on colon tumor cell growth. Here we show that Pf-2545920 selectively inhibits tumor cell growth, causes G1 cell cycle arrest, and induces apoptosis. The concentration range by which Pf-2545920 inhibits tumor cell growth parallels the concentration range required to increase intracellular cyclic nucleotide levels and activate PKA and PKG. Moreover, PDE10 knockdown by siRNA reduces the sensitivity of tumor cells to the growth inhibitory activity of Pf-2545920. Using the crystal structure of PDE10 to design novel inhibitors, a series of compounds were synthesized and screened for tumor cell growth inhibitory activity and PDE10 isozyme specificity. A lead compound, ADT-030 was found to inhibit tumor cell growth and PDE10 enzymatic activity with IC50 values in the nanomolar range, but did not significantly affect the growth of normal cells. Unlike Pf-2545920, ADT-030 exhibits high selectivity for activating PKG signaling without affecting PKA signaling. Inhibitors of PKA and PKG were used to confirm that the tumor cell growth inhibitory activity associated with PDE10 inhibition involves PKG activation, while PKA activation appears to be ancillary. These findings serve to validate PDE10 as a cancer target, whereby novel inhibitors can be designed to specifically activate cGMP/PKG signaling with a high degree of tumor cell selectivity. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza).
Citation Format: Kevin Lee, Nan Li, Xi Chen, Bing Zhu, Larry Yet, Luciana Madeira da Silva, Suzanne Russo, Adam B. Keeton, Michael R. Boyd, Gary A. Piazza. Validation of phosphodiesterase 10A as a cancer target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2015-4360
Abstract 4378: Targeting the embryonic morphogen Nodal reduces viability of doxorubicin-treated breast cancer cells in vitro
Authors: Bodenstine Thomas M. , Chandler Grace S. , Margaryan Naira V. , Strizzi Luigi , Gilgur Alina , Seftor Elisabeth A. , Seftor Richard E B , Khalkhali-Ellis Zhila , Ugolkov Andrey , Mazar Andrew P. , Hendrix Mary J C 
Published: August 2015

Abstract
Triple negative breast cancer represents an aggressive malignancy for which few targeted therapies exist. The embryonic morphogen Nodal is re-expressed in highly aggressive breast cancers and reduction of Nodal signaling decreases tumor cell metastatic characteristics. This represents a potential avenue for the development of therapeutics aimed at inhibiting the Nodal pathway. To explore this further, we evaluated Nodal expression in breast cancer cells following chemotherapy. In vitro treatment of MDA-MB-231 and MDA-MB-468 human breast cancer cell lines with Doxorubicin, a chemotherapy commonly used for the treatment of malignant breast cancer, resulted in the generation of surviving subpopulations that retained Nodal expression (&gt;80%) and remained viable. To validate these findings in vivo, we analyzed Doxorubicin treated metastatic patient derived breast cancer xenografts (PDX) which displayed a residual population of Nodal positive cells when analyzed by immunohistochemistry. Based on these findings, we hypothesize that targeting Nodal in a combinatorial approach with chemotherapy will lead to a reduction in remaining viable populations of cancer cells. When we utilized an anti-Nodal neutralizing antibody to inhibit Nodal signaling, antibody treatment reduced cell proliferation, attachment and increased rates of apoptosis in Doxorubicin treated breast cancer cell lines. Decreases in phosphorylation of Histone 3, a marker of cellular proliferation, and increases in the cleavage of PARP, correlating to induction of apoptosis, were noted in response to antibody treatment. These data suggest that Nodal signaling plays a critical role in the growth of metastatic breast cancer cells and targeting Nodal may improve therapeutic outcome in malignancies such as triple negative breast cancer. The initial results highlight translational potential for the development of humanized antibodies capable of inhibiting Nodal function.
Citation Format: Thomas M. Bodenstine, Grace S. Chandler, Naira V. Margaryan, Luigi Strizzi, Alina Gilgur, Elisabeth A. Seftor, Richard E B Seftor, Zhila Khalkhali-Ellis, Andrey Ugolkov, Andrew P. Mazar, Mary J C Hendrix. Targeting the embryonic morphogen Nodal reduces viability of doxorubicin-treated breast cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2015-4378
Abstract 4386: Docetaxel-trastuzumab stealth immunoliposome: design and non-clinical study in HER2+ and HER2- breast cancer models
Authors: Fanciullino Raphaelle R. , Brunel Jean-Michel , Correard Florian , Giacometti Sarah , Ciccolini Joseph 
Published: August 2015

Abstract
Targeted liposomal drug delivery is expected to enhance the therapeutic effects of anti-cancer agents through both active and passive targeting of tumor cells. We have developed a stealth liposomal formulation of docetaxel anchored with trastuzumab (HER2-ANC) to target HER2+ breast cancers. Pegylated SUV liposomes with 95% docetaxel encapsulation yield were obtained using the thin-film method. Homogenous distribution in liposome size of 100-150 nm diameter was achieved by extrusion, prior to anchoring trastuzumab through maleimide coupling. Anchoring was evidenced by electronic microscopy with anti-mouse gold antibody. HER2-ANC antiproliferative activity was assessed on a representative panel of human breast cancer cells expressing (SKBR3, MDA-MB451) or not expressing HER2 (MDA-MB231). Free docetaxel and trastuzumab combination was used as control. Cytotoxicity was evaluated in vitro on 2D culture cells by MMT assay, and in 3D spheroids co-cultured with HMEC endothelial cells. HER2-ANC proved to have a similar efficacy than the free combination, including in triple negative MDA-MB231 cells in 2D models. In 3D models, the immunoliposome displayed higher efficacy as compared with the free combination, possibly because of a better and deeper diffusion of the antibody inside the spheroids. Surprisingly, and although less marked, this difference in favor of HER2-ANC was observed as well with the triple negative MDA-MB231 cells, thus suggesting that a better delivery of docetaxel was achieved with the liposomal form. Fluorescence imaging showed that HER2-ANC was internalized inside tumor cells. Measurement of HER2 expression and immunofluorescence staining of alpha-microtubulline supported this increase in efficacy observed in vitro. After tagging HER2-ANC with DIR fluorescent probe, in vivo preliminary distribution studies in nude mice bearing both the HER2+ SKBR3 and HER2- MDA-MB231 tumors showed that a more specific tumor uptake is achieved in HER2+ tumors, thus suggesting that higher antiproliferative effect and lower toxicities can be expected in further efficacy studies. Overall, this proof of concept study strongly suggest that redesigning existing combinations of biologics and cytotoxics as immunoliposomes could help to optimize the efficacy/toxicity balance of anticancer treatments.
Citation Format: Raphaelle R. Fanciullino, Jean-Michel Brunel, Florian Correard, Sarah Giacometti, Joseph Ciccolini. Docetaxel-trastuzumab stealth immunoliposome: design and non-clinical study in HER2+ and HER2- breast cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4386. doi:10.1158/1538-7445.AM2015-4386