bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-039: 1,25 dihydroxyvitamin D3 and cisplatin combination modulate p73 in bladder cancer
Authors: Bunch Brittany L. , Woloszynska-Read Anna , Trump Donald L. , Johnson Candace S. 
Published: August 2015

Abstract
Cisplatin-based combination chemotherapy is the standard approach to therapy of advanced bladder cancer. While there is a substantial initial response rate and occasional complete response, long term control is not common. There is a need to develop new therapeutic approaches to bladder cancer. 1,25 dihydroxyvitamin D3 (1,25D3), the active metabolite of vitamin D, enhances the anti-tumor effects of cisplatin in preclinical bladder cancer models. We evaluated the mechanism of 1,25D3 potentiation of cisplatin cytotoxicity through in vitro studies in bladder cancer cell lines. Our studies suggest that enhanced cytotoxicity is mediated through modulation of p73. The ratio of the pro-apoptotic TAp73 isoform to the anti-apoptotic ΔNp73 isoform is important in determining cellular response to cisplatin. Our studies demonstrate that pretreatment with 1,25D3 (0.5 uM) for 24 hrs followed by cisplatin (0.75 ug/ml) for 48 hrs increases the ratio of TA/ΔNp73 mRNA transcripts 2-fold in the T24 bladder cancer cell line, and increases TAp73's transcriptional target, BAX approximately 3-fold compared to cisplatin alone. Protein levels of p73 and BAX, are also increased with 1,25D3 pretreatment followed by cisplatin in T24 cells as determined by western blot. Using a TransAm p53 binding assay after p53 immunodepletion, cisplatin treatment was found to decrease TAp73 functional ability to bind DNA by approximately half, although this has not yet been determined to be statistically significant. 1,25D3 pretreatment followed by cisplatin prevents the decrease in TAp73 DNA binding found after cisplatin alone. These data suggest an increase in TAp73 pro-apoptotic functional abilities resulting from 1,25D3 pretreatment followed by cisplatin in T24 cells. These findings suggest that 1,25D3 may have potential to be used in combination with cisplatin to increase the apoptotic response. Further studies are being performed to determine the requirement of TAp73 in 1,25D3 potentiation of cisplatin cytotoxicity by using T24 cells transfected with TAp73 shRNA in assays previously used to determine synergism, ie. MTT, clonogenic, and apoptosis assays. Supported by NCI grants CA067267 and CA016056.
Citation Format: Brittany L. Bunch, Anna Woloszynska-Read, Donald L. Trump, Candace S. Johnson. 1,25 dihydroxyvitamin D3 and cisplatin combination modulate p73 in bladder 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 LB-039. doi:10.1158/1538-7445.AM2015-LB-039
Abstract LB-046: Evaluation of known low-penetrance thyroid cancer risk alleles in a Hispanic population from South America
Authors: Estrada-Flórez Ana , Bohórquez-Lozano Mabel E. , Prieto-Sánchez Rodrigo , Mateus Gilbert F. , Rios Alejandro , Vélez Hoyos Alejandro , Duque Carlos S. , Ledda Mirko A. , Erazo Maria J. , Bolaños Fernando , Panqueba Cesar , Echeverry de Polanco María Magdalena , Carvajal-Carmona Luis G. 
Published: August 2015

Abstract
TC is one of the most common malignancy that shows familial inheritance with ∼8 fold increase in the risk of developing TC in first-degree relatives affected by this disease. Recent genome-wide association studies (GWAS) aimed at characterizing the risk loci for TC have identified five single nucleotide polymorphisms (rs966423, rs2439302, rs965513, rs116909374 and rs944289) associated with increased risk for TC. However, effect of these polymorphisms have bot been studied in any Hispanic population. Therefore, the aim of this study was to analyze the above-mentioned SNPs in 235 TC patients and 588 healthy controls from Central Colombia using KASP genotyping system. Genotype frequencies, Hardy Weinberg equilibrium (HWE) and association testing was carried out using Plink. The cumulative genetic risk was assessed using unweighted and weighted approaches. Significant associations between thyroid cancer risk and rs965513A (OR = 1.503, 95% CI: 1.203-1.886, P = 0.00038) and rs944289T (OR = 1.372, 95% CI: 1.095-1.699, P = 0.00488) was observed in our study. Consistent, yet not -significant associations were observed between disease risk and rs2439302T (OR = 1.177, 95% CI: 0.931-1.477, P = 0.1666) and rs116909374A (OR = 1.626, 95% CI: 0.799-3.766, P = 0.2443). For rs966423G, significant departure from HWE was observed therefore this SNP was excluded from further analysis. The combined analyses of rs2439302, rs965513, rs116909374 and rs944289 showed consistent associations between the number of disease alleles and cancer risk. Having three risk alleles increased disease risk by two-fold (OR = 2.09, 95% CI:1.46 - 3.02),while carrying five risk alleles was associated with nearly 4-fold increase in the disease risk (OR = 3.84, 95% CI:1.47 - 10.06). To our knowledge, this was the first study that assessed TC risk associated with known polymorphisms in the Hispanic population and suggest that these variants could be used in future risk prediction profiling studies in these populations.
Citation Format: Ana Estrada-Flórez, Mabel E. Bohórquez-Lozano, Rodrigo Prieto-Sánchez, Gilbert F. Mateus, Alejandro Rios, Alejandro Vélez Hoyos, Carlos S. Duque, Mirko A. Ledda, Maria J. Erazo, Fernando Bolaños, Cesar Panqueba, María Magdalena Echeverry de Polanco, Luis G. Carvajal-Carmona. Evaluation of known low-penetrance thyroid cancer risk alleles in a Hispanic population from South America. [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 LB-046. doi:10.1158/1538-7445.AM2015-LB-046
Abstract LB-075: The histone demethylase JMJD1A is essential to prostate cancer cells through regulation of c-Myc expression
Authors: Fan Lingling , Peng Guihong , Sahgal Natasha , Fazli Ladan , Gleave Martin , Zhang Yuji , Hussain Arif , Qi Jianfei 
Published: August 2015

Abstract
Histone demethylase JMJD1A controls gene expression by epigenetic regulation of H3K9 methylation marks. To investigate role of JMJD1A in the development and progression of prostate cancer, we knock down JMJD1A in prostate cancer cells and examine its effect on gene expression and cancer cell biology. We find that silencing of JMJD1A results in the lethality of prostate cancer cells concomitant with inhibition of cell proliferation, induction of apoptosis and cell cycle arrest. Profiling array analyses reveal c-Myc as one of the top transcriptional networks altered upon the JMJD1A inhibition. The gene ontology pathway analyses show that the primary functions of c-Myc targets regulated by JMJD1A are related to cell cycle, cell proliferation and cell survival. Mechanistically, JMJD1A promotes the recruitment of AR and induces demethylation at the c-Myc gene enhancer, thereby increasing the AR-dependent transcription of c-Myc mRNA. In a parallel pathway, JMJD1A binds to E3 ubiquitin ligase HUWE1, attenuates the HUWE1-induced degradation of c-Myc, and thus increases the c-Myc protein level. Together, JMJD1A controls the expression of c-Myc at transcriptional and post-translational levels. Re-expression of c-Myc in the JMJD1A-knockdown cells partly recues the growth of prostate cancer cells in vitro and in vivo. The protein level of c-Myc is positively correlated with that of JMJD1A in a subset of human prostate cancer specimens. Collectively, our findings identify a critical role of JMJD1A for the viability of prostate cancer cells through regulation of c-Myc expression.
Note: This abstract was not presented at the meeting.
Citation Format: Lingling Fan, Guihong Peng, Natasha Sahgal, Ladan Fazli, Martin Gleave, Yuji Zhang, Arif Hussain, Jianfei Qi. The histone demethylase JMJD1A is essential to prostate cancer cells through regulation of c-Myc expression. [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 LB-075. doi:10.1158/1538-7445.AM2015-LB-075
Abstract LB-103: Structural characterization of SPRY2-Cbl interactions
Authors: Zhang Na , Zhang Xuan , Washington Laurie , Anbanandam Asokan , Battaile Kevin , Gao Philip , Smalter Hall Aaron , Lovell Scott , Roy Anuradha , Hanzlik Robert , Perez Raymond 
Published: August 2015

Abstract
Sprouty 2 (SPRY2) is a feedback modulator of receptor tyrosine kinase (RTK)-ERK signaling, and a potential tumor suppressor. Cbl, an E3 ubiquitin ligase and scaffold protein, binds SPRY2 with high affinity, and sequesters or targets it for degradation. Cbl also binds several growth factor receptors. Hence SPRY2, Cbl and receptors are in a dynamic equilibrium. Truncation and site-mutagenesis studies previously mapped SPRY2-Cbl interactions to two discrete domains, TKB and RING. A pY binding pocket in the TKB SH2 region is critical for binding, but the role(s) of other TKB regions and/or RING are undefined. Interactions of three Cbl recombinant proteins (P47-G351 (TKBD), and two phosphomimetic RING active-conformation constructs, P47-D435 Y371D/E) with three SPRY2 peptides (P1: Q36-N53, a putative RING binder; P2: Q36-T60 (pY55), TKB binder; and P3: 54-60(pY55), a truncated TKB binder) were characterized by computational simulation, surface plasmon resonance spectroscopy (SPR), fluorescence polarization (FP), and X-ray crystallography. In silico modeling suggested possible low-affinity binding of P1 in the groove between TKBD SH2 and 4-helix (4H) regions and near the RING, but this was not confirmed by FP, SPR, or crystallography. Apo and P2 ligand-bound structures agreed with prior published data; three previously unknown 4H interaction sites were also identified. Data on the effects of site-specific 4H mutants on P2 binding affinities are pending. Binding affinities for P2 with the TKBD, Y371E, and Y371D constructs were 160±5, 92±9, and 45±3 nM, respectively, by SPR; FP results were similar. Direct interactions with the RING were not confirmed, but the higher P2 binding affinities observed with RING constructs suggest that this domain indirectly facilitates SPRY2 binding. Binding of P2 induced 16.9° rotation of the SH2 region and formation of new H-bonds to 4H, compressing the TKBD. Importantly, P4 induced identical conformational changes as P2, but had no direct contact with 4H. These observations are consistent with a refined model of SPRY2-Cbl interaction, where ligand docking at the pY SH2 site is sufficient to globally change TKB architecture, facilitating SPRY2 binding at previously unrecognized sites in the 4H region (Support: KU COBRE-PSF (NIH/RR017708, NIH/GM103420), KU Cancer Center, Kansas Bioscience Authority, and the George & Floriene Lieberman Endowment).
Citation Format: Na Zhang, Xuan Zhang, Laurie Washington, Asokan Anbanandam, Kevin Battaile, Philip Gao, Aaron Smalter Hall, Scott Lovell, Anuradha Roy, Robert Hanzlik, Raymond Perez. Structural characterization of SPRY2-Cbl interactions. [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 LB-103. doi:10.1158/1538-7445.AM2015-LB-103
Abstract LB-115: Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients
Authors: Ferrucci Pier Francesco , Gandini Sara , Battaglia Angelo , Alfieri Salvatore , Pala Laura , Di Giacomo Annamaria , Amato Giovanni , Antonini Cappellini Gian Carlo , Giannarelli Diana , Cocorocchio Emilia , Martinoli Chiara 
Published: August 2015

Abstract
Background: Ipilimumab, a recently approved immunomodulatory drug, improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to obtain clinical benefit from treatment. The aim of this study was to identify a criterion to select patients best suited to receive this drug.
Methods: Sixty-nine metastatic melanoma patients treated at the European Institute of Oncology with 3 mg/kg ipilimumab, were evaluated. Neutrophil to lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied. Findings were independently validated on a cohort of 27 patients treated with 10 mg/kg ipilimumab at the University Hospital of Siena and on a cohort of 88 treated in Rome.
Results: Best overall response and disease control rates were 9% and 27%, respectively. Median PFS and OS were 3 and 5 months, respectively. Pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in univariate and multivariate analyses. Patients with baseline NLR&lt;5 had a significantly improved PFS (HR = 0.38; 95% CI: 0.22-0.66; P = 0.0006) and OS (HR = 0.24; 95% CI: 0.13-0.46; P&lt;0.0001) compared with those with a NLR≥5.
Conclusions: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve as a selection criterion for this therapy.
Citation Format: Pier Francesco Ferrucci, Sara Gandini, Angelo Battaglia, Salvatore Alfieri, Laura Pala, Annamaria Di Giacomo, Giovanni Amato, Gian Carlo Antonini Cappellini, Diana Giannarelli, Emilia Cocorocchio, Chiara Martinoli. Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients. [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 LB-115. doi:10.1158/1538-7445.AM2015-LB-115
Abstract LB-120: HER2 as a potential predictive marker and target for therapy in cervical cancer
Authors: Halle Mari K. , Ojesina Akinyemi I. , Tangen Ingvild L. , Holst Frederik , Engerud Hilde R. , Bertelsen Bjørn I. , Krakstad Camilla , Salvesen Helga B. 
Published: August 2015

Abstract
Cervical cancer is the third leading cause of cancer in the female population worldwide, causing the death of more than 240,000 patients annually in developing countries. Increased molecular knowledge is crucial to identify robust prognostic and predictive biomarkers that can better guide treatment. The tumor response to trastuzumab is well established and strongly links to HER2 expression status evaluated by the Hercep Test, hence, it is essential to define the level of expression of this receptor using the FDA-approved Hercep Test to stratify cervical cancer patients with potential benefits from trastuzumab treatment.
Comprehensive molecular characterization has been conducted on 88 paired normal and tumor cases identifying ERBB2 to be frequently altered in cervical cancers. We here explore the protein expression of HER2 by immunohistochemical staining in a larger validation series (n = 220) and relate HER2 expression to the ERBB2 gene alterations, patients molecular profile and clinicopathological features.
We find a highly significant correlation between Hercep Test score and mRNA ERBB2 expression (p&lt;0.001). The level of ERBB2 mRNA was also significantly associated with copy number status (p = 0.007). Further clinocopathological parameters like high FIGO stage, high grade, adenocarcinomas and normal p53 status was significantly linked to high HER2 protein expression. Kaplan Meier survival analysis revealed that within the squamous cell carcinomas, high protein levels of HER2 was linked to poorer disease specific survival.
Our results show a link between ERBB2 amplification, high mRNA expression and protein levels for HER2 in aggressive cervical cancers. Further studies of HER2 as a potential predictive marker for response to trastuzumab treatment in cervical cancer are needed.
Citation Format: Mari K. Halle, Akinyemi I. Ojesina, Ingvild L. Tangen, Frederik Holst, Hilde R. Engerud, Bjørn I. Bertelsen, Camilla Krakstad, Helga B. Salvesen. HER2 as a potential predictive marker and target for therapy in cervical 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 LB-120. doi:10.1158/1538-7445.AM2015-LB-120
Abstract LB-135: E-cadherin as a buffer for mutated B-catenin: A genetic comparison of Apc and B-catenin mutations in vivo
Authors: Huels David J. , Ridgway Rachel A. , Sansom Owen J. 
Published: August 2015

Abstract
Wnt deregulation is a characteristic of many cancers, especially Colorectal Cancer (CRC). However, only the intestine harbours mutations in the tumour suppressor gene (TSG) Adenomatous Polyposis Coli (APC) which can be found in around ∼80% of CRC patients. Other cancers (e.g. hepatocellular carcinoma, solid pseudopapillary cancer) achieve Wnt deregulation by specific mutations of B-catenin (CTNNB1).
Using genetic approaches in the mouse intestine we compared mutations in APC and B-catenin in the level of Wnt activation, their kinetics and their ability to transform the intestinal epithelium in vitro and in vivo.
Deregulation of Wnt by mutation of B-catenin is much slower than by loss of APC, and only gradually increases Wnt activity. In contrast to loss of APC, Wnt deregulation by mutation of B-catenin is almost completely restricted to the small intestine of mice, and not the colon. We have evidence that the restriction of the B-catenin phenotype is due to different E-cadherin levels in the small intestine compared to the colon. Mutation of B-catenin in addition to reduction of E-cadherin levels synergises dramatically in vivo and is now able to transform the colon epithelium. We show that E-cadherin at the adherens junctions acts as buffer for the mutated B-catenin and slows down its accumulation in the cytoplasm.
These data shows a clear restriction of B-catenin mediated tumor initiation by E-cadherin. Interestingly, the other cancer types (hepatocellular carcinoma, solid pseudopapillary cancer) show a similar negative relationship of B-catenin mutation and E-cadherin expression.
Citation Format: David J. Huels, Rachel A. Ridgway, Owen J. Sansom. E-cadherin as a buffer for mutated B-catenin: A genetic comparison of Apc and B-catenin mutations in vivo. [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 LB-135. doi:10.1158/1538-7445.AM2015-LB-135
Abstract LB-147: Colonic crypt neuroendocrine cells regulate colonic stem cells during colorectal cancer development
Authors: Modarai Shirin R. , Opdenaker Lynn M. , Boman Bruce M. 
Published: August 2015

Abstract
Our studies on tissues from colon cancer patients show that in the development of CRC, stem cells (SC) overpopulation underlies tumor initiation and progression. Specifically, we have involved studying patients with Familial Adenomatous Polyposis (FAP) during CRC development, which carry cancer-predisposing germline mutations in the adenomatous polyposis coli (APC) gene. These results indicate that SC overpopulation caused by APC mutations is the driver mechanism. However, how the APC mutations cause SC overpopulation needs clarification.
Similar to SCs, Neuroendocrine cells (NECs) comprise ∼1% of the total cells in the colon and both reside in the crypt stem cell niche in the colonic epithelium. NECs are involved in autocrine and paracrine signaling to help regulate the function of surrounding cells. This leads to an overall goal of this project, to study the relationship between NECs and SCs in young-onset CRC, especially those individuals with a genetic predisposition to CRC. Our overall hypothesis is that NECs play a key role in maintaining the SC population in the normal colon and, aberrant signaling from NECs contributes to tumor initiation and increased stemness.
To begin to investigate underlying mechanisms, we studied human colon tissues with varying APC genotypes: (i) normal crypts (homozygous-wildtype APC); (ii) normal-appearing FAP crypts (heterozygous-mutant APC); (iii) adenomatous FAP crypts (homozygous-mutant APC); (iv) CRCs (homozygous-mutant APC& other mutations). Preliminary data from our laboratory has shown that in colon cancer progression: (i) there is a decrease in the number of cells that co-express both SC and NEC markers (ii) there is a decrease in the total number of NECs, and (iii) there is an increase in the total number of SCs. Furthermore, we have established an in vitro co-culture model system to study regulation of SCs by NECs. Results from our model show that SSTR1 and GLP-2R NEC signaling plays a role in modulating colonic SC populations. This in vitro model system can help analyze the interaction between SCs and NECs during CRC progression.
Taken together, our findings indicate that: (1) NE factors contribute to colonic SC regulation via an autocrine or paracrine mechanism in normal colon, and (2) dysregulation of these mechanisms contributes to colon cancer development. Using our established in vitro model system, we can track the changes in the SC and NEC population size, based on different conditions of anchorage independent growth and presence of potential therapeutic agents.
Citation Format: Shirin R. Modarai, Lynn M. Opdenaker, Bruce M. Boman. Colonic crypt neuroendocrine cells regulate colonic stem cells during colorectal cancer development. [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 LB-147. doi:10.1158/1538-7445.AM2015-LB-147