bluuebunny/crossref_metadata_2025_split huggingface dataset:
SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor
Authors: Chiang Cheng-Yao , Pan Chin-Chen , Chang Hong-Yi , Lai Ming-Derg , Tzai Tzong-Shin , Tsai Yuh-Shyan , Ling Pin , Liu Hsiao-Sheng , Lee Bi-Fang , Cheng Hong-Ling , Ho Chung-Liang , Chen Shu-Hui , Chow Nan-Haw 
Published: August 2015

Abstract
Purpose: Mass spectrometry–based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma.
Experimental Design: Shot-gun proteomics using liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines.
Results: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028). SH3BGRL3 expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P = 0.032). SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P &lt; 0.0001). SH3BGRL3 promotes the epithelial–mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway.
Conclusions: Evaluation of SH3BGRL3 expression status or urine content may identify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies. Clin Cancer Res; 21(24); 5601–11. ©2015 AACR.
Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2
Authors: Smith Bryan D. , Kaufman Michael D. , Leary Cynthia B. , Turner Benjamin A. , Wise Scott C. , Ahn Yu Mi , Booth R. John , Caldwell Timothy M. , Ensinger Carol L. , Hood Molly M. , Lu Wei-Ping , Patt Tristan W. , Patt William C. , Rutkoski Thomas J. , Samarakoon Thiwanka , Telikepalli Hanumaiah , Vogeti Lakshminarayana , Vogeti Subha , Yates Karen M. , Chun Lawrence , Stewart Lance J. , Clare Michael , Flynn Daniel L. 
Published: August 2015

Abstract
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood–brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases. Mol Cancer Ther; 14(9); 2023–34. ©2015 AACR.
Abstract AS03: Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer
Authors: Chung VY , Tan M , Tan TZ , Kuay KT , Ye J , Thiery JP , Huang RY 
Published: August 2015

Abstract
Epithelial ovarian cancer (EOC) is highly heterogeneous with five molecular subgroups, Epi-A, Epi-B, Mes, Stem-A and Stem-B, being identified. The mechanisms behind the clonal evolution and intertumoral molecular heterogeneity are not fully elucidated. Previously, we performed EOC profiling meta-analysis to identify epithelial-mesenchymal transition (EMT) as the crucial mechanism for molecular heterogeneity. Transcription factors SNAI1, SNAI2, ZEB1, ZEB1, TWIST1, and GRHL2 were identified as crucial regulators for the Mes subtype which has undergone EMT. Here, we utilized three in-vitro EOC cell lines, PEO1, OVCA420, and OVCA429, to model the EMT-driven clonal evolution by manipulating the expression levels of these EMT transcriptional regulators. We analysed the molecular subtypes of matched primary tumor versus peritoneal metastases. Six out of 11 pairs showed concordant molecular subtypes. We also analysed a dataset of matched primary tumor versus omental metastases. Four out of 9 pairs showed concordant molecular subtypes. Among the 10 pairs showing a shift of molecular subtypes, 5 out of 5 omental metastases were designated as Mes. The variation in the evolution of molecular heterogeneity can be explained by the differences in the EMT transcriptional cross-regulation of the in-vitro models. Manipulating EMT regulators in PEO1 did not induce any transcriptional cross-regulation with no molecular subtype switching observed. However, manipulating EMT regulators in OVCA420 and OVCA429 caused hierarchical transcriptional control and feedback loop regulation, respectively. The OVCA429 model showed molecular subtype switch from Epi-A to Mes. In conclusion, the heterogeneity caused by EMT-driven clonal evolution is the consequence of transcriptional feedback loops of EMT regulators.
Citation Format: Chung VY, Tan M, Tan TZ, Kuay KT, Ye J, Thiery JP & Huang RY. Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS03.
Abstract AS05: Metabolomic signatures in sera from early stage ovarian cancer patients
Authors: Gaul David A. , Jones Christina M. , Monge Maria Eugenia , Tran Long Q. , Matzuk Martin M. , McDonald John F. , Fernandez Facundo M. 
Published: August 2015

Abstract
PURPOSE: Lack of symptoms as well as the deficiency of highly specific biomarkers has resulted in only a quarter of ovarian cancer cases being diagnosed in stage I. Early detection combined with conventional therapies has resulted in 5-year survival rates up to 90%, while 5-year overall survival is less than 30% for women with advanced stage ovarian cancer. An effective screening strategy for early diagnosis would be particularly advantageous for ovarian cancer patients. Investigation into characteristic metabolomic patterns for disease has the potential to detect changes in cells, tissues, and biofluids that can aid in diagnosis at an early stage.
METHODS: Serum samples were collected from early-stage serous papillary or endometrioid ovarian cancer (n=26) and normal patients (n=40) and analyzed using ultra high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-MS) and tandem mass spectrometry (MS/MS). Metabolites were extracted from blood serum by precipitating proteins with methanol, lyophilization, and solvent reconstitution prior to MS analysis in both positive and negative electrospray ionization modes. Metabolic features were extracted with MZmine software. Untargeted multivariate statistical analysis employing support vector machine (SVM) learning methods, genetic algorithms and recursive feature elimination (RFE) selected a panel of metabolites that differentiates between the age-matched samples with better than 92% sensitivity and 91% specificity in all cases tested.
RESULTS: Comparison of metabolic phenotypes of ovarian cancer with normal metabolic signatures revealed unique metabolite patterns for ovarian cancer. From multivariate statistical analysis, panels consisting of 17-35 metabolic features from serum samples were found to differentiate between early stage cancer and normal with very high accuracy, sensitivity, and specificity.
CONCLUSIONS: Poor early diagnosis complicates collection of large patient cohorts for more detailed studies. Our preliminary work demonstrated that metabolites in serum samples may be useful for detecting early-stage ovarian cancer and support conducting larger, more focused studies.
(Grant support: Marsha Rivkin Ovarian Cancer Challenge Grant; Ovarian Cancer Research Fund (OCRF))
Citation Format: David A. Gaul, Christina M. Jones, Maria Eugenia Monge, Long Q. Tran, Martin M. Matzuk, John F. McDonald*, Facundo M. Fernandez*. Metabolomic signatures in sera from early stage ovarian cancer patients [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS05.
Abstract AS06: Development and characterization of an oviduct-specific model of high-grade serous carcinoma
Authors: Zhai Yali , Wu Rong , Hu Tom C. , Fearon Eric R. , Cho Kathleen R. 
Published: August 2015

Abstract
Recent studies suggest the most common and lethal type of “ovarian” cancer, high-grade serous carcinoma (HGSC), often arises from fallopian tube epithelium rather than the ovarian surface epithelium. Their intraperitoneal location and microscopic size make it very difficult to screen for, or study the biology of early tubal lesions in humans, as most are discovered incidentally in women with hereditary predisposition to ovarian cancer who elect prophylactic salpingo-oophorectomy for cancer risk-reduction. Although most cases of pelvic HGSC probably originate in the fallopian tube, roughly one-third lack evidence of tubal origin. These cases may arise from ectopic tubal-type epithelium (endosalpingiosis) present in the ovary, peritoneum, or at other sites. Mouse models that closely mimic the genetics and biology of human HGSCs may be useful for clarifying how tubal and non-tubal pelvic HGSCs develop and progress.
We have developed transgenic (Ovgp1-iCreERT2) mice allowing conditional (tamoxifen [TAM]-inducible) expression of Cre recombinase exclusively in the oviductal epithelium, using a single transgene. Using double transgenic Ovgp1-iCreERT2;R26LSL-eYFP mice in which TAM treatment activates eYFP reporter protein expression in oviductal epithelial cells, we have shown that tubal-type inclusion glands (endosalpingiosis) expressing both eYFP and OVGP1 are present in a subset of murine ovaries following treatment with TAM. The findings suggest that oviductal epithelium can detach from the oviduct and traffic to the ovaries, where it implants through breaks in the OSE and maintains its tubal-type differentiation. Preliminary data also suggest that the frequency of ovarian endosalpingiosis increases over time and by superovulating the mice. The latter finding raises the possibility that at least some of the protective effects of high parity and oral contraceptive use on human ovarian cancer risk is related to reduced likelihood of acquiring endosalpingiosis from which “ovarian” HGSCs may eventually arise.
We have further shown that Ovgp1-iCreERT2;Trp53fl/fl;Brca1fl/fl mice develop oviductal lesions identical to human serous tubal intraepithelial carcinomas (STICs) after TAM treatment and have identified additional genetic alterations that cooperate with Trp53 and Brca1 inactivation in oviductal HGSC pathogenesis in our model system. Murine models of HGSC that recapitulate their human tumor counterparts provide excellent in vivo systems with which to define the cellular and molecular events associated with HGSC development and progression.
Citation Format: Yali Zhai, Rong Wu, Tom C. Hu, Eric R. Fearon, Kathleen R. Cho. Development and characterization of an oviduct-specific model of high-grade serous carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS06.
Abstract AS15: DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer
Authors: Valle Blanca L. , Kuhn Elisabetta , Sidransky David , Guerrero-Preston Rafael 
Published: August 2015

Abstract
Background: Until recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors.
Purpose of study: Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium. Using the Infinium HumanMethylation 450 Array, that permits to quantitatively assess over 450,000 methylation sites, within and outside of CpG islands and more than 20,000 genes per sample, at single-nucleotide resolution, we have obtained the genome-wide methylation profile of HGSC and fallopian tubal epithelium. We conducted a pilot study by comparing the global methylation in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs.
Results: Our results identified the HIST1H2BB promoter as the most differentially methylated region when comparing HGSC with normal fallopian tube samples. Furthermore, we also found that HIST1H2BB is differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival.
Conclusions: Taken together, these results support the potential of HIST1H2BB promoter hypermethylation as a diagnostic and prognostic biomarker. Our findings could lead to the development of a biomarker for the diagnosis and/or prognosis of ovarian cancer and could contribute to the current understanding of the mechanisms of progression in ovarian cancer.
Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS15.
Abstract AS18: The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions
Authors: Anglesio Michael S , Bashashati Ali , Wang Yikan , Ha Gavin , Senz Janine , Yang Winnie , Kalloger Steve E , Prentice Leah M , Yanagida Satoshi , Salamanca Clara , Soukhatcheva Galina , Kazernis Anthony , Chang Hector , Mes-Mason Anne-Marie , Okamoto Aikou , Marra Marco A , Gilks Blake , Shah Sohrab P , Huntsman David G 
Published: August 2015

Abstract
Introduction: Clear Cell ovarian carcinomas (CCC) represent 10% of ovarian carcinomas, with outcomes for high-stage significantly worse than high-grade serous form. The complete mutational landscape, the molecular basis of the transformation of endometriosis, the putative precursor, and patterns of clonal evolution in CCC are not well understood.
Methods: Whole genome sequencing and gene expression profiling was done to uncover somatic alterations and measure effects on transcriptional networks. Targeted deep sequencing of primary tumors, metastases and endometriosis was also performed and statistical modeling approaches were used to validate mutations, quantify clonal diversity, and trace patterns of selection.
Results: Mutations in ARID1A (11/19) and PIK3CA (8/19) were by far the most frequent aberrations seen. Three other SWI/SNF components also showed somatic alteration: two in non-ARID1A mutant cases and a truncating mutation of ARID1B in an ARID1A-null case. Amongst 24 significant “candidate drivers” impacting expression, five “cancer genes” have been previously described: PIK3CA, ARID1A, CTNNB1, TP53, and PPP2R1A. We observed no association between PIK3CA or ARID1A status with disease stage, genomic instability, or mutation load. Deep sequencing data suggested multiple clones in every case. In cases with matching precursor lesions, we observed multiple mutations in at least one such lesion. In precursor lesions where tumor-matched somatic mutations were observed, ARID1A and PIK3CA mutations were also always present, if observed in the matched tumor.
Conclusions: ARID1A and PIK3CA mutations appear as early and histo-type defining events in CCC. Pattern of endometriosis transformation can be associated with somatic mutations in all cases, including histologically “Atypical” and non-atypical endometriosis. Finally, patterns of mutational conservation across the series of precursor lesions may present an opportunity for early screening of endometriosis tissues as an indicator of transformation potential.
Citation Format: Michael S Anglesio, Ali Bashashati, Yikan Wang, Gavin Ha, Janine Senz, Winnie Yang, Steve E Kalloger, Leah M Prentice, Satoshi Yanagida, Clara Salamanca, Galina Soukhatcheva, Anthony Kazernis, Hector Chang, Anne-Marie Mes-Mason, Aikou Okamoto, Marco A Marra, Blake Gilks, Sohrab P Shah, David G Huntsman. The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS18.
Abstract AS19: The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer
Authors: Fuh Katherine , Rankin Erinn , Wu Colleen , Diep Anh , Giaccia Amato J. 
Published: August 2015

Abstract
Objective: To evaluate the role of AXL in an immunocompetent model of ovarian cancer metastasis.
Methods: Immunohistochemical staining of ovarian cancer tissue microarrays of advanced stage, high-grade epithelial ovarian cancer specimens for AXL expression was performed and correlated with overall survival. Metastatic endometrioid ovarian cancer was generated through intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model. LSL-K-rasG12D/+Ptenfl/fl Axl+/+ and LSL-K-rasG12D/+Ptenfl/flAxl−/−were used to evaluate the role of AXL. Necropsy was performed to evaluate burden of the primary and metastatic tumors. Hematoxylin and eosin (H&E) staining was used to confirm tumor formation or lack of tumor. Western blotting was performed to evaluate protein expression.
Results: Of the 80 patient-derived primary ovarian tumor specimens, 76% (61) of advanced stage, high-grade epithelial ovarian cancer specimens had 3+ transmembrane AXL staining whereas 24% (19) of advanced stage, high-grade epithelial ovarian cancer specimens had no AXL staining. When correlated with overall survival, patients with tumors that had no AXL expression had a median survival of 53 months vs. 45 months for those with 3+AXL expression (p=0.12). The majority of intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl Axl+/+ mice had primary (78%) and metastatic tumor formation (86%) whereas the majority of LSL-K-rasG12D/+Ptenfl/flAxl−/− had primary tumor formation (64%) but few had metastatic tumors (28%) (p&lt;0.05). There was no difference in primary tumor weight between the two groups: 120mg for Axl+/+ vs. 110mg for Axl−/−. Metastatic tumors were microscopic and therefore unable to be resected and weighed prior to identification by H&E staining. Western blotting of primary and metastatic tumors from LSL-KrasG12D/+Ptenfl/fl Axl+/+ showed high AXL expression compared to no AXL expression in the ovaries of normal mice.
Conclusions: AXL expression in advanced stage epithelial ovarian cancer correlated with lower overall survival. Primary ovarian and metastatic tumors in this intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model express AXL. Deletion of the receptor tyrosine kinase, AXL, in this conditional genetically engineered mouse model of endometrioid ovarian cancer resulted in inhibition of metastatic tumor formation. AXL is a critical factor driving metastasis in this immunocompetent murine model of metastatic ovarian cancer.
Citation Format: Katherine Fuh, Erinn Rankin, Colleen Wu, Anh Diep, Amato J. Giaccia. The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS19.