bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fast Linear SVM Validation Based on Early Stopping in Iterative Learning
Authors: Famouri Mahmoud , Taheri Mohammad , Azimifar Zohreh 
Published: August 2015

Classification is an important field in machine learning and pattern recognition. Amongst various types of classifiers such as nearest neighbor, neural network and Bayesian classifiers, support vector machine (SVM) is known as a very powerful classifier. One of the advantages of SVM in comparison with the other methods, is its efficient and adjustable generalization capability. The performance of SVM classifier depends on its parameters, specially regularization parameter C, that is usually selected by cross-validation. Despite its generalization, SVM suffers from some limitations such as its considerable low speed training phase. Cross-validation is a very time consuming part of training phase, because for any candidate value of the parameter C, the entire process of training and validating must be repeated completely. In this paper, we propose a novel approach for early stopping of the SVM learning algorithm. The proposed early stopping occurs by integrating the validation part into the optimization part of the SVM training without losing any generality or degrading performance of the classifier. Moreover, this method can be considered in conjunction with the other available accelerator methods since there is not any dependency between our proposed method and the other accelerator ones, thus no redundancy will happen. Our method was tested and verified on various UCI repository datasets and the results indicate that this method speeds up the learning phase of SVM without losing any generality or affecting the final model of classifier.
Abstract A06: The chemokine receptor CXCR4 is essential for the maintenance of T cell acute lymphoblastic leukemia.
Authors: Pitt Lauren A. , Tikhonova Anastasia N. , Trimarchi Thomas , King Bryan , Hu Hai , Gong Yixiao , Tsirigos Aris , Sanchez-Martin Marta , Littman Dan R. , Ferrando Adolfo , Morrison Sean J. , Fooksman David R. , Aifantis Iannis , Schwab Susan 
Published: August 2015

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising in immature T cell progenitors. Despite improved survival rates, relapse remains a major therapeutic obstacle and intensive treatment regimens expose T-ALL patients to serious long-term side-effects. Hence more effective, less toxic treatment options are required. While the localization of leukemia cells determines the course of disease, little is known about T-ALL migration. Upon profiling chemokine receptor expression by T-ALL cells, we observed high surface levels of the CXCL12 receptor, CXCR4. Intravital imaging revealed that T-ALL cells are in direct contact with CXCL12-producing bone marrow stromal cells in vivo. Genetic targeting of CXCR4 in T-ALL cells resulted in a marked reduction of leukemia burden and significantly prolonged survival. Moreover, disruption of CXCR4 signaling with a small molecule inhibitor severely impaired T-ALL progression in mouse and human xenograft models of the disease. We found that CXCR4 promotes c-Myc expression, which is required in leukemia initiating cells. Given the relatively subtle role for CXCR4 in normal developing T cells, CXCR4 inhibition to our knowledge has not been proposed as a therapy for T cell malignancies. Our data strongly suggest that targeting CXCR4 could be a promising strategy for combating T-ALL.
Citation Format: Lauren A. Pitt, Anastasia N. Tikhonova, Thomas Trimarchi, Bryan King, Hai Hu, Yixiao Gong, Aris Tsirigos, Marta Sanchez-Martin, Dan R. Littman, Adolfo Ferrando, Sean J. Morrison, David R. Fooksman, Iannis Aifantis, Susan Schwab. The chemokine receptor CXCR4 is essential for the maintenance of T cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A06.
Abstract AS12: Integrating genomics, transcriptomics, and proteomics for the discovery of novel biomarkers to complement CA125 in ovarian cancer early detection
Authors: Boldt Clayton , Simmons Archana , Wang Hong , Baggerly Keith , Bast Robert , Hanash Samir 
Published: August 2015

Abstract
Recent work suggests that a 2-stage strategy incorporating serial measurements of the glycoprotein CA125 in patient serum and the Risk of Ovarian Cancer Algorithm (ROCA), followed by transvaginal ultrasound for women with high-risk scores, may have utility as a screening practice in the general population. However, CA125 only has a sensitivity of 50-60% for early stage disease, and is only present in approximately 80% of all ovarian cancers. Multiple marker panels have shown promise at increasing sensitivity and specificity over CA125 alone, but have not improved lead time for early cancer detection.
Therefore, we have taken an unbiased in-depth approach to identify novel plasma biomarkers to complement CA125 in ovarian cancer early detection. Using high-resolution quantitative mass spectrometry, we have profiled the plasma proteome of preclinical patient samples, taken 1 year prior to CA125 elevation and diagnosis, and healthy controls from the Normal Risk Ovarian Screening (NROS) study. With this approach, we have identified over 30 biomarker candidates that are elevated in at least 50% of preclinical samples relative to controls in triplicate experiments, including cancer-specific post-translational modifications.
As a means of preliminary validation of promising preclinical biomarkers, we have profiled the plasma proteome of 24 newly diagnosed, early stage ovarian cancer patients and 24 matched healthy controls. Further, half of these patients were selected with uninformative CA125 levels at diagnosis, allowing for the discovery of additional candidate biomarkers that may complement CA125.
Correlation of preclinical and newly diagnosed patient plasma data with publicly available genomic and transcriptomic data, as well as proteomic data previously collected from ovarian cancer cell lines resulted in a prioritized list of candidate protein biomarkers and autoantibodies in patient plasma that may improve detection and lead time over CA125. For the most promising candidates, monoclonal antibodies and MagPlex assays are being optimized in order to determine their performance as useful biomarkers in additional patient sera. Multimarker panels will be tested in a training set for the development of a screening algorithm that will be evaluated in preclinical sera to determine the optimized set that improves detection and lead time over CA125.
Citation Format: Clayton Boldt, Ph.D., Archana Simmons, Ph.D., Hong Wang, MS, Ph.D., Keith Baggerly, Ph.D., Robert Bast, Jr., M.D., Samir Hanash, M.D., Ph.D.. Integrating genomics, transcriptomics, and proteomics for the discovery of novel biomarkers to complement CA125 in ovarian cancer early detection [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 AS12.
Abstract AS21: Ovarian carcinoma CDK12 mutations misregulate DNA repair genes via deficient formation and function of the Cdk12/CycK complex
Authors: Ekumi Kingsley M. , Paculova Hana , Pospichalova Vendula , Bosken Christian A. , Bryja Vitezslav , Geyer Matthias , Blazek Dalibor , Barboric Matjaz 
Published: August 2015

Abstract
The Cdk12/CycK complex promotes gene expression by phosphorylating the C-terminal domain of RNA polymerase II. In previous work we found that CDK12/CycK complex maintains genomic stability via regulation of expression of several key DNA damage response genes such as BRCA1, ATR, FANCD2 or FANCI. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, the influence of these mutations on the Cdk12/CycK complex and their link to cancerogenesis remain ill-defined. Here, we show that most mutations interfere with the Cdk12/CycK complex formation, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations identifies coordinated down-regulation of key DNA damage response genes. Accordingly, we observed that the mutant Cdk12 proteins fail to promote the repair of DNA double strand breaks via homologous recombination. Together, we provide the molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations may elicit defects in multiple DNA repair pathways, leading to genomic instability that underlies the genesis of the cancer..
Citation Format: Kingsley M. Ekumi, Hana Paculova,Vendula Pospichalova, Christian A. Bosken,Vitezslav Bryja, Matthias Geyer, Dalibor Blazek, Matjaz Barboric. Ovarian carcinoma CDK12 mutations misregulate DNA repair genes via deficient formation and function of the Cdk12/CycK complex [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 AS21.
Abstract POSTER-BIOL-1308: Macrophage infiltration in high-grade serous carcinomas of humans and mice
Authors: Pejovic Tanja , Bean Yukie , Kim Jaeyeon , Matzuk Martin M. , Coffelt Seth B. 
Published: August 2015

Abstract
Over the past 10-15 years, focus on the immune system has reinvigorated cancer research and oncology. Both clinical and experimental evidence generated during this time has shown that immune cells and their molecular mediators represent viable targets for therapeutic manipulation. The immune cell composition of high-grade serous carcinoma (HGSC) consists primarily of macrophages and various T cell subsets. However, the functional contribution of each of these cell types is largely unknown. In order to gain insight into whether these cells are pro- or anti-tumorigenic, we generated tissue microarrays containing tumors from 169 patients with pretreated ovarian cancer and quantified the number of CD68+ macrophages in each biopsy. Tumors were divided into high- or low-infiltrated groups based on the median number of macrophages amongst all HGSCs. Interestingly, patients whose tumors were highly infiltrated with macrophages exhibited worsened overall survival, suggesting that macrophages function as pro-tumorigenic cells in these tumors. To investigate the role of macrophages in HGSC progression, we have begun to characterize their abundance and phenotype in tumors of Dicerflox/flox;Ptenflox/flox;Amhr2cre/+ mice, a genetically engineered mouse model of HGSC. Macrophages constituted the predominant stromal and immune cell population in both primary tumors and secondary metastatic lesions. By contrast, macrophages were only found at low frequency in normal oviduct and ovaries. Gene expression analysis of these Dicer/Pten-deficient mouse tumors also revealed the increase in many macrophage-associated genes, as compared with normal oviduct tissue. Taken together, our data from mice and humans strongly indicate a crucial role for macrophages in facilitating ovarian cancer progression. Current efforts are underway to understand how macrophages promote ovarian tumor progression.
Citation Format: Tanja Pejovic, Yukie Bean, Jaeyeon Kim, Martin M. Matzuk, Seth B. Coffelt. Macrophage infiltration in high-grade serous carcinomas of humans and mice [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 POSTER-BIOL-1308.
Abstract POSTER-BIOL-1317: Releasing the brakes on ovarian cancer cell survival: epigenetic suppression of RGS10 in ovarian cancer chemoresistance
Authors: Hooks Shelley 
Published: August 2015

Abstract
G-protein signaling pathways promote cell survival, which is aberrantly enhanced in chemoresistant ovarian cancer. Regulator of G-protein Signaling (RGS) proteins limit the strength of G-protein signaling, and therefore indirectly control cell survival. We have previously shown that RGS10 suppresses ovarian cancer cell growth and limits survival in the presence of cytotoxic chemotherapeutic drugs. Further, we have shown that RGS10 expression is suppressed in cell models of ovarian cancer chemoresistance, suggesting that ovarian cancer cells silence RGS10 expression to release the brakes on their growth and survival. However, the mechanisms governing RGS10 expression in ovarian cancer cells are poorly understood. In this study, we fully investigate the molecular mechanism of RGS10 suppression in ovarian cancer acquired chemoresistance, revealing key roles for epigenetic regulation by DNA hypermethylation and histone deacetylation. Pharmacological inhibition of DNA methyl-transferases (DNMTs) increases RGS10 expression in chemoresistant ovarian cancer cells, suggesting potential regulation by DNA methylation. Further, bisulfite sequencing analysis identified a region of the RGS10-1 promoter with significantly enhanced DNA methylation in chemoresistant A2780-AD cells relative to parental A2780 cells. More marked differences are observed in histone acetylation of the RGS10-1 promoter. Acetylated histone H3 associates with the RGS10-1 promoter was significantly lower in A2780-AD cells compared to parental cells, with a corresponding increase in histone deacetylase (HDAC) enzyme association. Further, both HDAC1 and DNMT1 exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 cooperatively contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.
Citation Format: Shelley Hooks, PhD. Releasing the brakes on ovarian cancer cell survival: epigenetic suppression of RGS10 in ovarian cancer chemoresistance [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 POSTER-BIOL-1317.
Abstract POSTER-BIOL-1324A: Loss of DYRK1A promotes transformation of the fallopian tube epithelial cells by oncogenic ras
Authors: Litovchick Larisa , Saini Siddharth , Karst Alison , Hu Lan , Drapkin Ronny , DeCaprio James A. 
Published: August 2015

Abstract
Purpose of the study: High-grade serous ovarian carcinoma (HGSOC) is an aggressive form of ovarian cancer that is characterized by nearly ubiquitous presence of somatic mutations in TP53 gene and widespread gene copy number variations. It is likely that some of these genetic alterations cooperate with TP53 mutations in the pathogenesis of HGSOC; however, the specific roles of individual genes that are frequently gained or lost in HGSOC are only beginning to emerge. We have previously characterised an important role of DYRK1A protein kinase in the ability of human cells to undergo G0/G1 cell cycle arrest and oncogenic-Ras induced senescence. DYRK1A is required for the assembly of the DREAM repressor complex that controls the genes involved in cell cycle progression; this function of DYRK1A could be promoted by LATS kinases of the Hippo tumor suppressor pathway. Analysis of the The Cancer Genome Atlas (TCGA) ovarian dataset revealed loss of heterozygosity (LOH) of DYRK1A gene in over 25% HGSOC tumors. Therefore, we sought to determine whether loss of DYRK1A function can contribute to ovarian carcinogenesis.
Experimental Procedures: A panel of human ovarian cancer cell lines was used to determine the levels of DYRK1A and its ability to suppress cell proliferation. The fallopian tube epithelial cell (FTEC) cell lines with stable shRNA knock-down of DYRK1A were used in transformation assays with ovarian cancer-relevant oncogenes. Bioinformatics analysis of the TGCA ovarian oncogenomic dataset was applied to determine whether DYRK1A loss in HGSOC could lead to perturbation of any specific gene expression programs.
Summary of Data: It was found that depletion of DYRK1A promotes oncogenic transformation of the FTEC cells expressing mutant p53R175H and oncogenic HRASG12V. Rescue of DYRK1A expression in these cells resulted in arrest of proliferation and senescence. DYRK1A protein levels were reduced in a subset of ovarian cancer cell lines; overexpression of active but not the kinase-inactive DYRK1A suppressed the proliferation of these cells. Gene Set Enrichment Analysis (GSEA) of the TCGA HGSOC dataset revealed upregulated expression of the DREAM target genes in a subset of samples with LOH of both DYRK1A and LATS1 genes.
Conclusion: Our findings support the role of DYRK1A as an ovarian tumor supressor and suggest that loss of DYRK1A function in HGSOC could lead to activation of transcription of the genes involved in cell proliferation.
Citation Format: Larisa Litovchick, Siddharth Saini, Alison Karst, Lan Hu, Ronny Drapkin, James A. DeCaprio. Loss of DYRK1A promotes transformation of the fallopian tube epithelial cells by oncogenic ras [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 POSTER-BIOL-1324A.
Abstract POSTER-BIOL-1327: Small cell carcinoma of the ovary, hypercalcemic type displays frequent inactivating germline and somatic mutations in SMARCA4
Authors: Ramos Pilar , Karnezis Anthony N. , Craig David W. , Sekulic Aleksandar , Russell Megan L. , Hendricks William P.D. , Corneveaux Jason J. , Barrett Michael T. , Shumansky Karey , Yang Yidong , Shah Sohrab P. , Prentice Leah M. , Marra Marco A. , Kiefer Jeffrey , Zismann Victoria L. , McEachron Troy A. , Salhia Bodour , Prat Jaime , Clarke Blaise A. , Pressey Joseph G. , Farley John H. , Anthony Stephen P. , Roden Richard B.S. , Cunliffe Heather E. , Huntsman David G. , Trent Jeffrey M. 
Published: August 2015

Abstract
Introduction: Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is arguably the most aggressive ovarian cancer. Most patients are diagnosed at an advanced stage, do not respond to chemotherapy, and die of disease within 1-2 years. It affects children and young women and is reported to occur in families. The cause of the disease is poorly understood. Therefore, we used next generation sequencing technology to identify the genetic basis of the disease.
Method: We performed whole genome, whole exome sequencing or targeted sequencing on tumours and germline samples from 17 SCCOHT patients and on the SCCOHT cell line BIN-67 and SCCOHT-1. Immunohistochemistry (IHC) was performed on formalin-fixed, paraffin-embedded tumors from 23 patients and on a tissue microarray of 485 primary ovarian tumours of other subtypes. BIN-67 cells harbouring biallelic inactivation of SMARCA4 were transduced with a lentivirus expressing wild type SMARCA4.
Result: We identified inactivating germline and somatic mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 79% (11/14) of SCCOHT patients, 2 of whom bore germline mutations, and in both cell lines. SMARCA4 protein was lost in 87% (20/23) of SCCOHT tumours but in only 0.4% (2/485) of other primary ovarian tumours. Reintroduction of wild-type SMARCA4 into BIN-67 cells resulted in altered cell morphology and growth arrest.
Conclusions: The mutation spectrum, IHC profile and cell culture phenotype implicate SMARCA4 as a critical tumour suppressor in SCCOHT pathogenesis.
Citation Format: Pilar Ramos, Anthony N. Karnezis, David W. Craig, Aleksandar Sekulic, Megan L. Russell, William P.D. Hendricks, Jason J. Corneveaux, Michael T. Barrett, Karey Shumansky, Yidong Yang, Sohrab P. Shah, Leah M. Prentice, Marco A. Marra, Jeffrey Kiefer, Victoria L. Zismann, Troy A. McEachron, Bodour Salhia, Jaime Prat, Blaise A. Clarke, Joseph G. Pressey, John H. Farley, Stephen P. Anthony, Richard B.S. Roden, Heather E. Cunliffe, David G. Huntsman, Jeffrey M. Trent. Small cell carcinoma of the ovary, hypercalcemic type displays frequent inactivating germline and somatic mutations in SMARCA4 [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 POSTER-BIOL-1327.
Abstract POSTER-BIOL-1328: Endothelin-1/endothelin a receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis
Authors: Teoh Jian-peng , Park Kyoung-mi , Wang Yongchao , Hu Qiuping , Kim Sangmi , Wu Guangyu , Huang Shuang , Maihle Nita , Kim Il-man 
Published: August 2015

Abstract
The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.
Citation Format: Jian-peng Teoh, Kyoung-mi Park, Yongchao Wang, Qiuping Hu, Sangmi Kim, Guangyu Wu, Shuang Huang, Nita Maihle, Il-man Kim. Endothelin-1/endothelin a receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis [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 POSTER-BIOL-1328.