bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1724: BRAF inhibition is enhanced by BH3-mimetic through BIM induction.
Authors: Frederick Dennie T. , Salas Fragomeni Roberto A. , Hoff Taylor , Cooper Zachary A. , Mier James W. , Wargo Jennifer A. , Sullivan Ryan J. 
Published: August 2014

Abstract
Vemurafenib (Vem) is a highly selective inhibitor of mutant BRAF, FDA-approved for the treatment of patients with BRAF-positive advanced melanoma. While response rates to Vem are high, the emergence of resistance is common, placing high priority in the development of strategies to enhance Vem efficiency. Navitoclax is a BH3-mimetic that binds and inactivates the anti-apoptotic proteins BCL-2, BCL-xl, and BCL-w and leads to apoptosis in tumors with low expression of another anti-apoptotic protein, MCL-1. Our data demonstrates that treatment of BRAF-mutant melanoma patients with Vem is associated with decreased expression of MCL-1 in addition to an increase in the pro-apoptotic, BH3-only protein BIM in serial biopsy samples. Therefore, we hypothesize that the combination of PLX-4720 (Vem analog) with navitoclax will result in increased anti-tumor activity. To test our hypothesis, we performed cell viability studies, Annexin:PI and ELISA apoptosis assays in addition to protein and mRNA analysis. In-vivo studies were performed in two BRAF mutant xenograft models using navitoclax and PLX-4720. In-vitro, our cell viability studies demonstrated that concurrent treatment with PLX-4720 and navitoclax results in an additive viability reduction in BRAF mutant but not in BRAF WT cell lines. The decrease in cell viability correlated to downmodulation of MCL-1 and BIM induction after PLX-4720 treatment, with further enhancement of BIM expression and PARP cleavage after adding navitoclax. In vivo, the navitoclax enhanced the efficacy of PLX-4720 in both xenograft models. The combination of a selective BRAF inhibitor with a BH3-mimetic may be a promising therapeutic strategy to enhance the clinical efficacy of BRAF inhibitors.
Citation Format: Dennie T. Frederick, Roberto A. Salas Fragomeni, Taylor Hoff, Zachary A. Cooper, James W. Mier, Jennifer A. Wargo, Ryan J. Sullivan. BRAF inhibition is enhanced by BH3-mimetic through BIM induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1724. doi:10.1158/1538-7445.AM2013-1724
Abstract 1735: Obatoclax enhances CDDP and trail-induced apoptosis in epithelial ovarian adenocarcinoma cells.
Authors: Martinez-Paniagua Melisa A. , Romero-Gonzalez Luis A. , Anguiano-Hernandez Yu Mei , Gonzalez-Torres Carolina , Vega Mario I. 
Published: August 2014

Abstract
Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. Ovarian cancer is the fifth cause of death in women and annually 13,850 deaths are reported in United States. Effective screening strategies are lacking and the majority of cases are diagnosed with advanced stage disease. Chemo is the conventional therapy after surgery but the initial response is between 60 to 80%, however, some patients that initially responded to the therapy suffer of recurrent disease or become resistant to the treatment. As a consequence, the overall 5 year survival is only about 30%. It is important to identify novel therapies for ovarian cancer to treat or sensitize tumor cells to the existence therapy. It has been suggested that the tumor cells become resistance due to an increased expression of antiapoptotic proteins especially from the Bcl2 family (Bcl-2, Bcl-XL, Mcl-1). Obatoclax is a small molecule that mimics the BH3 domain of the BH3 only family members and inhibits the effect of antiapoptotic Bcl-2 members. The objective of this study was to assess the susceptibility of ovarian cancer cell lines to chemo or immuno therapy mediated apoptosis by obatoclax and also to elucidate the mechanism. Four different epithelial ovarian adenocarcinomas cell lines (SKOV3, NIH-OVCAR-3, TOV112D and TOV21G) were treated with different concentrations of Obatoclax (nM-μM), CDDP (5-50μg/ml) or TRAIL (50-1200ng/ml) alone or with a combination of treatment to assess the viability, measured by the XTT kit (Roche). Basal and cell treated total protein expressions were assessed by western. Induction of apoptosis was measured by TUNEL. As a single agent, Obatoclax or CDDP inhibited the viability of the cells in a dose response form; TRAIL did not show an evident response. The combination of the treatment after selecting the IC50 and IC20 response showed an increased inhibition of the viability. TUNEL positive cells were measured and the induction of apoptosis was mediated by a caspase dependent manner and PARP cleavage. Our data suggest that obatoclax in combination with CDDP or TRAIL can enhance the induction of apoptosis in resistance cell lines, suggesting to be an optional treatment of patients with ovarian cancer.
Citation Format: Melisa A. Martinez-Paniagua, Luis A. Romero-Gonzalez, Yu Mei Anguiano-Hernandez, Carolina Gonzalez-Torres, Mario I. Vega. Obatoclax enhances CDDP and trail-induced apoptosis in epithelial ovarian adenocarcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1735. doi:10.1158/1538-7445.AM2013-1735
Abstract 1746: Coordination of overexpressed NIMA-related kinase 2 and TRF1 results in mitotic abnormalities in breast cancer cells.
Authors: Lee Jaehyung 
Published: August 2014

Abstract
NIMA-related kinase 2 (NEK2), a serine-threonine protein kinase, plays a role in features of mitotic progression including timing of mitotic entry, chromatin condensation, spindle organization and cytokinesis. Kinase death NEK2 mutant expression or NEK2 depleted cells lead to failure of centrosome separation while NEK2 overexpression results in premature centrosome separation. In addition, it has been revealed that telomeric repeat binding factor 1 (TRF1) interacts directly with NEK2. TRF1 not only regulates telomere length, but is also associated with cell cycle regulation. However, the interactions and correlations between NEK2 and TRF1 are far from clear. Here, we show that mitotic aberrations through NEK2 overexpression are likely to require TRF1. Our results demonstrate that NEK2 directly binds and phosphorylates TRF1 in vitro and in vivo through multiple sites on TRF1. NEK2 overexpression in breast cancer cells, MCF 7 and MDA-MB-231, results in increased numbers of centrosomes and multinucleated cells, which leads to cytokinetic failure and aneuploidization. Additionally, TRF1 depletion by siRNA prevents the occurrence of unaligned chromosomes by NEK2 overexpression during metaphase. Concurrent Nek2 overexpression and TRF1 depleted cells demonstrated ≤ 2 centrosomes per cell, similar to mock plasmid and negative control siRNA transfected cells. Therefore, we propose that TRF1 is required for overexpressed NEK2 to trigger abnormal mitosis and chromosomal instability.
Citation Format: Jaehyung Lee. Coordination of overexpressed NIMA-related kinase 2 and TRF1 results in mitotic abnormalities in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2013-1746
Abstract 1749: Cell cycle requirements shape ovarian cancer progression.
Authors: Taylor-Harding Barbie , Agadjanian Hasmik , Orsulic Sandra , Walsh Christine , Karlan Beth Y. , Wiedemeyer Wolf-Ruprecht 
Published: August 2014

Abstract
Acquired resistance to chemotherapeutic drugs and subsequent recurrence of drug-resistant cancer are serious challenges associated with epithelial ovarian cancer. Most high-grade tumors initially respond well to the combination of platinum and taxane-based agents but recur as platinum-resistant disease, which is incurable. In addition, a subset of primary tumors, including CCNE1-amplified tumors, are inherently less susceptible to standard chemotherapy. Studies by The Cancer Genome Atlas have revealed that CCNE1 (cyclin E) amplification is mutually exclusive with mutations in BRCA1 and BRCA2, which render ovarian cancer cells sensitive to DNA-damaging agents and PARP inhibitors, as a result of synthetic lethality. In order to develop a similar therapeutic concept for CCNE1-amplified cancers, we have studied responses and resistance mechanisms of human ovarian cancer cells to several pharmacological inhibitors of cyclin-dependent kinases (CDK). Functional and biochemical studies have established cyclin E as an activator of CDK, which phosphorylate the RB tumor suppressor. However, despite the functional importance of the RB pathway in cancer, CDK inhibitors (CDKi) have yet to make a significant impact on the management of solid tumors.
Here, we describe oncogenic pathways that are activated in CDKi-resistant cells and play critical roles in tumor progression and drug resistance. Targeting individual CDK or subsets of multiple CDK in vitro and in vivo, we found that cyclin E dependence was the main driving force that shaped tumor progression in different model systems of CCNE1-amplified and recurrent ovarian cancer. We identified robust and specific compensatory mechanisms that sustain cyclin E-associated activity in CDKi-resistant cells via activation of oncogenic signaling upstream of the cyclin E-RB-E2F axis. Specific targeting of cooperating oncogenes increased CDKi efficacy and prevented the outgrowth of CDKi-resistant cancer cells. Collectively, our results suggest that CDKi can be highly effective elements of combination therapy.
Citation Format: Barbie Taylor-Harding, Hasmik Agadjanian, Sandra Orsulic, Christine Walsh, Beth Y. Karlan, Wolf-Ruprecht Wiedemeyer. Cell cycle requirements shape ovarian cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1749. doi:10.1158/1538-7445.AM2013-1749
Abstract 1750: Clinically relevant paclitaxel concentrations cause chromosome missegregation rather than mitotic arrest.
Authors: Zasadil Lauren M. , Burkard Mark , Weaver Beth A. 
Published: August 2014

Abstract
Paclitaxel is a chemotherapeutic, microtubule-stabilizing drug used to treat a variety of cancers, including those of the breast. In the neoadjuvant setting, paclitaxel effects tumor shrinkage in up to half of patients. Identification of a biomarker to predict response to paclitaxel would reduce side effects and improve patient outcomes. It has long been known that micromolar concentrations of paclitaxel cause cells in culture to arrest in mitosis, which can lead to cell death. However, the concentration range found within patient tumors remains unclear, both because it has not been directly measured and because paclitaxel accumulates intracellularly up to 1000 fold. In a pilot clinical trial, we are directly measuring the intratumoral drug concentration in breast tumors following neoadjuvant paclitaxel treatment. Our preliminary data support the hypothesis that treatment of cultured cells with a low nanomolar concentration more accurately models the intratumoral drug levels in breast cancer patients. Unlike treatment with micromolar concentrations, treatment with low nanomolar paclitaxel does not cause a significant mitotic arrest. Rather, cells treated with low nanomolar paclitaxel frequently proceed through mitosis with multipolar mitotic spindles, resulting in chromosome missegregation and the production of two or more daughter cells. This alternative mechanism of action may explain why tumors treated with paclitaxel fail to show an increase in mitotic index. Previous studies have shown that low rates of chromosome missegregation are well tolerated, but high rates of chromosome missegregation cause cell death due to loss of both copies of one or more essential chromosomes. Therefore, the fidelity of chromosome segregation may be of use as a predictor of response to paclitaxel. In chromosomally stable breast cancer cells, exposure to paclitaxel for two days is sufficient to induce aneuploidy, and within three days there is an increase in cell death. However, a subset of cells are able to survive in low nM paclitaxel for over one week, and survival is higher than in cells which exhibit chromosomal instability (CIN), and have a preexisting rate of chromosome missegregation during division. In patients, chromosomal stability is of potential use as a predictive biomarker to select patients most likely to respond to paclitaxel treatment.
Citation Format: Lauren M. Zasadil, Mark Burkard, Beth A. Weaver. Clinically relevant paclitaxel concentrations cause chromosome missegregation rather than mitotic arrest. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2013-1750
Abstract 1752: Consequences of high Chromosome Instability (CIN) in SGO1(Shugoshin1) CIN model mice.
Authors: Yamada Hiroshi Y. , Zhang Yuting , Dai Wei , Rao Chinthalapally V. 
Published: August 2014

Abstract
Abstract
Mitotic errors have been suspected to be a cause of aneuploidy, rapid accumulation of mutations, and tumorigenesis. In addition, recent cell biological studies demonstrated that mitotic errors can result in DNA damage, which would also aid accumulation of mutations then carcinogenesis. However, no observations in vivo have been provided to support the cell biological observations to date. Previously we developed two strains of high Chromosome Instability (CIN) model mice, which show an increase in mitotic errors due to haploinsufficiency in chromosome cohesion system component Sgo1 or mitotic spindle checkpoint component BubR1. The pathways affected by these mutations are suggested to play a role in aging and carcinogenesis in human. Consistently, compared with wild type, both mice strains showed a significant risk for tumor development in colon with chemical carcinogenesis assays. In this study, we used these CIN mice to test whether (i) spontaneous carcinogenesis occurs in the mice, (ii) spontaneous DNA damage occurs in the mice, (iii) whether associated marker expressions are altered, and (iv) if so, whether it is affected by the age. In 12 month old (middle-age) SGO1 and BUBR1 mice, we observed an increase in spontaneous epithelial cancers, although the carcinogenic effect is not aggressive (p&lt;0.05 in SGO1). In histologically normal-looking liver tissue in the mice, increased signals of DNA damage marker pohspho-gamma-H2AX and p53 were observed (4∼5-fold higher in CIN mice), along with altered expressions of p16INK4A and Bcl2 (2∼6-fold higher in CIN mice), providing the first evidence for DNA damage in vivo with mutations that increase mitotic errors. In 4 month old (younger adult) SGO1 mice, significantly (p&lt;0.05) higher percentage of p-H2AX signal in comparison with wild type was also observed. The results demonstrate that mitotic error and CIN-causing mutation can cause higher DNA damage in the tissue-level, indicating that an additional path to carcinogenesis is at work in vivo. Marker analysis in the CIN model mice would indicate molecular consequences of this type of mutation and would lead to the discovery of novel cancer prevention drug targets.
Citation Format: Hiroshi Y. Yamada, Yuting Zhang, Wei Dai, Chinthalapally V. Rao. Consequences of high Chromosome Instability (CIN) in SGO1(Shugoshin1) CIN model mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1752. doi:10.1158/1538-7445.AM2013-1752
Abstract 1756: Intravital imaging of cancer cell cycle in the bone marrow.
Authors: Yano Shuya , Miwa Shinji , Tome Yasunori , Uehara Fuminari , Digman Michelle , Gratton Enrico , Hoffman Robert M. 
Published: August 2014

Abstract
The cell cycle of cancer cells in the bone marrow was imaged using a fluorescence ubiquitination cell cycle indicator (FUCCI). With FUCCI, quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). FUCCI-expressing cancer cells were injected into the bone marrow of tibia of mice. At the early stage after injection (7 days), approximately 90% of the cells were in G0/G1. In contrast, at late stage after injection (28 days more), in the endosteal lesion, approximately 80% of the cancer cells were in S/G2/M phases and in the central zone, approximately 75% of cancer cells were in G0/G1. Thus, cancer-cell location and time in the bone marrow determines cell cycle position and possibly dormancy. Thus, quiescent (dormant) cancer cells in the bone marrow need to be targeted as well as proliferating cancer cells, which is a significant current challenge.
Citation Format: Shuya Yano, Shinji Miwa, Yasunori Tome, Fuminari Uehara, Michelle Digman, Enrico Gratton, Robert M. Hoffman. Intravital imaging of cancer cell cycle in the bone marrow. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1756. doi:10.1158/1538-7445.AM2013-1756
Abstract 1759: Immunohistochemical detection of human telomerase reverse transcriptase in human cholangiocarcinoma and risk condition.
Authors: Endo Kanenori , Tsujitani Shunichi , Yoshimoto Miwa , Watanabe Jyoji , Tokuyasu Naruo , Sakamoto Teruhisa , Naka Takuji , Hirooka Yasuaki , Ikeguchi Masahide 
Published: August 2014

Abstract
Background/Aims: Telomerase activation plays a critical role in several human carcinogenesis through the maintenance of telomeres. The catalytic subunit of telomerase is human telomerase reverse transcriptase (hTERT), whose expression is the critical determinant of telomerase activity. Studies on hTERT in human cholangiocarcinoma (ChC) are rare, and there are no immunohistochemical studies on the correlations with its expressions and ChC patient's clinicopathological parameters.
Methods : HTERT Immunoreactivity was measured in cancerous parenchyma of 28 archival cases of human cholangiocarcinoma (ChC) compared with hyperplastic small biliary ducts in surrounding non-neoplastic liver. And hTERT immunoreactivity was also assessed in both large and small hyperplastic biliary ducts (HBDs) in 9 archival cases of primary sclerosing cholangitis (PSC), which is risk condition for human cholangiocarcinogenesis. Measurements of intrahepatic biliary duct sizes and quantitative microdensitometry measurements of immunostaining intensities were determined using a color video image analysis system. Micro-optical density values related to a standard optical density curve were generated for each set of measurements, using arbitrary units of immunostaining intensity ranging from 0 (nondetectable) to 255 (highest intensity).
Results : HTERT immunoreactivity was presented in nuclei of ChC and PSC cells. Mean micro-optical density values for hTERT in tumorous cells were almost 8-fold greater than that measured in small HBDs in surrounding non-tumorous liver within the same tissue sections. Although there was no significantly difference of tumor differentiation in hTERT expression, its expression was stronger in tubular type than in papillary type and in tubulopapillary type. In PSC cases, hTERT expression was significantly stronger in large HBDs (&gt;500μm cross-sectional diameter) than in small HBDs (&lt;500μm cross-sectional diameter).
Conclusion : Our findings suggest that hTRET protein in human ChC may emerge at a early stage in the progression of the malignant process. The results also suggest hTERT as potentially important targets relevant to chemoprevention or adjunct therapy of ChC.
Citation Format: Kanenori Endo, Shunichi Tsujitani, Miwa Yoshimoto, Jyoji Watanabe, Naruo Tokuyasu, Teruhisa Sakamoto, Takuji Naka, Yasuaki Hirooka, Masahide Ikeguchi. Immunohistochemical detection of human telomerase reverse transcriptase in human cholangiocarcinoma and risk condition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1759. doi:10.1158/1538-7445.AM2013-1759
Abstract 1763: Frequency of homologous recombination repair defects across breast cancer subtypes.
Authors: Timms Kirsten M. , Abkevich Victor , Neff Chris , Morris Brian , Potter Jennifer , Tran Thanh V. , Chen Jian , Sangale Zaina , Tikishvili Eliso , Zharkikh Andrey , Perry Michael , Gutin Alexander , Lanchbury Jerry 
Published: August 2014

Abstract
Introduction: Defects in homologous recombination (HR) repair have potential therapeutic relevance, and current clinical studies are focused on examining the efficacy of agents that exploit HR deficiency in triple negative breast cancer. A homologous recombination deficiency (HRD) score based on whole genome tumor LOH profiles has been developed that is highly correlated with defects in BRCA1/2, and other HR pathway genes, in ovarian cancer(1), and which predicts response to platinum-based neoadjuvant therapy in triple negative breast cancer(2). This study examines the frequency of BRCA1/2 defects and elevated HRD score across breast cancer subtypes as defined by IHC hormone receptor status.
Methods: A targeted custom hybridization panel was developed targeting BRCA1, BRCA2, and 50,000 selected SNPs across the entire human genome. This panel, in combination with sequencing on the Illumina HiSeq, was used to analyze approximately 50 randomly ascertained tumors from each of 4 breast cancer subtypes (triple negative, ER+/Her2-, ER-/Her2+, ER+/Her2+) for BRCA1/2 somatic and germline mutations, and SNP allele frequencies. HRD scores were calculated using LOH profiles reconstructed from the SNP analysis. A BRCA1 promoter methylation assay was also performed on all samples.
Results: BRCA1/2 somatic and germline mutations were detected in all breast cancer subtypes. BRCA1/2 mutations were observed most frequently in triple negative and ER+/Her2+ tumors. BRCA1 promoter methylation was confined almost exclusively to triple negative tumors. Association between elevated HRD score and BRCA defects was observed regardless of tumor type, and BRCA1/2 intact tumors with elevated HRD scores were observed in all breast cancer subtypes.
Conclusions: Elevated HRD score is significantly associated with BRCA1/2 defects in breast cancer. BRCA1/2 defects and elevated HRD scores were observed in all subtypes of breast cancer, suggesting the presence of HR defects in genes other than BRCA1/2 are present in all breast cancer subtypes. HRD score could potentially be used to facilitate the expansion of platinum or PARP inhibitor therapy beyond triple negative breast cancer into other subtypes.
Citation Format: Kirsten M. Timms, Victor Abkevich, Chris Neff, Brian Morris, Jennifer Potter, Thanh V. Tran, Jian Chen, Zaina Sangale, Eliso Tikishvili, Andrey Zharkikh, Michael Perry, Alexander Gutin, Jerry Lanchbury. Frequency of homologous recombination repair defects across breast cancer subtypes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1763. doi:10.1158/1538-7445.AM2013-1763