bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5131: Cadmium induces cytotoxicity in human bronchial epithelial cell in a p53-independent, nuclear factor NF-kappaB-dependent manner
Authors: Du Ji-Ying , Chen De-Ju , Xu Yan-Ming , Lau Andy T. Y. 
Published: May 2015

Abstract
Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well known carcinogens. Here, we report that in CdCl2-exposed human bronchial epithelial cells (BEAS-2B), the level of p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 μM) of Cd can up-regulate the protein levels of eukaryotic translation initiation factor 5A-1 (eIF-5A-1) and redox-sensitive transcription factor NF-κB p65 in a time- and dose-dependent manner. Moreover, there is an enhanced NF-κB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF-5A-1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF-5A-1 in Cd cytotoxicity. As eIF-5A-1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-κB might likely modulate eIF-5A-1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF-5A-1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB binding on eIF-5A-1 promoter region of Cd-treated cells. Taken together, our findings report for the first time a regulatory mechanism for the pro-apoptotic protein eIF-5A-1 in which its level is controlled in an NF-κB-dependent manner.
Citation Format: Ji-Ying Du, De-Ju Chen, Yan-Ming Xu, Andy T. Y. Lau. Cadmium induces cytotoxicity in human bronchial epithelial cell in a p53-independent, nuclear factor NF-kappaB-dependent manner. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5131. doi:10.1158/1538-7445.AM2014-5131
Abstract 5170: Linking tumor evolution and therapy response using diagnostic targeted next generation sequencing in colorectal cancer
Authors: Mamlouk Soulafa , Childs Liam , Redmer Thorben , Durek Pawel , Schumacher Dirk , Bläker Hendrik , Aust Daniela , Winterfeld Moritz von , Heinemann Volker , Modest Dominik , Möhr Kerstin , Morkel Markus , Schäfer Reinhold , Sers Christine 
Published: May 2015

Abstract
Complex sets of driver mutations critically control clinical course and treatment response in colorectal cancer (CRC). It is expected that multiple mutations in different signaling pathways interact to establish an individual cancer cell phenotype. Furthermore, mutational patterns can evolve under selective pressure, for instance during tumor metastasis or targeted therapy. Yet only few mutations, such as these in KRAS, NRAS and BRAF, are routinely assessed in the clinic today. With the introduction of next generation sequencing (NGS) many more genes can be simultaneously sequenced, allowing detailed analyses of mutational patterns.
We have assembled the CRC5.2 NGS panel for application with Ion Torrent PGM covering 100 frequently mutated genes with 784 amplicons (covering 21,000 COSMIC mutations), going well beyond the scope of commercially available cancer panels. In particular, exon coverage was optimized to embrace all genomic information related to drug sensitivity, using several drug and signaling network databases.
The German Consortium for Translational Cancer Research (DKTK) comprises the top cancer centers in Germany. As a part of this group, we employ our custom CRC5.2 panel for the analysis of mutational patterns in CRC. We address several key questions relevant for current diagnostics and treatment in colorectal cancer. In retrospective and prospective clinical studies, we assess mutational heterogeneity in primary tumors, synchronous and metachronous metastases of individual patients. In-depth NGS mutational analyses, transcriptome analysis and methylation studies will identify (epi-)genetic alterations occurring as a consequence of selective pressure during tumor evolution e.g. during metastasis, chemotherapy or targeted tumor therapy. Thus, we will uncover new links between cancer-specific mutations, clinical course and treatment response as well as novel mechanisms of secondary resistance. In addition we aim to identify novel predictive and prognostic mutational markers for the benefit of future CRC patients
Citation Format: Soulafa Mamlouk, Liam Childs, Thorben Redmer, Pawel Durek, Dirk Schumacher, Hendrik Bläker, Daniela Aust, Moritz von Winterfeld, Volker Heinemann, Dominik Modest, Kerstin Möhr, Markus Morkel, Reinhold Schäfer, Christine Sers. Linking tumor evolution and therapy response using diagnostic targeted next generation sequencing in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5170. doi:10.1158/1538-7445.AM2014-5170
Abstract 5492: Effect of GnRH analogues and pharmacoperone IN3 treatment in survival of prostatic cancer cells to radiation
Authors: Sanchez Catherine A. , Salgado Apolo , Castellon Enrique A. 
Published: May 2015

Abstract
Prostate cancer (PCa) is the second cause of cancer related death in men. Radiotherapy of localized tumours is highly effective and reduces the risk of urinary incontinence and impotence compared with radical surgery. Radiotherapy is more effective when associated with GnRH analogues (as leuprolide), which has been related with decreased circulating androgens due to hypophysis-testis axis blockade. We propose that GnRH analogues increase the cytotoxic effect of radiotherapy in PCa cells, effect that can be potentiated with IN3, a pharmacoperone that increases GnRH receptor (GnRHR) expression in cell membrane.
To demonstrate our hypothesis, we stablished primary cell cultures from PCa samples from patients of our Institutional Hospital (n=12). Cells were treated during 24 hr with 1 ug/ml IN3 (Merck Sharp & Dohme Corp., USA,) and then with different concentrations (20-80 ng/ml) of leuprolide (Sigma-Aldrich Co., USA) for 24 hr. Later, cells were irradiated at 3 Gy and we evaluated cell survival at 24 hr (through MTT), changes in cell cycle at 24 hr and apoptosis at 6 hr (through FACS). GnRHR expression in cell membrane after 24 hr of IN3 treatment was evaluated trough fluorescence microscopy. Results were evaluated using Anova and Kruskal-Wallis tests, followed by post-test of Dunn. P &lt;0.05.
As we previously described, we observed that leuprolide decreased PCa cell survival. When cells were pre-treated with IN3, GnRHR expression in cell membrane increased in about 60% and the effect of leuprolide treatment was higher. When cells were irradiated, cell survival decreased in 10%, this effect was higher when cells were previously treated with leuprolide (15%) and IN3/leuprolide (20%). This was related with an increase of 10% in apoptosis and cell cycle arrest in G2. The effect was dependant of leuprolide dose. At the dose used, IN3 had no effect in cell survival.
We concluded that leuprolide sensitizes cells from PCa to radiation, and this effect was increased with pretreatment with IN3 due, at least in part, for the increase of GnRHR expression in cell membrane, a receptor that decreases its expression during PCa progression. In clinical practice, leuprolide has direct effect over PCa cells, decreasing cancer cell survival and improving the cytotoxic effect of radiation. The utility of IN3 as a potential adjuvant therapy needs to be addressed.
Citation Format: Catherine A. Sanchez, Apolo Salgado, Enrique A. Castellon. Effect of GnRH analogues and pharmacoperone IN3 treatment in survival of prostatic cancer cells to radiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5492. doi:10.1158/1538-7445.AM2014-5492
Abstract 5510: ABT-737 synergizes with Vorinostat to induce apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines
Authors: Foster Kimberly A. , Premkumar Daniel R. , Jane Esther P. , Morales Alejandro , Pollack Ian F. 
Published: May 2015

Abstract
We have previously observed that glioma cells are differentially sensitive to ABT-737 and, when used as a single-agent, this drug failed to induce apopotsis. Identification of therapeutic strategies to enhance the efficacy of the Bcl-2 inhibitor ABT-737 in human glioma is of interest. Histone deacetylation inhibitors (HDACi) are currently being assessed clinically in patients with glioma, as regulation of epigenetic abnormalities is expected to produce pro-apoptotic effects. We hypothesized that cotreatment of glioma with a BH3-mimetic and HDACi may synergistically produce cell death. We assessed the combination of the Bcl-2 family inhibitor ABT-737 and the HDACi vorinostat in established and primary cultured glioma cells. We found that combined treatment with these agents led to significant cellular death when compared to either drug as a single agent and demonstrated activation of the caspase cascade. The enhanced apoptosis observed with the combination also appears dependent upon the loss of mitochondrial membrane potential, release of cytochrome c, smac/DIABLO and apoptosis-inducing factor to the cytosol. We observed that the upregulation of Noxa, truncation of Bid, and the activation of Bax caused by this combination were important factors for synergistic cell death. We demonstrated that Noxa functioned to occupy Mcl-1 in cells exposed to the combination, yet, contrary to studies in other malignancies, this combination in glioma occurred without the release of proapoptotic proteins Bim and Bak from Mcl-1. We showed this combination to be less effective in PTEN-deficient glioma cells. Both genetic manipulation of PTEN status and pharmacologic inhibition of PI3 kinase sensitized PTEN-deleted glioma cells to the combination. This study demonstrates that antagonizing apoptosis-resistance pathways, such as the Bcl-2 family, and regulating epigenetic aberrancies, such as histone regulation, may induce cell death. Moreover, we reiterate that therapies to target the PI3-kinase/Akt/mTor pathway may be additionally necessary in cancers lacking PTEN functionality.
Citation Format: Kimberly A. Foster, Daniel R. Premkumar, Esther P. Jane, Alejandro Morales, Ian F. Pollack. ABT-737 synergizes with Vorinostat to induce apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5510. doi:10.1158/1538-7445.AM2014-5510
Abstract 5517: PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion
Authors: Kim Min Jung , Cao Liangxian , Sheedy Josephine , Risher Nicole , Dumble Melissa , Lee Chang-Sun , Sydorenko Nadiya , Baiazitov Ramil , Du Wu , Moon Young-Choon , Weetall Marla L. , Colacino Joseph , Davis Thomas W. 
Published: May 2015

Abstract
The Polycomb group (PcG) transcription repressor BMI1 is highly expressed in human cancers and is required for the clonogenic self-renewal and tumorigenesis of human cancer cells including those in hematological cancer and neuroblastoma. PTC596 is efficacious in vivo across a range of xenograft tumor models, including models of glioblastoma, fibrosarcoma and leukemia as well as orthotopic models of GBM. With EC50 values of 30-200 nM in a variety of tumor cell lines, PTC596 selectively reduces the level of functional BMI1 protein resulting in the depletion of the tumor stem cell fraction. PTC596 induces the hyper-phosphorylation of BMI1 leading to its degradation and the reduction of polycomb repressive complex 1 (PRC1) activity. Mechanistic studies suggest that PTC596 inhibits APC/CCDC20 activity resulting in the persistent activation of CDK1 and CDK2 which mediate the hyperphosphorylation of BMI1. Studies are ongoing to elucidate the mechanism of PTC596 inhibition of APC/CCDC20 and its preferential depletion of the tumor stem cell fraction.
Citation Format: Min Jung Kim, Liangxian Cao, Josephine Sheedy, Nicole Risher, Melissa Dumble, Chang-Sun Lee, Nadiya Sydorenko, Ramil Baiazitov, Wu Du, Young-Choon Moon, Marla L. Weetall, Joseph Colacino, Thomas W. Davis. PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2014-5517
Abstract 5521: TTFields reduce cancer cell clonogenic potential through abnormal chromosome segregation during mitosis
Authors: Schneiderman Rosa S. , Giladi Moshe , Porat Yaara , Munster Mijal , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: May 2015

Abstract
TTFields cause mitotic arrest and cell death by the disruption of spindle microtubule arrangement and interference with cytokinesis. Recently it was reported that TTFields application results in reduced clonogenicity of cells surviving treatment. We hypothesized that TTFields can impair chromosome segregation during mitosis thus leading to a long term effect on surviving cancer cells.
A2780 human ovarian cancer cells were treated with TTFields for 24, 48 and 72 hours and the cytotoxic effect and clonogenic potential were determined. Abnormal mitotic figures were analyzed using fluorescence microscopy and cell karyotyping was performed using Giemsa staining and SKY analysis.
TTFields application led to 36, 52 and 43% cell growth inhibition after 24, 48 and 72 hours, respectively. Clonogenic assays revealed that only 12.9% of cells treated with TTFields for 72 hours maintained their ability to form colonies after 2 weeks. Immunofluorescence images revealed a significant increase in the number of abnormal mitotic figures amongst treated cells. Karyotyping analysis following 24 and 48 hours of TTFields application revealed 38.5% and 53.8% abnormal segregation events, respectively. After 24 hours of treatment, the proportion of cells with reduced and increased chromosomes number was equal, however, following 48 hours of treatment the population with a reduced chromosome number disappeared.
These results demonstrate that in addition to their cytotoxic effect leading to mitotic death, TTFields also lead to abnormal chromosome segregation. The surviving aneuploid cells are impaired, providing a possible explanation for the reduced clonogenic potential reported in cancer cells treated with TTFields.
Citation Format: Rosa S. Schneiderman, Moshe Giladi, Yaara Porat, Mijal Munster, Eilon D. Kirson, Uri Weinberg, Yoram Palti. TTFields reduce cancer cell clonogenic potential through abnormal chromosome segregation during mitosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5521. doi:10.1158/1538-7445.AM2014-5521
Abstract 5523: Study of the response of melanoma lines to BRAF/MEK inhibitors and combination drug treatments
Authors: Dastur Anahita , Benes Cyril 
Published: May 2015

Abstract
The serine-threonine protein kinase, BRAF, is a frequently mutated oncogene, found in cancers of the skin, thyroid and large intestine. It is especially prevalent in malignant melanoma, where it occurs in 40-60% of the cases. The most common BRAF mutation is the valine to glutamate substitution at position 600 of the kinase (V600E). This substitution, seen in ninety percent of the BRAF cases, leads to constitutive activation of the kinase, and the downstream MEK-ERK pathway. Appropriately, several drugs have been designed to inhibit BRAF, with a broad range of outcomes in clinical trials. Unfortunately, all patients, including those showing complete responses, develop resistance to single agent therapy. Our goal is to come up with effective drug combinations that would delay, or even prevent, the cancer from becoming resistant to treatment.
We used a panel of 43 melanoma lines, comprising of 28 BRAF mutants, 12 NRAS mutants and 3 lines that were wild type for these two genes. Besides BRAF and NRAS, we have the mutational status of 65 other commonly mutated cancer genes for all the lines. We assembled a set of 25 drugs targeting a wide range of proteins, including PI3K/mTOR inhibitors, the apoptosis machinery, as well as some epigenetic modulators. The melanoma lines were treated with these drugs, either (i) alone or (ii) in combination with the B-RAF inhibitor vemurafenib or (iii) in combination with the MEK inhibitor Selumetinib, for 72 hrs over a nine point, 256-fold concentration range. Viability and apoptosis were measured using cell titer glo (Promega).
The results from this pilot study are discussed here.
Note: This abstract was not presented at the meeting.
Citation Format: Anahita Dastur, Cyril Benes. Study of the response of melanoma lines to BRAF/MEK inhibitors and combination drug treatments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5523. doi:10.1158/1538-7445.AM2014-5523
Abstract 5524: 5-aza-2′-deoxycytidine, a DNA demethylating agent, inhibits metastatic melanoma invasiveness
Authors: Etiévant Chantal , Desjobert Cécile , Carrier Arnaud , Delmas Audrey , Tost Jorg , Favre Gilles , Riond Joelle , Arimondo Paola 
Published: May 2015

Abstract
Metastatic melanomas are the deadliest form of skin cancer and are very aggressive tumors showing highly invasive properties and a rapid chemoresistance to standard treatment (Dacarbazine) and to specific BRAF-V600E kinase inhibitors (Vemurafenib). Thus, targeting these tumors remains a major concern for novel therapeutic proposals.
Abnormal patterns of DNA methylation, an epigenetic modification that cells use to control gene expression, have been described in these tumors. These epigenetic modifications participate in melanoma formation and maintenance. The aim of our project is to characterize the DNA methylation changes that occur in the most aggressive form of melanoma and to reverse these changes by using clinically active DNA methyltransferase inhibitors (5-aza-2′-deoxycytidine, 5-aza-dC). To date a limited number of datasets have been published depicting the effects of inhibitors of DNA methylation on invasive capacities of metastatic melanoma cells. The work presented here, focuses on the study of the effects of DNA methylation inhibition on metastatic melanoma invasiveness.
We have set up an original method to quantify DNA methylation by FACS and shown that non cytotoxic nanomolar 5-aza-dC concentrations were able to demethylate DNA of WM-266-4 metastatic melanoma cells. Then using an in vitro 3D spheroids cell invasion assay and fluorescent microscopy to measure invasion capacities of metastatic cell lines, we showed that 5-aza-dC was able to inhibit invasion of WM-266-4 cells at these non-cytotoxic demethylating concentrations.
Citation Format: Chantal Etiévant, Cécile Desjobert, Arnaud Carrier, Audrey Delmas, Jorg Tost, Gilles Favre, Joelle Riond, Paola Arimondo. 5-aza-2′-deoxycytidine, a DNA demethylating agent, inhibits metastatic melanoma invasiveness. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5524. doi:10.1158/1538-7445.AM2014-5524
Abstract 5535: Gcn5 modulates the cellular response to oxidative stress induced by histone deacetylase inhibitors
Authors: Gaupel Ann-Christin , Begley Thomas J. , Tenniswood Martin P. 
Published: May 2015

Abstract
Aberrant histone post-translational modifications including acetylation are common in human cancers and result in dysregulation of gene expression. Our laboratory has focused on studying the effects of hydroxamic acid based HDAC inhibitors (HDACis) including TSA, SAHA and CG-1521.
We have employed a whole genome yeast deletion library screen to gain insight into the mechanism of the HDAC inhibitor CG-1521 and identify potential combinatorial drug targets. Gene ontology enrichment analysis shows that sensitive strains are highly enriched in processes regulating chromatin remodeling and transcription. Deletions of components of the SAGA HAT complex are highly overrepresented in the sensitive strains, including the catalytic subunit Gcn5. The gcn5 deletion strain displays increased sensitivity to CG-1521 induced cell death compared to the wild type strain, suggesting that the SAGA complex is required to reduce the effect of CG-1521 on cell growth. Gene expression analysis indicates that CG-1521 elicits an oxidative stress response in both the wild type and the gcn5 deletion strain. Gcn5 deletion substantially increases the level of oxidative stress induced by CG-1521 as measured by flow cytometry.
In the colorectal cancer cell line HT29, treatment with CG-1521 is accompanied by an increase in oxidative stress and co-treatment with the Gcn5 specific inhibitor MB-3 or RNAi-mediated knockdown of the human Gcn5 homologs, Gcn5 and PCAF, enhances the growth-inhibitory effect of CG-1521.
These studies have shown that disruption of the SAGA HAT complex with MB-3 or RNAi-mediated knockdown sensitizes tumor cells to CG-1521. Taken together, our work suggests that the combination of selective HAT and HDAC inhibitors may be an effective treatment of cancer.
Citation Format: Ann-Christin Gaupel, Thomas J. Begley, Martin P. Tenniswood. Gcn5 modulates the cellular response to oxidative stress induced by histone deacetylase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5535. doi:10.1158/1538-7445.AM2014-5535