bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 198: Resveratrol's Metabolomic biomarkers of efficacy: the missing link to chemoprevention.
Authors: Saud Shakir , Young Matthew , Karoly Ed , Bernard Chris , Colburn Nancy , Kim Young 
Published: August 2014

Abstract
Chemoprevention has received considerable attention over the last decade. The notion of using bioactive food components to reduce the risk of developing, or the recurrence of cancer has long been recognized. Resveratrol (a naturally occurring polyphenolic compound) has been studied extensively with considerable evidence demonstrating its efficacy as an anti-inflammatory and anti-cancer agent, with the most evidence for its role in colon cancer prevention. However, Resveratrol intervention studies in clinical trials still remains controversial, due to the lack of biomarkers of efficacy. Utilizing Metabolomic analysis we have identified biomarkers of efficacy in a pre-clinical model of inflammation-induced colorectal carcinogenesis.
Metabolomics is the process of identifying metabolites present in biological specimens. Our study has demonstrated the chemopreventative activity of Resveratrol in mice treated with the chemical carcinogen azoxymethane (AOM) and then exposed to colonic irritant dextran sodium sulfate (DSS) to induce inflammation-associated colon carcinogenesis. We found a diet enriched in Resveratrol resulted in a reduction in tumor incidence in AOM/DSS treated mice by 29 percent. Furthermore, we identified several biomarkers that are indicative of Resveratrol chemopreventive activities. Prior studies have shown Resveratrol's role in inhibiting several key enzymes important during the carcinogenesis process. We have correlated such findings with Metabolomic biomarkers. We found a significant reduction in Arachidonic acid, the limiting reagent of pro-inflammatory enzyme COX-2, and a reduction in spermidine a product of Ornithine decarboxylase, an enzyme that promotes proliferation. More intriguingly, we found biomarkers representing changes in bile acids by Resveratrol, which highlight chemopreventative activities that were not previously described. We found that Resveratrol treatment causes a reduction in tumorigenic secondary bile acids, deoxycholic acid and lithocholic acid, which are metabolic byproducts of intestinal bacteria. These data suggested that dietary supplementation with Resveratrol results in a healthy microbiome.
These pre-clinical studies should easily be translated into clinical studies designed to ascertain chemopreventive efficacy for bioactive compounds like Resveratrol, all with the objective to identify patients that will benefit from an intervention.
Citation Format: Shakir Saud, Matthew Young, Ed Karoly, Chris Bernard, Nancy Colburn, Young Kim. Resveratrol's Metabolomic biomarkers of efficacy: the missing link to chemoprevention. [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 198. doi:10.1158/1538-7445.AM2013-198
Abstract 1984: The Ikaros tumor suppressor regulates transcription of genes involved in cell signaling in human leukemia.
Authors: Payne Jonathon L. , Sloane Justin , Bamert Rebekka M. , Dovat Elanora , Li Hui , Bulathsinghala Marie , Gowda Chandrika , Song Chunhua , Dovat Sinisa 
Published: August 2014

Abstract
The IKZF1 gene encodes Ikaros, a DNA binding zinc finger protein that is essential for normal hematopoietic differentiation. Deletion or mutation of Ikaros has been associated with a both T and B-cell acute lymphoblastic leukemia (ALL), as well as acute and chronic myelogenous leukemias (AML and CML). Deletion of an Ikaros allele has also been identified as a poor prognostic marker in childhood B-ALL. Thus, Ikaros is established as a major tumor suppressor in hematopoietic malignancies. The Ikaros protein can activate or repress target gene expression via chromatin remodeling. The specific mechanisms by which Ikaros exerts its tumor suppressor activities are unknown. We have defined genome-wide occupancy of Ikaros in human leukemia using ChIP-SEQ and identified a large number of potential Ikaros target genes. The quantitative Chromatin Immunoprecipitation assay (qChIP) was used to identify genes whose expression is directly regulated by Ikaros. Using this technique we show that Ikaros binds to the promoter region of a gene that is part of a pro-oncogenic pathway, as well as a tumor suppressor gene. Both genes are essential components of cell signaling pathways. The promoter regions of the two novel target genes were cloned into luciferase reporter constructs and used to transiently transfect HEK 293T cells that were co-transfected with Ikaros or empty vector (as a control). Luciferase reporter assays demonstrate that Ikaros suppresses transcription of the gene that is involved in oncogenic transformation, while it positively regulates transcription of the tumor suppressor gene. In summary, we have identified two novel Ikaros target genes. Our results suggest that Ikaros exerts its tumor suppression function by regulating the expression of target genes involved in pro-oncogenic and tumor suppressor signaling in leukemia cells. These data identify mechanisms of the tumor suppressor activity of Ikaros in leukemia.
Citation Format: Jonathon L. Payne, Justin Sloane, Rebekka M. Bamert, Elanora Dovat, Hui Li, Marie Bulathsinghala, Chandrika Gowda, Chunhua Song, Sinisa Dovat. The Ikaros tumor suppressor regulates transcription of genes involved in cell signaling in human leukemia. [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 1984. doi:10.1158/1538-7445.AM2013-1984
Abstract 1987: Tumor suppressor ADAM23 mediates the HPV-associated carcinogenesis.
Authors: Yang Paul , Williams Drake W. , Kim Terresa , Shin Ki-Hyuk , Kang Mo , Park No-Hee , Kim Reuben H. 
Published: August 2014

Abstract
“High risk” human papillomaviruses (HPV) are known to cause or are closely associated with the development of human cervical, anal and some types of head and neck cancers. Integration of HPV DNA into host genome and subsequent expression of viral oncogenes, such as E6 and E7, are critical initial events for the HPV-associated cancer development; however, HPV infection alone is not sufficient to convert normal cells to malignant phenotypes, suggesting that other additional genetic and/or epigenetic events in the HPV-infected cells are required. The aim of the current study is to identify molecular determinants that are functionally linked to the pathogenesis of the HPV-associated cancers. We used HPV-16 harboring immortalized but non-transformed oral epithelial cells (HOK-16B), infected with high-throughput Decode RNAi lentiviral screening pools containing about 70,000 shRNAmir constructs capable of knocking down the target genes individually (3-4 constructs per gene), and selected them in DMEM-based high calcium/serum media in which HOK-16B cells are not permissive to survive. From the surviving colonies, we have identified several putative tumor suppressors including A Disintegrin and etalloproteinase domain-containing protein 23 (ADAM23). The function of ADAM23 was further validated such that singly knocking down in HOK-16B cells (HOK16B/ADAM23i) acquired proliferative potential in DMEM-based medium. HOK16B/ADAM23i cells also gained resistance to ionizing radiation (IR), cisplatin treatment, and differentiation as demonstrated by colonogenic assay, MTT assay, and the 3-dimensional raft culture systems, respectively. More importantly, the expression is largely diminished in squamous cell carcinoma (SCC) cell lines but more so in HPV-harboring SCC. We further found that ADAM23 expression is high in normal human oral epithelial tissues but low or none in HPV-positive OSCC tissue specimens as determined by immunohistochemical staining. Our data suggest that ADAM23 may play a role in development of HPV-associated cancers.
Citation Format: Paul Yang, Drake W. Williams, Terresa Kim, Ki-Hyuk Shin, Mo Kang, No-Hee Park, Reuben H. Kim. Tumor suppressor ADAM23 mediates the HPV-associated carcinogenesis. [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 1987. doi:10.1158/1538-7445.AM2013-1987
Abstract 1993: Identification of genetic interactors of BRCA2 in mouse embryonic stem cell model.
Authors: Ding Xia , Sharan Shyam 
Published: August 2014

Abstract
Breast cancer is the most prevalent cancer in women worldwide and mutations in breast cancer susceptible genes, BRCA1 and BRCA2 are the genetic factors conferring highest risk (40-70%) of developing breast cancer. Although BRCA proteins are known to maintain genomic stability mainly by homologous recombination-mediated DNA repair, detailed mechanisms of how BRCA loss induces tumorigenesis remain unclear. Interestingly, while inactivation of both alleles of BRCA1 or BRCA2 genes is necessary for tumor development, their loss in embryonic cells affects cell viability. To explain this paradox, we hypothesize that cells lacking BRCA1 or 2 are able to survive and are predisposed to tumorigenesis due to mutations in other genes such as those involved in cell cycle regulation or DNA damage response. In the current study, we propose to identify such genes using a mouse embryonic stem (mES) cell-based insertional mutagenesis screen. In mES cells with one mutant allele of Brca2 and the other flanked by loxP sites, cell death can be induced by Cre-mediated loss of the conditional allele. To identify genes whose up-regulation can rescue BRCA2 loss-induced cell death, we transduced these mES cells with murine stem cell retrovirus (MSCV) expressing Cre recombinase. We obtained Brca2-null ES cells that were rescued by the viral insertion and used them to clone the viral insertional sites. We identified several candidate genes that were upregulated in viable ES cells. One of these genes encodes a PDZ domain-containing protein, GIPC3. Expression of Gipc3 was elevated 3 to 4-fold in the rescued clone. Furthermore, we rescued the lethality of Brca2-null ES cells by overexpressing Gipc3. The rescued cells were hypersensitive to DNA damaging agents and exhibited an overall increase in genomic instability. Mechanistically, we found DNA damage-induced p21 expression to be attenuated in GIPC3 over-expressing clones. Because p21 is a key mediator of BRCA2 loss-induced cell death, we hypothesize that GIPC3 overexpression may inhibit p21 expression resulting in viable Brca2-null ES cells. We are now studying the detailed signaling pathway of how GIPC3 affects p21 expression. In addition, we are examining if Gipc3 overxpression can rescue the lethality of Brca2ko/ko embryos and contribute to tumorigenesis in Brca2ko/+ mice. We are also examining the expression of GIPC3 in human BRCA2-deficient tumors.
Citation Format: Xia Ding, Shyam Sharan. Identification of genetic interactors of BRCA2 in mouse embryonic stem cell model. [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 1993. doi:10.1158/1538-7445.AM2013-1993
Abstract 2010: Whole genome profiling to identify novel metastasis regulators in colorectal cancer.
Authors: Hauser Christine , Shavinskaya Anna , Hutter Barbara , Abba Mohammed , Tkachenko Olga , Lichter Peter , Eils Roland , Brors Benedikt , Allgayer Heike 
Published: August 2014

Abstract
Colorectal cancer is the second most common cancer and the second leading cause of cancer related death in men and women in Germany according to the Robert Koch Institute. The leading cause for cancer related mortality is the development of metastasis.
In our study, we aim to identify novel regulators of the metastatic process in colorectal cancer. To this end we employed next generation whole genome sequencing of resected tissues from patients with metastatic colorectal cancer. In particular, we sequenced samples from primary tumor, corresponding normal colon mucosa, metastasis and normal tissue from the metastatic site. The DNA from one patient was thereby sequenced on two different platforms, one being Illumina HiSeq the other Complete Genomics (CG). Additionally, we sequenced the transcriptome of this patient to correlate mRNA expression with genetic aberrations. This abstract focusses on the first results regarding metastatic aberrations.
The average read coverage for the samples sequenced with the Illumina platform was between 50-60x and for the samples sequenced with CG between 105-135x. In total 3607 SNVs were identified in coding regions in the metastasis with both platforms, 40 of these were in exonic regions and classified as high confidence with both platforms.
We also sequenced samples from an additional two patients on one sequencing platform each. One of the patients also presented with liver metastasis, the other one with a lung metastasis. These data were also compared to the data from the first patient to identify possible common aberrations as well as possible differences between the different metastatic sites. We identified several copy number changes occurring in the same chromosomal regions in different patients. Similarly, several genes affected by SNVs were common in two of the patients, while only high confidence APC mutations were common to all three patients. Seven additional genes were affected by high confidence SNVs in the two patients sequenced using the CG platform and three on the Illumina platform, two of which have not yet been characterized in the context of cancer or metastasis.
Citation Format: Christine Hauser, Anna Shavinskaya, Barbara Hutter, Mohammed Abba, Olga Tkachenko, Peter Lichter, Roland Eils, Benedikt Brors, Heike Allgayer. Whole genome profiling to identify novel metastasis regulators in colorectal cancer. [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 2010. doi:10.1158/1538-7445.AM2013-2010
Abstract 2024: Identification of novel oncogenes in a stage I small cell lung cancer through whole-genome sequencing.
Authors: Han Ji-Youn , Lee Yeon Su , Kim Byung Chul , Lee Sung Hoon , Lee Geon Kook , Cho Youn-Sung , Kim Hak-Min , Lee Jin Soo 
Published: August 2014

Abstract
Background: Small cell lung cancer (SCLC) is rapidly progressive and most cases are presented with advanced stage. It hampers access to early stage cancer samples, which are essential to understand the early development of this disease. We performed whole-genome sequencing (WGS) of a stage I SCLC to analyze the genomic feature of early tumorigenesis of SCLC.
Methods: We obtained normal and tumor genomic DNAs from a patient with stage I SCLC underwent curative resection and analyzed the normal and cancer genomes by WGS using 90 bp paired-end reads and validated the cancer variations by Sanger sequencing and single-nucleotide polymorphism (SNP) genotyping.
Results: WGS revealed a lot of SNVs, small insertion/deletions, and chromosomal abnormality. Chromosomes 4p, 5q, 13q, 15q, 17p, and 22q contained many block deletions. Especially, copy loss was observed in tumor suppressor genes RB1 and TP53, and copy gain in oncogene hTERT. Recurrent somatic mutations were found in two genes, TP53 and CREBBP. Novel non-synonymous (ns) single nucleotide variations (SNV) were found in C6ORF103 and SLC5A4 genes. Sequencing of SLC5A4 gene in 23 independent limited disease SCLC samples revealed another ns SNV in SLC5A4 gene, indicating ns SNVs in SLC5A4 gene are recurrent in early -stage SCLC. This cancer genome had mutated genes associated with Notch and WNT signaling pathways.
Conclusion: WGS analysis in this study provides the genomic landscape of early-stage SCLC, which may provide new insight into the early development of SCLC.
Citation Format: Ji-Youn Han, Yeon Su Lee, Byung Chul Kim, Sung Hoon Lee, Geon Kook Lee, Youn-Sung Cho, Hak-Min Kim, Jin Soo Lee. Identification of novel oncogenes in a stage I small cell lung cancer through whole-genome sequencing. [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 2024. doi:10.1158/1538-7445.AM2013-2024
Abstract 2029: Interactions between a selenophene compound and DNA polymerase eta.
Authors: Rietz Anne , Chen Yih-wen , Chou Kai-Ming 
Published: August 2014

Abstract
D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is a selenophene compound that has potent toxicity to various types of cancer cells but not for normal cells. More importantly, in vivo xenograft animal studies have also shown that D-501036 is a promising anticancer compound. Mechanistic studies indicated that D-501036 induces DNA double strand breaks in a dose dependent manner and blocks cell cycle progression at S-phase. D-501036 forms DNA adducts and the amount of DNA adducts increased with the concentration of D-501036. Therefore, we examined several DNA replication/repair mechanisms for their potential relationship with D-501036. Interestingly, we observed that D-501036 suppressed the expression of DNA lesion bypass polymerase η (pol η) more than 70% in both time and dose dependent manners in the ovarian Ovcar-4 cancer cells.
Pol η is the key enzyme to replicate across UV induced cyclobutane pyrimidine dimers (CPD) in DNA. Genetic defects in the pol η encoding gene result in a disease called Xeroderma Pigmentosum variant (XP-V). In addition to its biological function, biochemical studies have shown that pol η can also efficiently bypass cisplatin intrastrand crosslinked guanosines (Pt-GG). In consistence with the biochemical studies, cellular studies have shown that the expression of pol η reduces the cytotoxicity of cisplatin in Ovcar-4 cells. These results suggested that pol η plays an important role in modulating the cellular sensitivity to cisplatin. Although cisplatin is an important therapeutic agent for the treatment of ovarian cancer but the development of resistance against cisplatin has been a major drawback.
Given that D-501036 suppresses the expression of pol η, we performed a cytotoxicity study using the combination of D-501036 and cisplatin. Our results indicated that D-501036 can potentiate the sensitivity of Ovcar-4 cells to cisplatin more than 1,000- fold. Together, our results suggested that D-501036 is a promising compound that can be used to enhance the activity of cisplatin for the treatment of ovarian cancer. Further studies are undergoing to determine the mechanisms of action of D-501036, the information obtained will facilitate the development of new compounds to improve the treatment for ovarian cancer.
Citation Format: Anne Rietz, Yih-wen Chen, Kai-Ming Chou. Interactions between a selenophene compound and DNA polymerase eta. [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 2029. doi:10.1158/1538-7445.AM2013-2029
Abstract 2056: Anticancer bioactive peptide potentiates cisplatin chemotherapy efficacy to improve the quality of life in xenografted nude mice bearing human gastric cancer.
Authors: Su Xiulan , Dong Chao , Su Liya , Zhang Jialing , Wang Xuemei , Bai Xia , Cui Hongwei , Chen Zhong 
Published: August 2014

Abstract
A great challenge of cancer chemotherapy is to eliminate cancer cells and concurrently maintain the quality of life (QOL) for cancer patients. We previously found that anticancer bioactive peptide (ACBP) alone exhibited anti-tumor activity without measurable side effects. Thus, we hypothesize that ACBP and combined chemotherapy could lower the drug dose and improve the efficacy of treatment, leading to a better QOL. In this study, ACBP was isolated and purified from goat liver, and designated as ACBP-L. The anti-tumor activity of ACBP-L was titrated on human gastric cancer MGC-803 cell line in vitro by MTT assay, and its effect on cell morphology was observed through light and scanning electron microscopy. In vivo, MGC-803 tumors were grown in a xenograft nude mouse model, the body weight, food intake, volume and weight of tumors were measured. 18F- FDG PET/CT scan was used to examine the biological activity in tumors of live animals. Expression of Bcl-2, Bax, Caspase 3 and Caspase 8 in the tumor specimens was examined by RT-PCR and immunohistochemistry. Herein, we showed that ACBP-L inhibited MGC-803 cells in a dose and time dependent manner in vitro. In the MGC-803 xenograft nude mouse model, ACBP-L alone significantly inhibited tumor growth in vivo without measurable side effects. Treatment with the full dosage of Cisplatin alone (5mg/kg every 4 days) strongly suppressed tumor growth; however, the QOL in these mice had been significantly affected when measured by food intakes and body weight. The combinatory regiment of ACBP-L with a fewer doses of Cisplatin (5mg/kg every 10 days) resulted in a similar anti-tumor activity with improved QOL. The tumor tissues were harvested after treatment, and ACBP-L suppressed Bcl-2, and induced Bax, Caspase 3, and Caspase 8 protein expression more significantly than in the tissues harvested from Cisplatin alone treatment as detected by immunohistochemistry. The combinatory regiment induced stronger gene expression of Bax and Caspase 8. Our data demonstrated that ACBP-L could lower Cisplatin dose to achieve a similar anti-tumor efficacy as the higher dose of Cisplatin alone. This combined regiment improved QOL in the xenograft gastric cancer model through the modulation of apoptotic molecules.
Citation Format: Xiulan Su, Chao Dong, Liya Su, Jialing Zhang, Xuemei Wang, Xia Bai, Hongwei Cui, Zhong Chen. Anticancer bioactive peptide potentiates cisplatin chemotherapy efficacy to improve the quality of life in xenografted nude mice bearing human gastric cancer. [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 2056. doi:10.1158/1538-7445.AM2013-2056