bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3906: Gene expression profiling of ductal carcinoma in situ reveals novel alterations in the tumor and stromal compartments related to progession and outcome of invasive breast cancer
Authors: Witkiewicz Agnieszka K. , Ertel Adam , Kline Jessica , Davicioni Elai , Knudsen Erik S. 
Published: July 2012

Abstract
An increasing number of women are diagnosed with ductal carcinoma in situ (DCIS). DCIS is non-obligate precursor to invasive breast cancer. Mechanisms leading to development and progression of DCIS to invasive breast cancer (IBC) are still largely unknown. When DCIS and IBC coexist in the same lesion, their transcriptional profiles are nearly identical; however, there are very few studies investigating gene expression in pure DCIS. The goal of this study was to compare gene expression profiles of microdissected epithelial and stromal components of pure DCIS and IBC. Epithelium and stroma were laser microdissected from 10 cases of pure DCIS and 10 invasive breast carcinomas. DCIS and IBC were matched with regard to estrogen, progesterone receptor and HER2 expression. Gene expression was analyzed using Affymetrix Human Exon 1.0 ST microarrays. Analyses of gene expression in IBC and DCIS revealed a number of differentially expressed genes in the epithelial (n=211) and stromal (n=143) LCM obtained cells. In the epithelial compartment many of the genes specifically associated with IBC are part of previously described epithelial to mesenchymal transition, metastasis and myoepithelial cell gene expression signatures. Consistent with these findings, gene ontology analyses found overrepresentation of GO Biological Process terms such as ‘cell adhesion’ (44 genes, p = 1.47E-14), ‘extracellular matrix organization’ (16 genes, p = 3.46E-09), ‘skeletal system development’ (22 genes, p = 5.87E-07) and ‘vasculature development’ (14 genes, P = 4.56E-03). Applying differentially expressed epithelial genes to a larger invasive breast cancer dataset showed association with decreased metastasis free and progression free survival.
Our study reveals that pure dcis and invasive breast cancer are distinct at the transcriptome level. Future work will show if genes differentially expressed between IBC and pure DCIS may be useful for identifying at the time of diagnosis DCIS patients likely to progress to IBC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3906. doi:10.1158/1538-7445.AM2011-3906
Abstract 3908: Genomic profiling of gastric carcinoma in situ and adenomas by array-based comparative genomic hybridization
Authors: Tsukamoto Yoshiyuki , Uchida Masahiro , Noguchi Tsuyoshi , Uchida Tomohisa , Hijiya Naoki , Nakada Chisato , Matsuura Keiko , Murakami Kazunari , Fujioka Toshio , Moriyama Masatsugu 
Published: July 2012

Abstract
Although genomic copy number aberrations (CNAs) of gastric carcinoma at the advanced stage have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis, those of gastric carcinoma in situ (CIS) are still poorly understood. Furthermore, no reports have demonstrated correlations between CNAs and histopathologic features of gastric adenoma. In this study, we investigated CNAs of 20 gastric CISs (Vienna category 4.2), 20 adenomas including 7 low-grade adenomas (LGA; Vienna category 3) and 13 high-grade adenomas (HGA; Vienna category 4.1), using oligonucleotide-based array CGH. The most frequent aberrations in CIS were gains at 8q (85%) and 20q (50%), and losses at 5q (50%) and 17p (50%), suggesting that these CNAs are involved in the development of CIS. We found that the pattern of CNAs in HGA was quite different from those in LGA. The most frequent CNAs in HGA were gain at 8q (62%) and 7pq (54%), whereas those in LGA were gain at 7q21.3-q22.1 (57%) and loss at 5q (43%). Interestingly, gains at 8q and 7pq, both of which occurred most frequently in HGA, were not detected in any cases of LGA. Of note, 8q gain was detected most frequently in both HGA and CIS but undetected in LGA. Since HGA is believed to have a higher risk of progression to invasive carcinoma than LGA, these data suggest that 8q gain is important for the malignant transformation of gastric adenoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3908. doi:10.1158/1538-7445.AM2011-3908
Abstract 3913: Establishing a genomic profile of four gastric carcinoma cell lines using array CGH, FISH and cytogenetic analyses
Authors: Lu Xianglan , Hallford Gene , Wang Xianfu , Li Shibo , Lee Ji-Yun 
Published: July 2012

Abstract
Four gastric carcinoma cell lines (CRL-1739TM, CRL-5822TM, CRL-5971TM and CRL-5973TM), established in the 1970s and 1980s, were purchased from ATCC. These cell lines have been distributed throughout the world and are regularly used for biomedical research. Cytogenetic information is available for three of these cell lines, and two of the three are known to have complex chromosomal rearrangements, though these have not been well characterized. In part, this is due to the complexity of chromosomal changes and the limited ability of G-banded chromosome analysis. Establishing a genomic profile of these cell lines is vitally important, so that their genotypes and phenotypes can be compared. In the current study, G-banded chromosome analysis, array CGH and FISH analyses were performed on these 4 cell lines. The G-banded chromosome analysis was performed and followed by array CGH using 720k oligonucleotide based array chip. The imbalanced regions and chromosome rearrangements, detected by G-banded chromosome and array CGH analyses, were confirmed by FISH using the appropriate DNA probes. Based on the combined data generated by these assays, we established genomic profiles of each cell line; deletions, duplications, translocations and insertions and a chromosomal homogenous staining region. Deletions of 3p and 18q, duplication of 8q, 19q and extra chromosome 20 were found to be common. These findings are consistent with array CGH analyses of fresh gastric tumor samples (data to be presented separately). The results of this study are important as they will provide important information on the status of genomic profiles, allow the expression patterns of gene(s) to be compared, and provide a mechanism for monitoring the genomic changes in these cell lines. This information, we believe, will allow laboratories to make more informed decisions about the need for replacing existing cell lines due to changes in their biological characteristics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3913. doi:10.1158/1538-7445.AM2011-3913
Abstract 3915: α-Fetoprotein-producing hepatoma cells have increased Jagged1 gene copy numbers and their growth can be suppressed by gamma secretase inhibitor
Authors: Kawaguchi Kazunori , Honda Masao , Yamashita Taro , Takatori Hajime , Ueda Teruyuki , Kanno Masataka , Kaneko Shuichi 
Published: July 2012

Abstract
Background: Approximately 70% of patients with hepatocellular carcinoma (HCC) have abnormally high α-fetoprotein (AFP) levels, which increase with tumor progression and angiogenesis. We previously used cDNA microarray comparative genomic hybridization (aCGH) to demonstrate an association between hepatoma AFP-producing status and genomic copy number gain and loss. Although genomic copy number change is reported to be associated with some oncogenic factors, its relationship with molecular pathway aberration has not been elucidated. Here, we examined whether signal pathways are associated with both expression and genomic gain for the purpose of discovering clinically useful molecular targets in hepatoma patients.
Method: Changes in DNA copy number of hepatoma cells were analyzed using bacterial artificial chromosome (BAC)-aCGH and compared with gene expression profiles. Candidate genes were identified, and real-time PCR was used to confirm gene expression changes in AFP-producing cells. siRNA was used to inhibit gene expression and the effect of this on hepatoma cell growth was determined. Confirmation of genomic alteration was performed by real-time PCR on clinical HCC samples. Growth of hepatoma cells was examined following the application of an inhibitor of the identified signal transduction-related gene.
Results: The BAC clone was significantly amplified in some regions of chromosome 20p from hepatoma cells. This amplified region included the ligand for Notch signal transduction, Jagged1, which was shown to be up-regulated by microarray analysis and real-time PCR in AFP-producing hepatoma cells. Surgically treated AFP-up-regulated HCC samples were used to demonstrate the significant correlation between AFP and Jagged1 gene expression. Interestingly, tissue Jagged1 genomic gain and AFP expression were also correlated. The suppression of Jagged1 using siRNA in an AFP-producing cell line significantly repressed cell growth compared with an AFP-negative cell line. The inhibitor of the Notch pathway, gamma secretase inhibitor (GSI), is currently undergoing clinical trials for the treatment of Alzheimer's disease, and its effectiveness has been shown as a cancer therapy for solid tumors. Here, continuous application of GSI to hepatoma cells resulted in a significant suppression of cell growth.
Conclusion: The genomic amplification of Jagged1 contributes to the continuous mRNA expression that activates the Jagged1-Notch signaling pathway in hepatomas. GSI may be a promising candidate for use in the therapy of AFP-producing advanced HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3915. doi:10.1158/1538-7445.AM2011-3915
Abstract 3916: PML nuclear bodies are juxtaposed to DNA-DSBs following IR-induced DNA damage
Authors: Tse Kenneth Chor Kin , Harding Shane M. , Zafarana Gaetano , Ahmed Kashif , Dellaire Graham , Bazett-Jones David , Bristow Robert G. 
Published: July 2012

Abstract
The promyelocytic leukemia (PML) tumor suppressor protein aggregates in discrete PML nuclear bodies (PML-NBs) that are detectable by immunofluorescent microscopy. PML-NB number can change in response to cell cycle and various cell stresses, including DNA damage. Intra-nuclear γH2AX foci form following ionizing radiation (IR) as a function of dose and time and are used as an indicator of DNA double strand breaks (DNA-DSBs). However, whether PML-NBs are associated with exogenous or endogenous (e.g. DNA replication associated) damage was unclear.
Using G0-G1 synchronized human fibroblast (GM05757) to exclude endogenous DNA damage, we examined the intra-nuclear locales of γH2AX and other DNA repair biomarkers with respect to PML-NBs following IR. PML +/+ and -/- MEFs did not vary in DNA-DSB repair based on comet assay. Consistent with this, PML-NBs did not respond to immediate DNA damage. However, 3D-confocal microscopy studies showed that PML-NBs associated with the majority of residual γH2AX sites at later times (24h post-IR). Using quantitative microscopy, these associations were distinguishable as juxtaposition and not true co-localization (i.e., between γH2AX and DSB marker 53BP1). Continued presence of damage sensing and signaling proteins (MRE11, NBS1, MDC1 and 53BP1) and persistent kinase activity (DNA-PK, ATM, CHK2) was observed at these residual γH2AX sites. Absence of RAD51 and BRCA1 indicated that these were not replication-associated breaks and the exclusion of TRF2 suggested that these were not telomeric regions; rather PML-NBs associated specifically with unrepaired exogenous DSBs. Residual γH2AX sites were not enriched in eu- or heterochromatin. Interestingly, scanning electron imaging revealed a lower chromatin density near residual γH2AX foci, suggesting chromatin remodeling in the vicinity of unrepaired breaks. Live cell experiment using GFP-PML IV and mCherry-53BP1tudor domain suggested that PML-NB mobility facilitated the association with residual 53BP1 foci. Our data suggests that maintenance of genomic stability may depend, in part, on the association between PML-NBs and residual γH2AX foci.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3916. doi:10.1158/1538-7445.AM2011-3916
Abstract 3918: Haploinsufficiency of MRE11A reduces DNA repair capacity in bronchial epithelial cells in response to Bleomycin and BPDE
Authors: Liu Yanbin , Tenent Ivo , Willink Randy , Leng Shuguang , Dagucon Christopher , Belinsky Steven A. 
Published: July 2012

Abstract
Reduced DNA repair capacity (DRC) and polymorphisms in genes involved in the requisite repair pathways are associated with increased risk for lung cancer and promoter hypermethylation. A SNP (rs7117042) was identified in MRE11A that resulted in a 30% reduction in gene transcription and was associated with promoter methylation in sputum from cancer-free smokers. In vitro studies have also demonstrated that formation of DNA double strand breaks (DSB) can lead to gene promoter methylation. The purpose of this study was to identify genes in the DSB repair pathway that may be rate limiting for DNA repair in response to DNA damage and ultimately assess their effect on transformation and promoter methylation. A model for haploinsufficiency was created to simulate germ line sequence variation in the MRE11A, NBS, and XRCC3 gene by shRNA stable knockdown in immortalized human bronchial epithelial cells (HBEC2 and HBEC13). The clones with 50% and 75% knockdown of target genes were selected and cell lines were exposed to increasing doses of bleomycin and BPDE respectively with DRC determined by formation of micronuclei. MRE11A knockdown reduced DRC by 2- and 2.5-fold following exposure to BPDE and bleomycin, respectively compared to parental cell lines. DRC also varied by degree of gene knock down. Studies were extended to address the functional impact of the MRE11a SNP on DRC by challenging lymphocytes wild type or heterozygote for this SNP to bleomycin. A 30-40% reduction in DRC was seen in heterozygotes compared to wild type. Studies are ongoing to address the effect of chronic carcinogen exposure of HBECs with knock down of MRE11a on transformation efficiency and induction of gene promoter hypermethylation. These studies support a important role for MRE11A in the response of the cell to double-strand break damage. Supported by NIH R01 ES015262.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3918. doi:10.1158/1538-7445.AM2011-3918
Abstract 4075: Chemoresistant colorectal cancer cells exhibit high glycolytic activity
Authors: Tozzi Federico , Zhou Yunfei , Chen Jinyu , Bose Debashish , Fan Fan , Xia Ling , Wang Jinrong , Brusher Heather , Widger William , Ellis Lee M. , Waihua Zhang 
Published: July 2012

Abstract
Background: Overcoming drug resistance in colorectal cancer (CRC) requires an understanding the mechanisms by which cancer cells adapt to the genotoxic stress. We established oxaliplatin resistant CRC cells derived from HCT116 and HT29 cell lines (HCT116 OxR and HT29 OxR) (Yang AD et al, Clin Ca Res, 2007). The mechanisms by which these resistant clones reprogram their energy metabolism to gain a survival advantage remain unknown. In this study, we hypothesized that chemoresistant CRC cells would exhibit altered cellular metabolism in order to survive following chronic genotoxic stress.
Methods: The expression level of the glycolytic enzymes Glut1, hexokinase II (HK2), LDHA and HIF1α were detected by Western Blotting. Glucose uptake and lactate production was calculated by measuring the concentration of glucose and lactate in the culture media. Intracellular ATP/ADP levels, oxygen consumption and mitochondria ATP production were quantified. An in vivo xenograft study was used to compare the growth rate and angiogenesis of parental and oxaliplatin-resistant cells.
Results: Compared with the parental cells, both HT29-OxR and HCT116-OxR cells exhibited a metabolic phenotype with increased glycolysis as reflected by increased glucose uptake and lactate production. Glycolytic enzymes were upregulated in resistant cells including Glut1, HK2 and LDHA. HIF1α expression and VEGF levels in the conditioned media were increased in the resistant cells. The mitochondria of OxR cells demonstrated defective complex I/II substrate ATP production despite increased cellular oxygen consumption. Importantly, the OxR cells maintain higher levels of intracellular ATP and ATP/ADP ratio indicating a metabolic switch to glycolysis. In a tumor xenograft model, HT29 OxR cells grew significantly slower than parental HT29 cells. Interestingly, when OxR cells were mixed with parental HT29 cells (50:50 and 90:10), tumor growth and microvessel counts were significantly increased.
Conclusion: Oxaliplatin-resistant cells demonstrated: 1) high aerobic glycolytic activity, 2) an increase in HIF1α and glycolytic enzymes, and 3) defective mitochondria function. This metabolic switch provides more ATP production and likely contributes to the chemoresistant phenotype. Altering energy metabolism may provide a novel strategy to overcome drug-resistance in CRC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4075. doi:10.1158/1538-7445.AM2011-4075
Abstract 408: Expression of interferon-stimulated gene 15 is a novel prognostic predictor for patients with advanced stage high-grade serous ovarian adenocarcinoma
Authors: Tsai Ching-Chou , Zaid Tarrik M. , Co Chloe N. , Yeung, Tsz-Lun , Thompson Melissa S. , Carroll Amy , Yeung Zachary P. , Wong Kwong-Kwok , Mok Samuel C. 
Published: July 2012

Abstract
Objectives: Utilizing the transcriptome profiling approach to identify genes that are differentially expressed in normal ovaries, and serous borderline ovarian tumors of low-malignant potential (LMP), and low-grade ovarian serous carcinomas compared with high-grade ovarian serous carcinomas (HGSC), we identified ISG15, an ubiquitin-like molecule that is strongly up regulated by type I interferon, to be highly up-regulated in advanced stage HGSCs. We seek to validate the expression patterns of ISG15 and correlated them with clinical outcomes.
Methods: Over-expression of ISG15 was confirmed in ovarian cancer cell lines and tissue by real time PCR and immunohistochemistry, respectively. Immunolocalizaation of ISG15 was performed on 155 HGSCs, 10 serous LMPs, 10 normal ovaries, and 10 fallopian tubes. Expression levels of ISG15 were quantified by Image-Pro plus software. The correlation between overall survival and progression free survival and ISG15 expression levels was performed on 155 and 130 HGSC, respectively, using both Kaplan Meier and Cox Regression analyses.
Results: ISG15 expression was not detected in normal ovaries, fallopian tubes and LMPs. Over-expressed of ISG15 was confirmed in a majority of HGSC cell lines and tumor tissue. To further evaluate the clinical significance of nuclear ISG15 expression, both Cox and Kaplan-Meier analyses were performed on patients with HGSC. Multivariate Cox analysis showed that ISG15 expression levels were associated with improved overall survival (HR:0.9, P=0.011). In addition, using median ISF15 staining intensity as a cut-off, Kaplan-Meier analysis and log rank test demonstrated that strong ISG15 expression was associated with improved overall and progression free survival (P&lt;0.001 and P=0.002, respectively).
Conclusion: Over-expression of ISG15 is common in high-grade serous ovarian adenocarcinoma. The expression levels in tumor cells are strongly correlated with overall survivals, suggesting ISG15 may be a powerful prognostic marker for patients with HGSC. Further functional studies on the functional role of ISG15 in ovarian cancer progression are warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 408. doi:10.1158/1538-7445.AM2011-408
Abstract 4082: Protection of acetaminophen-induced cytotoxicity by diallyl sulfide in mouse macrophages and HepG2 cells
Authors: Raza Haider , John Annie 
Published: July 2012

Abstract
The nonsteroidal anti-inflammatory drugs (NSAIDs), including acetaminophen (APAP), have been reported to induce cytotoxicity in cancer and non-cancerous cells. The precise molecular mechanisms, however, are not well understood. Our previous studies on HepG2 cells treated with aspirin and mouse macrophage J774.2 cells treated with APAP strongly suggest cell cycle arrest and induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. Macrophages are known to play a critical role in toxicity as well as in protection of target tissues against the toxicity induced by NSAIDs. In the present study, we have demonstrated that macrophages are a more sensitive target for APAP -induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis, DNA fragmentation, cytochrome c release and PARP/caspase 3 activation was seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of reactive oxygen species (ROS) production and alterations in glutathione metabolism. In contrast to macrophages, our results also demonstrate a marked increase in glutathione transferase activity in APAP-treated HepG2 cells. This may explain the apparent resistance of HepG2 cells to APAP toxicity compared to the macrophages. Treatment of these cells with diallyl sulfide (DAS, 200 µmol/ml), a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 µmol/ml for 18h) exposure have also exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems. (Supported by Terry Fox Cancer Research Funds and a fund from FMHS Research Committee).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4082. doi:10.1158/1538-7445.AM2011-4082