bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5095: CGH+SNP microarrays for copy-neutral aberration detection in cancer research
Authors: Costa Paula , Curry Bo , Peter Brian , Anderson Paige , Sampas Nick , Ashutosh Ashutosh , Vadapalli Arjun , Ijpma Arne , Ruvolo Michael , Lucas Anne , LeProust Emily , Srinivasan Maithreyan , Ghosh Jayati , Fulmer-Smentek Stephanie , Witte Anniek De 
Published: August 2012

Abstract
Advances in cancer research have greatly benefited from high resolution copy number (CN) measurements provided by oligo array Comparative Genomic Hybridization (aCGH). The addition of single nucleotide polymorphism (SNP) measurements to CGH microarrays enables the detection of copy-neutral loss of heterozygosity (cnLOH) events and allelic imbalances arising from genomic instability during cancer development and progression. Nonetheless, cancer studies face challenges associated with genomes’ aneuploidy, polyclonality and mosaicism due to the admixtures of tumor and normal cells. In the quest to decipher tumor complexity, the power and sensitivity of Agilent's CGH+SNP platform has been expanded with new computational methods capable of determining clonal fraction, total CN and allele-specific CN in aneuploid samples. Genomic DNA from hematology-oncology samples, cell lines and a genotyped control sample was digested with AluI and RsaI restriction endonucleases to allow for SNP profiling at the enzymes’ restriction sites. Experimental and reference samples were differentially labeled and hybridized to the Agilent Cancer CGH+SNP microarray, containing ∼20K cancer associated CGH probes, ∼100K backbone probes and ∼60K SNP probes. The data were analyzed using algorithms with extended capability to determine clonal fraction, total and allele-specific CN of the aberrant clone. As expected, significant diversity was found in different chronic lymphocytic leukemia (CLL) tumors. In one CLL sample a small homozygous deletion and cnLOH were identified on chromosome 13. In another CLL case a trisomy of the entire chromosome 12 was observed, together with a small hemizygous deletion and cnLOH on chromosome 18. An Acute Lymphoblastic Leukemia (ALL) tumor sample was found to harbor an amplification on chromosome 6, as well as two small amplifications on chromosome X. To assess the ability of detecting low level mosaicism, we conducted a mixed sample experiment whereby a sample with a known aberration was mixed at known ratios with a matched sample not containing the aberration. The computed clonal fraction, total and allele-specific CN matched the expected values. We have shown that the new algorithms developed for cancer sample analysis determined the genotypes, total copy numbers and clonal fractions in aneuploid samples highly mixed with normal cell populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5095. doi:1538-7445.AM2012-5095
Abstract 5096: Targeted genome sequencing of 184 cancer-related genes for molecular targeted therapy in gastric cancer
Authors: Kim Hwang-Phill , Cho Geuna , Shin Jong-Yeon , Lee Won-Cheol , Yoon Young-Kwang , Han Sae-Won , Kim Jong-Il , Seo Jeong-Sun , Kim Tae-You 
Published: August 2012

Abstract
Cancer is a result of complex genetic alterations including mutations, copy number alterations, and gene fusions. Recent advance in sequencing technology enables comprehensive genome-wide study of the complex genetic alterations. Better understanding of the genetic alteration of cancer will ultimately lead to better treatment options and improved survival of the patients. We have established a set of cancer-related genes comprised of 184 genes for targeted sequencing using next generation sequencing technology. Targeted genome sequencing of the coding regions in the gene set was performed using the Illumina Genome Analyzer IIx. We analyzed the gene set in 13 gastric cancer cell lines. Average coverage depth was 140X. A total of 237 somatic sequence variations were found in 111 genes. The frequently mutated genes were ATM in 7, MSH6 in 6, TP53 in 5, and KRAS in 4 gastic cancer cells. Using the coverage data, we could also analyze copy number variations. Copy number gain (&gt;2.0 fold) was found in 5 genes, whereas copy number loss (&lt;2.0 fold) was found in 17 genes in gastric cancer cell lines. Moreover, the association between the genetic alterations and in vitro sensitivity to various targeted agents is being analyzed. The analyses are aimed at identifying sensitive/resistant mechanisms of the targeted agents and identification of novel therapeutic target. Validation and detailed analysis is currently underway. Targeted genome sequencing of cancer-related genes using NGS can be an accurate and efficient method for studying mutations and copy number variations with a single analysis. Moreover, investigational therapies with their molecular characteristics will reveal biomarkers that can be used to guide clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5096. doi:1538-7445.AM2012-5096
Abstract 5097: Genome-wide analysis of DNA copy number aberrations in gastric cancer
Authors: Tsukamoto Yoshiyuki , Noguchi Tsuyoshi , Uchida Tomohisa , Nakada Chisato , Aizawa Tetsuya , Hijiya Naoki , Matsuura Keiko , Moriyama Masatsugu 
Published: August 2012

Abstract
Genomic copy number aberrations (CNAs) are believed to play a major role in the development and progression of human cancers. Although many CNAs have been reported in gastric cancer, their relevance to gastric carcinogenesis are poorly understood. In this study, we investigated CNAs of 30 advanced gastric cancers (AGC) and 20 gastric carcinoma in situ (CIS) by using array comparative genomic hybridization (array CGH). By comparing the frequencies of CNAs in CISs with those in AGCs, we identified several CNAs that were more frequent in AGCs than CISs. Among them, gain of 20q13 was detected in almost all cases of AGC (29/30). We further analyzed the expression of genes located on 20q13 and found that 8 genes were upregulated more than 2-fold on average compared with normal tissues, suggesting that these genes may play an important role in the progression of gastric cancer. Taken together, our data may provide useful information about the involvment of genomic CNAs in gastric carcinogenesis. References: 1. Tsukamoto et al, J Pathol. 2008;216(4):471-82. 2. Uchida et al, J Pathol. 2010;221(1):96-105.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5097. doi:1538-7445.AM2012-5097
Abstract 5107: Unravelling the complexity of individual cancer genomes
Authors: Menghi Francesca , Woo XingYi , Gong Min , Rouam Sigrid L. , Bertrand Denis , Lee Wah H. , Wang Wendy , Rama Nona , Stronach Euan A. , Karuturi Krishna , Gabra Hani , Agarwal Roshan , Liu Edison T. 
Published: August 2012

Abstract
Ovarian cancer affects ∼ 204,000 women each year, and it is one of the leading causes of cancer-related death among women world-wide, as most patients present with advanced stage (III/IV) tumours, and only 40% survive 5 years after diagnosis. Improvement in the clinical management of ovarian patients is likely to derive from a better understanding of the molecular aberrations which initiate and maintain tumour growth as well as from the discovery of novel drug-able targets for the development of personalised targeted therapies. In this study, we comprehensively characterised the cancer genome of a patient diagnosed with grade III serous ovarian carcinoma, using a combination of massive-parallel sequencing technologies, including long distance DNA Paired-End-Tag (DNA-PET) sequencing, RNA-sequencing and exome-capture sequencing. This approach ensures deep coverage (from 50-180X) of critical mutational elements in a cancer genome. By comparing the genomic abnormalities identified in the tumour sample with those found in its normal counterpart (peripheral blood lymphocytes), we were able to compile a catalogue of all of the somatic events which occurred during oncogenesis and to define the overall complexity of this specific cancer genome. Interestingly, chromosomal arm loss appeared to be the predominant feature of this tumour, with more than 30% of the haploid genome being affected by a decrease in copy number. This associated with a prevalence of inter-chromosomal rearrangements, suggesting chromosomal translocations as a preferred consequence of genomic instability. Here we describe some examples of somatic translocation events causing the loss of tumour suppressor genes. Using this genotype as a possible model of ovarian carcinoma evolution, we aim to explain a subset of ovarian cancers displaying a similar chromosomal profile by applying an analysis of copy number variations, and to define common mechanisms of cancer gene loss.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5107. doi:1538-7445.AM2012-5107
Abstract 5118: A functional genetic approach in patient-derived glioblastoma stem cells reveals pre-mRNA splicing components to be cancer-lethal gene targets
Authors: Hubert Christopher G. , Ding Yu , Toledo Chad , Paddison Patrick J. , Olson James M. , Berndt Jason 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most aggressive and common form of brain cancer in adults and is among the deadliest cancers with a median survival period of 12-14 months. This poor prognosis despite aggressive therapy underscores the need for novel therapeutic targets specifically required by GBM cells. Many GBM are thought to arise from a neural stem cell (NSC) origin and, consistent with this premise, tumor-initiating GBM stem cells (GSCs) isolated from patients retain the NSC-like phenotype and molecular profile of primary tumors. Importantly, unlike serum-cultured cell lines, GSCs retain the developmental potential and specific genetic mutations acquired as each patient's tumor progressed from its cell of origin. We hypothesized that these genetic alterations driving GBM growth might also give rise to unique molecular vulnerabilities within the cancer cells. To identify such novel gene targets required for GBM cell growth, but which are dispensable to normal cells, we performed genome-scale RNAi screens in multiple patient-derived GSC isolates and simultaneously counter-screened against primary untransformed human NSCs. From these results, we identified and validated the existence of GBM-lethal genes that, when inhibited, render patient GSCs sensitive to cellular stresses arising within these transformed cells. From these targets, we show that GSCs have an increased requirement for the expression and function of multiple specific members of the pre-mRNA splicing machinery. Notably, loss of specific key splicing proteins resulted in cell cycle arrest and subsequent cell death only in GSCs, identifying the spliceosome as a specific molecular vulnerability in GBM. New treatment strategies for this disease are urgently needed. The identification of spliceosomal proteins as essential for the growth and maintenance of GSCs both adds to our understanding of glioblastoma biology and suggests novel targets for therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5118. doi:1538-7445.AM2012-5118
Abstract 5131: Identification of the genes that chemosensitize hepatocellular carcinoma cells to interferon-α and 5-fluorouracil therapy
Authors: Shiota Goshi , Sakabe Tomohiko , Nagano Hiroaki , Tsuchiya Hiroyuki 
Published: August 2012

Abstract
The increasing numbers of patients with hepatocellular carcinoma (HCC), which is characterized by an extremely poor prognosis, are causing serious problems worldwide. To improve their prognosis, the development of a more effective therapy is required. Combination therapy with interferon-α (IFN-α) and 5-fluorouracil (5-FU) was reported to provide benefits to patients with advanced HCC, although its efficacy is still unsatisfactory. In this study, taking advantage of functional screening, three chemosensitizing genes for this therapy against HCC cells were identified. Identification of chemosensitizing genes was performed using ribozyme-based functional screening. We constructed a plasmid DNA library expressing random ribozyme genes with ∼6.0 × 106 target recognition sequences. We performed a positive-selection strategy based on the ability of 5-FU to eliminate cells expressing a ribozyme that targets chemosensitivity-unrelated genes. The ribozyme library was transfected into HepG2 cells, which were subsequently treated with the IC50 dose of 5-FU. This cycle was repeated 10 times to fully concentrate the ribozymes targeting those genes involved in the sensitivity of 5-FU. Consequently, 100 target ribozyme recognition sequences that were recovered before screening and after 10 cycles of screening were subjected to a BLAST search to retrieve genes with homologous sequences. This analysis indicated 3 genes (PRKAG2, TGFBR2, and EXT1) as candidate genes. The chemosensitizing effects of these genes on IFN-α/5-FU as well as 5-FU treatment were confirmed by adenovirus-mediated gene transfer. In addition, the mechanisms of effects of these genes on enhancing effects on combination therapy with IFN-α/5-FU were also evaluated. Furthermore, to evaluate the relationship between their expression levels in tumor tissues and the clinical outcome of IFN-α/5-FU combination therapy in advanced HCC patients, mRNA expression was measured using real-time reverse transcription-polymerase chain reaction. As a result, PRKAG2, TGFBR2, and EXT1 were identified as novel chemosensitizing genes for the combination therapy against HCC. TGFBR2 and EXT1 induced transforming growth factor-β signal activation and endoplasmic reticulum stress, respectively. Moreover, PRKAG2 and TGFBR2 were suggested to be promising predictive markers for the clinical outcome of this therapy. In conclusion, the identified genes are promising candidates as targets to enhance the therapeutic effect of IFN-α/5-FU combination therapy in advanced HCC and could be used as predictive markers for response to this therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5131. doi:1538-7445.AM2012-5131
Abstract 5135: Functional genomic shRNA screens reveal that the canonical Wnt pathway protects lung cancer cells from EGFR inhibition
Authors: Casas Matias 
Published: August 2012

Abstract
Lung cancers are the leading cause of cancer deaths globally. In particular, non-small cell lung cancer (NSCLC) is a devastating disease, and is rarely curable. Hyperactivation of mitogenic signaling cascades is a hallmark of cancer development, including for lung cancers. Targeted therapies inhibiting specific receptor tyrosine kinases have shown clinical promise, but rarely produce complete responses and are not curative, suggesting the existence of escape mechanisms promoting cell survival. Using a loss-of-function, whole genome shRNA screen, we identified various components and mediators of the canonical Wnt pathway that contribute to the maintenance of NSCLC cells during inhibition of the epidermal growth factor receptor (EGFR). Modulation of tankyrases, casein kinases and different components of the Wnt pathway with shRNAs or small molecules, in vitro and in vivo, significantly increased the efficacy of EGFR inhibitors, thus revealing a critical role for the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt/β-catenin pathway together with EGFR inhibition in the clinic could lead to more durable remissions for non-small cell lung cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5135. doi:1538-7445.AM2012-5135
Abstract 5138: Development of a high-throughput screen for breast cancer metastatic potential
Authors: Harris Janelle L. , Khanna Kum Kum 
Published: August 2012

Abstract
Metastasis is a frequent cause of cancer-associated morbidity and mortality. Identification of genetic signatures or expression profiles which are associated with metastasis typically involves microarray analysis or genomic sequencing of isolated metastases, either in a clinical setting or animal models. In order to explore the contribution of individual genes to metastasis, we have developed an in vitro culture method for preferential expansion of breast cancer cells with high metastatic potential. Growing breast cancer cells in low growth factor, anchorage independent conditions maintains cells with low metastatic potential in a dormant or non-proliferative state while cells with more aggressive characteristics rapidly proliferate to form ascini. Low-throughput manual testing of this system is currently being carried out using two ‘dormant’ cell lines (PMC 42 LA and MCF-7) and one aggressive metastatic line (MDA MB 231) and ectopic expression of a subset of genes which we anticipate could promote metastasis (PTK2, MYLK, ROCK1, S100A4, Rad51 and ID1). In the high-content genetic screens, genes which cause a significant change in the number or size of ascini will be identified and validated in culture manually as well as in mouse models of breast cancer metastasis. The genetic data derived from these screens will identify genes which promote metastasis, yielding mechanistic information about the progress of metastatic disease. It will also provide convenient platform for testing therapeutic strategies to maintain micrometastases in a dormant state and prevent the onset of clinically relevant metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5138. doi:1538-7445.AM2012-5138
Abstract 5143: ErbB2 activation up-regulates glutaminase 1 expression via NF-κB pathway
Authors: Qie Shuo , Chu Clarissa , Li Weihua , Wang Chenguang , Reginato Mauricio , Sang Nianli 
Published: August 2012

Abstract
Active glutamine utilization is essential for cell proliferation in many tumors, for it provides critical carbon and nitrogen sources. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase. Previous studies have shown that c-Myc regulates glutaminolysis by increasing glutaminase expression in tumor cells. However, it remains unclear whether other oncogenic signaling pathways promote glutaminolysis. Breast cancer is the second most common cause of death for women in the United States and ErbB2 activation is one of the major causes of breast cancer. Using MCF10A and MCF10A-derived NeuT cells, we studied the effect of ErbB2 activation on glutaminase expression, and found that ErbB2 activation increased glutaminase 1 expression at both mRNA and protein levels. Knockdown of ErbB2 decreased glutaminase 1 expression in several human ErbB2-positive cell lines. Consistently, blocking ErbB2 signaling pathway by trastuzumab repressed glutaminase 1 expression. We further showed that in these cells, ErbB2-mediated up-regulation of glutaminase 1 was independent of c-Myc expression. In addition, we found that activation of PI3K/Akt or MAPK pathway was not sufficient to up-regulate glutaminase 1 expression. Instead, inhibition of NF-κB down-regulated glutaminase 1 expression whereas stimulation of NF-κB induced glutaminase 1 expression, suggesting a PI3K/Akt-independent activation of NF-κB signaling pathway up-regulates glutaminase 1. Finally, inhibition of glutaminase activity significantly decreased human breast cancer cell proliferation. Our data indicate that ErbB2 activation promotes glutaminase 1 expression via NF-κB in breast cancer cells, identifying another oncogenic signaling pathway which stimulates glutamine utilization. These findings may facilitate the identification of novel targets for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5143. doi:1538-7445.AM2012-5143
Abstract 5156: Hyperglycemia enhances IGF-I responses and alters the AMPK activation profile that protects against metformin-induced growth inhibition in pancreatic cancer cells
Authors: Karnevi Emelie , Said Katarzyna , Andersson Roland , Rosendahl Ann H. 
Published: August 2012

Abstract
Epidemiological studies have shown direct associations between type 2 diabetes (T2D) and obesity, both conditions associated with hyperglycemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients are diagnosed with either impaired glucose tolerance or new-onset T2D one or two years prior to their cancer diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin, an insulin-sensitizing and glucose lowering drug. We investigated the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin. We found that metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions, but that hyperglycemia protected against the metformin-induced growth inhibition. The antiproliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK(T172) together with a dose-dependent suppression of the insulin/insulin-like growth factor (IGF) signaling mediators IRS-1 and phosphorylated AKT. Furthermore, exposure to metformin during normal glucose led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose promoted a more robust IGF-I response and AKT activation, that stimulated AMPK(S485) phosphorylation and suppressed AMPK(T172) phosphorylation resulting in reduced antiproliferative and apoptotic effects by metformin. In conclusion, our results indicate that metformin has direct antitumor activities in pancreatic cancer cells involving AMPK(T172) activation and modulation of the insulin/IGF signaling pathways. However, hyperglycemic conditions enhance the insulin/IGF-I responses resulting in an altered AMPK activation profile that prevent metformin from fully switching of the growth promoting signals in pancreatic cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5156. doi:1538-7445.AM2012-5156