bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C20: MGMT promoter methylation and analysis of microsatellite instability in head and neck cancer by consensus markers
Authors: Dalay Nejat , Yalniz Zubeyde , Demokan Semra , Suoglu Yusufhan , Ulusan Murat 
Published: May 2012

Abstract
Head and neck cancer is the sixth most common cancer in the world and traditional prognostic indices are of limited use in predicting prognosis. Therefore, there is a need for a beter understanding of the molecular pathogenesis of the disease and a great effort is being made to determine new prognostic and predictive markers that could improve stratification of the patients
Polymorphic microsatellites are useful genetic markers and important tools for studying genetic alterations in tumors. Microsatellite instability refers to the impairment of the mismatch repair system resulting in gains or losses in the number of the tandem repeat units. Cells with mutated mismatch repair genes are not able to correctly repair these errors. The importance of microsatellite instability in head and neck cancer is not well established because of lack of comparable parameters, use of different markers, different criteria in classification and discrepancies concerning the loci examined. Recently it has been shown that mononucleotide markers are more sensitive and specific than dinucleotide markers for the detection of microsatelite instability. No standard approach for the study of MSI has been agreed to in HNC. In this study we analyzed the role and incidence of microsatellite instability in head and neck cancer with criteria and markers recommended by NCI which have been widely used for different types of cancer. We also analyzed methylation of the promoter region of the MGMT gene which functions in the repair pathway of alkylating nitrosocompounds. Microsatellite instability was analyzed in matching tumor and normal tissue samples from 99 patients with head and neck cancer using a panel of five (NR21, BAT25, BAT26, NR24 and MONO27) mononucletoide markers. Two pentanucleotide markers were used to correctly identify the individual tumor and normal tissue samples. The analyses were performed on an ABI Prism 310 capillary electrophoresis system. Microsatellite instability was observed in 26 patients (26.2%). The most frequently affected markers were BAT 25 and NR21 which displayed changes in repeat length in 19 and 11 patients, respectively. Among the microsatellite-positive patients 17 tumor samples (17.1%) displayed high degrees of instability while the remaining 9 samples were instable in only one locus. In five patients instability was observed in three or more loci. Instability was more frequent in tumors with advanced stages. Significant methylation of the MGMT gene was observed in most patients. In 31 patients both alleles were methylated, while in 65 samples partial methylation was observed.
Citation Information: Cancer Res 2009;69(23 Suppl):C20.
Abstract C23: Therapy of triple-negative breast tumors by targeting the MYC oncogene pathway
Authors: Horiuchi Dai , Kusdra Leonard , Klein-McDowell Molly , Creasman Katelyn J. , Goga Andrei 
Published: May 2012

Abstract
Human breast cancers that lack expression of the estrogen and progesterone nuclear receptors and with low HER2 expression are known as “gtriple-negative” tumors. These are amongst the most aggressive breast cancers and no targeted therapeutics exists for this subclass of human tumors.
MYC is a proto-oncogene transcription factor that plays a key role in cell cycle transition of mammalian cells. Increased expression of MYC is estimated to occur in ∼ 20–50% of human breast cancers. Genomic amplification of the MYC locus, 8q24, is correlated with decreased patient survival, and MYC-over-expression in breast cancer cells has been associated with a resistance to anti-hormonal therapies that seek to inhibit ER signaling. Furthermore, MYC has recently been shown to be one of the genes unique to high-grade mammary tumors. Thus, these prior studies suggest that the level of MYC expression might be useful as a biomarker and that the inhibition of MYC function may be a useful therapeutic approach against this difficult-to-treat type of breast cancer. However, while MYC is strongly implicated in breast tumorigenesis, no direct small molecule inhibitors of its transcriptional activity are available in clinical practice.
An alternative approach to directly inhibiting MYC is to find “synthetic-lethal” combinations that selectively kill those cells with elevated MYC levels without affecting normal cells. The term “synthetic-lethality” refers to a genetic context in which a mutation in a gene, which itself does not cause lethality, can cause lethality when combined with a mutation in another gene.
Using engineered cells, we have previously demonstrated that inhibiting cyclin-dependent kinase 1 (CDK1) can kill cells that over-express MYC. We have now used a panel of breast cancer cell lines established from human patients to show that (1) those breast cancers that are receptor-negative have significantly higher levels of MYC protein, (2) that the MYC pathways are critical for the survival and proliferation of this tumor subset, (3) CDK1 inhibition in triple-negative breast cancer cells results in the initiation of apoptosis mediated by mitochondria-dependent intrinsic pathway, and that (4) this apoptotic event is specifically achieved by altering the balance between pro-survival and pro-apoptotic members of the Bcl-2 family proteins. Our results present a novel treatment strategy for “triple-negative” breast cancers by targeting the MYC pathways via CDK inhibitors.
Citation Information: Cancer Res 2009;69(23 Suppl):C23.
Abstract C25: A five-gene signature is associated with tumor progression and poor prognosis in colorectal cancer
Authors: Hao Jummei , Li Guangqiu , Sui Hongmei , Si-Ma Xueqing , Liu Chao , Ding Yanqing , Li Jianming 
Published: May 2012

Abstract
In order to develop an experimentally derived molecular signature closely associated with survival of colorectal cancer (CRC) patients from mouse tumor models, we isolated single cell-derived progenies (SCPs) from SW480 CRC cell line and compared their metastatic potential in an orthotopic implantation model of murine CRC. We compared the differences in the gene expression profiles of a high metastatic variant SCP51, a low metastatic variant SCP58 and their parent SW480/EGFP. We found that 143 genes were commonly differentially expressed between SCP51 and SCP58 cells, SCP58 and SW480/EGFP. Using Gene-annotation enrichment analysis of DAVID, 80 genes were found in top ten clusters of the analysis. Thirty-two genes of above the 80-gene set were found to be involved in metastasis by Genclip, a text mining program. We selected five genes (LYN, SDCBP, MAP4K4, DKK1 and MID1) for immunohistochemical analysis in a cohort of 181 CRC patients. Results showed those LYN, SDCBP, MAP4K4, MID1 and five-gene signatures were significantly correlated with overall survival in patients with CRC. We also found that LYN, MAP4K4 and MID1 but not SDCBP and DKK1 expression was closely correlated with lymph node metastasis and Dukes classification in patients with CRC. Our five-gene signature was closerly associated with survival of CRC patients and could be used as a potential prognostic factor for CRC.
Citation Information: Cancer Res 2009;69(23 Suppl):C25.
Abstract C31: Identification of causal genetic events in oral cancer progression
Authors: Hughes Shevaun E. , Tsui Ivy F. L. , Poh Catherine , Garnis Cathie 
Published: May 2012

Abstract
Background: Oral cancer is one of the world's leading causes of cancer death, with late stage disease diagnoses and high rates of recurrence accounting for poor survival rates. Like many solid tumors, oral cancer develops through a series of histopathological stages from dysplasia, to carcinoma in situ (CIS), to invasive disease. Escalating genomic instability and the accumulation of critical gene alterations is thought to drive disease progression. Causal gene changes remain to be identified for oral cancer. The objective of this study is to determine the essential gene alterations underpinning oral cancer progression.
Hypothesis: Since cancers arise through the accumulation of genetic alterations, gene changes detected in the earliest stages of disease are the foundation of observed cancer phenotypes and essential for oral tumorigenesis.
Experimental Approaches: Oral premalignant lesions and tumor samples were obtained from the Oral Biopsy Service of British Columbia and are associated with well annotated patient information (including disease outcomes). High resolution tiling-path array comparative genomic hybridization was used to define segmental DNA changes for each sample. Recurring regions of DNA alteration detected in premalignant lesions known to progress and preserved in later stage disease were flagged as critical events. Our list of candidate genes within these regions will be refined by analysis of publicly available genomic and gene expression data from oral tumors.
Results: Whole genome copy number profiles from over 100 oral lesions and tumors have been successfully generated using array comparative genomic hybridization. From this data we have identified several molecular subgroups associated with initiation and progression of oral cancer.
Significance: With knowledge of the key genes fueling oral tumorigenesis, we will be able to derive novel biomarkers capable of predicting disease behavior as well as gain a better understanding of the molecular pathways and gene networks responsible for driving oral cancer progression.
Citation Information: Cancer Res 2009;69(23 Suppl):C31.
Abstract C34: Amplified loci on chromosomes 8 and 17 predict Tamoxifen resistance in ER+ breast tumors
Authors: Bilal Erhan , Ganesan Shridar , Bhanot Gyan 
Published: May 2012

Abstract
Most ER+ breast cancers are treated with anti-estrogens like Tamoxifen which disrupt the Estrogen growth pathway. However, not all ER+ cases respond to this therapy. This study aims to identify genetic markers associated with increased sensitivity or resistance to Tamoxifen using outlier analysis. We collected 268 ER+ samples of gene expression data from three separate published studies on Tamoxifen treated patients with follow-up information on distant metastasis-free survival time. Genes were associated with Kaplan-Meyer survival curves based on their outlier profile and filtered, using the long-rank test, for differential survival distributions at p-value&lt;0.05. Additional correlation analysis and PCA clustering were used to identify pathways and chromosomal regions enriched with gene markers correlated with Tamoxifen response. We find significantly over-expressed cell cycle genes correlated with poor survival together with an enrichment of chromosomal regions 17q21.33–q25.1, 17q12, 8p11.2 and 8q24.3. These amplicons were previously documented in breast cancer and contain known oncogenes ERBB2, LSM1, WHSC1L1 and HSF1 associated with more aggressive forms of the disease. Since the majority of samples enriched in the cell cycle pathway also have at least one of the amplicons, this suggests the amplifications on chromosomes 8 and 17 are associated with increased proliferation. In addition to this, a relative Oncotype DX™ score was calculated for samples using normalized expression levels and published weights. This analysis showed that high Oncotype DX™ scores are generated by tumors having either the HER2 amplicon (highest Oncotype DX™ scores), or one of the other amplicons on chromosomes 17 and 8. In contrast, low Oncotype DX™ scores were found only for tumors that do not exhibit any of the identified chromosomal aberrations. This implies that amplicons 17q21.33–q25.1, 8p11.2 and 8q24.3 may be responsible for higher proliferation and poor outcome in the setting of Tamoxifen treatment clinically observed in a subset of ER+, HER2− breast cancers. These results have significant implications for the development of targeted treatments for Tamoxifen-resistent ER+ breast cancers as well as in improving current methods of drug response prediction.
Citation Information: Cancer Res 2009;69(23 Suppl):C34.
Abstract C4: Sp2: A regulator of stem cell differentiation and tumorigenesis
Authors: Kim Tae-Hyung , Horowitz Jonathan M. 
Published: May 2012

Abstract
Transcription factors regulate gene expression and de-regulation of their activities can transform normal cells into tumor cells. The Sp-family of transcription factors consists of nine distinct proteins (Sp1-9) that are evolutionarily-conserved and share a common DNA-binding domain. Sp2 is one of several poorly-characterized members of this transcription factor family. Previous data from our lab and others has indicated that Sp2 is over-expressed in human prostate cancer and in murine skin squamous cell carcinoma. To determine if the de-regulated expression of Sp2 is oncogenic, transgenic mice over-expressing mouse Sp2 via the keratin 5 (K5) promoter were generated. This promoter drives expression of linked genes in basal cells of stratified epithelia, such as skin. Two different transgenic lines (Family A and C) were derived and characterized. The transgenes carried by Family A and C mice were localized to chromosomes 6 and 5, respectively. Endogenous genes were not disrupted by transgene integration in Family A, whereas transgene integration in Family C mice occurred within the latrophilin 3 (Lphn3/CIRL3) locus. Homozygous Family A and C animals develop normally and are indistinguishable from wild-type and hemizygous littermates until post-natal day 2. Family C animals invariably perish at this time due to skin deterioration whereas homozygous Family A animals develop skin lesions on post-natal day 4, are runted and developmentally retarded and perish prior to post-natal day 13. Immunohistochemical staining revealed that that an expanded population of K5-negative, K14-positive progenitor cells inundates all epidermal cell layers of homozygous Family A animals. Expression of markers of differentiated basal keratinocytes (e.g., keratin 10, loricrin) is decreased in homozygous Family A animals. The expression level of keratin 6, a marker of epidermal wounding, inflammation, and/or tumorigenesis is increased in Family A animals beginning at post-natal day 4 as is the expression and distribution of CD34, a hair follicle stem cell marker. Hemizygous Family A animals progress to adulthood unremarkably, however 70% exhibit varying degrees of alopecia (hair loss) beginning at 1 month of age. Family C hemizygotes do not develop alopecia, however an expanded pool of progenitor cells renders these animals susceptible to wound-induced neoplasia, and the incidence of papilloma formation rises with an age-dependent increase in Sp2 levels. Sp2 expression in Family A hemizygotes is insufficient to promote wound-induced neoplastic growth, but epidermal differentiation is slowed sufficiently to retard rates of wound healing. These and other results have led us to speculate that Sp2 functions to limit stem cell differentiation and thus its over-expression contributes to the outgrowth of poorly-differentiated, tumorigenic cells.
Citation Information: Cancer Res 2009;69(23 Suppl):C4.
Abstract C40: Salicylic acid-based small molecule inhibitors of Stat3 show potent and selective activity in a variety of human cancer cell lines
Authors: Page Brent D. G. , Fletcher Steven , Schimmer Aaron , Turkson James , Gunning Patrick T. 
Published: May 2012

Abstract
Signal transducer and activator of transcription 3 (Stat3) protein is an oncogenic transcription factor that exhibits aberrant functioning in many types human cancer. Constitutive Stat3 activation causes over-expression of anti-apoptotic proteins and makes cancer cells resistant to natural apoptotic processes. Inhibiting Stat3 reduces the expression of anti-apoptotic proteins and can selectively kill cancerous cells. We have identified several salicylic acid based inhibitors of Stat3 that show potent activity in vitro and in whole cell assays. In silico docking studies have revealed S3I-201, a known Stat3 inhibitor, exhibits incomplete occupation of Stat3's SH2 domain. A thorough structure activity relationship study has provided a series of compounds that more completely occupy Stat3's SH2 domain and show potent and highly selective activity against Stat3 and a variety of human cancers. Inhibitor design, synthesis, in vitro and in vivo assays and preliminary metabolic studies will be discussed.
Citation Information: Cancer Res 2009;69(23 Suppl):C40.
Abstract C50: Novel silicon derivatives of indomethacin: Generation of potent COX-2 selective agents with improved anticancer activity
Authors: Zakai Uzma I. , Gately Stephen , West Robert 
Published: May 2012

Abstract
Elevated tumor cyclooxygenase-2 is associated with poor overall survival in patients with a variety of cancers. Patients with elevated COX-2 that receive a COX-2 inhibitor have demonstrated improved survival. Indomethacin (IM) is a COX-non-selective inhibitor with demonstrated anticancer activity in patients. The anticancer effects of IM are related to inhibition of COX-2 as well as COX-independent targets. We now report the synthesis and activity of novel IM-sila- amide derivatives where strategic silicon addition results in COX-2 selective IM derivatives that demonstrate activity in mouse models of human cancers and are devoid of the COX-1 associated toxicities. The sila-IM compounds demonstrated improved inhibition of purified human COX-2, IC50 0.2 µM and limited inhibition of COX-1 up to 10 µM. Sila-IM derivatives were also found to be potent inhibitors of NFκB transcription activating function at concentrations below 1.0 µM. A sila-IM derivative Silexsyn was tested in various animal models of human cancer following oral administration. Significant activity was observed in models of non-small cell lung cancer and pancreas cancer. Potent synergism was observed for Silexsyn in combination with EGFR inhibitors. A synthetic methodology incorporating a heteroatom in the amino-functional silane has been developed and used to generate second-generation sila-IM derivatives that could have improved pharmacological properties. The introduction of silicon into an approved scaffold represents an efficient strategy for the rapid production of biologically relevant therapeutics for the treatment of cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):C50.
Abstract C55: Involvement of oxidative stress in the antitumor effect of mTOR inhibitors in mantle cell lymphoma
Authors: Tardif Heather L. , Tome Margaret E. , Briehl Margaret M. 
Published: May 2012

Abstract
Existing treatments for mantle cell lymphoma (MCL) are non-curative, demonstrating a need for a refined treatment approach. MCLs are aggressive lymphomas, usually characterized by over-expression of cyclin D1. Recent clinical trials have shown promising results with the use of mammalian target of rapamycin (mTOR) inhibitors. While cyclin D1 can be regulated through the mTOR pathway, treatment with mTOR inhibitors often inhibit MCL growth without altering cyclin D1. Thus, the anti-tumor activity of mTOR inhibitors is likely mediated through other key targets. One potential target is C/EBPβ-LIP, a transcription factor regulated through the mTOR pathway. One target of C/EBPβ gene regulation is manganese superoxide dismutase (MnSOD), an antioxidant defense enzyme with tumor suppressor activity in some cell types. MnSOD catalyzes the dismutation of superoxide to hydrogen peroxide. Thus, it removes one form of reactive oxygen species (ROS) while generating another. Previous studies in our laboratory have shown that C/EBPβ-LIP levels decrease with mTOR inhibitor treatment in proportion to increasing MnSOD levels. We hypothesize that the anti-tumor effect of mTOR inhibitors in MCL is mediated by the increase in MnSOD protein expression and accumulation of ROS, specifically hydrogen peroxide. Here we investigated the effect of rapamycin on MnSOD and the levels of ROS in two human MCL-derived cell lines. High MnSOD levels correlated with increased sensitivity of cells treated with rapamycin. To investigate the biological effects of increased MnSOD expression, we measured overall ROS levels (DCFH) and the rate of hydrogen peroxide efflux with the fluorescent probe Amplex Red, which is indicative of changes to hydrogen peroxide levels in the cells. These results showed that both overall ROS and hydrogen peroxide levels increased in parallel with MnSOD expression. These increases in hydrogen peroxide were not due to decreased levels of catalase or glutathione peroxidase. Treatment with the general ROS scavenger, N-acetyl cysteine, reduced overall ROS, cellular levels of hydrogen peroxide, and the growth inhibitory effect of rapamycin. These findings indicate that rapamycin-induced cytostatic effect is characterized by generation of ROS, specifically hydrogen peroxide. This is likely due to the increased levels of MnSOD. By understanding the key signaling molecules in the anti-proliferative effects of rapamycin, we may be able to identify additional predictive markers to improve the therapeutic value of mTOR inhibitors, or study drug combinations that will enhance the effect of ROS-induced cytotoxicity.
Citation Information: Cancer Res 2009;69(23 Suppl):C55.
Abstract C59: Human papillomavirus genotype distribution in northern India: Implications for vaccination
Authors: Patro A. Raj Kumar , Dar Lalit , Bhatla Neerja , Gulati Arti , Kriplani Alka , Pati Sunil Kumar , Kumar Pankaj , Broor Shobha 
Published: May 2012

Abstract
Background: Cervical cancer caused by human papilloma virus (HPV), is the commonest cancer in Indian women, with an estimated 132000 new cases and 76000 deaths annually. More than 100 HPV genotypes have been identified in humans of which at least 40 HPV types are found in the genital tract. Several high-risk HPV types are known to cause the disease. There are only limited data available on the genotype distributions in this region.
Methods: During the period three different cross-sectional studies were carried out: (1) a hospital-based cross-sectional study in which 106 women presenting with invasive cervical cancer; (2) a hospital-based cross-sectional study in which 524 women presenting to have an unhealthy cervix were invited to participate; (3) a community-based cross-sectional study in which 465 women also underwent HPV testing. HPV typing in these studies was done by using L1 consensus PCR followed by reverse line blot hybridization assay (Roche).
Results: In the hospital-based population, among 106 invasive cervical cancers the six commonest HPV types were HPV-16, -18, -45, -59, -33 and 73. HPV-16/18, singly or in combination, were seen in 83% of cases. (2) In the hospital-based population, among the 524 symptomatic hospital subjects, the overall HPV prevalence was 15.5 % and the six commonest HPV types were as follows: HPV -16, -89, -39, -52, -33 and 18. Among the HPV positive women accounted for HPV-16/18 were associated with 34.3%, 45.4% and 65.7% of normal, low-grade and high-grade disease respectively. Among (3) the community-based women, the overall HPV prevalence was 7 % and the six commonest HPV types were as follows: HPV- 16, - 45, -52, -31, -66, and -18.
Conclusions: A wide spectrum of HPV types is seen in north Indian women, with HPV-16/18 are the commonest types in all populations. However, thereafter there is considerable variation. It is estimated that the HPV -16/18 vaccine would reduce over 75% of the total cancer burden in this region. The community population is from a confined geographical area whereas the hospital population includes not only residents of Delhi and neighbouring areas but also further states of North India as well as neighboring countries of Nepal and Bangladesh. Thus more studies are required to establish the true picture of HPV type-distribution in this large and diverse region.
Citation Information: Cancer Res 2009;69(23 Suppl):C59.