bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4509: Mitochondrial DNA copy number is inversely associated with overall survival in non-small cell lung cancer
Authors: Hildebrandt Michelle A. T. , Pu Xia , Lippman Scott M. , Wu Xifeng 
Published: August 2012

Abstract
Mitochondria play an important role in generating energy for vital cellular functions. Alterations in mitochondria function due to mutations or copy number changes can potentially lead to tumorigenesis. Although previous studies have investigated the effect of mitochondrial DNA (mtDNA) depletion on cancer risk, no studies have assessed constitutive mtDNA copy number as a prognostic marker for overall survival in non-small cell lung cancer (NSCLC). Towards this, we measured mtDNA content by a quantitative real-time PCR assay in peripheral blood lymphocytes collected prior to treatment from 1,134 NSCLC cases seen at MD Anderson Cancer Center. A significant inverse dose-response trend was identified for mtDNA content and NSCLC risk (p-value: 0.0076). Those with the highest tertile of mtDNA content had the greatest reduction in risk of dying (HR: 0.81, 95% CI: 0.82-0.97, p-value: 0.014) and a highly significantly enhanced median survival time of 20.20 months compared to only 14.11 months for those with the lowest mtDNA content (p-value: 6.7x10-5). It is known that exposure to tobacco smoke results in the production of reactive oxygen species that can damage mtDNA. Therefore, we also performed stratified analysis based on smoking status. The effect in ever smokers (N=951) mirrored that of the overall population with a significant reduction in risk of death with increasing mtDNA content (p-trend: 0.008) and a dramatic nearly seven month survival advantage for those patients with the highest mtDNA content compared to the lowest (20.73 months compared to 13.98 months, respectively, p-value: 4.1x10-5). Interestingly, mtDNA content was not significant with overall survival in never smokers (N=183), suggesting that the effect in the overall population was driven by the ever smokers and that mtDNA alterations do not play a major role in the course of disease for this unique subgroup of NSCLC patients. Together, these results demonstrate that mtDNA content is a potential prognostic biomarker in NSCLC that can be measured non-invasively prior to treatment to provide needed information regarding course of disease to identify those at high risk for a poor outcome.
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 4509. doi:1538-7445.AM2012-4509
Abstract 4511A: KMO as a novel diagnostic and prognostic biomarker in canine mammary gland tumors
Authors: Chiang Yi-Lun , Lei Han-Long , Liao Albert Tai-Ching , Chu Rea-Min , Lin Chen-Si 
Published: August 2012

Abstract
The purpose of this study is to verify the candidate genes KMO associated with the progressive growth of canine transmissible venereal tumor (CTVT) in clinical application as biomarkers for spontaneous canine mammary gland tumors (cMGT). Canine mammary gland tumor shares similar characteristics with human breast cancer in histopathology and biological behavior. Both of them are hormonal-dependent, and they have similar genetic aberrations, signature profiles and cell signal pathways. These facts suggest that canine mammary gland tumor could be a referable tumor model for human breast cancer research. Our previous study has shown screening the gene expression of kynurenine 3-monooxygenase (KMO), an enzyme involved in tryptophan metabolism, could predict tumor malignancy and survival time of cMGT-suffering dogs. Here we intend to confirm KMO as a real cancer biomarker by investigating its protein expression in a serious of 54 cMGT cases, 29 of them were benign and 25 malignant collected at the Veterinary Hospital of National Taiwan University (VHNTU) with immunohistochemistry. The results indicated that KMO discriminated malignant cMGTs from benign ones, and about 73.3% of malignant cMGT showed strong expression of KMO. In addition, patients with strong KMO expression had markedly lower overall survival rate than those with negative or weak ones. Comparing to KMO investigations, increasing Human epidermal growth factor receptor 2 (HER-2) manifestation was also shown to correlate with tumor size and cMGT stages. A positive correlation between KMO and Ki-67 expression was found in our cMGT cases and it suggests KMO may contribute to tumor development by promoting cell proliferation. This study demonstrated KMO as a potential biomarker in tumor diagnosis and prognosis. It might offer new perspectives for clinical applications of cMGT and perhaps lead to advance in human breast cancer research.
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 4511A. doi:1538-7445.AM2012-4511A
Abstract 4517: Syndecan-2 methylation is an early detection biomarker for colorectal cancer with high sensitivity and specificity in small serum sample volumes
Authors: Hoehn Benjmain D. , Oh TaeJeong , Kim Na Y. , Moon Young H. , Kim Nam K. , Kim Tae S. , Shin Sang S. , Lee Seung H. , Jang Ik-Soon , An Sungwhan , Chung Hyun C. 
Published: August 2012

Abstract
BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality in the world. Epigenetics has been a useful tool in the development of sensitive and specific screening tests for CRC. Targeting genes highly methylated in CRC has allowed us to develop an accurate method to select novel candidate genes and validate their sensitivity and selectivity through testing in clinical samples. METHODS: We performed CpG microarray analysis using methylation enriched DNA from tumors and matched normal appearing tissues to identify genes methylated in CRC. We then applied a step-wise filtering method to narrow our field of candidate genes. Six genes were verified for high methylation-positivity in CRC cell lines and underwent negative selection in healthy normal samples using bisulfate-pyrosequencing. Genes SORCS3, SIM1, SDC2 were selected for low levels of methylation in normal tissue followed by verification with MSP-pyrosequencing. RESULTS: SDC2 was then selected because of high methylation levels in tumor and very low levels in normal tissue. SDC2 methylation levels were measured in 133 tumors and were found to be significantly methylated at all stages. Next, 500αl sera samples from 42 CRC patients were tested using qMSP which demonstrated sensitivity at 71.4% and specificity 92.9%. CONCLUSIONS: This study utilized refined technologies to identify and validate a novel candidate SCD2 for CRC screening in serum with high sensitivity and selectivity using only 500αl. These findings demonstrate a new level of candidate selection, verification and application that we feel will meet the need for a new minimally-invasive screening test.
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 4517. doi:1538-7445.AM2012-4517
Abstract 4523: Stool proteomics reveals new candidate biomarkers for colorectal cancer screening
Authors: Bosch Linda JW , de Wit Meike , Oudgenoeg Gideon , Hiemstra Annemieke , Mongera Sandra , Piersma Sander R. , Pham Thang V. , Grieken Nicole CT van , Droste Jochim S. Terhaar sive , Oort Frank A. , van Turenhout Sietze T. , Larbi Ilhame Ben , Mulder Chris JJ , Carvalho Beatriz , Jimenez Connie R. , Fijneman Remond JA , Meijer Gerrit A. 
Published: August 2012

Abstract
Background Colorectal Cancer (CRC) screening can save many lives. Many invitational large scale screening programs worldwide use stool tests like the fecal immunochemical tests (FIT), which detects human hemoglobin. Tumor-specific biomarkers have the potential to improve the performance of these tests but so far, no protein-based fecal test has proved better than the FIT. Although most biomarker discoveries are done in tumor-tissues, the presence and/or chemical nature of biomarkers may be different in samples that ultimately will be used for screening like stool. Measuring biomarkers directly in stool samples may therefore yield candidate CRC biomarkers that are stable in the fecal environment. Aim The aim of the present study was to identify tumor-specific protein based biomarkers for the early detection of CRC, by applying in-depth proteomics to stool samples from CRC patients and healthy controls. Material and method Stool samples were obtained from 10 subjects with negative colonoscopy and from 12 CRC patients. Proteins were analyzed by in-depth proteomics using gel electrophoresis and nano Liquid Chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Resulting MS/MS spectra were searched against the human IPI database (version 3.62). Proteins were analyzed by hierarchical cluster analysis and visualized in a heat map. Non-paired statistical analysis of spectral count data from human proteins was performed using a beta-binomial test. Verification of candidate biomarkers was performed by Selected Reaction Monitoring Mass Spectometry (SRM-MS). Results In total 830 human proteins were identified of which 221 were present at different levels in stool samples from CRC patients compared to control subjects. Of these, 134 proteins were significantly enriched in CRC. Unsupervised hierarchical cluster analysis revealed two clusters. One cluster contained nine CRC stool samples, the other cluster contained all ten control stool samples together with three CRC stool samples. SRM-MS analysis of selected candidate biomarkers on the same stool samples verified the results obtained by LC-MS/MS. Conclusion Proteome profiling on stool revealed 134 proteins significantly enriched in CRC compared to control stool samples, of which a sub set could be verified by SRM-MS. Validation in an independent series of stool samples collection (n=200) by SRM-MS is in process.
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 4523. doi:1538-7445.AM2012-4523
Abstract 4525: p21 as a predictive marker of pathologic complete response after 5-FU based chemoradiotherapy for patients with rectal cancer
Authors: Sim Sung Hoon , Kang Mi-Hyun , Kim Yu Jung , Lee Keun-Wook , Kim Duck-Woo , Kang Sung-Bum , Jang Na Young , Kim Jae-Sung , Lee Hye Seung , Kim Jee Hyun 
Published: August 2012

Abstract
Purpose: Pre-operative chemoradiation therapy (CRT) is standard treatment in clinical stage T3/4 or node positive rectal cancer, however, there are no established biomarker that can predict pathological response and clinical outcome to CRT. The aim of this study was to evaluate the correlation between expression of molecular markers and pathological response and clinical outcomes in patients with rectal cancer who received 5-FU based chemoradiotherapy. Experiment design: Immunohistochemical stain was performed in tissue arrays constructed from core tissue specimens taken before treatment and from operative specimens from 120 patients who received 5-FU based pre-operative CRT and surgery between June 2003 and Dec. 2008. Expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1a and ALDH1 were assessed and correlated with tumor regression grades and disease free survival. Results Of 120 patients (M/F 77/43, median age:63), 23 (19.2%) patients achieved pathologic complete remission; Dworak grade 1: 18 (15%), grade 2: 51 (42.5%); Grade 3: 28 (23.3%), and Grade 4: 23 (19.2%). In the analysis of association between marker expressions and tumor regression grades, low p21 expression at pretreatment biopsy was significantly associated with grade 4 (total regression) (p=0.039) and better disease free survival (5yr DFS rate - low vs high p21: 89% vs 54%, p=0.001). In the multivariate analysis, low p21 expression level in pre-treatment biopsy was significantly associated with better DFS (p=0.003, HR 0.20; 95% CI 0.72, 0.57) and the score difference of p21 expression between pre- and post treatment tissue was also significant (p=0.002, HR 0.09; 95% CI 0.02, 0.39). Low CD166 expression level at pretreatment biopsy was associated with better DFS (p=0.003; HR 0.19; 95% CI 0.07, 0.58). Low ypN stage and high tumor regression grade also have significantly a good effect on DFS as well (p= 0.001, 0.018 respectively). Conclusion Our results showed low p21 and CD166 expression at pretreatment biopsy was associated with tumor regression and good prognosis in patients treated with 5-FU based chemoradioatherapy. Larger, prospective trials and functional studies are warranted to determine the role of p21 and CD166 as predictive biomarker of response to chemoradiotherapy.
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 4525. doi:1538-7445.AM2012-4525
Abstract 4526: Lumican and Versican predict good outcome in stage II and III colon cancer
Authors: de Wit Meike , Belt Eric J. , van Diemen Pien M. Delis , Carvalho Beatriz , Coupé Veerle M. , Stockmann Hein B. , Bril Herman , Belien Jeroen A. , Fijneman Remond J. , Meijer Gerrit A. 
Published: August 2012

Abstract
Background and Purpose: Tumor stroma plays an important role in the progression and metastasis of colon cancer. The glycoproteins versican and lumican are overexpressed in colon carcinomas and are associated with the formation of tumor stroma. The aim of the present study was to investigate the potential prognostic value of versican and lumican expression in the epithelial and stromal compartment of stage II and III colon cancer. Methods: Clinicopathological data and tissue samples were collected from stage II (n=226) and stage III (n=160) colon cancer patients. Tissue microarrays (TMAs) were constructed with cores taken both from the center and the periphery of the tumor. These were immunohistochemically stained for lumican and versican. Expression levels were scored on digitized slides. Statistical evaluation was performed using SPSS. Results: Versican expression by epithelial cells in the periphery of the tumor, i.e., near the invasive front, was correlated to a longer disease free survival (DFS) for the whole cohort (P=0.01), stage III patients only (P=0.01), stage III patients with microsatellite instable (MSI) tumors (P=0.04) and stage III patients with microsatellite stable (MSS) tumors who did not receive adjuvant chemotherapy (P=0.006). Lumican expression in epithelial cells overall in the tumor was correlated to a longer disease specific survival (DSS) in stage II patients (P=0.05) and to a longer DFS and DSS in MSS stage II patients (P=0.02 and P=0.004). Conclusion: In the present series, protein expression of versican and lumican predicted good clinical outcome for stage III and stage II colon cancer patients, respectively.
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 4526. doi:1538-7445.AM2012-4526
Abstract 4581: Pim-1 kinase inhibition in the absence of FLT3 inhibition results in cytostatic effects in acute myeloid leukemia cells
Authors: Natarajan Karthika , Burcu Mehmet , Baer Maria R. 
Published: August 2012

Abstract
The serine threonine kinase Pim-1 regulates expression of proteins involved in cell cycle, proliferation, apoptosis and drug resistance. Pim-1 has been identified as a potential therapeutic target in acute myeloid leukemia (AML). Notably, it is overexpressed downstream of FLT3 with internal tandem duplication (ITD), present in 30% of AML cases and associated with adverse treatment outcomes. SGI-1776 is the only Pim inhibitor in clinical testing to date, but testing was discontinued due to QTc prolongation. SGI-1776 has been used in laboratory studies of AML, but is also a FLT3 inhibitor, and effects of Pim-1 and FLT3 inhibition have been difficult to distinguish, particularly in cells with FLT3-ITD. To better characterize the effects of Pim-1 inhibition in AML, we compared SGI-1776 (from SuperGen, Inc., Dublin, CA) with two Pim inhibitors without FLT3 inhibitory activity, SMI-4a and quercetagetin in FLT3-wt and FLT3-ITD cells in 96-hour WST-1 cell viability, flow cytometric cell cycle and apoptosis, colony formation and liquid culture proliferation assays. SGI-1776 had no effect on cell cycle in FLT3-wt cells at concentrations up to 5 μM, and caused apoptosis at 10 μM, while G1 arrest and apoptosis occurred at 100 nM in FLT3-ITD cells, and SMI-4a and quercetagetin did not alter cell cycle nor induce apoptosis in FLT3-wt nor FLT3-ITD cell lines. IC50 (μM) comparisons are summarized below: In liquid culture assays, all three Pim inhibitors slowed proliferation of all cell lines, indicating a cytostatic effect. Thus FLT3 inhibition plays a substantial role in the cellular effects of SGI-1776, and Pim inhibitors without FLT3 inhibitory activity appear to have primarily cytostatic effects in AML cells. Other Pim kinase inhibitors in development should be characterized with regard to pro-apoptotic versus cytostatic effects.

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 4581. doi:1538-7445.AM2012-4581
Abstract 4602: Preclinical evaluation of the AKT inhibitor MK2206 in nasopharyngeal carcinoma cell lines
Authors: Ma Brigette B. , Lui Vivian WY , Hui Connie , Lau Cecilia , Ng Margaret , Tsao S W. , Hui Edwin P. , Wong C H. , Yan Li , Chan Anthony TC 
Published: August 2012

Abstract
MK2206 is an allosteric inhibitor of AKT with potent activity in cancer cell lines that exhibit genetic aberrations in the PI3K-AKT-PTEN pathway. AKT is frequently activated in nasopharyngeal carcinoma (NPC), while PIK3CA amplification is found in 40-70% of NPC tissues. The preclinical activity of MK2206 was evaluated in NPC cell lines: HONE-1-EBV, HONE-1, CNE-2, HNE-1, and 2 cell lines with PIK3CA amplifications, HK-1 and C666-1. All 6 cell lines showed increased basal level of activated (p-)AKT(ser473), p-GSK3β, p-mTOR, pi-p70S6K and p-4EBP1, except in C666-1 cells where p-70S6K and p-4EBP1 were weakly expressed. Basal expression of p-MAPK was most pronounced in HK-1, CNE-2 and HONE-1-EBV, and weakly expressed in C666-1 and HONE-1. The effect on cell growth was evaluated by exposing cells to increasing concentrations (conc) of MK2206 (100pM, 2nM, 20nM, 0.2µM, 2µM, 30µM) for up to 72 hrs followed by MTT assay. Over 95% of growth inhibition was achieved in all cell lines with respective IC50 values of: CNE-2=0.39µM, HK-1 = 0.48µM, HONE-1= 1.51µM, C666-1= 1.64µM, HNE-1= 1.92µM, HONE1-EBV= 2.36µM. CNE-2, HONE-1-EBV and C666-1 were selected for assessing the effect on AKT signaling, apoptosis, cell cycle and synergism with chemotherapy. Treatment of these cells with MK2206 at IC50 conc for 15 and 24 hours, resulted in G1 arrest in CNE-2 and HONE-1-EBV, and G2 arrest in C666-1 cells. Apoptosis (increased cleaved PARP) was detected in CNE-2 cells only. MK2206 reduced the expression of p-AKT, p-mTOR, p-BAD, p-FKHD and p-GSK3β in CNE-2, HONE-1-EBV and C666-1 cells, while the level of p-4EBP1 level was significantly reduced in C666-1 and CNE-2 cells only. The effect on p-70S6K expression in all 3 cell lines was minimal. MK2206 increased expression of p-MAPK in HONE1-EBV-1 and C666-1 cells, but not CNE-2 cells. A supra-additive effect on cell growth was observed when cisplatin was added to MK2206, while the effect of adding paclitaxel to MK2206 was minimal in all 3 cell lines. Our result suggests that MK2206 has activity in NPC in vitro. The increased expression of p-MAPK observed in some cell lines suggests the presence of compensatory MAPK activation as described with mTOR inhibitors in other cancers. MK-2206 is currently under clinical investigation in recurrent NPC.
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 4602. doi:1538-7445.AM2012-4602
Abstract 461: Involvement of α9β1 integrin-iNOS pathway in matrix metalloproteinase-9 and/or urokinase plasminogen activator receptor-mediated glioma cell migration
Authors: Veeravalli Krishna Kumar , Ponnala Shivani , Zhuang Thompson , Chetty Chandramu , Rao Jasti S. 
Published: August 2012

Abstract
Src tyrosine kinase activates inducible nitric oxide synthase (iNOS) and, in turn, nitric oxide (NO) production as a means to transduce cell migration. Src tyrosine kinase plays a key proximal role to control α9β1 signaling. Our recent studies have clearly demonstrated the role of α9β1 integrin in matrix metalloproteinase-9 (MMP-9) and/or urokinase plasminogen activator receptor (uPAR)-mediated glioma cell migration. In the present study, we aimed to investigate the involvement of α9β1 integrin-iNOS pathway in MMP-9- and/or uPAR-mediated glioma cell migration. Immunohistochemical analysis of the glioblastoma multiforme (GBM) tissue array revealed the prominent presence of iNOS in several clinical GBM samples. In addition, immunofluorescence analysis of U251 glioma cell lines and 5310 glioma xenograft cells showed a prominent expression of iNOS. Transcriptional inactivation of MMP-9 and/or uPAR by respective shRNA reduced iNOS expression in both U521 and 5310 glioma cells. RT-PCR analysis revealed elevated iNOS mRNA expression in these glioma cells after transfection with MMP-9- or uPAR-overexpressing plasmids. Wound healing and spheroid migration assays showed a significant inhibition of the migration potential of MMP-9- or uPAR-overexpressed U251 glioma cells after treatment with L-NAME, an inhibitor of iNOS. Similarly, Matrigel invasion assay revealed a significant inhibition of the invasion potential of the control or MMP-9/uPAR-overexpressed U251 and 5310 glioma cells after L-NAME treatment. Further, we noticed a prominent reduction of iNOS expression in the tumor regions of nude mice brains, which were injected with 5310 glioma cells, after MMP-9 and/or uPAR knockdown. Integrin α9β1 regulates iNOS activity via Src tyrosine kinase; Src coordinates subsequent signaling pathways through activation of FAK and tyrosine phosphorylation of the adaptor protein p130Cas. Western blot analysis of MMP-9 and/or uPAR shRNA treated U251 and 5310 glioma cells revealed significant reductions in the protein expression of cSrc, phosphoSrc, FAK and p130Cas after simultaneous downregulation of both MMP-9 and uPAR. Taken together, our results from the present and earlier studies clearly demonstrate that α9β1 integrin-mediated cell migration utilizes the iNOS pathway, and inhibition of the migratory potential of these glioma cells by simultaneous knockdown of MMP-9 and uPAR could be attributed to the reduced α9β1 integrin and iNOS levels. Therefore, our results highlight the possible involvement of α9β1 integrin-iNOS pathway in MMP-9- and/or uPAR-mediated glioma cell migration.
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 461. doi:1538-7445.AM2012-461