bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2989: Depletion of the Topoisomerase I binding proteins BTBD1 and BTBD2 alters the DNA damage response in tumor cells treated with camptothecin
Authors: Kurtis Christian , D'Arpa Peter , Cutler Mary L. 
Published: February 2011

Abstract
The Topoisomerase I (Top1) binding proteins BTBD1 and BTBD2 belong to a family of structurally related proteins of diverse function. BTBD1 and BTBD2 are highly homologous (&gt;80% identity) and are comprised of an N-terminal BTB/POZ domain, typically involved in protein-protein interactions, followed by a related BACK (BTB and C-terminal Kelch) domain. The carboxy-terminal half of these proteins have been shown to be the Top1 binding portion (Xu et al., 2002) and contain a PHR domain found in certain E3 ubiquitin ligases. Understanding the role of BTBD1 and 2 proteins, with an emphasis on the effects of their depletion by RNAi and concomitant treatment of cells with the Top1 specific camptothecin (CPT) family of chemotherapeutic agents, is the focus of this present study. Treatment of cells with CPT and related analogues results in Top1 mediated DNA damage that was assayed by detection of the phosphorylation of DNA damage response elements (DDRE), including ATM, ATR, Chk1 and H2A.X, by Western blot. We have observed a &gt;5-fold activation of the basal levels of DDRE in cells in which BTBD1 and BTBD2 have been depleted by RNAi. Furthermore, the response to CPT in these cells is temporally accelerated compared to cells treated with a non-specific control siRNA and CPT. In addition, immunofluorescent studies have revealed that there is a clearing of Top1 from the nucleoli of BTBD1 and 2-depleted cells even in the absence of CPT treatment. Recently characterized members of the BTB family of proteins have been shown to be involved in the repair of DNA damage (Munoz et al., 2009). It appears that BTBD1 and 2 proteins are involved in the response to DNA damage induced by Top1 specific drugs and as such open a new area of study with potential for development of novel combination therapies.
Xu L, et al., BMC Genomics. 2002. 3(1).
Muñoz IM, et al., Mol Cell. 2009. 35:116-27.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2989.
Abstract 2990: Analysis of chromatin structure in the Myeloid-Lymphoid Leukemia gene translocation breakpoint cluster region
Authors: Horrell Jeremy C. , Aldrich Aileen M. , Super Heidi J. Gill 
Published: February 2011

Abstract
The Myeloid-Lymphoid Leukemia (MLL) gene fuses to &gt;50 different loci as the result of reciprocal translocations associated with several subtypes of human acute leukemia. In every case, the fusion point in MLL is within the same 8 kilobase pair (kbp) region, called the MLL breakpoint cluster region (bcr). Despite this conserved breakpoint, no translocation mechanism has been definitively described. Recently, electrophoretic mobility shift assay (EMSA) was used to determine protein binding characteristics in the MLL bcr. Proteins were noted to bind at the extreme 5’ and 3’ boundaries of the MLL bcr, but not in an internal region near the 3’ end of the MLL bcr which includes the translocation breakpoint hot spot in infant and therapy-related acute myeloid leukemia patients. The limited mobility observed with the protein-DNA complexes indicate a large protein or multiple proteins may bind at the 5’ and 3’ ends of the MLL bcr. Binding occurred with nuclear proteins from hematopoetic cells, but not with nuclear proteins from fibroblast cells and was sequence-specific as shown by competitor assays. Analysis of the most 5’ region of the MLL bcr showed several discontinuous regions are important for protein binding. Our results suggest that specific protein-DNA interactions may define the limits of the MLL bcr, and that the previously described internal hotspot does not bind the same protein complex. Binding of proteins at the boundaries of the MLL bcr prompted a study of chromatin organization within the same regions of the MLL bcr. Our initial hypothesis was that the MLL bcr regions which bound the protein complex would be relatively nucleosome depleted. Using chromatin immunoprecipitation assay (ChIP), we consistently showed a lack of histone H3 at the extreme 5’ end of the MLL bcr in Hela cells, and in the B-cell leukemia cell line, REH, suggesting a nucleosome-depleted region. In repeated experiments the 3’ MLL boundary showed minimal histone H3 binding, suggesting this area is also relatively free of nucleosomes. The internal breakage hot spot showed prominent H3 binding consistent with the presence of nucleosomes. The chromatin study suggests that the MLL bcr boundary regions are more exposed, especially in the 5’ region. This further supports our EMSA findings, that the MLL bcr may be bordered by large DNA-protein complexes. The project described was supported by NIH Grant Number P20 RR016741 from the North Dakota INBRE Program of the National Center for Research Resource, and by a Minot State University institutional research grant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2990.
Abstract 2994: Benzene induces leukemia-related chromosome loss in myeloid progenitor cells
Authors: Zhang Luoping , Lan Qing , Ji Zhiying , Li Guilan , Guo Weihong , Shen Min , Hubbard Alan , Vermeulen Roel , Rappaport Stephen , Rothman Nathaniel , Smith Martyn T. 
Published: February 2011

Abstract
Benzene, a common environmental pollutant, is an established cause of acute myeloid leukemia (AML) and other blood disorders, such as myelodysplastic syndromes (MDS). However, the precise mechanisms by which it produces leukemia and related disorders remain unclear. Previously, we reported that benzene exposure, at and below the current US occupational standard of 1 ppm, significantly reduced essentially all types of peripheral blood cell counts in shoe workers in China (Lan et al, 2004). This suggests a toxic effect of benzene on bone marrow since all peripheral blood cells arise from stem and early progenitor cells located in the bone marrow, which are also the target cells for leukemia induction. A portion of these stem and early progenitor cells circulate in the blood making it possible to measure their proliferation potential. We previously showed that colony formation from blood myeloid progenitor cells (including CFU-GM and CFU-GEMM) significantly declined with increasing benzene exposure and was more sensitive to the effects of benzene than was the number of mature blood cells (Lan et al, 2004). We have now investigated the effect of different levels of benzene exposure on the loss and gain of chromosomes 7 and 8, as these are the most common cytogenetic changes observed in AML and MDS and are thought to be causally related to the disease process. CFU-GM cells were cultured in methylcellulose colony-forming assays (StemCell Technologies) from a subset (n = 42) of the workers studied previously (18 workers exposed to &lt;10 ppm, 10 exposed to &gt;10 ppm benzene and 14 unexposed controls) for cytogenetic analysis by interphase FISH (fluorescence in situ hybridization) microscopically. Here, we report that benzene exposure above and below 10 ppm caused significant increases in the loss (monosomy) of chromosomes 7 and 8 in comparison to controls and that the trend with increasing exposure was significant (ptrend &lt; 0.01). The gain (trisomy) of both chromosomes 7 and 8 was not significantly affected by benzene exposure in the 42 subjects studied here. In conclusion, interphase cytogenetic analysis of the loss of chromosomes 7 and 8 in myeloid progenitors is a potential biomarker for the effects of benzene exposure in humans. Further, our results support the idea that the loss of chromosome 7 in early myeloid progenitor cells is a probable mechanism contributing to benzene-induced AML and MDS. Supported by NIEHS-NIH grant RO1-ES06721 and Intramural Funds from NCI.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2994.
Abstract 2998: MicroRNA expression signatures in human ovarian tumor progression
Authors: Zhao Jian-jun , Kong William , Lin Jianhong , Wey Jennifer , Yang Hua , coppola domenico , Lee Yi-Chun , Wenham Robert , Lancaster Johnathan , Sellers Thomas , Cheng Jin Q. 
Published: February 2011

Abstract
Differential expression of a number of miRNAs has previously been detected between normal ovaries and epithelial ovarian cancer (EOC). However, miRNA expression signatures have not been demonstrated between primary human ovarian surface epithelial (HOSE) cell, cystadenoma, low malignant potential (LMP) ovarian tumor and ovarian carcinoma as well as fallopian tube. Here, we performed miRNA profiling in normal primary OSE cells, normal fallopian tube and ovarian tumors, including 7 cystadnomas, 6 LMP and 49 ovarian carcinomas, as well as 15 ovarian cancer cell lines and 5 HIOSE cell lines. While deregulated dozen miRNAs were observed in different histological types of cysadenoma, LMP and ovarian carcinoma compared to primary OSE and fallopian tube, there are no significantly common changed miRNAs between serous adenoma and LMP, as well as between mucinous adenoma and LMP. However, 3 miRNAs were co-downregulated and 7 miRNAs were co-upregulated in serous LMP and carcinoma. When comparing mucinous LMP and carcinoma, only 3 miRNAs were co-deregulated. In addition, 3 and 6 miRNAs were co-deregulated in mucinous and serous adenoma and carcinoma, respectively. While miRNA expression patterns are distinct among four histological types of ovarian carcinoma examined, upregulation of miR-221/222 family was found to have significant poor prognosis value in serious carcinoma (p&lt;0.05). These results support the notion that majority of ovarian carcinoma are derived neither from cystadenoma nor from LMP. Further cluster analysis suggests that the serious ovarian cancer may be derived from fallopian tube or/and OSE. Also our data suggest that commonly deregulated miRNAs between adenoma, LMP and carcinoma could serve as not only early markers but also initiation pathogenetic factors in this malignancy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2998.
Abstract 2999: Assessment of microRNA expression in two-dimensional histopathological fields of breast cancer
Authors: Rosenberg Alex M. , Zoon Christine K. , Clark Elizabeth S. , Armani Michael D. , Shapiro Benjamin , Smela Elisabeth , Hanson Jeffrey C. , Rodriguez-Canales Jaime , Emmert-Buck Michael R. , Tangrea Michael A. 
Published: February 2011

Abstract
Breast cancer is the second most common type of cancer among women with an expected ∼192,000 newly diagnosed cases in the United States this year alone. Early detection methods are becoming increasingly important for guiding treatment options and decisions. Currently, standard molecular diagnostic tests of breast cancer characterize patient cases by estrogen receptor (ER), progesterone receptor (PR) and Her2neu status. The recently discovered biomolecule, microRNA (miRNA), is being assessed as a novel diagnostic tool; however, since miRNA is a regulatory molecule it is likely that expression is cell-type and location specific, thus studies that don't specifically study malignant and normal cells may mask miRNA patterns within tissue. The goal of our study was to evaluate miRNA expression within sub-regions of formalin-fixed paraffin-embedded breast cancer tissue. Utilizing a combination of laser-based and manual microdissection techniques, we evaluated the expression of several breast cancer associated miRNA via TaqMan chemistry. We dissected selected areas of tumor and normal cells, as well as a grid-like pattern over entire tissue sections to separately evaluate each histopathological region. The data suggest there is heterogeneity of miRNA expression within the tumor and the surrounding normal tissue. In order study this phenomenon in more detail, we are now adapting a new two-dimensional amplification (2D-PCR) device to measure miRNA levels across tissue specimens with fine resolution. This approach to examining miRNA profiles in tissue sections may lead to novel findings with diagnostic or prognostic implications for breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2999.
Abstract 30: ERG oncoprotein expression in prostate cancer: Potential for ERG-based stratification
Authors: Tan Shih-Han , Furusato Bungo , Young Denise , Dobi Albert , Sun Chen , Mohamed Ahmed , Thangapazham Rajesh , Chen Yongmei , McMaster Gary , Sreenath Taduru , Petrovics Gyorgy , McLeod David G. , Srivastava Shiv , Sesterhenn Isabell A. 
Published: February 2011

Abstract
Introduction: Prevalent gene fusions involving regulatory sequences of the androgen receptor (AR) regulated prostate associated genes (predominantly TMPRSS2) and protein coding sequences of nuclear transcription factors in the ETS gene family (primarily ERG), result in frequent overexpression of ERG in prostate tumors. Emerging studies suggest oncogenic functions of ERG in prostate cancer (CaP). Despite numerous reports of gene fusions and mRNA expression, ERG oncoprotein in CaP still remains to be defined. Using an anti-ERG monoclonal antibody (ERG-MAb) developed by our group, a global view of ERG oncoprotein expression has been established in the context of multi-focal CaP.
Experimental procedures: Specificity of the ERG MAb was established using wt ERG and TMPRRSS2-ERG encoded proteins expressed in HEK 293 cells and ERG si RNA treated VCaP cells harboring TMPRRSS2-ERG fusion. ERG expression in formalin fixed paraffin embedded (FFPE), whole mount-prostate specimens was optimized by immuno-histochemistry assay. TMPRSS2-ERG fusion status in representative specimens was analyzed by b-DNA assay or fluorescent in situ hybridization (FISH).
Results: Through exhaustive evaluations of 132 whole-mount prostates (227 tumor foci and over 200,000 benign glands), we demonstrate 99.9 % specificity of an anti-ERG monoclonal antibody. Specimens from over 60% patients had one or more ERG positive tumor focus. Over 80% concordance was noted between the presence of ERG protein and the common TMPRSS2-ERG fusion (A type) transcript in representative specimens from 35 pateints.
Conclusions: Unequivocal association of focally ERG positive PIN lesions with ERG positive carcinoma (80 out of 80 specimens) and vice versa (52 out of 52 specimens) strongly affirms biological role of ERG in clonal progression of prostate tumors. Taken together, the homogeneous and strong ERG expression in individual tumors establishes the potential for ERG based stratification of prostate cancers.
Funding sources: NIH Grants RO1 DK065977 and Center for Prostate Disease Research Program HU001-04-C-1502
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 30.
Abstract 300: Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation
Authors: Kobayashi Takashi , Inoue Takahiro , Shimizu Yosuke , Terada Naoki , Yamasaki Toshinari , Nakamura Eijiro , Toda Yoshinobu , Nishiyama Hiroyuki , Kamoto Toshiyuki , Ogawa Osamu 
Published: February 2011

Abstract
Ras homolog-enriched in brain (Rheb), a small GTP-binding protein, is associated with prostate carcinogenesis through activating mammalian target of rapamycin (mTOR) signaling pathway. This study aimed to elucidate whether Rheb promotes proliferation of prostate cancer cells and can act as a potent therapeutic target in prostate cancer. Rheb mRNA and protein expression was higher in more aggressive, androgen-independent prostate cancer cell lines PC3, DU145 and C4-2, compared with the less aggressive LNCaP. Rheb expression was higher in human prostate cancer tissues than in benign prostatic epithelia. Forced expression of Rheb in LNCaP cells accelerated proliferation without enhancing androgen receptor transactivity. Attenuation of Rheb expression or treatment with the mTOR inhibitor rapamycin decreased proliferation of PC3 and DU145 cells, with a decrease in the activated form of p70S6 kinase, one of the main targets of mTOR. Rheb potentiates proliferation of prostate cancer cells and inhibition of Rheb or mTOR can lead to suppressed proliferation of aggressive prostate cancer cell lines in vitro. Rheb and the mTOR pathway are therefore probable targets for suppressing prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 300.
Abstract 3003: Immune cell-related microRNA-155 is associated with human liver cirrhosis and hepatocellular carcinoma
Authors: Budhu Anuradha S. , Yu Zhipeng , Forgues Marshonna , Tang Zhao You , Croce Carlo M. , Wang Xin Wei 
Published: February 2011

Abstract
Liver cirrhosis, a major hepatocellular carcinoma (HCC) risk factor, is caused by chronic liver disease (CLD) of various etiologies with ambiguous underlying mechanisms. Gene profiling has illustrated that CLD etiologies differ and are associated with cytokine up-regulation. Recently, microRNAs (miRNAs), noncoding-RNA gene regulators, have been utilized as effective molecular biomarkers in many cancer types, including HCC. We investigated whether unique miRNAs are associated with CLD and HCC. We examined miRNA array profiles of 58 human liver tissue specimens with end-stage CLD (hepatitis B virus, hepatitis C virus, Wilson's disease, autoimmune hepatitis, alcoholic liver disease and primary biliary cirrhosis) and a normal liver pool. We compared the differentially expressed miRNAs between CLDs and normal liver, among CLDs and between etiologically equivalent CLD and HCC. Significant differentially expressed CLD-miRNAs were validated by quantitative-real time PCR (qRT-PCR). MiRNA and immune cell expression was measured in CLD, HCC or human peripheral blood mononuclear cells (PBMC) by qRT-PCR or immunohistochemistry. Correlation analysis between etiology-specific miRNAs and mRNAs were performed, followed by pathway analysis of the correlating mRNAs. Statistical class comparison analyses revealed that unique miRNAs were associated with each CLD group and among CLD etiologies, with only one miRNA commonly altered among CLDs (p=0.05; 10 fold cross-validation; 10k permutation). miRNA expression correlated well between array and qRT-PCR analyses (spearman r= 0.53-0.83, p= 0.03-0.001). We also found that many CLD-miRNA alterations were maintained in HCC. In particular, immune-related miR-155 was significantly up-regulated in CLDs, HCC, nontumor tissue, metastasis tissue specimens and PBMC treated with pro-metastatic colony stimulating factor 1 (CSF1) or osteopontin (OPN). MiR-155 was associated with T regulatory cells (Treg) and both were elevated by pro-inflammatory cytokines. Moreover, high miR-155 expression in nontumor tissues was associated with poor overall HCC patient survival (p=0.0244). Correlation analysis revealed that miR-155 was associated with distinct gene expression pathways in each CLD etiology. In sum, CLD miRNAs are mainly etiologically distinct and are coupled to immune responses and tumorigenesis. Our work suggests that miR-155 may modulate Tregs and hence, functionally contribute to CLD and HCC progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3003.
Abstract 3009: Evaluating the role of cell cycle inhibition in celecoxib toxicity through microRNA analysis
Authors: Heaford Andrew C. , Erbe Christy B. , Bock Jonathan M. 
Published: February 2011

Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is a major health problem worldwide, with over 45,000 new cases predicted to occur in the United States in 2009. Adjuvant therapies that can augment established treatments for SCCHN without causing significant additional morbidity are needed for this disease. Cyclooxygenase-2 (COX-2) inhibition has emerged as a potential adjuvant to established treatment regimens for SCCHN with this concept in mind, as COX-2 is known to be overexpressed in SCCHN. Celecoxib is a COX-2 specific NSAID with known antineoplastic activity against many human tumors, and is currently being used in clinical trials as a chemopreventive agent and adjuvant to established chemotherapy and radiation therapy protocols. The underlying mechanism of celecoxib toxicity remains poorly understood. Previous work from our laboratory has demonstrated marked inhibition of cell cycle progression through the G1 phase and induction of apoptosis following treatment with celecoxib in SCCHN, leading to cell cycle phase-specific toxicity to S and G2 phase cells and induction of p21waf1/cip1 with downstream inhibition of nuclear E2F activity. We therefore hypothesize that decreasing the observed cell cycle inhibition induced by celecoxib treatment may augment celecoxib toxicity by inducing cells to progress through more highly toxic cell cycle phases during celecoxib exposure. Further understanding of the mechanism of G1 arrest following celecoxib administration is therefore needed to effectively exploit this potential toxicity. MicroRNAs have been implicated in the control of cell cycle transition in several recent publications in stem cells and human cancers, and we believe that they may be involved in the cell cycle arrest seen after celecoxib treatment in SCCHN. To evaluate this hypothesis, SCCHN cells were exposed to celecoxib for 24 hours and G1 arrest was confirmed via flow cytometry. RNA and protein were extracted from celecoxib-treated and control cells and microRNA expression profiles were established by quantitative real-time PCR microarray analysis. Alterations in cell cycle gene expression across the cell cycle were assessed by similar microarray, and targets were confirmed by further western blotting and PCR analysis. Correlations between microRNA alterations in celecoxib-treated cells and cell cycle control genes were observed and extrapolated. These data provide a microRNA and cell cycle gene expression signature for celecoxib treatment in SCCHN, and further illustrate the potential role that microRNA expression plays in control of G1 cell cycle checkpoint kinetics and subsequent celecoxib toxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3009.