bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2958: Quantitative and correlative analysis of variant UGT1A mRNA expression in human liver
Authors: Jones Nathan R. , Chen Gang , Lazarus Philip 
Published: February 2011

Abstract
UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of various endogenous and xenobiotic compounds including several carcinogens and chemotherapeutic agents. UGTs are divided into two sub-families based on sequence homology. The nine UGT1A family members are encoded by a single locus on chromosome 2q37, where each family member has a unique exon 1 and shares exons 2-5. A recently identified exon 5b in the common region of the UGT1A gene cluster leads to the expression of 18 additional mRNA species from this locus. In vitro studies indicate that the proteins encoded by these variant mRNAs negatively modulate the activity of the wild type isoforms. It is hypothesized that inter-individual variation in the ratio of wild type to variant mRNA expression may affect glucuronidation capacity. The goal of this study was to quantitatively examine variant UGT1A mRNA expression in individual human liver specimens to better assess the importance of splicing variants in overall UGT1A activity. To differentiate between the 5’ (exon 1) and 3’ (exon 5) splice variants, a nested, quantitative PCR reaction was developed that allows both variants to be distinguished simultaneously. Results of the study indicate that there is a 406-, 278-, 58-, and 139-fold inter-individual variation in the expression ratio of wild-type to variant mRNA for UGTs 1A1, 1A4, 1A6, and 1A9, respectively, in the 10 human livers examined. UGT1A variant expression reached as high as 8.2-fold more than wild-type UGT1A1, 2.9-fold higher than wild-type UGT1A4, 0.13-fold lower than wild-type UGT1A6, and 0.46-fold lower than wild-type UGT1A9. Even though the expression ratio of wild-type to variant mRNA differs widely between different individuals, results indicate that the expression ratio is consistent for all UGTs examined within a single individual. The correlation between the expression ratio of UGTs 1A1 and 1A4 in different individuals is highly significant (R2 = 0.9661, p&lt;0.0001). Similarly, the correlation between the expression ratio of UGT1A1 and UGT1A6, UGT1A1 and UGT1A9, UGT1A4 and UGT1A6, UGT1A4 and UGT1A9, and UGT1A6 and UGT1A9 are all significant (R2=0.5265, p=0.0269; R2=0.8994, p=0.0003; R2=0.5782, p=0.0174; R2=0.9610, p&lt;0.0001; R2=0.582, p=0.0277, respectively). Together, these data suggest that UGT1A variant expression could significantly impact overall UGT1A activity and that there is a high correlation between wild-type : variant mRNA expression ratios across the entire UGT1A locus within individuals. Future studies will be conducted to determine whether a difference in the UGT1A expression ratio has an impact on glucuronidation capacity in vivo.
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 2958.
Abstract 2969: Localization and characterization of ST7 in cancer
Authors: Charong Nurdina , Patmasiriwat Pimpicha , Zenklusen Jean Claude 
Published: February 2011

Abstract
ST7 has been proposed as a tumor suppressor gene at the chromosome region 7q31.1-q31.2. In order to gain some insight into its role in cancer, localization and verification of ST7 expression levels were performed. Various types of ST7 expression vectors tagged with sequences of GFP, YFP or V5 were created using gateway cloning system and full length ST7 cDNA isolated from a human adult brain cDNA library. Cytosolic ST7 expression in HCT-116, MCF-7 and PC-3 cell lines was detected via the fluorescence signal of the fusion proteins. ST7 translocation from cytoplasm to nucleus has not been observed in any of the conditions assayed. A cell cycle synchronization study demonstrated that both ST7 and SERPINE1 were over expressed when cells were arrested. Expression of these genes was found to be substantially diminished when the cells re-entered cell division status. In addition, we also found that Survivin, MMP13, and CyclinD1 were differentially expressed during cell cycle. Our findings suggest that ST7 mediates tumor suppression through regulation of the genes involved in maintaining cellular structure of the cell and involved in oncogenic pathways.
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 2969.
Abstract 2972: Intestinal p53 deletion leads to accumulation of chromosomal instability without promoting tumor formation
Authors: Begus-Nahrmann Yvonne , Lechel André , Rudolph Lenhard 
Published: February 2011

Abstract
Background:
Colorectal cancer is after lung cancer the second biggest cancer threat for humans and the tumor burden is rising steadily during human ageing. One important issue during human ageing is the accumulation of DNA damage inducing a p53 dependent response leading to p21-dependent senescence or apoptosis. It has been shown that deletion of DNA repair proteins as well as other components of the DNA damage pathway leads to tumor formation.
Methods:
In this approach we investigated the role of the tumor suppressor p53 with and without telomere dysfunction in intestinal tumor formation. Late generation of iG4 mTerc−/−; p53lox/lox and iF1 mTerc+/− p53lox/lox mice were crossed to Villin-Cre-ERT2 transgenic mouse model. In 1 month old mice Tamoxifen was injected on 5 consecutive days leading to functional deletion of the Trp53 gene.
Results:
In aging IF1 Terc+/− p53 deletion did not induce an obvious intestinal phenotype including tumor formation until 24 months. In contrast to p21 deletion the deletion of p53 significantly shortened the lifespan of iG4 Terc−/− Trp53−/− animals compared to iG4 Terc−/− Trp53+/+. This reduction correlated with earlier appearance of crypt atrophy and weight loss but was not associated with tumor formation. Deletion of the Trp53 gene resulted in an abrogation of the p21-dependent senescence and accumulation of DNA damage in the intestinal epithelium of both p53 deleted cohorts. Moreover this correlated with an accumulation of intestinal stem cells carrying high levels of DNA damage. On contrary to p21 deletion the deletion of p53 impaired the depletion of chromosomal instable intestinal stem cells in aging telomere dysfunctional mice.
Conclusion:
These results provide first proof that deletion of p53 is not able to promote tumorigenesis in the intestinal epithelium of mice and that p53 induction has a protective role preventing accumulation of damaged intestinal stem cells in aging telomere dysfunctional mice.
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 2972.
Abstract 2974: Cep57 is a novel regulator of centriole overduplication in tumor cells
Authors: Cuevas Rolando A. , Duensing Anette , Duensing Stefan 
Published: February 2011

Abstract
Abnormal multipolar mitoses are commonly observed in human cancers where they can increase the risk for chromosome segregation errors, numerical chromosomal instability and malignant progression. The mitotic spindle poles are formed by centrosomes and tumor cells frequently show abnormal centrosomes numbers. The molecular mechanisms leading to numerical centrosome aberrations are not understood in detail. The centrosome consists of two centrioles, which normally duplicate in synchrony with the cell division cycle. We recently identified a novel mechanisms leading to abnormal centriole numbers in tumor cells in which maternal centrioles generate more than the normal one daughter at the same time (centriole multiplication). Using a siRNA library screen enriched for centrosomal proteins, we identified Cep57 as a novel protein involved in centriole multiplication. Cep57 was found to localize to centrosomes and to co-localize and functionally interact with Polo-like kinase 4 (PLK4), a master regulator of centriole duplication control. Cep57 overexpression was found to promote abnormal centrosome and centriole numbers as well as mitotic abnormalities with a significant number of cells showing multipolar metaphases as well as multipolar anaphases and telophases. Cep57 maps to chromosome 11q21, a region that is amplified in several cancer types including hematological malignancies and prostate cancer. Taken together, we identified Cep57 as regulator of centriole duplication in tumor cells and a candidate oncogene. Experiments to target the Cep57-PLK4 axis with small molecules to prevent cell division errors and malignant progression are currently under way.
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 2974.
Abstract 2980: Role of XPA and p53 genes in the induction of centrosomal amplification in mice exposed to Zidovudine (AZT)
Authors: Nostrand Terri A. , Momot Dariya , Poirier Miriam C. , Olivero Ofelia A. 
Published: February 2011

Abstract
In cultured cells, exposure to the highly-effective nucleoside reverse transcriptase inhibitor (NRTI) Zidovudine (AZT) induces genomic instability, causing cell cycle arrest, micronuclei, sister chromatid exchanges, and shortened telomeres. In previous studies, we demonstrated for the first time that AZT induced centrosomal amplification (defined as &gt; 2 centrosomes /cell), a novel manifestation of genotoxicity. Here, bone marrow cells from wild type C57BL/6J mice and their transgenic counterparts with genotypes XPA −/− p53 +/+, XPA−/−p53 +/− and XPA−/−p53 −/−, were cultured in vitro to obtain homogeneous populations of mesenchymal-derived fibroblasts. Wild type, and DNA repair- / p53-deficient cells (n=3/group) were exposed to 0, 10 or 100 μM AZT for 24 hr, and centrosomal amplification was examined by immunohistochemical (IHC) staining with an anti-pericentrin antibody. Values for centrosomal amplification (% of cells with ≥2 centrosomes/cell) were 12.2, 15.2 and 19.7% in wild type (XPA +/+ p53 +/+) cells exposed to 0, 10 or 100 μM AZT, respectively. Values for centrosomal amplification were 18.0, 28.7 and 33.9 % for XPA −/− p53 +/+cells, and 21.6, 29.3 and 39.5% for XPA−/−p53 +/− cells, after exposure to 0, 10 and 100 μM AZT, respectively. For XPA−/−p53 −/− cells there were 18.4, 22.9 and 29.0% of cells with centrosomal amplification after exposure to 0, 10 and 100 µM AZT, respectively. Statistical analysis (by ANOVA) showed significance between each of the three transgenic groups, when compared to the wild type cells (p= 0.0025). The data suggest that loss of both XPA alleles confers genomic instability, but that additional loss of p53 does not further enhance instability. Whereas nucleotide excision repair is not considered to impact NRTI intracellular processing, these data would argue that lack of intact nucleotide excision repair enhances genomic instability in AZT-exposed cells.
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 2980.
Abstract 299: Blockade of Rictor impairs mTORC1 inhibitor-induced upregulation of IGF-IR and Her2 expression in human gastrointestinal cancer cells
Authors: Lang Sven Arke , Moser Christian , Hackl Christina , Fichtner-Feigl Stefan , Schlitt Hans J. , Geissler Edward K. , Stoeltzing Oliver 
Published: February 2011

Abstract
Inhibition of mTOR signaling has recently gained increasing interest for therapy of human gastrointestinal cancer. However, treatment with mTOR inhibitors such as rapamycin only blocks mTORC1 (Raptor, mTOR, mLST8) whereas mTORC2 (Rictor, mTOR, mLST8) is not affected in most cancer cells. This might lead to activation of signaling intermediates such as Akt in mTORC2 dependant manner which has been implicated in resistance to anti-neoplastic therapy. Hence, we hypothesized that inhibition of mTORC2 by Rictor blockade might prevent induction of signaling pathways and improve anti-cancer effects of mTOR inhibitors. Human gastrointestinal cancer cells (TMK-1, HPAF-II) were used for the experiments. mTOR inhibition was performed with rapamycin (Wyeth Phama) and mTORC2 blockade was achieved by siRNA (Invitrogen) against Rictor. Effects on signaling intermediates and receptor expression were determined by Western blotting and RT-PCR, respectively. The results show that mTOR inhibition with rapamycin leads to phosphorylation of Akt on both phosphorylation sites in human cancer cells. mTORC2 blockade by siRNA disrupts activation of Akt as shown by diminished phosphorylation on Thr308. Surprisingly, mTOR blockade with rapamycin showed up-regulation of total IGF-IR and Her2 expression in tumor cells on mRNA and protein level. This effect was reversible by mTORC2 blockade with Rictor siRNA or direct inhibition of Akt signaling using Ly290004. Together, our results show that inhibition of mTOR with rapamycin leads to up-regulation of IGF-IR and Her2 expression in cancer cells in Akt/mTORC2 dependant manner. Blockade of Rictor can prevent these effects providing a basis for combined anti-cancer therapy strategies.
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 299.
Abstract 2992: Transcriptional silencing of amplicons by histone deacetylase inhibition
Authors: Kim Tae Hoon , Kim Yoon Jung , Cecchini Katharine R. , Radke Susan , Kumar Amanika , Geyda Kimberly , Narayan Murli , Tuck David , Harris Lyndsay 
Published: February 2011

Abstract
Inhibition of cancer cell growth by histone deacetylase (HDAC) inhibitors has been observed in a number of malignancies. Multiple mechanisms have been proposed to explain the cancer-specific cytotoxic effect of HDAC inhibition, including transcriptional activation of pro-apoptotic and differentiation programs that become epigenetically silenced during tumorigenesis. Here, we report a direct transcriptional repression mechanism of histone deacetylase inhibition that selectively targets genomic amplicons, providing genetic and epigenetic alterations as a basis for the cancer selective cytotoxicity of these drugs. Our study implicates distinct epigenetic structures at the oncogenic amplicons that might be targeted for cancer drug development.
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 2992.
Abstract 3000: MicroRNA-21 as a biomarker for benefit from adjuvant therapy in resectable pancreatic adenocarcinoma
Authors: Voortman Johannes , Hwang Jin-Hyeok , Giovannetti Elisa , Steinberg Seth M. , Kim Yong-Tae , Funel Niccola , Park Joo Kyung , Kim Min A. , Kang Gyeong Hoon , Kim Sun-Whe , Chiaro Marco Del , Peters Godefridus J. , Giaccone Giuseppe 
Published: February 2011

Abstract
Many pancreatic adenocarcinoma patients who undergo surgical resection receive adjuvant chemotherapy and/or combined modality treatment. However, only a subset of patients benefit from additional therapy. The aim of this study was to evaluate the expression of several potential markers of treatment outcome. Resected tumors of a cohort of 82 pancreatic adenocarcinoma patients from Korea were analyzed for protein expression of 20 markers by immunohistochemistry and expression of 7 microRNAs using quantitative real-time PCR. A second validation cohort of 45 resected Italian patients was analyzed for microRNA-21 (miR-21) expression. Korean and Italian cases consisted of FFPE and frozen specimens, respectively. Univariate and multivariate analyses were used to compare biological parameters and survival endpoints.
In the Korean cohort, Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N=52) showed that lower than median miR-21 expression was associated with a significantly lower HR for death (0.316; 95% CI: 0.166-0.600; p-value: 0.0004) and recurrence (0.521; 95% CI: 0.280-0.967; p-value: 0.04). Expression status of miR-21 was the single most predictive biomarker for treatment outcome from all factors evaluated. No significant association of miR-21 expression status with prognosis was detected in patients not treated with adjuvant therapy. In the independent cohort of 45 Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was also significantly correlated with longer overall and disease-free survival confirming its predictive value.
Concluding, low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of pancreatic cancer cases, using both FFPE and frozen tumor specimens. These data provide evidence that miR-21 expression may allow stratification of pancreatic cancer patients for adjuvant treatment. This is the first strong predictive marker for adjuvant therapy in radically resected pancreatic cancer and further prospective studies are warranted.
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 3000.
Abstract 3007: Hsa-miR-9 expression patterns are associated with metastatic recurrence in patients with clear cell renal cell carcinoma through hypermethylation of the gene in tumor tissue
Authors: Hildebrandt Michelle A.T. , Gu Jian , Lin Jie , Ye Yuanqing , Tan Weiqi , Tamboli Pheroze , Wood Christopher G. , Wu Xifeng 
Published: February 2011

Abstract
The long-term prognosis for patients with clear cell renal cell carcinoma (ccRCC) is dramatically altered by the development of metastatic recurrence. However, there are very few indicators that can predict which patient will develop a recurrence. MicroRNA gene expression has been shown to be associated with RCC development, and here we show that it can also help to identify patients at increased recurrence risk. We utilized genome-wide microRNA arrays to measure expression levels in tumors from 74 ccRCC patients and identified hsa-miR-9 as a candidate for recurrence risk (Hazard Ratio: 2.6, 95% Confidence Interval: 1.55-4.38) resulting in a reduction in median time to recurrence by 30 months (P-value = 0.0038). This observation was validated in a replication sample of an additional 254 ccRCC tumors. We further showed that the genes encoding for hsa-miR-9 were significantly hypermethylated in tumors compared to adjacent normal tissues (P-value &lt; 0.001 for both miR-9-1 and miR-9-3) resulting in decreased expression, and that the methylation of these genes was more significant in tumor DNA obtained from patients who developed a recurrence (P-value = 0.012 and 0.009 for miR-9-1 and miR-9-3, respectively). Furthermore, methylation of miR-9-1 and miR-9-3 were independently associated with a reduction in time to recurrence. Hsa-miR-9 has been shown to play a role in tumor development for other cancers, and our results demonstrate that it has similar functions in ccRCC while also playing a role in the development of metastatic recurrence.
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 3007.
Abstract 3011: MicroRNA expression profiles in benign and aggressive canine mast cell tumors
Authors: Fenger Joelle M. , Lin Tzu-yin , Taccioli Cristian , Volinia Stefano , Kisseberth William C. , London Cheryl A. 
Published: February 2011

Abstract
Introduction: MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) 18-24 nucleotides in length that regulate gene expression primarily by targeting mRNAs according to the degree of complementarity with their 3’ untranslated region (UTR). MiRNAs are often dysregulated in cancer, suggesting they play a role in tumorigenesis. Canine mast cell tumors (MCT) are a common cutaneous tumor of dogs whose biological behavior varies from relatively benign disease that is cured with surgical excision to aggressive, locally invasive, highly metastatic disease that is poorly responsive even to multimodality therapy. We hypothesize that high grade MCTs possess a unique miRNA expression signature distinct from that found in benign MCTs and that this contributes to their aggressive behavior. In this study, we sought to determine which miRNAs are differentially expressed in benign and aggressive canine MCT.
Methods: Total RNA was isolated by the Trizol (Invitrogen) method from 12 biologically low grade (surgical cure) and 12 biologically high grade (patient died from MCT disease). Mature miRNA expression analysis of preamplified cDNA was done using TaqMan Low Density Arrays (TLDAs), interrogating the expression profile of 378 miRNAs, 151 of whose mature sequences are 100% conserved between human and dog (Sanger miRBase release 12). Normalization was performed with the small nuclear RNA U6 and microRNA expression was calculated utilizing the comparative Ct method. Statistical analysis was performed with RealTime Statminer software (Integromics). P-values of &lt;0.05 were considered statistically significant.
Results: The expression of specific miRNAs was significantly different in biologically low grade and high grade MCTs. 51 miRNAs were differentially expressed in high grade versus low grade tumors (p&lt;0.05). MiRNAs with known importance in human tumorigenesis, including several members of the miR 17-92 cluster (hsa-miR-17, −18a, −18b) and its paralog, the miR-106b-25 cluster (hsa-miR-106b, −93, −25) were significantly overexpressed in high grade tumors as compared to low grade tumors.
Conclusion: Our findings indicate that specific miRNAs contribute to the biologically aggressive canine MCT phenotype. Hierarchical clustering revealed distinct miRNA expression signatures in high grade tumors compared to low grade tumors. Characterization of miRNA expression in canine MCTs will facilitate our understanding the biology of this disease and has the potential to identify diagnostic/prognostic factors and targets for therapeutic intervention.
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 3011.