bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 798: Adenomas in Lynch syndrome: Diagnostically useful
Authors: Rosty Christophe , Walsh Michael , Buchanan Daniel , Arnold Sven , Clendenning Mark , Walters Rhiannon , Hopper John , Jenkins Mark , Jass Jeremy , Young Joanne 
Published: February 2011

Abstract
Background: Debate continues as to the usefulness of testing adenomas for loss of mismatch repair (MMR) proteins to identify individuals with suspected Lynch syndrome. Several studies have suggested that it is only worthwhile testing large, proximal adenomas exhibiting high grade dysplasia while others report disappointing “hit rates” even from known mutation carriers. Screening of unselected early-onset adenomas for MMR deficiency has yielded disappointing results.
Design: We tested 88 adenomas from 49 proven mutation carriers (23 female and 26 male) from 37 Lynch syndrome families (12 MLH1, 21 MSH2, 3 MSH6 and 1 PMS2) enrolled in the Australasian Colorectal Cancer Family Study which is part of the Colon Collaborative Family Registry (C-CFR). The average age of diagnosis of first polyp studied was 49.1 ± 9.6 years (ranging from 30.3 to 72.0 years).
All polyps were tested by immunohistochemistry (IHC) for the four MMR proteins MLH1, MSH2, MSH6 and PMS2. In addition, microsatellite instability testing using a panel of 10 markers (incorporating the standard NCI panel) was performed on 69 adenomas. All polyps were subjected to a standard review by one specialist pathologist (JJ). The majority of adenomas included in the present study were tubular adenomas (n = 61), with 22 tubulovillous adenomas, 1 villous adenoma, and 4 traditional serrated adenomas.
Results: Overall, abnormal immunohistochemical results (loss of expression) were noted for 73/88 (82.9%) of the adenomas from MMR gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. MSI testing was concordant with immunohistochemistry in 66/69 (95.6%) cases. There was no statistical difference in patient ages at the time of polypectomy between MMR deficient and intact adenomas (49.6 ± 9.5 yrs vs. 49.8 ± 11.6 yrs). 15/88 (17.1%) polyps demonstrated normal MMR IHC. Six of these polyps came from four individuals who had other polyps which demonstrated abnormal IHC), whilst the remaining nine adenomas came from nine individuals for whom other adenomas had not been tested. Of these 9 cases, however, three had been diagnosed with Lynch syndrome-spectrum tumours which showed appropriate loss of MMR protein(s)
Conclusions: Diagnostic testing of adenomas from patients from Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority (82.9%) of adenomas from carriers show appropriate loss of MMR proteins and a high level of concordant microsatellite instability. We were unable to demonstrate an association between adenoma grade, size or site and MMR deficiency.
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 798.
Abstract 8: Reptin is required for the transcription of telomerase reverse transcriptase and overexpressed in gastric cancer
Authors: Li Wenjuan , Jia Jihui , Zeng Jiping , Li Qiao , Björkholm Magnus , Xu Dawei 
Published: February 2011

Abstract
Telomerase is activated in oncogenesis, which confers an immortal phenotype to cancer cells. The AAA+ ATPases Reptin and Pontin have recently been identified to be required for telomerase biogenesis by maintaining telomerase RNA (hTER) stability. Given their roles in chromatin remodeling and transcription regulation, we determined the effect of Reptin and Pontin on the transcription of the telomerase reverse transcriptase (hTERT) gene, a key component of the telomerase complex. The depletion of Reptin or Pontin in gastric and cervical cancer cells led to significant decreases in hTERT mRNA, but hTERT promoter activity was inhibited in only Reptin-depleted cells. Reptin interacted with the c-MYC oncoprotein and its stimulatory effect on the hTERT promoter was significantly dependent on functional E-boxes in the promoter. Moreover, Reptin bound to the hTERT proximal promoter and the loss of the Reptin occupancy led to dissociation of c-MYC from the hTERT promoter in Reptin-depleted cancer cells. We further demonstrated that Reptin inhibition dramatically impaired clonogenic potential of gastric cancer cells and that Reptin was over-expressed in primary gastric cancer specimens. Collectively, the hTERT gene is a direct target of Reptin, and hTERT transcription requires constitutive expression of Reptin and its cooperation with c-MYC. Thus Reptin regulates telomerase at two different levels. This finding, together with the requirement of Reptin for clonogenic potentials of cancer cells and its widespread over-expression in primary gastric cancer, suggests that Reptin may be a putative cancer therapeutic target.
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 8.
Abstract 80: Streptozotocin-induced cytotoxicity and mitochondrial dysfunction in human hepatoma HepG2 cells
Authors: Raza Haider , John Annie 
Published: February 2011

Abstract
Streptozotocin (STZ) is an antibiotic often used in the treatment of different types of cancers, including the liver cancer. STZ is also highly cytotoxic to the normal pancreatic beta-cells and therefore is being commonly used to develop experimental type 1 diabetes in rat and mouse models. Resistance towards STZ-induced cytotoxicity in cancer cells has also been reported. The precise molecular mechanism of STZ cytotoxicity/resistance in different tissues and carcinomas is, however unclear. STZ increases cellular oxidative stress by producing reactive oxygen (ROS) and nitrogen (RNS) species. We have investigated the mechanism of cytotoxicity of STZ in HepG2 cancer cells in culture. Cells were treated with different doses of STZ for different time intervals and the cytoxicity was studied by observing the alterations in oxidative stress, mitochondrial redox and respiratory functions. STZ induces ROS and RNS formation and oxidative stress as measured by an increase in the lipid peroxidation and nitrate production as well as alterations in the GSH metabolism. The mitochondria appear to be a more sensitive target for STZ toxicity than extramitochondrial compartments. The mitochondrial membrane potential was altered in STZ treated cells. Activities of the mitochondrial respiratory electron transporting enzymes; complex I and cytochrome c oxidase were also modulated resulting in the inhibition of ATP synthesis. The ROS-sensitive mitochondrial aconitase activity was also inhibited suggesting the involvement of oxidative stress in STZ-induced mitochondrial toxicity. The nuclear translocation of oxidative stress marker protein, NF-kB was increased in STZ treated cells. The expression of Hsp70, an oxidative stress marker protein, was also increased in the drug treated cells. The apparent absence of apoptotic markers such as cytochrome c release and the activation of caspase 3 in STZ treated HepG2 cells suggest that the intrinsic mitochondrial apoptosis pathway may not be primarily involved in STZ-induced cytotoxicity. The results suggest that STZ-induced cytotoxicity in HepG2 cells is mediated, at least in part, by the increase in ROS/RNS production, oxidative stress and mitochondrial dysfunction. This study may be significant in better understanding the mechanisms of STZ action in chemotherapy and drug resistance. The study is supported by Research Committee grant and a grant from Terry Fox Cancer Research funds.
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 80.
Abstract 803: Expression of poly(adenosine diphosphate-ribose) polymerase (PARP) and p53 in epithelial ovarian cancer
Authors: Godoy Heidi E. , Mhawech-Fauceglia Paulette , Beck Amy , Miller Austin , Lele Shashikant , Odunsi Kunle 
Published: February 2011

Abstract
Objectives:
PARP, poly(adenosine diphosphate-ribose) polymerase, is a damage sensing protein that is essential to the repair of DNA single-strand breaks. P53 acts as a “genome guardian” molecule that in response to DNA damage mediates cell cycle arrest or induces apoptosis. PARP and p53 function synergistically in repairing DNA damage and suppressing chromosomal rearrangements. The aim of this study was to determine the expression of PARP and p53 in epithelial ovarian cancer (EOC) and correlate with clinico-pathologic characteristics.
Methods:
PARP and p53 was examined using immuno-histochemistry applied on a tissue microarray of 189 EOC. PARP and p53 expression were examined in relation to clinco-pathologic variables, including age of diagnosis, stage, grade, histologic type, optimal debulking, progression free survival and overall survival. Progression free survival and overall survival were estimated by Kaplan-Meier method, and statistical significance was calculated by the log-rank test.
Results:
PARP expression was demonstrated in 61% (115/189) of specimens and 99/185 (54%) samples exhibited p53 staining. PARP positive tumors tended to have higher grade (P = 0.03) and complete response to initial treatment (P = 0.009). Patients with positive p53 staining tended to have higher stage of disease (P = 0.004) and there was a trend of patients with positive p53 and weak PARP expression to increase the likelihood of disease progression (OR 2.25 (CI 0.389-13)). The median follow-up was 40 months. However, there were no significant associations between PARP and p53 expression. There was no significant difference in disease free or overall survival for PARP or p53.
Conclusion:
This study indicates that PARP and p53 are upregulated in EOC with higher grade tumors and more advanced stages, respectively, and may serve as a marker of aggressive disease behavior. Additional studies are warranted to evaluate the role of PARP and p53 expression as a predictor of response to initial treatment, and to identify patients that may benefit from alternative treatments in the adjuvant setting.
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 803.
Abstract 806: Upregulation of Krüppel-like Factor 4 (KLF-4) expression as a potential tumor progression gene product in non-Hodgkin's lymphoma
Authors: Vega Mario I. , Hernandez-Atenógenes Miriam , Vazquez-Islas Juan C. , Martinez-Miguel Bernardo , Martinez-Paniagua Melisa A. , Antonio-Andres Gabriela , Rivera-Pazos Clara M. , Maldonado-Valenzuela Altagracia , Martinez-Maza Otoniel , Huerta-Yepez Sara , Bonavida Benjamin 
Published: February 2011

Abstract
Krüppel-like factor 4 (KLF-4) is highly expressed in epithelial tissues such as gut and skin. Several studies based on clinical evidence suggest that KLF-4 functions as a tumor suppressor in cancer of colon, bladder, stomach and in leukemia. In contrast, KLF-4 expression is increased in primary breast ductal carcinomas and in oral dermal squamous cell carcinomas, suggesting that KLF-4 is important in tumor development and progression. However, KLF-4 expression in lymphomas has not been investigated. Our preliminary studies have examined KLF-4 expression in lymphoma cell lines and a TMA containing fresh tissues derived from patients with several types of lymphoma. There was a significant higher expression of KLF-4 in Burkitt's lymphoma compared with other lymphomas such as follicular or DLBCL. These findings suggest that KLF-4 may be considered as a new biomarker in Non-Hodgkin's lymphoma (NHL). Further analyses based on the clinical outcome revealed that KLF-4 protein expression was significantly associated with poor patient's survival. The increased KLF-4 expression was associated with an inferior survival duration (P= 0.002). The survival for 12 patients who had a tumor with weak KLF-4 expression and 13 patients with negative KLF-4 expression was significantly longer than the 30 patients with strong KLF-4 expression (P&lt; 0.001). Other variables that affected survival in univariate analyses included stages and completeness of resection were shown to have statistically significant effect on survival (P=0.001), however age or sex did not have a statistically significant effect on survival. These data provide the first clinical and causal evidences that alterations of KLF-4 expression can play a critical role in the development and progression of NHL.
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 806.
Abstract 813: Prognostic impact of the expression of cancer stem cell markers CD166, CD44, EpCAM, ALDH1 and CD133 in colorectal cancer
Authors: Iezzi Giandomenica , Lugli Alessandro , Muraro Manuele G. , Mele Valentina , Hostettler Isabel , Tornillo Luigi , Carafa Vincenza , Spagnoli Giulio C. , Terracciano Luigi , Zlobec Inti 
Published: February 2011

Abstract
Background: The aim of this study was to elucidate the prognostic impact of the putative cancer stem cell (CSC) markers CD166, CD44s, EpCAM, ALDH1 and CD133 by immunohistochemistry in colorectal cancer and determine their value as potential biomarkers of clinical outcome.
Methods: Using the tissue microarray technique, immunohistochemistry was performed on samples from 1420 primary colorectal cancer patients with full clinico-pathological data and 57 normal tissues. Expression was evaluated semi-quantitatively and receiver operating characteristics (ROC) curve analysis was used to identify reliable cut-off scores for positivity. Prognostic effects were subsequently validated using 101 randomly selected whole tissue sections. Invasive potential was tested using 3 colorectal cancer cell lines. Surgically excised colorectal cancer specimens were enzymatically digested and expression of CD166, CD44s and CD133 on tunour cells was evaluated by flow-cytometry. Cells were then injected in limiting amounts s.c. in NOD/SCID mice and allograft outgrowth was monitored by standard methods.
Results: A significant increase in CD166, CD44s and CD133 expression and a decreased expression of EpCAM and ALDH1 was noted in tumour compared to normal mucosa (p&lt;0.001, all markers). Loss of membranous CD166, CD44s and EpCAM expression was associated with features of tumour progression, in particular with an infiltrating tumour border configuration (CD166: p&lt;0.001; CD44s: p=0.002; EpCAM:p=0.005). Loss of CD166 and CD44s had a significant negative impact on survival time (p&lt;0.001), which was further confirmed by evaluating corresponding whole tissue sections (p=0.006). CD44-/CD166- cells from 3 colorectal cancer cell lines exhibited in vitro significantly higher invasive potential than their positive counterparts. On the other hand, the ability of cancer cells to initiate tumours in immunodeficient mice was significantly (p=0.03) correlated with their content in CD133+, but not in CD166+/CD44+ cells.
Conclusions: Our findings indicate that loss of expression of CD166 and CD44s is linked to an aggressive tumour phenotype and, particularly, to the presence of an infiltrating tumour margin, possibly implicating these proteins in events at the invasive tumour front. Remarkably, the number of CD133+ cells, while important for tumour initiation in immunodeficient hosts, appears to be prognostically irrelevant in possibly immunocompetent 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 813.
Abstract 814: A systemic miRNA signature predictive of early breast cancer
Authors: Heneghan Helen M. , Miller Nicola , Kelly Ronan , Nugent Mary , Kerin Michael J. 
Published: February 2011

Abstract
Background:
The potential of miRNAs as novel tumor markers has been the focus of much recent attention due to their tissue specificity and unique ability to predict clinicopathological parameters with superior accuracy to mRNA expression profiling. Recent reports have documented altered serum or plasma miRNAs in a variety of cancers including prostate, colon, lung and breast. However it is unknown whether the specific miRNAs reported to be altered in these studies are tumor specific or a general cancer phenomenon. We wished to determine whether a panel of 9 circulating ‘oncomirs’ were tumor specific or similarly expressed in all cancers, and thus identify systemic miRNA signatures predictive of specific cancers.
Methods:
Using a real-time quantitative PCR approach, expression levels of a panel of 9 oncogenic miRNAs were quantified in blood specimens from 163 cancer patients (breast, colon, renal, prostate and melanoma) and 44 age-matched disease free control individuals. Advanced QBase Plus software and SPSS were used for biostatistical analysis of the data, and correlation with clinicopathological variables.
Results:
Our panel of circulating miRNAs were detectable at various levels in the circulation of all cancer patients. Expression of general oncomirs such as let 7a and miR-21 were similarly expressed in all cancers. However other specific miRNAs were remarkably different between cancer types. MiR-10b and miR-145 were significantly decreased in the circulation of colon cancer patients compared to other cancers (p=0.000 and p=0.017 respectively). MiR-195, miR-342 and miR-181c were found to be breast cancer specific; elevated levels of these three miRNAs could reliably differentiate breast cancer patients from healthy controls and from patients with other malignancies with high sensitivities (area under curve by ROC analysis: 0.941, 0.963, and 0.926 respectively). Furthermore, systemic miR-195 was detectable in patients with in-situ disease, levels increased progressively as stage of disease advanced, and decreased significantly post curative tumor resection to levels comparable with controls (p=0.001).
Conclusion:
These findings suggest that individual malignancies, in particular breast cancers, display specific systemic miRNAs profiles, which could aid in early diagnosis and in discriminating one cancer from another. This is of major clinical importance as it illustrates the potential for systemic miRNAs as sensitive and specific yet non-invasive cancer biomarkers.
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 814.
Abstract 823: Identification of FISH biomarkers to detect chromosome abnormalities associated with prostate adenocarcinoma in tumor and field effect environment
Authors: Zhang Ying , Perez Thomas , Blondin Beth , Escarzaga Diana , Coon John , Morrison Larry , Pestova Katerina 
Published: February 2011

Abstract
Introduction. The focal nature of prostate cancer (CA) contributes to needle biopsy sampling error with false negative rates of 15-30%. Here we used fluorescence in situ hybridization (FISH) analysis to assess molecular abnormalities in prostate specimens as an aid to CA diagnosis. We also evaluated the feasibility of combined immunofluorescence and FISH to facilitate assessment of chromosomal abnormalities.
Experimental Procedure. 33 radical prostatectomy (RP) specimens from patients with adenocarcinoma of the prostate were evaluated by FISH with MYC, LPL, PTEN and centromere 8 probes. For each specimen, a tissue section was scribed by a pathologist to mark the tumor region(s). For 17 of the RP cases, a second section was available with only histologically benign tissue. FISH signals were enumerated in 50-100 cells per section. 26 hyperplasia (BPH) specimens, served as controls. Immunofluorescence (IF) with AMACR antibody was also used in the same assay with FISH.
Results. Chromosomal copy number abnormalities were observed in most RP specimens, both within tumor regions and extending beyond histologically evident tumor, while few abnormalities were observed in the BPH specimens, using a cut-off value for FISH positivity based on the mean +/- 2 SD of cells with less than or greater than 2 signals in BPH specimens. A combination of MYC gain, LPL loss, PTEN loss or chromosome 8 aneusomy within the scribed tumor regions identified adenocarcinoma in 82% (27/33) of RP specimens, with a specificity of 81% relative to BPH (χ2 p&lt;0.001). When detected in regions of normal histology, these abnormalities correlated with adenocarcinoma in 47% (8/17 RP specimens, χ2 p=0.05 relative to BPH). IF combined with FISH facilitated selection of the abnormal regions of interest for molecular assessment in the heterogeneous prostate specimens. The IF-staining closely correlated with morphological assessment of tumor by a trained pathologist.
Conclusions. This study identified FISH probes for detection of chromosomal abnormalities associated with prostate CA that could potentially serve as a diagnostic aid in biopsy specimens. This study also indicates that chromosome abnormalities are present in RP specimens within regions of normal histology, indicating a substantial tumor field effect. Therefore, a molecular test based on FISH to measure abnormal MYC, LPL, PTEN and centromere 8 copy numbers may allow detection of cancer otherwise missed by histopathological examination and thus improve diagnosis of prostate cancer by reducing sampling error of needle biopsies.
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 823.