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Shishir K Maithel - One of the best experts on this subject based on the ideXlab platform.
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reply to an analysis of human equilibrative nucleoside transporter 1 ribonucleoside reductase subunit m1 ribonucleoside reductase subunit m2 and Excision Repair cross complementing gene 1 expression in patients with resected pancreas adenocarcinoma i
Cancer, 2013Co-Authors: Sarah B Fisher, Shishir K MaithelAbstract:BACKGROUND: Tumor overexpression of Excision Repair Cross-Complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined. METHODS: A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS: The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS. CONCLUSIONS: High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy.
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an analysis of human equilibrative nucleoside transporter 1 ribonucleoside reductase subunit m1 ribonucleoside reductase subunit m2 and Excision Repair cross complementing gene 1 expression in patients with resected pancreas adenocarcinoma implicatio
Cancer, 2013Co-Authors: Sarah B Fisher, Shishir K MaithelAbstract:BACKGROUND Tumor overexpression of Excision Repair Cross-Complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined. METHODS A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS. CONCLUSIONS High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy.
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an analysis of human equilibrative nucleoside transporter 1 ribonucleoside reductase subunit m1 ribonucleoside reductase subunit m2 and Excision Repair cross complementing gene 1 expression in patients with resected pancreas adenocarcinoma
Cancer, 2013Co-Authors: Sarah B Fisher, Sameer H Patel, Pelin Bagci, David A Kooby, Bassel F Elrayes, Charles A Staley, Volkan N Adsay, Shishir K MaithelAbstract:BACKGROUND: Tumor overexpression of Excision Repair Cross-Complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined. METHODS: A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS: The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS. CONCLUSIONS: High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy. Cancer 2013. © 2012 American Cancer Society.
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Excision Repair cross complementing gene 1 ribonucleotide reductase subunit m1 ribonucleotide reductase subunit m2 and human equilibrative nucleoside transporter 1 expression and prognostic value in biliary tract malignancy
Cancer, 2013Co-Authors: Sarah B Fisher, Sameer H Patel, David A Kooby, Bassel F Elrayes, Charles A Staley, Volkan N Adsay, Kevin E Fisher, Matthew G Lim, Alton B Farris, Shishir K MaithelAbstract:BACKGROUND: Tumor expression of Excision Cross-Complementing gene-1 (ERCC1), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2), is associated with the efficacy of platinum and gemcitabine chemotherapy. The authors of this report recently demonstrated that high ERCC1 and RRM2 expression levels are independent negative prognostic markers for survival in early stage pancreas cancer. The differential expression and prognostic value of these biomarkers in biliary tract malignancy (BTM) is unknown. METHODS: In total, 63 patients who had tissue available for analysis were selected from a prospective database of all patients (n = 104) who underwent resection of BTM (intrahepatic, hilar, or distal cholangiocarcinoma; gallbladder carcinoma) between January 2000 and December 2008. Immunohistochemistry for ERCC1, hENT1, RRM1, and RRM2 expression was performed. Staining was scored by a single pathologist who was blinded to patient outcomes. RESULTS: The median patient age was 67 years. The median overall survival (OS) was 16.2 months, and the median follow-up was 32.7 months. Only 3 BTMs (4.8%) had high ERCC1 expression, and 92.1% and 81% of BTMs exhibited high hENT1 and RRM1 expression, respectively. RRM2 expression varied, and 32% of tumors demonstrated high RRM2 expression. ERCC1 and RRM1 were not associated with OS. High RRM2 expression was associated with a trend toward improved OS (30.8 months vs 16.2 months; P = .06), and high hENT1 expression was associated with improved OS (17.7 months vs 9.5 months; P = .04). CONCLUSIONS: Most BTMs exhibited low ERCC1 expression and high hENT1 and RRM1 expression, whereas RRM2 expression levels varied. High expression of hENT1 was associated with improved OS. These findings may have implications for the selection of chemotherapy agents (gemcitabine vs platinum) and the stratification of patients in chemotherapy trials that assess outcome. Cancer 2013. © 2012 American Cancer Society.
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an analysis of ercc1 hent1 rrm1 and rrm2 expression in resected pancreas adenocarcinoma implications for adjuvant treatment
Journal of Clinical Oncology, 2012Co-Authors: Sarah B Fisher, Sameer H Patel, Pelin Bagci, David A Kooby, Bassel F Elrayes, Charles A Staley, Volkan N Adsay, Shishir K MaithelAbstract:206 Background: Tumor overexpression of Excision Repair cross complementing gene 1 (ERCC1) was recently shown to be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Ribonucleotide reductase 1 and 2 (RRM) and human equilibrative nucleotide transporter 1 (hENT1) are integral to DNA synthesis and cellular transport and are implicated as poor prognostic factors in other malignancies. Their role in PAC is not well defined. Methods: A prospective database (n=220) was used to randomly select 95 pts who underwent pancreaticoduodenectomy for PAC between 1/00-10/08. IHC analysis was performed on tumor samples for RRM1 and 2, hENT1, and ERCC1. Main outcomes were recurrence-free (RFS) and overall survival (OS). Results: Median age was 63 yrs; median FU, RFS, and OS was 49, 10.6 and 15.5 mo. Median tumor size was 3cm, 26% had a positive margin, 34% were poorly differentiated, 61% had positive lymph nodes (LN), 88% had perineural invasion (PNI), and 45% had lymphovascular invasion (LVI...
David C Christiani - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in ercc1 and ercc2 xpd genes and carcinogen dna adducts in human lung
Lung Cancer, 2015Co-Authors: Li Su, David C ChristianiAbstract:Objectives In this exploratory study, we aimed to investigate whether polymorphisms in Excision Repair Cross-Complementing group 1 (ERCC1) and Excision Repair Cross-Complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide Excision Repair (NER) pathways associated with DNA adducts in human lung tissue. We also analyzed the association stratified by the major histologic subtypes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQCC).
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abstract 4479 polymorphisms in the nucleotide Excision Repair genes ercc1 and ercc2 xpd and carcinogen dna adducts in human lung
Cancer Research, 2012Co-Authors: Li Su, John C Wain, Eugene J. Mark, David C ChristianiAbstract:Objectives Excision Repair Cross-Complementing group 1 (ERCC1) and Excision Repair Cross-Complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide Excision Repair (NER) pathways that removes DNA damage caused by tobacco smoking carcinogen such as polycyclic aromatic hydrocarbons (PAHs). However, no studies have examined their role in DNA adducts in target human lung tissue, a dosimeter for lung cancer risk. Therefore, we investigated whether the polymorphisms in SNPs in NER pathways associated with the DNA adduct formation in human lung tissue. We further analyzed these relationship divided by adenocarcinoma and squamous cell carcinoma, main type of non-small cell lung cancer (NSCLC). Methods The study population consisted of 135 lung cancer patients from the Massachusetts General Hospital (MGH). Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (TaqMan method). DNA adduct levels were measured as relative adduct levels per 1010 nucleotides by 32P-postlabeling in the lung. Multiple regression models were used to estimate adjusted percent change in DNA adduct levels associated with genotypes of the NER genes ERCC1 and ERCC2/XPD. Results After adjusting for potential confounders, DNA adduct levels in lung increased by 73.5% [95% confidence interval (CI), –22.6 to 288.9] for the ERCC2/XPD rs1799793AA genotype and by 43.7% (95% CI, –30.0 to 194.6) for ERCC2/XPD rs1052559GG genotype compared with their corresponding wild type homozygous genotypes in overall lung cancer patients, but it did not reach statistical significance. We found that DNA adducts levels in lung increased by 166.6% (95% CI, –5.0 to 648.3, P = 0.07) for ERCC2/XPD rs1799793AA genotype in patients with squamous cell carcinoma and the trend was borderline significant (P for trend = 0.06). Conclusions Polymorphisms of DNA Repair genes, ERCC2/XPD Asp312Asn, may affect increased level of DNA adducts in the lung. Further large scale studies are needed to confirm our findings. Supported by NIH grants CA074386, CA092824, and CA90578. 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 4479. doi:1538-7445.AM2012-4479
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polymorphisms in the dna Repair genes xrcc1 and ercc2 smoking and lung cancer risk
Cancer Epidemiology Biomarkers & Prevention, 2003Co-Authors: Wei Zhou, John C Wain, Li Su, David P Miller, Sally W Thurston, Li Lian Xu, Thomas J Lynch, David C ChristianiAbstract:XRCC1 (X-ray Cross-Complementing group 1) and ERCC2 (Excision Repair Cross-Complementing group 2) are two major DNA Repair proteins. Polymorphisms of these two genes have been associated with altered DNA Repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms ( Asp312Asn and Lys751Gln ) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism ( Gln/Gln versus Arg/Arg ) was 1.3 [95% confidence interval (CI), 1.0–1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2–5.0), whereas for heavy smokers (≥55 pack-years), the OR decreased to 0.5 (95% CI, 0.3–1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7–16.6) for nonsmokers and 0.3 (95% CI, 0.1–0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk.
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gene environment interaction for the ercc2 polymorphisms and cumulative cigarette smoking exposure in lung cancer
Cancer Research, 2002Co-Authors: Wei Zhou, John C Wain, Li Su, David P Miller, Sally W Thurston, Li Lian Xu, Thomas J Lynch, David C ChristianiAbstract:Excision Repair Cross-Complementing group 2 (ERCC2), a major DNA Repair protein, is involved in nucleotide Excision Repair and basal transcription. The ERCC2 polymorphisms have been associated with altered DNA Repair capacity. We investigated two ERCC2 polymorphisms, Asp312Asn and Lys751Gln, in 1092 Caucasian lung cancer patients and 1240 spouse and friend controls. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. The overall adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.47 (95% CI, 1.1–2.0) for the Asp312Asn polymorphism (Asn/Asn versus Asp/Asp) and 1.06 (95% CI, 0.8–1.4) for the Lys751Gln polymorphism (Gln/GlnversusLys/Lys). Gene-smoking interaction analyses revealed that the adjusted ORs for each of the two polymorphisms decreased significantly as pack-years increased. When comparing individuals with Asn/Asn + Gln/Gln versus individuals with Asp/Asp + Lys/Lys, the fitted ORs (95% CIs) were 2.56 (95% CI, 1.3–5.0) in nonsmokers and 0.69 (95% CI, 0.4–1.2) in heavy smokers (80 pack-years; P
Gerold Bepler - One of the best experts on this subject based on the ideXlab platform.
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abstract 3472 Excision Repair cross complementing group 1 ercc1 and regulatory subunit of ribonucleotide reductase rrm1 as prognostic and predictive markers for ovarian cancer
Cancer Research, 2013Co-Authors: Jun Zhou, Quratulain Ahmed, Wei Chen, Robert Morris, Rouba Alifehmi, Gerold BeplerAbstract:Background: Ninety percent of ovarian cancers are epithelial in nature (EOC); the standard approach for treatment is surgery followed by platinum and taxane based chemotherapy. Gemcitabine has been evaluated recently in combination with platinum and taxane for platinum sensitive recurrence and as a single agent for platinum refractory or resistant recurrent EOC. ERCC1 and RRM1 are involved in DNA synthesis and Repair derived from genotoxic stress, and they have also been reported as predictive markers for therapeutic efficacy in patients with lung and pancreatic cancers. Their expression, association and clinical significance in ovarian carcinoma remain uncertain. Design: 198 archived cases of epithelial cell ovarian cancer were reviewed and divided into three subtypes: borderline tumor (BLT), Type I and Type II. 2mm TMAs were developed with duplicate cores per case. Immunofluorescence combined with Automated Quantitative Analysis (AQUA) was used to assess the expression of ERCC1 and RRM1. The average of duplicate cores was used for analysis and Greedy search was used for establishing the high and low score cutoff points. Results: 44 cases (22%) were BLT, 29 (15%) were Type I tumors, 121 (61%) were Type II tumors, and 4 cases (4%) were unclassified. Type II tumors were significantly higher among elderly Caucasian women (p
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ercc1 expression is a predictor of survival in resected patients with non small cell lung cancer
Chest, 2005Co-Authors: George R Simon, Swati Sharma, Alan B Cantor, Prudence Smith, Gerold BeplerAbstract:Study objectives Proteins of the nucleotide Excision Repair pathway Repair DNA damage. The Excision Repair Cross-Complementing ( ERCC ) gene family reduces damage to DNA by nucleotide Excision and Repair. Impaired nuclear Excision Repair could lead to increased genomic instability that in turn could lead to a more malignant phenotypic behavior of tumors. We therefore evaluated the effect of intratumoral ERCC1 expression on survival in non-small cell lung cancer (NSCLC) patients who underwent surgical resection for cure Design Resected tumor and the corresponding normal lung specimens from 51 patients with NSCLC who underwent surgical resection were immediately frozen in liquid nitrogen. Total RNA was extracted, reverse transcribed, and amplified with intron-spanning primers. Quantitation for ERCC1 was done using the Taqman procedure, and gene expression was normalized using 18S rRNA expression as internal reference with ERCC1 levels expressed a unit-less ratio Results Tumoral ERCC1 expression ranged from 4.96 to 2,008, with a median value of 54.76. Using an ERCC1 value of 50 to dichotomize the cohort, there was a statistically significant difference in median survival for patients with ERCC1 expression > 50 (94.6 months) compared to Conclusions We conclude that resected NSCLC patients with high ERCC1 expression (> 50) have a better survival when compared to patients with low ERCC1 expression (
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ribonucleotide reductase messenger rna expression and survival in gemcitabine cisplatin treated advanced non small cell lung cancer patients
Clinical Cancer Research, 2004Co-Authors: Rafael Rosell, Dolores Isla, Mariano Provencio, Gerold Bepler, Kathleen D Danenberg, Jose Javier Sanchez, Miquel Taron, Vincente Alberola, Carlos Camps, Pilar DizAbstract:Purpose: No chemotherapy regimen, including the widely used combination of gemcitabine/cisplatin, confers significantly improved survival over any other in metastatic non-small cell lung cancer (NSCLC); however, the selection of patients according to key genetic characteristics can help to tailor chemotherapy. Ribonucleotide reductase subunit M1 (RRM1) is involved in DNA synthesis and Repair and in gemcitabine metabolism, and the Excision Repair Cross-Complementing group 1 ( ERCC1 ) gene has been related to cisplatin activity. Experimental Design: Patients were part of a large randomized trial carried out from September 1998 to July 2000, comparing gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus gemcitabine/vinorelbine followed by vinorelbine/ifosfamide. We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR. Results were correlated with survival using the Kaplan-Meier method. Results: A total of 100 patients were assessed. There was a strong correlation between RRM1 and ERCC1 mRNA expression levels (Spearman r = 0.410; P versus 3.6 months; 95% confidence interval (CI), 9.6–17.8 months; P = 0.009]. Median survival was also significantly longer among patients with low mRNA expression levels of both RRM1 and ERCC1 (not reached), than among those with high levels of both genes (6.8 months; 95% CI, 2.6–11.1 months; P = 0.016). Conclusions: RRM1 mRNA expression is a crucial predictive marker of survival in gemcitabine/cisplatin-treated patients. Genetic testing of RRM1 mRNA expression levels can and should be used to personalize chemotherapy.
Volkan N Adsay - One of the best experts on this subject based on the ideXlab platform.
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an analysis of human equilibrative nucleoside transporter 1 ribonucleoside reductase subunit m1 ribonucleoside reductase subunit m2 and Excision Repair cross complementing gene 1 expression in patients with resected pancreas adenocarcinoma
Cancer, 2013Co-Authors: Sarah B Fisher, Sameer H Patel, Pelin Bagci, David A Kooby, Bassel F Elrayes, Charles A Staley, Volkan N Adsay, Shishir K MaithelAbstract:BACKGROUND: Tumor overexpression of Excision Repair Cross-Complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined. METHODS: A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS: The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS. CONCLUSIONS: High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy. Cancer 2013. © 2012 American Cancer Society.
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Excision Repair cross complementing gene 1 ribonucleotide reductase subunit m1 ribonucleotide reductase subunit m2 and human equilibrative nucleoside transporter 1 expression and prognostic value in biliary tract malignancy
Cancer, 2013Co-Authors: Sarah B Fisher, Sameer H Patel, David A Kooby, Bassel F Elrayes, Charles A Staley, Volkan N Adsay, Kevin E Fisher, Matthew G Lim, Alton B Farris, Shishir K MaithelAbstract:BACKGROUND: Tumor expression of Excision Cross-Complementing gene-1 (ERCC1), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2), is associated with the efficacy of platinum and gemcitabine chemotherapy. The authors of this report recently demonstrated that high ERCC1 and RRM2 expression levels are independent negative prognostic markers for survival in early stage pancreas cancer. The differential expression and prognostic value of these biomarkers in biliary tract malignancy (BTM) is unknown. METHODS: In total, 63 patients who had tissue available for analysis were selected from a prospective database of all patients (n = 104) who underwent resection of BTM (intrahepatic, hilar, or distal cholangiocarcinoma; gallbladder carcinoma) between January 2000 and December 2008. Immunohistochemistry for ERCC1, hENT1, RRM1, and RRM2 expression was performed. Staining was scored by a single pathologist who was blinded to patient outcomes. RESULTS: The median patient age was 67 years. The median overall survival (OS) was 16.2 months, and the median follow-up was 32.7 months. Only 3 BTMs (4.8%) had high ERCC1 expression, and 92.1% and 81% of BTMs exhibited high hENT1 and RRM1 expression, respectively. RRM2 expression varied, and 32% of tumors demonstrated high RRM2 expression. ERCC1 and RRM1 were not associated with OS. High RRM2 expression was associated with a trend toward improved OS (30.8 months vs 16.2 months; P = .06), and high hENT1 expression was associated with improved OS (17.7 months vs 9.5 months; P = .04). CONCLUSIONS: Most BTMs exhibited low ERCC1 expression and high hENT1 and RRM1 expression, whereas RRM2 expression levels varied. High expression of hENT1 was associated with improved OS. These findings may have implications for the selection of chemotherapy agents (gemcitabine vs platinum) and the stratification of patients in chemotherapy trials that assess outcome. Cancer 2013. © 2012 American Cancer Society.
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an analysis of ercc1 hent1 rrm1 and rrm2 expression in resected pancreas adenocarcinoma implications for adjuvant treatment
Journal of Clinical Oncology, 2012Co-Authors: Sarah B Fisher, Sameer H Patel, Pelin Bagci, David A Kooby, Bassel F Elrayes, Charles A Staley, Volkan N Adsay, Shishir K MaithelAbstract:206 Background: Tumor overexpression of Excision Repair cross complementing gene 1 (ERCC1) was recently shown to be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Ribonucleotide reductase 1 and 2 (RRM) and human equilibrative nucleotide transporter 1 (hENT1) are integral to DNA synthesis and cellular transport and are implicated as poor prognostic factors in other malignancies. Their role in PAC is not well defined. Methods: A prospective database (n=220) was used to randomly select 95 pts who underwent pancreaticoduodenectomy for PAC between 1/00-10/08. IHC analysis was performed on tumor samples for RRM1 and 2, hENT1, and ERCC1. Main outcomes were recurrence-free (RFS) and overall survival (OS). Results: Median age was 63 yrs; median FU, RFS, and OS was 49, 10.6 and 15.5 mo. Median tumor size was 3cm, 26% had a positive margin, 34% were poorly differentiated, 61% had positive lymph nodes (LN), 88% had perineural invasion (PNI), and 45% had lymphovascular invasion (LVI...
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differential expression of ercc1 in pancreas adenocarcinoma high tumor expression is associated with earlier recurrence and shortened survival after resection
Annals of Surgical Oncology, 2011Co-Authors: Shishir K Maithel, David A Kooby, Bassel F Elrayes, Charles A Staley, Ipek Coban, Peter J Kneuertz, John S Kauh, Juan M Sarmiento, Volkan N AdsayAbstract:Background Increased tumor expression of Excision Repair Cross-Complementing gene-1 (ERCC1) is associated with decreased survival in patients with various cancers. Its effect in pancreatic adenocarcinoma (PAC) is not defined.
Yalin Huang - One of the best experts on this subject based on the ideXlab platform.
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role of vascular endothelial growth factor in neuronal dna damage and Repair in rat brain following a transient cerebral ischemia
Journal of Neuroscience Research, 2002Co-Authors: Zeng Jin Yang, Lingmei Zhang, Shi Duo Lu, Yalin HuangAbstract:The antisense knockdown technique and confocal laser scanning microscopic analysis were used to elucidate vascular endothelial growth factor (VEGF) induction and its effect on DNA damage and Repair in rat brain following a transient middle cerebral artery occlusion. Immunohistochemical study and in situ hybridization showed that the expression of VEGF and its mRNA was enhanced in the ischemic core and penumbra of ischemic brain. Western blot analysis further illustrated that VEGF induction was time-dependently changed in these areas. Double-staining analysis indicated that VEGF-positive staining existed in the neuron, but not in the glia, and it colocalized with Excision Repair Cross-Complementing group 6 (ERCC6) mRNA, a DNA Repair factor. VEGF antisense oligodeoxynucleotide infusion reduced VEGF induction and resulted in an enlargement of infarct volume of the brain caused by ischemia. Moreover, it also increased the number of DNA damaged cells and lessened the induction of ERCC6 mRNA in ischemic brains. These results suggest that the induction of endogenous VEGF in ischemic neurons plays a neuroprotective role probably associated with the expression of ERCC6 mRNA. © 2002 Wiley-Liss, Inc.
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neuroprotection by melatonin against ischemic neuronal injury associated with modulation of dna damage and Repair in the rat following a transient cerebral ischemia
Journal of Pineal Research, 2002Co-Authors: Weihong Ge, Lingmei Zhang, Yalin Huang, Jin GuAbstract:: In the present study, double fluorescence staining combined with confocal laser scanning microscopy analysis were used to examine the effects of melatonin on ischemia-induced neuronal DNA strand breaks and its possible mechanisms in a transient middle cerebral artery (MCA) occlusion model. Results showed that melatonin dose-dependently reduced infarct areas and decreased both DNA double and single strand breaks (DSB and SSB) and enhanced cell viability in the peri-ischemic brain regions. Furthermore, Bcl-2 induction in the ischemic brain was further enhanced by melatonin treatment. Double staining analysis indicated that the cells costained for Bcl-2 and TdT-mediated-deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), a DSB marker, displayed a relative regular morphology compared with the cells only stained with TUNEL. Transient ischemia induced an expression of Excision Repair Cross-Complementing factor 6 (ERCC6) mRNA, a gene essential for the preferential Repair of nuclear Excision Repair, in the injured neurons. Double labeling showed that ERCC6 only co-localized with proliferating cell nuclear antigen (PCNA), a member of the nuclear Excision Repair complex, but not with TUNEL. Melatonin further and statistical significantly up-regulated ERCC6 mRNA expression in the peri-ischemic region of rat brains. The results suggest that neuroprotection by melatonin against ischemic injury may be related to modulation of apoptosis and DNA Repair capacity.
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neuronal ercc6 mrna expression in rat brain induced by a transient focal cerebral ischemia
Acta Pharmacologica Sinica, 1999Co-Authors: Xiang Ling, Lingmei Zhang, Yalin Huang, Weili Bao, Fengyan SunAbstract:AIM: To study whether the Excision Repair Cross-Complementing group 6 (ERCC6) is involved in the neuronal pathophysiological process following cerebral ischemia-reperfusion injury. METHODS: A transient middle cerebral artery occlusion (MCAO) was used to induce cerebral ischemia-reperfusion injury in rat brain. Northern blot was used to check a specific signal for oligonucleotide probe. The expression of ERCC6 mRNA in the rat brain was observed by in situ hybridization. The specific cellular distribution of ERCC6 mRNA in the neuron or glia of the rat brain was analyzed by double staining combined with confocal laser scanning microscopic analysis. RESULT: The expression of ERCC6 mRNA in the penumbra area increased following ischemia and reperfusion with a time-dependent manner. ERCC6 was expressed on d 2, reached peak values on d 3, and kept high level even on d 14 of reperfusion following ischemia. Number of ERCC6 mRNA expressive cell in the penumbra area on d 1, d 2, d 3, d 7, d 14 of reperfusion following ischemia were (0 +/- 0), (253 +/- 56), (816 +/- 355), (341 +/- 185), (128 +/- 95) x 10(6) cells/m2, respectively. Confocal microscopic analysis showed that ERCC6 mRNA coexpressed with phosphopyruvate hydratase in the neurons and with glial fibrillary acidic protein (GFAP) in a few proliferation astrocyte glia. CONCLUSION: The expression of transcription-Repair coupling factor ERCC6 mRNA in the neuron and glia was induced by ischemia-reperfusion injury.
