Polymorphisms of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) in ovarian cancer risk

Glutathione S-transferases (GSTs) are ubiquitous, multifunctional phase II metabolic enzymes responsible for the detoxification of estrogen involved in the development of ovarian cancer. Data from epidemiological studies show conflicting results that remain to be further clarified. We estimated in this study the genetic effects of GSTM1 and GSTT1 polymorphisms on ovarian cancer risk. Eligible studies of the two polymorphisms and ovarian cancer risk were identified from China National Knowledge Infrastructure (CNKI), PubMed, Embase, and Web of Science. We summarized all data and performed a meta-analysis. Odds ratio (OR) and 95 % CI was calculated by using the fixed effects model to estimate the associations. Eight eligible studies were finally identified providing 2,397 cases and 2,910 controls for GSTM1 polymorphism and 2,049 cases and 2,668 controls for GSTT1 polymorphism. The overall data showed that carries of the GSTM1 null genotype did not have significantly increased ovarian cancer risk compared with those who carried the GSTM1 present genotype (null vs. present—OR, 1.01; 95 % CI, 0.91–1.11; heterogeneity, P?=?0.672). Similarly, for GSTT1 polymorphism, we observed no association under the investigated model in the overall analysis (null vs. present—OR, 1.02; 95 % CI, 0.89–1.17; heterogeneity, P?=?0.372), and in the subgroup of Caucasian subjects (null vs. present—OR, 0.99; 95 % CI, 0.86–1.14; heterogeneity, P?=?0.959). The meta-analysis does not provide a strong evidence for causal associations between GSTM1 and GSTT1 polymorphisms and risk of ovarian cancer in Caucasians.     

Thrombospondin-1 (TSP-1) and Survivin (S) expression in non-Hogkin's lymphomas

Survivin (S) is a member of inhibitor of apoptosis family (IAP) and is expressed in the majority of malignant tumors but undetectable in normal differentiated adult tissues. S is an encouraging target for cancer therapy. TSP-1 is a multifunctional protein regulating cell growth, motility and apoptosis in both physiological and pathological conditions. The role of TSP-1 in cancer progression remains controversial. We aimed to determine the pathogenetic and prognostic role of TSP-1 and S in non-Hodgkin's lymphomas (NHL). S and TSP-1 expressions were looked for in 177 cases with NHL. S was found to be positive in 94 of the cases (53%). TSP-1 was found to be positive in 31 of the cases (17.5%). There was a strong association between S and TSP-1 and also aggressive histology with S and TSP-1. The overall survival (OS) times were longer in cases without S expression than cases with S expression (p=0.0514). Although the OS was shorter in TSP-1 expressing cases as compared with TSP-1 (-) cases, difference was not significant (p=0.2428). In conclusion, S and TSP-1 expressions were detected in 53 and 17.5% of the cases with NHL, and are associated with aggressive histology and shorter OS.     

Genetic variability in the metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)

Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years before diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis (1992-1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p < 10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017) passed multiple testing adjustment at FDR q = 1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p = 0.019) did not, FDR q = 0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V.     

Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors

BackgroundTesticular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs.Patients and methodsSurgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome.ResultsNone of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16–1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15–1.23, P = 0.040) compared with patients with high PD-L1 expression.ConclusionsIn this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.     

Expressions of Poly（ADP-ribose） Glycohydrolase（PARG） and Membrane Type 1 Matrix Metalloproteinase（MT1-MMP） in Colorectal Carcinoma

Objective  

To investigate the significance of Poly (ADP-ribose) glycolhydrolase (PARG) and membrane type 1 matrix metalloproteinase (MT1-MMP) expressions in human colorectal carcinoma.     

Aberrant expression of p21(WAF1/CIP1) and p27(KIP1) in cervical carcinoma

An immuno-histochemical study of p21 and p27 expression in cervical carcinoma was performed in 73 patients. Positive p21 and p27 staining was detected in 35.6 and 11% of tumour tissues, respectively. p21 expression was significantly correlated with advanced disease stage and negative human papilloma virus infection whilst positive p27 staining was not correlated with any clinical and pathological parameters studied. Kaplan-Meier estimation indicated that survival might be related to disease stage, tumour grade and p21 expression. Cox regression analysis confirmed that advanced stage disease and poorly differentiated tumour are independent prognostic factors for cervical carcinoma.     

Circulating levels of endothelin-1 (ET-1) and its precursor (Big ET-1) in breast cancer early diagnosis

Deregulation of the endothelin system, comprised of endothelin-1 (ET-1), its isoforms (ET-2 and ET-3) and their receptors (ET(A)R and ET(B)R), is under investigation in various types of human cancer. ET-1 has been suggested to participate in breast cancer development and progression, while Big ET-1, its biological precursor, has also been found elevated in breast cancer patients. In the present study, we investigated plasma ET-1 and Big ET-1 levels in patients with suspicious mammographic lesions, in order to assess their potential application as diagnostic biomarkers in the early estimation of breast disease. The study consisted of 94 patients (Group A to 30 patients with invasive ductal carcinoma: Group B, 30 with ductal carcinoma in situ; and group C, 34 with papilloma or ductal hyperplasia), who underwent an image-guided vacuum-assisted breast biopsy, and 30 healthy controls (group D). ET-1 and Big ET-1 plasma levels were measured with enzyme-linked immunosorbent assay. ET-1 levels did not exhibit significant differences between patients and healthy controls (Group A to 0.92 fmol/mL; Group B: 0.90 fmol/mL; Group C: 0.66 fmol/mL; and Group D: 0.86 fmol/mL). In contrast, Big ET-1 levels were significantly higher in patients with invasive or in situ carcinoma compared to healthy controls (Group A: 0.69 fmol/mL; Group B, 0.62 fmol/mL; and group D: 0.39 fmol/mL; p < 0.001 and p < 0.01). Plasma Big ET-1 may provide a useful tool for the early detection of invasive or noninvasive ductal breast cancer. The utilization of such a diagnostic tool would greatly assist in the modern management of breast cancer.     

X-RAY REPAIR CROSS-COMPLEMENTING GROUP 1 （XRCC1） Arg 399 Gin POLYMORPHISM AND AFLATOXIN B1 （AFB1）-RELATED HEPATOCELLULAR CARCINOMA （HCC） IN GUANGXI POPULATION

In Guangxi Zhuang Autonomous Region,Hepatocellular carcinoma(HCC)is one of the maincancer killers,the incidence rate of which is5～40/1,000,000per year.Clinic-epidemiological evidencesuggests AFB1exposure is the most cause[1].However,the exact mechanisms of AFB1hepatocarcinogenesishave not been fully elucidated.Recently,there is agrowing realization that genetic constitution is ofimportance in determining individual’s susceptibility toHCC.This genetic susceptibility may result frominhe…     

The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats

Summary A few cases of liver involvement have been reported in patients receiving treatment with the antineoplastic nitrosourea CCNU. A single oral dose of 20 or 50 mg/kg CCNU in female Wistar rats induced an important increase in transaminases between day 2 and day 6, followed by a second, moderate increase between day 21 and day 28. Alkaline phosphatases and conjugated hyperbilirubinemia (threefold-increase) were noted for the two doses and were greater for the highest dose. Histological and ultrastructural studies disclosed hepatic lesions of two types: during the first phase of transaminase increase, inflammation of the portal tracts; during the second phase marked dilation of bile canaliculi and numerous filamentous bundles distributed at random throughout the liver cell cytoplasm like normal microtubules. Thus, CCNU induced pericholangitis and intrahepatic cholestasis with microtubular abnormalities. The long-term evolution of hepatic alterations revealed that in the 3rd month after a single oral dose of 20 mg/kg CCNU, lesions were persistent but stable; no reversibility was observed in the 3rd month after 50 mg/kg CCNU, and evolution towards cholangiolysis and biliary cirrhosis was noted. We suggest that CCNU causes a bimodal hepatotoxicity in rats: an early and prolonged ductal injury and a delayed anti-liver cell microtubule toxicity.     

Nuclear receptor 4A1 (NR4A1) antagonists target paraspeckle component 1 (PSPC1) in cancer cells

Paraspeckles compound 1 (PSPC1) is a multifunctional protein that plays an important role in cancer cells, where PSPC1 is a master regulator of pro-oncogenic responses that includes activation of TGFβ (TGFβ1), TGFβ-dependent EMT, and metastasis. The pro-oncogenic activities of PSPC1 closely resembled those observed for the orphan nuclear receptor 4A1 (NR4A1, Nur77) and knockdown of NR4A1 decreased expression of PSPC1 in MDA-MB-231 breast, H1299 lung, and SNU449 liver cancer cells. Similar results were observed in these same cell lines after treatment with bisindole–derived (CDIMs) NR4A1 antagonists. Moreover, PSPC1-dependent regulation of TGFβ, genes associated with cancer stem cells and epithelial to mesenchymal transition (EMT) were also downregulated after NR4A1 silencing or treatment of breast, lung, and liver cancer cells with CDIM/NR4A1 antagonists. Results of chromatin immunoprecipitation (ChIP) assays suggest that NR4A1 regulates PSPC1 through interaction with an NBRE sequence in the PSPC1 gene promoter. These results coupled with in vivo studies showing that NR4A1 antagonists inhibit breast tumor growth and downregulate PSPC1 in tumors indicate that the pro-oncogenic nuclear PSPC1 factor can be targeted by CDIM/NR4A1 antagonists.     

Disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in bile duct-cannulated rats: stereoselective metabolism and tissue distribution.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a chiral compound, and the primary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major carcinogen in tobacco smoke. The goal of the present work was to study the pharmacokinetics and stereoselective metabolism and tissue retention of NNK and NNAL in the rat. Groups of rats were dosed with [5-(3)H]NNK (n = 3) or racemic [5-(3)H]NNAL (n = 3) at a target dose of 8.45 micromol/kg and were killed at selected time points for tissue collection. Separate groups of rats (n =5 per group) received the same dose of either NNK or NNAL and serial sampling of blood, bile and urine was carried out over 24 h. All samples were analyzed by C(18) reversed-phase HPLC with gradient elution and radioflow detection. A gas chromatograph-thermal energy analyzer (GC-TEA) was used to separate the (R)-/(S)-NNAL enantiomers. Racemic NNAL and NNK had large volumes of distribution (321 +/- 137 ml for NNK and 2772 +/- 1423 ml for NNAL) and similar total body clearances (12.8 +/- 2.0 ml/min for NNK and 8.6 +/- 2.6 ml/min for NNAL). The results indicated that the enantiomers of NNAL are stereoselectively metabolized and excreted. The glucuronide of (R)-NNAL, ((R)-NNAL-Gluc) was identified as the major metabolite in the bile after administration of either NNK or NNAL. (R)-NNAL was the major NNAL enantiomer in the bile or urine samples. At 24 h after racemic NNAL administration, NNAL comprised an average of 75.4% of total radioactivity in the lung with an (S)-/(R)-ratio of >20. The stereoselective localization of (S)-NNAL to lung tissue may contribute to the lung selectivity of NNK carcinogenesis. The present studies suggest a need to look beyond metabolic activation as the sole mechanism for lung carcinogenesis.