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miRNA play role in post transcriptional regulation of genes and serves a range of biological functions such as initiation, development, metastasis etc. which are also hallmarks of cancer. Hence, we evaluated miRNA 181a, miRNA 30c and miRNA 570 in bladder cancer risk association among North Indians. miRNA 570 C/G (rs4143815), miRNA 30c A/G (rs928508) and miRNA 181a C/T (rs12537) single nucleotide polymorphisms (SNPs) were genotyped by allelic discrimination TaqMan assay in 100 bladder cancer (BC) patients and 100 healthy controls. No significant difference was found in the genotype frequencies of the candidate SNPs among cases and controls. However, combined effect of miRNA 570-miRNA 30c (CG + AA) p = 0.005, OR = 0.223, 95% CI and miRNA 570-miRNA 181a (CG + CC) p = 0.003, OR = 0.169, 95% CI conferred association with no risk of BC. miRNA 181a C/T (rs12537), miRNA 30c A/G (rs928508) and miRNA 570 C/G (rs4143815) should be further validated in large sample size to be used as a risk predictor for bladder cancer among North Indians. [ABSTRACT FROM AUTHOR]

X-ray repair cross-complementing group 1 (XRCC1) plays a key role in the base excision repair pathway, as a scaffold protein that brings together proteins of the DNA repair complex. Several studies have reported contradictory results for XRCC1 exon 6 C>T (rs1799782) gene polymorphism and cancer risk in Indian population has provided inconsistent results. Therefore, we have performed this meta-analysis to evaluate the relationship between XRCC1 exon 6 C>T gene polymorphism and risk of cancer by published studies. We searched PubMed and Google scholar web databases to cover all studies published on association between XRCC1 exon 6 C>T gene polymorphism and cancer risk. The meta-analysis was carried out and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to appraise the strength of association. In order to derive a more precise estimation of the association, A total of 3197 confirmed cancer cases and 3819 controls were included from eligible seventeen case-controls studies. Results from overall pooled analysis demonstrated suggested that that variant allele (T vs. C: OR 1.301, 95% CI 1.003–1.688, p = 0.047) was associated with the risk of overall cancer. Other genetic models; heterozygous (TC vs. CC: OR 1.108, 95% CI 0.827–1.485, p = 0.491), homozygous (TT vs. CC: OR 1.479, 95% CI 0.877–2.493, p = 0.142), dominant (TT+TC vs. CC: OR 1.228, 95% CI 0.899–1.677, p = 0.196) and recessive (TT vs. TC+CC: OR 1.436, 95% CI 0.970–2.125, p = 0.071) did not reveal statistical association. Publication bias observation was also considered and none was detected during the analysis. The present meta-analysis suggested that the variant allele T of XRCC1 exon 6 gene polymorphism was associated with the risk of cancer. It is therefore pertinent to confirm this finding in a large sample size to divulge the mechanism of this polymorphism and cancer risk in Indian population. [ABSTRACT FROM AUTHOR]

Multitude of gene-altering capabilities in combination with ease of design and low cost have all led to the adoption of the sophisticated and yet simple gene editing system that are clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR). The CRISPR/Cas9 system holds promise for the correction of deleterious mutations by taking advantage of the homology directed repair pathway and by supplying a correction template to the affected patient's cells. CRISPR is a tool that allows researchers to edit genes very precisely, easily and quickly. It does this by harnessing a mechanism that already existed in bacteria. Basically, there's a protein that acts like a scissors and cuts the DNA, and there's an RNA molecule that directs the scissors to any point on the genome one wants which results basically a word processor for genes. An entire gene can be taken out, put one in, or even edit just a single letter within a gene. Several platforms for molecular scissors that enable targeted genome engineering have been developed, including zinc-finger nucleases, transcription activator-like effector nucleases and, most recently, CRISPR/CRISPR-associated-9 (Cas9). The CRISPR/Cas9 system's simplicity, facile engineering and amenability to multiplexing make it the system of choice for many applications. CRISPR/Cas9 has been used to generate disease models to study genetic diseases. Improvements are urgently needed for various aspects of the CRISPR/Cas9 system, including the system's precision, delivery and control over the outcome of the repair process. However, there are still some glitches to be mended like how to regulate gene drives and its safeguards. The creation of gene knockouts is one of the first and most widely used applications of the CRISPR-Cas9 system. Nuclease-active Cas9 creates a double-strand break at the single guide RNA-targeted locus. These breaks can be repaired by homologous recombination, which can be used to introduce new mutations. When the double-strand break is repaired by the error-prone nonhomologous end joining process, indels are introduced which can produce frame shifts and stop codons, leading to functional knockout of the gene. Precedence modification have to be done on mechanism of CRISPR/Cas9, including its biochemical and structural implications incorporating the latest improvements in the CRISPR/Cas9 system, especially Cas9 protein modifications for customization. Current applications, where the versatile CRISPR/Cas9 system is to be used to edit the genome, epigenome, or RNA of various organisms is debated. Although CRISPR/Cas9 allows convenient genome editing accompanied by many benefits, one should not ignore the significant ethical and biosafety concerns that it raises. Conclusively lot of prospective applications and challenges of several promising techniques adapted from CRISPR/Cas9. Is discussed. Although many mechanistic questions remain to be answered and several challenges to be addressed yet, the use of CRISPR-Cas9-based genome technologies will increase our knowledge of disease process and their treatment in near future. Undoubtedly this field is revolutionizing in current era and may open new vistas in the treatment of fatal genetic disease. [ABSTRACT FROM AUTHOR]

DNA repair capacity is essential in maintaining cellular functions and homeostasis. Identification of genetic polymorphisms responsible for reduced DNA repair capacity may allow better cancer prevention. Double strand break repair pathway plays critical roles in maintaining genome stability. Present study was conducted to determine distribution of XRCC3 Exon 7 (C18067T, rs861539) and XRCC7 Intron 8 (G6721T, rs7003908) gene polymorphisms in North Indian population and compare with different populations globally. The genotype assays were performed in 224 normal healthy individuals of similar ethnicity using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Allelic frequencies of wild type were 79% (C) in XRCC3 Exon 7 C > T and 57% (G) in XRCC7 Intron 8 (G > T) 57% (G) observed. On the other hand, the variant allele frequency were 21% (T) in XRCC3 Exon 7 C > T and 43% (T) in XRCC7 Intron 8 G > T respectively. Major differences from other ethnic populations were observed. Our results suggest that frequency in these DNA repair genes exhibit distinctive pattern in India that could be attributed to ethnicity variation. This could assist in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups. [ABSTRACT FROM AUTHOR]

The ABCB1 gene encodes a permeability glycoprotein, which is one of the most extensively studied human adenosine-triphosphate (ATP)-dependent efflux transporters. Permeability glycoprotein is expressed in the apical membranes of tissues such as intestine, liver, blood-brain barrier, kidney, placenta, and testis and contributes to intracellular drug disposition. It is also highly expressed in tumor cells conferring drug resistance, which is one of the major problems in the efficacy of cancer chemotherapy treatment. ABCB1 is highly polymorphic, and three well-known single-nucleotide polymorphisms such as 1236C.T, 2677G.T/A, and 3435C.T have been found to be associated with altered messenger RNA levels, protein folding, and drug pharmacokinetics. Many association studies and meta-analyses have demonstrated the clinical impact of ABCB1 polymorphisms in breast cancer treatment outcomes with respect to therapeutic response, chemotoxicity, and overall survival. Therefore, the aim of this review was to evaluate the effects of ABCB1 polymorphisms on the outcome of breast cancer treatment which, in future, would be important for tailoring individualized anticancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: Free to total prostate specific antigen ratio (f/t PSA) has been used to help improving specificity of PSA in the range of 4-10 ng/ml based on the data on population based screening. There is no data on test characteristics of f/t PSA in men presenting with clinical symptoms of benign prostatic hyperplasia (BPH). This study is aimed to determine the usefulness of f/t PSA in symptomatic men. Methodology: From January 2006 to June 2012, men of 50-75 years with lower urinary tract symptoms (LUTS), normal rectal examination and PSA between 4-20 ng/ml had free and total PSA assessment. Men with clinical evidence of prostatitis, retention, history of 5α blocker reductase inhibitors and those who had surgery or biopsy on the prostate in last 3 months were excluded. Receiver operating characteristic curves were derived for f/t PSA and total PSA. The effect of age, prostate volume and Gleason score on the f/t PSA was also analyzed. All statistical analyses were performed on SPSS 16 (Chicago, USA). Results: Out of 170 men with the mean age of 67.4 ± 6.6 years, 43 (25.3%) had cancer on biopsy. Area under the curve for predicting the presence or absence of prostate cancer in all the men with f/t ratio was 0.63 (confidence interval [CI]: 0.54-0.71). The median value of f/t PSA for men with cancer was 5.5% (1-25%) and 9.2% (1-63%) for those with no cancer. Cut-offs derived at 95% specificity at PSA between 4-10 ng/ml and 4-20 ng/ml were 0.5% and 1% respectively. The specificity of f/t PSA ratio at cut-off levels 7%, 10% and 15% was 73%, 60%, 45% for PSA range of 4-10 ng/ml and 63%, 47% and 35% for PSA range of 4-20 ng/ml PSA. Age, prostate volume and Gleason grade did not show any effect on f/t PSA. Conclusion: In men with LUTS the specificity of various f/t PSA ratio cut-offs; described for population based screening, is too low to be used as an aid to defer the decision of biopsy in PSA ranges of 4-20 ng/ml. [ABSTRACT FROM AUTHOR]

Background and Objective: Chemotherapeutic drug treatment outcomes are genetically determined. Polymorphisms in genes encoding phase II drug metabolizing enzyme glutathione- S-transferase (GST) can possibly predict treatment outcomes, and can be of prognostic significance in breast cancer patients. The aim of this study was to determine the role of genetic variations in GST in predicting response to, and toxicity of, anthracycline-based chemotherapy in breast cancer patients. Method: Two hundred and seven patients treated with anthracycline-based chemotherapy were genotyped for GSTM1 and GSTT1 deletion polymorphisms, and GSTP1 Ile 105Val (rs1695), by polymerase chain reaction (PCR)/ PCR-restriction fragment length polymorphism (RFLP). Genetic variations were correlated with tumor response to neo-adjuvant chemotherapy (NACT) in 100 patients, and with chemo-toxicity in 207 who received adjuvant chemotherapy or NACT, using Chi-square and logistic regression. Higher order gene–gene interactions with treatment outcomes were characterized by multifactor dimensionality reduction (MDR) analysis. Results: In single-locus analysis, Ile/Val and Ile/Val + Val/Val genotypes of the GSTP1 Ile 105Val (rs1695) polymorphism reached statistical significance with grade 2–4 anemia ( P = 0.019, P = 0.027). On performing gene–gene interaction analysis, GSTM1 null- GSTP1 Ile/Val was significantly associated with response to NACT ( P = 0.032). On evaluating higher order gene–gene interaction models by MDR analysis, GSTM1 and GSTP1 Ile 105Val; GSTM1 and GSTT1; and GSTT1 and GSTP1 Ile 105Val showed significant association with treatment response, grade 2–4 anemia, and dose delay/reduction due to neutropenia ( P = 0.046, P = 0.027, P = 0.026), respectively. Conclusion: Multi-analytical strategies may serve as a better tool for characterization of pharmacogenetic-based breast cancer treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. Materials & Methods: A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. Results: No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. Conclusions: These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility. [ABSTRACT FROM AUTHOR]

Dysregulation of apoptosis plays a crucial role in carcinogenesis. Thus, genetic alterations within caspase genes would be expected to provoke a deficient apoptotic signaling thereby facilitating the development of prostate cancer (PCa). In the present study we investigated whether three different polymorphisms in the caspase-5 and -3 genes are differentially expressed in PCa. In a hospital-based case control study in northern India, we genotyped 192 PCa patients and 225 unrelated healthy controls for caspase-5 (G>C) (T>C) and caspase-3 (G>A) polymorphisms using amplification refractory mutation system and polymerase chain restriction fragment length polymorphism methods. Data were statistically analyzed and variant genotype GG of caspase-3 demonstrated increased risk for PCa (odds ratio [OR]=2.72, p=0.005). Similarly variant allele carrier (AG+GG) (OR=1.53, p=0.034) and G allele (OR=1.54, p=0.005) were also statistically associated with PCa risk. High risk for PCa was also observed with respect to caspase-5 (CC) diplotypes (OR=21.67, p=0.012, Pc=0.048). We observed significantly enhanced risk for PCa due to interaction between caspase-3 and -5 gene polymorphisms. In association of genotypes with clinical characteristics, heterozygous TC genotype of caspase-5 (T>C) conferred risk with high Gleason grade tumor (OR=2.35, p=0.042). In case-only analysis, interaction of environmental risk factors and genotypes did not further modulate the risk for PCa. Our observations suggested positive association of caspase-3 and diplotype analysis of caspase-5 to be associated with PCa risk. Interaction of caspase-3 and -5 genotypes also modulated the PCa risk. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of cellular functions through post-transcriptional regulations on target genes. Common genetic variants (single-nucleotide polymorphisms, SNPs) in pre-miRNA genes may alter their expression and/or maturation effecting thousands of target mRNAs, resulting in varied functional consequences. Three common SNPs ( hsa-mir-146a G>C rs2910164, hsa-mir-196a2 C>T rs11614913, and hsa-mir-499 T>C rs3746444) in pre-miRNAs were investigated to evaluate their association with urinary bladder cancer risk. The hospital-based case-control study comprised of 212 histologically confirmed patients with urinary bladder cancer and 250 healthy controls who were unrelated, of similar ethnicity, and age and gender matched. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism methodology. Our results showed that the heterozygous genotype of rs11614913 was higher in cases than controls but the results were marginally significant ( p = 0.055; odds ratio, 1.44). Smoking had no impact in modulating the effect of any of the three miRNA SNPs studied. No association was observed with either the tumor stage or grade in patients with bladder cancer. Even though there was no association between the individuals carrying the variant genotypes of the three miRNA studied and bladder cancer risk, marginal significance of heterozygousity in rs11614913 suggested further characterization of miRNA SNPs in a large cohort of varied ethnicity. This could further provide new prospects for understanding the underlying mechanisms between miRNAs and disease etiology. [ABSTRACT FROM AUTHOR]

Increased vascular endothelial growth factor (VEGF) production promotes enhanced endothelial permeability, enhanced leukocyte migration into the allograft, thereby leading to a clinically recognized rejection episode. Interleukin-18 (IL-18), a potent proinflammatory cytokine, may also be involved in mechanisms of kidney allograft rejection. The present study was, therefore, undertaken to investigate the association of functional polymorphisms in VEGF (2578C>A, 1154A>G) and IL-18 (607C>A, 137G>C) genes with risk of allograft rejection in renal transplant recipients of North India. Two hundred renal transplant recipients, 150 matched recipients-donors, and 200 unrelated healthy individuals were genotyped by amplification refractory mutation specific polymerase chain reaction and by polymerase chain reaction-restriction fragment length polymorphism. Variant allele VEGF 1154A>G ( p = 0.56; odds ratio [OR] = 1.32) and variant allele ( p = 0.004, OR = 1.54) and variant genotype ( p = 0.007, OR = 3.26) of IL-18 607C>A, GC of IL-18 137G>C ( p = 0.043, OR = 0.63) were significantly different in healthy individuals as compared with the patients with renal transplant. When 114 nonrejectors were compared with 36 rejectors (150 recipients) for association with allograft rejection, significant association was observed in heterozygous genotype of VEGF 2578C>A ( p = 0.033), VEGF 1154A>G ( p = 0.024). In IL-18 137G>C, CC genotype, C allele showed protective association with allograft rejection. Kaplan-Meier analysis indicated a higher mean time for first rejection episode in CA genotype carriers (31 months) as compared with AA (29 months) for VEGF 2578C>A (log p = 0.035). In VEGF, the haplotypes A-A and A-G (2578-1154) were associated with reduced risk and in IL-18 607A-137G, they were associated with high risk for allograft rejection. This observation suggests these polymorphisms are an ideal marker for prediction of pretransplant allograft outcome. [ABSTRACT FROM AUTHOR]

OBJECTIVE • To investigate, by genotyping CASP8 (- 652 6N del/ins) and CASP9 (-1263 A > G; - 293 19N del/ins), whether inactivation of apoptosis by genetic polymorphism of caspases 8 and 9 play an integral role in the mechanism of cancer development. • To investigate the role of these polymorphisms in susceptibility to early development of hormone refractory prostate cancer. PATIENTS AND METHODS • The study included 175 histologically confirmed cases of prostate cancer and 198 age and ethnicity matched healthy controls. • CASP9 - 1263 A > G polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. • CASP9 - 293 del/ins and CASP8 - 652 del/ ins polymorphisms were genotyped and the deletion pattern analysed by polyacrylamide gel electrophoresis. RESULTS • Our results demonstrated that presence of CASP9 - 1263 G allele was associated with reduced risk for prostate cancer (odds ratio 0.6, 95%CI 0.39-0.92, P = 0.02). Other variant CASP9 was not associated with prostate cancer risk. • Coincidentally, the presence of CASP9 - 1263 G allele was associated with increased risk for progression of prostate cancer to bone metastasis (odds ratio - 2.28, 95%CI 1.14-4.53, P = 0.02). • CASP8-652 ( + / - ) genotype was associated with increased hazard for early development of hormone refractory prostate cancer (hazard ratio 2.44, 95%CI 1.2-5.85, P = 0.045). CONCLUSION • Our results support the hypothesis that variants of CASP9 may influence the susceptibility to prostate cancer and its progression to bone metastasis. • CASP8 polymorphism may influence the progression of prostate cancer disease to a hormone refractory state. [ABSTRACT FROM AUTHOR]

DNA repair gene alterations may cause a reduction in DNA repair capacity and influence an individual's susceptibility to carcinogenesis. We hypothesized that single nucleotide polymorphisms of DNA repair genes may be a risk factor for prostate cancer (PCa) susceptibility, influencing expression of homologous recombination ( XRCC3) and nonhomologous end-joining ( XRCC7) genes and conferring predisposition to PCa. In a case-control study, genotyping was done in 192 patients with PCa and 224 age matched unrelated healthy controls of similar ethnicity to determine variants in XRCC3 Exon 7 (C18067T, rs861539), IVS5-14 (A17893G, rs1799796), and XRCC7 Intron 8 (G6721T, rs7003908) by polymerase chain reaction-restriction fragment-length polymorphism methods. Variant genotype GG (odds ratio [OR], 2.23; p = 0.003) and combined genotype TG + GG (OR, 1.541; p = 0.049), G allele of XRCC7 Intron 8 (G > T), demonstrated significant risk for PCa (OR, 1.529; p = 0.002). Stratification on bases of Gleason grade and bone metastasis, significant risk with high Gleason grade for CT genotype of XRCC3 Exon 7, and variant genotype GG of XRCC7 Intron 8 were observed. Our results strongly support that common sequence variants (GG) genotype of XRCC7 may increase risk of PCa. G allele being a risk allele in our study also suggests that this polymorphism be used as a marker for the PCa susceptibility. [ABSTRACT FROM AUTHOR]

Background. Matrix metalloproteinases (MMPs), especially basement membrane-degrading MMP-9 and MMP-2, play an important role in immune-mediated tissue destruction of the allograft by allowing influx of leucocytes and mononuclear cells into the graft. The present study was, therefore, undertaken to investigate the association of functional polymorphisms in MMP-9 (836A>G, 1721G>C and 2003G>A) and MMP-2 (−735C>T) genes with risk of allograft rejection in renal transplant recipients of North India.Methods. Three hundred and six renal transplant recipients categorized into 228 non-rejecters and 78 rejecters were genotyped for MMP-9 and MMP-2 polymorphisms by polymerase chain reaction–restriction fragment length polymorphism methodology.Results. A significant difference in genotype/allele frequencies was observed between healthy individuals in comparison to non-rejecters/rejecters for MMP-9 836A>G, MMP-9 2003G>A and MMP-2 −735C>T. Mutant allele carriers for MMP-9 2003G>A [GA+AA−; odds ratio (OR) = 0.45, 95% confidence intervals (95% CI) = 0.24–0.85, P = 0.014] and MMP-2 −735C>T (CT+TT−; OR = 0.40, 95% CI = 0.18–0.91, P = 0.029) demonstrated significantly reduced risk for allograft rejection. The mean time to first rejection episode was significantly higher in GA/AA and CT/TT genotype recipients for MMP-9 2003G>A (log P = 0.026) and MMP-2 −735C>T (log P = 0.003), respectively. Haplotypes with mutant alleles for MMP-9 1721C>G-2003G>A and mutant allele genotype combinations for both MMP-9 2003G>A and MMP-2 −735C>T conferred significantly reduced risk for allograft rejection.Conclusion. Mutant alleles for MMP-9 2003G>A and MMP-2 −735C>T are associated with reduced risk for allograft rejection and improved allograft survival in North Indian transplant recipients and could serve as an ideal marker to predict pre-transplant allograft outcome. [ABSTRACT FROM AUTHOR]

Perturbations in the cell cycle and apoptotic genes have been implicated in human malignancies. Cell cycle ( MDM2 and Cyclin D1) and apoptotic ( Fas) genes that are differentially expressed in urinary bladder cancer (UBC) were investigated with the susceptibility to UBC in northern India. A total of 212 UBC patients and age- and sex-matched 250 controls were investigated for MDM2 G309T, Cyclin D1 G870A, and Fas A670G polymorphisms by polymerase chain reaction and restriction fragment length polymorphism. MDM2 309GG was at reduced risk for developing UBC when compared with TT genotype ( p = 0.027; odds ratio, 0.55). GG genotype was also associated with reduced risk in nonmuscle invasive bladder cancer (NMIBC) and muscle invasive BC ( p = 0.006 and p = 0.049). Cyclin D1 AA genotype was associated with high risk in NMIBC (intermediate risk) stage ( p = 0.015; odds ratio, 4.55). MDM2–Cyclin D1 interaction revealed overall protective effect. The GG genotype of MDM2 also showed a protective effect and high recurrence-free survival in Bacillus Calmette–Guerin-treated NMIBC patients (log rank p = 0.008). MDM2 GG genotype had protective effect and MDM2T309G polymorphism had profound influence in Bacillus Calmette–Guerin-treated UBC patients in the North Indian population. [ABSTRACT FROM AUTHOR]

Background: Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients.Materials and Methods: The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp(312)Asn (G > A), Lys751Gln (A > C), and APEX1 Asp(148)Glu (T > G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods.Results: Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2 (312)AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, P ( c ) = 0.048). Patients with the ERCC2 (312)AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA + AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1-3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys(751)Gln and APEX1 Asp(148)Glu) polymorphisms and risk of recurrence.Conclusion: Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients. [ABSTRACT FROM AUTHOR]

To investigate the association between two Xeroderma pigmentosum group C polymorphism ( XPC Lys939Gln and insertion/deletion PAT −/+ in intron 9) and bladder cancer (BC) susceptibility. Genotyping was performed in 208 BC patients and 245 controls by PCR–RFLP method. XPC PAT +/+ genotype was associated with elevated risk of BC ( p = 0.021, OR = 2.49). XPC Lys939Gln AC + CC genotype was significantly associated with risk in invasive stage of BC ( p = 0.041, OR = 2.52). Haplotype analysis revealed that variant genotypes C of XPC Lys939Gln and + of PAT, C+ were significantly associated with risk of BC ( p = 0.004, OR = 1.70). The CC genotype of Lys939Gln was associated with high risk for recurrence in BCG-treated patients (HR = 3.21, p = 0.036) thus, showing reduced recurrence-free survival (AC + CC/AA = 36/60 months; log rank p = 0.045). Polymorphisms and haplotypes in XPC appear to influence susceptibility to BC risk. The variant C allele at Lys939Gln may be responsible for early recurrence in BCG-treated patients. [ABSTRACT FROM AUTHOR]

Interindividual variation in prostate cancer (PCa) susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the base excision repair and nucleotide excision repair pathway. Two of the common single-nucleotide polymorphisms X-ray repair cross-complementing group 1 ( XRCC1) and Xeroderma pigmentosum group D ( XPD) genes in PCa, which is one of the most common neoplasias in men all over the world, have been studied. In a case–control study of 171 PCa patients and 200 age-matched healthy controls, of similar ethnicity, genotyping was done to determine XPD exon 10 (G23592A), exon 23 (A35931C), and XRCC1 exon 6 (C26304T), exon 9 (G27466A), exon 10 (G23591A) gene polymorphisms by amplification refractory mutation-specific and polymerase chain reaction–restriction fragment length polymorphism methods, respectively. We observed that XPD exon 10 variant AA genotype was associated with increased risk for PCa (adjusted odds ratio [OR] 2.63, 95% confidence interval [95% CI] 1.40–4.92, p = 0.003), and XRCC1 exon 9 GA genotype was also statistically associated with PCa (adjusted OR 2.61, 95% CI 1.53–4.43, p < 0.001). However, XPD exon 23 (A>C) and XRCC1 exon 6 (C>T) and exon 10 (G>A) did not have significantly increased risk for PCa. The haplotype analysis of XPD exon 10 and exon 23 G-C (OR 3.44, 95% CI 2.15–5.51, p < 0.0001) and A-A (OR 4.96, 95% CI 3.08–7.98, p < 0.0001) was associated with a significant increase in PCa risk. Similarly, the combined analysis of XRCC1 exon 6, exon 9, and exon 10 C-G-A (OR 2.93, 95% CI 1.91–4.50, p < 0.001) and C-A-G (OR 2.48, 95% CI 1.62–3.80, p < 0.001) demonstrated statistically significant risk in PCa. XRCC1 exon 9 GA genotype showed protective association with high grade of PCa. Our results suggest a positive association of XRCC1 exon 9 and XPD exon 10 genotypes that may play an important role in the pathophysiology and may modulate the risk of PCa. [ABSTRACT FROM AUTHOR]

Summary: The calcineurin inhibitors (CNIs), cyclosporine (CsA) and tacrolimus (Tac), have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. Both CsA and Tac are well known for highly variable dose requirement in individuals. Although therapeutic drug monitoring, by measuring whole blood C2 level for CsA and T0 level for Tac, is routinely performed to maintain therapeutic blood concentrations, both, allograft rejection due to under-immunosuppression and chronic CNI toxicity due to over-dose occur in day to day clinical practice. Moreover, some patients do not reach target concentrations with recommended starting doses and therefore have an increased risk of under-immunosuppression and acute rejection. The poor correlation between dose, blood concentration and therapeutic response provided the rationale for searching complementary strategies to manage immunosuppressants beyond therapeutic drug monitoring. In recent years, the field of pharmacogenetics with an aim to identify the inherited basis for inter-individual differences in drug response has provided important information concerning the role of drug metabolizing and drug transporter gene variants in response to immunosuppressive therapy in transplant recipients. The key proteins involved in metabolism and transport of CsA and Tac include cytochome P450IIIA (CYP3A), encoded by CYP3A4 and CYP3A5 genes and P-glycoprotein (P-gp), encoded by ABCB1 gene, also known as multidrug resistance 1 gene (MDR1). P-glycoprotein acts as transporter on the surface of enterocytes, hepatocytes and lymohocytes and CYP3A influence pharmacokinetics of drugs by metabolism in the small intestine and liver. Several polymorphisms with a significant impact on protein expression and function have been described. An attractive hypothesis has emerged that such inter-individual differences in CsA/Tac pharmacokinetics may partly result from genetic polymorphisms in genes for drug metabolism and drug transport. The present review therefore, highlights the importance of performing pharmacogenetic analysis of CNIs in renal transplant recipients, taking into account different studies conducted till date, with the ultimate aim of personalized immunosuppressive therapy. [Copyright &y& Elsevier]

End-stage renal disease (ESRD) is associated with the inflammatory state characterized by infiltrating macrophages/lymphocytes, a major source of cytokines and chemokines. This study examined the role of genetic polymorphisms in cytokine, IL-10, and chemokine receptors, CCR2 and CCR5, with susceptibility to ESRD. Polymorphisms in IL-10 (−1082 G/A, PCR-RFLP; −819 C/T, ARMS-PCR), CCR2 ( Val/Ile, PCR-RFLP), and CCR5Δ32 were detected in 184 ESRD patients and 180 controls. Our results demonstrated a significant difference in genotype frequencies of IL-10 −1082G/A ( p < 0.001), IL-10 −819C/T ( p = 0.007), and CCR2Val/Ile ( p = 0.033) between ESRD patients and controls. However, only low-producing genotype AA of IL-10 −1082G/A showed significantly threefold higher risk for all ESRD patients (odds ratio [OR] = 3.164, 95%CI = 1.74–5.72) as well as patients with only inflammatory causes of renal diseases (OR = 2.979, 95%CI = 1.61–5.52). No risk was seen in variant genotype of other genes. The genotypic frequencies of CCR5Δ32 were comparable in patients and controls ( p = 0.203). In haplotype analysis, A-T haplotype (low producer) of IL-10 showed 1.7-fold risk ( p > 0.05). No risk was seen for CCR2 and CCR5 haplotypes. The AA genotype of IL-10 −1082G/A polymorphism was associated with increased susceptibility to ESRD. This study implies the basis for defined antiinflammatory approaches to impede renal disease progression. [ABSTRACT FROM AUTHOR]

Variations in glutathione-S-transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in susceptibility to carcinogens present in cigarette smoke and tobacco. The present study aimed to explore the association of GSTM3 intron 6 polymorphism with susceptibility to prostate cancer (PCa), and to assess risks associated with cigarette smoking, tobacco chewing and alcohol consumption in PCa patients of North India. The study included 135 PCa patients and 169 controls. All subjects were genotyped for 3-bp deletion in intron 6 of GSTM3. Risk of developing prostate cancer associated with GSTM3 AB + BB was 2.5-fold (OR = 2.51, P = 0.028) as compared to AA genotype. Patients who were either smokers and/or had alcohol habits demonstrated a strong association with GSTM3 (AB + BB) genotype (OR = 4.11, P = 0.046; OR = 4.38, P = 0.027, respectively). Our results suggested GSTM3 (AB + BB) genotype to be significantly associated with PCa risk. The risk was even more apparent in case of cigarette smokers and alcohol consumers. [ABSTRACT FROM AUTHOR]

Glutathione S-transferases (GSTs) play an important role in detoxification of various toxic compounds like carcinogens in cigarette smoke and tobacco by conjugating to toxic compounds and inactivating their hazardous effect. Variation in Glutathione S-Transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in cancer susceptibility due to various carcinogens. We therefore, investigated association of GSTM1, GSTM3 and GSTT1 variants with susceptibility to benign prostate hyperplasia (BPH) and cigarette, tobacco chewing and alcohol consumption as confounding factors in 141 BPH and 184 healthy controls. Results showed increased risk for BPH susceptibility in patients with GSTM1 null genotype (OR-2.03, p = 0.013) and smoking (OR-3.12, p = 0.028), tobacco chewing (OR-2.54, p = 0.039) and alcohol habits (OR-3.39, p = 0.010). Null genotype of GSTM1 with cigarette, tobacco and alcohol habits predisposed increased risk for BPH. [ABSTRACT FROM AUTHOR]

The cellular alterations that give rise to cancer initiate changes in cytokine expression. Though IL-6 is known to play a major role in proliferation of tumor cells, IL-4 upregulates androgen receptors and prostate-specific antigen (PSA). The present study was undertaken to evaluate the association of IL-4 and IL-6 gene polymorphisms for the susceptibility to prostate cancer (PCa) risk. Our study included 200 controls and 200 histologically confirmed cases of PCa. Polymorphisms in IL-4 (intron 3, by VNTR analysis) and IL-6 ( −174 G/C, by amplification refractory mutation system, i.e., ARMS-PCR) were genotyped in all the subjects. There was no significant association of IL-4 and IL-6 gene polymorphisms with the risk of PCa. Nevertheless, twofold risk with progression to bone metastasis (odds ratio = 2.09; 95% confidence interval = 1.16–3.75; p = 0.014) in PCa patients was observed. No association with other confounding factors such as PSA level, Gleason score, and lifestyle-associated risk factors like tobacco chewing and cigarette smoking was seen. Our study suggests that an IL-6 gene variant may be associated with prostate progression and bone metastasis. [ABSTRACT FROM AUTHOR]

End-stage renal disease has been associated with an inflammatory state. TGF- β plays a critical role in antiinflammation counteracting inflammatory cytokines, wound healing, and tissue repair. We, therefore, speculated the protective role of TGF- β in renal inflammation rather than inducing fibrosis. Three polymorphisms of TGF- β (713-8delC), i.e., C deletion in intron sequence 8 base prior to exon-5 by PCR-RFLP and codon-10, Leu/Pro, and codon-25, Arg/Pro by Amplification Refractory Mutation System (ARMS-PCR) techniques were genotyped in 228 end-stage renal disease (ESRD) patients and 180 controls. Linkage disequilibrium (LD) and haplotype analysis was performed by Arlequin software. Our data showed positive association between codon-10 polymorphism and ESRD risk ( P < 0.001; OR 4.845, 95% CI 2.57–9.11 for Pro/Pro). However, genotype frequencies were comparable in patients and controls for 713-8delC, while in the case of codon-25, a trend of higher frequency of Pro/Pro genotype (16.2% versus 10.0%) was observed but the P-value did not reach significant ( P = 0.187). Significant association of codon-10 Pro/Pro was observed in patients with glomerulonephritis ( P = 0.001; OR 4.138, 95%CI 2.1–8.13). LD was found significant between codon-10 and 25 ( P = 0.021). Haplotype “Pro-Pro” showed 1.8-fold higher risk for ESRD ( p = 0.003; OR = 1.867, 95%CI = 1.229–2.838). A combined analysis of the effect of TGF- β (codon-10) with C-deletion and codon-25 showed significant difference for TGF- β10-TGF- βC-del ( P = 0.010). In conclusion, the present study suggests that low-producing genotype (Pro/Pro) of TGF- β (codon-10) polymorphism is associated with ESRD. Haplotype analysis further suggested that “Pro-Pro” (low producer) is associated with higher risk for ESRD. Thus, high-producing genotype of TGF- β may be beneficial and may play a potential role in the resolution of renal inflammation. [ABSTRACT FROM AUTHOR]

Earlier studies suggest that end-stage renal disease (ESRD) is associated with inflammatory state and have become a major cause of morbidity and mortality worldwide. This study speculated the role of interleukins (IL)-2, -4, and -6 cytokines gene polymorphism with risk of susceptibility to ESRD. Polymorphism in IL-2 (−330 T/G, polymerase chain reaction [PCR]-restriction fragment length polymorphism), IL-4 (intron-3, variable number of tandem repeat, variable number tandem repeats analysis), and IL-6 (-174 G/C, amplification refractory mutation system, i.e. ARMS-PCR) were genotyped in 193 ESRD patients and 180 controls. Significant difference was observed in genotype frequencies of IL-4 and IL-6 between ESRD patients and control group ( p < 0.001 and p = 0.032, respectively). Patients had higher frequency of homozygous B2B2 genotype (IL-4) than controls (62.7% vs 46.7) and GG genotype of IL-6 (73.1% vs 60.6%). The genotypic frequencies of IL-2 were comparable in patients and controls ( p = 0.102). Significant association of IL-4 was also observed in patients with glomerulonephritis ( p = 0.001). Combination of low IL-4 and high IL-6 genotypes were significantly associated with ESRD showing the highest risk, i.e. >threefolds risk (odds ratio=3.48, 95%CI=1.88–6.42; p < 0.001) among the four possible combinations taking high IL-4 and low IL-6 as reference. Our study suggests that polymorphism in IL-4 and IL-6 may be associated with susceptibility to ESRD. Further, combined analysis implicated a higher risk in ESRD patients with low IL-4 and high IL-6 producing genotypes. This study provided the basis for defined anti-inflammatory approaches to limit renal disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Bladder cancer is a disease characterized by multiple recurrences. Some investigators assume urokinase to be involved in the causation of bladder cancer, although there is lack of genetic evidence. Our aim was to evaluate whether polymorphism of the urokinase gene is associated with transitional cell carcinoma (TCC) of the urinary bladder. Materials and Methods: The study included 100 patients (mean age 62.5 ± 10.2 years) with TCC of urinary bladder and 150 healthy controls (mean age 60 ± 11.5 years) living in the same area. Polymerase chain reaction (PCR)-based restriction analysis was used to identify the C/T polymorphism of the urokinase gene. Genotyping distribution and allelic frequencies between patients and controls were compared. Results and Conclusion: There was a significant difference in the frequency distribution of the urokinase gene 3′-UTR C/T polymorphism in bladder cancer patients as compared to the normal control group (p < 0.05), but no significant difference in allelic frequencies or in carriage rates between bladder cancer patients and normal controls were observed. Our study suggests that urokinase gene polymorphism may be associated with bladder cancer and can thus serve as a potential genetic marker in screening for the possible causes of bladder cancer. Perhaps analysis of patients with superficial bladder TCC and mutated urokinase might help clarify this aspect in large cohort studies in different populations. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D plays an important role in the proliferation and differentiation of normal and malignant cells. In several studies polymorphism in the vitamin D receptor (VDR) gene has been reported to be associated with prostate cancer (CaP). The rationale of this study was to determine the association between the VDR (Fok-I) polymorphism and the risk of developing CaP. Materials and Methods: Polymorphism was detected by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method in 128 CaP patients (age range 43–89 years) and 147 age-matched controls (age range 42–91 years). PCR products were designated as F or f allele according to the absence or presence of a restriction site. Results and Conclusions: The frequencies of the FF, Ff and ff genotypes were 60.9, 35.2 and 3.9% in CaP patients and 42.2, 46.9 and 10.9% in healthy controls, respectively. The genotype frequency distribution between CaP and the control group was statistically significant (p = 0.003). However, the distribution of genotypes was not significantly associated with the Gleason score. The present study thus demonstrates that the FF genotype (or F allele) of the VDR gene plays an important role in determining the risk of CaP and could be postulated as a good candidate genetic marker. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To examine the association of glutathione-S-transferase (GST) gene polymorphisms in patients with sporadic prostate cancer, in a North Indian population, as GSTs are active in detoxifying a wide variety of endogenous or exogenous carcinogens, and genetic polymorphisms of GSTM1, GSTT1 and GSTP1 have been assessed to evaluate the relative risk of various cancers.We assessed 127 patients with prostate cancer and 144 age-matched controls, all from North India. The GSTT1 and GSTM1 null genotypes were identified by multiplex polymerase chain reaction (PCR) in peripheral blood DNA samples, and GSTP1-313 A/G polymorphism was determined by PCR/restriction fragment length polymorphism.There was a significant association in null alleles of the GSTM1 (odds ratio 2.239, 95% confidence interval 1.37–3.65,P = 0.001) and GSTT1 (1.891, 1.089–3.282,P = 0.026) with prostate cancer risk, and in the -313 G alleles (Val) of the GSTP1 gene (2.48, 1.51–4.08,P < 0.001). The combined analysis of these three genotypes showed a further increase in the risks of prostate cancer (7.23, 2.42–22.6,P < 0.001).The GSTP1-313 G polymorphism, and null alleles of GSTM1 and GSTT1, are strong predisposing risk factors for sporadic prostate cancer in North India. [ABSTRACT FROM AUTHOR]

Introduction: The Internet is a massive expanding body of information, which is likely to play a significant role for clinicians and researchers in patient health care across the world. Since its inception in December 1969, the Internet has grown rapidly and is anticipated to expand 100% in the coming next few years. This review illustrates to the urologists many uses of the Internet and hopefully provides a useful resource for professional and personal use. Our aim was to explain the origin, functions, use and impact of the Internet and to provide a list of important website addresses related to urology. Materials and Methods: We undertook a detail scan of the Internet and identified a large number of websites pertaining to urology. The sites were then thoroughly searched to evaluate their potential usefulness to urology clinicians and researchers. Lists of website addresses were then compiled according to specific sub-areas of urology. Results and Conclusion: This overview of the Internet and a compilation of important website addresses is expected to stimulate and instruct urologists in the use of the Web in patient health care delivery and research. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present study was conducted (1) to examine whether the GSTT1- and GSTM1-null genotypes are risk factors for bladder cancer, and (2) to study possible association of tobacco usage and age strata with genotype of these patients. This case control study was undertaken over a period of 19 months and included 106 bladder cancer patients and 182 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. Genotype frequencies among patients and controls were assessed and the association of the genotypes with smoking habits and gender of the patients were statistically determined by the χ2 test. Frequencies of null genotypes in GSTT1 and GSTM1, were 16% (29/182) and 30% (54/182), respectively, in control individuals. The frequencies of GSTT1- and GSTM1-null genotypes in bladder cancer patients were 26% (28/106) and 40% (42/106), respectively. In conclusion, our study demonstrated that the null genotypes of GSTT1 and GSTM1 were substantially at higher risk for bladder carcinoma compared to the normal healthy controls. The GSTT1- and GSTM1-null genotypes did not show significant association with tobacco usage in bladder cancer patients. However, the null genotypes were statistically significant in female relative to male bladder cancer patients. [ABSTRACT FROM AUTHOR]