Association of Common Single Nucleotide Polymorphisms of Candidate Genes with Gallstone Disease: A Meta-Analysis.

Numerous studies have investigated the relationship between various candidate gene polymorphisms and gallbladder stone disease (GSD) across ethnic populations; however, the results are often inconsistent. This meta-analysis aims to comprehensively evaluate the influence of common ABCG8 T400K, ABCG8 D19H, ABCG8 C54Y, ApoB100 EcoRI, ApoB100 XbaI, ApoE HhaI, CETP TaqI, CYP7A1 Bsa, LRPAP1 I/D and TNF-α A308G polymorphisms on the risk of gallbladder stone disease. 33 Full-text articles with 9250 cases and 12,029 healthy controls (total 21,279 subjects) were analyzed using the RevMan software (V5.1) and the Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) a Random-effects model was applied. Begg's funnel plots, Fail-safe number, Egger's regression intercept and Begg and Mazumdar rank correlation tests were performed for the potential publication bias and sensitivity analysis. The studies were also sub-grouped into European and non-European groups to find out role of ethnicity, if any, on GSD risk. Studies included in quantitative synthesis were ABCG8 T400K rs4148217 (cases/controls, n = 671/1416) (4 studies), ABCG8 D19H rs11887534 (n = 1633/2306) (8 studies), ABCG8 C54Y rs4148211 (n = 445/1194) (3 studies), ApoB100 EcoRI rs1042031 (n = 503/390) (4 studies), ApoB100 XbaI rs693 (n = 1214/1389) (9 studies), ApoE HhaI rs429358 (n = 1335/1482) (12 studies), CETP TaqI rs708272 (n = 1038/1025) (5 studies), CYP7A1 Bsa rs3808607 (n = 565/514) (3 studies), LRPAP1 I/D rs11267919 (n = 849/900) (3 studies), TNF-α A308G rs1800629 (n = 997/1413) (3 studies). The combined results displayed significant association of ABCG8 D19H (GC + CC) [OR with 95%CI = 2.2(1.7-2.8); p < 0.00001], ABCG8 Y54C (GA + GG) [OR with 95%CI = 0.65(0.5-0.9); p = 0.01]. APOB100 EcoRI (GG vs. AA) [OR with 95%CI = 0.51(0.3-0.9); p = 0.05], (GG vs. GA) [OR with 95%CI = 0.6(0.4-0.9); p = 0.04], (GA + AA) [OR with 95%CI = 0.6(0.4-0.9); p = 0.006]. APOB Xba I (X- vs. X+) [OR with 95%CI = 0.53(0.3-0.8); p = 0.006. APOE Hha I (E4/E4 vs. E3/E3) [OR with 95%CI = 3.5(1.1-14.9); p = 0.04] and LRPAP1 I/D (ID + II) [OR with 95%CI = 1.27(1.0-1.6); p = 0.03] with the GSD risk. It was found that ABCG D19H was significantly associated with GSD in both European and Non-European populations. While APOB XbaI and LRPAP1 I/D markers were associated with gallstone disease only in Non- European population. Additionally, APOE HhaI and APOB 100 ECoRI were found to be associated with GSD only in European population. The results of quantitative synthesis suggest that the ABCG8 D19H polymorphism was associated with the increased risk of GSD in both European and Non-European populations, APOE Hha I and LRPAP1 I/D polymorphisms were associated with the increased risk of GSD in European and Non-European population respectively. However, no association was found in ABCG8 T400K, CETP Taq1, CYP7A1 Bsa and TNF-A308G polymorphisms with Gallstone Disease.

Survivin: A molecular biomarker in cancer.

Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death, is highly expressed in most cancers and is associated with a poor clinical outcome. Survivin has consistently been identified by molecular profiling analysis to be associated with high tumour grade cancers, different disease survival and recurrence. Polymorphisms in the survivin gene are emerging as powerful tools to study the biology of the disease and have the potential to be used in disease prognosis and diagnosis. The survivin gene polymorphisms have also been reported to influence tumour aggressiveness as well as survival of cancer patients. The differential expression of survivin in cancer cells compared to normal tissues and its role as a nodal protein in a number of cellular pathways make it a high target for different therapeutics. This review discusses the complex circuitry of survivin in human cancers and gene variants of survivin, and highlights novel therapy that targets this important protein.

Raising cut-off value of prostate specific antigen (PSA) for biopsy in symptomatic men in India to reduce unnecessary biopsy.

BACKGROUND & OBJECTIVES: The characteristics of prostate specific antigen (PSA) for trans-rectal ultrasonography guided prostate biopsy in men with lower urinary tract symptoms (LUTS) are not well defined. This study was carried out to analyse the threshold of PSA for biopsy in symptomatic men in India. METHODS: From January 2000 to June 2011, consecutive patients who had digital rectal examination (DRE) and PSA testing done for LUTS were included in this study. PSA was done with ELISA technique. Patients with acute or chronic prostatitis, prostatic abscess, history of surgery on prostate within the previous three months and patients on 5α-reductase inhibitors or on urethral catheter were excluded. RESULTS: Of the 4702 patients evaluated, 70.9 per cent had PSA of less than 4 ng/ml and 29.1 per cent had PSA of more than 4 ng/ml. Of these, 875 men with a mean age of 65.72±7.4 (range 50-75 yr) had trans rectal ultrasonography (TRUS) guided biopsy. Twenty five men had biopsy at PSA level of <4 ng/ml due to positive DRE, 263 at 4.1-10ng/ml, 156 at 10.1-20 ng/ml and 431 at >20 ng/ml. Positive predictive value of PSA in ranges of 4.1-10, 10.1-20, >20 ng/ml was 15.2, 24 and 62.6 per cent, respectively with negative DRE. PSA cut-off to do biopsy was derived by ROC curve as 5.82 ng/ml for all the men. When the subjects were further stratified on the basis of DRE findings, a cut-off of 5.4 ng/ml was derived in men with normal DRE. INTERPRETATION & CONCLUSIONS: A cut-off for biopsy in symptomatic men with negative DRE could safely be raised to 5.4 ng/ml, which could avoid subjecting 10 per cent of men to undergo unnecessary biopsy.

Associations between IL-1RA polymorphisms and small intestinal bacterial overgrowth among patients with irritable bowel syndrome from India.

BACKGROUND: Low-grade inflammation (controlled by pro and anti-inflammatory molecules), induced by gut microbes in patients with small intestinal bacterial overgrowth (SIBO), may be associated with irritable bowel syndrome (IBS). Polymorphisms of IL-RA gene (anti-inflammatory) was evaluated in IBS and healthy subjects (HS); small intestinal mucosal IL-1α and ß levels (pro-inflammatory) in relation to the presence of SIBO were evaluated in a subset of patients. METHODS: Two hundred and twenty-one IBS patients and 273 age- and gender-matched HS were included. Exactly 209 of 221 patients (Rome III) and 273 HS were genotyped (PCR) for IL-1RA polymorphism. Mucosal IL-1α and ß levels (pg/mg of biopsy) were estimated (ELISA) in 82/221 patients with and without SIBO (≥10(5)  CFU/mL upper gut aspirate bacteria). KEY RESULTS: Genotype 1/1 (IL-1RA over-producer) was less frequent among patients than controls (p = 0.007); genotypes 1/3 (p = 0.012, OR = 3.301, 95% CI = 1.31-8.35) and 2/3 (both under-producers; p = 0.009, OR = 7.703, 95% CI = 1.66-35.82) were commoner among IBS. Fifteen of 82 (18.3%) patients had SIBO. Levels of IL-1α and ß were higher among patients with SIBO than without (IL-1α: 35.4 [20.1-66.8] vs 25.5 [4.2-65.3], p < 0.001; IL-1ß: 206.8 [133.5-365.9] vs 93.1 [25.5-197.7], p < 0.001) and those with bloating than without (p = 0.012; p = 0.015). IL-1ß was higher among patients with Bristol stool type 6 than those with type 1-2 (p = 0.002) and type 3-5 (p = 0.007). CONCLUSIONS & INFERENCES: Polymorphisms 1/1 (IL-1RA over-producer) was infrequent and 1/3 and 2/3 (under-producers) frequent among IBS. Increased IL-1α and ß levels were associated with SIBO. Increased IL-1ß level was predominantly associated with bloating and loose stools (Bristol type 6).

Influence of ABCB1 genetic variants in breast cancer treatment outcomes.

BACKGROUND: Transportation of anticancer drugs such as anthracyclines across the membrane is regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 (ABCB1). Polymorphisms in the ABCB1 gene (1236C>T, 2677G>T/A, 3435C>T) have been found to be associated with intrinsic and acquired cross resistance to these anticancer drugs. Therefore, the aim of this study is to evaluate the influence of ABCB1 gene polymorphisms in breast cancer treatment outcomes in terms of response and toxicity. METHOD: Response to neo-adjuvant chemotherapy was evaluated in 100 patients while grade 2-4 toxicity was followed in 207 patients, who had undergone FEC/FAC chemotherapy. Genotyping for ABCB1 polymorphisms was done by PCR-RFLP. Chi square and logistic regression analyses were used to calculate Odd's ratio using SPSS ver 17.0. A meta analysis was also performed using Comprehensive Meta Analysis Ver 2. RESULTS: In response evaluation, 1236C>T polymorphism was significantly associated with treatment response for CT genotype [OR=5.17(1.3-20.2), P=0.018] and in dominant model (CC vs CT+TT) [OR=4.63(1.25-17.0), P=0.021]. In the toxicity group, the T allele of 1236C>T was associated with grade 2-4 tocxicity [OR 1.48(1.00-2.20), P=0.049] and the association was also significant in the recessive model [OR 1.88(1.05-3.39), P=0.033]. For other two SNPs 2677G>T/A and 3435C>T no association was seen with either treatment response or grade 2-4 toxicity. In meta analysis, no overall association was found. CONCLUSION: In our study, significant association was seen for ABCB1 1236C>T polymorphism with treatment response. The meta analysis did not show overall association with treatment outcomes.

Association of death receptor 4, Caspase 3 and 5 gene polymorphism with increased risk to bladder cancer in North Indians.

PURPOSE: Perturbed apoptosis due to missense alterations in candidate tumor suppressor gene Death receptor 4 (DR4) and in caspases (Casp) lead to deregulated cell proliferation and cancer predisposition. Some data indicate that normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. To test our proposal we examined whether six single nucleotide polymorphisms (SNPs) of the DR4 and Casp3, 5 genes contrive the risk of bladder cancer (BC) in a North Indian population. MATERIALS AND METHODS: Genotyping was performed in 200 BC patients and 225 controls by Allele-specific PCR and by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In DR4 Arg141His, BC patients having AA genotype (p = 0.036; OR = 2.51. In Casp5Leu13Phe G > C, significant association was observed with GC (p = 0.025; OR = 1.78) and also in GC + CC (p = 0.026; OR = 1.68). C allele carriers in Casp5Ala90Thr T > C showed low risk of BC (p = 0.036; OR = 0.83). While in Casp3 G > A, AG (p = 0.003; OR = 2.11), GG (p = 0.050; OR = 2.18), G allele (p < 0.001; OR = 1.85) and its carrier AG + GG (p = 0.001; OR = 2.12) have shown significant BC risk. Significant association between DR4 Ala228Glu polymorphism and smoking was observed in BC risk. Haplotype analysis demonstrated that DR4 (Thr209Arg-Arg141His-Ala228Glu) C-G-C is associated with 1.8 folds (OR = 1.85; p = 0.033) risk. GG genotype of Casp3 G > A polymorphism showed increased risk of recurrence (p = 0.009; HR = 5.20). CONCLUSION: This study provided new support for the association of DR4 and Casp3, 5 in BC development, the tumorigenic effect of which was observed to be more enhanced in case of smoking exposure.

Do polymorphisms in XRCC4 influence prostate cancer susceptibility in North Indian population?

OBJECTIVE: XRCC4 play a key role in nonhomologous end-joining repair pathway. Alterations in DNA repair gene have been shown to reduce DNA repair capacity thereby inflicting carcinogenesis. METHODS: In a hospital-based case-control study, 192 prostate cancer (PCa) and 224 healthy controls. They were genotyped for XRCC4 G-1394T (rs6869366), intron 3 (rs28360071) intron 7 (rs28360317) and intron 7 (rs1805377), polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. RESULT: Carriers of GG genotype of rs6869366 were at reduced risk. Del/Del of rs28360071 and 28360317 demonstrated increased risk. The haplotype analysis was observed to be associated with a significant increase in PCa risk. Combined genotype of rs6869366, rs28360071 and rs1805377 have shown significant risk with high Gleason grade. CONCLUSION: Our results suggested that the variant genotype of XRCC4 rs28360071 and rs28360317 and haplotype analysis may be associated with PCa risk.

Association of interferon-gamma +874A polymorphism with the risk of developing cervical cancer in north-Indian population.

OBJECTIVE: Interferon gamma (IFN-gamma) is a pro-inflammatory cytokine playing a pivotal role in both innate and adaptive immune responses. A single nucleotide polymorphism located in the first intron of the human IFN-gamma gene can influence the secretion of cytokine. Therefore, we aimed to investigate the association of IFN-gamma T/A gene polymorphism with the risk of cervical cancer. DESIGN: Case-control study. SETTING: Uttar Pradesh State in India. SAMPLE: Two hundred cases with histologically proven cancer of the cervix and healthy controls (n = 230), age and ethnicity matched were recruited in this study. METHODS: Genotyping was performed for bi-allelic +874 (T/A) polymorphism of IFN-gamma by amplification refractory mutation system method. MAIN OUTCOME MEASURES: Low producer IFN-gamma +874 AA genotype was associated with high risk for cervical cancer, which further modulated the increased risk in tobacco users. RESULTS: IFN-gamma AA genotype which is low producer of IFN-gamma was associated with increased risk of cervical cancer (OR = 2.43, P = 0.003). Allele A was at 1.54-fold increased risk of cervical cancer (OR=1.54, P = 0.002). The AA genotype showed statistically significant risk with high stage (III + IV) of cervical cancer (OR = 4.99, P = 0.001). In tobacco users, AA genotype showed significantly increased susceptibility to cervical cancer (OR = 5.08, P = 0.010). CONCLUSION: Variation in IFN-gamma +874 AA genotype because of ethnicity in north-Indian population may represent an important susceptibility biomarker for cervical cancer risk as well as other diseases and should be explored further.

Impact of chemokine receptor CCR2 and CCR5 gene polymorphism on allograft outcome in North Indian renal transplant recipients.

The CC chemokine receptors, CCR2 and CCR5, contribute to the trafficking of leucocytes into the sites of the immune response in transplanted kidney. Therefore, the inter-individual differences in CCR2 and CCR5 gene expression, due to single-nucleotide polymorphism, have the potential to influence various immune responses within the graft, eventually deciding the allograft outcome. In this study, we genotyped 296 North Indian renal transplant recipients and 277 healthy controls for CCR2V64I and CCR5-Delta32 polymorphisms by sequence-specific primers and restriction fragment length polymorphism and examined their association with allograft outcome. The frequency of CCR2+/64I (heterozygous) and CCR2-64I/64I (homozygous mutant) genotype were comparatively higher in non-rejecters when compared with transplant recipients experiencing one or more than one rejection episode (20.4% versus 8.2%), thereby resulting in a significantly reduced risk of allograft rejection (OR = 0.331, P = 0.026). The Kaplan-Meier curve also suggested higher mean time for the first rejection episode in CCR2-64I allele carriers (32.83 +/- 1.36 months) when compared with CCR2+/+ recipients (28.09 +/- 0.93 months, log P = 0.027). The CCR5-Delta32 variant had no profound effect on allograft outcome. In conclusion, our study confirmed CCR2-64I allele to be associated with reduced risk for allograft rejection in North Indian transplant recipients influencing allograft outcome.

Nonprogressive juvenile-onset spinal muscular atrophy: A clinico-radiological and CAG repeat study of androgen receptor gene.

BACKGROUND: Occurrence of nonprogressive juvenile-onset spinal muscular atrophy (SMA) predominantly in males suggests a possibility of X-linked disorder but there is no such report addressing this problem. AIMS: To evaluate CAG repeat expansion of androgen receptor (AR) gene in patients with nonprogressive juvenile-onset SMA. SETTING: Tertiary medical teaching institute. SUBJECTS AND METHODS: Patients fulfilling the diagnostic criteria of nonprogressive juvenile-onset SMA were included. Detailed clinical evaluation and pedigree charting were done in all. Nerve conduction study, electromyography and cervical spinal MRI were carried out. From peripheral venous blood, DNA was separated and AR gene CAG repeat exon polymorphism was assayed using polymerase chain reaction (PCR) in conjugation with genotyping and Gene scan soft ware. Number of CAG repeats was compared with normal controls. RESULTS: 25 patients with nonprogressive juvenile-onset SMA from 24 families were included and their mean age was 22.2 years. Age at the time of disease onset ranged between 15 and 30 years with a mean duration of illness 2.6 years. None of the patients had testicular atrophy or gynecomastia. C7-T1 myotomal wasting and weakness although was unilateral to begin with but became bilateral in 16 and 4 more patients had evidences of subclinical involvement of the other side as revealed by EMG. Spinal MRI revealed cord atrophy at C6-8 vertebral level in 16 patients. CAG repeat study of AR gene was carried out in 16 patients. The number of CAG repeats in patients ranged between 15 and 39 (median 21) which were within the normal range. CONCLUSION: Abnormal CAG repeat expansion of AR gene is not found in patients with nonprogressive juvenile-onset SMA.

Interleukin-1 receptor antagonist gene polymorphism and obesity: A pilot study from north India.

The main adverse consequences of excess bodyweight are cardiovascular disease, type II diabetes, and several cancers, IL-1Ra serum concentration has been reported earlier to increase in human obesity and it is therefore assumed that the polymorphism of IL-1Ra may influence cytokine production. We designed this study to investigate whether the IL-1Ra polymorphism was associated with obesity. A total number of 103 individuals; 19 lean (BMI<25 Kg/m(2)), 51 overweight (BMI 25-29.9 Kg/m(2)) and 33 obese (BMI≥30.0 Kg/m(2)) were enrolled in this study. Genotyping was performed using a polymerase chain reaction PCR amplification of the intron-2 fragment harboring a variable number of tandem repeat (VNTR) nucleotide sequences 86 pb of tandem repeat. The PCR products were separated on 2% agarose gel. Statistical analysis was performed using SPSS software (version 11.5). We found no significant difference in genotype and allele frequencies between the three groups; lean vs. overweight and lean vs. obese (p=0.323; 0.202; 0.123 and 0.068 resp). However, an increased risk for obesity had a propensity to be higher in those having genotype II/II. This genotype has been reported to be a 'high producer' of IL-1Ra. Although no statistically significant relationship between IL-1Ra polymorphism and BMI was observed, however, a trend towards an increase of allele(*)II in overweight and obese group was observed. This may suggest that IL-1Ra appears to be induced by inflammatory stimuli as well as obesity-associated factors. This is relatively a pilot study: but nevertheless, may assist in identifying the pathophysiological cause for obesity.

Interleukin-1beta and receptor antagonist (IL-1Ra) gene polymorphisms and the prediction of the risk of end-stage renal disease.

Cytokines play an important role in the pathogenesis of kidney disease and its progression to end-stage renal disease (ESRD). Inflammation is regulated by the genes of the interleukin 1 (IL-1) gene cluster. Therefore, it was hypothesized that a polymorphism in this gene cluster may be associated with the risk of ESRD. Polymorphisms in the IL-1 gene cluster were examined in a cohort of 222 ESRD patients and 206 controls of similar ethnicity. These individuals were genotyped for IL-1 beta (promoter -511 and exon-5 +3953) genes and a variable number of tandem repeats (VNTR) in the IL-1 receptor antagonist gene (IL-1Ra). There was significant difference in genotype frequencies between ESRD patients and control group for IL-1beta (promoter region and exon-5) and IL-1Ra gene polymorphism (p < 0.001, 0.006 and < 0.001, respectively). A significant difference was observed in IL-1Ra for 1/1 (410/410) and 1/2 (410/240) genotypes, and the risk for ESRD was higher in those carrying the 1/1 genotype (p = 0.014, OR = 1.692, and p < 0.001, OR = 0.163). Also identified was a novel, rare allele of a single copy of 86 bp in ESRD patients as compared with the controls. The haplotype 'T-E2-1' frequency distribution between patients and controls revealed greater than threefold risk (p = 0.001, OR = 3.572, 95% CI = 1.589-8.032). Genetic linkage between the IL-1beta promoter region and exon-5 and between the IL-1beta promoter and IL-1Ra of IL-1 gene demonstrated a strong association among the variants in controls (D' = 0.42, p < 0.001, and D' = 0.39, p=0.001). Thus, the three polymorphisms within the IL-1 cluster are associated with ESRD. This finding is perhaps one of the strongest associations between genotype and ESRD reported, and it suggests that the IL-1 gene cluster affects the risk of development of ESRD.

Internet resources and biochemistry.

The Internet is a massive expanding body of information, which is likely to play a significant role for clinical Biochemists and researchers in patient health care across the world. This expansion has been matched by an increase in the number of individuals using the Internet. 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 Biochemists many uses of the Internet and hopefully provides a useful resource for professional and personal use. To explain the origin, functions, use and impact of the Internet and to provide a list of important website addresses related to Biochemistry. We undertook a detail scan of the Internet and identified a large number of websites pertaining to Biochemistry. The sites were then thoroughly searched to evaluate their potential usefulness to Biochemists, clinicians and researchers. This overview of the Internet and a compilation of important web-site addresses are expected to stimulate and inculcate Biochemists in the use of the web in teaching, training and research.

Effect of antibiotics on Oxalobacter formigenes colonization of human gastrointestinal tract.

BACKGROUND AND PURPOSE: Oxalobacter formigenes is a bacterium residing in the human gastrointestinal tract that degrades oxalate and reduces its availability for absorption. This bacterium is assumed to be antibiotic sensitive, and repeated antibiotic therapies could eradicate it. The aim of the present study was to determine the differences in the colonization by O. formigenes of individuals who had been on antibiotics for at least 5 days at the time of sample collection and individuals who had not taken antibiotics for at least 3 months. PATIENTS AND METHODS: Stool samples were collected from 80 individuals without stone disease (35 with and 45 without antibiotic consumption) and 100 patients with stone disease (20 with and 80 without antibiotic consumption). Oxalobacter formigenes was detected by a polymerase chain reaction-based method, and the presence/absence of O. formigenes was correlated with urinary oxalate concentrations. RESULTS: Lower percentages of individuals without stone disease and with stone disease who were consuming antibiotics had O. formigenes colonization than individuals without antibiotic consumption. Urinary oxalate concentrations were higher in the individuals without O. formigenes than in colonized individuals. CONCLUSION: Our observations confirm a direct association between antibiotic consumption and absence of O. formigenes. Absence of intestinal O. formigenes could represent a pathogenic factor in calcium oxalate urolithiasis when antibiotics are prescribed generously.

Microsatellite instability as prognostic marker in bladder tumors: a clinical significance.

BACKGROUND: Carcinoma of urinary bladder is one of the leading causes of death in India. Successful treatment of bladder cancer depends on the early detection & specific diagnostic approaches. In the present study, microsatellite instability (MSI) has been evaluated as a prognostic marker in patients with superficial urinary bladder cancer in lower urinary tract for determining risk of recurrence. METHODS: A total of 44 patients with bladder tumors diagnosed with Transitional Cell Carcinomas [TCC] from lower urinary tract were selected for the study. Tumors were staged and graded according to AJCC-UICC (1997) classification and patients were followed with cystoscopy as per the protocol. Polymerase chain reaction (PCR) was done to amplify microsatellite sequences at mononucleotide BAT - 26, BAT - 40, TGFbeta RII, IGFIIR, hMSH3, BAX and dinucleotide D2S123, D9S283, D9S1851 and D18S58 loci in blood (control) and tumor DNA. PCR products were separated on 8% denaturing polyacrylamide gel and visualized by autoradiography. RESULTS: MSI was observed in 72.7% of tumors at BAT - 26, BAT - 40, D2S123, D9S283, D9S1851 and D18S58 loci. Good association of MSI was seen with tumor stage and grade. MSI - High (instability at > 30% of loci) was frequently observed in high stage (40.6%) and high grade (59.4%) tumors. Of 24 tumors of Ta-T1 stage with different grades, 11 (9/18 high grade and 2/6 low grade tumors) recurred in the mean duration of 36 months. MSI positivity was significantly high in patients who had one or more recurrences (p = 0.02 for high grade and 0.04 for low grade tumors). CONCLUSIONS: MSI may be an independent prognostic marker for assessing risk of recurrence in superficial tumors irrespective of the grade. Further studies on progression would help in stratifying the patients of T1G3 for early cystectomy vs bladder preservation protocol.

Free radical injury and antioxidant status in patients with benign prostate hyperplasia and prostate cancer.

Reactive oxygen species and other free radicals are known to be the mediators of phenotypic and genotypic changes that lead from mutation to neoplasia. There are some primary antioxidants such as glutathione peroxidase (GPx), glutathione S-transferases (GSTs) and reduced glutathione, which protect against callular and molecular damage caused by the reactive oxygen metabolites (ROMs). The present study was conducted to determine the level of malondialdehyde (MDA), as an index of lipid peroxidation, along with the GPx, GSTs activities and level of reduced glutathione in 45 prostate cancer (PC) patients, 55 benign prostate hyperplasia (BPH) patients as compared to the controls. Significant higher levels of MDA and GSTs activities in the serum, (P<0.005) and significant lower levels of reduced GSH concentration and GPx activity in blood haemolysates (P<0.05) of PC and BPH patients were observed as compared to the controls. The relatively higher GSTs activity and low level of reduced GSH may be due to the response of increased reactive oxygen metabolites production in the blood. The higher MDA and lower GPx activities may be inadequate to detoxify high levels of H(2)O(2) into H(2)O leading to the formation of the(*)OH radical followed by MDA. This result hypothesizes that oxidant-antioxidant imbalance may be one of the major factor responsible for the development of prostate cancer and benign prostate hyperplasia.

Polymorphism of GSTM1 and GSTT1 genes in prostate cancer: a study from North India.

BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. The genetic polymorphisms of GSTM1 and GSTT1 genes have been studied earlier to evaluate the relative risk of various cancers. AIM, SETTING AND DESIGN: In the present study, we examined the association of the GSTM1 and GSTT1 gene polymorphisms with sporadic prostate cancer patients in north Indian population. MATERIAL AND METHODS: This case control study was undertaken over a period of 24 months and included 103 prostate cancer patients and 117 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. STATISTICAL ANALYSIS: Difference in genotype prevalence and association between case and control group were assessed by the Chi square and Fisher Exact tests. RESULTS: Frequencies of null genotypes in GSTT1 and GSTM1, was 11% (13/117) and 30% (35/117) respectively in control individuals. The frequencies of GSTT1 and GSTM1 null genotypes in prostate cancer patients were 34% (35/103) and 53% (55/103) respectively. CONCLUSION: Our study demonstrates that the null genotypes of GSTT1 and GSTM1 are substantially at higher risk for prostate carcinoma as compared to the normal healthy controls. The GSTT1 and GSTM1 null genotypes did not show significant association with tobacco usage in prostate cancer patients. However, the null genotypes were significantly stratified in 50-60 year-old patients when incidence of prostate cancer is high.

Study of interleukin-1 receptor antagonist (IL-1Ra) gene polymorphism in healthy individuals from Northern India.

Cytokines play a key role in immune responses and inflammation. IL-1Ra is a naturally occurring structural variant of IL-1 that competitively inhibits receptor binding of IL-1. We have investigated the polymorphism in intron-2 of the interleukin-1 receptor antagonist gene in North Indian population. This genetic variation has been of great interest due to its possible association with a variety of human diseases primarily of epithelial and endothelial cell origin such as urolithiasis etc. Allele frequencies of the IL-1Ra polymorphism vary among different populations but there is no data till date reported from India. The present study was carried out to determine the IL-1Ra gene Polymorphism in 165 normal unrelated individuals from North India. We obtained an allelic frequency of 63.94, 30.61, 4.55, 0.90 for A, B, C and D allele and percentage of genotypes AA, BB, CC, DD, A/B, A/C, A/D and B/C were 49.7, 18.2, 2.42, 0.60, 24.2, 3.63, 0.60, 0.60 respectively. Our results suggested that the frequency and distribution of this polymorphism in India is substantially different from other populations and ethnic groups.

Evaluation of microsatellite instability in tumors of central nervous system: A pilot study.

Microsatellite instability (MSI) characterized by alterations at simple repetitive genomic sequences is a distinct mechanism in tumorogenesis. Central nervous system (CNS) tumors have been reported to exhibit MSI, indicator of defective mismatch repair system with controversies. The present study was undertaken to examine sixteen primary brain and two spinal tumors for MSI at six mono: BAT-26, BAT-40, BAX, TGFßRII, IGFIIR and hMSH3 and four dinucleotide loci: D2S123, D9S1851, D9S283 and D18S58. Polymerase chain reaction (PCR) was done to amplify tumour and blood DNA, analyzed on 8% denaturing Polyacrylamide gel followed by autoradiography. Out of 18 CNS tumors examined, 39% exhibited MSI at BAT-26, BAT-40, D9S1851, D9S283 and D18S58 in tumoral DNA. However, no alteration was observed at BAX, TGFßRII, IGFIIR, hMSH3 and D2S123 loci. Low incidence of MS1-high hypothesizes role of MSI in evolution of CNS tumors but not in cancer initiation or progression.

Re-evaluation of reading frame-shift hypothesis in Duchenne and Becker muscular dystrophy.

The reading frame hypothesis has been proposed to explain the molecular basis of two allelic forms of muscular dystrophies, Duchenne/Becker muscular dystrophy (D/BMD). To evaluate the hypothesis in Indian D/BMD patients, we analyzed deletion of dystrophin exons in 147 DMD and 19 BMD patients. Our studies showed deviation of more than 30% from the reading frame hypothesis in DMD patients (47/147). The present results implicate a need to reevaluate the reading frame hypothesis.