CYP1B1 gene polymorphisms have higher risk for endometrial cancer,and positive correlations with estrogen receptor alpha and estrogen receptor beta expressions

The estradiol metabolites by CYP1B1 received particular attention because of their causative role in malignant transformation of endometrium. We hypothesize that polymorphisms of CYP1B1 gene can predict higher incidence of endometrial cancer. To test this hypothesis, the genetic distributions of six different CYP1B1 gene polymorphisms were investigated, by sequence-specific PCR and direct DNA sequencing, in 113 Japanese endometrial cancer patients and 202 healthy controls. We also investigated whether the expression of estrogen receptors (ERalpha and ERbeta), progesterone receptor, and androgen receptor genes are influenced by the CYP1B1 genotypes in endometrial cancer. The results of our study demonstrated that the distributions of CYP1B1 genotypes at codons 119 and 432 were significantly different between endometrial cancer patients and healthy normal controls. The relative risks of 119T/T and 432G/G in endometrial cancer were calculated as 3.32 and 2.49 compared with wild-types. The 119T/T showed significant correlation for positivities of ERalpha and ERbeta. The 432G/G also showed weak correlations for ERalpha positivity. Other loci, intron 1, codon 48, and codon 449 were not different between endometrial cancer patients and healthy normal control. This is the first report that demonstrates that the rare polymorphisms at codons 119 and 432 of CYP1B1 gene have higher risk for endometrial cancer, and positive correlations with ERalpha and ERbeta expressions in endometrial cancer.     

Comparing glaucomatous optic neuropathy in primary open angle and chronic primary angle closure glaucoma eyes by optical coherence tomography

PURPOSE: To comparatively evaluate the optic nerve head (ONH) using Optical Coherence Tomography (OCT) in normal subjects, primary open angle glaucoma (POAG) and chronic primary angle closure glaucoma (CPACG) patients. METHODS: A total of 138 normal eyes (138 subjects) and 139 glaucomatous eyes (139 patients), were evaluated in this cross-sectional observational study. The ONH was imaged on OCT using the optic disc scan. Disc area, cup area, rim area, vertical integrated rim area (VIRA), rim volume (horizontal integrated rim volume), average cup/disc ratio, horizontal and vertical cup/disc ratios, and cup volume were evaluated. Additionally, cup depth and slope of the temporal ONH were also measured. These ONH parameters were compared between normal subjects and eyes with early POAG and CPACG. Correlation of mean deviation and corrected pattern standard deviation on full threshold 30-2 perimetry, with measured ONH parameters was carried out amongst the two groups. RESULTS: There was a significant difference in disc area (2.38 +/- 0.5, 2.77 +/- 0.4, 2.62 +/- 0.4 mm(2), p < 0.01), cup area (0.88 +/- 0.6, 1.99 +/- 0.7, 1.60 +/- 0.7 mm(2), p < 0.01), rim area (1.48 +/- 0.4, 0.86 +/- 0.4, 0.96 +/- 0.4 mm(2), p < 0.01), VIRA (1.64 +/- 0.3, 1.23 +/- 0.3, 1.22 +/- 0.4 mm(2), p < 0.01), rim volume (0.34 +/- 0.2, 0.1 +/- 0.1, 0.15 +/- 0.1 mm(3), p < 0.01) and cup/disc ratio (0.36 +/- 0.2, 0.69 +/- 0.1, 0.63 +/- 0.2, p < 0.01) in normal vs POAG vs CPACG eyes respectively. A comparison of ONH parameters between early POAG and early CPACG showed a significant difference in the disc area (2.85 +/- 0.3, 2.57 +/- 0.4 mm(2), p = 0.03), cup area (2 +/- 0.5, 1.34 +/- 0.5 mm(2), p < 0.01), rim area (0.96 +/- 0.4, 1.21 +/- 0.5 mm(2), p = 0.009), rim volume (0.12 +/- 0.1, 0.18 +/- 0.1 mm(3), p < 0.01) and cup/disc ratio (0.67 +/- 0.1, 0.53 +/- 0.2, p < 0.01). The parameters with the highest area under the receiver operator characteristic (AROC) curves for differentiating normal and early POAG eyes were rim volume, 0.89, VIRA, 0.84, and rim area, 0.76. The AROC values (normal vs early CPACG eyes) were 0.75 for rim volume, 0.72 for VIRA, and 0.66 for rim area. CONCLUSION: OCT may serve as a useful diagnostic modality in distinguishing a normal optic disc from a glaucomatous one, even in the early stages of glaucoma. Rim volume, VIRA and rim area can be used to differentiate normal from early glaucoma (both early POAG and CPACG), and most efficiently early POAG eyes. CPACG eyes have smaller discs, a smaller cup, smaller cup/disc ratio, and a larger rim area when compared with eyes with POAG.     

Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA.

PURPOSE: We hypothesized that combined methylation analysis of Wnt antagonist genes could serve as a panel of biomarkers for diagnosis, staging, and prognosis in renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: Samples (n = 62) of RCC and corresponding normal renal tissue (NRT) were analyzed using methylation-specific PCR for methylation of six Wnt antagonist genes (sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of RCC detection, the methylation score (M score) for multigene methylation analysis was developed. Receiver operator characteristic curve analysis was used to determine the optimal sensitivity/specificity of the M score. In addition, the M score was compared with the clinicopathologic outcome. Thirty-three serum DNA samples were also used to investigate the methylation status of Wnt antagonist genes. RESULTS: The methylation levels of all Wnt antagonists were significantly higher in RCC than in NRT. In multivariate regression analysis, the methylation level of sFRP-1 was a significant independent predictor of RCC, whereas for sFRP-2 and sFRP-4 there was a trend toward significance as independent predictors. The M score of Wnt antagonist genes was significantly higher in RCC than in NRT. Overall, the M score had a sensitivity of 79.0% and a specificity of 75.8% (area under the curve, 0.808) as a diagnostic biomarker. In addition, the M score could significantly distinguish grade, pT category, M category, and overall survival of RCC patients. The M score was independent of age and gender in predicting overall survival by the Cox proportional hazards model. In RCC patients, 72.7% of the methylation-specific PCR results had identical methylation in samples of tumor and serum DNA. No serum DNA in normal controls showed aberrant methylation of the Wnt antagonist genes. In addition, the methylation status of Wnt antagonist genes in serum DNA was significantly correlated with tumor grade and stage. CONCLUSIONS: This is the first report showing that M score analysis of Wnt antagonist genes can serve as an excellent epigenetic biomarker panel for detection, staging, and prognosis of RCC using serum DNA.     

Deletion of chromosome 11p15, p12, q22, q23-24 loci in human prostate cancer

Loss of heterozygosity (LOH) on chromosome 11 is frequently altered in various epithelial cancers. The present study was designed to investigate LOH on chromosome 11 in microdissected samples of normal prostatic epithelium and invasive carcinoma from the same patients. For this purpose, DNA was extracted from the microdissected normal and tumor cells of 38 prostate cancers, amplified by polymerase chain reaction PCR and analyzed for LOH on chromosome 11 using 9 different polymorphic DNA markers (D11S1307, D11S989, D11S1313, D11S898, D11S940, D11S1818, D11S924, D11S1336 and D11S912). LOH on chromosome 11 was identified in 30 of 38 cases (78%) with at least one marker. Four distinct regions of loss detected were: 1) at 11p15, at loci between D11S1307 and D11S989; 2) at 11p12, on locus D11S131 (11p12); 3) at 11q22, on loci D11S898, D11S940 and D11S1818; and 4) at 11q23-24, on loci between D11S1336 and D11S912. We found 25% of the tumors with LOH at 11p15; 39% had LOH at 11p12; 66% had LOH at 11q22; and 47% had LOH at 11q23-24. These deletions at 11p15, 11p12, 11q22 and 11q23-24 loci were not related to the stage or grade of the tumor. Int. J. Cancer 72:283–288, 1997. © 1997 Wiley-Liss, Inc.     

A review on convenient synthesis of substituted coumarins using reuseable solid acid catalysts

Due to growing concern about chemicals and their impact on the environment, cleaner reaction conditions are needed to be incorporated into chemical synthetic procedures. Recently, the use of heteropolyacid catalysts, mainly reuseable solid acid catalysts, has gained a leading role in organic synthesis due to their environmental and economic considerations and industrial utilization. The high catalytic activity, moisture sensitivity, reusability and inexpensive makes solid supported reagents attractive substituents to conventional Lewis acids. Nowadays synthesis of coumarins and their derivatives has attracted considerable attention from organic and medicinal chemists for many years as a large number of natural products contain this heterocyclic nucleus. In continuation with our investigations into the synthesis of substituted coumarins and due to several advantages of heterogeneous catalysts viz. cost-effective, no side products, high yield of desired products and no toxic waste material, here we report a new approach for the synthesis of substituted coumarins using solid acid catalysts.

Due to growing concern about chemicals and their impact on the environment, cleaner reaction conditions are needed to be incorporated into chemical synthetic procedures.     

Post-penetrating keratoplasty glaucoma: Risk factors, management and visual outcome

Purpose: To evaluate the incidence, associated risk factors, graft status and treatment modalities in patients with post-penetrating keratoplasty glaucoma. Methods: A retrospective analysis of 747 consecutive penetrating keratoplasties was undertaken at a tertiary eye care centre. The frequency of post-penetrating keratoplasty glaucoma was determined and correlated with the pre-operative corneal diagnosis, lens status and associated surgeries performed during penetrating keratoplasty. The response to antiglaucoma therapy (i. e. medical, surgical or cyclo-destructive procedures) and graft outcome was also evaluated. Results: The incidence of post-penetrating keratoplasty glaucoma was 10.6% (79/747). Pre-operative corneal diagnosis of adherent leucomas was significantly associated with the development of postoperative glaucoma. Post-penetrating keratoplasty glaucoma was significantly higher in aphakes (odds ratio (OR) 6.6; confidence interval (CI) 3.81–11.69) compared with phakic or pseudophakic eyes. Associated vitrectomy (OR 2.32; CI 1.16–4.73) and anterior segment reconstruction (OR 3.31; CI 1.43–7.72) were other high-risk factors. Most patients responded to medical therapy (41/79; 51.9%), whereas filtering surgery and cyclodestructive procedures were performed in 29.1 (23/79) and 19% (15/79) of eyes, respectively. Despite clear grafts in 39 eyes (49.4%), visual acuity of 6/18 or better was achieved in 15 eyes (18.9%). Conclusions: A high incidence of post-penetrating keratoplasty glaucoma occurs in eyes with adherent leucomas. Anterior vitrectomy and associated surgeries further accentuate the risk. Anti-glaucoma threrapy may not achieve optimum visual outcome, despite a clear graft.     

CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility.

PURPOSE: The chemokine CXCL12 and its receptor CXCR4 have been found to be associated with cancer metastasis. A single nucleotide polymorphism of CXCL12 G801A has been described and is regarded as a target for cis-acting factor that has the ability to up-regulate CXCL12 expression. Currently, there are no reports investigating the role of CXCL12 G801A polymorphism in prostate cancer (PC). EXPERIMENTAL DESIGN: We genotyped CXCL12 G801A and p53Arg72Pro in 167 PC patients and 167 age-matched healthy subjects. Genotyping was done with PCR-RFLP and confirmed by direct DNA sequencing. To investigate the effect of the CXCL12 G801A polymorphism on CXCL12 and CXCR4 expression, immunohistochemistry was done in genotyped PC tissues. RESULTS: A significant increase in the GA + AA genotype of the CXCL12 G801A polymorphism was observed in PC patients compared with healthy controls. The frequency of CXCL12 AA genotype was significantly higher in a group of patients with lymph node metastasis (23%) compared with those without metastasis (7%). The frequency of CXCL12 expression in AA + GA genotype carriers was significantly higher than that in GG genotype carriers. Among the carriers with CXCL12 GA + AA genotypes, CXCR4 expression was also significantly higher compared with those with the GG genotype. Moreover, among the groups with both CXCL12- and CXCR4-positive staining, the frequency of the CXCL12 GA + AA genotype was high. Although we did not find a significant relationship between the frequency of the Arg/Pro + Pro/Pro genotype of p53 Arg72Pro and susceptibility in PC, there was a combined effect of CXCL12 GA + AA genotype and the p53 72Arg/Pro + Pro/Pro genotype on the frequency of PC. These results indicate that the p53 codon 72 polymorphism may interact with CXCL12 G801A. CONCLUSIONS: This is the first report showing that CXCL12 G801A polymorphism may be a risk factor for PC. Moreover, this study suggests that this polymorphism can be an important marker for detecting microinvasion and PC metastasis.