Premature ovarian failure (POF) is a major side effect of chemotherapy in young cancer patients. To develop pharmaceutical agents for preserving fertility, it is necessary to understand the mechanisms responsible for chemotherapy-induced follicle loss. Here, we show that treatment with cisplatin, a widely used anticancer drug, depleted the dormant follicle pool in mouse ovaries by excessive activation of the primordial follicles, without inducing follicular apoptosis. Moreover, we show that co-treatment with the antioxidant melatonin prevented cisplatin-induced disruption of the follicle reserve. We quantified the various stages of growing follicles, including primordial, primary, secondary, and antral, to demonstrate that cisplatin treatment alone significantly decreased, whereas melatonin co-treatment preserved, the number of primordial follicles in the ovary. Importantly, analysis of the PTEN/AKT/FOXO3a pathway demonstrated that melatonin significantly decreased the cisplatin-mediated inhibitory phosphorylation of PTEN, a key negative regulator of dormant follicle activation. Moreover, melatonin prevented the cisplatin-induced activating phosphorylation of AKT, GSK3β, and FOXO3a, all of which trigger follicle activation. Additionally, we show that melatonin inhibited the cisplatin-induced inhibitory phosphorylation and nuclear export of FOXO3a, which is required in the nucleus to maintain dormancy of the primordial follicles. These findings demonstrate that melatonin attenuates cisplatin-induced follicle loss by preventing the phosphorylation of PTEN/AKT/FOXO3a pathway members; thus, melatonin is a potential therapeutic agent for ovarian protection and fertility preservation during chemotherapy in female cancer patients.

We examined CMT1A duplication of 17p11.2-p12, mutations of PMP22, MPZ (P0), GJB1 (Cx32), EGR2 and NEFL genes in 57 Korean families with patients diagnosed as having Charcot-Marie-Tooth (CMT) disease. The CMT1A duplication was present in 53.6% of 28 CMT type 1 patients. In the 42 CMT families without CMT1A duplication, 10 pathogenic mutations were found in 9 families. The 10 mutations were not detected in 105 healthy controls. Seven mutations ( c.318delT (p.Ala106fs) in PMP22, c.352G>A (p.Asp118Asn), c.449-1G>T (3'-splice site), c.706A>G (p.Lys236Glu) in MPZ, c.408T>C (p.Val136Ala), c.502T>C (p.Cys168Arg) in GJB1, and c.1001T>C (p.Leu334Pro) in NEFL) were determined to be novel. The mutation frequencies of PMP22 and MPZ were similar to those found in several European populations, however, it appeared that mutations in GJB1 are less frequent in East Asian CMT patients than in European patients. We described the identified mutations and phenotype-genotype correlations based on nerve conduction studies.

By analysis of a large number of subjects and a more specific patient selection, we showed the first genetic evidence that MTHFR C677T, MS A2756G and MTRR A66G genotypes were independently associated with male infertility. Each SNP of the three enzymes may have a different impact on the folate cycle during spermatogenesis.

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Objective— MicroRNAs play a role in atherosclerosis-related diseases, such as cerebrovascular or cardiovascular disease. However, the effect of miR-146a , miR-149 , miR-196a2 , and miR-499 polymorphisms on stroke and silent brain infarction (SBI) susceptibility has not been reported. Methods and Results— Using polymerase chain reaction-amplified DNA, microRNA polymorphisms were analyzed in 678 patients with ischemic stroke, 373 patients with SBI, and 553 control subjects. The miR-146a C>G polymorphism and miR-146a G/ -149 T/ -196a2 C/ -499 G allele combination was significantly associated with ischemic stroke prevalence. For SBI prevalence, there were no statistically significant genetic markers. However, some allele combinations were associated with increased SBI incidence (C-T-C-G and G-T-T-A of miR-146a / -149 / -196a2 / -499 ). In subgroup analyses, miR-146a C>G increased stroke risk in female, normotensive, and nondiabetic groups. There were significant combined effects between microRNA polymorphisms and homocysteine/folate levels on ischemic stroke and SBI prevalence. Conclusion— The miR-146a G allele and miR-146a G/ -149 T/ -196a2 C/ -499 G allele combination were associated with ischemic stroke pathogenesis. The combined effects between microRNA polymorphisms and homocysteine/folate levels may contribute to stroke and SBI prevalence.

MicroRNAs (miRNAs) are small, 18- to 22-nucleotide non-coding RNAs that regulate target gene expression. Although recent studies focused on various diseases that harbor the miR-146aC>G (rs2910164), 149C>T (rs2292832), 196a2C>T (rs11614913), and 499A>G (rs3746444) polymorphisms, the role of miRNA genetic variants in colorectal cancer is still unknown. The present study aimed to evaluate the role of four miRNA polymorphisms in patients with colorectal cancer. We enrolled 446 colorectal cancer patients and 502 control subjects from the Korean population. We found a significantly increased colorectal cancer risk with the miR-196a2CC genotype compared with the TT/CT genotype (AOR = 1.50; 95% CI = 1.11-2.04; P = 0.01; FDR-P = 0.04). In the stratified analyses, we observed both weak and strong association data. We found stronger associations of the miR-196a2 variants in the non-diabetic and rectal cancer groups than other stratified groups. Our data suggest that the miRNA variants could affect the development of colorectal cancer in the Korean population.

PurposeAngiogenesis plays an important role in the growth, progression, and metastasis of tumors. Vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival in several cancers. We investigated the present case-control study to determine whether there is an association between the VEGF 936C > T polymorphism and stomach cancer.Patients and MethodsThe association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene with stomach cancer development was evaluated in a case-control study of 154 Korean stomach cancer patients. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.ResultsOur results revealed significant association of T allele-bearing genotypes with increased risk for stomach cancer development. Genotype frequencies of the VEGF 936C > T polymorphisms were significantly different between patient and control groups (CT, AOR: 2.007, 95% CI: 1.277 - 3.156, TT, AOR: 4.790, 95% CI: 1.174 - 19.539, CT + TT, AOR: 2.147, 95% CI: 1.382 - 3.337). When stratified by gender and age, genotype frequencies were significantly different for stomach cancer in women and in patients younger than 55 years (in women, CT, OR: 3.049, 95% CI: 1.568 - 5.930, CT+TT, OR: 3.132, 95% CI: 1.638 - 5.990; in < 55 years, CT, OR: 3.306, 95% CI: 1.413 - 7.732, CT + TT, OR: 3.967, 95% CI: 1.729 - 9.104). In addition, this association partially remained in cases with intestinal and diffuse-type stomach cancer.ConclusionOur present study suggests that the VEGF 936C > T polymorphism is a susceptibility factor for stomach cancer, at least in Korean.

The MTHFR 677TT genotype may be a genetic risk factor for male infertility, especially with severe OAT and non-obstructive azoospermia in unexplained infertile males.