BackgroundBeclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival. Beclin 1 mapped to human chromosome 17q21. It is widely expressed in normal mammary epithelial cells. Although down-regulated expression with mono-allelic deletions of beclin 1 gene was frequently observed in breast tumors, whether there was other regulatory mechanism of beclin 1 was to be investigated. We studied the expression of beclin 1 and explored the possible regulatory mechanisms on its expression in breast tumors.Methods20 pairs of tumors and adjacent normal tissues from patients with sporadic breast invasive ductal cancer (IDCs) were collected. The mRNA expression of beclin 1 was detected by real-time quantitative RT-PCR. Loss of heterozygosity (LOH) was determined by real-time quantitative PCR and microsatellite methods. The protein expression of beclin 1, p53, BRCA1 and BRCA2 was assessed by immunohistochemistry. CpG islands in 5' genomic region of beclin 1 gene were identified using MethylPrimer Program. Sodium bisulfite sequencing was used in examining the methylation status of each CpG island.ResultsDecreased beclin 1 mRNA expression was detected in 70% of the breast tumors, and the protein levels were co-related to the mRNA levels. Expression of beclin 1 mRNA was demonstrated to be much higher in the BRCA1 positive tumors than that in the BRCA1 negative ones. Loss of heterozygosity was detected in more than 45% of the breast tumors, and a dense cluster of CpG islands was found from the 5' end to the intron 2 of the beclin 1 gene. Methylation analysis showed that the promoter and the intron 2 of beclin 1 were aberrantly methylated in the tumors with decreased expression.ConclusionsThese data indicated that LOH and aberrant DNA methylation might be the possible reasons of the decreased expression of beclin 1 in the breast tumors. The findings here shed some new light on the regulatory mechanisms of beclin 1 in breast cancer.
There is evidence that immunoglobulin (Ig) E antibody may be a critical component of protective immunity against Schistosoma mansoni and S. haematobium reinfection. In the present study, 555 individuals aged 3-67 years infected with S.japonicum received praziquantel treatment before the transmission season commenced; 45 d later, blood samples from 265 individuals who had no S. japonicum egg in their stool were examined by enzyme-linked immunosorbent assay for specific isotypic antibodies. Single, non-conditional logistic regression analysis showed that exposure intensity, age, soluble egg antigen (SEA)-IgE, SEA-IgM and soluble adult worm antigen-IgG4 were relevant to reinfection; multiple, non-conditional logistic regression analysis showed that exposure intensity was still a significant factor for reinfection while the SEA-IgE antibody level was associated with resistance to reinfection with S. japonicum, with a protective index of 2.00. It is suggested that this population in an area endemic for schistosomiasis japonica exhibits acquired immunity.
Key Points Question Is metformin associated with improved outcomes among women with polycystic ovarian syndrome undergoing in vitro fertilization? Findings This meta-analysis of 12 randomized clinical trials, which collectively included 1123 women, found that metformin treatment was associated with a decreased risk of ovarian hyperstimulation syndrome among women with polycystic ovarian syndrome undergoing in vitro fertilization but had no association with clinical pregnancy or live birth rates in the total population studied. However, among women with a body mass index of 26 or greater, metformin treatment was associated with an improved clinical pregnancy rate. Meaning The findings of this study suggest that metformin treatment should be carefully considered for women with polycystic ovarian syndrome undergoing in vitro fertilization and may be more preferred among women with a body mass index of 26 or greater.
Primary ovarian insufficiency (POI) leads to infertility and premature menopause in young women. The genetic etiology of this disorder remains unknown in most patients. Using whole exome sequencing of a large Chinese POI pedigree, we identified a heterozygous 5 bp deletion inducing a frameshift in BNC1, which is predicted to result in a non-sense-mediated decay or a truncated BNC1 protein. Sanger sequencing identified another BNC1 missense mutation in 4 of 82 idiopathic patients with POI, and the mutation was absent in 332 healthy controls. Transfection of recombinant plasmids with the frameshift mutant and separately with the missense mutant in HEK293T cells led to abnormal nuclear localization. Knockdown of BNC1 was found to reduce BMP15 and p-AKT levels and to inhibit meiosis in oocytes. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility, significantly increased serum follicle-stimulating hormone, decreased ovary size and reduced follicle numbers, consistent with POI. We report haploinsufficiency of BNC1 as an etiology of human autosomal dominant POI.
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