XRCC1 Deficiency Sensitizes Human Lung Epithelial Cells to Genotoxicity by Crocidolite Asbestos and Libby Amphibole

Background: Asbestos induces DNA and chromosomal damage, but the DNA repair pathways protecting human cells against its genotoxicity are largely unknown. Polymorphisms in XRCC1 have been associated with altered susceptibility to asbestos-related diseases. However, it is unclear whether oxidative DNA damage repaired by XRCC1 contributes to asbestos-induced chromosomal damage

Hernia fibroblasts lack β-estradiol induced alterations of collagen gene expression

BACKGROUND: Estrogens are reported to increase type I and type III collagen deposition and to regulate Metalloproteinase 2 (MMP-2) expression. These proteins are reported to be dysregulated in incisional hernia formation resulting in a significantly decreased type I to III ratio. We aimed to evaluate the β-estradiol mediated regulation of type I and type III collagen genes as well as MMP-2 gene expression in fibroblasts derived from patients with or without history of recurrent incisional hernia disease. We compared primary fibroblast cultures from male/female subjects without/without incisional hernia disease. RESULTS: Incisional hernia fibroblasts (IHFs) revealed a decreased type I/III collagen mRNA ratio. Whereas fibroblasts from healthy female donors responded to β-estradiol, type I and type III gene transcription is not affected in fibroblasts from males or affected females. Furthermore β-estradiol had no influence on the impaired type I to III collagen ratio in fibroblasts from recurrent hernia patients. CONCLUSION: Our results suggest that β-estradiol does not restore the imbaired balance of type I/III collagen in incisional hernia fibroblasts. Furthermore, the individual was identified as an independent factor for the β-estradiol induced alterations of collagen gene expression. The observation of gender specific β-estradiol-dependent changes of collagen gene expression in vitro is of significance for future studies of cellular response

A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA

Abstract Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or “early” form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3′ end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or “late” phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.</jats:p

A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA

Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or “early” form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3′ end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or “late” phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.</jats:p

Histology of the vaginal wall in women with pelvic organ prolapse: a literature review.

INTRODUCTION AND HYPOTHESIS: The pathophysiology of pelvic organ prolapse (POP) is incompletely understood. The purpose of this study is to describe the current knowledge about histology of the vaginal wall and its possible involvement in the pathogenesis of pelvic organ prolapse. METHODS: Eligible studies were selected through a MEDLINE search covering January 1986 to December 2012. The research was limited to English-language publications. RESULTS: Investigations of changes in the vaginal tissue that occur in women with genital prolapse are currently still limited and produced contrary results. The heterogeneity of the patients and the control groups in terms of age, parity and hormonal status, of the localization of biopsies and the histological methods as well as the lack of validation of the quantification procedures do not allow clear and definitive conclusions to be drawn. CONCLUSIONS: This review shows that current knowledge of the histological changes observed in women with POP are inconclusive and relatively limited. More studies are needed in this specific field to better understand the mechanisms that lead to POP