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Background Although endometriosis may benefit from primary prevention measures, the epidemiological risk factors identified are equivocal. Two genome-wide association studies (GWAS) have been conducted for endometriosis in two different ethnic populations but results are still to be replicated consistently and across various ethnicities. To confirm the association of GWAS-derived susceptibility loci, we conducted a replication Italian case-control study and a meta-analysis. Methods An independent set of 305 laparoscopically-proven endometriosis patients and 2710 controls were recruited. Four SNPs— CDKN2BAS rs1333049, rs7521902 close to WNT4 , rs12700667 in an inter-genic region on 7p15.2 and fibronectin 1 rs1250248—were selected for this association study. Results Rs1333049 risk allele G frequency resulted significantly higher in endometriosis patients compared with controls (OR 1.32, 95% CI 1.11 to 1.57), confirming the role of this locus also in the Caucasian population. The meta-analysis showed that rs7521902 was associated with endometriosis at a genome-wide significance (pmeta=2.23×10−9) while for rs1250248, a genome-wide significant pmeta value of 3.89×10−9 was detected only in association with severe forms. An epistatic interaction between rs7521902 and rs1250248 (OR 1.56, p=1.19×10−2) was found especially in presence of ovarian disease (OR=2.15, p=3.12×10−4). Conclusions We confirm WNT4 , CDKN2BAS and FN1 as the first identified common loci for endometriosis.

The searches for drugs that exhibit antineoplastic activity and regulate blood pressure are among the most prevalent and compelling research activities today. Amazingly, there is ample precedence for the antiproliferative action of vitamin-D-related compounds and their role as endocrine suppressors of renin biosynthesis. We have recently synthesized a number of novel calcitriol analogs of the gemini family and originally selected for further studies an epimeric pair related to 19-nor-calcitriol whose 21-methyl group was replaced by a 5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl group. While maintaining the acceptable calcemic responses, the IC50 concentrations of interferon-gamma release were reduced and the antiproliferative activity and inhibition of renin mRNA expression enhanced. Replacing the geminal methyl groups on the calcitriol-related side chain of these gemini compounds with trideuteriomethyl moieties further boosted the potency in the colon cancer model in mice some 10-fold, reduced NMU-induced breast cancer carcinogenesis in rats and decreased the IC(50) values for renin mRNA inhibition into the pM range.

Objective: To test the possibility of using transgenic knockout mice in the study of endometriosis and to investigate specific immunologic aspects of the disease. Design: Experimental blinded study. Setting: Academic research center. Animal(s): Thirty-two mice with experimentally induced endometriosis. Intervention(s): Endometriosis was induced in 8 β 2 -microglobulin–deficient BALB/c mice and 7 wild-type BALB/c controls. Similarly, endometriosis was induced in 8 interleukin-12–deficient C57BL/6 mice and in 9 wild-type C57BL/6 controls. Main Outcome Measure(s): Weight and surface area of endometriotic lesions. Result(s): Total weight and surface area of endometriotic lesions was markedly lower in β 2 -microglobulin–deficient BALB/c mice than in wild-type BALB/c controls. A slight but statistically insignificant increase in total weight and surface area of lesions was observed in interleukin-12–deficient C57BL/6 mice compared to wild-type C57BL/6 controls. Conclusion(s): Knockout transgenic mice can be used successfully for the study of endometriosis; however, in these animals, the redundancy of the immunologic cytokine-mediated regulatory mechanisms may lead to compensation from the remaining genome. Results from β 2 -microglobulin–deficient mice support the critical role of the immune system in the pathogenesis of the disease.

Macrophage-derived chemokine (MDC) has been reported to inhibit different HIV-1 strains in activated peripheral blood mononuclear cells (T cell blasts), although other investigators have not confirmed these findings. Here we demonstrate that MDC inhibits the replication of CCR5-dependent (R5) HIV-1BaLin monocyte-derived macrophages (MDM), but not in T cell blasts, although with variable potency depending on donor variability. Analysis of HIV-1BaLproviral DNA synthesis in MDM indicated that the suppressive effect of MDC did not involve inhibition of early events such as entry or reverse transcription. Finally, an inverse correlation was observed between the levels of endogenous MDC secreted by uninfected MDM of different donors and the efficiency of different HIV strains, including two primary isolates with different coreceptor usage, to replicate in these cells. Thus, MDC represents an example of a chemokine inhibiting HIV replication in macrophages acting at one or more postentry levels in the virus life cycle.