Linkage Analysis in Autoimmune Addison’s Disease: NFATC1 as a Potential Novel Susceptibility Locus

BackgroundAutoimmune Addison’s disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered.MethodsDNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach.ResultsIn a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10^-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene.ConclusionThis linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.     

Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: Preliminary results of a double-blind randomized study of the eortic breast cancer cooperative group

We investigated whether estrogenic recruitment could enhance the antitumor effect of chemotherapy in 165 patients with advanced breast cancer, presumably sensitive to hormonal treatments (ER + and/or PgR + lesions). The therapeutic regimen consisted of: (a) estrogenic suppression by aminoglutethimide 1 g/day + hydrocortisone 40 mg/day; surgical castration in premenopausal patients only; (b) FAC (5FU 500 mg/m²; ADM 50 mg/m²; CPA 500 mg/m²) for 3 weeks; (c) following randomization, exactly 24h prior to chemotherapy, patients had to take 1 tablet of either placebo (PL) or 50 μg ethinylestradiol (EE2). Tolerance, responses, time to progression and median survival were identical in both groups. Thus, EE2 before chemotherapy did not contribute to the efficacy of this particular therapeutic regimen, which yielded an overall response rate of 64%. We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice, so that this approach remains experimental.     

Umbilical cord blood mesenchymal stem cells protect amyloid-β42 neurotoxicity via paracrine

AIM:To understand the neuroprotective mechanism of human umbilical cord blood-derived mesenchymal stem cells(hUCB-MSCs) against amyloid-β42(Aβ42) exposed rat primary neurons.METHODS:To evaluate the neuroprotective effect of hUCB-MSCs,the cells were co-cultured with Aβ42-exposed rat primary neuronal cells in a Transwell apparatus.To assess the involvement of soluble fac-tors released from hUCB-MSCs in neuroprotection,an antibody-based array using co-cultured media was conducted.The neuroprotective roles of the identified hUCB-MSC proteins was assessed by treating recombi-nant proteins or specific small interfering RNAs(siRNAs) for each candidate protein in a co-culture system.RESULTS:The hUCB-MSCs secreted elevated levels ofdecorin and progranulin when co-cultured with rat pri-mary neuronal cells exposed to Aβ42.Treatment with recombinant decorin and progranulin protected from Aβ42-neurotoxicity in vitro.In addition,siRNA-mediat-ed knock-down of decorin and progranulin production in hUCB-MSCs reduced the anti-apoptotic effects of hUCB-MSC in the co-culture system.CONCLUSION:Decorin and progranulin may be involved in anti-apoptotic activity of hUCB-MSCs exposed to Aβ42.