Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan–Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20–34) compared with 34 years (95% CI: 30–40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04–2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28–37) compared with 41 years (95% CI: 32–48, HR=1.44, 95% CI: 1.08–1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28–34) compared with 44 years of age (95% CI: 38–53) in wild-type individuals (HR=2.48, 95% CI: 1.47–4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.     

Correlates of Substance Misuse,Transactional Sex,and Depressive Symptomatology Among Partnered Gay,Bisexual and Other Men Who Have Sex with Men in South Africa and Namibia

AIDS and Behavior - Despite having some of the world’s highest rates of HIV, there is a lack of knowledge on correlates of transmission risk among gay, bisexual and other men who have sex...     

Convergent ethical issues in HIV/AIDS,tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics,Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban,South Africa

Background  

Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges.     

Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene

De novo activating mutations in the calcium-sensing receptor (CASR) gene are a common cause of sporadic isolated hypoparathyroidism. Here, we describe a family in which two affected siblings were found to be heterozygous for a novel F788L mutation in the fifth transmembrane domain encoded by exon 7 of the CASR. Both parents and the third sibling were clinically unaffected and genotypically normal by direct sequencing of their leukocyte exon 7 PCR amplicons. However, the mother was revealed to be a mosaic for the mutation by sequence analysis of multiple subclones as well as denaturing HPLC of the CASR exon 7 leukocyte PCR product. A functional analysis of the mutation was performed by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. The mutant CASR was expressed at a similar level as the wild type. The F788L mutant produced a significant shift to the left relative to the wild-type CASR in the MAPK response to increasing extracellular calcium concentrations. This is the first report of mosaicism for an activating CASR mutation and suggests that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely.     

A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis

OBJECTIVE: To establish linkage and replicate the association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis (JIA). METHODS: Three hundred twenty-one Caucasian simplex families from the UK were genotyped for polymorphisms of MIF using SNaPshot ddNTP primer extension, or by a fluorescently labeled primer method, and capillary gel electrophoresis. The functional significance of the promoter polymorphisms was studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. RESULTS: MIF was linked and associated with JIA (P = 0.0016). Specifically, a 2-point promoter haplotype, CATT(7)-MIF-173*C, was found to be transmitted in excess (38 transmitted: 21 not transmitted) in the JIA patients. Conditional extended transmission disequilibrium test and pairwise extended transmission disequilibrium test predicted functional interaction between the 2 polymorphic positions. The interaction of the CATT repeat with MIF-173*G/C was found to be specific to the cell type. CONCLUSION: Replication of an association and linkage of MIF with JIA has been established. Functional interaction between the polymorphic positions on the linked haplotype has also been shown. The molecular mechanism of this interaction is currently being investigated.     

Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis

OBJECTIVE: To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA). METHODS: Denaturing high-performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety-two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single-nucleotide polymorphism (SNP) identified in the 5'-flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. RESULTS: A tetranucleotide repeat CATT((5-7)) beginning at nucleotide position -794 and 3 SNPs at positions -173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA-specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the JIA patients for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele had an increased risk of JIA (34.8% versus 21.6%) (odds ratio 1.9, 95% confidence interval 1.4-2.7; P = 0.0002). Furthermore, the MIF-173* G and C variants resulted in altered expression of MIF in a cell type-specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF-173*C allele (P = 0.04). CONCLUSION: The -173-MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type-specific regulation of MIF, which may be central to understanding its role in inflammation.     

Defining the role of prolactin as an invasion suppressor hormone in breast cancer cells

Prolactin hormone (PRL) is well characterized as a terminal differentiation factor for mammary epithelial cells and as an autocrine growth/survival factor in breast cancer cells. However, this function of PRL may not fully signify its role in breast tumorigenesis. Cancer is a complex multistep progressive disease resulting not only from defects in cell growth but also in cell differentiation. Indeed, dedifferentiation of tumor cells is now recognized as a crucial event in invasion and metastasis. PRL plays a critical role in inducing/maintaining differentiation of mammary epithelial cells, suggesting that PRL signaling could serve to inhibit tumor progression. We show here that in breast cancer cells, PRL and Janus-activated kinase 2, a major kinase involved in PRL signaling, play a critical role in regulating epithelial-mesenchymal transformation (EMT), an essential process associated with tumor metastasis. Activation of the PRL receptor (PRLR), achieved by restoring PRL/JAK2 signaling in mesenchymal-like breast cancer cells, MDA-MB-231, suppressed their mesenchymal properties and reduced their invasive behavior. While blocking PRL autocrine function in epithelial-like breast cancer cells, T47D, using pharmacologic and genetic approaches induced mesenchymal-like phenotypic changes and enhanced their invasive propensity. Moreover, our results indicate that blocking PRL signaling led to activation of mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) and transforming growth factor-beta/Smad signaling pathways, two major prometastatic pathways. Furthermore, our results indicate that following PRL/JAK2 inhibition, ERK1/2 activation precedes and is required for Smad2 activation and EMT induction in breast cancer cells. Together, these results highlight PRL as a critical regulator of epithelial plasticity and implicate PRL as an invasion suppressor hormone in breast cancer.     

Short and long-term post-operative outcomes of duodenum preserving pancreatic head resection for chronic pancreatitis affecting the head of pancreas: a?systematic review and meta-analysis

Background

To evaluate the short and long term outcomes of duodenum preserving pancreatic head resection (DPPHR) procedures in the treatment of painful chronic pancreatitis.

Methods

A systematic literature search was performed to identify all comparative studies evaluating long and short term postoperative outcomes (pain relief, morbidity and mortality, pancreatic exocrine and endocrine function).

Results

Five published studies fulfilled the inclusion criteria including 1 randomized controlled trial comparing the Beger and Frey procedure. In total, 323 patients underwent surgical procedures for chronic pancreatitis, including Beger (n = 138) and Frey (n = 99), minimal Frey (n = 32), modified Frey (n = 25) and Berne''s modification (n = 29). Two studies comparing the Beger and Frey procedure were entered into a meta-analysis and showed no difference in post-operative pain (RD = −0.06; CI −0.21 to 0.09), mortality (RD = 0.01; CI −0.03 to 0.05), morbidity (RD = 0.12; CI −0.00 to 0.24), exocrine insufficiency (RD = 0.04; CI −0.10 to 0.18) and endocrine insufficiency (RD = −0.14 CI −0.28 to 0.01).

Conclusion

All procedures are equally effective for the management of pain for chronic pancreatitis. The choice of procedure should be determined by other factors including the presence of secondary complications of pancreatitis and intra-operative findings. Registration number CRD42015019275. Centre for Reviews and Dissemination, University of York, 2009.