Protease-activated receptor 2 signalling promotes dendritic cell antigen transport and T-cell activation in vivo

Deficiency of protease-activated receptor-2 (PAR2) modulates inflammation in several models of inflammatory and autoimmune disease, although the underlying mechanism(s) are not understood. PAR2 is expressed on endothelial and immune cells, and is implicated in dendritic cell (DC) differentiation. We investigated in vivo the impact of PAR2 activation on DCs and T cells in PAR2 wild-type (WT) and knockout (KO) mice using a specific PAR2 agonist peptide (AP2). PAR2 activation significantly increased the frequency of mature CD11chigh DCs in draining lymph nodes 24 hr after AP2 administration. Furthermore, these DCs exhibited increased expression of major histocompatibility complex (MHC) class II and CD86. A significant increase in activated (CD44+ CD62−) CD4+ and CD8+ T-cell frequencies was also observed in draining lymph nodes 48 hr after AP2 injection. No detectable change in DC or T-cell activation profiles was observed in the spleen. The influence of PAR2 signalling on antigen transport to draining lymph nodes was assessed in the context of delayed-type hypersensitivity. PAR2 WT mice that were sensitized by skin-painting with fluorescein isothiocyanate (FITC) to induce delayed-type hypersensitivity possessed elevated proportion of FITC+ DCs in draining lymph nodes 24 hr after FITC painting when compared with PAR2 KO mice (0·95% versus 0·47% of total lymph node cells). Collectively, these results demonstrate that PAR2 signalling promotes DC trafficking to the lymph nodes and subsequent T-cell activation, and thus provides an explanation for the pro-inflammatory effect of PAR2 in animal models of inflammation

Alta proporción de mutaciones fundadoras de BRCA1/2 en familias hispanas con cáncer de mama/ovario de Colombia

8 páginasIn South America, a high proportion of the population is of Hispanic origin with an important representation in Colombia. Since nothing is known about the contribution of BRCA1 and BRCA2 germline mutations to hereditary breast/ovarian cancer in the Hispanic population from Colombia, we conducted the first study of 53 breast/ovarian cancer families from this country. Comprehensive BRCA mutation screening was performed using a range of techniques, including DHPLC, SSCP, and PTT, followed by DNA sequencing analysis. Thirteen deleterious germline mutations (24.5%) were identified in 53 families, comprising eight in BRCA1 and five in BRCA2. The two recurrent BRCA1 mutations, 3450 delCAAG and A1708E, accounted for 100% of all BRCA1 mutations identified in this cohort and the recurrent 3034 delACAA BRCA2 mutation for 40% of all BRCA2 mutations. Haplotype analyses suggested that each of these mutations has arisen from a common ancestor. The prevalence of BRCA1 or BRCA2 mutations was 50% in multiple case breast cancer families, and was 33% for the breast-ovarian cancer families. Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Colombia. The spectrum of mutations differed completely to that previously reported in Hispanic families of predominantly Mexican origin from Southern California [1] suggesting that specific genetic risk assessment strategies for the different Hispanic populations in South America and in the United States need to be developedEn América del Sur una alta proporción de la población es de origen hispano con una importante representación en Colombia. Dado que no se sabe nada sobre la contribución de las mutaciones de la línea germinal BRCA1 y BRCA2 al cáncer de mama/ovario hereditario en la población hispana de Colombia, realizamos el primer estudio de 53 familias con cáncer de mama/ovario de este país. Se realizó una detección exhaustiva de mutaciones BRCA utilizando una variedad de técnicas, incluidas DHPLC, SSCP y PTT, seguidas de un análisis de secuenciación de ADN. Se identificaron trece mutaciones nocivas de la línea germinal (24,5%) en 53 familias, ocho en BRCA1 y cinco en BRCA2. Las dos mutaciones recurrentes de BRCA1, 3450 delCAAG y A1708E, representaron el 100 % de todas las mutaciones de BRCA1 identificadas en esta cohorte y la mutación recurrente 3034 delACAA BRCA2 representó el 40 % de todas las mutaciones de BRCA2. Los análisis de haplotipos sugirieron que cada una de estas mutaciones surgió de un ancestro común. La prevalencia de mutaciones BRCA1 o BRCA2 fue del 50% en familias con casos múltiples de cáncer de mama y del 33% para las familias con cáncer de mama y ovario. Nuestros hallazgos muestran que las mutaciones BRCA representan una proporción sustancial del cáncer de mama/ovario hereditario en Colombia. El espectro de mutaciones difería completamente del reportado previamente en familias hispanas de origen predominantemente mexicano del sur de California [1], lo que sugiere que es necesario desarrollar estrategias específicas de evaluación de riesgos genéticos para las diferentes poblaciones hispanas en Sudamérica y Estados Unidos

High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia

Q2Q1225-232In South America, a high proportion of the population is of Hispanic origin with an important representation in Colombia. Since nothing is known about the contribution of BRCA1 and BRCA2 germline mutations to hereditary breast/ovarian cancer in the Hispanic population from Colombia, we conducted the first study of 53 breast/ovarian cancer families from this country. Comprehensive BRCA mutation screening was performed using a range of techniques, including DHPLC, SSCP, and PTT, followed by DNA sequencing analysis. Thirteen deleterious germline mutations (24.5%) were identified in 53 families, comprising eight in BRCA1 and five in BRCA2. The two recurrent BRCA1 mutations, 3450 delCAAG and A1708E, accounted for 100% of all BRCA1 mutations identified in this cohort and the recurrent 3034 delACAA BRCA2 mutation for 40% of all BRCA2 mutations. Haplotype analyses suggested that each of these mutations has arisen from a common ancestor. The prevalence of BRCA1 or BRCA2 mutations was 50% in multiple case breast cancer families, and was 33% for the breast-ovarian cancer families. Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Colombia. The spectrum of mutations differed completely to that previously reported in Hispanic families of predominantly Mexican origin from Southern California [1] suggesting that specific genetic risk assessment strategies for the different Hispanic populations in South America and in the United States need to be developed

Outcomes for Infants Born in Perinatal Centers Performing Fewer Surgical Ligations for Patent Ductus Arteriosus: A Swiss Population-Based Study

Objective To assess patent ductus arteriosus treatment variation between Swiss perinatal centers and to determine its effect on outcome in a population-based setting. Study design This was a retrospective cohort study of infants born less than 28 weeks of gestation between 2012 and 2017. Outcomes between surgically ligated and pharmacologically treated infants as well as infants born in centers performing ≤10% ligation (“low” group) and >10% (“high” group) were compared using logistic regression and 1:1 propensity score matching. Matching was based on case-mix and preligation confounders: intraventricular hemorrhages grades 3-4, necrotizing enterocolitis, sepsis, and ≥28 days’ oxygen supply. Results Of 1389 infants, 722 (52%) had pharmacologic treatment and 156 (11.2%) received surgical ligation. Compared with infants who received pharmacologic treatment, ligated infants had greater odds for major morbidities (OR 2.09, 95% CI 1.44-3.04) and 2-year neurodevelopmental impairment (OR 1.81, 95% CI 1.15-2.84). Mortality was comparable after restricting the cohort to infants surviving at least until day 10 to avoid survival bias. In the “low” group, 34 (4.9%) of 696 infants were ligated compared with 122 (17.6%) of 693 infants in the “high” group. Infants in the “high” group had greater odds for major morbidities (OR 1.49, 95% CI 1.11-2.0). Conclusions Our analysis identified a burden on infants receiving surgical ligation vs pharmacologic treatment in a population-based setting where there was no agreed-on common procedure. These results may guide a revision of patent ductus arteriosus treatment practice in Switzerland