Early Appearance of TNF-α and Other Cytokines in Bronchus Associated Lymphoid Tissues (BALT) from Growing Wistar Rats. What is the Role of TNF-α?

Several different cytokines trigger the development of determined cell subsets in BALT of growing Wistar rats. Early appearance (4 days post partum) of γδT cells in BALT has been shown, as well as its role in up-regulating TNF-α production. In the present report, we studied in the BALT: (1) the profile of the cytokines, TNF-α, INF-γ and IL-10 and (2) in TCR γδ+ cells, the existence of a colocalization with TNF-α as well as with INF-γ. All the cytokines studied were observed at an early stage of BALT development by immunohistochemistry and in bronchoalveolar cells (BAL cells) by flow cytometry and western blot. (1) The principal cytokine found at 4 days of age in BALT cells was TNF-α that increases along BALT development. The same behavior was found for cells containing IL-10 and INF-γ. (2) TCR γδ+ cells colocalize mainly with TNF-α as it has been shown by immunohistochemistry in BALT and by flow cytometry when we studied BAL

Genetic variation in interleukin-28B predicts SVR in hepatitis C genotype 1 Argentine patients treated with PEG IFN and ribavirin

BACKGROUND AND AIMS: Genetic variations in the interleukin 28B (IL28B) gene have been associated with viral response to PEG-interferon-α/ribavirin (PR) therapy in hepatitis C virus (HCV) genotype 1 infected patients from North America, Europe and Asia. The importance of these IL28B variants for Argentine patients remains unknown. MATERIAL AND METHODS: IL28B host genotypes (rs8099917 and rs12979860) were determined in a population of Argentine patients with European ancestry. Results were analyzed looking for their association with sustained virologic response (SVR) to PR therapy and compared with other baseline hosts' biochemical, histological and virological predictors of response. RESULTS: We studied 102 patients, 60% were men, and 40% of them were rs8099917 TT and 18% rs12979860 CC. Mean baseline serum HCV RNA was 1.673.092 IU/mL and mean F score was: 2.10 ± 1.18 (21% cirrhotic). SVR rate was higher in rs8099917 TT genotypes (55%) when compared to GT/GG (25%) (p = 0.002) and in rs1512979860 CC (64%) than in CT/TT (30%) (p = 0.004). The univariate analysis showed that rs8099917 TT (OR 3.7; 95 %CI 1.5-8.7; p = 0.002), rs12979860 CC (OR 4.6; 95%CI 1.5-13.7; p = 0.006), low viral load (OR 4.6; 95% CI 1.7-12.6; p = 0.002) and F0-2 (OR 8.5; 95% CI 2.3-30.6; p = 0.001) were significantly associated with SVR. In the multivariate analysis, rs12979860 CC, rs8099917 TT, viral load < 400.000 IU/mL and F0-2 were associated with SVR rates (p = 0.029, p = 0.012, p = 0.013 and p = 0.004, respectively). CONCLUSION: IL28B host genotypes should be added to baseline predictors of response to PR therapy in Latin American patients with European ancestry.Fil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Hospital Universitario Austral; ArgentinaFil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Marciano, Sebastián. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Hospital Italiano; ArgentinaFil: Galdame, Omar. Hospital Italiano; ArgentinaFil: Adrover, Raúl. Centro de Hepatologia; ArgentinaFil: Cocozzella, Daniel. Centro de Hepatologia; ArgentinaFil: Delettieres, Dreanina. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Martínez, Alfredo. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Gadano, Adrián. Hospital Italiano; ArgentinaFil: Mandó, Oscar G.. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Silva, Marcelo O.. Hospital Universitario Austral; Argentin

BRCA1 and BRCA2 analysis of argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin

Background: The spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history. Methods: The study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2). Discussion: We found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component. This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews. © 2012 Solano et al.Fil: Solano, Angela Rosario. Universidad de Buenos Aires; Argentina. Centro de Internación E Investigación Clínica; ArgentinaFil: Aceto, Gitana Maria. University Of G. D'annunzio Chieti And Pescara;Fil: Delettieres, Dreanina. Centro de Internación E Investigación Clínica; ArgentinaFil: Veschi, Serena. University Of G. D'annunzio Chieti And Pescara;Fil: Neuman, Maria Isabel. Universidad de Buenos Aires; ArgentinaFil: Alonso, Eduardo. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Chialina, Sergio. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Chacón, Reinaldo Daniel. Universidad de Buenos Aires; ArgentinaFil: Renato, Mariani-Costantini. University Of G. D'annunzio Chieti And Pescara;Fil: Podesta, Ernesto Jorge. Universidad de Buenos Aires; Argentin

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA