Genotype-phenotype features of germline variants of the TMEM127 pheochromocytoma susceptibility gene: A 10-year update

Purpose: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main Outcome Analysis: Clinical, genetic, and functional associations were determined. Results: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P <. 001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P <. 001) and clustered disproportionately within transmembrane regions (P <. 01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.Fil: Armaiz Pena, Gustavo. University Of Texas Health Science Center At San Antonio;; Estados UnidosFil: Flores, Shahida K.. No especifíca;Fil: Cheng, Zi Ming. No especifíca;Fil: Zhang, Xhingyu. No especifíca;Fil: Esquivel, Emmanuel. No especifíca;Fil: Poullard, Natalie. No especifíca;Fil: Vaidyanathan, Anusha. No especifíca;Fil: Liu, Qianqian. No especifíca;Fil: Michalek, Joel. No especifíca;Fil: Santillan Gomez, Alfredo A.. No especifíca;Fil: Liss, Michael. No especifíca;Fil: Ahmadi, Sara. No especifíca;Fil: Katselnik, Daniel. No especifíca;Fil: Maldonado, Enrique. No especifíca;Fil: Salgado, Sarimar Agosto. No especifíca;Fil: Jimenez, Camilo. No especifíca;Fil: Fishbein, Lauren. No especifíca;Fil: Hamidi, Oksana. No especifíca;Fil: Else, Tobias. No especifíca;Fil: Lechan, Ron. Tufts Medical Center; Estados UnidosFil: Tischler, Art S.. Tufts Medical Center; Estados UnidosFil: Benn, Diana E.. No especifíca;Fil: Dwight, Trisha. University of Technology Sydney; AustraliaFil: Clifton Bligh, Rory. University of Technology Sydney; AustraliaFil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Vincent, Deepa. Massachusetts Institute of Technology; Estados UnidosFil: Aronin, Neil. Massachusetts Institute of Technology; Estados UnidosFil: Biondi, Bernadette. University of Naples Federico II; ItaliaFil: Koops, Maureen. University of Texas Health San Antonio; Estados UnidosFil: Bowhay Carnes, Elizabeth. No especifíca;Fil: Gimenez Roqueplo, Anne Paule. No especifíca;Fil: Alvarez Eslava, Andrea. No especifíca;Fil: Bruder, Jan M.. No especifíca;Fil: Kitano, Mio. No especifíca;Fil: Burnichon, Nelly. No especifíca;Fil: Ding, Yanli. No especifíca;Fil: Dahia, Patricia L. M.. No especifíca

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

La corrupción no es inherente al ser humano. Estudio acerca de la confianza en las zonas mineras de los departamentos de Antioquia, Bolívar y Córdoba

La corrupción es un fenómeno universal que se presenta en todas las sociedades. Sin embargo, muchas han logrado contrarrestar sus efectos negativos a través de políticas públicas y esfuerzos sociales sostenidos encaminados a promover la transparenci

Enhanced ceria nanoflakes using graphene oxide as a sacrificial template for CO oxidation and dry reforming of methane

© 2018 The Authors The development of novel fabrication methods to produce ceria catalysts with good high-temperature stability is critical for their implementation across a range of different applications. Herein, graphene oxide flakes are used as a sacrificial template in the synthesis of ceria particles to replicate the graphene oxide's two-dimensionality. While performing the synthesis without graphene oxide results in large agglomerations of ceria crystallites, the addition of graphene oxide during the synthesis results in ceria nanoflakes (400 °C) which results in improved catalytic performance for the oxidation of carbon monoxide. This resistance versus sintering has also a beneficial effect when ceria flakes are used as catalytic support of nickel particles. Improved metal dispersion and high metal-support interaction leads to lower sintering during the dry reforming of methane than similarly prepared un-templated ceria nickel catalysts. These results demonstrate the advantage of using graphene oxide as a sacrificial template for the production of sintering-resistant catalysts with good catalytic performance at high temperatures

Accountability societal: herramienta de gobernanza contra la corrupción

Este artículo se ocupa de exponer el contenido conceptual del término accountabilty mediante un rastreo de sus antecedentes filosófico-políticos en las tradiciones liberal, republicana y democrática, que permiten relacionarlo con la noción de rendició

CS21 positive multidrug-resistant ETEC clinical isolates from children with diarrhea are associated with self-aggregation, and adherence.

Background: Enterotoxigenic Escherichia coli (ETEC) colonize the human intestinal mucosa using pili and non-pili colonization factors (CFs). CS21 (also designated Longus) is one of the most prevalent CFs encoded by a 14 kb lng DNA cluster located in a virulence plasmid of ETEC; yet limited information is available on the prevalence of CS21 positive ETEC isolates in different countries. The aim of this study was to evaluate the prevalence of CS21 among ETEC clinical isolates from Mexican and Bangladeshi children under five years old with diarrhea and to determine the phenotypic and genotypic features of these isolates. Methods: ETEC clinical isolates positive to lngA gene were characterized by genotype, multidrug-resistance, self-aggregation, biofilm formation and adherence to HT-29 cell line.Results: A collection of 303 E. coli clinical isolates were analyzed, the 81.51% (247/303) were identified as ETEC, 30.76% (76/247) were st+/lt+, and 25.10% (62/247) were positive for the lngA gene. Among the lngA+ ETECs identified, 50% of isolates (31/62) were positive for LngA protein. The most frequent serotype was O128ac:H12 found in 19.35% (12/62) of lngA+ ETEC studied. Multidrug-resistance (MDR) lngA+ ETEC isolates was identified in 65% (39/60), self-aggregation in 48.38% (30/62), and biofilm formation in 83.87% (52/62). ETEC lngA+ isolates were able to adhere to HT-29 cells at different levels. Two lngA isogenic mutants were constructed in the ETEC E9034A and ETEC73332 clinical isolate, showing a 77% and 98% reduction in adherence respectively with respect to the wild type.Conclusion: ETEC isolates that har the lngA gene showed features associated with self-aggregation, and adherence to HT-29 cells important characteristics in the human gut colonization process and pathogenesis

. Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update

Purpose: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main outcome analysis: Clinical, genetic, and functional associations were determined. Results: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance