Failure of SOX9 Regulation in 46XY Disorders of Sex Development with SRY, SOX9 and SF1 Mutations

In human embryogenesis, loss of SRY (sex determining region on Y), SOX9 (SRY-related HMG box 9) or SF1 (steroidogenic factor 1) function causes disorders of sex development (DSD). A defining event of vertebrate sex determination is male-specific upregulation and maintenance of SOX9 expression in gonadal pre-Sertoli cells, which is preceded by transient SRY expression in mammals. In mice, Sox9 regulation is under the transcriptional control of SRY, SF1 and SOX9 via a conserved testis-specific enhancer of Sox9 (TES). Regulation of SOX9 in human sex determination is however poorly understood.We show that a human embryonal carcinoma cell line (NT2/D1) can model events in presumptive Sertoli cells that initiate human sex determination. SRY associates with transcriptionally active chromatin in NT2/D1 cells and over-expression increases endogenous SOX9 expression. SRY and SF1 co-operate to activate the human SOX9 homologous TES (hTES), a process dependent on phosphorylated SF1. SOX9 also activates hTES, augmented by SF1, suggesting a mechanism for maintenance of SOX9 expression by auto-regulation. Analysis of mutant SRY, SF1 and SOX9 proteins encoded by thirteen separate 46,XY DSD gonadal dysgenesis individuals reveals a reduced ability to activate hTES.We demonstrate how three human sex-determining factors are likely to function during gonadal development around SOX9 as a hub gene, with different genetic causes of 46,XY DSD due a common failure to upregulate SOX9 transcription

Two recombinant human interferon-beta 1a pharmaceutical preparations produce a similar transcriptional response determined using whole genome microarray analysis

Objectives: Recombinant human interferon-beta (IFN-b) is a well-established treatment for multiple sclerosis (MS). The regulatory process for marketing authorization of biosimilars is currently under debate in certain countries. In the EU, EMEA has clearly defined the process including overarching and product-specific guidelines, which includes clinical testing. Biosimilarity needs to be based on comparability criteria, including at least molecular characterization, biological activity relevant for the therapeutic effect and relative bioavailability (“bioequivalence”). In the case of such complex diseases as MS, where the effect of treatment is not so directly measurable, in vitro tools can provide additional data to support comparability. Genomic microarrays assays might be useful to compare multisource biopharmaceuticals. The aim of the present study was to compare the pharmacodynamic genomic effects (in terms of transcriptional regulation) of two recombinant human IFN-β1a preparations on lymphocytes of multiple sclerosis patients using a whole genome microarray assay. Methods: We performed an ex vivo whole genome expression profiling of the effect of two preparations of IFN-β1a on non-adherent mononuclears from five relapsing-remitting MS patients analyzing microarrays (CodeLink™ Human Whole Genome). Patients blood was drawn, PBMCs isolated and cultured in three different conditions: culture medium (control), 1,000 U/ml of IFN-β1a (BLA- (STOFERON™, Bio Sidus) and 1,000 U/ml of IFN-β1a (REBIF™, Serono) RNA was purified from non-adherent cells (mostly lymphocytes), amplified and hybridized. Raw data were generated by CodeLink™ proprietary software. Data normalization, quality control and analysis of differential gene expression between treatments were done using linear model for microarray data. Functional annotation analysis of IFN-β1a MS treatment transcription was done using DAVID. Results: Out of the approximately 45,000 human sequences examined, no evidence of differential regulation was found when both treatments were compared (minimum adjusted p-value > 0.999). The IFN-β1a effect differentially regulated the expression of 868 genes. The expression of standard markers such as GTP cyclohidrolase, MxA, and OAS isoenzymes A and B changed as a consequence of the action of IFN-β1a. Conclusions: This exhaustive and highly sensitive assay did not show differences in the genomic expression profile of these two products under the assayed experimental conditions. These results suggest that this technology might be useful for the initial comparison of biosimilars, being part of a comprehensive comparability program that includes clinical testing.Fil: Sterin Prync, Aída Edith. Bio Sidus S.A.; ArgentinaFil: Yankilevich, Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Bio Sidus S.A.; ArgentinaFil: Barrero, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Bello, R.. Bio Sidus S.A.; ArgentinaFil: Marangunich, L.. Bio Sidus S.A.; ArgentinaFil: Vidal, A.. Bio Sidus S.A.; ArgentinaFil: Criscuolo, M.. Bio Sidus S.A.; ArgentinaFil: Benasayag, L.. Centro Neurológico Integral ; ArgentinaFil: Famulari, A. L.. Fundación Argentina contra las Enfermedades Neurológicas del Envejecimiento; ArgentinaFil: Domínguez, R. O.. Fundación Argentina contra las Enfermedades Neurológicas del Envejecimiento; ArgentinaFil: Kauffman, Marcelo Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Bio Sidus S.A.; ArgentinaFil: Diez, Roberto Alejandro. Bio Sidus S.A.; Argentin

Datos epidemiologicos y pronósticos del Registro Argentino de Sindromes Mielodisplásicos (SMD)

Los SMD son un grupo heterogéneo de trastornos clonales. El curso clínico es variable, desde un cuadro estable a un pronto fallecimiento por transformación leucémica o por complicaciones de las citopenias. Esta variabilidad complica la decisión terapéutica, siendo fundamental la caracterización pronóstica de los pacientes previo al tratamiento.El IPSS (International Prognostic Scoring System),ampliamente utilizado, fue revisado en 2012 (IPSS-R), redefiniéndose los grupos citogenéticos,niveles de citopenias y el porcentaje de blastos en MO. El sistema del MD Anderson (MDA-S) incluyela leucemia mielomonocítica crónica mielo-proliferativa y SMD secundarios. Otros factores pronósticos están en debate. El Registro Argentino de SMD fue creado en 2008 y colaboran 17 instituciones. Los estudios descriptivos son útiles para estrategiasen salud pública, y necesarios para establecer características epidemiológicas, para validar factores pronósticos y clasificaciones internacionales, permitiendo adecuar esquemas terapéuticos. Por ende,nuestro objetivo fue evaluar las características de los pacientes de nuestro registro.Se analizaron 532 pacientes (89%: SMD primario), mediana de edad: 72 años (17-95), relación M/F: 1,3. Durante el seguimiento(mediana: 18 meses), 104 (19,5%) pacientes evolucionaron a leucemia aguda y 211 (39,7%) fallecieron. La edad, sexo, blastos en MO, nivel dehemoglobina, recuento plaquetario y de neutrófilos, cariotipo, LDH y mielofibrosis fueron variables pronósticas estadísticamente significativas. Las clasificaciones FAB y OMS, y los sistemas pronósticoIPSS, IPSS-R, WPSS según niveles de hemoglobina, MDA-S y el índice de comorbilidad de Charlson permitieron discriminar grupos con diferentes evolución (Kaplan-Meier y Long-Rank, p<0,05). Nuestros resultados confirman la utilidad de variables y sistemas pronósticos en nuestra población.Fil: Flores, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Carlos G. Durand; ArgentinaFil: Basquiera, Ana L. Hospital Privado Centro Medico de Córdoba; ArgentinaFil: Kornblihtt, Laura Inés. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Sakmann, Federico. FUNDALEU; ArgentinaFil: Prates, Virginia. Hospital Italiano de La Plata; ArgentinaFil: Schutz, Natalia. Hospital Italiano; ArgentinaFil: Viñuales, S. Hospital Italiano; ArgentinaFil: Fantl, Dorotea. Hospital Italiano; ArgentinaFil: Cardenas, María Paula. Hospital Italiano; ArgentinaFil: Benasayag, Silvia. Fundagen; ArgentinaFil: Crisp, Renée. Ministerio de Salud de la Nación. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Pintos, Noemí. Sanatorio Dr. Julio Méndez; ArgentinaFil: Santos, Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Iastrebner, Marcelo. Sanatorio Sagrado Corazón ; ArgentinaFil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

La atención gerenciada en América Latina. Transnacionalización del sector salud en el contexto de la reforma Managed care in Latin America: transnationalization of the health sector in a context of reform

Este artículo presenta resultados de la investigación comparativa "Atención Gerenciada en América Latina: Su Papel en la Reforma de los Sistemas de Salud", realizada por equipos de Argentina, Brasil, Chile, Ecuador y Estados Unidos. El objetivo del estudio fue analizar el proceso de exportación de la atención gerenciada, especialmente desde Estado Unidos, y su incorporación en los países latinoamericanos. Los métodos utilizados incluyeron técnicas cualitativas y cuantitativas. La adopción de la atención gerenciada muestra el proceso de transnacionalización del sector salud. Nuestros hallazgos demuestran el ingreso de los principales capitales financieros multinacionales en el sector privado de seguros y de prestadores de salud, y su intencionalidad de participar en la administración de las instituciones estatales y de los fondos de la seguridad social médica. Concluimos que este proceso de cambio sustancial, que implica la paulatina adopción de la atención gerenciada, es facilitado por las transformaciones operadas a nivel ideológico.<br>This article presents the results of the comparative research project "Managed Care in Latin America: Its Role in Health Reform". The project was conducted by teams in Argentina, Brazil, Chile, Ecuador, and the United States. The study's objective was to analyze the process by which managed care is exported, especially from the United States, and how managed care is adopted in Latin American countries. Our research methods included qualitative and quantitative techniques. Adoption of managed care reflects transnationalization of the health sector. Our findings demonstrate the entrance of large multinational financial capital into the private insurance and health services sectors and their intention of participating in the administration of government institutions and medical/social security funds. We conclude that this basic change involving the slow adoption of managed care is facilitated by ideological changes with discourses accepting the inexorable nature of public sector reform