RESUMEN
Orofacial clefts (OFCs) rank as the second most common congenital birth defect in the United States after Down syndrome and are the most common head and neck congenital malformations. They are classified as cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). OFCs have significant psychological and socio-economic impact on patients and their families and require a multidisciplinary approach for management and counseling. A complex interaction between genetic and environmental factors contributes to the incidence and clinical presentation of OFCs. In this comprehensive review, the embryology, classification, epidemiology and etiology of clefts are thoroughly discussed and a "state-of-the-art" snapshot of the recent advances in the genetics of OFCs is presented.
Asunto(s)
Fisura del Paladar/genética , Animales , Labio Leporino/patología , Estudio de Asociación del Genoma Completo/métodos , Humanos , Secuenciación del Exoma/métodosRESUMEN
In this study, we assess arginine auxotrophy in ovarian cancer cells and attempt to target them using arginine deprivation induced by a pegylated recombinant human Arginase I cobalt [HuArgI (Co)-PEG5000]. Ovarian cancer cells were sensitive to [HuArgI (Co)-PEG5000]-induced arginine deprivation with IC50 values in the low pM range. Addition of excess L-citrulline rescued only one of three cell lines tested, indicating that the majority of cell lines are completely auxotrophic for arginine. The expression pattern of argininosuccinate synthetase (ASS1) confirmed the degree of auxotrophy of ovarian cancer cell lines with completely auxotrophic cells not expressing ASS1 and partially auxotrophic cells expressing the enzyme. Ovarian cancer cell lines were negative for annexinV staining while showing loss of membrane integrity and absence of caspase activation, indicating caspase-independent, non-apoptotic cell death. [HuArgI (Co)-PEG5000]-induced arginine deprivation led to extensive and prolonged activation of autophagy, which proved to be deleterious to cell survival since its inhibition led to a significant decrease in cytotoxicity. This indicates that the activation of autophagy following arginine-deprivation, rather than being protective, mediates cell cytotoxicity leading to death by autophagy.