Pharmacogenomic and structural analysis of constitutive G-protein coupled receptor activity

Premi a l'excel·lència investigadora. Àmbit de les Ciències de la Salut. 2008G-protein coupled receptors (GPCRs) respond to a chemically diverse plethora of signal transduction molecules. The notion that GPCRs also signal without an external chemical trigger, i.e. in a constitutive or spontaneous manner, resulted in a paradigm shift in the field of GPCR pharmacology. With the recognition of constitutive GPCR activity and the fact that GPCR binding and signaling can be strongly affected by a single point mutation, GPCR pharmacogenomics obtained a lot of attention. For a variety of GPCRs, point mutations have been convincingly linked to human disease. Mutations within conserved motifs, known to be involved in GPCR activation, might explain the properties of some naturally occurring constitutively active GPCR variants linked to disease. A brief history historical introduction to the present concept of constitutive receptor activity is given and the pharmacogenomic and the structural aspects of constitutive receptor activity are described

Factors associated with tocolytic hospitalizations in Taiwan: evidence from a population-based and longitudinal study from 1997 to 2004

<p>Abstract</p> <p>Background</p> <p>The use of tocolytic hospitalization in antenatal care is controversial and worthy of more research. We investigated individual, institutional, and area factors that affect the use of tocolytic hospitalizations in Taiwan where fertility has rapidly declined.</p> <p>Methods</p> <p>Longitudinal data from the 1996 to 2004 National Health Insurance Research Database in Taiwan were used to identify tocolytic hospitalizations. The probit model was used to estimate factors associated with tocolytic hospitalizations.</p> <p>Results</p> <p>The decline in fertility was significantly associated with the probability of tocolytic hospitalizations. Several physician and institutional factors-including physician's age, hospital ownership, accreditation status, bed size, and teaching status-were also significantly correlated to the dependent variables.</p> <p>Conclusions</p> <p>The provision of inpatient tocolysis is influenced not only by clinical considerations but also by physician, institutional, and area factors unrelated to clinical need. Fertility declines in Taiwan may have led obstetricians/gynecologists to provide more tocolysis to make up for their lost income. If the explanation is further validated, reimbursement policies may need to be reviewed to correct for overuse of inpatient tocolysis. The correlation could also be explained by the increasing use of artificial reproductive technologies and higher social value of newborns. In addition, the physician and institutional variations observed in the study indicate potential misuse of inpatient tocolysis that warrant further investigation.</p

Automation of the generation of accessible digital educational material for students with visual disabilities

El aprendizaje en línea ha crecido en los últimos años, donde las instituciones educativas están ofreciendo cursos o programas de estudio en diferentes áreas de conocimiento. El aprendizaje en línea permite a los estudiantes participar activamente en actividades de aprendizaje cooperativo, interactuando sin las nociones preconcebidas de discapacidad que otros participantes podrían tener, lo que afecta la relación. Sin embargo, estas ventajas a menudo no se han convertido en una realidad para la mayoría de las personas con discapacidad, especialmente en el contexto educativo. Por ejemplo, las páginas web de los cursos no son accesibles para personas con discapacidades visuales, lo que hace que la experiencia de tomar un curso sea frustrante y tediosa. Este artículo propone un enfoque de desarrollo basado en modelos para apoyar el diseño y la generación de material educativo accesible, por ejemplo, objetos de aprendizaje accesibles (LO). Este enfoque proporciona una infraestructura de software que incluye: (i) Un lenguaje específico de dominio y su editor gráfico correspondiente que admite el diseño accesible de LO. Ayudar a los maestros durante el diseño instruccional y permitirles describir los requisitos de accesibilidad para estudiantes con discapacidades visuales. (ii) Un motor de generación de LO que toma como artefactos de diseño de entrada y genera el código fuente que implementa LO accesible. Abstraer a los docentes de los aspectos tecnológicos (por ejemplo, instrucciones del lenguaje de programación) necesarios para construir LO con características de accesibilidad. La aplicabilidad de este enfoque se ilustra usando el DSL y el motor de generación para diseñar e implementar automáticamente un LO accesible de acuerdo con el perfil de accesibilidad especificado durante el diseño. Finalmente, el LO generado se publicó en el Learning Management System Moodle. © 2020, Springer Nature Switzerland AG.Online learning has grown in the last years, where educational institutions are offering courses or study programs in different knowledge areas. Online learning allows students to participate actively in cooperative learning activities, interacting without the preconceived notions of disability that other participants could have, which affects the relationship. However, these advantages have often not become a reality for most people with disabilities, especially in the educational context. For instance, courses’ web pages are not accessible for people with visual disabilities, which makes the experience of taking a course frustrating and tedious. This article proposes a Model-Driven Development approach for supporting the design and generation of accessible educational material, for example, accessible Learning Objects (LO). This approach provides a software infrastructure that includes: (i) A Domain-Specific Language and its corresponding graphic editor that supports accessible LO’s design. Helping teachers during the instructional design and allowing them to describe accessibility requirements for students with visual disabilities. (ii) A LO’s generation engine that takes as input design artifacts and generates the source code that implements accessible LO. Abstracting teachers from technological aspects (e.g., programming language instructions) necessary to construct LO with accessibility features. The applicability of this approach is illustrated by using the DSL and the generation engine to design and automatically implement an accessible LO according to the accessibility profile specified during design. Finally, the generated LO was published in the Learning Management System Moodle. © 2020, Springer Nature Switzerland AG.Quit

Targeting the Hedgehog pathway in cancer

The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy

Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas.

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in patched homologue 1 (PTCH 1) or smoothened (SMO), two conducting proteins of the Hedgehog (Hh) pathway. They rarely progress deeply and metastasize; however, if they do, these advanced BCC become amenable to treatment by inhibiting the Hedgehog and the P13K–mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development