New drugs are not enough­drug repositioning in oncology: An update.

Drug repositioning refers to the concept of discovering novel clinical benefits of drugs that are already known for use treating other diseases. The advantages of this are that several important drug characteristics are already established (including efficacy, pharmacokinetics, pharmacodynamics and toxicity), making the process of research for a putative drug quicker and less costly. Drug repositioning in oncology has received extensive focus. The present review summarizes the most prominent examples of drug repositioning for the treatment of cancer, taking into consideration their primary use, proposed anticancer mechanisms and current development status.

Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment.

Immortality is one of the main features of cancer cells. Tumor cells have an unlimited replicative potential, principally due to the holoenzyme telomerase. Telomerase is composed mainly by dyskerin (DKC1), a catalytic retrotranscriptase (hTERT) and an RNA template (hTR). The aim of this work is to develop new inhibitors of telomerase, selecting the interaction between hTR⁻DKC1 as a target. We designed two models of the human protein DKC1: homology and ab initio. These models were evaluated by different procedures, revealing that the homology model parameters were the most accurate. We selected two hydrophobic pockets contained in the PUA (pseudouridine synthase and archaeosine transglycosylase) domain, using structural and stability analysis. We carried out a docking-based virtual screen on these pockets, using the reported mutation K314 as the center of the docking. The hDKC1 model was tested against a library of 450,000 drug-like molecules. We selected the first 10 molecules that showed the highest affinity values to test their inhibitory activity on the cell line MDA MB 231 (Monroe Dunaway Anderson Metastasis Breast cancer 231), obtaining three compounds that showed inhibitory effect. These results allowed us to validate our design and set the basis to continue with the study of telomerase inhibitors for cancer treatment.

Criterios en el retiro de los suministros de oxígeno subutilizados en casa / Criteria in the removal of oxygen supplies underused at home

El estudio tuvo como objetivo identificar los criterios en el retiro de los suministros de oxígeno subutilizados en casa por parte de población adulta. Se realizó un estudio observacional, descriptivo y de corte transversal. La población de estudio correspondió a 65 adultos entre 22 y 92 años, pertenecientes al programa de terapia respiratoria de la IPS SISANAR en Cali, Colombia. Se diseñó un instrumento de recolección de datos dirigida a los pacientes con oxígeno domiciliario. Fue utilizado el paquete estadístico SPSS versión 17.0 para el análisis de los datos, los cuales fueron revisados y validados. Las frecuencias y porcentajes se calcularon, así como los intervalos de confianza al 95%. Entre los resultados se encontró que el 93,86% de los pacientes tenían saturaciones de oxígeno superior al 90%, sin soporte de oxígeno. Además, un 58,46 % de los pacientes no había utilizado los suministros de oxígeno, permaneciendo almacenados en su casa por períodos de más de tres meses. Se concluye que es importante identificar y registrar formalmente por parte del equipo dedicado al cuidado respiratorio de los pacientes domiciliarios, los criterios en el retiro de los suministros de oxigeno subutilizados en el hogar, con el fin de optimizar su uso, tomando decisiones objetivas en cuanto el retiro o continuación de la oxigenoterapia domiciliaria. El seguimiento de pautas de prescripción en estos casos puede producir ahorros significativos en los sistemas de salud del país.

Objective: Identify criteria in the removal of underused oxygen supplies at home. Methodology: An observational, descriptive and cross-sectional study was conducted. The studied population consisted of 65 adults aged between 22 and 92; these patients were part of the respiratory therapy program of the SISANAR institution in Cali ­ Colombia. An instrument of data collection was designed, for patients with home oxygen. SPSS version 17.0 was used to analyze the data which was reviewed and validated. The frequencies and percentages were calculated as well as confidence intervals at 95%. Results: It was found that 93.86% of patients had higher oxygen saturations above 90%, with unsupported oxygen. Also, the 58.46 % of patients who had not even used their oxygen supplies, which were remained stored at home for periods longer than three months. Conclusion: It is important that the team dedicated to respiratory home care identifies and makes a formal record of the patients, the removal of the underused oxygen supplies with the purpose of optimizing their use, making objective decisions regarding the continuation of home oxygen therapy. The Monitoring of prescribing patterns in these cases can produce significant savings in health systems for the country.

Novel insights into the evolution and structural characterization of dyskerin using comprehensive bioinformatics analysis.

Dyskerin is a conserved nucleolar protein. Several related genetic diseases are caused by defects in dyskerin. We hypothesized that having a comprehensive bioinformatic analysis of dyskerin will help to develop new drugs for this diseases. We predicted protein domains and compared sequences and structures to detect the universe of dyskerin-like proteins. We identified conserved features of shared domains in the three superkingdoms. We analyzed the phylogenetic diversity, confirming that there is a strong structural conservation. Also, we studied the relationship of dyskerin-like proteins with other proteins through an integrative protein-protein interaction approach. Most of them are conserved among homologous eukaryotic and archaeal proteins. Our results highlighted the preservation of proteins interacting with dyskerin. We identified conserved dyskerin interactor proteins between the different eukaryotes organisms. Furthermore, we studied the existence of dyskerin-like proteins in different species. Also, we compared and analyzed the secondary structure with the hydrophobic profile, confirming that all have hydrophilic properties highly conserved among proteins. The greatest difference was observed in the NTE and CTE regions. Another aspect studied was the comparison and analysis of tertiary structures. In our knowledge, this is the first time that these analyses were performed in such a comprehensive manner.

Neurogenic differentiation of human adipose-derived stem cells: relevance of different signaling molecules, transcription factors, and key marker genes.

Since numerous diseases affect the central nervous system and it has limited self-repair capability, a great interest in using stem cells as an alternative cell source is generated. Previous reports have shown the differentiation of adipose-derived stem cells in neuron-like cells and it has also been proved that the expression pattern of patterning, proneural, and neural factors, such as Pax6, Mash1, Ngn2, NeuroD1, Tbr2 and Tbr1, regulates and defines adult neurogenesis. Regarding this, we hypothesize that a functional parallelism between adult neurogenesis and neuronal differentiation of human adipose-derived stem cells exists. In this study we differentiate human adipose-derived stem cells into neuron-like cells and analyze the expression pattern of different patterning, proneural, neural and neurotransmitter genes, before and after neuronal differentiation. The neuron-like cells expressed neuronal markers, patterning and proneural factors characteristics of intermediate stages of neuronal differentiation. Thus we demonstrated that it is possible to differentiate adipose-derived stem cells in vitro into immature neuron-like cells and that this process is regulated in a similar way to adult neurogenesis. This may contribute to elucidate molecular mechanisms involved in neuronal differentiation of adult human non-neural cells, in aid of the development of potential therapeutic tools for diseases of the nervous system.

Transcriptional characterization of Wnt and Notch signaling pathways in neuronal differentiation of human adipose tissue-derived stem cells.

Since the nervous system has limited self-repair capability, a great interest in using stem cells is generated to repair it. The adipose tissue is an abundant source of stem cells and previous reports have shown the differentiation of them in neuron-like cells when cultures are enriched with growth factors involved in neurogenesis. Regarding this, it could be thought that a functional parallelism between neurogenesis and neuronal differentiation of human adipose stem cells (hASCs) exists. For this reason, we investigated the putative involvement of Notch and Wnt pathways in neuronal differentiation of hASCs through real-time PCR. We found that both Wnt and Notch signaling are present in proliferating hASCs and that both cascades are downregulated when cells are differentiated to a neuronal phenotype. These results are in concordance with previous works where it was found that both pathways are involved in the maintenance of the proliferative state of stem cells, probably through inhibition of the expression of cell-fate-specific genes. These results could support the notion that hASCs differentiation into neuron-like cells represents a regulated process analogous to what occurs during neuronal differentiation of NSCs and could partially contribute to elucidate the molecular mechanisms involved in neuronal differentiation of adult human nonneural tissues.