Diseño de un proyecto de investigación: Terapias complementarias en oncología pediátrica

Las terapias complementarias en oncología pediátrica se encuentran en auge en la actualidad por diversos factores, como favorecer el resultado de las terapias convencionales, disminuir los niveles de estrés y ansiedad, facilitar la manera de afrontar la enfermedad, mejorar la adherencia al tratamiento y la estancia del paciente en el centro hospitalario. De ahí, que sea interesante diseñar un proyecto de investigación que englobe las terapias complementarias más usadas (juegoterapia, musicoterapia, arteterapia y terapia grupal), con el principal objetivo de reducir el nivel de estrés y ansiedad en pacientes hospitalizados de oncología pediátrica de 12 a 14 años. Durante el proyecto se realizará un total de 24 sesiones (8 de juegoterapia, 8 de musicoterapia, 4 de arteterapia y 4 de terapia grupal), organizadas previamente por el equipo de trabajo, formado por los oncólogos pediátricos correspondientes a la unidad, 2 enfermeras, 1 TCAE, 1 psicólogo y 1 terapeuta ocupacional. El equipo de enfermería compuesto por 3 miembros (2 enfermeras y una TCAE de apoyo) será el encargado de dirigir todas las terapias diseñadas. Son numerosos estudios los que se encuentran en la bibliografía acerca de las terapias complementarias, pero muchos de ellos carecen de evidencia científica, de ahí la importancia de realizar este tipo de proyectos. La futura aplicación de este proyecto de investigación ayudará a estudiar la eficacia de las terapias complementarias en la disminución del nivel de estrés y ansiedad de pacientes oncológicos pediátricos hospitalizados. La implicación de los padres o tutores de los menores, durante el proceso de hospitalización, será una actuación positiva frente a las terapias, potenciando la utilidad de las mismas.Grado en Enfermerí

Coinfección por SARS-CoV-2 y Legionella pneumophila

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Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer

Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson's, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development

Subtyping treatment-seeking gaming disorder patients

Background and aims: Gaming Disorder (GD) is characterized by a pattern of persistent and uncontrolled gaming behavior that causes a marked impairment in important areas of functioning. The evolution of the worldwide incidence of this disorder warrants further studies focused on examining the existence of different subtypes within clinical samples, in order to tailor treatment. This study explored the existence of different profiles of patients seeking treatment for GD through a data-driven approach. Methods: The sample included n = 107 patients receiving treatment for GD (92% men and 8% women) ranging between 14 and 60 years old (mean age = 24.1, SD = 10). A two-step clustering analysis approach explored the existence of different underlying GD profiles based on a broad set of indicators, including sociodemographic features, clinical course of the condition (e.g., onset or evolution), psychopathological symptoms, and personality traits. Results: Two GD profiles emerged. The first cluster grouped together patients who presented with a lower psychological impact (n = 72, 66.1%), whereas the second cluster comprised patients with a higher psychological impact (n = 35, 32.7%). Cluster comparisons revealed that those patients presenting the higher impact were older, with a later onset of pathological gaming patterns, and more pronounced psychopathological symptoms and dysfunctional personality profiles. Conclusions: GD severity is influenced by specific demographic, clinical, and psychopathological factors. The identification of two separate profiles provides empirical evidence that contributes to the conceptualization of this disorder, as well as to the development of reliable and valid screening tools and effective intervention plans focused on the precise characteristics of the treatment-seeking patients

Women and gambling disorder: Assessing dropouts and relapses in cognitive behavioral group therapy

Background: Gender-specific literature focused on gambling disorder (GD) is scarce, and women with GD have been understudied. Therefore, the aim of this study was to estimate the short-term effectiveness in women with GD (n = 214) of a group standardized cognitive-behavioral therapy (CBT) and to identify the most relevant predictors of the primary therapy outcomes (dropout and relapse). Methods: The manualized CBT consisted of 16 weekly outpatient group sessions. Women were provided with resources to obtain a better understanding of the GD, to improve self-control and to manage risk situations. Results: The dropout risk was higher for women with lower GD severity and higher psychopathological distress. Among other factors, lower education levels were a significant predictor of the relapse risk and and the frequency of relapses was higher for divorced women with a preference for non-strategic gambling and with substances consumption. Conclusions: Our findings evidence women-specific predictors of the primary therapy outcomes. The results highlight the need to design psychological interventions that address dropout and relapse risk factors in women

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

BackgroundWhole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts.MethodsWe developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA).ResultsClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes.ConclusionsClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses

Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis

[Background] Zalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy.[Methods] Using in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies.[Results] Zalypsis resistance was dependent on the expression levels of PDGFRα or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRα/β, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug.[Conclusions] RTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials.The AC lab was supported by grants to from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028), Consejeria de Ciencia e Innovacion (CTS-6844), and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer Reviewe

Raloxifene and n-acetylcysteine ameliorate TGF-signalling in fibroblasts from patients with recessive dominant epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.This work was supported by grants CTQ2014-52213-R, CTQ2015-64402-C2-1-R and CTQ2015-64402-C2-2-R (Spanish Ministry of Economy and Competitiveness, MINECO), CM S2011/BMED-2353 (Comunidad de Madrid), and FEDER Funds and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (ISCIII).Peer reviewe