Stability of intracellular calcium in cardiac myocytes

The relationship between alternations in cardiac contractions, known as alternans, and the dynamics of intracellular calcium has been proven in several studies. In this paper, we will study a simple model two-variable model that sets the conditions for alternans due to refractoriness in calcium release. To perform this study, a theoretical background on dynamical systems will be provided, specially focused on the geometrical point of view and the use of Poincaré maps. A second chapter of theoretical background will focus on bifurcation theory and the main types of local bifurcations will be reviewed. The goal of this is to have enough knowledge to perform a complete study of the model while understanding the biological part of it and, eventually, link period doubling bifurcations to cardiac alternans

Un modelo de atención integral al paciente crónico complejo

INTRODUCCIÓN. El aumento de la esperanza de vida ha compor­tado un incremento de patologías crónicas. La evolución de las enfermedades crónicas es causa de disfunciones orgáni­cas y sistémicas, las cuales causan limitaciones físicas y psí­quicas que obligan a establecer ayudas para poder realizar las tareas vitales básicas. La Atención Primaria (AP) tiene un papel clave en el segui­miento de la fragilidad, cronicidad y complejidad de la po­blación, pero para atender la alta complejidad de forma ade­cuada es preciso conocer y coordinar los distintos recursos existentes en el territorio. DESARROLLO DEL MODELO DE ACTUACIÓN: CREACIÓN DE UNA UNIDAD FUN­CIONAL. La AP debe garantizar la equidad, la accesibilidad, la longitudinalidad y la continuidad asistencial, sin olvidar que los resultados en salud deben ser óptimos. En el SAP Delta del Llobregat existen varios proveedores de la salud, por lo que se elaboró un plan estratégico centra­do en la coordinación i/o conciliación de todos los dispositi­vos implicados en la asistencia para dar una atención integral a la persona. Los pacientes incluidos en este programa debían estar identificados como PCC, en fase evolucionada y tributaria de seguimiento intensivo. CONCLUSIONES. La identificación de las persones catalogadas como PCC y en situación de riesgo clínico permite un segui­miento exhaustivo a fin de evitar exacerbaciones y la hi

Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, which results in an aberrant form of the protein (mhtt). This leads to motor and cognitive deficits associated with corticostriatal and hippocampal alterations. The levels of STriatal-Enriched protein tyrosine Phosphatase (STEP), a neural-specific tyrosine phosphatase that opposes the development of synaptic strengthening, are decreased in the striatum of HD patients and also in R6/1 mice, thereby contributing to the resistance to excitotoxicity described in this HD mouse model. Here, we aimed to analyze whether STEP inactivation plays a role in the pathophysiology of HD by investigating its effect on motor and cognitive impairment in the R6/1 mouse model of HD. We found that genetic deletion of STEP delayed the onset of motor dysfunction and prevented the appearance of cognitive deficits in R6/1 mice. This phenotype was accompanied by an increase in pERK1/2 levels, a delay in the decrease of striatal DARPP-32 levels and a reduction in the size of mhtt aggregates, both in the striatum and CA1 hippocampal region. We also found that acute pharmacological inhibition of STEP with TC-2153 improved cognitive function in R6/1 mice. In conclusion, our results show that deletion of STEP has a beneficial effect on motor coordination and cognition in a mouse model of HD suggesting that STEP inhibition could be a good therapeutic strategy in HD patients

Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma

Altres ajuts: This work was supported in part by grants from La Marató TV3 (Exp. 20130710), Deutsche José Carreras Leukämie Stiftung (DJCSL 10R/2016), Fundación Científica Asociación Española Contra el Cáncer (AECC-AIO2017), Fundacion Bancaria 'La Caixa', TerCel (SG/11/2008)Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B-cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30-chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30-CAR T to improve efficacy of CD30-CAR therapy, using a targeting epitope within the non-cleavable part of CD30 receptor, and memory stem T cells (T) to improve engraftment, persistence and antitumor activity. T cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30-CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30-CAR T cells when the tumor was established. CD30-CAR T cells generated and expanded ex vivo, despite CD30 expression and fratricide killing of CD30 + CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo, showing high persistence and long-lasting immunity. In addition, highly enriched CD30-CAR T products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect. This study supports the use of a refined CD30-CAR T cells with highly enriched T products to improve clinical efficacy of CAR T for Hodgkin lymphoma. We have studied the efficacy of a redesigned CD30-chimeric antigen receptor (CAR) targeting a proximal epitope to enhance the antitumor efficacy. CD30-CAR T cells show potent in vivo antitumor effect in different Hodgkin lymphoma models, and overcome inhibition by soluble CD30. CD30-CAR memory stem T-cell products show long-term persistence, improved tumor homing and long-lasting immunity

Central sleep apnoea is related to the severity and short-term prognosis of acute coronary syndrome

Objective To evaluate the relation of central sleep apnoea (CSA) to the severity and short-term prognosis of patients who experience acute coronary syndrome (ACS). Methods Observational study with cross-sectional and longitudinal analyses. Patients acutely admitted to participating hospitals because of ACS underwent respiratory polygraphy during the first 24 to 72 h. CSA was defined as an apnoea-hypopnoea index (AHI) >15 events·h-1 (>50% of central apnoeas). ACS severity (Killip class, ejection fraction, number of diseased vessels and peak plasma troponin) was evaluated at baseline, and short-term prognosis (length of hospitalization, complications and mortality) was evaluated at discharge.This work was supported by: ResMed Ltd. (Australia); Fondo de InvestigacioÂn Sanitaria (PI10/02763 and PI10/02745), Fondo Europeo de Desarrollo Regional (FEDER), Una manera de hacer Europa; the Spanish Respiratory Society (SEPAR); the Catalonian Cardiology Society, Esteve-Teijin (Spain); Oxigen Salud (Spain); and ALLER. This project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no [609396]. Cofunded by Ministerio de EconomõÂa y Competitividad [COFUND2014-51501]

Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples

Bone metastasis; MiRNAs; Prostate cancerMetàstasi òssia; MiRNAs; Càncer de pròstataMetástasis ósea; MiRNAs; Cáncer de próstataAbout 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.The study was supported by grants CPII18/00027 and PI18/01017 to A.S.; PI17/02248 to J.M.; grants PI09/00496, PI13/00173 and postdoctoral fellowship CD12/00475 of Instituto de Salud Carlos III (ISCIII), pre-doctoral fellowship of Vall d’Hebron Research Institute (VHIR), postdoctoral fellowship PERIS of Departament de Salut Govern de Catalunya to M.O.; BBVA and PID2019-104948RB-100 to M.G. (Marc Guiu) and R.R.G.; RD12/0036/0035 of Red Temática de investigación cooperativa en cancer (RTICC), and 2014SGR1330 from “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya”

Uso del simulador dental, SIMODONT®, en Odontopediatría: comparación de habilidades manuales con Simodont® versus Tipodonto en dientes temporales de acrílico

Desde que se iniciaron los estudios de Odontología se han utilizado escenarios de simulación para intentar desarrollar habilidades motoras y destrezas manuales en los estudiantes. Actualmente, los simuladores virtuales hápticos 3D de alta fidelidad están siendo ampliamente utilizados en la docencia de la práctica odontológica como herramienta didáctica. Estos simuladores permiten al estudiante realizar actividades de la profesión en un entorno seguro y controlado. En el curso 2022/2023 vamos a implantar el uso simuladores dentales, Simodont, en las prácticas preclínicas de Odontopediatría que se imparte en el Grado en Odontología. Además queremos valorar si la adquisión de conocimiento teóricos previos influye en la evaluación de las prácticas preclínicas en nuestra disciplina. Para el desarrollo de este proyecto primero se les pasará a los alumnos un cuestionario sobre preparaciones cavitarias, posteriormente realizarán las practicas preclínicas sobre dientes temporales de acrílicos sobre fantomas, en ellos realizarán preparaciones cavitarias en dientes temporales de acrílicos. Posteriormente, realizarán los mismos tratamientos pero en los simuladores dentales. Se establecerá una rúbrica para evaluar las preparaciones dentarias. Dichos procedimientos serán evaluados por dos profesores integrantes de este proyecto a ciegas. Una vez concluidas las prácticas se les pasará a los alumnos una encuesta de satisfacción y de opinión sobre el uso de simuladores. Se analizarán todos los resultados obtenidos y entre los miembros integrantes de este proyecto se redactará un documento de consenso sobre las posibles mejoras o modificaciones en el uso de simuladores dentales en Odontopediatría.Depto. de Especialidades Clínicas OdontológicasFac. de OdontologíaFALSEsubmitte

18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: results from Neo-ALTTO

Molecular imaging receives increased attention for selecting patients who will benefit from targeted anticancer therapies. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) enrolled 455 women with invasive human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared rates of pathologic complete response (pCR) to neoadjuvant lapatinib, trastuzumab, and their combination. Each anti-HER2 therapy was given alone for 6 wk, followed by 12 wk of the same therapy plus weekly paclitaxel. The early metabolic effects of the anti-HER2 therapies on the primary tumors and their predictive values for pCR were assessed in a subset of patients. Methods: eighty-six patients underwent (18)F-FDG PET/CT at baseline and weeks 2 and 6 of anti-HER2 treatment. An imaging core laboratory provided central validation, and 2 independent reviewers, masked to assigned treatment arm and clinical outcomes, performed consensus (18)F-FDG PET/CT readings. Maximum standardized uptake value (SUVmax) reductions from baseline were used to measure metabolic response. Results: seventy-seven of the 86 enrolled patients presented an evaluable baseline (18)F-FDG PET/CT scan; of these, 68 and 66 were evaluable at weeks 2 and 6, respectively. Metabolic responses in the primary tumors were evident after 2 wk of targeted therapy and correlated highly with metabolic responses at week 6 (R(2) = 0.81). pCRs were associated with greater SUVmax reductions at both time points. Mean SUVmax reductions for pCR and non-pCR, respectively, were 54.3% versus 32.8% at week 2 (P = 0.02) and 61.5% versus 34.1% at week 6 (P = 0.02). (18)F-FDG PET/CT metabolic response rates at weeks 2 and 6 were 71.6% and 60%, respectively using European Organization for Research and Treatment of Cancer criteria; pCR rates were twice as high for (18)F-FDG PET/CT responders than nonresponders (week 2: 42% vs. 21%, P = 0.12; week 6: 44% vs. 19%, P = 0.05). Conclusion: early metabolic assessment using (18)F-FDG PET/CT can identify patients with an increased likelihood of pCR after neoadjuvant trastuzumab, lapatinib, or their combination when given with chemotherapy