Terapias e indicaciones huérfanas de los fármacos en la distrofia miotónica tipo I

Motivación: La distrofia miotónica tipo I (DM1), o enfermedad de Steinert, es una enfermedad rara multisistémica eminentemente muscular causada por la repetición expandida del triplete (CTG)n en la región 3’ UTR del gen que codifica para la proteína serina-treonina quinasa de la distrofia miotónica (DMPK). Así, esto provoca la desregulación de la función de las proteínas reguladoras del splicing, que a su vez, supone la alteración de ciertos mecanismos y rutas celulares, de los cuales, destaca el splicing aberrante de los transcritos típicos de la DM1.Hasta la fecha no se ha descubierto ninguna cura para la enfermedad, por lo que actualmente la DM1 es un problema social y sanitario de primera magnitud, ya que es la forma más común de las distrofias en adultos y presenta una prevalencia de 1/20.000 en adultos, por lo que en nuestro país podría afectar a unas 2.350 personas aproximadamente. Además, al no conocerse con exactitud los mecanismos moleculares responsables de la misma, es bastante complicado encontrar una cura. Por tanto, en el presente proyecto se estudia el estado de arte de la enfermedad y se pretende caracterizar fisiopatológicamente la DM1 en profundidad, para posteriormente tratar de desarrollar una terapia efectiva contra la misma.Métodos: En este proyecto de una duración de tres años, se llevará a cabo una caracterización fisiopatológica completa a nivel celular de la DM1. Con tal fin, pensamos que los modelos celulares (células HeLa transfectadas, fibroblastos y mioblastos de pacientes) serían muy adecuados para, posteriormente, realizar un cribado masivo farmacológico y genético de una gran cantidad de moléculas y fármacos que puedan tener aplicaciones huérfanas, principalmente aquellas de bajo peso molecular que puedan ser administradas sistemáticamente. Apostamos por este método de análisis por su rapidez, versatilidad y capacidad de automatización. Finalmente, aquellos compuestos con los que se obtengan mejores resultados se validarán con experimentos más detallados.Conclusiones: Este proyecto podría tener un importante impacto tanto bibliométrico, como clínico. Por un lado, el beneficio clínico para los pacientes sería vital. Por otro lado, el impacto bibliométrico del proyecto sería indiscutible, ya que todas las características fisiopatológicas de la enfermedad que se descubran aportarían un conocimiento sumamente importante, poniendo de manifiesto la necesidad de la investigación en las enfermedades raras

Efficient Modelling of Ion Structure and Dynamics in Inorganic Metal Halide Perovskites

Metal halide perovskites (MHPs) are nowadays one of the most studied semiconductors due to their exceptional performance as active layers in solar cells. Although MHPs are excellent solid-state semiconductors, they are also ionic compounds, where ion migration plays a decisive role in their formation, their photovoltaic performance and their long-term stability. Given the above-mentioned complexity, molecular dynamics simulations based on classical force fields are especially suited to study MHP properties, such as lattice dynamics and ion migration. In particular, the possibility to model mixed compositions is important since they are the most relevant to optimize the optical band gap and the stability. With this intention, we employ DFT calculations and a genetic algorithm to develop a fully transferable classical force field valid for the benchmark inorganic perovskite compositional set CsPb(Br_xI_(1-x))_3 (x = 0,1/3,2/3,1). The resulting force field reproduces correctly, with a common set of parameters valid for all compositions, the experimental lattice parameter as a function of bromide/iodide ratio, the ion-ion distances and the XRD spectra of the pure and mixed structures. The simulated thermal conductivities and ion migration activation energies of the pure compounds are also in good agreement with experimental trends. Our molecular dynamics simulations make it possible to predict the compositional dependence of the ionic diffusion coefficient on bromide/iodide ratio and vacancy concentration. For vacancy concentrations of around 9 10^21 cm^-3, we obtained ionic diffusion coefficients at ambient temperature of 10^-11 and 10^-13 cm2/s for CsPbBr3 and CsPbI3, respectively. Interestingly, in comparison with the pure compounds, we predict a significantly lower activation energy for vacancy migration and faster diffusion for the mixed perovskites

Shoc2/Sur8 protein regulates neurite outgrowth

This is an openaccess article distributed under the terms of the Creative Commons Attribution License.-- et al.The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF-induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth.GL, TG and LMD were recipients of fellowships from the Ministerio de Educación y Ciencia (MEC) (to GL, TG), and Fondo de Investigaciones Sanitarias (FIS) (to LMD). LSR held a postdoctoral research contract from CIBERNED. This work was supported by FIS grant (PI10/00815) to JLO; CIBERNED to MC; SAF2008-01951, Comunidad Autónoma de Madrid (CAM) SSAL-0202-2006-01 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) to TI; FIS grant PI12/00775 and ISCIII-RETIC (Red Temática de Investigación Cooperativa en Cáncer) RD12/0036/0027 from the Instituto de Salud Carlos III to PSG; and FIS grants (PI09/0562 and PI13/00703), ISCIIIRETIC (RD06/0020/0003 and RD12/0036/0021), and the Spanish Association Against Cancer (AECC) to JMR.Peer Reviewe

Shoc2/Sur8 Protein Regulates Neurite Outgrowth

The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF-induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth.This work was supported by FIS grant (PI10/00815) to JLO; CIBERNED to MC; SAF2008-01951, Comunidad Autónoma de Madrid (CAM) S-SAL-0202-2006-01 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) to TI; FIS grant PI12/00775 and ISCIII-RETIC (Red Temática de Investigación Cooperativa en Cáncer) RD12/0036/0027 from the Instituto de Salud Carlos III to PSG; and FIS grants (PI09/0562 and PI13/00703), ISCIII-RETIC (RD06/0020/0003 and RD12/0036/0021), and the Spanish Association Against Cancer (AECC) to JMR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Machine Learning-Based Analysis in the Management of Iatrogenic Bile Duct Injury During Cholecystectomy: a Nationwide Multicenter Study

Background Iatrogenic bile duct injury (IBDI) is a challenging surgical complication. IBDI management can be guided by artificial intelligence models. Our study identified the factors associated with successful initial repair of IBDI and predicted the success of definitive repair based on patient risk levels. Methods This is a retrospective multi-institution cohort of patients with IBDI after cholecystectomy conducted between 1990 and 2020. We implemented a decision tree analysis to determine the factors that contribute to successful initial repair and developed a risk-scoring model based on the Comprehensive Complication Index. Results We analyzed 748 patients across 22 hospitals. Our decision tree model was 82.8% accurate in predicting the success of the initial repair. Non-type E (p < 0.01), treatment in specialized centers (p < 0.01), and surgical repair (p < 0.001) were associated with better prognosis. The risk-scoring model was 82.3% (79.0-85.3%, 95% confidence interval [CI]) and 71.7% (63.8-78.7%, 95% CI) accurate in predicting success in the development and validation cohorts, respectively. Surgical repair, successful initial repair, and repair between 2 and 6 weeks were associated with better outcomes. Discussion Machine learning algorithms for IBDI are a novel tool may help to improve the decision-making process and guide management of these patients

Lymphovascular Invasion at the Time of Radical Prostatectomy Adversely Impacts Oncological Outcomes.

Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan-Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7-23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6-2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6-3.0). The same relationship was seen across D'Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis

Prediction Model of Soles Muscle Depth Based on Anthropometric Features: Potential Applications for Dry Needling

This study was conducted to investigate if anthropometric features can predict the depth of the soleus muscle, as assessed with ultrasound imaging, in a sample of healthy individuals to assist clinicians in the application of dry needling. A diagnostic study to calculate the accuracy of a prediction model for soleus muscle depth, as assessed with ultrasonography, in the middle-third and distal-third of the calf, based on anthropometric features such as age, height, weight, body mass index (BMI), calf length, mid-third and distal-third calf girth, was conducted on 48 asymptomatic healthy subjects (75% male) involving a total of 96 calves. Multiple linear regression analyses were used to determine which variables contributed significantly to the variance in the soleus muscle depth at middle-third and distal-third of the calf by gender. Women were found to have a deeper soleus muscle than men (p < 0.001). Weight, height, BMI, and mid-third calf perimeter explained 69.9% of variance in men, whereas mid-third calf perimeter, calf length, height, and distal-third calf girth explained 73% of the variance in women of the distal-third soleus depth (p < 0.001). Additionally, mid-third calf girth and calf length explained 28.8% of variance in men, whereas mid-third calf perimeter, calf length, and weight explained 67.8% of variance in women of the mid-third soleus depth (p < 0.001). This study identified anthropometric features that predict soleus muscle depth, as assessed with ultrasound, in asymptomatic individuals, but these features are different in men and women. Our findings could assist clinicians in choosing the proper length of the needle to avoiding passing through the soleus during dry needling