On the way to real time protein-ligand sampling

Protein-ligand binding free energy is one of the keystones of drug design, and developing a fast method to calculate it would have great impact in personalized medicine. However, it is a daunting task for computational methods, since the conformational space is rugged, having a lot of metastable states that hinder the exploration. Using PELE and an adaptive sampling scheme, one can quickly get thermodynamic properties by traversing the conformational space on a simulation time scale (24h). We show the performance on a new benchmark of a series of different families of proteins and ligands with a large range of binding free energy differences (about 8 kcal/mol)

Binding free energy and ligand orientation calculations using a Monte Carlo method with Markov Sate analysis

Computing binding free energies has great implications in drug design. Using PELE technique, it has been shown that one can get quick and accurate estimations by means of a Markov state model3. We improved our methodology to compute faster binding relative free energy differences, mainly by analysis reducing the sampled region. This possibility opens a way in all-atom drug lead optimization by efficiently scoring a list of potential candidates in terms of binding affinities (approximately in 24hours), while still modeling accurately the protein-drug induced fit. Furthermore, we added information of the ligand orientation allowing us to obtain a better insight of the entrance mechanism. First, we show benchmark results - a series of benzamidine-like inhibitors in trypsin. Then, we apply our method to a more realistic scenario: the binding to a glucocorticoid receptor, and we show the performance for a new benchmark with a larger range of binding free energies (~14 kcal/mol). Simulations are obtained with our new in-house code PELE++, an improvement over the technique presented in references [1,2], (paper in preparation)

Estrategias de enseñanza y satisfacción percibida por los estudiantes de la escuela profesional de enfermería de la Universidad César Vallejo - San Juan de Lurigancho, 2015

El propósito planteado en esta investigación fue determinar el nivel de relación entre Estrategias de Enseñanza y Percepción de satisfacción por los estudiantes de la Escuela Profesional de Enfermería de la Universidad Cesar Vallejo sede San Juan de Lurigancho, 2015. Este estudio se desarrolló el segundo semestre del año 2015, con una muestra de tipo censal de 123 estudiantes, del tercer y cuarto año académico de la Escuela en mención, a quienes se aplicó un cuestionario referente al objetivo propuesto. Es una investigación teórica, básica o pura, pertenece a un diseño no experimental y transversal; aplicando la descripción y análisis correlacional de variables, se determinó que las Estrategias de enseñanza y la satisfacción percibida por los estudiantes tienen relación entre sí. Los datos estadísticos levantados que sustentan este estudio provienen de los resultados obtenidos de los instrumentos aplicados. La conclusión más importante a la que se llegó fue: La presencia de una relación positiva entre las estrategias de enseñanza y satisfacción percibida por los alumnos en la referida Escuela Profesional de Enfermería, año académico 2015, con un nivel de significancia de 0,05 y Rho de Spearman = 0,454 y p-valor = 0,000 < 0,05

Kikuchi-Fujimoto Disease Associated with Myasthenia Gravis: A Case Report

Kikuchi-Fujimoto disease is a self-limited benign condition of unknown etiology characterized by cervical lymphadenopathy, fever, and leucopenia. An autoimmune hypothesis has been suggested and an association with systemic lupus erythematosus, Sjogren's disease, and antiphospholipid syndrome has been noted. We report a 27-year-old male who presented for evaluation of weakness and he was diagnosed with seropositive generalized myasthenia gravis and underwent a thymectomy. He was stable until five months post-thymectomy, when he developed a high fever associated with nontender cervical lymphadenopathy, chills, and night sweats. Histopathology of a cervical lymph gland biopsy was compatible with Kikuchi-Fujimoto lymphadenitis. He improved spontaneously and was asymptomatic at the followup six months later. Our case expands the association of Kikuchi-Fujimoto disease with autoimmune disorders to include myasthenia gravis

Survival and adverse events of elderly patients treated with sorafenib for hepatocellular carcinoma

Elderly patients; Hepatocellular carcinoma; SorafenibPacients d'edat avançada; Carcinoma hepatocel·lular; SorafenibPacientes de edad avanzada; Carcinoma hepatocelular; SorafenibIntroduction: The first-line treatment for advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab, but its availability is not universal and elderly patients are underrepresented in clinical trials. There is little evidence of efficacy and tolerability in elderly patients under systemic treatment. The aims of this study were to characterize the profile of elderly patients treated with sorafenib, assess their survival and safety profile in order to extrapolate their eligibility for systemic treatment. Methods: Retrospective multicentre study of HCC patients aged ≥75 years old treated with sorafenib from January 2008 to December 2019. Demographic data, baseline characteristics, and variables related to HCC and sorafenib were recorded. Overall survival (OS) and safety were analyzed. Results: The study included 206 patients from 11 hospitals, median age 77.9 years; 71.4% men and 62.6% stage Barcelona Clinic Liver Cancer- C (BCLC-C). The main causes of cirrhosis were hepatitis C (60.7%) and alcohol (14.7%). Most patients (84.5%) started with sorafenib 800mg and 15.5% at lower dosage. Arterial hypertension (AHT) (74.2 vs 62.2%; standardized mean differences (STD): 26) and baseline ECOG-PS>0 (45.3 vs 34.7%; STD: 38.2) differed significantly between patients receiving low and full doses. Median OS was 15.4 months (18.2 in BCLC-B vs 13.6 in BCLC-C). OS was not modified by comorbidities, age or period with more expertise. Conclusions: Sorafenib appears to be safe in elderly patients with HCC. This is the first study to characterize the profile of elderly patients to be considered for systemic treatment. These findings could be used as the reference profile for elderly candidates for atezolizumab-bevacizumab

Procesos avanzados de oxidación para el tratamiento de residuos líquidos peligrosos procedentes de los laboratorios de Ingeniería de Procesos

Mediante el presente estudio se optimizaron las condiciones de operación y se evaluó la eficiencia del proceso de fotooxidación, a través del seguimiento de la degradación de la demanda química de oxígeno (DQO) y del carbono orgánico total (COT) de aguas consideradas como residuos líquidos peligrosos procedentes de los laboratorios de Ingeniería de Procesos de la Universidad EAFIT. De acuerdo con los resultados obtenidos, el proceso foto-Fenton es un método efectivo para la degradación de la materia orgánica contenida en este tipo de residuos, logrando en alta medida la recuperación de esta agua, haciéndolas altamente biodegradables por métodos biológicos sin la previa adaptación de microorganismos

Thermo-fluid numerical simulation of the crotch absorbers’ cooling pinholes for alba storage ring

The ALBA Synchrotron Light Facility crotch absorbers, that remove the unused storage ring radiation, incorporate an internal cooling system composed by a number of parallel pinholes and by the corresponding stainless steel inner tubes inserted into each of them. Water flows in the resulting annular sections to evacuate the total heat power. Around each inner tube, a spiral wire is fixed along the whole length with a given pitch height in order to enhance the convection heat transfer. The influence of several design parameters on the absorber thermo-fluid behaviour has been evaluated by means of the CFD software ANSYS CFX¿. In particular, the wall heat transfer coefficients and the pressure losses through a single pinhole have been evaluated for a range of different flow rates and pitch heights. Moreover, some modifications of the end wall geometry have been simulated as well as the effect of reversing the flow direction inside the channels. Finally, the critical crotch absorber type 3 has also been simulated and the limiting pitch height-flow rate combinations have been found based on the available driving pressure of the cooling system.Postprint (published version

Survival and adverse events of elderly patients treated with sorafenib for hepatocellular carcinoma

Elderly patients; Hepatocellular carcinoma; SorafenibPacientes ancianos; Carcinoma hepatocelular; SorafenibPacients grans; Carcinoma hepatocel·lular; SorafenibIntroduction: The first-line treatment for advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab, but its availability is not universal and elderly patients are underrepresented in clinical trials. There is little evidence of efficacy and tolerability in elderly patients under systemic treatment. The aims of this study were to characterize the profile of elderly patients treated with sorafenib, assess their survival and safety profile in order to extrapolate their eligibility for systemic treatment. Methods: Retrospective multicentre study of HCC patients aged ≥75 years old treated with sorafenib from January 2008 to December 2019. Demographic data, baseline characteristics, and variables related to HCC and sorafenib were recorded. Overall survival (OS) and safety were analyzed. Results: The study included 206 patients from 11 hospitals, median age 77.9 years; 71.4% men and 62.6% stage Barcelona Clinic Liver Cancer- C (BCLC-C). The main causes of cirrhosis were hepatitis C (60.7%) and alcohol (14.7%). Most patients (84.5%) started with sorafenib 800mg and 15.5% at lower dosage. Arterial hypertension (AHT) (74.2 vs 62.2%; standardized mean differences (STD): 26) and baseline ECOG-PS>0 (45.3 vs 34.7%; STD: 38.2) differed significantly between patients receiving low and full doses. Median OS was 15.4 months (18.2 in BCLC-B vs 13.6 in BCLC-C). OS was not modified by comorbidities, age or period with more expertise. Conclusions: Sorafenib appears to be safe in elderly patients with HCC. This is the first study to characterize the profile of elderly patients to be considered for systemic treatment. These findings could be used as the reference profile for elderly candidates for atezolizumab-bevacizumab.AS: Travel grants from Tillots, Ferring, Norgine, Alfasigma, Jansen, Abbvie. MC: None. ZV: None. SM-M: None. VS: Travel grants from Bayer. Consultancy LEO Pharma. MP: None. LC: None. RG: None. AG: None. BM: Consultancy: Bayer-Shering Pharma, Eisai-Merck. Conferences/lectures: Eisai, MSD, Roche. Research grant: Lab Viñas. Funding: BM is funded by grants PI18/00961 and PI21/00714 from Instituto de Salud Carlos III. DH. None. AC. None. SM. Conferences/lectures: Bayer. Travel grants: Bayer, and Eisai. MRo. None. MRe. Consultancy: Bayer-Shering Pharma, BMS, Roche, Ipsen, AstraZeneca, Lilly. BTG/Paid conferences: Bayer-Shering Pharma, BMS, Gilead, Lilly. Research Grants: Bayer-Shering Pharma, Ipsen. MV. Travel grants: Gilead, MSD, Bayer, Abvie. Conferences/lectures: MSD, Gilead, Abvie, Eisai