Atom-based 3D-chiral quadratic indices. Part 3: prediction of the binding affinity of the stereoisomers of fenoterolto the β2 adrenergic receptor

The non-stochastic and stochastic atom-based three dimensional(3D)-chiral quadratic indices are applied to predictthe binding affinities of 26 stereoisomers of fenoterol with the  β2-adrenoceptor (β2-AR). The prediction of β2-ARbinding affinities of the stereoisomers is carried out by multiple linear regression analysis. Two statistically significant QSAR models are obtained when non-stochastic (R 2= 0.941 and  s = 0.19) and stochastic (R2 = 0.947 and s =0.18) 3D-chiral quadratic indices are used. These models show adequate predictive power (assessed by the leaveone-out cross-validation experiment), yielding values of  q2= 0.909 ( scv = 0.219) and q2 = 0.917 (scv = 0.208), respectively. These models compare favorably with a 3D-QSAR equation obtained with the CoMFA method (R 2 = 0.920, q2= 0.847 and  scv = 0.309). The results of our work demonstrate the usefulness of our topological approach for theprediction of biological activity, even in those studies in which the three-dimensional configuration of the chemicalsplay an important role in the bioactivity

Prediction of the Binding Affinity between Fenoterol Derivatives and the β2-Adrenergic Receptor Using Atom-Based 3D-Chiral Linear Indices

The non-stochastic and stochastic atom-based 3D-chiral quadratic indices were applied to the study of the β2-adrenoceptor (β2-AR) agonist effect (binding affinities) between a set of 26 stereoisomers of fenoterol, reported with this activity. Linear multiple regression analysis was carried out to predict the β2-AR binding affinities of the stereoisomers. Two statistically significant QSAR models, able to describe more than the 92% of the variance of the experimental binding affinities, were obtained using non-stochastic (R2 = 0.924 and s = 0.21) and stochastic (R2 = 0.92 and s = 0.22) 3D-chiral linear indices, respectively. The predictability and stability (robustness) of the obtained models (assessed by the leave-one-out cross-validation experiment) yielded values of q2 = 0.893 (scv = 0.237) and q2 = 0.886 (scv = 0.245), respectively. The results obtained with our approach were slightly better than the results of a 3D-QSAR model, obtained with the CoMFA method (R2 = 0.920, q2 = 0.847 and scv = 0.309). The results of our work demonstrate the usefulness of our topological approach for drug discovery of new lead compounds, even in those studies in which the three-dimensional configuration of the chemicals play an important role in the biological activity.Los índices lineales 3D-quirales no-estocásticos y estocásticos basados en relaciones de átomos son aplicados al estudio del efecto agonista (afinidad de unión) sobre el receptor adrenérgico β2 (β2-AR) entre una serie de 26 estereoisómeros del fenoterol, a los cuales se les ha reportado esta actividad. Una regresión lineal múltiple es llevada a cabo para predecir la afinidad de unión β2-AR de los estereoisómeros. Se obtienen dos modelos QSAR estadísticamente significativos, capaces de describir más del 92 % de la varianza experimental de las afinidades de unión, empleando los índices lineales 3D-quirales no-estocásticos (R2 = 0.924 y s = 0.21) y estocásticos (R2 = 0.92 y s = 0.22) respectivamente. El poder predictivo y la robustez de los modelos obtenidos (comprobados mediante una validación cruzada dejando-uno-fuera) alcanzan valores de q2 = 0.893 (scv = 0.237) y q2 = 0.886 (scv = 0.245), correspondientemente. Los resultados obtenidos con nuestro enfoque fueron ligeramente superiores a aquellos resultados obtenidos previamente con un modelo 3D-QSAR, empleando el método CoMFA (R2 = 0.920, q2 = 0.847 y scv = 0.309). Los resultados de nuestro trabajo demuestran la utilidad de nuestro enfoque topológico para el descubrimiento de nuevos compuestos líderes candidatos a fármacos, incluso para estudios en los cuales las conformaciones tridimensionales de los compuestos juegan un rol fundamental en la actividad biológica.Ciencias Experimentale

Pyrosequencing versus methylation-specific PCR for assessment of MGMT methylation in tumor and blood samples of glioblastoma patients

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue

Metodología sistemática de análisis de patologías en morteros

En la actualidad, existe una clara necesidad de implantar metodologías que contribuyan a facilitar la comunicación entre los profesionales de diferentes campos del conocimiento implicados en el ámbito de las patologías en construcción, para disminuir la subjetividad inherente a cada profesional a la hora de tomar decisiones con respecto a la aplicación de técnicas analíticas que permitan identificar el problema que se ha producido. Con este trabajo se busca aprovechar las sinergias existentes entre los agentes implicados en el proceso constructivo con conocimientos transversales en el campo del análisis, conservación, reparación y restauración en su caso, cuya finalidad sería la de obtener mayor número de datos de entrada y, por tanto, enriquecer los contenidos y las conclusiones previas a la fase de intervención propiamente dicha, desarrollando una metodología para la selección de técnicas analíticas y/o ensayos aplicables a una patología en cada caso concreto. El presente trabajo de investigación, el cual se encuentra en fase inicial, tiene como objetivo final desarrollar una propuesta metodológica que sirva de guía a los profesionales implicados en el proceso constructivo, a la hora de seleccionar las técnicas de análisis y/o ensayos más adecuados de análisis para el estudio de las distintas patologías que pudieran aparecer en los diferentes tipos de morteros y para cada caso concreto. La investigación se inicia llevando a cabo una recopilación de todas las patologías posibles, ya sean comunes o de escasa incidencia, en todo tipo de morteros y aplicaciones constructivas. Esto se hará en base al análisis bibliográfico, consultas a laboratorios especializados y a datos estadísticos, así como a diversos grupos de investigación especializados en la materia. Una vez estudiadas y clasificadas todas las patologías en función de la tipología de mortero y su función constructiva, se establecerán para cada una de ellas las técnicas posibles de análisis que permitan establecer la causa u origen más probable de la lesión en cuestión. El paso final será desarrollar una propuesta metodológica que será validada mediante la aplicación del método Delphi de manera que permita establecer el grado de idoneidad de las diferentes técnicas de análisis para cada patología, pudiendo seleccionar las más apropiada en función de su adecuación al problema y a la casuística que lo acompaña. Este método de pronóstico consiste en una consulta a un grupo de expertos en forma individual por medio de la interacción sucesiva de un cuestionario apoyado por los resultados promedio de la ronda anterior con el fin de generar convergencia de opiniones de manera que se comprobaría, verificando o modificando la hipótesis planteada en la metodología propuesta

A smart digital health platform to enable monitoring of quality of life and frailty in older patients with cancer: a mixed-methods, feasibility study protocol

Objectives: LifeChamps is an EU Horizon 2020 project that aims to create a digital platform to enable monitoring of health-related quality of life and frailty in patients with cancer over the age of 65. Our primary objective is to assess feasibility, usability, acceptability, fidelity, adherence, and safety parameters when implementing LifeChamps in routine cancer care. Secondary objectives involve evaluating preliminary signals of efficacy and cost-effectiveness indicators. Data Sources: This will be a mixed-methods exploratory project, involving four study sites in Greece, Spain, Sweden, and the United Kingdom. The quantitative component of LifeChamps (single-group, pre-post feasibility study) will integrate digital technologies, home-based motion sensors, self-administered questionnaires, and the electronic health record to (1) enable multimodal, real-world data collection, (2) provide patients with a coaching mobile app interface, and (3) equip healthcare professionals with an interactive, patient-monitoring dashboard. The qualitative component will determine end-user usability and acceptability via end-of-study surveys and interviews. Conclusion: The first patient was enrolled in the study in January 2023. Recruitment will be ongoing until the project finishes before the end of 2023. Implications for Nursing Practice: LifeChamps provides a comprehensive digital health platform to enable continuous monitoring of frailty indicators and health-related quality of life determinants in geriatric cancer care. Real-world data collection will generate “big data” sets to enable development of predictive algorithms to enable patient risk classification, identification of patients in need for a comprehensive geriatric assessment, and subsequently personalized care

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Prediction of the Binding Affinity between Fenoterol Derivatives and the b2 Adrenergic Receptor Using Atom-Based 3D-Chiral LinearIndices

The non-stochastic and stochastic atom-based 3D-chiral quadratic indices were applied to the study of the β2 - adrenoceptor (β2 -AR) agonist effect (binding affinities) between a set of 26 stereoisomers of fenoterol, reported with this activity. Linear multiple regression analysis was carried out to predict the β2 -AR binding affinities of the stereoisomers. Two statistically significant QSAR models, able to describe more than the 92% of the variance of the experimental binding affinities, were obtained using non-stochastic (R2 = 0.924 and s = 0.21) and stochastic (R2 = 0.92 and s = 0.22) 3D-chiral linear indices, respectively. The predictability and stability (robustness) of the obtained models (assessed by the leave-one-out cross-validation experiment) yielded values of q2 = 0.893 (scv = 0.237) and q2 = 0.886 (scv = 0.245), respectively. The results obtained with our approach were slightly better than the results of a 3DQSAR model, obtained with the CoMFA method (R2 = 0.920, q2 = 0.847 and scv = 0.309). The results of our work demonstrate the usefulness of our topological approach for drug discovery of new lead compounds, even in those studies in which the three-dimensional configuration of the chemicals play an important role in the biological activity.Los índices lineales 3D-quirales no-estocásticos y estocásticos basados en relaciones de átomos son aplicados al estudio del efecto agonista (afinidad de unión) sobre el receptor adrenérgico β2 (β2 -AR) entre una serie de 26 estereoisómeros del fenoterol, a los cuales se les ha reportado esta actividad. Una regresión lineal múltiple es llevada a cabo para predecir la afinidad de unión β2 -AR de los estereoisómeros. Se obtienen dos modelos QSAR estadísticamente significativos, capaces de describir más del 92 % de la varianza experimental de las afinidades de unión, empleando los índices lineales 3D-quirales no-estocásticos (R2 = 0.924 y s = 0.21) y estocásticos (R2 = 0.92 y s = 0.22) respectivamente. El poder predictivo y la robustez de los modelos obtenidos (comprobados mediante una validación cruzada dejando-uno-fuera) alcanzan valores de q2 = 0.893 (scv = 0.237) y q2 = 0.886 (scv = 0.245), correspondientemente. Los resultados obtenidos con nuestro enfoque fueron ligeramente superiores a aquellos resultados obtenidos previamente con un modelo 3D-QSAR, empleando el método CoMFA (R2 = 0.920, q2 = 0.847 y scv = 0.309). Los resultados de nuestro trabajo demuestran la utilidad de nuestro enfoque topológico para el descubrimiento de nuevos compuestos líderes candidatos a fármacos, incluso para estudios en los cuales las conformaciones tridimensionales de los compuestos juegan un rol fundamental en la actividad biológica

In silico Antibacterial Activity Modeling Based on the TOMOCOMD-CARDD Approach

In the recent times, the race to cope with the increasing multidrug resistance of pathogenic bacteria has lost much of its momentum and health professionals are grasping for solutions to deal with the unprecedented resistance levels. As a result, there is an urgent need for a concerted effort towards the development of new antimicrobial drugs to stay ahead in the fight against the ever adapting bacteria. In the present report, antibacterial classification functions (models) based on the topological molecular computational design-computer aided &#8216;&#8216;rational&#8217;&#8217; drug design (TOMOCOMD-CARDD) atom-based non-stochastic and stochastic bilinear indices are presented. These models were built using the linear discriminant analysis (LDA) method over a balanced chemical compounds dataset of 2230 molecular structures, with a diverse range of structural and molecular mechanism modes. The results of this study indicated that the non-stochastic and stochastic bilinear indices provided excellent classification of the chemical compounds (with accuracies of 86.31% and 84.92%, respectively, in the training set). These models were further externally validated yielding correct classification percentages of 86.55% and 87.91% for the non-stochastic and stochastic bilinear models, respectively. Additionally, the obtained models were compared with those reported in the literature and demonstrated comparable results, although the latter were built over much smaller datasets and with much higher degrees of freedom. Finally, simulated ligand-based virtual screening of 116 compounds, recently identified as potential antibacterials, was performed yielding 86.21% and 83.62% of correct classification, respectively, and thus demonstrating the utility of the obtained TOMOCOMD-CARDD models in the search of novel compounds with desirable antibacterial activity

A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01).

Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome. Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948). From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P  Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS. 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.3. Extending adjuvant temozolomide was linked to increased toxicities