Protocol of a first-in-human clinical trial to evaluate the safety, tolerability, and preliminary efficacy of the bispecific CD276xCD3 antibody CC-3 in patients with colorectal cancer (CoRe_CC-3).

Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide in men and women. In the metastasized stage, treatment options and prognosis are limited. To address the high medical need of this patient population, we generated a CD276xCD3 bispecific antibody termed CC-3. CD276 is expressed on CRC cells and on tumor vessels, thereby allowing for a "dual" anticancer effect. Methods and analysis: This first-in-human clinical study is planned as a prospective multicenter trial, enrolling patients with metastatic CRC after three lines of therapy. During the dose-escalation part, initially, an accelerated titration design with single-patient cohorts is employed. Here, each patient will receive a fixed dose level (starting with 50 µg for the first patient); however, between patients, dose level may be increased by up to 100%, depending on the decision of a safety review committee. Upon occurrence of any adverse events (AEs) grade ≥2, dose-limiting toxicity (DLT), or reaching a dose level of ≥800 µg, the escalation will switch to a standard 3 + 3 dose design. After maximum tolerated dose (MTD) has been determined, defined as no more than one of the six patients experiencing DLT, an additional 14 patients receive CC-3 at the MTD level in the dose-expansion phase. Primary endpoints are incidence and severity of AEs, as well as the best objective response to the treatment according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints include overall safety, efficacy, survival, quality of life, and pharmacokinetic investigations. Ethics and dissemination: The CD276xCD3 study was approved by the Ethics Committee of the Medical Faculty of the Heinrich Heine University Düsseldorf and the Paul-Ehrlich-Institut (P00702). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: ClinicalTrials.cov Registry (NCT05999396) and EU ClinicalTrials Registry (EU trial number 2022-503084-15-00).

Physical Environment vs. Social Environment: What Factors of Age-Friendliness Predict Subjective Well-Being in Men and Women?

"Age-Friendly Cities and Communities" is an initiative launched by the WHO in 2007 that has spread to more than 1000 cities and communities around the world. This initiative is based on an integrated physical and social environment for older people, and a model of participatory, collaborative governance. An enabling social environment setting is just as important as material conditions in determining well-being in later life. The objective of this study is to analyze the interaction between age-friendliness (physical and social) and subjective well-being in women and men aged 55 and over in the Basque Country. The methodology was based on a survey of a representative sample (n = 2469 individuals). In order to know the predictive power of age-friendliness over subjective well-being, linear regression models separated by gender were constructed. The predictive models of age-friendliness are composed by different variables for men and women. In both cases, the physical environment variables do not remain in the final model. Among the predictors of well-being in men, the coexistence stands out as a safety and support network. In women, the neighborhood has proved to be a very important resource. The conclusions of this study contribute to literature and interventions promoting more effective strategies that enhance older people well-being, considering the gender perspective.

Implantación efectiva de la Cuádruple Hélice basada en el Modelo de Innovación en envejecimiento activo / Effective implementation of the Quadruple Helix-Based Innovation Model for active ageing

Se presenta una experiencia práctica de implantación de la Cuádruple Hélice basada en el Modelo de Innovación de los Reference Sites de la Comisión Europea, a través del método Design Thinking. Este método establece que, para alcanzar con éxito el diseño de una solución digital, deben cubrirse cinco fases ineludibles: empatizar, definir, idear, prototipar y evaluar. Se utilizó un diseño de investigación-acción y se aplicaron técnicas cualitativas de recogida y análisis de información en cada fase: metasíntesis cualitativa, grupos focales, entrevistas biográficas, foros profesionales y comunitarios, técnicas de prototipado y testeo con personas usuarias. La aplicación sistemática de este método ha facilitado la consolidación de un modelo de trabajo cooperativo, en el que interactúan los principales agentes interesados en el envejecimiento activo y saludable. Se han creado así productos y servicios que satisfacen mejor las necesidades de las personas usuarias, haciéndolas parte activa del proceso de creación

This paper shows an experience of the practical implementation of the Quadruple Helix-Based Innovation Model of Reference Sites of the European Commission through the Design Thinking method. This method establishes that, in order to successfully achieve the design of a digital solution, five unavoidable phases must be covered: empathize, define, ideate, prototype and test. The process was approached using the research action design. Qualitative data collection and analysis techniques were applied in each phase: qualitative meta-synthesis, focus groups, biographical interviews, professional and community forums and techniques of prototyping and testing with users. The systematic application of this method has facilitated the consolidation of a cooperative work model in which the main key agents in active and healthy ageing interact. Thus, products and services have been developed to better meet the needs of the users, making them an active part of the creation process

[Effective implementation of the Quadruple Helix-Based Innovation Model for active ageing]. / Implantación efectiva de la Cuádruple Hélice basada en el Modelo de Innovación en envejecimiento activo.

This paper shows an experience of the practical implementation of the Quadruple Helix-Based Innovation Model of Reference Sites of the European Commission through the Design Thinking method. This method establishes that, in order to successfully achieve the design of a digital solution, five unavoidable phases must be covered: empathize, define, ideate, prototype and test. The process was approached using the research action design. Qualitative data collection and analysis techniques were applied in each phase: qualitative meta-synthesis, focus groups, biographical interviews, professional and community forums and techniques of prototyping and testing with users. The systematic application of this method has facilitated the consolidation of a cooperative work model in which the main key agents in active and healthy ageing interact. Thus, products and services have been developed to better meet the needs of the users, making them an active part of the creation process.

Structure-function analysis for the hydroxylation of Δ4 C21-steroids by the myxobacterial CYP260B1.

Myxobacterial CYP260B1 from Sorangium cellulosum was heterologously expressed in Escherichia coli and purified. The in vitro conversion of a small focused substrate library comprised of Δ4 C21-steroids and steroidal drugs using surrogate bovine redox partners shows that CYP260B1 is a novel steroid hydroxylase. CYP260B1 performs the regio- and stereoselective hydroxylation of the glucocorticoid cortodoxone (RSS) to produce 6ß-OH-RSS. The substrate-free crystal structure of CYP260B1 (PDB 5HIW) was resolved. Docking of the tested ligands into the crystal structure suggested that the C17 hydroxy moiety and the presence of either a keto or a hydroxy group at C11 determine the selectivity of hydroxylation.

Validez de contenido de la escala de barreras para la rehabilitación cardiaca / Content validity of the scale of barriers to cardiac rehabilitation

Introducción: La ausencia de instrumentos con adecuadas propiedades psicométricas adaptados para Colombia, que evalúen las barreras de acceso a los programas de rehabilitación cardiovascular justifica esta investigación. Objetivo: Determinar la validez de contenido de la Escala de Barreras para la Rehabilitación Cardiaca en población colombiana. Métodos y materiales: Se realizó un estudio de pruebas diagnósticas. En la primera fase se requiririeron dos traductores de lengua materna español y uno de lengua materna inglesa para la traducción y retrotraducción del cuestionario original. En la segunda fase se realizó la adaptación transcultural y se evaluó la validez de contenido mediante un panel de cuatro expertos con experiencia en investigación, medicina deportiva y rehabilitación cardiaca. Resultados: El instrumento fue traducido y adaptado al español colombiano. El panel de expertos decidió eliminar el ítem 18 de la escala original. El índice de validez de contenido fue aceptable para la mayoría de los ítems, excepto para los ítems 10, 15 y 18, por lo cual se realizaron modificaciones en palabras, frases o conjugaciones verbales según las recomendaciones del panel. Por otra parte, el Indice de Validez de Contenido en relevancia fue de 0,86 y en pertinencia de 0,88. Conclusión: Se cuenta con un instrumento que evalúa barreras de acceso a los programas de rehabilitación cardiovascular adaptada a población colombiana y con validez de contenido, por lo cual los resultados que se obtengan de la aplicación de la escala serán válidos. No obstante, se sugiere continuar con la evaluación de la reproducibilidad del instrumento.

Introduction: This research was based on the absence of instruments with appropriate psychometric properties, adapted for Colombia, which evaluate the barriers of access to cardiovascular rehabilitation programs. Objective: To determine the validity of content of the barriers scale for the cardiac rehabilitation in Colombian population. Methods and materials: A study of diagnostic tests was done. In the first phase, two native speakers of Spanish and one of English were required to translate and retro translate the original questionnaire. In the second phase, the transcultural adaptation was done and the validity of content was assessed by a panel of four experts with experience in research, sports medicine and cardiac rehabilitation. Results: The instrument was translated and adapted to the Colombian Spanish. The panel of experts decided to remove the item 18 from the original scale. The content validity index was acceptable for the majority of the items, except for items 10, 15 and 18, where modifications were made in terms of words, phrases or conjugations according to the recommendations of the panel. On the other hand, the IVC in relevance was 0.86 and relevance of 0.88. Conclusion: There is an instrument that evaluates the barriers of access to cardiovascular rehabilitation adapted to the Colombian population programs and with content validity, so the results to be obtained from the application of the scale will be valid. However, it is suggested to continue with the evaluation of the reproducibility of the instrument.

Low muscle strength is associated with metabolic risk factors in Colombian children: the ACFIES study.

PURPOSE: In youth, poor cardiorespiratory and muscular strength are associated with elevated metabolic risk factors. However, studies examining associations between strength and risk factors have been done exclusively in high income countries, and largely in Caucasian cohorts. The aim of this study was to assess these interactions in schoolchildren in Colombia, a middle income Latin American country. METHODS: We measured body mass index, body composition, handgrip strength (HG), cardiorespiratory fitness (CRF) and metabolic risk factors in 669 low-middle socioeconomic status Colombian schoolchildren (mean age 11.52±1.13, 47% female). Associations between HG, CRF and metabolic risk factors were evaluated. RESULTS: HG and CRF were inversely associated with blood pressure, HOMA index and a composite metabolic risk score (p<0.001 for all) and HG was also inversely associated with triglycerides and C-reactive protein (CRP) (both p<0.05). Associations between HG and risk factors were marginally weakened after adjusting for CRF, while associations between CRF and these factors were substantially weakened after adjusting for HG. Linear regression analyses showed inverse associations between HG and systolic BP (ß = -0.101; p = 0.047), diastolic BP (ß = -0.241; p> = 0.001), HOMA (ß = -0.164; p = 0.005), triglycerides (ß = -0.583; p = 0.026) and CRP (ß = -0.183; p = 0.037) but not glucose (p = 0.698) or HDL cholesterol (p = 0.132). The odds ratios for having clustered risk in the weakest quartile compared with the strongest quartile were 3.0 (95% confidence interval: 1.81-4.95). CONCLUSIONS: In Colombian schoolchildren both poorer handgrip strength/kg body mass and cardiorespiratory fitness were associated with a worse metabolic risk profile. Associations were stronger and more consistent between handgrip and risk factors than between cardiorespiratory fitness and these risk factors. Our findings indicate the addition of handgrip dynamometry to non-invasive youth health surveillance programs would improve the accuracy of the assessment of cardio-metabolic health.

Higher household income and the availability of electronic devices and transport at home are associated with higher waist circumference in Colombian children: the ACFIES study.

BACKGROUND: The current "epidemic" of childhood obesity is described as being driven by modern lifestyles with associated socioeconomic and environmental changes that modify dietary habits, discourage physical activity and encourage sedentary behaviors. OBJECTIVE: To evaluate the association between household income and the availability of electronic devices and transport at home, and the values of waist circumference (WC), as an indicator of abdominal obesity, in children and adolescents from Bucaramanga, Colombia. METHODS: Cross-sectional study of public elementary and high school population, of low-middle socioeconomic status. RESULTS: A total of 668 schoolchildren were recruited. After adjusting for potential confounders, significant positive associations between waist circumference and higher household income (p = 0.011), and waist circumference and the availability of electronic devices and transport at home (p = 0.026) were found. CONCLUSIONS: In low-middle socioeconomic status schoolchildren in a developing country, those from relatively more affluent families had greater waist circumference, an association that is opposite to that observed in developed countries. This finding could be related to higher income family's ability to purchase electronic devices and motorized transport which discourage physical activity and for their children to buy desirable and more costly western fast food.

Human cytochrome P450 4F11: heterologous expression in bacteria, purification, and characterization of catalytic function.

Human cytochrome P450 (P450) 4F11 is still considered an "orphan" because its function is not well characterized. A bacterial expression system was developed for human P450 4F11, producing approximately 230nmol P450 from a 3-l culture of Escherichia coli. P450 4F11 was purified and utilized for untargeted substrate searches in human liver extract using a liquid chromatography/mass spectrometry-based metabolomic and isotopic labeling approach (Tang et al., 2009 [19]). Four fatty acids-palmitic, oleic, arachidonic, and docosahexaenoic-were identified in human liver and verified as substrates of P450 4F11. The products were characterized as omega-hydroxylated fatty acids by gas chromatography-mass spectrometry analysis of their trimethylsilyl derivatives. Kinetic analysis of the oxidation products confirmed that the fatty acids are substrates oxidized by P450 4F11. P450 4F11 also exhibited low activity for some drug N-demethylation reactions but none for activation of several pro-carcinogens.