Quality of Life in Mexican Older Adults: Factor Structure of the SF-36 Questionnaire.

The evaluation of quality of life may enable researchers to produce information that may improve health care and the quality of older people's lives. This research has two main goals: the first is to assess the psychometric properties of the SF-36 Health Questionnaire (construct validity and internal consistency), and the second, to calculate the factorial invariance of the questionnaire in two random, independent samples (i.e., cross-validation). The total sample consisted of 970 elderly subjects from the cities of Chihuahua and Monterrey, Mexico, with an average age of 71.18 (SD = 7.69). The factor structure of the SF-36 was analyzed through confirmatory factor analysis (CFA). The analyses show an adequate four-factor structure. The four-factor structure (Physical Function, Body Pain, Physical Role and Psychological Health) shows adequate reliability and validity indices. In addition, the results from the CFA analyses for the subsamples provide strong evidence of the stability of the four-factor structure. Future research should consider replicating the present findings in larger samples.

Factor Structure of the AUDIM-M Dimensional Self-Concept Questionnaire in Mexican Adolescents.

Self-concept is one of the most relevant variables in the field of personality, and a negative self-perception can pose a risk to the adolescent's development. The present study aimed to analyze the psychometric properties proposed by Aguirre and collaborators for the dimensional self-concept questionnaire (AUDIM-M). The total sample was 560 adolescents from the city of Chihuahua, Chihuahua, with a mean age of 12.96 ± 0.88 years. The factor structure of the questionnaire was analyzed using confirmatory factor analysis. The analyses show that a four-factor structure is viable and adequate (GFI 0.964; RMSEA 0.057; CFI 0.950). The four-factor structure (personal self-concept, physical self-concept, social self-concept, and academic self-concept), according to statistical and substantive criteria, shows adequate indicators of reliability and validity adjustment. The model obtained coincides with that proposed by Aguirre et al. Improving adolescents' self-concept undoubtedly contributes to their quality of life, hence the need for valid and reliable instruments for its measurement; this study could be a first approach for future research.

Validation of a Computerized Version of the Trait Subscale of the Physical Appearance State and Trait Anxiety Scale in Mexican Preadolescents.

Anxiety is a feeling of fear, dread or restlessness and can develop into a weight-related disorder. The objective was to analyze the psychometric properties of the trait anxiety subscale of the Physical Appearance State and Trait Anxiety Scale (PASTAS), as well as the invariance in Mexican preadolescents. The sample consisted of 604 participants, 285 female and 319 male, whose ages ranged between 11 and 12 years (M = 11.37; SD = 0.48). The questionnaire's factor structure was analyzed using confirmatory factor analyses. The analyses show the viability and adequacy of a two-factor structure (weight and non-weight factors) both for the total sample and for the populations of male and female. The two-factor structure showed adequate reliability and validity fit indicators. The factor structure, the factor loadings and intercepts are considered invariant according to the variable sex; however, differences between female and male participants were found for levels of anxiety caused by physical appearance. In conclusion, the PASTAS can be considered a convenient instrument to assess the variables related to anxiety generated by one's physical appearance, as well as allowing more participants to be quickly assessed.

Evidence of Validity and Reliability of the Lasher and Faulkender Anxiety about Aging Scale in Mexican Older Adults.

Anxiety about aging is an important mediating factor in attitudes and behavior toward elderly individuals as well as a mediating factor in the adjustment to one's own aging processes. The aim of this study was to analyze the factor structure, internal consistency and factorial invariance by sex of the Lasher and Faulkender Anxiety about Aging Scale. The sample consisted of 601 Mexican older adults, 394 women and 207 men, with a mean age of 70.69 ± 8.10 years. The factor structure of the questionnaire was analyzed using confirmatory factor analysis. Analyses show that a four-factor structure is feasible and adequate. The four-factor structure (fear of the elderly, psychological concerns, physical appearance and fear of loss), according to statistical and substantive criteria, showed adequate reliability and validity indicators. However, the obtained model does not fully coincide with that proposed by the questionnaire authors, although it continues to support the multi-factor component of anxiety about aging. On the other hand, the factor structure, the factor loadings and the intercepts are considered invariant in the two populations (men and women); however, there are differences between populations on the means of the physical appearance and fear of loss factors.

Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.

Composition Factor Analysis and Factor Invariance of the Physical Appearance State and Trait Anxiety Scale (PASTAS) in Sports and Non-Sports Practitioner Mexican Adolescents.

The purpose of the present study was to adapt and validate the Physical Appearance State and Trait Anxiety Scale (PASTAS) for Mexican adolescents, verifying the factor invariance by sports and non-sports practitioners. A sample of 930 Mexican adolescents (46.0% females), aged 11-15 years old, voluntarily participated in the study. A total of 415 participants regularly played sports in a club and/or regularly participated in sports competitions and 515 were non-sports practitioners. The adolescents filled out the trait version of the PASTAS questionnaire, which was previously translated and adapted for Mexican-speaking adolescents following the International Test Commission guidelines. The results of the confirmatory factor analyses showed an adequate measurement model for the original two-factor structure (e.g., GFI = 0.913; RMSEA = 0.078; CFI = 0.943). The internal consistency of the two dimensions was excellent (α and Ω = 0.92-0.93). Additionally, the results of the factorial invariance analyses showed an appropriate fit of the two-structure model (e.g., GFI = 0.96; CFI = 0.98; RMSEA = 0.04) among both sports and non-sports practitioners. The proposed trait version of the PASTAS questionnaire adapted to a Mexican-speaking population shows adequate psychometric properties among Mexican adolescents. The Mexican version of the PASTAS questionnaire supports the original two-factor structure (i.e., factor related to the body weight and factor not related to body weight) among adolescents. Additionally, the factorial invariance analyses support the equivalence of the two-factor structure among both sports and non-sports practitioners.

Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer.

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.

¿Qué predice la realización de dietas? Dietas, grasa corporal e insatisfacción corporal en un modelo de ecuaciones estructurales / What does dieting predict? Diets, body fat and body dissatisfaction in a structural equations

Resumen Introducción: Actualmente existe una tendencia a la realización de dietas no saludables, siendo particularmente vulnerable el estudiantado universitario debido a la asunción de responsabilidades en la adquisición de hábitos alimentarios. Objetivos: El propósito de esta investigación ha sido verificar el ajuste de un modelo teórico, con ecuaciones estructurales, para la explicación del número de dietas a través del porcentaje de grasa y la insatisfacción corporal. Las participantes han sido 244 universitarias mexicanas, con una edad media de 19.98 años (DE=1.24). Los instrumentos utilizados han sido el porcentaje de grasa, el número de dietas para perder peso realizadas durante los dos últimos años y el Cuestionario IMAGEN para evaluar los distintos componentes de la insatisfacción corporal. Resultados: Se ha obtenido un ajuste satisfactorio siendo significativas la mayoría de las relaciones hipotetizadas. Se destaca que solo el planteamiento de cambio y el componente comportamental tiene un efecto directo en el número de dietas. También se resalta la capacidad mediadora de los factores de insatisfacción corporal entre las variables porcentaje de grasa y número de dietas. Conclusiones: Teniendo en cuenta el efecto total (efectos directos e indirectos), el componente comportamental, seguido por los componentes malestar emocional, perceptivo y planteamiento de cambio de la insatisfacción corporal, son las variables con mayor poder explicativo sobre el número de dietas. El porcentaje de grasa no muestra efecto directo sobre el número de dietas.

Abstract Introduction: Currently there is a trend towards unhealthy diets with university students being particularly vulnerable due to the assumption of responsibility for the acquisition of eating habits. Objective: The purpose of this research has been to fit the theorical model for the explication of the number of diets through percentage of body fat and body dissatisfaction through structural equations. The participants have been 244 Mexican college women, whose average age was 19.88 years (DE=1.24). The used tools have been the percentage body fat, the number of diets to lose weight for the last two years and the IMAGE Questionnaire to measure the different components of body dissatisfaction. Results: A satisfactory fit has been obtained, with most of the hypothesized relationships being significant. It is highlighted that only the change approach and the behavioral component have a direct effect on the number of diets. The mediating capacity of the body dissatisfaction factors between the variable's percentage of body fat and number of diets is also highlighted. Conclusions: Considering the total effect (direct and indirect effects), the behavioral component, followed by the emotional discomfort, perceptual discomfort and the change approach components of body dissatisfaction are the variables with the greatest explanatory power on the number of diets. The percentage of body fat shows no direct effect on the number of diets.

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.

Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1.

Poly-ADP-ribosyltransferases play a critical role in DNA repair and cell death, and poly(ADP-ribosyl) polymerase 1 (PARP1) is a particularly important therapeutic target for the treatment of breast cancer because of its synthetic lethal relationship with breast cancer susceptibility proteins 1 and 2. Numerous PARP1 inhibitors have been developed, and their efficacy in cancer treatment is attributed to both the inhibition of enzymatic activity and their ability to trap PARP1 on to the damaged DNA, which is cytotoxic. Of the clinical PARP inhibitors, talazoparib is the most effective at trapping PARP1 on damaged DNA. Biochemically, talazoparib is also suspected to be a potent inhibitor of PARP5a/b (tankyrase1/2 [TNKS1/2]), which is an important regulator of Wnt/ß-catenin pathway. Here we show using competition experiments in cell lysate that, at a clinically relevant concentration, talazoparib can potentially bind and engage TNKS1. Using surface plasmon resonance, we measured the dissociation constants of talazoparib, olaparib, niraparib, and veliparib for their interaction with PARP1 and TNKS1. The results show that talazoparib has strong affinity for PARP1 as well as uniquely strong affinity for TNKS1. Finally, we used crystallography and hydrogen deuterium exchange mass spectroscopy to dissect the molecular mechanism of differential selectivity of these PARP1 inhibitors. From these data, we conclude that subtle differences between the ligand-binding sites of PARP1 and TNKS1, differences in the electrostatic nature of the ligands, protein dynamics, and ligand conformational energetics contribute to the different pharmacology of these PARP1 inhibitors. These results will help in the design of drugs to treat Wnt/ß-catenin pathway-related cancers, such as colorectal cancers.

Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors.

A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.

[Not Available]. / Composición factorial de una escala de autoeficacia en el cuidado de la alimentación y salud física en universitarios mexicanos.

Introducción: la autoeficacia es un importante factor mediador hacia cómo los individuos sienten, piensan, se motivan y se comportan. La expectativa de autoeficacia es un predictor importante de las intenciones y acciones de los individuos frente a diversas situaciones, siendo por tanto necesaria su medición. Objetivos: el presente estudio pretende indagar las propiedades psicométricas para una escala de autoeficacia en el cuidado de la alimentación y salud fisca, comprobando su estructura y su invarianza factorial. Métodos: la muestra se compuso de 1.313 estudiantes universitarios de las licenciaturas de Educación Física y Motricidad Humana que se imparten en la Universidad (omitido por anonimato), con una edad media de 20,46 años (± 1,87). La estructura factorial del cuestionario se analizó a través de análisis factoriales confirmatorios. Resultados: los análisis mostraron la adecuación de una estructura de cinco factores (ejercicio físico, cuidado de la alimentación, afrontamiento de problemas, evitación del consumo de tabaco y evitación del consumo de alcohol), mostrando adecuados índices de ajuste de fiabilidad (valores superiores a 0,85) y validez (GFI = 0,907; RMSEA = 0,053; CFI = 0,960), y explicando más del 70% de la varianza. Además, los resultados de los análisis factoriales llevados a cabo con dos submuestras indicaron fuertes evidencias de estabilidad de la estructura factorial (diferencia de CFI inferiores a 0,01). Conclusiones: la escala de autoeficacia en el cuidado de la alimentación y salud física es adecuada y puede usarse en estudios científicos. Futuras investigaciones deberían corroborar estos hallazgos.

Criterion-Related Validity of the Distance- and Time-Based Walk/Run Field Tests for Estimating Cardiorespiratory Fitness: A Systematic Review and Meta-Analysis.

OBJECTIVES: The main purpose of the present meta-analysis was to examine the criterion-related validity of the distance- and time-based walk/run tests for estimating cardiorespiratory fitness among apparently healthy children and adults. MATERIALS AND METHODS: Relevant studies were searched from seven electronic bibliographic databases up to August 2015 and through other sources. The Hunter-Schmidt's psychometric meta-analysis approach was conducted to estimate the population criterion-related validity of the following walk/run tests: 5,000 m, 3 miles, 2 miles, 3,000 m, 1.5 miles, 1 mile, 1,000 m, ½ mile, 600 m, 600 yd, » mile, 15 min, 12 min, 9 min, and 6 min. RESULTS: From the 123 included studies, a total of 200 correlation values were analyzed. The overall results showed that the criterion-related validity of the walk/run tests for estimating maximum oxygen uptake ranged from low to moderate (rp = 0.42-0.79), with the 1.5 mile (rp = 0.79, 0.73-0.85) and 12 min walk/run tests (rp = 0.78, 0.72-0.83) having the higher criterion-related validity for distance- and time-based field tests, respectively. The present meta-analysis also showed that sex, age and maximum oxygen uptake level do not seem to affect the criterion-related validity of the walk/run tests. CONCLUSIONS: When the evaluation of an individual's maximum oxygen uptake attained during a laboratory test is not feasible, the 1.5 mile and 12 min walk/run tests represent useful alternatives for estimating cardiorespiratory fitness. As in the assessment with any physical fitness field test, evaluators must be aware that the performance score of the walk/run field tests is simply an estimation and not a direct measure of cardiorespiratory fitness.

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.

C-H methylation of heteroarenes inspired by radical SAM methyl transferase.

A practical C-H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature's methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.

A simple litmus test for aldehyde oxidase metabolism of heteroarenes.

The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) as a source of CF2H radical for a rapid and inexpensive chemical "litmus test" for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO.

Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators.

The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.

Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists.

Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.

Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer.

High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.