Targeted and Oxygen-Enriched Nanoplatform for Enhanced Photodynamic Therapy: In Vitro 2D Cell and 3D Spheroid Model Evaluation.

Hypoxic microenvironment and limited penetration of photosensitizers within solid tumors are two crucial factors that restrict photodynamic therapy (PDT) efficacy. Herein, a new fluorinated mixed micelle (M60@PFC-Ce6) is developed as a tumor-penetrating and oxygen-enriching nanoplatform, which consists of chlorin e6 (Ce6) and perfluorocarbons (PFCs) co-loaded into fluorinated micelles to relieve hypoxia conditions as well as folate as targeting ligand that facilitates the selective biodistribution within tumor solids. The incorporation of fluorinated copolymers into mixed micelles exhibits not only a great increase in the oxygen-loading capacity, but also improves the stability of liquid PFCs emulsion within micelles without leakage. M60@PFC-Ce6 shows excellent oxygen delivery capability, good intracellular reactive oxygen species (ROS) generation, and superior phototoxicity in vitro for both 2D monolayer of cells and 3D multicellular spheroid model. These results indicate the enriched oxygen delivery and increased cellular uptake resulting from folate-targeted ability to enhance ROS production and PDT efficacy. The penetration study of M60@PFC-Ce6 into a 3D spheroid confirms that small micellar size and folate-conjugation are beneficial for micelles to penetrate and accumulate within spheroids. Thus, a new nanoplatform with enriched oxygen-carrying amounts, better drug penetration, and stable micellar properties that relieve tumor hypoxia and improve PDT efficacy is provided.

Circular RNAs Modulate Cancer Hallmark and Molecular Pathways to Support Cancer Progression and Metastasis.

Circular RNAs (circRNAs) are noncoding products of backsplicing of pre-mRNAs which have been established to possess potent biological functions. Dysregulated circRNA expression has been linked to diseases including different types of cancer. Cancer progression is known to result from the dysregulation of several molecular mechanisms responsible for the maintenance of cellular and tissue homeostasis. The dysregulation of these processes is defined as cancer hallmarks, and the molecular pathways implicated in them are regarded as the targets of therapeutic interference. In this review, we summarize the literature on the investigation of circRNAs implicated in cancer hallmark molecular signaling. First, we present general information on the properties of circRNAs, such as their biogenesis and degradation mechanisms, as well as their basic molecular functions. Subsequently, we summarize the roles of circRNAs in the framework of each cancer hallmark and finally discuss the potential as therapeutic targets.

Targeted and oxygen-enriched polymeric micelles for enhancing photodynamic therapy.

Photodynamic therapy (PDT) has been emerged as an alternative therapeutic modality in treatment of several malignant tumors. However, the therapeutic efficacy of PDT is often limited by the solubility of photosensitizers, tumor hypoxia and lack of target specificity to cancer cells. In this study, we developed a folate-conjugated fluorinated polymeric micelle (PFFA) to deliver the hydrophobic photosensitizer (chlorin e6, Ce6) to overcome these limitations. The fluorinated micelles exhibit the low critical micelle concentration, good long-term stability, higher oxygen-carrying capacity and better singlet oxygen generation efficiency compared to non-fluorinated micelles, indicating the potential to improve the PDT efficacy in hypoxic conditions. Cytotoxicity of PDT effect and cellular uptake demonstrate the higher cell growth inhibition to HeLa cells upon irradiation attributed to the selective internalization of Ce6-loaded PFFA micelles (PFFA-Ce6). All results demonstrate the PFFA-Ce6 micelles with targeting function and oxygen-carrying capacity can serve as a promising drug delivery system for hydrophobic photosensitizers and improvement on PDT efficacy.

Improving Individual Brain Age Prediction Using an Ensemble Deep Learning Framework.

Brain age is an imaging-based biomarker with excellent feasibility for characterizing individual brain health and may serve as a single quantitative index for clinical and domain-specific usage. Brain age has been successfully estimated using extensive neuroimaging data from healthy participants with various feature extraction and conventional machine learning (ML) approaches. Recently, several end-to-end deep learning (DL) analytical frameworks have been proposed as alternative approaches to predict individual brain age with higher accuracy. However, the optimal approach to select and assemble appropriate input feature sets for DL analytical frameworks remains to be determined. In the Predictive Analytics Competition 2019, we proposed a hierarchical analytical framework which first used ML algorithms to investigate the potential contribution of different input features for predicting individual brain age. The obtained information then served as a priori knowledge for determining the input feature sets of the final ensemble DL prediction model. Systematic evaluation revealed that ML approaches with multiple concurrent input features, including tissue volume and density, achieved higher prediction accuracy when compared with approaches with a single input feature set [Ridge regression: mean absolute error (MAE) = 4.51 years, R 2 = 0.88; support vector regression, MAE = 4.42 years, R 2 = 0.88]. Based on this evaluation, a final ensemble DL brain age prediction model integrating multiple feature sets was constructed with reasonable computation capacity and achieved higher prediction accuracy when compared with ML approaches in the training dataset (MAE = 3.77 years; R 2 = 0.90). Furthermore, the proposed ensemble DL brain age prediction model also demonstrated sufficient generalizability in the testing dataset (MAE = 3.33 years). In summary, this study provides initial evidence of how-to efficiency for integrating ML and advanced DL approaches into a unified analytical framework for predicting individual brain age with higher accuracy. With the increase in large open multiple-modality neuroimaging datasets, ensemble DL strategies with appropriate input feature sets serve as a candidate approach for predicting individual brain age in the future.

Equipment Anomaly Detection for Semiconductor Manufacturing by Exploiting Unsupervised Learning from Sensory Data.

In-line anomaly detection (AD) not only identifies the needs for semiconductor equipment maintenance but also indicates potential line yield problems. Prompt AD based on available equipment sensory data (ESD) facilitates proactive yield and operations management. However, ESD items are highly diversified and drastically scale up along with the increased use of sensors. Even veteran engineers lack knowledge about ESD items for automated AD. This paper presents a novel Spectral and Time Autoencoder Learning for Anomaly Detection (STALAD) framework. The design consists of four innovations: (1) identification of cycle series and spectral transformation (CSST) from ESD, (2) unsupervised learning from CSST of ESD by exploiting Stacked AutoEncoders, (3) hypothesis test for AD based on the difference between the learned normal data and the tested sample data, (4) dynamic procedure control enabling periodic and parallel learning and testing. Applications to ESD of an HDP-CVD tool demonstrate that STALAD learns normality without engineers' prior knowledge, is tolerant to some abnormal data in training input, performs correct AD, and is efficient and adaptive for fab applications. Complementary to the current practice of using control wafer monitoring for AD, STALAD may facilitate early detection of equipment anomaly and assessment of impacts to process quality.

Effect of class-based lifestyle intervention on the management of childhood obesity.

OBJECTIVES: Childhood obesity is prevalent in southern Taiwan and lifestyle interventions for the management of childhood obesity are challenging. How to overcome the barriers of implementation programs is crucial. We offered lunchtime education and integrated it into education programs. Finally, we evaluated whether such an intervention could change unhealthy behaviors and reduce obesity tendency among elementary students. METHODS: This was a prospective cohort study, conducted at an elementary school from September 2015 to July 2018. We distributed a lifestyle questionnaire to assess the students' dietary habits and physical activities before our intervention. We offered class-based interactive nutrition programs and record the behavior and weight change each semester. The body mass index (BMI) of the students were obtained each semester, and they were categorized as underweight, normal, overweight, and obese according to the age-specific BMI. RESULTS: In total, 279 students were followed for 3 consecutive years. The most prevalent unhealthy dietary habit was the consumption of sweetened beverages in approximately 76% of the students. At the end of the study, the percentage of normal weight increased and the overall percentage of overweight/obesity decreased in both groups. At the end of the study, the BMI-time curve became flatter than that of Kaohsiung (regional) city and approached the national standard. It indicates that the increase in average BMI was effectively delayed with our intervention. CONCLUSIONS: Lunchtime education is an innovative way to provide class-based education programs in school that yielded behavior changes and are effective approaches for delaying childhood obesity.

Factor structure of a social-emotional screening instrument for preschool children / Estrutura fatorial de um instrumento de rastreio socioemocional em crianças pré-escolares / Estructura factorial de un instrumento de investigación socio-emocional en niños en edad preescolar

Screening tools in health and education provide quick indicators that anticipate diagnostic evaluation and treatment. Faced with the socio-emotional competences of children, the Ages & Stages Questionnaires: Social-Emotional (ASQ:SE) was used in the population of children enrolled in public pre-schools in the city of Rio de Janeiro during 2011. The objective of this work was to investigate aspects of its validity and reliability. Data from 23,334 children (50.6% boys) being an average age of 5 years old (SD: 3 months) and enrolled in 625 pre-schools were analyzed. After an intensive data analysis, the Exploratory and Confirmatory Factor Analysis, the results were favorable to the multidimensional model with a social and emotional dimension: χ2 (463) = 46363.495, p <0.001; RMSEA = 0.067; CFI = 0.918; TLI = 0.913. Reliability indicators were adequate. The results confirmed validity aspects of the ASQ:SE, thereby verifying its use for children aged 5 years old. (AU)

Instrumentos de rastreio em saúde e educação oferecem indicadores rápidos que antecipam a avaliação diagnóstica e o tratamento. Frente às competências socioemocionais infantis, o Ages & Stages Questionnaires: Social-Emotional (ASQ:SE) foi utilizado na população de crianças matriculadas em pré-escolas públicas do município do Rio de Janeiro durante 2011. Posto isso, o objetivo desse trabalho foi investigar aspectos de validade e fidedignidade desse instrumento. Dados de 23.334 crianças (50.6% meninos), com idade média de 5 anos de idade (DP: 3 meses) e matriculadas em 625 pré-escolas foram analisados. A partir da Análise Fatorial Exploratória e Confirmatória, os resultados foram favoráveis ao modelo com um fator emocional e outro social: χ2 (463) = 46363.495, p < 0,001; RMSEA = 0,067; CFI = 0,918; TLI = 0,913. Indicadores de fidedignidade foram adequados. Os resultados evidenciaram aspectos de validade do ASQ:SE e possibilitam seu uso em crianças com 5 anos de idade. (AU)

Instrumentos de rastreo en salud y educación ofrecen indicadores rápidos que anticipan la evaluación de diagnóstico y tratamiento. Ante las competencias socio-emocionales infantiles, el Ages & Stages Cuestionarios: Social-Emocional (ASQ:SE) fue utilizado con la población de niños preescolares de escuelas públicas del municipio de Rio de Janeiro en el año 2011. El objetivo de este trabajo fue investigar aspectos de validez y veracidad de este instrumento. Fueron analizados datos de 23.334 niños (50.6% de sexo masculino) con edad promedio de 5 años(DE: 3 meses) matriculados en 625 escuelas preescolares. A partir del Análisis Factorial Exploratorio y Confirmatorio, los resultados fueron favorables al modelo con un factor emocional y otro social: X2(463) = 46363.495, p<0,001;RMSEA = 0,067;CFI =0,918;TLI =0,913. Los indicadores de veracidad fueron adecuados y los resultados señalaron aspectos válidos del ASQ:SE que posibilitan su uso en niños con 5 años de edad. (AU)

Adapting and validating a developmental assessment for chinese infants and toddlers: The ages & stages questionnaires: Inventory.

The Chinese government has announced the 2013 Guidelines for developing a national system for early detection of disability among children under 6 years of age. However, given limited resources, challenges exist with developmental measures required in the 2013 Guidelines. In order to meet the needs for a more accurate and cost-efficient measure for developmental assessment, the Ages & Stages Questionnaires: Inventory (ASQ:I) was translated into Simplified Chinese, and validated on a regional sample of 812 Chinese children ages from 1 to 25 months. Results indicated that the Chinese ASQ:I domain scores increased across children's age. When dividing the sample into seven age intervals, Cronbach's alpha in each interval ranged from 0.59 to 0.96 across five domains. When using the whole sample for analyses, item expected a posteriori/plausible value (EAP/PV) reliability was above 0.99 in all domains, test-retest reliability using intra-class correlation analyses ranged from 0.95 to 0.99, and the agreement with the concurrent measure ranged from 0.29 to 0.89. Domain scores on the ASQ:I correctly predicted 92-99% of participating children's disability status. Findings suggested that the Chinese ASQ:I has adequate psychometric properties and thus provides a promising alternative measure for screening and progress monitoring in young children in China. Implications for future research and implementation are discussed.

Symptoms Relevant to Surveillance for Ovarian Cancer.

To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported.

ADAPTING A PARENT-COMPLETED, SOCIOEMOTIONAL QUESTIONNAIRE IN CHINA: THE AGES & STAGES QUESTIONNAIRES: SOCIAL-EMOTIONAL.

The Ages & Stages Questionnaire: Social-Emotional (ASQ:SE; Squires, Bricker, & Twombly, 2002a), developed in the United States, was translated and adapted for use in China. Lack of valid and reliable instruments for identifying social and emotional delays in young children is a worldwide issue. Professionals in China have recently focused efforts on developing methods for early identification of social, emotional, and behavioral issues in the birth-to-5 population. Following the guidelines of the International Test Commission, the ASQ:SE was translated into Simplified Chinese (ASQ:SE-C) to collect a normative sample of 2,528 children across China. Data were analyzed to evaluate the psychometric properties of the ASQ:SE-C, using both classical test theory and item response theory, including generating cutoff points appropriate for the Chinese sample. A panel of Chinese experts was surveyed to assess face validity and estimated utility of the newly adapted tool. Discussions of research findings and implications for future studies are provided.

CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling During the Early-Stage Cell Reprogramming.

PARP1 and poly(ADP-ribosyl)ation (PARylation) have been shown to be essential for the initial steps of cellular reprogramming. However, the mechanism underlying PARP1/PARylation-regulated activation of pluripotency loci remains undetermined. Here, we demonstrate that CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during reprogramming. We found that this interaction is mediated through the interplay of the CHD1L macro-domain and the PAR moiety of PARylated-PARP1. Chromatin immunoprecipitation assays demonstrated the co-occupancy of CHD1L and PARP1 at Pou5f1, Nanog, and Esrrb pluripotency loci. Knockdown of CHD1L significantly blocked the binding activity of PARP1 at pluripotency loci and inhibited the efficiency of PARP1-driven reprogramming. Notably, we found that CHD1L-promoted reprogramming requires both a PARP1-interacting domain and DNA helicase activity, partly contributing to the chromatin-remodeling states of pluripotency loci. Taken together, these results identify CHD1L as a key chromatin remodeler involved in PARP1/PARylation-regulated early-stage reprogramming and pluripotency in stem cells.

The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

A study in healthy male volunteers was completed to evaluate the safety, tolerability, and pharmacokinetics of a single oral dose of the antiparasitic moxidectin (MOX). This drug is registered worldwide as a veterinary antiparasitic agent for use in companion and farm animals. This is the first study of MOX in humans. All subjects were between the ages of 18 and 45 years, with normal cardiac, hematologic, hepatic, and renal function. Doses of MOX studied were 3, 9, 18, and 36 mg in cohorts of 6 subjects each (5:1, MOX:placebo). At the 9-mg and 36-mg doses, two separate cohorts were completed, one in the fasted state and one after the consumption of a high-fat breakfast. For all other cohorts, administration was in the fasted state. Safety and tolerability were assessed by physical examinations, ongoing evaluation of adverse events (AEs), and measurement of laboratory values. Pharmacokinetic (PK) samples were collected just prior to dosing and at various time points until 80 days postdose. Safety assessments from all dose groups studied suggested that MOX was generally safe and well tolerated, with a slightly higher incidence of transient, mild, and moderate central nervous system AEs as the dose increased as compared to placebo. The PKs of MOX were dose proportional within the dose range studied, and the elimination half-life (t1/2 elim) was long (mean: 20.2-35.1 days). At the 9-mg and 36-mg doses, a high-fat breakfast was shown to delay and increase the overall absorption but did not increase maximal concentrations when compared to administration in the fasted state. In summary, the results from this study indicate that MOX is safe and well tolerated in humans between the doses of 3 mg and 36 mg.