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Introduction: Prospective memory (PM) is the ability to create and execute future tasks. It is comprised of two components: cue detection and intention retrieval. PM is essential for performing high-level goals, a proficiency extremely important in college populations. Anxiety is a prevalent psychological experience in college populations that may be associated with impairments in PM. The present study examined PM performance and anxiety in college students, using neurophysiology to measure the mechanism of impairment. Methods: After self-reporting anxiety levels, 80 participants completed an event-based, focal PM task while two event-related potentials were recorded from an electroencephalogram: the N300 to assess cue detection, and the prospective positivity to assess intention retrieval. Results: The results demonstrated that, when controlling for age and gender, higher state anxiety was significantly associated with lower PM accuracy (ß = -0.27, p = 0.020) and lower prospective positivity amplitude (ß = -0.04, p = 0.021). Lower prospective positivity amplitude was significantly associated with lower PM accuracy (ß = 0.27, p = 0.015). Higher state anxiety was significantly indirectly associated with lower PM accuracy mediated by lower prospective positivity amplitude (ab = -0.11, p = 0.047). Discussion: These findings suggest intention retrieval could be a key component in supporting PM for college students with high state anxiety.
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The NIMH Research Domain Criteria (RDoC) initiative seeks to utilize multidimensional patterns of socio-cognitive behavior to improve understanding of mental illness. We aimed to evaluate the psychometric properties of a subset of RDoC tasks. Specifically, we investigated two positive valence tasks and five cognitive tasks. Participants (N = 320) were recruited through an online research platform. We used generalizability theory to estimate reliability, and factor analysis to examine factor structure. Reliability was average to excellent with some notable exceptions. Factor analysis results raised concerns about whether the factor structure of task scores aligns with the proposed RDoC model. Effects of cognitive manipulations generally supported the construct representation of tasks. Results indicate that the majority of RDoC task scores examined have acceptable reliability or can be made reliable through modest increases in task length. Future research in diverse populations is needed to better understand the factor structure of RDoC cognitive and positive valence measures.
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The ease of expression and engineering of single domain antibodies, known as nanobodies, make them attractive alternatives to conventional antibodies in point-of-care diagnostics such as lateral flow assays. In lateral flow assays, gold nanoparticle bioconjugates serve as labels which display affinity molecules on the gold surface. While examples of nanobody gold nanoparticle bioconjugates exist, few utilise the simple one-step approach of physisorption owing to undesirable nanoparticle aggregation and loss of functionality. Here we show that engineering nanobodies into multivalent structures can significantly enhance their functionality when physisorbed onto gold nanoparticles. This approach enables resulting bioconjugates to withstand multiple processing steps required for long-term nanoparticle storage within lateral flow assays. Specifically, we show that the trivalent version of VHHV nanobody (VHH3) against the S1 protein of SARS-CoV-2 can be immobilised onto gold nanoparticles through passive adsorption. Unlike its monovalent and bivalent nanobody counterparts, using VHHV3 preserves nanoparticle stability under salt stress, blocking, washing, and freeze-drying conditions while maintaining picomolar sensitivity to the S1 protein. We anticipate that this facile strategy is a significant advancement towards the integration of nanobodies in lateral flow assay development.
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Procollagen C-endopeptidase enhancer 2, known as PCPE2 or PCOC2 (gene name, PCOLCE2) is a glycoprotein that resides in the extracellular matrix, and is similar in domain organization to PCPE1 / PCPE, PCOC1 (PCOLCE1 /PCOLCE). Due to the many similarities between the two related proteins, PCPE2 has been assumed to have biological functions similar to PCPE. PCPE is a well-established enhancer of procollagen processing activating the enzyme, BMP-1. However, reports show that PCPE2 has a strikingly different tissue expression profile compared to PCPE. With that in mind and given the paucity of published studies on PCPE2, this review examines the current literature citing PCPE2 and its association with specific cell types and signaling pathways. Additionally, this review will present a brief history of PCPE2's discovery, highlighting structural and functional similarities and differences compared to PCPE. Considering the widespread use of RNA sequencing techniques to examine associations between cell-specific gene expression and disease states, we will show that PCPE2 is repeatedly found as a differentially regulated gene (DEG) significantly associated with a number of cellular processes, well beyond the scope of procollagen fibril processing.
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Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.
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BACKGROUND: Stereotactic Radiosurgery (SRS) is an emerging alternative to whole-brain radiotherapy (WBRT) for treating multiple brain metastases (BM), reducing toxicity and improving tumor control. The CYBER-SPACE trial compared SRS based on either SPACE or MPRAGE MRI sequence for avoiding or delaying WBRT in patients with 1-10 BM. METHODS: Patients with 1-10 untreated BM were randomized 1:1 to receive SRS of all lesions based on either SPACE or MPRAGE MRI sequences. If subsequently new BM occurred, SRS was repeated. WBRT was indicated upon occurrence of >10 new BM, leptomeningeal disease or exhausted SRS-radiotolerance. The primary outcome was freedom from WBRT indication (WBRTi). Secondary outcomes included overall survival (OS), safety, and quality of life. RESULTS: 202 patients were randomized; SPACE n=99, MPRAGE n=103. 12-month WBRTi-free survival was 77.1% (95%-CI: 69.5%-83.1%) overall, 78.5% (95%-CI: 66.7%-86.5%) for SPACE, and 76.0% (95%-CI: 65.2%-83.9%) for MPRAGE (HR=0.84, 95%-CI: 0.43-1.63, p=0.590). Patients with 5-10 BM had shorter WBRTi-free survival (HR=3.13, 95%-CI: 1.53-6.40, p=0.002). Median OS was 13.1 months overall, 10.5 months for SPACE, and 15.2 months for MPRAGE (HR=1.10, 95%-CI: 0.78-1.56, p=0.585). Neurologic death rate was 10.1%. Predictors for longer OS included Karnofsky Performance Status >80% (HR=0.51, 95%-CI: 0.33-0.77, p=0.002) and concurrent immunotherapy (HR=0.34, 95%-CI: 0.23-0.52, p<0.001). CONCLUSIONS: The more sensitive SPACE sequence did not improve outcomes over MPRAGE. SRS with thorough monitoring and immediate re-treatment for new lesions decreases the need for WBRT and achieves low neurologic death rates. SRS should be considered a favorable alternative to WBRT for patients with 1-10 BM.
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Purpose: Superior sulcus tumors are frequently treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery via a trimodal approach. The INKA study evaluated the replacement of photon irradiation by carbon ion radiation therapy (C12-RT) in this regimen. Methods and Materials: The prospective INKA study included patients with locally advanced non-small cell superior sulcus tumors (
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PURPOSE: Augmented reality navigation in liver surgery still faces technical challenges like insufficient registration accuracy. This study compared registration accuracy between local and external virtual 3D liver models (vir3DLivers) generated with different rendering techniques and the use of the left vs right main portal vein branch (LPV vs RPV) for landmark setting. The study should further examine how registration accuracy behaves with increasing distance from the ROI. METHODS: Retrospective registration accuracy analysis of an optical intraoperative 3D navigation system, used in 13 liver tumor patients undergoing liver resection/thermal ablation. RESULTS: 109 measurements in 13 patients were performed. Registration accuracy with local and external vir3DLivers was comparable (8.76 ± 0.9 mm vs 7.85 ± 0.9 mm; 95% CI = -0.73 to 2.55 mm; p = 0.272). Registrations via the LPV demonstrated significantly higher accuracy than via the RPV (6.2 ± 0.85 mm vs 10.41 ± 0.99 mm, 95% CI = 2.39 to 6.03 mm, p < 0.001). There was a statistically significant positive but weak correlation between the accuracy (dFeature) and the distance from the ROI (dROI) (r = 0.298; p = 0.002). CONCLUSION: Despite basing on different rendering techniques both local and external vir3DLivers have comparable registration accuracy, while LPV-based registrations significantly outperform RPV-based ones in accuracy. Higher accuracy can be assumed within distances of up to a few centimeters around the ROI.
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Realidad Aumentada , Hepatectomía , Imagenología Tridimensional , Neoplasias Hepáticas , Cirugía Asistida por Computador , Humanos , Hepatectomía/métodos , Masculino , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Cirugía Asistida por Computador/métodos , Anciano , Vena Porta/cirugía , Vena Porta/diagnóstico por imagen , Puntos Anatómicos de Referencia , Ultrasonografía Intervencional/métodosRESUMEN
Immune activation status determines non-small cell lung cancer (NSCLC) prognosis, with reported positive/negative associations for T helper type 2 (TH2) responses, including allergen-specific IgE and eosinophils. Our study seeks to explore the potential impact of these comorbid immune responses on the survival rates of patients with NSCLC. Our retrospective study used data from the Data Warehouse of the German Center for Lung Research (DZL) and Lung Biobank at Thoraxklinik Heidelberg. We estimated the association of blood eosinophilia and neutrophilia on survival rates in an inflammatory cohort of 3143 patients with NSCLC. We also tested sensitization to food and inhalants and high-sensitivity C-reactive protein (hs-CRP) in a comorbidity cohort of 212 patients with NSCLC. Finally, we estimated the infiltration of immune-relevant cells including eosinophils, T-cells, and mast cells in a tissue inflammatory sub-cohort of 60 patients with NSCLC. Sensitization to at least one food or inhalant (sIgE) was higher in patients with adenocarcinoma (adeno-LC) than the non-adenocarcinoma (non-adeno-LC). Furthermore, hs-CRP was higher in non-adeno-LC compared with adeno-LC. Peripheral inflammation, particularly eosinophilia and neutrophilia, was associated with poor survival outcomes in NSCLC with a clear difference between histological subgroups. Finally, blood eosinophilia was paralleled by significant eosinophil infiltration into the peritumoral tissue in the lung. This study provides novel perspectives on the crucial role of peripheral inflammation, featuring eosinophilia and neutrophilia, with overall survival, underscoring distinctions between NSCLC subgroups (adeno-LC vs. non-adeno-LC). Peripheral eosinophilia enhances eosinophil infiltration into tumors. This sheds light on the complex interplay between inflammation, eosinophil infiltration, and NSCLC prognosis among various histological subtypes. Further studies are required to underscore the role of eosinophils in NSCLC among different histological subgroups and their role in shaping the tumor microenvironment.
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Carcinoma de Pulmón de Células no Pequeñas , Eosinofilia , Eosinófilos , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Femenino , Masculino , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/inmunología , Eosinófilos/patología , Eosinófilos/inmunología , Eosinofilia/patología , Eosinofilia/inmunología , Eosinofilia/mortalidad , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Inflamación/patología , Inflamación/inmunología , Neutrófilos/inmunología , Neutrófilos/patología , PronósticoRESUMEN
INTRODUCTION: Latinx Millennial caregivers are an understudied minority group in the United States. Due to life stage and cultural values, these caregivers struggle to balance conflicting priorities with career, family, and caregiving. They also face systemic barriers and healthcare disparities. METHODS: Participants (N = 29) were recruited locally and nationally. Qualitative data were collected using five focus groups and one individual interview. Interviews were analyzed by seven coders using thematic analysis with an inductive approach. RESULTS: Meta-themes included (a) the Latinx experience with culture, immigrant status, and structural barriers; and (b) being a super caregiver: being everything to everyone. Additional main themes were identified including family well-being, occupational and financial well-being, social support dynamics, challenges and rewards of family caregiving, and coping strategies. DISCUSSION: Clinical interventions for Latinx Millennial caregivers should address cultural background, value of family/community, and systemic barriers for care and support.
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Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing's syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients.
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INTRODUCTION: Molecular profiling of lung cancer is essential to identify genetic alterations that predict response to targeted therapy. While deep learning shows promise for predicting oncogenic mutations from whole tissue images, existing studies often face challenges such as limited sample sizes, a focus on earlier stage patients, and insufficient analysis of robustness and generalizability. METHODS: This retrospective study evaluates factors influencing mutation prediction accuracy using the large Heidelberg Lung Adenocarcinoma Cohort (HLCC), a cohort of 2356 late-stage FFPE samples. Validation is performed in the publicly available TCGA-LUAD cohort. RESULTS: Models trained on the larger HLCC cohort generalized well to the TCGA dataset for mutations in EGFR (AUC 0.76), STK11 (AUC 0.71) and TP53 (AUC 0.75), in line with the hypothesis that larger cohort sizes improve model robustness. Variation in performance due to pre-processing and modeling choices, such as mutation variant calling, affected EGFR prediction accuracy by up to 7 %. DISCUSSION: Model explanations suggest that acinar and papillary growth patterns are critical for the detection of EGFR mutations, whereas solid growth patterns and large nuclei are indicative of TP53 mutations. These findings highlight the importance of specific morphological features in mutation detection and the potential of deep learning models to improve mutation prediction accuracy. CONCLUSION: Although deep learning models trained on larger cohorts show improved robustness and generalizability in predicting oncogenic mutations, they cannot replace comprehensive molecular profiling. However, they may support patient pre-selection for clinical trials and deepen the insight in genotype-phenotype relationships.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Mutación , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Femenino , Masculino , Receptores ErbB/genética , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Proteína p53 Supresora de Tumor/genética , Aprendizaje ProfundoRESUMEN
BACKGROUND: There is increasing evidence that air pollution and noise may have detrimental psychological impacts, but there are few studies evaluating adolescents, ground-level ozone exposure, multi-exposure models, or metrics beyond outdoor residential exposure. This study aimed to address these gaps. METHODS: Annual air pollution and traffic noise exposure at home and school were modelled for adolescents in the Greater London SCAMP cohort (N=7555). Indoor, outdoor and hybrid environments were modelled for air pollution. Cognitive and mental health measures were self-completed at two timepoints (baseline aged 11-12 and follow-up aged 13-15). Associations were modelled using multi-level multivariate linear or ordinal logistic regression. RESULTS: This is the first study to investigate ground-level ozone exposure in relation to adolescent executive functioning, finding that a 1 interquartile range increase in outdoor ozone corresponded to -0.06 (pâ¯<â¯0.001) z-score between baseline and follow-up, 38â¯% less improvement than average (median developmentâ¯+â¯0.16). Exposure to nitrogen dioxide (NO2), 24-hour traffic noise, and particulate matterâ¯<â¯10⯵g/m3 (PM10) were also significantly associated with slower executive functioning development when adjusting for ozone. In two-pollutant models, particulate matter and ozone were associated with increased externalising problems. Daytime and evening noise were associated with higher anxiety symptoms, and 24-hour noise with worse speech-in-noise perception (auditory processing). Adjusting for air pollutants, 24-hour noise was also associated with higher anxiety symptoms and slower fluid intelligence development. CONCLUSIONS: Ozone's potentially detrimental effects on adolescent cognition have been overlooked in the literature. Our findings also suggest harmful impacts of other air pollutants and noise on mental health. Further research should attempt to replicate these findings and use mechanistic enquiry to enhance causal inference. Policy makers should carefully consider how to manage the public health impacts of ozone, as efforts to reduce other air pollutants such as NO2 can increase ozone levels, as will the progression of climate change.
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Contaminantes Atmosféricos , Contaminación del Aire , Cognición , Exposición a Riesgos Ambientales , Salud Mental , Ozono , Material Particulado , Humanos , Adolescente , Londres , Contaminación del Aire/estadística & datos numéricos , Contaminación del Aire/efectos adversos , Masculino , Estudios Longitudinales , Femenino , Cognición/efectos de los fármacos , Ozono/análisis , Material Particulado/análisis , Niño , Contaminantes Atmosféricos/análisis , Ruido del Transporte/efectos adversos , Estudios de Cohortes , Dióxido de Nitrógeno/análisis , Ruido/efectos adversosRESUMEN
OBJECTIVES: The primary objective was to compare sensory processing measures in people attending specialist orthopaedic consultation for management of persistent shoulder pain with control participants. The secondary objective was to compare the groups' sociodemographic, clinical, general health and lifestyle, and psychological characteristics. DESIGN: Observational cross-sectional. METHODS: Participants with shoulder pain for ≥3 months, who attended a public hospital orthopaedic department (n = 119), and community participants without shoulder pain (n = 44) underwent a standardized quantitative sensory testing protocol, measuring pressure pain threshold, temporal summation, and conditioned pain modulation. Sociodemographic, clinical, general health and lifestyle, and psychological characteristics were also collected. RESULTS: Participants with shoulder pain had significantly lower pressure pain thresholds at all sites (ie, local and widespread mechanical hyperalgesia) and significantly decreased conditioned pain modulation effect (ie, descending inhibition of nociception) than control participants. There was no significant difference between groups for temporal summation. Participants with shoulder pain had decreased general health and function, less healthy lifestyles, and poorer psychological health compared with controls. CONCLUSION: People referred to specialist orthopaedic care for management of persistent shoulder pain had clinical signs of altered sensory processing and poor health outcomes. J Orthop Sports Phys Ther 2024;54(10):1-10. Epub 25 July 2024. doi:10.2519/jospt.2024.12512.
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Umbral del Dolor , Dolor de Hombro , Humanos , Estudios Transversales , Masculino , Femenino , Dolor de Hombro/terapia , Persona de Mediana Edad , Adulto , Derivación y Consulta , Anciano , Dimensión del Dolor , Hiperalgesia/terapia , Hiperalgesia/fisiopatología , Ortopedia , Estilo de VidaRESUMEN
The influence of solvent properties on ion generation by swab spray ionization was investigated. The ability of a variety of solvents of different relative permittivity, surface tension, and viscosity to form a stable and reproducible electrospray was examined. It is demonstrated that in swab spray ionization, a crucial balance between solvent composition, applied potential, and the solvent flow fed to the swab head must be maintained. The solvent composition was found to significantly affect the shape of the Taylor cone and the emerging cone jet, which eventually have an impact on the resulting ion yield. The results indicate that the relative permittivity of solvents measured under standard conditions is the main factor governing jet shaping, and consequently, the ionization efficacy. Short jets, which are required for maximum ion yield, were observed for solvents with relative permittivity εr higher than 25. Solvents exhibiting lower relative permittivity required the addition of 20% to 60% methanol to limit the jet length and to avoid the ineffective dripping pulsation. The observed effects were compared to conventional electrospray ionization and paper spray ionization.
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Longitudinal research can assess how diverging development of multiple cognitive skills during infancy, as well as familial background, are related to the emergence of neurodevelopmental conditions. Sensorimotor and effortful control difficulties are seen in infants later diagnosed with autism; this study explored the relationships between these skills and autism characteristics in 340 infants (240 with elevated familial autism likelihood) assessed at 4-7, 8-10, 12-15, 24, and 36 months. We tested: (1) the relationship between parent-reported effortful control (Rothbart's temperament questionnaires) and sensorimotor skills (Mullen Scales of Early Learning), using random intercept cross-lagged panel modelling; (2) whether household income and maternal education predicted stable individual differences in cognition; (3) sensorimotor and effortful control skills as individual and interactive predictors of parent-reported autism characteristics (Social Responsiveness Scale) at 3 years, using multiple regression; and (4) moderation of interactions by familial likelihood. Sensorimotor skills were longitudinally associated with effortful control at the subsequent measurement point from 12-15 months. Socioeconomic status indicators did not predict stable between-infant differences in sensorimotor or effortful control skills. Effortful control skills were longitudinally related to 3-year autism characteristics from the first year of life, with evidence for an interaction with sensorimotor skills at 24 months. Effects of effortful control increased with age and were particularly important for infants with family histories of autism. Results are discussed in relation to different theoretical frameworks: Developmental Cascades and Anterior Modifiers in the Emergence of Neurodevelopmental Disorders. We suggest a role for 24-month effortful control in explaining the emergent autism phenotype. RESEARCH HIGHLIGHTS: Sensorimotor skills longitudinally predicted effortful control from 12-15 months onward but effortful control did not longitudinally predict sensorimotor skills during infancy. Measures of effortful control skills taken before the age of 1 predicted continuous variation in autism characteristics at 36 months, with associations increasing in strength with age. Effortful control (measured at 12-15 and 24 months) was a stronger predictor of 36-month autism characteristics in infants with elevated familial likelihood for autism. The relationship between 24-month sensorimotor skills and 36-month autism characteristics was stronger in infants with weaker effortful control skills.
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Trastorno Autístico , Humanos , Lactante , Preescolar , Femenino , Masculino , Trastorno Autístico/fisiopatología , Estudios Longitudinales , Desarrollo Infantil/fisiología , Temperamento/fisiología , Cognición/fisiologíaRESUMEN
The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.
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Capecitabina , Citidina Desaminasa , Mesotelioma Maligno , Pemetrexed , Neoplasias Pleurales , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Capecitabina/farmacología , Animales , Línea Celular Tumoral , Mesotelioma Maligno/tratamiento farmacológico , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/patología , Citidina Desaminasa/metabolismo , Citidina Desaminasa/genética , Ratones , Pemetrexed/farmacología , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , Cisplatino/farmacología , Cisplatino/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Mesotelioma/tratamiento farmacológico , Mesotelioma/metabolismo , Mesotelioma/patología , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
The adult mammalian heart harbors minute levels of cycling cardiomyocytes (CMs). Large numbers of images are needed to accurately quantify cycling events using microscopy-based methods. CardioCount is a new deep learning-based pipeline to rigorously score nuclei in microscopic images. When applied to a repository of 368,434 human microscopic images, we found evidence of coupled growth between CMs and cardiac endothelial cells in the adult human heart. Additionally, we found that vascular rarefaction and CM hypertrophy are interrelated in end-stage heart failure. CardioCount is available for use via GitHub and via Google Colab for users with minimal machine learning experience.