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Tumor-on-chips (ToCs) are useful platforms for studying the physiology of tumors and evaluating the efficacy and toxicity of anti-cancer drugs. However, the design and fabrication of a ToC system is not a trivial venture. We introduce a user-friendly, flexible, 3D-printed microfluidic device that can be used to culture cancer cells or cancer-derived spheroids embedded in hydrogels under well-controlled environments. The system consists of two lateral flow compartments (left and right sides), each with two inlets and two outlets to deliver cell culture media as continuous liquid streams. The central compartment was designed to host a hydrogel in which cells and microtissues can be confined and cultured. We performed tracer experiments with colored inks and 40 kDa fluorescein isothiocyanate dextran to characterize the transport/mixing performances of the system. We also cultured homotypic (MCF7) and heterotypic (MCF7-BJ) spheroids embedded in gelatin methacryloyl hydrogels to illustrate the use of this microfluidic device in sustaining long-term micro-tissue culture experiments. We further demonstrated the use of this platform in anticancer drug testing by continuous perfusion of doxorubicin, a commonly used anti-cancer drug for breast cancer. In these experiments, we evaluated drug transport, viability, glucose consumption, cell death (apoptosis), and cytotoxicity. In summary, we introduce a robust and friendly ToC system capable of recapitulating relevant aspects of the tumor microenvironment for the study of cancer physiology, anti-cancer drug transport, efficacy, and safety. We anticipate that this flexible 3D-printed microfluidic device may facilitate cancer research and the development and screening of strategies for personalized medicine.
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Antineoplásicos , Neoplasias da Mama , Impressão Tridimensional , Esferoides Celulares , Humanos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Esferoides Celulares/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Feminino , Células MCF-7 , Hidrogéis/química , Dispositivos Lab-On-A-Chip , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Dextranos/química , Gelatina/química , Doxorrubicina/farmacologia , Doxorrubicina/química , Sobrevivência Celular/efeitos dos fármacos , MetacrilatosRESUMO
Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system.
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Neoplasias Encefálicas , Pericitos , Microambiente Tumoral , Pericitos/imunologia , Pericitos/patologia , Pericitos/metabolismo , Humanos , Microambiente Tumoral/imunologia , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Glioma/imunologia , Glioma/patologia , Glioma/metabolismo , Glioblastoma/imunologia , Glioblastoma/patologia , Glioblastoma/metabolismo , Progressão da Doença , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
Resumen La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inma durez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteracio nes estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbi do, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones es tructurales y/o funcionales del cerebro subyacentes pue den ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.
Abstract The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually as sociated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical di sorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may indepen dently cause the predisposition to epilepsy and comor bid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.
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Introducción: la disfagia es la alteración en los mecanismos de la deglución que coexiste con múltiples enfermedades y condiciones. El conocimiento amplio de esta alteración generará mejores diagnósticos y tratamientos para el mejoramiento de la calidad de vida de estos pacientes. Aunque esta alteración podría ser del dominio común por especialistas en el área de la salud, principalmente la oral, no existe información reciente del nivel de conocimiento sobre la disfagia en el personal odontológico. Objetivo: determinar el nivel de conocimiento sobre la disfagia en un grupo de profesionales de la salud oral de Ciudad Juárez, Chihuahua. Material y método: se realizó un estudio trasversal descriptivo en un grupo de 241 odontólogos (pasantes de servicio social, odontólogos generales, periodoncistas, endodoncistas, rehabilitadores, odontopediatras y ortodoncistas) a través de una encuesta, los reactivos utilizados fueron sobre conocimiento de la disfagia, métodos de diagnóstico, signos y síntomas, tratamiento y complicaciones. Resultados: la mitad de la población encuestada refirió conocer los trastornos de la deglución (64.7%). Contrastantemente, al utilizar el término «disfagia¼, la postura del conocimiento disminuyó considerablemente (40.7%). Finalmente, los valores más bajos de la encuesta se mostraron en la falta de conocimiento sobre identificación de signos y síntomas de la disfagia (36.1%), métodos de diagnóstico (20.7%), tratamientos (18.7%) y complicaciones (23.2%). Conclusión: existe un bajo conocimiento de los trastornos de la deglución autopercibido por los profesionales de la odontología, lo que sugiere la búsqueda de los factores que ocasionan la falta del conocimiento de los profesionales del área odontológica (AU)
Introduction: dysphagia is the alteration in swallowing mechanisms that coexists with multiple diseases and conditions. The broad knowledge of this alteration will generate better diagnoses and treatments for the improvement of the quality of life of these patients. Although this alteration could be common domain by specialists in the area of health, mainly oral, there is no recent information on the level of knowledge about dysphagia in dental personnel. Objective: to determine the level of knowledge about dysphagia in a group of oral health professionals from Ciudad Juárez, Chihuahua. Material and methods: a descriptive cross-sectional study was carried out in a group of 241 dentists (social service intern, general dentists, periodontists, endodontists, rehabilitators, pediatric dentists and orthodontists) through a survey, the reagents used were on knowledge of dysphagia, diagnostic methods, signs and symptoms, treatment and complications. Results: half of the surveyed population reported knowing swallowing disorders (64.7%). In contrast, when using the term «dysphagia¼ the posture of knowledge decreased considerably (40.7%). Finally, the lowest values in the survey were found in the lack of knowledge about identification of signs and symptoms of dysphagia (36.1%), diagnostic methods (20.7%), treatments (18.7%) and complications (23.2%). Conclusion: there is a low knowledge of self-perceived swallowing disorders by dentists, which suggests the search for the factors that cause the lack of knowledge of dental professionals (AU)
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/terapia , Odontólogos/educação , Sinais e Sintomas , Epidemiologia Descritiva , Estudos Transversais , México/epidemiologiaRESUMO
BACKGROUND: The neuronal transdifferentiation of adult bone marrow cells (BMCs) is still considered an artifact based on an alternative explanation of experimental results supporting this phenomenon obtained over decades. However, recent studies have shown that following neural induction, BMCs enter an intermediate cellular state before adopting neural-like morphologies by active neurite extension and that binucleated BMCs can be formed independent of any cell fusion events. These findings provide evidence to reject the idea that BMC neural transdifferentiation is merely an experimental artifact. Therefore, understanding the intermediate states that cells pass through during transdifferentiation is crucial given their potential application in regenerative medicine and disease modelling. METHODS: In this study, we examined the functional significance of the variety of morphologies and positioning that cell nuclei of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) can adopt during neural-like differentiation using live-cell nuclear fluorescence labelling, time-lapse microscopy, and confocal microscopy analysis. RESULTS: Here, we showed that after neural induction, hBM-MSCs enter an intermediate cellular state in which the nuclei are able to move within the cells, switching shapes and positioning and even generating cellular protrusions as they attempt to contact the cells around them. These findings suggest that changes in nuclear positioning occur because human cell nuclei somehow sense their environment. In addition, we showed the process of direct interactions between cell nuclei, which opens the possibility of a new level of intercellular interaction. CONCLUSIONS: The present study advances the understanding of the intermediate stage through which hBM-MSCs pass during neural transdifferentiation, which may be crucial to understanding the mechanisms of these cell conversion processes and eventually harness them for use in regenerative medicine. Importantly, our study provides for the first time evidence that the nuclei of hBM-MSC-derived intermediate cells somehow sense their environment, generating cellular protrusions to contact other cells. In summary, human mesenchymal stromal cells could not only help to increase our understanding of the mechanisms underlying cellular plasticity but also facilitate the exact significance of nuclear positioning in cellular function and in tissue physiology.
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Células-Tronco Adultas , Neurônios , Adulto , Humanos , Diferenciação Celular/fisiologia , Extensões da Superfície Celular , Núcleo Celular , Células da Medula Óssea , Células CultivadasRESUMO
The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually associated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical disorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may independently cause the predisposition to epilepsy and comorbid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.
La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inmadurez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteraciones estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbido, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones estructurales y/o funcionales del cerebro subyacentes pueden ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.
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Epilepsia , Recém-Nascido , Humanos , Epilepsia/diagnóstico , Convulsões/etiologia , Encéfalo , ComorbidadeRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.
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Esclerose Lateral Amiotrófica , Humanos , Animais , Neurônios Motores , Modelos Animais de DoençasRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work, we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with an unknown physiological substrate, displays an immune function by controlling inflammatory and type-I interferon (IFN) responses in microglia which are detrimental to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as an effector protein regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting its binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in the ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK inhibitor to ALS model mice can modulate Ser492-phospho-Brd4 levels, suppress microglial activation, and modify the disease course, indicating a pathophysiological role of MOK kinase in ALS and neuroinflammation.
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Esclerose Lateral Amiotrófica , Proteínas que Contêm Bromodomínio , Proteínas Quinases Ativadas por Mitógeno , Doenças Neurodegenerativas , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Modelos Animais de Doenças , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas que Contêm Bromodomínio/genética , Proteínas que Contêm Bromodomínio/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismoRESUMO
The digital elevation models (DEMs) are the primary and most important spatial inputs for a wide range of hydrological applications. However, their availability from multiple sources and at various spatial resolutions poses a challenge in watershed modeling as they influence hydrological feature delineation and model simulations. In this study, we evaluated the effect of DEM choice on stream and catchment delineation and streamflow simulation using the SWAT model in four distinct geographic regions with diverse terrain surfaces. Performance evaluation metrics, including Willmott's index of agreement, and nRMSE combined with visual comparisons were employed to assess each DEM's performance. Our results revealed that the choice of DEM has a significant impact on the accuracy of stream and catchment delineation, while its influence on streamflow simulation within the same catchment was relatively minor. Among the evaluated DEMs, AW3D30 and COP30 performed the best, closely followed by MERIT, whereas TanDEM-X and HydroSHEDS exhibited poorer performance. All DEMs displayed better accuracy in mountainous and larger catchments compared to smaller and flatter catchments. Forest cover also played a role in accuracy, mainly due to its association with steep slopes. Our findings provide valuable insights for making informed data selection decisions in watershed modeling, considering the specific characteristics of the catchment and the desired level of accuracy.
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Monitoramento Ambiental , Modelos Teóricos , Monitoramento Ambiental/métodos , Rios , Florestas , Hidrologia/métodosRESUMO
Most mosquito-transmitted pathogens grow or replicate in the midgut before invading the salivary glands. Pathogens are exposed to several immunological factors along the way. Recently, it was shown that hemocytes gather near the periostial region of the heart to efficiently phagocytose pathogens circulating in the hemolymph. Nerveless, not all pathogens can be phagocyted by hemocytes and eliminated by lysis. Interestingly, some studies have shown that pericardial cells (PCs) surrounding periostial regions, may produce humoral factors, such as lysozymes. Our current work provides evidence that Anopheles albimanus PCs are a major producer of Cecropin 1 (Cec1). Furthermore, our findings reveal that after an immunological challenge, PCs upregulate Cec1 expression. We conclude that PCs are positioned in a strategic location that could allow releasing humoral components, such as cecropin, to lyse pathogens on the heart or circulating in the hemolymph, implying that PCs could play a significant role in the systemic immune response.
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Anopheles , Cecropinas , Animais , Fagocitose , Imunidade , Pericárdio , HemócitosRESUMO
Introducción: la Candida albicans (C. albicans) es un patógeno fúngico que puede causar infecciones superficiales o potencialmente mortales. Los biofilms de C. albicans muestran rasgos fenotípicos únicos, el más destacado es su notable resistencia a una amplia variedad de agentes antimicóticos. Una de las alternativas para inhibir el crecimiento de este microorganismo es el ozono debido a sus propiedades bactericidas, fungicidas y virucidas; sin embargo, escasa información ha sido reportada en C. albicans. Objetivo: el objetivo de este estudio fue evaluar el efecto fungicida del ozono en C. albicans. Material y métodos: la metodología consistió en agregar ozono a tubos de ensayo con medios de caldo nutritivo en diversas concentraciones y tiempos de ozonización. El efecto fungicida fue determinado con la determinación del número de colonias de C. albicans en agar nutritivo a través de procedimiento microbiológicos estandarizados por triplicado. Resultados: todas las muestras con ozono mostraron adecuados niveles de inhibición de crecimiento del microorganismo. Además, el efecto fungicida del ozono se encontró para ser significativamente dependiente del tiempo de ozonización y de la concentración. Conclusión: el uso de terapia con ozono podría tener potencial en el control de infecciones micóticas causadas por la presencia de C. albicans (AU)
Introduction: Candida albicans (C. albicans) is a fungal pathogen that can cause superficial or life-threatening infections. Biofilms of C. albicans display unique phenotypic traits, the most prominent being their remarkable resistance to a wide variety of antifungal agents. One of the alternatives to inhibit the growth of this microorganism is ozone due to its bactericidal, fungicidal and virucidal properties; however, little information has been reported on C. albicans. Objective: the objective of this study was to evaluate the fungicidal effect of ozone on C. albicans. Material and methods: the methodology consisted in adding ozone to test tubes with nutrient broth media in various concentrations and ozonation times. The fungicidal effect was determined by determining the number of colonies of C. albicans in nutrient agar through standardized microbiological procedures in triplicate. Results: all the ozone samples showed adequate levels of growth inhibition of the microorganism. Furthermore, the fungicidal effect of ozone was found to be significantly dependent on ozonation time and concentration. Conclusion: the use of ozone therapy could have potential in the control of fungal infections caused by the presence of C. albicans (AU)
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Candida albicans/efeitos dos fármacos , Técnicas In Vitro , Contagem de Colônia Microbiana/métodos , Crescimento Bacteriano , Ozonização , Interpretação Estatística de Dados , Meios de CulturaRESUMO
OBJECTIVE: The study has dual objectives. Our first objective (1) is to develop a community-of-practice-based evaluation methodology for knowledge-intensive computational methods. We target a whitebox analysis of the computational methods to gain insight on their functional features and inner workings. In more detail, we aim to answer evaluation questions on (i) support offered by computational methods for functional features within the application domain; and (ii) in-depth characterizations of the underlying computational processes, models, data and knowledge of the computational methods. Our second objective (2) involves applying the evaluation methodology to answer questions (i) and (ii) for knowledge-intensive clinical decision support (CDS) methods, which operationalize clinical knowledge as computer interpretable guidelines (CIG); we focus on multimorbidity CIG-based clinical decision support (MGCDS) methods that target multimorbidity treatment plans. MATERIALS AND METHODS: Our methodology directly involves the research community of practice in (a) identifying functional features within the application domain; (b) defining exemplar case studies covering these features; and (c) solving the case studies using their developed computational methods-research groups detail their solutions and functional feature support in solution reports. Next, the study authors (d) perform a qualitative analysis of the solution reports, identifying and characterizing common themes (or dimensions) among the computational methods. This methodology is well suited to perform whitebox analysis, as it directly involves the respective developers in studying inner workings and feature support of computational methods. Moreover, the established evaluation parameters (e.g., features, case studies, themes) constitute a re-usable benchmark framework, which can be used to evaluate new computational methods as they are developed. We applied our community-of-practice-based evaluation methodology on MGCDS methods. RESULTS: Six research groups submitted comprehensive solution reports for the exemplar case studies. Solutions for two of these case studies were reported by all groups. We identified four evaluation dimensions: detection of adverse interactions, management strategy representation, implementation paradigms, and human-in-the-loop support. Based on our whitebox analysis, we present answers to the evaluation questions (i) and (ii) for MGCDS methods. DISCUSSION: The proposed evaluation methodology includes features of illuminative and comparison-based approaches; focusing on understanding rather than judging/scoring or identifying gaps in current methods. It involves answering evaluation questions with direct involvement of the research community of practice, who participate in setting up evaluation parameters and solving exemplar case studies. Our methodology was successfully applied to evaluate six MGCDS knowledge-intensive computational methods. We established that, while the evaluated methods provide a multifaceted set of solutions with different benefits and drawbacks, no single MGCDS method currently provides a comprehensive solution for MGCDS. CONCLUSION: We posit that our evaluation methodology, applied here to gain new insights into MGCDS, can be used to assess other types of knowledge-intensive computational methods and answer other types of evaluation questions. Our case studies can be accessed at our GitHub repository (https://github.com/william-vw/MGCDS).
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Multimorbidade , Planejamento de Assistência ao Paciente , HumanosRESUMO
Tumor-on-chips have become an effective resource in cancer research. However, their widespread use remains limited due to issues related to their practicality in fabrication and use. To address some of these limitations, we introduce a 3D-printed chip, which is large enough to host ~1 cm3 of tissue and fosters well-mixed conditions in the liquid niche, while still enabling the formation of the concentration profiles that occur in real tissues due to diffusive transport. We compared the mass transport performance in its rhomboidal culture chamber when empty, when filled with GelMA/alginate hydrogel microbeads, or when occupied with a monolithic piece of hydrogel with a central channel, allowing communication between the inlet and outlet. We show that our chip filled with hydrogel microspheres in the culture chamber promotes adequate mixing and enhanced distribution of culture media. In proof-of-concept pharmacological assays, we biofabricated hydrogel microspheres containing embedded Caco2 cells, which developed into microtumors. Microtumors cultured in the device developed throughout the 10-day culture showing >75% of viability. Microtumors subjected to 5-fluorouracil treatment displayed <20% cell survival and lower VEGF-A and E-cadherin expression than untreated controls. Overall, our tumor-on-chip device proved suitable for studying cancer biology and performing drug response assays.
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Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor development and growth depends on close interactions between cancer cells and cells in the tumor microenvironment. During embryonic development, morphogenetic signals and direct cell contacts control cell proliferation, polarity, and morphogenesis. Cancer cells communicate with cells in the tumor niche through molecular signals and intercellular contacts, thereby modifying the vascular architecture and antitumor surveillance processes and consequently enabling tumor growth and survival. While looking for cell-to-cell signaling mechanisms that are common to both brain development and cancer progression, we have studied the infiltration process in glioblastoma multiforme (GBM), which is the most malignant primary brain tumor and with the worst prognosis. Cell-to-cell contacts, by means of filopodia-like structures, between GBM cells and brain pericytes (PCs) are necessary for adequate cell signaling during cancer infiltration; similarly, contacts between embryonic regions, via cytonemes, are required for embryo regionalization and development. This GBM-PC interaction provokes two important changes in the physiological function of these perivascular cells, namely, (i) vascular co-option with changes in cell contractility and vascular malformation, and (ii) changes in the PC transcriptome, modifying the microvesicles and protein secretome, which leads to the development of an immunosuppressive phenotype that promotes tumor immune tolerance. Moreover, the GTPase Cdc42 regulates cell polarity across organisms, from yeast to humans, playing a central role in GBM cell-PC interaction and maintaining vascular co-option. As such, a review of the molecular and cellular mechanisms underlying the development and maintenance of the physical interactions between cancer cells and PCs is of particular interest.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/metabolismo , Pericitos/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Microambiente TumoralRESUMO
Background: Surveys of back pain sufferers in the United States, China, Russia, and Germany were performed to better understand self-reported causes of acute nonspecific back pain and acute lower back pain among individuals engaging in sports and their preferred treatments. Methods: In each country, 1000 participants were surveyed (Step 1) to identify a population of nonspecific acute back pain sufferers, understand pain and treatment characteristics, and generate profiles for individuals with long-lasting (≥7 days) acute lower back pain. Subsequently, 200 participants with acute lower back pain episodes (7-21 days) and sports participation were identified in each country and completed surveys (Step 2) about sociodemographic, pain, treatment characteristics, and causes/triggers of long-lasting acute lower back pain episodes. Results: In the United States, China, Russia, and Germany, respectively, 59%, 49%, 61%, and 63% of respondents reported ≥1 episode of nonspecific acute back pain in the previous 6 months. Average numbers of monthly nonspecific acute back pain episodes in the United States, Russia, Germany, and China were 2.5, 1.8, 1.3, and 0.8, respectively. Prevalence of acute lower back pain associated with sports/leisure activities ranged from 20% (Russia and Germany) to 46% (China). Onset of long-lasting acute lower back pain was between ages 30 and 33 years, limiting usual activities and reducing walking distance in 60% to 85% of respondents across all countries. Acute lower back pain started post-exercise within the first day for ≥75% of respondents. Most popular nonprescription and prescription treatments for acute lower back pain were creams/gels in Russia, creams/gels and oral painkillers in Germany, oral painkillers in the United States, and hot/cold patches in China. Conclusion: These results help to better understand acute back pain triggers, features, and treatment preferences among sports participants in different countries. Further research is warranted to develop preventative strategies. Trial Registration: Not applicable.
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The COVID-19 pandemic spread around the world is due to the enormous capacity of the SARS-CoV-2 coronavirus to be transmitted between humans, causing a threat to global public health. It has been shown that the entry of this virus into cells is highly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Currently, we have no precise knowledge of how this receptor expresses in the brain of human fetus and, as a consequence, we do not know how susceptible the neural cells in the developing brain are to being infected through the vertical transmission of this virus, from mother to fetus. In this work, we describe the expression of ACE2 in the human brain at 20 weeks of gestation. This stage corresponds to the period of neuronal generation, migration, and differentiation in the cerebral cortex. We describe the specific expression of ACE2 in neuronal precursors and migratory neuroblasts of the dentate gyrus in the hippocampus. This finding implies that SARS-CoV-2 infection during the fetal period may affect neuronal progenitor cells and alter the normal development of the brain region where memory engrams are generated. Thus, although vertical transmission of SARS-CoV-2 infection was reported in few cases, the massive infection rate of young people in terms of the new variants leads to the possibility of increasing the ratio of congenital infections and originating cognitive alterations, as well as neuronal circuit anomalies that may represent vulnerability to mental problems throughout life.
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COVID-19 , SARS-CoV-2 , Humanos , Adolescente , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Pandemias , Peptidil Dipeptidase A , Hipocampo/metabolismo , Giro Denteado/metabolismoRESUMO
Resumen La pandemia COVID-19 se extendió por todo por a la enorme capacidad del coronavirus SARS-CoV-2 para transmitirse entre humanos. El COVID-19 es una amenaza para la salud pública mundial. La entrada de este virus en las células se ve muy facilitada por la presencia de la enzima convertidora de angiotensina 2 (ACE2) en la membrana celular. Hoy en día no tenemos un conocimiento preciso de cómo se expresa este receptor en el cerebro durante el desarrollo humano y, como consecuencia, no sabemos si las células neurales en desarrollo son susceptibles de ser infectadas a través de la transmisión de madre a feto. Revisamos en este artículo los conocimientos sobre la expresión de ACE2 en el cerebro humano en desarrollo, con especial atención a la etapa fetal. Esta etapa corresponde al periodo de formación de la corteza cerebral. La posibilidad de infección por SARS-CoV-2 durante el periodo fetal puede alterar el desarrollo normal de la corteza cerebral. Así pues, aunque se han publicado pocos casos demostrando la transmisión vertical de la infección por SARS-CoV-2, el gran número de jóvenes infectados puede representar un problema sanitario que necesite seguimiento, por la posibilidad de que se originen alteraciones cognitivas y anomalías en el desarrollo de los circuitos corticales, que pueden representar predisposición a padecer problemas mentales a lo largo de la vida.
Abstract The COVID-19 pandemic spread around the world due to the enormous transmission of the SARS-CoV-2 among humans. COVID-19 represents a threat to global public health. The entry of this virus into cells is greatly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Today we do not have a precise understanding of how this receptor expresses in the brain during human development and, as a consequence, we do not know whether neural cells in the developing brain are susceptible to infection. We review the knowledge about ACE2 expression in the developing human brain, with special attention to the fetal stage. This stage corresponds to the period of the cerebral cortex formation. Therefore, SARS-CoV-2 infection during the fetal period may alter the normal development of the cerebral cortex. Although few cases have been published demonstrating vertical transmission of SARS-CoV-2 infection, the large number of infected young people may represent a problem which requires health surveillance, due to the possibility of cognitive alterations and abnormalities in the development of cortical circuits that may represent a predisposition to mental problems later in life.
RESUMO
Clinical Practice Guidelines (CPGs) include recommendations aimed at optimising patient care, informed by a review of the available clinical evidence. To achieve their potential benefits, CPG should be readily available at the point of care. This can be done by translating CPG recommendations into one of the languages for Computer-Interpretable Guidelines (CIGs). This is a difficult task for which the collaboration of clinical and technical staff is crucial. However, in general CIG languages are not accessible to non-technical staff. We propose to support the modelling of CPG processes (and hence the authoring of CIGs) based on a transformation, from a preliminary specification in a more accessible language into an implementation in a CIG language. In this paper, we approach this transformation following the Model-Driven Development (MDD) paradigm, in which models and transformations are key elements for software development. To demonstrate the approach, we implemented and tested an algorithm for the transformation from the BPMN language for business processes to the PROforma CIG language. This implementation uses transformations defined in the ATLAS Transformation Language. Additionally, we conducted a small experiment to assess the hypothesis that a language such as BPMN can facilitate the modelling of CPG processes by clinical and technical staff.
Assuntos
Algoritmos , Sistemas Automatizados de Assistência Junto ao Leito , HumanosRESUMO
Phlebia radiata is a widespread white-rot basidiomycete fungus with significance in diverse biotechnological applications due to its ability to degrade aromatic compounds, xenobiotics, and lignin using an assortment of oxidative enzymes including laccase. In this work, a chemical screen with 480 conditions was conducted to identify chemical inducers of laccase expression in P. radiata. Among the chemicals tested, phenothiazines were observed to induce laccase activity in P. radiata, with promethazine being the strongest laccase inducer of the phenothiazine-derived compounds examined. Secretomes produced by promethazine-treated P. radiata exhibited increased laccase protein abundance, increased enzymatic activity, and an enhanced ability to degrade phenolic model lignin compounds. Transcriptomics analyses revealed that promethazine rapidly induced the expression of genes encoding lignin-degrading enzymes, including laccase and various oxidoreductases, showing that the increased laccase activity was due to increased laccase gene expression. Finally, the generality of promethazine as an inducer of laccases in fungi was demonstrated by showing that promethazine treatment also increased laccase activity in other relevant fungal species with known lignin conversion capabilities including Trametes versicolor and Pleurotus ostreatus.
RESUMO
The COVID-19 pandemic spread around the world due to the enormous transmission of the SARSCoV-2 among humans. COVID-19 represents a threat to global public health. The entry of this virus into cells is greatly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Today we do not have a precise understanding of how this receptor expresses in the brain during human development and, as a consequence, we do not know whether neural cells in the developing brain are susceptible to infection. We review the knowledge about ACE2 expression in the developing human brain, with special attention to the fetal stage. This stage corresponds to the period of the cerebral cortex formation. Therefore, SARS-CoV-2 infection during the fetal period may alter the normal development of the cerebral cortex. Although few cases have been published demonstrating vertical transmission of SARS-CoV-2 infection, the large number of infected young people may represent a problem which requires health surveillance, due to the possibility of cognitive alterations and abnormalities in the development of cortical circuits that may represent a predisposition to mental problems later in life.
La pandemia COVID-19 se extendió por todo por a la enorme capacidad del coronavirus SARS-CoV-2 para transmitirse entre humanos. El COVID-19 es una amenaza para la salud pública mundial. La entrada de este virus en las células se ve muy facilitada por la presencia de la enzima convertidora de angiotensina 2 (ACE2) en la membrana celular. Hoy en día no tenemos un conocimiento preciso de cómo se expresa este receptor en el cerebro durante el desarrollo humano y, como consecuencia, no sabemos si las células neurales en desarrollo son susceptibles de ser infectadas a través de la transmisión de madre a feto. Revisamos en este artículo los conocimientos sobre la expresión de ACE2 en el cerebro humano en desarrollo, con especial atención a la etapa fetal. Esta etapa corresponde al periodo de formación de la corteza cerebral. La posibilidad de infección por SARS-CoV-2 durante el periodo fetal puede alterar el desarrollo normal de la corteza cerebral. Así pues, aunque se han publicado pocos casos demostrando la transmisión vertical de la infección por SARS-CoV-2, el gran número de jóvenes infectados puede representar un problema sanitario que necesite seguimiento, por la posibilidad de que se originen alteraciones cognitivas y anomalías en el desarrollo de los circuitos corticales, que pueden representar predisposición a padecer problemas mentales a lo largo de la vida.