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Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
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Inmunidad Innata , Nucleotidiltransferasas , Humanos , Animales , Nucleotidiltransferasas/metabolismo , Inmunidad Innata/genética , Transducción de Señal/genética , ADN/metabolismo , Receptores de Reconocimiento de PatronesRESUMEN
Astragalus polysaccharide-containing 3D-printed scaffold shows great potential in traumatic skin repair. This study aimed to investigate its repairing effect and to combine it with proteomic technology to deeply resolve the related protein expression changes. Thirty SD rats were divided randomly into three groups (n = 10 per group): the sham-operated group, the model group and the scaffold group. Subsequently, we conducted a comparative analysis on trauma blood perfusion, trauma healing rate, histological changes, the expression of the YAP/TAZ signalling pathway and angiogenesis-related factors. Additionally, neonatal skin tissues were collected for proteomic analysis. The blood perfusion volume and wound healing recovery in the scaffold group were better than that in the model group (p < 0.05). The protein expression of STAT3, YAP, TAZ and expression of vascular-related factor A (VEGFA) in the scaffold group was higher than that in the model group (p < 0.05). Proteomic analysis showed that there were 207 differential proteins common to the three groups. Mitochondrial function, immune response, redox response, extracellular gap and ATP metabolic process were the main groups of differential protein changes. Oxidative phosphorylation, metabolic pathway, carbon metabolism, calcium signalling pathway, etc. were the main differential metabolic pathway change groups. Astragalus polysaccharide-containing 3D-printed scaffold had certain reversals of protein disorder. The Astragalus polysaccharide-containing 3D-printed scaffold may promote the VEGFs by activating the YAP/TAZ signalling pathway with the help of STAT3 into the nucleus, accelerating early angiogenesis of the trauma, correcting the protein disorder of the trauma and ultimately realizing the repair of the wound.
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Planta del Astrágalo , Polisacáridos , Impresión Tridimensional , Proteómica , Ratas Sprague-Dawley , Piel , Andamios del Tejido , Cicatrización de Heridas , Animales , Cicatrización de Heridas/efectos de los fármacos , Proteómica/métodos , Polisacáridos/química , Planta del Astrágalo/química , Andamios del Tejido/química , Piel/metabolismo , Ratas , Transducción de Señal , MasculinoRESUMEN
Fiber tract segmentation is a prerequisite for tract-based statistical analysis. Brain fiber streamlines obtained by diffusion magnetic resonance imaging and tractography technology are usually difficult to be leveraged directly, thus need to be segmented into fiber tracts. Previous research mainly consists of two steps: defining and computing the similarity features of fiber streamlines, then adopting machine learning algorithms for fiber clustering or classification. Defining the similarity feature is the basic premise and determines its potential reliability and application. In this study, we adopt geometric features for fiber tract segmentation and develop a novel descriptor (FiberGeoMap) for the corresponding representation, which can effectively depict fiber streamlines' shapes and positions. FiberGeoMap can differentiate fiber tracts within the same subject, meanwhile preserving the shape and position consistency across subjects, thus can identify common fiber tracts across brains. We also proposed a Transformer-based encoder network called FiberGeoMap Learner, to perform segmentation based on the geometric features. Experimental results showed that the proposed method can differentiate the 103 various fiber tracts, which outperformed the existing methods in both the number of categories and segmentation accuracy. Furthermore, the proposed method identified some fiber tracts that were statistically different on fractional anisotropy (FA), mean diffusion (MD), and fiber number ration in autism.
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Trastorno Autístico , Sustancia Blanca , Humanos , Trastorno Autístico/diagnóstico por imagen , Trastorno Autístico/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen de Difusión Tensora/métodos , Reproducibilidad de los Resultados , Procesamiento de Imagen Asistido por Computador/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen de Difusión por Resonancia Magnética/métodosRESUMEN
BACKGROUND: There is evidence indicating that both lipoprotein(a) [Lp(a)] and fibrinogen (FIB) are associated with mortality, However, the impact of their combination on mortality has not been determined. Thus, the aim of this study was to examine the association between the combination of Lp(a) and FIB with all-cause and cause-specific mortality. METHODS: This prospective cohort study enrolled 4,730 participants from the third National Health and Nutrition Examination Survey. The exposure variables included Lp(a), FIB and their combination, while the outcome variables consisted of all-cause, cardiovascular disease (CVD) and cancer-related mortality. Multivariate COX regression, subgroup analysis, sensitivity analysis and restricted cubic spline (RCS) were used to investigate the association between Lp(a), FIB and their combination with all-cause, CVD and cancer-related mortality. RESULTS: Over a median follow-up period of 235 months, 2,668 individuals died, including 1,051 deaths attributed to CVD and 549 deaths due to cancer. Multivariate Cox regression analyses revealed independent associations between both Lp(a) and FIB with all-cause, CVD, and cancer-related mortality. Compared to participants in the 1st to 50th percentiles of both Lp(a) and FIB, those in the 90th to 100th percentiles exhibited multivariable adjusted HRs of 1.813 (95% CI: 1.419-2.317, P < 0.001), 2.147 (95% CI: 1.483-3.109, P < 0.001) and 2.355 (95% CI: 1.396, 3.973, P = 0.001) for all-cause, CVD and cancer-related mortality, respectively. Subgroup and sensitivity analyses did not substantially attenuate the association between the combination of high Lp(a) and high FIB with the risk of all-cause and CVD-related mortality. Additionally, the RCS analysis showed that the relationship between Lp(a) and the risk of all-cause and cancer-related mortality, as well as the relationship between FIB and the risk of cancer-related mortality, were linear (P for nonlinearity > 0.05). Conversely, the relationship between Lp(a) and the risk of CVD-related mortality, as well as the relationship between FIB and the risk of all-cause and CVD-related mortality, were nonlinear (P for nonlinearity < 0.05). CONCLUSIONS: High levels of Lp(a) and FIB together conferred a greater risk of mortality from all-cause, CVD and cancer.
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Enfermedades Cardiovasculares , Causas de Muerte , Fibrinógeno , Lipoproteína(a) , Neoplasias , Encuestas Nutricionales , Humanos , Neoplasias/mortalidad , Lipoproteína(a)/sangre , Enfermedades Cardiovasculares/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Fibrinógeno/análisis , Adulto , Estados Unidos/epidemiología , Anciano , Factores de RiesgoRESUMEN
Bicyclol, an innovative hepatoprotective drug, was approved by the Chinese National Medical Products Administration (NMPA) in 2001 to treat Hepatitis B and drug-induced liver injury. Two active metabolites of bicyclol have been identified as M2 and M3. To evaluate the impact on drug safety and efficacy of possible drug-drug interactions (DDIs) associated with these metabolites, a sufficient quantity of these metabolites is required. Herein, we report a concise novel route for the synthesis of M2 and M3 using the Suzuki-Miyaura coupling as the key step. Furthermore, we complete the gram-scale syntheses of M2 and M3.
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Compuestos de Bifenilo , Enfermedad Hepática Inducida por Sustancias y Drogas , Compuestos de Bifenilo/farmacología , Sustancias Protectoras , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológicoRESUMEN
The study aimed to explore the association between five heavy metals exposure (Cadmium, Lead, Mercury, Manganese, and Selenium) and mortality [all-cause, cardiovascular disease (CVD), and cancer-related]. We integrated the data into the National Health and Nutrition Examination Survey from 2011 to 2018 years. A total of 16,092 participants were recruited. The link between heavy metals exposure and mortality was analyzed by constructing a restricted cubic spline (RCS) curve, Cox proportional hazard regression model, and subgroup analysis. The RCS curve was used to show a positive linear relationship between Cadmium, Lead, and all-cause mortality. In contrast, there was a negative linear correlation between Mercury and all-cause mortality. Additionally, Manganese and Selenium also had a J-shaped and L-shaped link with all-cause mortality. The positive linear, positive linear, negative liner, J-shaped, and L-shaped relationships were observed for Cadmium, Lead, Mercury, Manganese, and Selenium and CVD mortality, respectively. Cadmium, Lead, Mercury, and Selenium were observed to exhibit positive linear, U-shaped, negative linear, and L-shaped relationships with cancer-related mortality, respectively. There was an increase and then a decrease in the link between Manganese and cancer-related morality. This study revealed the correlation between the content of different elements and different types of mortality in the U.S. general population.
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Enfermedades Cardiovasculares , Mercurio , Metales Pesados , Neoplasias , Selenio , Humanos , Cadmio/análisis , Manganeso , Selenio/análisis , Causas de Muerte , Encuestas Nutricionales , Estudios de Cohortes , Mercurio/análisisRESUMEN
Lipid metabolism plays an important role in the repair of skin wounds. Studies have shown that acupuncture is very effective in skin wound repair. However, there is little knowledge about the mechanism of electroacupuncture. Thirty-six SD rats were divided into three groups: sham-operated group, model group and electroacupuncture group, with six rats in each group. After the intervention, orbital venous blood was collected for lipid metabolomics analysis, wound perfusion was detected and finally the effect of electroacupuncture on skin wound repair was comprehensively evaluated by combining wound healing rate and histology. Lipid metabolomics analysis revealed 11 differential metabolites in the model versus sham-operated group. There were 115 differential metabolites in the model versus electro-acupuncture group. 117 differential metabolites in the electro-acupuncture versus sham-operated group. There were two differential metabolites common to all three groups. Mainly cholesteryl esters and sphingolipids were elevated after electroacupuncture and triglycerides were largely decreased after electroacupuncture. The electroacupuncture group recovered faster than the model group in terms of blood perfusion and wound healing (p < 0.05). Electroacupuncture may promote rat skin wound repair by improving lipid metabolism and improving local perfusion.
RESUMEN
Lipid metabolism plays an important role in the repair of skin wounds. Studies have shown that acupuncture is very effective in skin wound repair. However, there is little knowledge about the mechanism of electroacupuncture. Thirty-six SD rats were divided into three groups: sham-operated group, model group and electroacupuncture group, with 12 rats in each group. After the intervention, local skin tissues were collected for lipid metabolomics analysis, wound perfusion and ferroptosis-related indexes were detected and finally the effect of electroacupuncture on skin wound repair was comprehensively evaluated by combining wound healing rate and histology. Lipid metabolomics analysis revealed 37 differential metabolites shared by the three groups, mainly phospholipids, lysophospholipids, glycerides, acylcarnitine, sphingolipids and fatty acids, and they could be back-regulated after electroacupuncture. The recovery of blood perfusion and wound healing was faster in the electroacupuncture group than in the model group (p < 0.05). The levels of GPX4, FTH1, SOD and GSH-PX, which are related to ferroptosis, were higher in the electroacupuncture group than in the model group (p < 0.05). The levels of ACSL4 and MDA were lower in the electroacupuncture group than in the model group (p < 0.05). Electroacupuncture may promote skin wound repair by improving lipid metabolism and inhibiting ferroptosis in local tissues.
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Electroacupuntura , Ferroptosis , Animales , Ratas , Ratas Sprague-Dawley , Metabolismo de los Lípidos , Ácidos GrasosRESUMEN
The preparation of biodegradable scaffolds loaded with cells and cytokine is a feature of tissue-engineered skin. IPSCs-based tissue-engineered skin treatment for wound repair is worth exploring. Healthy human skin fibroblasts were collected and reprogrammed into iPSCs. After gene modification and induction, CK19+ /Integrinß1+ /CD200+ VEGF165 gene-modified iPS-HFSCsGFP were obtained and identified by a combination of immunofluorescence and RT-qPCR. Astragalus polysaccharide-containing 3D printed degradable scaffolds were prepared and co-cultured with VEGF165 gene-modified iPS-HFSCsGFP , and the biocompatibility and spatial structure of the tissue-engineered skin was analysed by cell counting kit-8 (CCK8) assay and scanning electron microscopy. Finally, the tissue-engineered skin was transplanted onto the dorsal trauma of nude mice, and the effect of tissue-engineered skin on the regenerative repair of total skin defects was evaluated by a combination of histology, immunohistochemistry, immunofluorescence, RT-qPCR, and in vivo three-dimensional reconstruction under two-photon microscopy. CK19+ /Integrinß1+ /CD200+ VEGF165 gene-modified iPS-HFSCsGFP , close to the morphology and phenotype of human-derived hair follicle stem cells, were obtained. The surface of the prepared 3D printed degradable scaffold containing 200 µg/mL astragalus polysaccharide was enriched with honeycomb-like meshwork, which was more conducive to the proliferation of the resulting cells. After tissue-engineered skin transplantation, combined assays showed that it promoted early vascularization, collagen and hair follicle regeneration and accelerated wound repair. VEGF165 gene-modified iPS-HFSCsGFP compounded with 3D printed degradable scaffolds containing 200 µg/mL astragalus polysaccharide can directly and indirectly participate in vascular, collagen, and hair follicle regeneration in the skin, achieving more complete structural and functional skin regenerative repair.
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Trasplante de Piel , Factor A de Crecimiento Endotelial Vascular , Ratones , Animales , Humanos , Trasplante de Piel/métodos , Factor A de Crecimiento Endotelial Vascular/genética , Ratones Desnudos , Estudios de Factibilidad , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Colágeno , Polisacáridos/farmacología , Impresión TridimensionalRESUMEN
BACKGROUND: Porcine epidemic diarrhea virus (PEDV) variant strains cause great economic losses to the global swine industry. However, vaccines do not provide sufficient protection against currently circulating strains due to viral mutations. This study traced the molecular characteristics of the most recent isolates in China and aimed to provide a basis for the prevention and treatment of PEDV. METHODS: We obtained samples from a Chinese diarrheal swine farm in 2022. Reverse transcription polymerase chain reaction and immunofluorescence were used to determine the etiology, and the full-length PEDV genome was sequenced. Nucleotide similarity was calculated using MEGA to construct a phylogenetic tree and DNASTAR. Mutant amino acids were aligned using DNAMAN and modeled by SWISS-MODEL, Phyre2 and FirstGlance in JMOL for protein tertiary structure simulation. Additionally, TMHMM was used for protein function prediction. RESULTS: A PEDV virulent strain CH/HLJJS/2022 was successfully isolated in China. A genome-wide based phylogenetic analysis suggests that it belongs to the GII subtype, and 96.1-98.9% homology existed in the whole genomes of other strains. For the first time, simultaneous mutations of four amino acids were found in the highly conserved membrane (M) and nucleocapsid (N) proteins, as well as eight amino acid mutations that differed from the vast majority of strains in the spike (S) protein. Three of the mutations alter the S-protein spatial structure. In addition, typing markers exist during strain evolution, but isolates are using the fusion of specific amino acids from multiple variant strains to add additional features, as also demonstrated by protein alignments and 3D models of numerous subtype strains. CONCLUSION: The newly isolated prevalent strain CH/HLJJS/2022 belonged to the GII subtype, and thirteen mutations different from other strains were found, including mutations in the highly conserved m and N proteins, and in the S1° and COE neutralizing epitopes of the S protein. PEDV is breaking through original cognitions and moving on a more complex path. Surveillance for PEDV now and in the future and improvements derived from mutant strain vaccines are highly warranted.
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Infecciones por Coronavirus , Virus de la Diarrea Epidémica Porcina , Enfermedades de los Porcinos , Vacunas Virales , Porcinos , Animales , Filogenia , Mutación , Vacunas Virales/genética , Aminoácidos/genética , China/epidemiología , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/veterinaria , Enfermedades de los Porcinos/epidemiologíaRESUMEN
AIMS: Individuals with diabetes have increased cardiovascular risk. Although PCSK9 inhibitors bring about a wide reduction in lipids, there is uncertainty about the effects for diabetic patients. We conducted a systematic review and meta-analysis to assess the efficacy and safety of PCSK9 inhibitors for diabetes. DATA SYNTHESIS: We performed a meta-analysis comparing treatment with PCSK9 inhibitors versus controls up to July 2022. Primary efficacy endpoints were percentage changes in lipid profile parameters. We used random effects meta-analyses to combine data. Subgroups of diabetic patients (by diabetes type, baseline LDL-C, baseline HbA1c and follow-up time) were also compared. We included 12 RCTs comprising 14,702 patients. Mean reductions in LDL-C were 48.20% (95% CI: 35.23%, 61.17%) in patients with diabetes. Reductions observed with PCSK9 inhibitors were 45.23% (95% CI: 39.43%, 51.02%) for non-HDL-cholesterol, 30.39% (95% CI: 24.61%, 36.17%) for total cholesterol, 11.96% (95% CI: 6.73%, 17.19%) for triglycerides, 27.87% (95% CI: 22.500%, 33.17%) for lipoprotein(a), 42.43% (95% CI: 36.81%, 48.06%) for apolipoprotein B; increases in HDL-C of 5.97% (95% CI: 4.59%, 7.35%) were also observed. There was no significant difference in fasting plasma glucose (FPG) (WMD: 2.02 mg/mL; 95% CI: -1.83, 5.87) and HbA1c (WMD: 1.82%; 95% CI: -0.63, 4.27). Use of a PCSK9 inhibitor was not associated with increased risk of treatment-emergent adverse event (TEAE) (p = 0.542), serious adverse event (SAE) (p = 0.529) and discontinuations due to AEs (p = 0.897). CONCLUSIONS: PCSK9 inhibitor therapy should be considered for all diabetic individuals at high risk of atherosclerotic cardiovascular disease. REGISTRATION CODE IN PROSPERO: CRD42022339785.
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Anticolesterolemiantes , Diabetes Mellitus , Humanos , Inhibidores de PCSK9 , Proproteína Convertasa 9 , LDL-Colesterol , Hemoglobina Glucada , Anticuerpos Monoclonales Humanizados/efectos adversos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamiento farmacológico , Colesterol , Inhibidores Enzimáticos , Anticolesterolemiantes/efectos adversosRESUMEN
BACKGROUND AND AIM: To determine trends in lipid profiles and lipid control in US adults with diabetes and assess variation in these trends across sex and race/ethnicity from 2007 to 2018. METHODS AND RESULTS: Serial cross-sectional analysis of data from diabetic adults participating in the National Health and Nutrition Examination Survey (NHANES; 2007-2008 to 2017-2018). Among the 6116 participants included (weighted mean age, 61.0 years; 50.7% men), age-adjusted TC (p for trend < 0.001), LDL-C (p for trend < 0.001), TG (p for trend = 0.006), TG/HDL-C (p for trend = 0.014) and VLDL-C (p for trend = 0.015) decreased significantly. Age-adjusted LDL-C levels were consistently higher in women than in men over the study period. Age-adjusted LDL-C improved significantly for diabetic whites and blacks but did not change significantly for the other races/ethnicity. Lipid parameters improved for non-coronary heart disease (CHD) diabetic adults, except for HDL-C, while no lipid parameter significantly changed for diabetic adults with concomitant CHD. Among diabetic adults receiving statin therapy, age-adjusted lipid control remained unchanged from 2007 to 2018, as did adults with concomitant CHD. However, age-adjusted lipid control improved significantly for men (p for trend < 0.01) and diabetic Mexican Americans (p for trend < 0.01). In 2015-2018, female diabetic participants receiving statins had lower odds of achieving lipid control (OR: 0.55; 95% CI: 0.35-0.84; P = 0.006) than men. Differences in lipid control across different races/ethnicities no longer existed. CONCLUSIONS: Lipid profiles improved in the US adults with diabetes from 2007 to 2018. Although rates of lipid control did not improve nationally in adults receiving statins, these patterns varied by sex and race/ethnicity.
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Diabetes Mellitus , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Masculino , Adulto , Humanos , Femenino , Estados Unidos/epidemiología , Persona de Mediana Edad , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Encuestas Nutricionales , Triglicéridos , Estudios Transversales , HDL-Colesterol , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiologíaRESUMEN
Context: Lung squamous cell carcinoma (LUSC) accounts for 30% of non-small-cell lung cancers (NSCLC), and an effective pharmacological treatment for LUSC isn't yet available. The Xihuang Pill is a potent Chinese medicinal preparation widely prescribed for the management of LUSC. Objective: The study intended to use the network-pharmacology method to ascertain the effective active ingredients, targets of action, and cellular-signal transduction involved in the prevention and treatment of LUSC when using the Xihuang Pill and to identify the mechanism of action of the pills against LUSC, to provide a more adequate scientific basis for subsequent studies. Design: The research team performed a genetic study. Setting: The study took place at Shanghai. Outcome Measures: The research team: (1) created the feature sets, for both the LUSC and normal features, using the Cancer Genome Atlas' (TCGA's) LUSC dataset; (2) performed a weighted correlation network analysis (WGCNA) of the differentially expressed genes (DEGs) using the R package WGCNA; (3) searched for the chemical components of the Xihuang Pill using the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP) and the Herb Group Identification Platform, and (4) selected the novel the Matthews correlation coefficient (MCC) algorithm to screen the hub genes. Results: The study found 8713 DEGs between the LUSC and normal groups. The top ten, important, downregulated genes included: (1) advanced glycosylation end product (AGER), (2) chitinase, acidic pseudogene 2 (CHIAP2), (3) CD300 molecule like family member G (CD300LG), (4) solute carrier family 6 member 4 (SLC6A4), (5) carboxypeptidase B2 (CPB2), (6) claudin 18 (CLDN18), (7) gamma-glutamyltransferase light chain 1 (GGTLC1), (8) gastrokine 2 (GKN2), (9) progastricsin (PGC), and (10) pulmonary surfactant-associated protein C (SFTPC). The top 10 upregulated genes included: (1) cancer susceptibility 9 (CASC9), (2) homeobox C13 (HOXC13), (3) keratin 6a (KRT6A), (4) desmoglein 3 (DSG3), (5) keratin 16 (KRT16), (6) forkhead box E1 (FOXE1), (7) preferentially expressed antigen in melanoma (PRAME), (8) calmodulin-like protein 3 (CALML3), (9) KRT68, and (10) aldo-keto reductase family 1 member B10 (AKR1B10). The study found 41 active ingredients and 843 targets for the Xihuang Pill. The PPI network included 10 hub genes, including cyclin dependent kinase 1 (CDK1), cyclin B1 (CCNB1), cyclin B2 (CCNB2), polo-like kinase 1 (PLK1), aurora kinase B (AURKB), baculoviral IAP repeat containing 5 (BIRC5), cyclin A2 (CCNA2), aurora kinase A (AURKA), centrosome-associated protein E (CENPE), and threonine tyrosine kinase (TTK), which were the principal target genes at the core of the gene-pathway network for the drug compound to central-target relationship. The enrichment analyses used the overlapping genes and the 10 hub genes and found 390 biological processes (BPs), 25 molecular functions (MFs), 43 cellular components (CCs), and 10 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The main enrichment occurred in the regulation of protein serine-threonine kinase activity, mitotic nuclear division, progesterone-mediated oocyte maturation, and the cell cycle. Conclusions: The study found the targets and relevant pathways of the hub genes of Xihuang Pill using biological analysis and molecular docking and demonstrated the interactions of critical chemical compounds with the hub's targeted genes were. More research is necessary to further determine whether the Xihuang Pill can improve LUSC patients' survival rate by regulation of those genes.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Farmacología en Red , Simulación del Acoplamiento Molecular , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , China , Pulmón , Claudinas , Antígenos de Neoplasias , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
BACKGROUND: The simulation is one of the basic methods of medical education, which is often used for procedural skills training. However, the existing simulator lacks internal anatomical landmarks. The study developed a mixed-reality stimulator and evaluated its usability and feasibility in lumbar puncture training. METHODS: The study recruited 40 subjects, including medical students, residents and faulty with varied levels of experience. Before training, participants completed the questionnaire about the basic information and watched a presentation about mixed reality. After practicing on mixed-reality stimulator, which provided internal anatomical structure, the examination was carried out and the results were documented. At the end of the training, trainees completed a survey of MR technology. RESULTS: In this study, participants generally believed that the MR technology was very realistic (90%), and that the presentation of internal anatomy could help the operation (95%). Moreover, 72.5% and 75%, respectively, strongly agreed that the MR technology promoted learning and should be used in medical training. After this training, the success rate of puncture and the puncture time were significantly improved in experienced and non-experienced participants. CONCLUSION: The existing simulator was easy to be transformed into MR simulator. This study showed the usability and feasibility of MR simulator in lumbar puncture training. As a potentially good tool to simulated medical skills training, next, MR technology would be developed and evaluated in more clinical skills teaching scenarios.
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Realidad Aumentada , Educación Médica , Entrenamiento Simulado , Humanos , Proyectos Piloto , Punción Espinal/métodos , Simulación por Computador , Competencia ClínicaRESUMEN
The transforming growth factor type ß receptor I (TGF-ß R1, also known as activin-like kinase 5 or ALK5) plays a significant role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis. Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. Herein, a novel series of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives was synthesized and identified as ALK5 inhibitors. Among them, compound 8h inhibited ALK5 autophosphorylation and NIH3T3 cell activity with IC50 values of 25 nM and 74.6 nM, respectively. Compound 8h also showed favorable pharmacokinetic profile and ameliorated hERG inhibition. More importantly, 30 mg/kg oral administration of 8h could significantly induce tumour growth inhibition in CT26 xenograft model without obvious toxicity.
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Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Células 3T3 NIH , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND AND AIMS: A novel non-insulin-based metabolic score for insulin resistance (METS-IR) index has been proposed as a simple and reliable alternative insulin resistance (IR) marker, but its the predictive value in asymptomatic adults with coronary artery calcification (CAC) remains unclear. METHODS AND RESULTS: We enrolled 1576 participants without cardiovascular disease (CVD), who underwent multidetector computed tomography. Logistic regression, restricted cubic spline models and receiver operating characteristic (ROC) curves were used to examine the association between METS-IR, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride glucose index (TyG index) and CAC. In multivariate logistic regression analysis, the increase in METS-IR was independently associated with a higher prevalence of CAC (all P < 0.05 in Models 1-3). Furthermore, restricted cubic splines indicated that the significance of METS-IR in predicting CAC was higher than that of other IR indexes. In ROC curve analysis, without considering the P value, the area under the curve of CAC predicted by METS-IR was higher than that of other IR indexes (METS-IR, 0.607; TyG index, 0.603; TG/HDL-C, 0.577). CONCLUSION: Compared with other IR indexes, METS-IR may have better discrimination ability in predicting the incidence of CAC in asymptomatic adults without CVD.
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Enfermedad de la Arteria Coronaria , Resistencia a la Insulina , Síndrome Metabólico , Adulto , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Triglicéridos , HDL-Colesterol , Biomarcadores , Glucosa , Síndrome Metabólico/epidemiologíaRESUMEN
BACKGROUND AND AIMS: The relationship between hemoglobin glycation index (HGI) and the diagnosis and prognosis of cardiovascular disease (CVD) has been verified by previous studies. However, it remains unknown whether HGI has a predictive effect on subclinical myocardial injury (SC-MI). The purpose of the present study was to explore the relationship between HGI and SC-MI in the general population free from CVD. METHODS AND RESULTS: The present study included 6009 participants free of CVD from the third National Health and Nutrition Examination Survey. Binary Logistic regression analysis was used to tested the association between HGI and SC-MI. As results, the HGI was significantly higher in participants with SC-MI compared with those without, and the HGI was positively correlated with SC-MI and other metabolic disorder parameters. Each 1-unit increase of HGI and glycated hemoglobin A1c (HbA1c) was independently associated with higher risk of SC-MI (P < 0.05), while fasting plasma glucose (FPG) was no longer a predictive indicator of SC-MI with the increase of confounding factors [OR (95% CI): 1.001 (0.999-1.003), P = 0.305]. And in the subgroup analysis, HGI, only in participants without diabetes, was independently associated with higher risk of SC-MI, while HbA1c and FPG had no independent predictive role in both diabetic and non-diabetic participants. CONCLUSIONS: HGI was a significant predictor of SC-MI in the general population free from CVD.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Glucemia/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Hemoglobina Glucada/metabolismo , Hemoglobinas , Humanos , Encuestas Nutricionales , Factores de RiesgoRESUMEN
BACKGROUND: Coronary artery tortuosity (CAT) is regarded as a variation of vascular anatomy, and its relationship with coronary artery calcification (CAC) score is still not well clarified. Studying the correlation between coronary artery calcification scores and CAT to determine specific prevention and intervention populations seems to have more meaningful. METHODS: The study is a cross-sectional retrospective study, including 1280 patients. CAT is defined as the presence of at least three consecutive curvatures of more than 45°measured during systole or diastole of a major epicardial coronary artery. Multivariable regression analysis was used to adjust the clinical parameters directly affecting CAT. RESULTS: Of these individuals, 445 (35%) were evaluated having CAT, of which females are higher than males (59.1% vs. 40.9%). Moderate CAC score (101-400) (odds ratio (OR) 1.49, 95% confidence interval [95%CI] 1.05-2.10, P = 0.025) revealed significantly associated with CAT on univariable analysis. However, multivariable analysis after adjusting for confounding factors only indicated that CAT was positively correlated with female (OR 1.68, 95%CI 1.30-2.17, P < 0.001), hypertension (OR 1.35, 95% CI 1.04-1.75, P = 0.024), and age (OR 1.02, 95% CI 1.01-1.03, P = 0.001), while was negatively associated with body mass index (BMI) 24-27.9(OR 0.76, 95% CI 0.58-1.00, P = 0.044), and BMI > 28 (OR 0.46, 95% CI 0.31-0.68, P < 0.001). Further analysis stratified by gender showed that compared with non-CAT, CAT was significantly linked with moderate CAC score (OR 1.79, 95% CI 1.00-3.20, P = 0.048), hypertension (OR 1.54, 95% CI 1.07-2.22, P = 0.021), and high-density lipoprotein (HDL) (OR 1.86, 95% CI 1.07-3.24, P = 0.028), while was negatively related to BMI > 28 (OR 0.51, 95% CI 0.31-0.84, P = 0.008) in female patients. CONCLUSIONS: CAT is more likely to be found in females, connected with hypertension, age, and BMI. No significant correlation is found between the presence of tortuosity and calcium score or diameter stenosis on multivariable analysis. Whereas the CAT is associated with moderate CAC score in correlation analysis when women are selected as the main group.
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Enfermedad de la Arteria Coronaria , Calcificación Vascular , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Calcificación Vascular/diagnóstico por imagenRESUMEN
To expand the potential use of in-shoe motion sensors (IMSs) in daily healthcare or activity monitoring applications for healthy subjects, we propose a real-time temporal estimation method for gait parameters concerning bilateral lower limbs (GPBLLs) that uses a single IMS and is based on a gait event detection approach. To validate the established methods, data from 26 participants recorded by an IMS and a reference 3D motion analysis system were compared. The agreement between the proposed method and the reference system was evaluated by the intraclass correlation coefficient (ICC). The results showed that, by averaging over five continuous effective strides, all time parameters achieved precisions of no more than 30 ms and agreement at the "excellent" level, and the symmetry indexes of the stride time and stance phase time achieved precisions of 1.0% and 3.0%, respectively, and agreement at the "good" level. These results suggest our method is effective and shows promise for wide use in many daily healthcare or activity monitoring applications for healthy subjects.
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Marcha , Zapatos , Fenómenos Biomecánicos , Pie , Voluntarios Sanos , Humanos , Extremidad InferiorRESUMEN
Up to 30% of patients with metastatic castration-resistant prostate cancer (CRPC) patients carry altered DNA damage response genes, enabling the use of poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in advanced CRPC. The proto-oncogene mesenchymal-epithelial transition (MET) is crucial in the migration, proliferation, and invasion of tumour cells. Aberrant expression of MET and its ligand hepatocyte growth factor is associated with drug resistance in cancer therapy. Here, we found that MET was highly expressed in human CRPC tissues and overexpressed in DU145 and PC3 cells in a drug concentration-dependent manner and is closely related to sensitivity to PARP inhibitors. Combining the PARP inhibitor olaparib with the MET inhibitor crizotinib synergistically inhibited CRPC cell growth both in vivo and in vitro. Further analysis of the underlying molecular mechanism underlying the MET suppression-induced drug sensitivity revealed that olaparib and crizotinib could together downregulate the ATM/ATR signaling pathway, inducing apoptosis by inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, enhancing the olaparib-induced antitumour effect in DU145 and PC3 cells. In conclusion, we demonstrated that MET inhibition enhances sensitivity of CRPC to PARP inhibitors by suppressing the ATM/ATR and PI3K/AKT pathways and provides a novel, targeted therapy regimen for CRPC.