RESUMO
BACKGROUND: Cyclosporin A is a calcineurin inhibitor which has a narrow therapeutic window and high interindividual variability. Various population pharmacokinetic models have been reported; however, professional software and technical personnel were needed and the variables of the models were limited. Therefore, the aim of this study was to establish a model based on machine learning to predict CsA trough concentrations in Chinese allo-HSCT patients. METHODS: A total of 7874 cases of CsA therapeutic drug monitoring data from 2069 allo-HSCT patients were retrospectively included. Sequential forward selection was used to select variable subsets, and eight different algorithms were applied to establish the prediction model. RESULTS: XGBoost exhibited the highest prediction ability. Except for the variables that were identified by previous studies, some rarely reported variables were found, such as norethindrone, WBC, PAB, and hCRP. The prediction accuracy within ±30% of the actual trough concentration was above 0.80, and the predictive ability of the models was demonstrated to be effective in external validation. CONCLUSION: In this study, models based on machine learning technology were established to predict CsA levels 3-4 days in advance during the early inpatient phase after HSCT. A new perspective for CsA clinical application is provided.
Assuntos
Ciclosporina , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/efeitos adversos , Estudos Retrospectivos , População do Leste Asiático , Transplante Homólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Aprendizado de MáquinaRESUMO
The present study was designed to elucidate whether the mechanism by which osthole decreases collagenI/III contents and their ratio is regulating the TGF-ß/Smad signaling pathway in TGF-ß1-overexpressed mouse cardiac fibroblasts (CFs). These CFs were cultured and treated with different concentrations of osthole. Our results showed that the TGF-ß1 expression in the CFs transfected with that the recombinant expression plasmids pcDNA3.1(+)-TGF-ß1 was significantly enhanced. After the CFs were treated with 1.25-5 µg·mL-1 of osthole for 24 h, the mRNA and protein expression levels of collagensIand III were reduced. The collagen I/III ratio was also reduced. The mRNA and protein expression levels of TGF-ß1, TßRI, Smad2/3, P-Smad2/3, Smad4, and α-SMA were decreased, whereas the expression level of Smad7 was increased. These effects suggested that osthole could inhibit collagen I and III expression and reduce their ratio via the TGF-ß/Smad signaling pathway in TGF-ß1 overexpressed CFs. These effects of osthole may play beneficial roles in the prevention and treatment of myocardial fibrosis.
Assuntos
Colágeno/genética , Cumarínicos/farmacologia , Fibroblastos/efeitos dos fármacos , Miocárdio/citologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética , Actinas/genética , Animais , Células Cultivadas , Colágeno/biossíntese , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genéticaRESUMO
BACKGROUND: Osthole, a natural coumarin and bioactive compound isolated from the fruit of Cnidium monnieri (L.) Cusson, was reported to prevent isoprenaline-induced myocardial fibrosis in mice by inhibiting the transforming growth factor-ß1 (TGF-ß1) expression, but the underlying mechanism is still unclear. The aim of this study is to illuminate whether the mechanism of osthole inhibiting collagen I and III expressions is associated with Smad signaling pathway in mouse cardiac fibroblasts (CFs) treated with TGF-ß1. METHODS: The mouse CFs stimulated with TGF-ß1 were cultured and treated with osthole 1.25-5µg/ml for 24h. The expressions of α-SMA, collagen I, collagen III, TGF-ß receptor I (TßRI), Smad2/3, phospho-Smad2/3 (P-Smad2/3), Smad4 and Smad7 were detected by real-time PCR method and western blot method, respectively. RESULTS: After treatment with TGF-ß1 and osthole in CFs, the levels of α-SMA expression and collagen I and III were reduced by osthole treatment. Accordingly, the ratio of collagen I/III had a similar changing trend. Besides, the levels of TßRI, Smad2/3, P-Smad2/3 and Smad4 expressions were decreased, while the level of Smad7 expression was increased after treatment with osthole. CONCLUSION: The present results demonstrated that osthole could inhibit the collagen I and III expressions and their ratio in CFs treated with TGF-ß1 via Smad signaling pathway, which might be one of its anti-fibrotic action mechanisms.