Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole. coadministrated 13 1 3 1/ practice CYPC CYP C CYP2C1 drugdrug drug interactionsDDIs interactions interactions(DDIs (PBPK error AUC024, AUC024 AUC AUC0 24, 24 AUC0-24 tmax population 146h h PMs, PMs , (PMs) IMs (IMs metabolizersEMs, metabolizersEMs EMs metabolizers(EMs) respectively CYP2C AUC02 2 AUC0-2 (PMs metabolizers(EMs AUC0-

RESUMO OBJETIVO O câncer de pulmão é a principal causa de mortes relacionadas ao câncer. Para reduzir a mortalidade por câncer de pulmão e encontrar câncer de pulmão em um estágio inicial, é necessária uma triagem por tomografia de baixa dose. Uma meta-análise foi emitida para testemunhar se a triagem poderia reduzir a mortalidade por câncer de pulmão e investigar o melhor programa de triagem. MÉTODOS Pesquisamos PubMed, Web of Science, biblioteca Cochrane, ScienceDirect e relevante banco de dados chinês. Ensaios clínicos controlados aleatórios, em que os participantes eram fumantes com mais de 49 anos (tabagismo >15 anos ou parar de fumar 10 ou 15 anos atrás) foram incluídos. RESULTADOS Nove estudos RCT preencheram os critérios. O rastreamento de LDCT pôde encontrar mais cânceres de pulmão (RR=1,58, IC 95%=1,25-1,99, P<0,001) e mais cânceres de estágio I do pulmão (RR=3,45, IC 95%=2,08-5,72, P<0,001) em comparação com raio X do tórax ou nenhum grupo de triagem. Ele indicou uma redução estatisticamente significativa na mortalidade específica do câncer de pulmão (RR=0,84, IC 95%=0,75-0,95, P=0,004), mas sem uma redução estatisticamente significativa na mortalidade por todas as causas (RR=1,26, IC 95%=0,89-1,78, P=0,193). Anualmente, o rastreamento de LDCT foi sensível em encontrar mais cânceres de pulmão. CONCLUSÕES A triagem de TC de baixa dose é eficaz para encontrar mais cânceres de pulmão e diminuir as mortes por câncer de pulmão. Para encontrar mais cânceres de pulmão em estágio inicial, a triagem anual de tomografia de baixa dose pode ser melhor do que a triagem bianual.

SUMMARY OBJECTIVE Lung cancer is the leading cause of cancer-related death. To reduce lung cancer mortality and detect lung cancer in early stages, low dose CT screening is required. A meta-analysis was conducted to verify whether screening could reduce lung cancer mortality and to determine the optimal screening program. METHODS We searched PubMed, Web of Science, Cochrane library, ScienceDirect, and relevant Chinese databases. Randomized controlled trial studies with participants that were smokers older than 49 years (smoking >15 years or quit smoking 10 or 15 years ago) were included. RESULTS Nine RCT studies met the criteria. LDCT screening could find more lung cancer cases (RR=1.58, 95%CI=1.25-1.99, P<0.001) and more stage I lung cancers (RR=3.45, 95%CI=2.08-5.72, P<0.001) compared to chest-X ray or the no screening group. This indicated a statistically significant reduction in lung-cancer-specific mortality (RR=0.84, 95%CI=0.75-0.95, P=0.004), but without a statistically reduction in mortality due to all causes (RR=1.26, 95%CI=0.89-1.78, P=0.193). Annually, LDCT screening was sensitive in finding more lung cancers. CONCLUSIONS Low-dose CT screening is effective in finding more lung cancer cases and decreasing the deaths from lung cancer. Annual low-dose CT screening may be better than a biennial screening to detect more early-stage lung cancer cases.

Abstract: To investigate the mechanism of different exercise patterns on neurological function after focal cerebral ischaemia in rats. Rats with focal cerebral cerebral ischaemia were randomly divided into an aerobic exercise group, an exhaustive exercise group and a control group, with 8 rats in each group. A score for nerve function in each group was calculated, and the ultrastructure of nerve cells was observed. Levels of NO and NOS in the brain motor area of the rats were measured in each group. The aerobic exercise group had lower nerve function scores than the exhaustive exercise group and higher scores than the control group (P<0.05). Under transmission electron microscopy, irregular shapes and organs were observed in nerve cells in the control group, while regular cell shapes and organs were observed in the aerobic exercise group. The aerobic exercise group and exhaustive exercise group had higher measures of NO content, NOS activity and eNOS, nNOS and iNOS gene expression than the control group, but eNOS expression in the aerobic exercise group and iNOS expression in the exhaustive exercise group were clearly higher according to RT-PCR (P<0.05). Aerobic exercise can promote the expression of NOS, mainly in eNOS, which can promote nerve repair.

Abstract Purpose: To investigate the protective effects of Polygonatum sibiricum polysaccharide (PSP) on acute heart failure (AHF) in rats. Methods: Sixty rats were randomly divided into control, model, and low-, middle- and high-dose PSP groups, 12 rats in each group. The low-, medium- and high-dose PSP groups were intragastrically administrated with 100, 200 and 400 mg/kg PSP for 5 days, respectively. On the sixth day, the AHF model was established by intraperitoneal injection of adriamycin. After 24h, the cardiac function, serum biochemical indexes, myocardial ATPase and succinate dehydrogenase levels and apoptosis related protein expressions were determined. Results: Compared with model group, in high-dose PSP group the heart rate, left ventricular systolic pressure, ±dp/dtmax, serum superoxide dismutase level, myocardial Na+-K+-ATPase, Ca2+-Mg2+-ATPase and succinate dehydrogenase levels and myocardial Bcl-2 and Caspase-3 protein expression levels were significantly increased (P<0.05), the left ventricular end diastolic pressure, serum cTnI, CK-MB, TNF-α, IL-6, malondialdehyde and nitric oxide levels and myocardial Bax and cleaved Caspase-3 protein expression levels were significantly decreased (P<0.05). Conclusions: Polysaccharide can prevent the acute heart failure induced by adriamycin. The mechanism may be related to its anti-oxidative stress, anti-inflammation and inhibition of cardiac myocyte apoptosis.

Abstract This study examines the correlation between risk perception, knowledge, social influence, self-efficacy, and cyber bullying behavior from the perspective of the attitude-social influence-efficacy model. The samples in this survey are adolescents who have had cyber bullying behavior or have witnessed their peers’ cyber bullying behavior. The results showed that attitude towards cyber bullying affected cyber bullying intention, and that intention also influenced cyber bullying behavior. Social influence also had an impact on cyber bullying intention and cyber bullying behavior. In fact, intention was a mediator between attitude and behavior, as well as between social influence and behavior.

Resumen Este estudio examina la correlación entre la percepción de riesgo, el conocimiento, la influencia social, la autoeficacia y el comportamiento del acoso cibernético desde la perspectiva del modelo de influencia social. Las muestras en esta encuesta son adolescentes que han tenido un comportamiento de acoso cibernético o han presenciado el comportamiento de acoso cibernético de sus compañeros. Los resultados mostraron que la actitud hacia el acoso cibernético afectó la intención de acoso cibernético, y esa intención también influyó en el comportamiento del acoso cibernético. La influencia social también tuvo un impacto en la intención de acoso cibernético y el comportamiento de acoso cibernético. De hecho, la intención era un mediador entre la actitud y el comportamiento, así como entre la influencia social y el comportamiento.

Gene networks have been broadly used to predict gene functions based on guilt by association (GBA) principle. Thus, in order to better understand the molecular mechanisms of esophageal squamous cell carcinoma (ESCC), our study was designed to use a network-based GBA method to identify the optimal gene functions for ESCC. To identify genomic bio-signatures for ESCC, microarray data of GSE20347 were first downloaded from a public functional genomics data repository of Gene Expression Omnibus database. Then, differentially expressed genes (DEGs) between ESCC patients and controls were identified using the LIMMA method. Afterwards, construction of differential co-expression network (DCN) was performed relying on DEGs, followed by gene ontology (GO) enrichment analysis based on a known confirmed database and DEGs. Eventually, the optimal gene functions were predicted using GBA algorithm based on the area under the curve (AUC) for each GO term. Overall, 43 DEGs and 67 GO terms were gained for subsequent analysis. GBA predictions demonstrated that 13 GO functions with AUC>0.7 had a good classification ability. Significantly, 6 out of 13 GO terms yielded AUC>0.8, which were determined as the optimal gene functions. Interestingly, there were two GO categories with AUC>0.9, which included cell cycle checkpoint (AUC=0.91648), and mitotic sister chromatid segregation (AUC=0.91597). Our findings highlight the clinical implications of cell cycle checkpoint and mitotic sister chromatid segregation in ESCC progression and provide the molecular foundation for developing therapeutic targets.

Abstract The aim of this paper is to identify and investigate an endophytic fungus (strain 28) that was isolated from Houttuynia cordata Thunb, a famous and widely-used Traditional Chinese Medicine. Based on morphological methods and a phylogenetic analysis of ITS sequences, this strain was identified as Chaetomium globosum. An antifungal activity bioassay demonstrated that the crude ethyl acetate (EtOAc) extracts of strain 28 had a wide antifungal spectrum and strong antimicrobial activity, particularly against Exserohilum turcicum (Pass.) Leonard et Suggs, Botrytis cinerea persoon and Botrytis cinerea Pers. ex Fr. Furthermore, the fermentation conditions, extraction method and the heat stability of antifungal substances from strain 28 were also studied. The results showed that optimal antifungal activity can be obtained with the following parameters: using potato dextrose broth (PDB) as the base culture medium, fermentation for 4–8 d (initial pH: 7.5), followed by extraction with EtOAc. The extract was stable at temperatures up to 80 °C. This is the first report on the isolation of endophytic C. globosum from H. cordata to identify potential alternative biocontrol agents that could provide new opportunities for practical applications involving H. cordata.