miR-34a/DRP-1-mediated mitophagy participated in cisplatin-induced ototoxicity via increasing oxidative stress.

PURPOSE: Cisplatin is a widely used and effective chemotherapeutic agent for most solid malignant tumors. However, cisplatin-induced ototoxicity is a common adverse effect that limits the therapeutic efficacy of tumors in the clinic. To date, the specific mechanism of ototoxicity has not been fully elucidated, and the management of cisplatin-induced ototoxicity is also an urgent challenge. Recently, some authors believed that miR34a and mitophagy played a role in age-related and drug-induced hearing loss. Our study aimed to explore the involvement of miR-34a/DRP-1-mediated mitophagy in cisplatin-induced ototoxicity. METHODS: In this study, C57BL/6 mice and HEI-OC1 cells were treated with cisplatin. MiR-34a and DRP-1 levels were analyzed by qRT‒PCR and western blotting, and mitochondrial function was assessed via oxidative stress, JC-1 and ATP content. Subsequently, we detected DRP-1 levels and observed mitochondrial function by modulating miR-34a expression in HEI-OC1 cells to determine the effect of miR-34a on DRP-1-mediated mitophagy. RESULTS: MiR-34a expression increased and DRP-1 levels decreased in C57BL/6 mice and HEI-OC1 cells treated with cisplatin, and mitochondrial dysfunction was involved in this process. Furthermore, the miR-34a mimic decreased DRP-1 expression, enhanced cisplatin-induced ototoxicity and aggravated mitochondrial dysfunction. We further verified that the miR-34a inhibitor increased DRP-1 expression, partially protected against cisplatin-induced ototoxicity and improved mitochondrial function. CONCLUSION: MiR-34a/DRP-1-mediated mitophagy was related to cisplatin-induced ototoxicity and might be a novel target for investigating the treatment and protection of cisplatin-induced ototoxicity.

Prevalence and predictors of medication non-adherence in children with inflammatory bowel disease in China: A cross-sectional study.

Background: Non-adherence to physician-prescribed medications, especially oral medications, is common in children with inflammatory bowel disease (IBD), and medication non-adherence is associated with poorer outcomes in IBD. Therefore, understanding and improving medication adherence in children with IBD is critical for optimizing treatment and improving treatment outcomes. Despite the relatively high prevalence of IBD in children in China, to date, very little is known about medication adherence in these patients. Objective: The aim of this study was to investigate the prevalence of medication non-adherence and its risk factors in children with IBD in China to provide a basis for developing adherence improvement strategies. Methods: A cross-sectional design was employed. Children (aged <18 years) with IBD who visited the Children's Hospital, Zhejiang University School of Medicine, from September 2020 to December 2021 were included. Data were collected by a general information questionnaire, the 4-item Medication Adherence Report Scale (MARS-4) and Crohn's and Colitis Knowledge (CCKNOW) questionnaire. Subsequently, forward stepwise binary logistic regression analysis was performed to determine independent predictors of medication non-adherence. Results: A total of 119children were included in this study. The results showed that 33 (27.73%) and 86 (72.27%) children had poor and good medication adherence, respectively. Of these, 83 (69.75%) had forgotten to take their medications sometimes, often, or always. On binary logistic regression, we found that the incidence of medication non-adherence in children with IBD course of 3 years and above [OR 4.82 (95%CI: 1.47-15.88); p = 0.01] was significantly higher than that in children with course of 3 months to 1 year, whereas children with higher parental CCKNOW scores [OR 0.77 (95%CI: 0.67-0.88); p = 0.00] had significantly lower incidence of medication non-adherence than those with lower parental CCKNOW scores, and the results of the correlation between parental knowledge scores of the four categories and children's medication adherence showed that drug knowledge scores (r = 0.36, p < 0.00) and complication knowledge scores (r = 0.24, p = 0.01) were positively correlated with medication adherence. Conclusion: Poor medication adherence in children with IBD in China was common, and forgetting to take medication was the main barrier. Longer disease duration (3 years and above) in children could act as a risk factor for medication adherence, whereas higher level of parental knowledge about IBD could act as a protective factor, and one interesting novel finding was that the level of parental knowledge about drug and complication were significantly correlated with medication adherence in children with IBD. Our results may inform on the design and implementation of medication adherence interventions for children with IBD.

Integrated analysis of immune- and apoptosis-related lncRNA-miRNA-mRNA regulatory network in children with Henoch Schönlein purpura nephritis.

Background: Long noncoding RNAs (lncRNAs) play important roles in the regulation of immunological and apoptotic function. This study aimed to explore the critical immune- and apoptosis-related lncRNAs in the occurrence and development of Henoch-Schönlein purpura nephritis (HSPN) in children. Methods: Differential analysis was employed to identify the differentially expressed lncRNAs, as well as the immune- and apoptosis-related mRNAs in children with HSPN. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to validate the immunological and apoptotic roles of the differentially expressed immune- and apoptosis-related lncRNAs and mRNAs. Spearman's correlation analysis was performed to analyze the differentially expressed lncRNAs and immune- and apoptosis-related messenger RNAs (mRNAs). Based on the competing endogenous RNA (ceRNA) mechanism, the immune- and apoptosis-related lncRNA-microRNA (miRNA)-mRNA regulatory network was then constructed in children with HSPN. The expression levels of the lncRNAs in the lncRNA-miRNA-mRNA regulatory network were further confirmed by quantitative real-time polymerase chain in the peripheral blood samples of children with HSPN. Results: By intersecting the differentially expressed immune-related and apoptosis-related genes through GO and KEGG analyses, a total of 43 genes were identified in children with HSPN, and 100 lncRNAs highly correlated with the above genes were identified by correlation analysis. The immune- and apoptosis-related lncRNA-miRNA-mRNA regulatory network was then established based on ceRNA mechanism. Dysregulation of a total of 11 lncRNAs were discovered, including upregulated SNHG3, LINC00152, TUG1, GAS5, FGD5-AS1, DLEU2, and SCARNA9; and downregulated SNHG1, NEAT1, DISC1-IT1, and PVT1. The validation conducted in the clinical samples also suggested that the above lncRNAs in the specific regulatory network may act as potential biomarkers with prognosis in children with HSPN. Conclusions: LncRNAs may play essential regulatory roles in the occurrence and development of HSPN in children, and the immune- and apoptosis-related lncRNA-miRNA-mRNA regulatory network might be the underlying molecular mechanism that dissects the disease pathogenesis. In addition, the dysregulated lncRNAs in the regulatory network may be novel biomarkers for the diagnosis and therapy of HSPN in children.

Corrigendum: Impact of sampling time variability on tacrolimus dosage regimen in pediatric primary nephrotic syndrome: Single-center, prospective, observational study.

[This corrects the article DOI: 10.3389/fphar.2021.726667.].

The impact of ibuprofen on valproic acid plasma concentration in pediatric patients.

The combination of valproic acid (VPA) and ibuprofen are common in children with epilepsy. Three case reports investigated that ibuprofen might decrease the plasma concentration of VPA, however, no cohort study was published to evaluate the interaction of ibuprofen on VPA plasma concentration in pediatric patients.Data from patients with measured VPA trough concentrations (C0) were retrospectively collected in a Chinese teaching and tertiary Children's Hospital from January 2017 to June 2019. The samples measured within 6 weeks of the last ibuprofen administration were considered ibuprofen combination samples. Patients with paired samples before and after ibuprofen administration were additionally analysed. The effects of ibuprofen on the VPA through concentration to dose (C0/D) ratio were investigated. The proportion of samples with achieved target concentrations of VPA (50-100 mg/L) and the corresponding required dosage were compared. Moreover, subgroup analysis according to the interval between the last ibuprofen dosage and C0 measurement was performed.A total of 616 samples from 434 patients, of whom 16 had paired samples, were included. VPA C0/D decreased when ibuprofen was administered by 7.5% and 30.6% of the total samples and paired samples, respectively. The interaction was significant within 1 week of the last ibuprofen dose. No significant differences were observed in the proportion of target concentration achieved and VPA dose requirement when ibuprofen was combined.A moderate effect of ibuprofen on VPA C0/D was observed within 1 week of ibuprofen administration; the target concentration and required doses of VPA were comparable.

Impact of Intraoperative Salvaged Blood Autotransfusion During Obstetric Hemorrhage on the Coagulation Function: A Retrospective Cohort Analysis.

OBJECTIVE: This study aimed to explore the effect of intraoperative blood salvage (autotransfusion) on coagulation function in the rescue of an obstetric hemorrhage. METHODS: A total of 65 pregnant women who were diagnosed with placenta previa in our Hospital and gave birth in the hospital were enrolled in the study. All the patients underwent thromboelastography, routine blood tests, and blood coagulation series + D-dimer before and within 30 min of the autologous blood transfusion. The differences in various indicators were evaluated. RESULTS: (1) After the autotransfusion, the hemoglobin and neutrophil counts were significantly higher than beforehand, and the platelet count was significantly reduced; the differences were statistically significant (p < .05). (2) There were no significant differences in prothrombin time (PT), fibrinogen, and D-dimer levels before and after the autotransfusion (p > .05). The activated partial thromboplastin time after autotransfusion was shorter than that beforehand, and the difference was statistically significant (p < .05). (3) There were no significant differences in the R value, K value, α value, and MA value of the thromboelastogram before and after the autotransfusion (p > .05). CONCLUSION: After the recovery autotransfusion, the hemoglobin of patients with a massive obstetric hemorrhage increased significantly, while the platelet count decreased, but the coagulation function and thromboelastogram did not change significantly, indicating the autotransfusion did not affect the coagulation function of the obstetric hemorrhage rescue. Thus, it would appear that intraoperative blood salvage can be safely used in the clinical rescue of massive hemorrhaging during cesarean section.

Advances in Nanoparticle Drug Delivery Systems for Anti-Hepatitis B Virus Therapy: A Narrative Review.

Chronic hepatitis B (CHB) is an infectious viral disease that is prevalent worldwide. Traditional nucleoside analogues, as well as the novel drug targets against hepatitis B virus (HBV), are associated with certain critical factors that influence the curative effect, such as biological stability and safety, effective drug delivery, and controlled release. Nanoparticle drug delivery systems have significant advantages and have provided a basis for the development of anti-HBV strategies. In this review, we aim to review the advances in nanoparticle drug delivery systems for anti-hepatitis B virus therapy by summarizing the relevant literature. First, we focus on the characteristics of nanoparticle drug delivery systems for anti-HBV therapy. Second, we discuss the nanoparticle delivery systems for anti-HBV nucleoside drugs, gene-based drugs, and vaccines. Lastly, we provide an overview of the prospects for nanoparticle-based anti-HBV agents.

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study.

Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown. Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5-10 ng/ml. Results: We found that 32 and 68% of samples were respectively collected early (2-180 min) and delayed (4-315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5-1, 1-2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml. Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.

Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms.

PURPOSE: To evaluate the role of diltiazem on tacrolimus sparing in pediatric primary nephrotic syndrome (PNS) and its relation to CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms. METHODS: The PNS children treated with tacrolimus and with steady-state trough concentration (C0) were retrospectively collected. The impacts of diltiazem on tacrolimus dose-adjusted C0 (C0/D), target concentration achievement, and required dose were evaluated. Meanwhile, the relationship between the polymorphisms (including CYP3A4*1G, CYP3A5*3, ABCB1-C3435T, and SCLO1B3) and dose-sparing effect were investigated. RESULTS: A total of 71 children with 535 concentrations, including 16 children with concomitant diltiazem, were involved. Significantly increased C0/D (94.0 vs 83.8 ng/mL per mg/kg, p = 0.038) and lower required daily dose of tacrolimus (0.056 vs 0.064 mg/kg, p = 0.003) were observed in patients co-administered with diltiazem. Subpopulation carrying CYP3A4*1G, CYP3A5*1, ABCB1-3435TT, or SLCO1B3-699AA was presented with enhanced increment in tacrolimus C0/D by 38.8-102.9%. CONCLUSION: Moderate effect of diltiazem on tacrolimus sparing, which might relate to the polymorphisms of CYP3A4, CYP3A5, ABCB1, and SLCO1B3, was documented.

Repetitive transcranial magnetic stimulation on chronic tinnitus: a systematic review and meta-analysis.

BACKGROUND: Although the clinical efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) in the treatment of chronic tinnitus have been frequently examined, the results remain contradictory. Therefore, we performed a systematic review and meta-analysed clinical trials examining the effects of rTMS to evaluate its clinical efficacy and safety. METHODS: Studies of rTMS for chronic tinnitus were retrieved from PubMed, Embase, and Cochrane Library through April 2020. Review Manager 5.3 software was employed for data synthesis, and Stata 13.0 software was used for analyses of publication bias and sensitivity. RESULTS: Twenty-nine randomized studies involving 1228 chronic tinnitus patients were included. Compared with sham-rTMS, rTMS exhibited significant improvements in the tinnitus handicap inventory (THI) scores at 1 week (mean difference [MD]: - 7.92, 95% confidence interval [CI]: - 14.18, - 1.66), 1 month (MD: -8.52, 95% CI: - 12.49, - 4.55), and 6 months (MD: -6.53, 95% CI: - 11.406, - 1.66) post intervention; there were significant mean changes in THI scores at 1 month (MD: -14.86, 95% CI: - 21.42, - 8.29) and 6 months (MD: -16.37, 95% CI: - 20.64, - 12.11) post intervention, and the tinnitus questionnaire (TQ) score at 1 week post intervention (MD: -8.54, 95% CI: - 15.56, - 1.52). Nonsignificant efficacy of rTMS was found regarding the THI score 2 weeks post intervention (MD: -1.51, 95% CI: - 13.42, - 10.40); the mean change in TQ scores 1 month post intervention (MD: -3.67, 95% CI: - 8.56, 1.22); TQ scores 1 (MD: -8.97, 95% CI: - 20.41, 2.48) and 6 months (MD: -7.02, 95% CI: - 18.18, 4.13) post intervention; and adverse events (odds ratios [OR]: 1.11, 95% CI: 0.51, 2.42). Egger's and Begg's tests indicated no publication bias (P = 0.925). CONCLUSION: This meta-analysis demonstrated that rTMS is effective for chronic tinnitus; however, its safety needs more validation. Restrained by the insufficient number of included studies and the small sample size, more large randomized double-blind multi-centre trials are needed for further verification.

Population Pharmacokinetic Study of Vancomycin in Chinese Pediatric Patients with Hematological Malignancies.

STUDY OBJECTIVES: Vancomycin is a primary antibiotic for the treatment of severe infections in children with malignant hematological disease. However, precise dosing of vancomycin is difficult in children because of high interindividual variability and limited data of pharmacokinetic profiles. The present study aims to develop a population pharmacokinetic (PPK) model for vancomycin in Chinese pediatric patients with hematological malignancies. DESIGN: This was a retrospective pharmacokinetic study. SETTING: The setting for this study was a tertiary-care children's hospital. PATIENTS: This study included 92 pediatric patients with hematological malignancies who received vancomycin and experienced therapeutic drug monitoring from February 2017 to December 2018. MEASUREMENTS AND MAIN RESULTS: A PPK model was generated with a nonlinear mixed effects model. In addition, required doses to achieve target therapeutic concentrations were simulated based on the final model. A one-compartment model with first-order elimination fit the concentration data best. Actual body weight (BW) and glomerular filtration rate (GFR) were the significant influential factors on the clearance (CL) of vancomycin. The final PPK model for CL was CL (L/h) = 4.18  ×GFR/1450.741×BW/25K , K =  BW-0.856/BW-0.856+6.53-0.856 , and the volume of distribution was 22.3 L. The model proved to be robust and reliable. Reference dosing regimens were proposed based on the final model. CONCLUSIONS: A PPK model of vancomycin was established for Chinese pediatric patients with hematological malignancies using a nonlinear mixed effects model, which provided a reference for the clinical application of vancomycin.

Underlying Mechanism of Insulin Resistance: A Bioinformatics Analysis Based on Validated Related-Genes from Public Disease Databases.

BACKGROUND The underlying mechanism of insulin resistance is complex; bioinformatics analysis is used to explore the mechanism based differential expression genes (DEGs) obtained from omics analysis. However, the expression and role of most DEGs involved in bioinformatics analysis are invalidated. This study aimed to disclose the mechanism of insulin resistance via bioinformatics analysis based on validated insulin resistance-related genes (IRRGs) collected from public disease-gene databases. MATERIAL AND METHODS IRRGs were collected from 4 disease databases including NCBI-Gene, CTD, RGD, and Phenopedia. GO and KEGG analysis of IRRGs were performed by DAVID. Then, the STRING database was employed to construct a protein-protein interaction (PPI) network of IRRGs. The module analysis and hub genes identification were carried out by MCODE and cytoHubba plugin of Cytoscape based on the primary PPI network, respectively. RESULTS A total of 1195 IRRGs were identified. Response to drug, hypoxia, insulin, positive regulation of transcription from RNA polymerase II promoter, cell proliferation, inflammatory response, negative regulation of apoptotic process, glucose homeostasis, cellular response to insulin stimulus, and aging were proposed as the crucial functions related to insulin resistance. Ten insulin resistance-related pathways included the pathways of insulin resistance, pathways in cancer, adipocytokine, prostate cancer, PI3K-Akt, insulin, AMPK, HIF-1, prolactin, and pancreatic cancer signaling pathway were revealed. INS, AKT1, IL-6, TP53, TNF, VEGFA, MAPK3, EGFR, EGF, and SRC were identified as the top 10 hub genes. CONCLUSIONS The current study presented a landscape view of possible underlying mechanism of insulin resistance by bioinformatics analysis based on validated IRRGs.

PEGylated versus non-PEGylated drugs: A cross-sectional analysis of adverse events in the FDA Adverse Event Reporting System (FAERS) Database
.

OBJECTIVE: PEGylation is commonly used to optimize pharmacological properties and improve the clinical response of drugs. Due to the inherent toxicity of polyethylene glycol (PEG) and pharmacological changes induced by PEGylation, the safety may be altered and required to be explored. This study explored the adverse events (AEs) associated with PEGylation by comparing pharmacovigilance data of PEGylated and parent drugs. MATERIALS AND METHODS: We conducted a disproportionality analysis of spontaneous reports associated with PEGylated and corresponding parent medications from the FDA Adverse Event Reporting System database recorded between the 1st quarter of 2004 and the 4th quarter of 2018 at the level of preferred terms (PTs) and standard MedDRA queries (SMQs), respectively. The AEs probably different in risk due to changed pharmacological effects and inherent toxicity of PEG were analyzed. RESULTS: A total of 259,428 cases associated to six drug pairs (filgrastim, asparaginase, interferon α-2a, interferon α-2b,interferon ß-1a, and liposomal doxorubicin) were collected. Although 95% of PTs were comparable between the two groups, PTs of deep vein thrombosis, pancreatitis acute, diabetes mellitus, liver disorder, disorientation, aphasia and infection, and SMQ of embolic and thrombotic events were significantly alleviated by PEGylation. No PT was significantly enhanced by PEGylation. CONCLUSION: The pharmacovigilance profiles of PEGylated and non-PEGylated agents were similar. Further clinical assessment is required to validate the pharmacovigilance data.

Cost-effectiveness analysis of cetuximab combined with chemotherapy as a first-line treatment for patients with RAS wild-type metastatic colorectal cancer based on the TAILOR trial.

OBJECTIVES: Cetuximab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX-4) is superior to FOLFOX-4 alone as a first-line treatment for patients with metastatic colorectal cancer with RAS wild-type (RAS wt mCRC), with significantly improved survival benefit by TAILOR, an open-label, randomised, multicentre, phase III trial. Nevertheless, the cost-effectiveness of these two regimens remains uncertain. The following study aims to determine whether cetuximab combined with FOLFOX-4 is a cost-effective regimen for patients with specific RAS wt mCRC in China. DESIGN: A cost-effectiveness model combined decision tree and Markov model was built to simulate pateints with RAS wt mCRC based on health states of dead, progressive and stable. The health outcomes from the TAILOR trial and utilities from published data were used respectively. Costs were calculated with reference to the Chinese societal perspective. The robustness of the results was evaluated by univariate and probabilistic sensitivity analyses. PARTICIPANTS: The included patients were newly diagnosed Chinese patients with fully RAS wt mCRC. INTERVENTIONS: First-line treatment with either cetuximab plus FOLFOX-4 or FOLFOX-4. MAIN OUTCOME MEASURES: The primary outcomes are costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: Baseline analysis disclosed that the QALYs was increased by 0.383 caused by additional cetuximab, while an increase of US$62 947 was observed in relation to FOLFOX-4 chemotherapy. The ICER was US$164 044 per QALY, which exceeded the willingness-to-pay threshold of US$28 106 per QALY. CONCLUSIONS: Despite the survival benefit, cetuximab combined with FOLFOX-4 is not a cost-effective treatment for the first-line regime of patients with RAS wt mCRC in China. TRIAL REGISTRATION NUMBER: TAILOR trial (NCT01228734); Post-results.

Evaluation of Concentration Errors and Inappropriate Dose Tailoring of Tacrolimus Caused by Sampling-Time Deviations in Pediatric Patients With Primary Nephrotic Syndrome.

BACKGROUND: Tacrolimus dosing is routinely tailored based on its trough level (C0) drawn by therapeutic drug monitoring in pediatric patients with primary nephrotic syndrome. However, this concentration is often inaccurate owing to inappropriate practice, such as deviation of sampling time (DST). The quantitative relationship between DST and C0 remains unclear. METHODS: Tacrolimus concentration at nominal sampling times (12 hours after last dose) and 32 deviation scenarios (12 ± 4 hours every 15 minutes) was predicted using a previously validated population pharmacokinetic model based on 162 scenarios of 100 primary nephrotic syndrome patients involved in the population pharmacokinetic model and derived virtual patients. Concentration error (CE) and relative CE (RCE) were evaluated, and the correlation between DST and RCE was evaluated by subgroup analysis using linear regression. Ultimately, the inappropriate dosing possibly misled by incorrect C0 was simulated in a real-patient cohort according to the target range (5-10 ng/mL). RESULTS: Approximately 7% of RCE was caused at every 1-hour of DST. DST was the most major contributor of RCE (r = 0.773-0.804). Patients with early sampling, older age, high body weight, high dose, low aspartate transaminase level, high corticosteroid dose, and without combination of azole antifungal agents were revealed to have high RCE. Approximately 7%-36% and 9%-25% of inappropriate dose tailoring may be caused by early and delayed sampling, respectively. In addition, patients with early sampling or high-dose tacrolimus had a higher risk of inappropriate dosing than patients with delayed sampling [hazard ratio = 1.53, 95% confidence interval (CI): 1.03-2.27, P = 0.048], and low-dose tacrolimus (P < 0.0001). CONCLUSIONS: A moderate bias of concentration and dose tailoring was revealed within 4 hours of DST. In addition, a high risk of bias was found in patients with early sampling and high-dose tacrolimus.

Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis-Menten pharmacokinetic model.

BACKGROUND: Little is known about the population pharmacokinetics (PPK) of tacrolimus (TAC) in pediatric patients with primary nephrotic syndrome (PNS). In this study, we aimed to compare the predictive performance between nonlinear and linear PK models and investigate the significant factors influencing TAC PK characteristics in pediatric PNS. METHODS: Data were obtained from 71 pediatric patients with PNS, along with 525 TAC trough concentrations at steady-state. Patients' demographic, medical, and treatment details were collected. Genetic polymorphisms of CYP3A4*1G, CYP3A5*3, and ABCB1-C3435T were analyzed. The PPK models were developed using nonlinear mixed-effects model (NONMEM®) software. Two modeling strategies, linear compartmental and nonlinear Michaelis-Menten (MM) models, were evaluated and compared. RESULTS: Body weight, age, daily dose of TAC, co-therapy drugs (including azole antifungal agents and diltiazem), and CYP3A5*3 genotype were the important factors in the final linear model (one-compartment model), whereas only body weight, co-therapy drugs, and CYP3A5*3 genotype were the important factors in the final nonlinear MM model. Apparent clearance and volume of distribution in the final linear model were 7.13 L/h and 142 L, respectively. The maximal dose rate (Vmax) of the nonlinear MM model was 1.92 mg/day and the average concentration at steady-state at half-Vmax (Km) was 1.98 ng/mL. The nonlinear model described the data better than the linear model. Dosing regimens were proposed based on the nonlinear PK model. CONCLUSION: Our findings demonstrated that the nonlinear MM model showed better predictive performance than the linear compartmental model, providing reliable support for optimizing TAC dosing and adjustment in children with PNS.

Impact of CYP3A4/5 and ABCB1 polymorphisms on tacrolimus exposure and response in pediatric primary nephrotic syndrome.

Aim: To evaluate the impact of CYP3A4*1G, CYP3A5*3 and ABCB1-C3435T polymorphisms on tacrolimus concentrations, efficacy and tolerance in pediatric primary nephrotic syndrome. Methods: Dose-adjusted concentrations (C0/D), daily dose, frequency and time to relapse, cumulative remission days, and adverse reactions in 65 Chinese patients with various genotypes were retrospectively collected and compared. Results: C0/D increased in CYP3A4*1/*1, CYP3A5*3/*3 and CYP3A4*1/*1-3A5*3/*3 diplotype carriers by 38.4, 69.7 and 40.9% compared with CYP3A4*1/*1G, CYP3A5*1/*3 and noncarriers, respectively. Recurrence risks were decreased in CYP3A4*1/*1 (0.43 of hazard ratio to *1/*1G) and CYP3A5*3/*3 carriers (0.43 of hazard ratio to *1/*3). None of polymorphisms was linked to adverse reactions. Conclusion: The genotypes of CYP3A4*1G and CYP3A5*3 rather than ABCB1-C3435T potentially predicted tacrolimus exposure and clinical response in pediatric primary nephrotic syndrome.

Up-regulated lncRNA XIST contributes to progression of cervical cancer via regulating miR-140-5p and ORC1.

BACKGROUND: The study purpose was to make investigation into the influence of XIST on cervical cancer progression and what's more its potential mechanism. METHODS: The cervical cancer data sets (lncRNA, miRNA, and mRNA) obtained from TCGA were analyzed with the "mixOmics" R package. Then, the expression of XIST, miR-140-5p, and ORC1 were detected using qRT-PCR and western blot in both tissues and cervical cancer cell lines (Hela and C33A) to verify the bioinformatics analyses results. CCK-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) assays, cell cycle assay and cell apoptosis assay were practiced. Besides, immunohistochemistry staining was operated for the detection of the Ki-67, E-cadherin and vimentin expression in cervical cancer tissues and the apoptosis-related proteins expression (c-caspase3, Bcl-2, total PARP and cleaved PARP) was verified through western blot. And in vivo experiments were implemented. RESULTS: MiR-140-5p was down-regulated but XIST and ORC1 were up-regulated in cervical cancer tissues and cell lines. Knocking down of the XIST or ORC1 memorably suppressed cell proliferation, blocked cell cycle, decreased the expression of Bcl-2 while increased the apoptosis rate and the expression of c-caspase3 and cleaved PARP in HeLa and C33A cells. Besides, the results of immunohistochemistry staining showed knocking down the expression of XIST improved the expression levels of E-cadherin and decreased Ki-67 and vimentin expression. And overexpression of miR-140-5p also could inhibit the progression and reverse the influence of XIST and ORC1 in HeLa and C33A cells. CONCLUSION: Our study indicated the effects of XIST/miR-140-5p/ORC1 axis on the progression of cervical cancer which will shed new light on epigenetic diagnostics and therapeutics in cervical cancer.

Long noncoding RNA OPA-interacting protein 5 antisense transcript 1 upregulated SMAD3 expression to contribute to metastasis of cervical cancer by sponging miR-143-3p.

OBJECTIVES: SMAD3 is pivotal in the biology functions of various tumors. This study is aiming to study the relationship among SMAD3, long noncoding RNAs (lncRNAs) OPA-interacting protein 5 antisense transcript 1 (OIP5-AS1), and miR-143-3p, and their effects on cervical cancer. METHODS: In our research, real-time polymerase chain reaction and western blot assay were conducted to detect the expression level of messenger RNA and protein in tumor tissues and cells. Transfection of lncRNA OIP5-AS1, miR-143-3p, or SMAD3 was performed to investigate their potential effects on the function of cell as well as the relationship among them in cervical cell lines via 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) together with transwell assays or dual-luciferase reporter assay respectively. RESULTS: SMAD3, lncRNA OIP5-AS1 expression is significantly enhanced in cervical cancer tissues and cell lines, but miR-143-3p was inhibited. LncRNA OIP5-AS1 is demonstrated to mediate the physiological process of cervical cancer cells. Moreover, silencing SMAD3 via siRNA suppressed cell number, viability, migration and invasion, whereas overexpression of OIP5-AS1 promoted these abilities. Furthermore, lncRNA OIP5-AS1 exert its function via sponging miR-143-3p to regulate SMAD3 expression. CONCLUSIONS: LncRNA OIP5-AS1 promoted SMAD3 expression via mediating miR-143-3p to promote migration and invasion of cervical cancer cells.

Positive Expression of SMYD2 is Associated with Poor Prognosis in Patients with Primary Hepatocellular Carcinoma.

Purpose: SET and MYND domain-containing protein2 (SMYD2), a histone lysine methyltransferases, is a candidate human oncogene in multiple tumors. However, the expression dynamics of SMYD2 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. Methods: The SMYD2 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry (IHC) in HCC tissues and matched adjacent non-tumorous tissues. SMYD2 was silenced in HCC cell lines to determine its role in tumor proliferation and cell cycle progression, and the possible mechanism. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results: The SMYD2 expression in HCC tissues were significantly up-regulated at both mRNA and protein levels as compared with the matched adjacent non-tumorous tissues. By IHC, positive expression of SMYD2 was examined in 122/163 (74.85%) of HCC and in 10/59 (16.95%) of tumor-adjacent tissues. Positive expression of SMYD2 was correlated with tumor size, vascular invasion, differentiation and TNM stage (P < 0.05). In univariate survival analysis, a significant association between positive expression of SMYD2 and shortened patients' survival was found (P < 0.05). Importantly, SMYD2 expression together with vascular invasion (P < 0.05) provided significant independent prognostic parameters in multivariate analysis. Functionally, SMYD2 silenced markedly inhibited cell proliferation and cell cycle progression in SMMC-7721 cell. Conclusions: Our findings provide evidences that positive expression of SMYD2 in HCC may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with HCC.