Delayed or missed antiseizure medications (ASMs) doses are common during long-term or lifelong antiepilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used ASMs.To explore remedial dosing regimens, Monte Carlo simulation was used based on previously identified and published population pharmacokinetic models. Six remedial strategies for delayed or missed doses were investigated. The deviation time outside the individual therapeutic range was used to evaluate each remedial regimen. The influences of patients' demographics, concomitant medication, and scheduled dosing intervals on remedial regimens were assessed. RxODE and Shiny in R were used to perform Monte Carlo simulation and recommend individual remedial regimens.The recommended remedial regimens were highly correlated with delayed time, scheduled dosing interval, and half-life of the ASM. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affects the clearance of the ASM, may also influence the remedial regimens. A web-based dashboard was developed to provide individualized remedial regimens for the delayed or missed dose, and a user-defined module with all parameters that could be defined flexibly by the user was also built.Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of ASMs in pediatric and adult patients with epilepsy.
Existing research has established the pepsinogen ratio (PGR) as a complex biomarker, not only as an independent predictor for various gastrointestinal diseases but also in its association with atherosclerotic cardiovascular diseases. However, the precise mechanism linking changes in PGR to cardiovascular pathologies remains unclear. The objective of this study is to quantitatively elucidate the association between PGR and brachial-ankle pulse wave velocity (baPWV) as an indicator of atherosclerotic progression.We conducted a cross-sectional study that analyzed clinical data from 465 patients who underwent health screenings. One-way Analysis of Variance (ANOVA) identified potential risk factors affecting baPWV. Multiple logistic regression was employed to evaluate if PGR serves as an independent risk factor for elevated baPWV after accounting for these variables. Generalized additive models and smoothed curve fitting were utilized to investigate the possibility of a nonlinear association between PGR and baPWV. When such nonlinearity was found, threshold effect analysis pinpointed the inflection point in this relationship, followed by segmented correlation analyses.PGR negatively correlated with both right baPWV (RbaPWV) and left baPWV (LbaPWV) after adjusting for confounders. Smoothed curve analyses revealed nonlinear relationships, with inflection points at 22.5 for RbaPWV and 22.3 for LbaPWV. For PGR values below 22.5, a significant negative correlation with RbaPWV was observed (β = - 6.3 cm/s, P < 0.001). Conversely, for PGR values above 22.5, no significant linear relationship was found (P = 0.141). Similarly, when PGR was below 22.3, a strong negative correlation with LbaPWV was detected (β = - 7.0 cm/s, P < 0.001), but such correlation was absent for higher PGR levels (P = 0.273).The study reveals that PGR is associated with RbaPWV and LbaPWV in a nonlinear manner. Specifically, lower levels of PGR were linearly and inversely correlated with baPWV, but this relationship became nonlinear at higher PGR levels. These findings suggest that modulating PGR levels may offer a therapeutic strategy for managing atherosclerosis.
Triple-negative breast cancer (TNBC) represents one of the subtypes of breast cancer with high aggressiveness. Long noncoding RNAs (lncRNAs) are well-known to function as crucial regulators in human cancers which include TNBC. Nevertheless, the specific role of the lncRNA C5orf66-AS1 in TNBC is unclear. In this study, we tested C5orf66-AS1 expression in TNBC cells using quantitative real-time PCR (qRT-PCR) and used functional assays to detect cell behaviors, which showed that C5orf66-AS1 was highly expressed in TNBC cells and that C5orf66-AS1 knockdown attenuated cell proliferation, migration, and invasion while promoting cell apoptosis. Through a luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and chromatin immunoprecipitation (ChIP) assay, we identified the binding capacity of C5orf66-AS1 to RNAs. Furthermore, miR-149-5p was proven to be sponged by C5orf66-AS1. CCCTC-binding factor (CTCF) was confirmed as the target of miR-149-5p and could transcriptionally activate C5orf66-AS1 expression in TNBC cells. We also discovered that C5orf66-AS1 activated the Wnt/β-catenin signaling pathway by upregulating catenin beta 1 (CTNNB1). Importantly, CTNNB1 could be targeted by miR-149-5p. In rescue assays, it was proven that overexpressing CTCF and CTNNB1 or inhibiting miR-149-5p could totally reverse the inhibitory effect of silencing C5orf66-AS1 on TNBC progression. In short, the lncRNA C5orf66-AS1 acted as an oncogene to facilitate TNBC malignancy.
AbstractBackground: Adherence to antiseizure medications (ASMs) is crucial for the success of treatment. However, current recommendations for assessing medication adherence through therapeutic drug monitoring (TDM) may overlook individual patient characteristics, potentially leading to misjudgments. This study aims to evaluate the capability of a Bayesian approach in assessing adherence for 14 ASMs using TDM. Method: A Bayesian framework incorporating population pharmacokinetics was used to assess adherence using TDM data. Additionally, the impact of patient characteristics, concomitant medications, sampling times, and prior adherence probability was examined. Results: With essential patient information, such as age, weight, and scheduled dosing regimen, the Bayesian approach effectively assessed recent adherence for all investigated ASMs. The concentration thresholds varied by ASM and were influenced by patients' characteristics. To facilitate individual adherence evaluations, a web-based dashboard was developed. Conclusion: The integration of Bayesian methods with pharmacokinetics significantly enhances the reliability of TDM in assessing adherence to ASMs.
Hepatocellular carcinoma (HCC) is a common malignant tumor in the world, especially in China. As a member of the inhibitor of differentiation (Id) family, Id4 has been reported to function in many cancer types, but relatively little is known about its role in HCC. The purpose of this study was to investigate the potential relationship between Id4 and HCC development and the underlying mechanism involving the function of Id4 in HCC.We used quantitative real-time polymerase chain reaction and Western blotting to examine the RNA and protein expression of Id4. In addition, we used Cell Counting Kit-8 assay and colony formation assay to identify the function of Id4 in the regulation of cell proliferation in human HCC.We found that the expression of Id4 protein was up-regulated in tumor tissues from HCC patients. Overexpression of Id4 promoted HCC cell proliferation, clonogenicity in vitro, and tumorigenicity in vivo. Id4 knockdown experiments showed that silencing Id4 blocked the proliferation and colony formation ability of HCC cells in vitro. Furthermore, overexpression of CCAAT/enhancer-binding protein β inhibited Id4 expression in HCC cells.Id4 may be developed as a potent therapeutic agent for the treatment of HCC, but more details about the underlying mechanisms of action are needed.
Tubercidin (TBN), an adenosine analog with potent antimycobacteria and antitumor bioactivities, highlights an intriguing structure, in which a 7-deazapurine core is linked to the ribose moiety by an N-glycosidic bond. However, the molecular logic underlying the biosynthesis of this antibiotic has remained poorly understood. Here, we report the discovery and characterization of the TBN biosynthetic pathway from Streptomyces tubercidicus NBRC 13090 via reconstitution of its production in a heterologous host. We demonstrated that TubE specifically utilizes phosphoribosylpyrophosphate and 7-carboxy-7-deazaguanine for the precise construction of the deazapurine nucleoside scaffold. Moreover, we provided biochemical evidence that TubD functions as an NADPH-dependent reductase, catalyzing irreversible reductive deamination. Finally, we verified that TubG acts as a Nudix hydrolase, preferring Co2+ for the maintenance of maximal activity, and is responsible for the tailoring hydrolysis step leading to TBN. These findings lay a foundation for the rational generation of TBN analogs through synthetic biology strategy, and also open the way for the target-directed search of TBN-related antibiotics.
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