Population pharmacokinetics of cyclosporine A in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation.

PURPOSE: To establish the population pharmacokinetics (PPK) model of cyclosporine A(CsA) in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT), aiming at providing a reference for clinical dose individualization of CsA. METHODS: Children with thalassemia who underwent allogeneic HSCT were enrolled retrospectively. The PPK structural model and the random variable model of CsA were established on NONMEN. And goodness of fit plots (GOFs), visual predictive check (VPC), and bootstrap and normalized prediction distribution errors (NPDE) were used to evaluate the final model. RESULTS: A one-compartment model with first-order absorption was employed to fit the base model. A total of 74 pediatric patients and 600 observations of whole blood concentration were included. The final model included weight (WT) in clearance (CL), alongside post-operative day (POD), fluconazole (FLUC), voriconazole (VORI), posaconazole (POSA), and red blood cell count (RBC) significantly. All the model evaluations were passed. CONCLUSION: In the PPK model based on the pediatric cohort on CsA with thalassemia undergoing allogeneic HSCT, WT, POD, FLUC, VORI, POSA, and RBC were found to be the significant factors influencing CL of CsA. The reliability and robustness of the final model were excellent. It is expected that the PPK model can assist in individualizing dosing strategy clinically.

Drug closed-loop management system using mobile technology.

BACKGROUND: Drug closed-loop management reflects the level of hospital management and pharmacist service. It is a challenge for hospital pharmacists to realize the whole-process closed-loop management of drugs in hospital pharmacies. Therefore, this study aimed to evaluate the operational effect of using mobile technology to build a closed-loop drug management system. METHODS: Using mobile technology, replacing the traditional paper dispensing model and constructing a multinode information collection system according to the Healthcare Information and Management Systems Society Standard, we reformed the hospital information system and inpatient pharmacy workflow and then evaluated the new approach using statistical methods. RESULTS: After the transformation, the entire process of drug data can be traced. Closed-loop management, as well as real-time data verification and control, thereby improves the work efficiency and reduces the drug dispensing time. By reducing the work error rate, the number of dispensing errors decreased from 5 to 1 case/month. The comprehensive dispensing process can achieve the whole workflow of paperless operation and reduce the use of paper A4 by 180,000 pieces per year. CONCLUSIONS: Mobile technology can improve the service level of pharmacies, enhance the level of drug management and hospital quality management, ensure the safety of medication for inpatients, and significantly reduce the amount of paper used.

Mode selection of post-earthquake recovery and reconstruction of traditional villages using dependency analytic process: taking Xiluo-Buzi village in the 2022 M6.8 Luding earthquake as an example.

Introduction: Traditional villages are precious historical and cultural heritage sites. The selection of post-earthquake recovery and reconstruction (PERR) mode directly affects the village cultural heritage protection and the development direction of post-disaster reconstruction. A scientific and comprehensive feasibility evaluation for selecting the PERR mode of traditional villages can provide sufficient evidence for the recovery efforts in earthquake-stricken villages. Method: The author summarizes three PERR modes and constructs an evaluation index system for the selection of PERR modes of traditional villages. Based on the interrelationship of the indicators, the author has preliminarily established the Dependency Analytic Process (DAP), Based on this method, a model of traditional village PERR mode selection is constructed, and an empirical analysis is carried out in the case of the earthquake-stricken area of Xieluo-buzi Village in 2022 M6.8 Luding earthquake, to discuss the selection of PERR modes of traditional villages. Results: The authors have explored the application of the DAP in the selection of PERR modes for traditional villages and verified the effectiveness of the method. Since a large amount of actual research work is required to conduct an assessment, it is believed that with the widespread applications of the DAP, its superiority and practicality will be further demonstrated. Conclusion: The protection of traditional villages is a dynamic protection process, in which the will of the indigenous people is respected, the social network of the indigenous people is maintained, and the fair rights of the indigenous people to participate in the implementation of the project and to enjoy the preferential policies and resource benefits are guaranteed, as they are the real main body of the heritage protection, so that the traditional village ethnic heritage can be inherited and developed permanently in the protection. DAP is applicable to the comprehensive evaluation of multiple factors, particularly in situations where the importance of the indicators is difficult to be distinguished from each other. This is a new method to determine the weight vector, which has a broad application prospect.

Protective effect of 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione, isolated from Averrhoa carambola L., against Aß1-42-induced apoptosis in SH-SY5Y cells by reversing Bcl-2/Bax ratio.

BACKGROUND AND PURPOSE: Aß1-42-induced neurotoxicity has been considered as a possible mechanism to aggravate the onset and progression of Alzheimer's disease (AD). In this study, we aim to determine the protective effect of DMDD on the apoptosis of SH-SY5Y cells induced by Aß1-42 and elucidate potential mechanism of DMDD's protective function in apoptosis. EXPERIMENTAL APPROACH: CCK-8, AnnexinV-FITC/PI flow cytometry, and transmission electron microscopy analysis were used to determine the protection of DMDD on Aß1-42-evoked apoptosis of SH-SY5Y cells. Cytochrome c release, JC-1 staining, and measuring the protein of Bcl-2 family by Western blot were applied to elucidate the mechanism of DMDD's protective function in apoptosis. KEY RESULTS: Three concentration of DMDD (5 µmol/L, 10 µmol/L, and 20 µmol/L) rescues the cell viability loss and apoptosis of SH-SY5Y cells cultivated in Aß1-42. The expressions of cleaved Caspase-3, -8, -9, the cytochrome c release, and mitochondrial membrane potential loss were inhibited by DMDD in Aß1-42-insulted SH-SY5Y cells. The Western blot analysis showed that DMDD pretreatment clearly downregulated the protein of Bax and upregulated Bcl-2. Moreover, the Bcl-2/Bax ratio was obviously decreased in cells only exposed to Aß1-42, but, which was suppressed by treated with DMDD. CONCLUSION AND IMPLICATIONS: DMDD attenuated the apoptosis of SH-SY5Y cells induced by Aß1-42 through reversing the Bcl-2/Bax ratio.

Adaptor heat shock protein complex formation regulates trafficking of the asialoglycoprotein receptor.

In the asialoglycoprotein receptor (ASGPR) endocytic pathway, internalized receptors pass through early, recycling, and sorting endosomal compartments before returning to the cell surface. Sorting motifs in the cytoplasmic domain (CD) and protein interactions with these sequences presumably direct receptor trafficking. Previous studies have shown that association of a potential sorting heat shock protein (HSP) heterocomplex with the ASGPR-CD was regulated by casein kinase 2 (CK2)-mediated phosphorylation. Mass spectrometry and immunoblot analyses identified five of these ASGPR-CD-associated proteins as the molecular chaperones glycoprotein 96, HSP70, HSP90, cyclophilin A, and FK 506 binding protein. The present study was undertaken to determine whether any of the adaptor protein complexes (AP1, AP2, or AP3) were selectivity associated with the ASGPR-CD. In conjunction with molecular chaperones, AP2 and AP1 were recovered from a CK2 phosphorylated agarose-GSH-GST-ASGPR-CD matrix. Binding of AP3 was independent of the phosphorylation status of the CD matrix. Inhibition of CK2-mediated phosphorylation with tetrabromobenzotriazole prevented AP recovery within an immunoadsorbed ASGPR complex. Rapamycin, which dissociates the HSP heterocomplex from ASGPR-CD, thereby altering receptor trafficking also, inhibited AP association. Similar results were obtained with an inhibitor of HSP90 heterocomplex formation, geldanmycin. The data presented provide evidence that recruitment of AP1 and AP2, which is necessary for appropriate receptor trafficking, is mediated by the interaction of AP with the ASGPR-CD-bound HSP complex.

Phosphorylation-dependent interaction of the asialoglycoprotein receptor with molecular chaperones.

A membrane protein trafficking mutant (Trf1) of HuH-7 alters the asialoglycoprotein (ASGPR) and transferrin receptor subcellular distribution. Expression cloning of a cDNA complementing the trf1 mutation led to the discovery of a novel casein Kinase 2 catalytic subunit (CK2alpha"). To purify potential CK2alpha" phosphorylation-dependent sorting proteins from cytosol, the ASGPR cytoplasmic domain was expressed as a GST fusion protein and immobilized on glutathione-agarose. In the absence of phosphorylation, only trace amounts of cytosol protein were bound and eluted. When the fusion protein was phosphorylated, a heterocomplex of potential sorting proteins was recovered. Mass spectrometer and immunoblot analysis identified five of these proteins as gp96, HSP70, HSP90, cyclophilin-A, and FKBP18. Treatment of HuH-7 with rapamycin to disrupt the heterocomplex reduced surface ASGPR binding activity by 65 +/- 5.7%. In Trf1 cells, surface-binding activity was 48 +/- 7% of that in HuH-7 and was not further reduced by rapamycin treatment. Immunoanalysis showed significantly fewer surface receptors on rapamycin-treated HuH7 cells than on nontreated cells, with no affect on the level of surface receptors in Trf1 cells. The data presented provide evidence that phosphorylation of the ASGPR cytoplasmic domain is required for the binding of specific molecular chaperones with the potential to regulate receptor trafficking.

Translated Alu sequence determines nuclear localization of a novel catalytic subunit of casein kinase 2.

Casein kinase 2 (CK2) is a tetrameric enzyme constitutively expressed in all eukaryotic tissues. The two known isoforms of the catalytic subunit, CK2alpha and CK2alpha', have been reported to have distinct tissue-dependent subcellular distributions. We recently described a third isoform of the catalytic subunit, designated CK2alpha", which is highly expressed in liver. Immunoblot analysis of HuH-7 human hepatoma cell fractions as well as immunofluorescent microscopy revealed that CK2alpha" was exclusively localized to the nucleus and preferentially associated with the nuclear matrix. CK2alpha and CK2alpha' were found in nuclear, membrane, and cytosolic compartments. Deletion of the carboxy-terminal 32 amino acids from the CK2alpha" sequence resulted in release of the truncated green fluorescent protein fusion protein from the nuclear matrix and redistribution to both the nucleus and the cytoplasm. Demonstration that the carboxy terminus is necessary but not sufficient for nuclear retention indicates that the underlying mechanism of CK2alpha" nuclear localization is dependent on the secondary structure of the holoenzyme directed by the carboxy-terminal sequence.