Pharmacokinetic Behavior of Vincristine and Safety Following Intravenous Administration of Vincristine Sulfate Liposome Injection in Chinese Patients With Malignant Lymphoma

Objective: This phase Ia study was designed to assess the pharmacokinetic (PK) characters of free vincristine (F-VCR, refer to as non-liposomal VCR and VCR released from liposome) and total vincristine (T-VCR, the sum of both liposomal VCR and F-VCR), urinary excretion and safety of intravenous administration of vincristine sulfate liposomes injection (VSLI) in Chinese patients with malignant lymphoma and compare the results with those for conventional vincristine sulfate injection (VSI).Methods: In the phase Ia, randomized, open-label, two sequence cross-over study, patients from one group were exposed to treatment 1 including cytoxan (cyclophosphamide power injection), hydroxyrubicin (adriamycin power injection), oncovin (VSI), and prednisone tablets (standard CHOP scheme) before crossed over to treatment 2 (modified CHOP scheme in which VSI was replaced with VSLI). Patients from another group received treatments in reverse order.Results: In this phase Ia study, a total of eight subjects participated. VCR elimination from the circulation after injection of VSLI was characterized by a significantly increased maximum concentration (Cmax, 86.6 ng/mL) and plasma area under the plasma concentration-time curve from zero to infinity (AUC0-Inf, 222.1 ng/mL h), markedly decreased distribution volume (Vz, 224.1 L) and plasma clearance (CL, 8.9 L/h) compared to lower Cmax (26.6 ng/mL) and AUC0-Inf (95.1 ng/mL h), larger Vz (688.8 L) and CL (22.1 L/h) for VSI. The small proportion of F-VCR following infusion of VSLI in circulation was reflected by very low Cmax (1.8 ng/mL) and AUC0-Inf (50.5 ng/mL h). Less than 3% of the administered dose of VSLI was excreted in urine and the extent was similar to that for VSI. The elimination percentage of 40–21–14% for VSI changed to 6.2–24–39% for VSLI at intervals of 0–5, 5–13 and 13–25 h, respectively. Significant difference of toxicity between VSLI and VSI was not observed.Conclusion: VSLI exhibits higher AUC0-Inf of T-VCR, lower CL and Vz compared with VSI. VSLI was well tolerated, maybe due to the markedly decreasing AUC0-Inf of F-VCR. The majority of VCR was enveloped in liposome and VCR was released gradually from liposome following injection of VSLI. Liposomal encapsulation of VCR does not alter the route and extent of VCR excretion in urine

Isolation and Characterization of Minipig Perivascular Stem Cells for Bone Tissue Engineering

Human subcutaneous adipose tissue has been recognized as a rich source of tissue resident mesenchymal stem/stromal cells (MSC) in recent years. The current study was designed to sort the minipig (mp) perivascular stem cells (PSCs) and investigate the osteogenic potential. Purification of human PSCs was achieved via fluorescence-activated cell sorting (FACS) from human liposuction samples [cluster of differentiation (CD)45-CD34-CD146+ perithelial cells and CD45-CD34+CD146- adventitial cells]. Subsequently, PSCs were isolated from mp adipose tissue samples (n=9), characterized and, using purified mpPSCs (obtained by FACS, which is used in human PSC purification), the mpPSC osteogenic and adipogenic potential was evaluated by Alizarin Red S and Oil Red O staining in vitro, respectively. The cell morphometry was observed following cell isolation and culture, and hematoxylin and eosin staining was performed to identify the fat tissue structure and vascular distribution. Osteogenic and adipogenic differentiation-associated gene expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that the same antigens used for human PSC identification and isolation were working in mp tissue (CD45, CD146 and CD34). The two cell groups: CD45-CD34-CD146+ pericytes and CD45-CD34+CD146- adventitial cells were successfully isolated from the subcutaneous fat in the posterior neck of mps, mpPSCs accounted for 8.6% of the stromal vascular fraction (SVF) with 1.4% pericytes and 7.2% adventitial cells. mpPSCs demonstrated characteristics of MSCs, including cell surface marker expression, colony forming unit-fibroblast inclusion, and the stronger osteogenic and adipogenic differentiation potential than that of the non-selected vascular stromal cells. The mRNA expression levels of osteocalcin, collagen, type I, α1 and peroxisome proliferator-activated receptor-γ in the mpPSCs group were significantly higher than those of the unsorted pSVF group (P\u3c0.05). Thus, the current study successfully isolated and cultured CD146+ and CD34+ cell populations from mp tissues, characterized the cells\u27 PSC-like phenotype and identified their distinctly osteogenic and adipogenic potential. © Spandidos Publications. All rights reserved

Immediate Versus Delayed Topotecan after First-line Therapy in Small Cell Lung Cancer

Background and objective How to prolong progression free survival (PFS) and overall survival (OS) of patients with small cell lung cancer (SCLC) has been one of the hottest issues. We retrospectively reviewed our data to compare the survival of immediate with delayed topotecan after first-line therapy in SCLC. Methods In our retrospective study, 53 patients with SCLC were divided into two groups as follow: patients receiving topotecan-containing regimen as maintenance/consolidation (maintenance/consolidation chemotherapy group) and salvage chemotherapy (salvage chemotherapy group). The Log-rank test was used to assess the difference in OS between two groups. Cox regression model was used for the multivariable analysis of independent prognostic factors. Results Twenty-nine patients received topotecan as maintenance/consolidation treatment, whereas 24 patients salvage chemotherapy. The response rates were 51.7% and 41.7%, respectively. The median survival time were 20 months and 27 months respectively (P=0.89). Multivariate Cox regression analyses identified sex and stage as independent prognostic factors. Conclusion Efficacy of first-line therapy was improved by topotecan maintenance/consolidation treatment, which did not result in any significant survival benefits in SCLC

Characterization of Montmorillonite–Biochar Composite and Its Application in the Removal of Atrazine in Aqueous Solution and Soil

Atrazine is a widely used triazine herbicide, which poses a serious threat to human health and aquatic ecosystem. A montmorillonite–biochar composite (MMT/BC) was prepared for atrazine remediation. Biochar samples were characterized by using scanning electron microscope (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectrometer (XPS). Structural and morphological analysis of raw biochar (BC) and MMT/BC showed that MMT particles have been successfully coated on the surface of biochar. Sorption experiments in aqueous solution indicated that the MMT/BC has higher removal capacity of atrazine compared to BC (about 3.2 times). The sorption of atrazine on the MMT/BC was primarily controlled by both physisorption and chemisorption mechanisms. The amendment of MMT/BC increased the sorption capacity of soils and delayed the degradation of atrazine. Findings from this work indicate that the MMT/BC composite can effectively improve the sorption capacity of atrazine in aquatic environment and farmland soil and reduce the environmental risk.Characterization of Montmorillonite–Biochar Composite and Its Application in the Removal of Atrazine in Aqueous Solution and SoilpublishedVersio

Effects of Working Memory, Strategy Use, and Single-Step Mental Addition on Multi-Step Mental Addition in Chinese Elementary Students

The aim of this paper was to examine the roles of working memory, single-step mental addition skills, and strategy use in multi-step mental addition in two independent samples of Chinese elementary students through different approaches to manipulate two dimensions of task characteristics (the primary task). In Study 1, we manipulated strategy types through the dimension of schema automaticity (whether intermediate sums were 10s) and the dimension of working memory load (WML, two steps versus four steps). A hierarchical linear model (HLM) analysis was conducted at case level, strategy level, and individual level. In Study 2, we manipulated task characteristics through schema automaticity (one-time versus two-time regrouping) and the WML (partial versus complete decomposition). A three-level HLM analysis was applied. The general findings of Study 1 and Study 2 suggested that shorter response time on single-step mental addition corresponded to shorter response time on multi-step mental addition. The use of strategies (from easier to more difficult strategies) negatively predicted response time on multi-step mental addition. Easier strategy was associated with shorter response time on multi-step mental addition. Better phonological loop was associated with shorter response time on multi-step mental addition. The findings in both studies highlighted the important role of phonological loop in mental addition in Chinese children, suggesting that the involvement of a specific subcomponent of working memory in mental arithmetic might be subject to linguistic, instructional, and contextual factors

Effective noninvasive zygosity determination by maternal plasma target region sequencing

Background: Currently very few noninvasive molecular genetic approaches are available to determine zygosity for twin pregnancies in clinical laboratories. This study aimed to develop a novel method to determine zygosity by using maternal plasma target region sequencing. Methods: We constructed a statistic model to calculate the possibility of each zygosity type using likelihood ratios (Li) and empirical dynamic thresholds targeting at 4,524 single nucleotide polymorphisms (SNPs) loci on 22 autosomes. Then two dizygotic (DZ) twin pregnancies, two monozygotic (MZ) twin pregnancies and two singletons were recruited to evaluate the performance of our novel method. Finally we estimated the sensitivity and specificity of the model in silico under different cell-free fetal DNA (cff-DNA) concentration and sequence depth. Results/Conclusions: We obtained 8.90 Gbp sequencing data on average for six clinical samples. Two samples were classified as DZ with L values of 1.891 and 1.554, higher than the dynamic DZ cut-off values of 1.162 and 1.172, respectively. Another two samples were judged as MZ with 0.763 and 0.784 of L values, lower than the MZ cut-off values of 0.903 and 0.918. And the rest two singleton samples were regarded as MZ twins, with L values of 0.639 and 0.757, lower than the MZ cut-off values of 0.921 and 0.799. In silico, the estimated sensitivity of our noninvasive zygosity determination was 99.90% under 10% total cff-DNA concentration with 2 Gbp sequence data. As the cff-DNA concentration increased to 15%, the specificity was as high as 97% with 3.50 Gbp sequence data, much higher than 80% with 10% cff-DNA concentration. Significance: This study presents the feasibility to noninvasively determine zygosity of twin pregnancy using target region sequencing, and illustrates the sensitivity and specificity under various detecting condition. Our method can act as an alternative approach for zygosity determination of twin pregnancies in clinical practice.Multidisciplinary SciencesSCI(E)2ARTICLE6null

Polymer Nanoparticle-Based Chemotherapy for Spinal Malignancies

Malignant spinal tumors, categorized into primary and metastatic ones, are one of the most serious diseases due to their high morbidity and mortality rates. Common primary spinal tumors include chordoma, chondrosarcoma, osteosarcoma, Ewing’s sarcoma, and multiple myeloma. Spinal malignancies are not only locally invasive and destructive to adjacent structures, such as bone, neural, and vascular structures, but also disruptive to distant organs (e.g., lung). Current treatments for spinal malignancies, including wide resection, radiotherapy, and chemotherapy, have made significant progress like improving patients’ quality of life. Among them, chemotherapy plays an important role, but its potential for clinical application is limited by severe side effects and drug resistance. To ameliorate the current situation, various polymer nanoparticles have been developed as promising excipients to facilitate the effective treatment of spinal malignancies by utilizing their potent advantages, for example, targeting, stimuli response, and synergetic effect. This review overviews the development of polymer nanoparticles for antineoplastic delivery in the treatment of spinal malignancies and discusses future prospects of polymer nanoparticle-based treatment methods

Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects

HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) as pharmacodynamics endpoints. A three-compartment model best described HR7056 pharmacokinetics. Total clearance was 1.49 L min−1, central volume was 2.1 L, inter-compartmental clearances were 0.96 and 0.27 L min−1, respectively. The population mean pharmacodynamic parameters were as follows: BIS, E0: 95.3; IC50: 503 ng mL−1; γ: 1.5; ke0: 0.0855 min−1; Imax: 47.9 and MOAA/S, IC50: 436 ng mL−1; γ: 1.5; ke0: 0.05 min−1; Imax: 27.9. The model simulation will enable maintenance doses to be given more accurately for future study.Clinical Trial Registration: identifier: NCT0197007