miR-483-5p通过下调CDK15促进肾上腺皮质癌增殖和侵袭

目的探讨miR-483-5p在肾上腺皮质癌中的作用及其可能的作用机制。方法荧光定量PCR法检测miR-483-5p和CDK15在肾上腺皮质癌组织和细胞系中的表达,CCK-8增殖试验测定miR-483-5p对细胞增殖的影响,Transwell法检测ACC细胞侵袭性的变化。荧光素酶试验和挽救实验验证miR-483-5p与CDK15相关的分子机制。结果miR-483-5p在肾上腺皮质癌组织中高表达(2.36±1.02 vs 1.09±0.43),CDK15在肾上腺皮质癌组织中低表达(0.57±0.26 vs 1.06±0.32)。荧光素酶检测证实CDK15是miR-483-5p的直接靶点。过表达miR-483-5p可通过下调CDK15的表达促进ACC细胞的增殖(24 h:0.26±0.03 vs 0.23±0.04,48 h:0.56±0.05 vs 0.41±0.03,72 h:0.73±0.04 vs 0.59±0.03)和侵袭能力(95.78±4.66 vs 23.89±2.52)。结论miR-483-5p可通过下调CDK15的表达促进肾上腺皮质癌的发生发展,其可作为肾上腺皮质癌的潜在生物标志物及治疗肾上腺皮质癌的新的作用靶点。     

Stability criteria for continuous‐time systems with additive time‐varying delays

This paper studies the problem of stability analysis for continuous‐time systems with two additive time‐varying delay components. By taking the independence and the variation of the additive delay components into consideration, more general type of Lyapunov functionals are defined. Together with a tighter estimation of the upper bound of the cross‐product terms derived from the derivatives of the Lyapunov functionals, less conservative delay‐dependent stability criteria are established in terms of LMIs. Combining with a reciprocally convex combination technique, the newly obtained stability conditions are also less complex. Two numerical examples are given to illustrate the effectiveness and the significant improvement of the proposed method. Copyright © 2013 John Wiley & Sons, Ltd.     

Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, K_I/k_inact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro–in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2-specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2 μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp^®. A modest (2–6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded.     

Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.     

Development of a System for Additive Manufacturing of Ceramic Matrix Composite Structures Using Laser Technology

Ceramic matrix composites (CMCs) are refractory ceramic materials with damage-tolerant behavior. Coming from the space industry, this class of materials is increasingly being used in other applications, such as automotive construction for high-performance brake discs, furnace technology, heat coatings for pipe systems and landing flaps on reusable rocket sections. In order to produce CMC faster and more cost-efficiently for the increasing demand, a new additive manufacturing process is being tested, which in the future should also be able to realize material joints and higher component wall thicknesses than conventional processes. The main features of the process are as follows. A ceramic fiber bundle is de-sized and infiltrated with ceramic suspension. The bundle infiltrated with matrix material is dried and then applied to a body form. During application, the matrix material is melted by laser radiation without damaging the fiber material. For the initial validation of the material system, samples are pressed and analyzed for their absorption properties using integrating sphere measurement. With the results, a suitable processing laser is selected, and initial melting tests of the matrix system are carried out. After the first validation of the process, a test system is set up, and the first test specimens are produced to determine the material parameters.     

Exercise‐induced ventricular tachycardia in a case with hypertrophic cardiomyopathy taking cibenzoline

We report a 17‐year‐old woman with hypertrophic cardiomyopathy (HCM) successfully resuscitated from ventricular fibrillation while taking cibenzoline. During exercise–stress testing before implanting an implantable cardioverter–defibrillator, ventricular tachycardia was induced and thought to be a proarrhythmia due to the use‐dependent effect of the Na channel blockade with cibenzoline. In patients with arrhythmogenic substrates such as HCM, it is critical to pay attention to the proarrhythmic effects of class I antiarrhythmic drugs while increasing heart rate.     

Quantitative Relationships Between the Cytotoxicity of Flavonoids on the Human Breast Cancer Stem‐Like Cells MCF7‐SC and Their Structural Properties

As some breast cancer‐related deaths can be attributed to the metastasis of cancer stem cells, chemotherapeutic agents targeting breast cancer stem cells are of interest as a potential treatment. Flavonoids that exhibit cytotoxicity on breast cancer stem cells have rarely been observed. Thus, the objective of this study was to measure potential cytotoxic effects of 42 different flavonoids on the human breast cancer stem‐like cell line, MCF7‐SC. The relationship between flavonoid structural properties and cytotoxicity has not been reported previously; therefore, we determined quantitative structure–activity relationships using both comparative molecular field analysis and comparative molecular similarity analysis. Further biological experiments including Western blot analysis, flow cytometry, and immunofluorescence microscopy were also conducted on the most cytotoxic 8‐chloroflavanone.