Small interfering RNAs (siRNAs) are an emerging class of RNA interference (RNAi) therapeutics with unique pharmacokinetic properties. Five siRNA drugs based on two delivery systems have been approved, and an increasing number of siRNA drugs have already moved to the clinical study phase. Physiologically-based pharmacokinetic (PBPK) modeling is a useful tool and has been demonstrated to have wide ranging utility in drug development and regulatory review. However, PBPK modeling is still in its infancy in guiding the development of siRNA-based drugs in the context of its widespread use in small and large molecule areas. This article reviews the pharmacokinetic profiles of siRNA drugs, outlines the current state of PBPK model building in siRNA drug development, and describes the key parameters required for model building. This article provides insights into the future applications of PBPK models and for optimizing the key parameters when building the model for siRNA drug development.

Background Protein kinase B (Akt) is the center of multiple cellular signaling pathways,and it participates in the regulation of cell function,such as proliferation,migration,and metabolism of cells.Phosphoinositide 3-kinase (PI3K) promotes activation of Akt and therefore triggers many signal pathways.PI3K inhibitor can silent Akt,but whether it can affect the biological behavior of lens epithelial cells (LECs) during the posterior capsular opacity (PCO) is worthy of investigation.Objective This study was to explore the effect of LY294002,a PI3K inhibitor,on Akt activation in human LECs.Methods Human LECs strain,HLEC-B3 cells,were cultured and passaged.The cells were incubated to 96-well plate for 24 hours,then LY294002 was added with the final concentration at 0,10,20,30,40,50,60,70,80 μmol/L,respectively.After incubation for 24 hours,cell counting kit-8 (CCK-8) was used to detect the inhibitory rate of cell proliferation.Transforming growth factor-β2 (TGF-β2) of 10 μg/L was added in the medium of cells as TGF-β2 group,TGF-β2 + LY294002 (20 μmol/L) was used to coculture the other group of cells,and the cells without TGF-β2 and LY294002 served as the control group.Phosphorylation of Akt (p-Akt) in the cells was detected by laser scan confocal immunofluorescence microscope.The expression level of p-Akt was evaluated using Western blot.Results CCK-8 assay showed that the A value of the cells was gradually reduced with the increase of LY294002 concentration (Fgroup =9.72,P =0.00),but the A value was significant raised along with the lapse of time (Ftime =1737.54,P=0.00).Confocal immunofluorescence revealed that a little of p-Akt was expressed in the control cells.After induced by TGF-β2,lots of red fluorescence of p-Akt was seen in cells around the cell membranes.But in the TGF-β2+LY294002 co-culture cells,the fluorescence of Akt was much weaker.Western blot showed that the expression level of p-Akt was 0.91±0.08,1.48±0.13 and 0.95±0.19 in the control group,TGF-β2 group and TGF-β2 +LY294002 group,respectively,with a significant difference among the three groups (F =15.04,P =0.00).Conclusions LY294002 can inhibit the activation of Akt induced by TGF-β2.LY294002 may have utility in the prevention and treatment of PCO.

Animals ; Biomarkers, Tumor ; blood ; genetics ; metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; MicroRNAs ; blood ; genetics ; metabolism ; Neoplasms ; blood ; diagnosis ; genetics ; metabolism ; Prognosis

Objective To investigate the effect of vascular tortuosity and bending radius on the new type knitting stents (LVIS stent ) releasing on the cavernous sinus segment of internal carotid artery. Methods From December 2015 to January 2016,31 consecutive patients with wide-neckedaneurysm treated with LVIS stents and the proximal end of the stent released in the cavernous segment at the Department of Neurosurgery,Changhai Hospital,the Second Military Medical University were enrolled. According to whether the stents completely adhered to the walls or not after the first release,they were divided into two groups:a satisfactorily release group (n =23 )or an unsatisfactorily release group (n =8 ). The differences of vascular tortuosity and bending radius of the 2 groups were compared.Results Thevascular tortuosities of the satisfactorily release group and the unsatisfactorily release group were 118° ± 23° and 147° ± 19° respectively. There was significant difference (P=0. 028). The vascular bending radii were 3. 4 ± 0. 7 mm and 2. 8 ± 0. 7 mm respectively. There was significant difference (P=0. 042). The mean vascular tortuosity was larger and the mean vascular bending radius was smaller in the unsatisfactorily release group. Conclusions The greater the vascular tortuosity,the smaller the vascular bending radius may be connected with the unsatisfactorily release in the LVIS stent. The evaluation of vascular tortuosity is conductive to the guidance of the stent release technique before stent implantation.

BRCA1 Protein ; genetics ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; Designer Drugs ; therapeutic use ; Humans ; Lung Neoplasms ; drug therapy ; Precision Medicine ; methods ; Tubulin ; genetics ; Xeroderma Pigmentosum Group D Protein ; genetics

Objective To prepare and characterize monoclonal antibody against a malaria vaccine candidate, PfCP-2.9 chimeric protein of Plasmodium falciparum. Methods BALB/c mice were immunized with PfCP-2.9,and the spleen cells were used for fusion with SP2/0 cells. The monoclonal antibodies were analyzed by ELISA,Western blotting as well as growth inhibition assay. Result A monoclonal antibody was obtained. It interacted with the PfCP-2.9 recombinant protein by ELISA and Western blotting. The interaction of the monoclonal antibody with the protein was reduction-sensitive,indicating that the antibody recognized a conformational epitope. Moreover,the antibody also recognized the cultured parasites of P.falciparum by indirect immunofluorescent antibody test(IFA). When tested by growth inhibition assay,the antibody significantly inhibited parasite growth in vitro of 56% inhibition rate at the antibody concentration of 0.3 mg/ml. Conclusion A monoclonal antibody against PfCP-2.9 malaria vaccine candidate has been obtained,which recognizes a conformational epitope of the protein and natural protein.

Colonic Neoplasms ; diagnostic imaging ; pathology ; Digestive System Neoplasms ; diagnostic imaging ; pathology ; Esophageal Neoplasms ; diagnostic imaging ; pathology ; Gastrointestinal Stromal Tumors ; diagnostic imaging ; pathology ; Humans ; Positron-Emission Tomography ; methods ; Rectal Neoplasms ; diagnostic imaging ; pathology ; Stomach Neoplasms ; diagnostic imaging ; Tomography, X-Ray Computed ; methods

The concepts of cold and hot herbal properties in traditional Chinese medicine (TCM), reflecting the efficacy trends of medicinal herbs, have the Fuzzy characteristics. It is suited for the application of Fuzzy mathematics in research of herbal properties. For a comprehensive evaluation of herbal properties, this work constructed and made a practice of the Fuzzy discrimination model regarding the biological performance of Chinese materia medica.

Hydrocortisone-induced yang-deficiency animal model has now become the generally accepted model of yang deficiency. However, assessing the most appropriate dose of hydrocortisone is a long-term challenge. For analyzing the modeling dose, the authors have built several kinds of yang-deficiency models induced by hydrocortisone at different doses, and analyzed the experimental data with various mathematical statistical methods. In order to discuss the effects of the modeling dose on the basis of previous research, the authors introduced Ridit analysis.

OBJECTIVE:To evaluate the efficacy and safety of tiotropium bromide in the treatment of COPD patients and pro-vide evidence-based reference for the clinical treatment. METHODS:PubMed,EMBase,Medline,Cochrane Library,CJFD,Wan-Fang and VIP database were retrieved to collect the randomized controlled trial(RCT)of tiotropium bromide(test group)vs. place-bo(control group)in the treatment of COPD. The data was extracted and the quality was evaluated by Rev Man 5.0 software. RE-SULTS:A total of 19 studies were included,involving 16 318 patients. Meta-analysis shows that the FEV1[MD=0.13,95%CI (0.12,0.14),P<0.001],FVC[MD=0.20,95%CI(0.20,0.25),P<0.001] in test group were higher than control group,SGRQ score [MD=-2.94,95%CI(-3.38,-2.49),P<0.001] and COPD exacerbation rate[RR=0.83,95%CI(0.77,0.90),P<0.001] in test group were lower than those in control group ,but the dry mouth rate was higher than that of control group[RR=2.07,95%CI(1.34, 3.20),P<0.001],there were significant differences in 2 groups . CONCLUSIONS:Tiotropium bromide has good efficacy in the treatment of COPD. However,it may cause dry mouth. Due to the methodological limitations of included studies,it remians to be further verified by large-sample and high-quality RCT.