Venous system diseases mainly include varicose veins and venous malformations of lower limbs and the genital system. Most of them are chronic diseases that cause serious clinical symptoms to patients and affect their health and quality of life. Sclerotherapy has become the first-line therapy for venous system diseases. However, there are problems such as incomplete fibrosis and vascular recanalization after sclerotherapy, and improper operation will cause serious adverse consequences. Therefore, exploring a safe and effective sclerotherapy strategy is essential for developing clinically successful sclerotherapy. To solve the above problems, we proposed a new sclerotherapy strategy with a dual mechanism of "vascular damage and plasmin (PLA) system inhibition." We intended to construct a novel cationic surfactant (AEO_x-TA) by reacting tranexamic acid (TA), a parent structure, with fatty alcohol polyoxyethylene ether (AEO_x) by ester bonds. AEO_x-TA could damage vascular endothelium and initiate a coagulation cascade effect to induce thrombus. Furthermore, AEO_x-TA could be degraded by esterase and release the parent drug, TA, which could inhibit the PLA system to inhibit the degradation of thrombus and extracellular matrix and promote the process of vascular fibrosis. In addition, such surfactant-based sclerosants have foam-forming properties, and they can be blended with polyvinyl alcohol (PVA) to prepare a highly stable foam formulation (AEO_x-TA/P), which can achieve a precise drug delivery and prolonged drug retention time, thereby improving drug efficacy and reducing the risk of ectopic embolism. Overall, the novel cationic surfactant AEO_x-TA provides a new avenue to resolve the bottleneck: surfactant sclerosants' efficiency is relatively low in the current sclerotherapy.

Objective To explore the mechanism by which CD137 signal regulates the aging of vas-cular smooth muscle cells(VSMCs).Methods Thirty 8-week-old male C57BL/6J mice were ran-domly divided into a young group(8 weeks old)and an aged group(80 weeks old),with 30 mice in each group.After corresponding periods of feeding,the mice were euthanized,and the plasma and aortic blood vessels were isolated.In the cell experiments,normal VSMCs were divided into a control group,bleomycin(BLM)group,combined agonist group,and combined inhibitor group.The cellular senescence level of VSMCs was assessed using a cellular senescence β-galactosidase staining kit.Western blotting and PCR were employed to examine the expression of senescence-related proteins in tissues and cells,while ELISA was utilized to measure the expression of senes-cence-related inflammatory factors.Results The expression of CD137 and γ-H2AX in the aorta was significantly higher,while that of PCNA was obviously lower in the aged group than the young group(P＜0.05).The plasma level of CD137 was notably higher in the aged group than the young group(154.0±4.1 pg/ml vs 98.0±2.3 pg/ml,P＜0.05).Compared with the normal control group,there were significantly more aged VSMCs in the BLM group(P＜0.05).While,treatment of combined agonist resulted in larger amount of aged VSMCs when compared with the BLM group(P＜0.05),which was reversed by combined inhibitor treatment(P＜0.05).The levels of TNF-α,IL-6 and IL-1β were significantly elevated in the BLM group than the normal control group(P＜0.05).The combined agonist group had even higher levels of TNF-α,IL-6,and IL-1βthan the BLM group(P＜0.05),but the levels were decreased in the combined inhibitor group(P＜0.05).Compared with the normal control group,the expression of Bcl-2,γ-H2AX,P53,and P21 were significantly increased in the BLM group,combined agonist group,and combined inhibi-tor group,while that of PCNA was significantly decreased(P＜0.05).Compared with the BLM group,the expression of P53 and P21 in the combined agonist group showed an increase(P＜0.05),and the expression of P53 was significantly decreased in the combined inhibitor group(P＜0.05).Conclusion CD137 signal regulates the P53/P21 pathway to promote VSMC aging.

Objective To evaluate and analyze the accuracies of 3 software solutions based on deep learning techniques in the automatic segmentation of head and neck organs at risk(OAR).Methods The automatic segmentation accuracies of 3 software(PV-iCurve,RT-Mind,and AccuContour)were evaluated with Dice similarity coefficient(DSC),Hausdorff distance(HD),center of mass deviation(COMD),false negative rate(FNR),false positive rate(FPR),Jaccard coefficient(JC),sensitivity index(SI),and inclusive index(II)using the manual contours of head and neck OAR as the gold standard.Results The FNR,JC,SI of brain,the FPR,II of brainstem,the FPR,FNR,JC,SI of eye_L,the FPR,FNR,SI,II of mandible,the FPR,FNR,SI,II of parotid_L,and the DSC,FPR,JC,II of spinal cord manifested significant differences among the 3 software(P<0.05);but the HD,FNR,SI of brainstem,and the HD of spinal cord revealed trivial differences among the 3 software(P>0.05).Conclusion Through the comparison of multiple parameters,it is found that the accuracies of 3 software are different in OAR segmentation,which makes it difficult to make overall horizontal comparisons.Therefore,these parameters are for reference only and cannot be used as criteria for evaluating the segmentation results in clinic.Although all 3 software achieve preferable segmentation outcomes,scrutiny and manual modifications before clinical practice are still necessary.

The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design.

Objective: To investigate whether CD137-CD137L signaling could affect the secretion of mouse vascular smooth muscle cells (VSMCs) -derived exosomes through autophagy mediated Rab7 pathway. Methods: Primary thoracic aorta VSMCs from C57BL/6J mouse were obtained by tissue block adherence method. VSMCs between the third to fifth passages were used and VSMCs were divided into 4 groups: control group, CD137 agonist group, lentivirus control group, Rab7 lentiviral interference group. VSMCs in CD137 agonist group were treated with recombinant protein of CD137L (10 μg/ml), VSMCs in lentivirus control group were treated with lentiviral followed by recombinant protein of CD137L (10 μg/ml), VSMCs in Rab7 lentiviral interference group were treated with Rab7 lentiviral intervention followed by recombinant protein of CD137L (10 μg/ml). Western blot was used to detect the protein expression of LC3Ⅱ, p62, Rab7, CD9, CD81 and Hsc70. Fluorescence microscopy was used to track the changes of autophagy in cells infected with mRFP-GFP-LC3. Transmission electron microscope was used to observe the morphology and size of VSMCs-derived exosomes. The nanoparticle tracking analysis(NTA) was used to detect the concentration and size of exosomes in each group. Results: (1) The expressions of Rab7, LC3Ⅱ and p62 protein in VSMCs of CD137 activation group were significantly higher than those in control group (all P<0.05). The expressions of Rab7, LC3Ⅱ and p62 protein in Rab7 lentivirus interference group was lower than in CD137 activation group (all P<0.05), while the expressions were similar between the lentivirus control group and the CD137 activation group (all P>0.05). (2) The total number of fluorescent spots and yellow fluorescent spots in the VSMCs of the CD137 activation group were higher than those in the control group (all P<0.05), and the number of yellow fluorescent spots was higher than that of the red fluorescent spots in the VSMCs of the CD137 activation group ((50.3±0.9) vs. (10.3±1.5)/cell). The total numbers of fluorescent spots and yellow fluorescent spots in VSMCs of Rab7 lentivirus interference group were lower than those of CD137 activation group (both P<0.05), and the number of red fluorescent spots in VSMCs was higher than that of yellow fluorescent spots ((40.7±4.0) and (10.7±1.2)/cell) in the Rab7 lentiviral interference group. The total numbers of fluorescent spots and yellow fluorescent spots in the VSMCs were similar between the lentivirus control group and the CD137 activation group (all P>0.05). (3) Under transmission electron microscopy, the size of the VSMCs-derived exosomes was about 30-150 nm. The exosome markers (CD9, CD81) could be detected in vesicles by Western blot. NTA results showed that the concentration of VSMCs-derived exosomes was significantly higher in the CD137-activated group than in the control group (P<0.05), which was significantly lower in the Rab7 lentiviral interference group than in the CD137-activation group (P<0.05) and was similar between the lentivirus control group and the CD137 activation group (P>0.05). The expression of Hsc70 protein in exosomes secreted by CD137 activation group was higher than that in the control group (P<0.05). The expression of Hsc70 protein in exosomes was lower in Rab7 lentivirus interference group than in the CD137 activation group (P<0.05), which was similar between the lentivirus control group and the CD137 activation group (P>0.05). The expression of LC3Ⅱ protein in exosome was higher in CD137 activation group than in control group (P<0.05), which was lower in Rab7 lentivirus interference group than in CD137 activation group (P<0.05), which was similar between the lentivirus control group and the CD137 activation group (P>0.05). Conclusion The CD137-CD137L signaling may affect the secretion of mouse VSMCs-derived exosomes through modulating the Rab7 pathway mediated autophagy.

Objective: To develop a convolution neural network (CNN) model to classify multi-sequence MR images of the prostate. Methods: ResNet18 convolution neural network (CNN) model was developed to classify multi-sequence MR images of the prostate. A deep residual network was used to improve training accuracy and test accuracy. The dataset used in this experiment included 19 146 7-sequence prostate MR images (transverse T₁WI, transverse T₂WI, coronal T₂WI, sagittal T₂WI, transverse DWI, transverse ADC, transverse PWI), from which a total of 2 800 7-sequence MR images was selected as a training set. Three hundred and eighty eight 7-sequence MR images were selected as test sets. Accuracy was used to evaluate the effectiveness of ResNet18 CNN model. Results: The classification accuracy of the model for transverse DWI, sagittal T₂WI, transverse ADC, transverse T₁WI, and transverse T₂WI was as high as 100.0% (44/44,52/52), and the accuracy for transverse PWI was also as high as 96.7% (116/120). The accuracy for coronal T₂WI was 77.5% (31/40). 0.8% (1/120) of transverse PWI was incorrectly assigned to transverse T₂WI, and 2.5% (3/120) incorrectly assigned to sagittal T₂WI. 15.0% (6/40) of coronal T₂WI was incorrectly assigned to transverse T₂WI, and 7.5% (3/40) to sagittal T₂WI. Conclusion The experimental results show the effectiveness of our deep learning method regarding accuracy in the prostate multi-sequence MR images detection.

Objective To investigate whether CD137?CD137L signaling could affect the secretion of mouse vascular smooth muscle cells (VSMCs)?derived exosomes through autophagy mediated Rab7 pathway. Methods Primary thoracic aorta VSMCs from C57BL/6J mouse were obtained by tissue block adherence method. VSMCs between the third to fifth passages were used and VSMCs were divided into 4 groups: control group, CD137 agonist group, lentivirus control group, Rab7 lentiviral interference group. VSMCs in CD137 agonist group were treated with recombinant protein of CD137L (10 μg/ml), VSMCs in lentivirus control group were treated with lentiviral followed by recombinant protein of CD137L (10 μg/ml), VSMCs in Rab7 lentiviral interference group were treated with Rab7 lentiviral intervention followed by recombinant protein of CD137L (10 μg/ml). Western blot was used to detect the protein expression of LC3Ⅱ, p62, Rab7, CD9, CD81 and Hsc70. Fluorescence microscopy was used to track the changes of autophagy in cells infected with mRFP?GFP?LC3. Transmission electron microscope was used to observe the morphology and size of VSMCs?derived exosomes. The nanoparticle tracking analysis(NTA) was used to detect the concentration and size of exosomes in each group. Results (1) The expressions of Rab7, LC3Ⅱand p62 protein in VSMCs of CD137 activation group were significantly higher than those in control group (all P<0.05). The expressions of Rab7, LC3Ⅱ and p62 protein in Rab7 lentivirus interference group was lower than in CD137 activation group (all P<0.05), while the expressions were similar between the lentivirus control group and the CD137 activation group (all P>0.05). (2) The total number of fluorescent spots and yellow fluorescent spots in the VSMCs of the CD137 activation group were higher than those in the control group (all P<0.05), and the number of yellow fluorescent spots was higher than that of the red fluorescent spots in the VSMCs of the CD137 activation group ((50.3 ± 0.9) vs. (10.3 ± 1.5)/cell). The total numbers of fluorescent spots and yellow fluorescent spots in VSMCs of Rab7 lentivirus interference group were lower than those of CD137 activation group (both P<0.05), and the number of red fluorescent spots in VSMCs was higher than that of yellow fluorescent spots ((40.7 ± 4.0) and (10.7 ± 1.2)/cell) in the Rab7 lentiviral interference group. The total numbers of fluorescent spots and yellow fluorescent spots in the VSMCs were similar between the lentivirus control group and the CD137 activation group (all P>0.05). (3) Under transmission electron microscopy, the size of the VSMCs?derived exosomes was about 30-150 nm. The exosome markers (CD9, CD81) could be detected in vesicles by Western blot. NTA results showed that the concentration of VSMCs?derived exosomes was significantly higher in the CD137?activated group than in the control group (P<0.05), which was significantly lower in the Rab7 lentiviral interference group than in the CD137?activation group (P<0.05) and was similar between the lentivirus control group and the CD137 activation group (P>0.05). The expression of Hsc70 protein in exosomes secreted by CD137 activation group was higher than that in the control group (P<0.05). The expression of Hsc70 protein in exosomes was lower in Rab7 lentivirus interference group than in the CD137 activation group (P<0.05), which was similar between the lentivirus control group and the CD137 activation group (P>0.05). The expression of LC3Ⅱprotein in exosome was higher in CD137 activation group than in control group (P<0.05), which was lower in Rab7 lentivirus interference group than in CD137 activation group (P<0.05), which was similar between the lentivirus control group and the CD137 activation group (P>0.05). Conclusion The CD137?CD137L signaling may affect the secretion of mouse VSMCs?derived exosomes through modulating the Rab7 pathway mediated autophagy.

Objective To develop a convolution neural network (CNN) model to classify multi?sequence MR images of the prostate. Methods ResNet18 convolution neural network (CNN) model was developed to classify multi?sequence MR images of the prostate. A deep residual network was used to improve training accuracy and test accuracy. The dataset used in this experiment included 19 146 7?sequence prostate MR images (transverse T1WI, transverse T2WI, coronal T2WI, sagittal T2WI, transverse DWI, transverse ADC, transverse PWI), from which a total of 2 800 7?sequence MR images was selected as a training set. Three hundred and eighty eight 7?sequence MR images were selected as test sets. Accuracy was used to evaluate the effectiveness of ResNet18 CNN model. Results The classification accuracy of the model for transverse DWI, sagittal T2WI, transverse ADC, transverse T1WI, and transverse T2WI was as high as 100.0% (44/44,52/52), and the accuracy for transverse PWI was also as high as 96.7% (116/120). The accuracy for coronal T2WI was 77.5% (31/40). 0.8% (1/120) of transverse PWI was incorrectly assigned to transverse T2WI, and 2.5% (3/120) incorrectly assigned to sagittal T2WI. 15.0% (6/40) of coronal T2WI was incorrectly assigned to transverse T2WI, and 7.5% (3/40) to sagittal T2WI. Conclusion The experimental results show the effectiveness of our deep learning method regarding accuracy in the prostate multi?sequence MR images detection.

To increase the dissolution rate and extent of valsartan, valsartan nanosuspensions have been prepared. Controlled precipitation assisted with sonication is utilized to prepare valsartan nanosuspensions, the concentration of the drug, stabilizer and costablizer had a great effect on the stability of the preparation according to the pre-experiment. So the method of central composite design-response surface is used to optimize the prescription based on the above three factors and the particle size as the response value. The software Origin 8.0 is used to draw the view of the three-dimensional effects and 2D contour map, to get the optimal prescription area. Valsartan nanosuspensions were prepared. The mean diameter and zeta potential are about 216.6 nm and -57.7 mV, respectively. Compared with the microsuspensions and commercial preparation, the dissolution of valsartan nanosuspensions was faster and the bioavailability can be enhanced to some extent.

To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).