The purpose of this study was to investigate the pharmacokinetic interaction between sunitinib and ramipril in rats. Eighteen male SD rats were divided into three groups, with each group being assigned to orally receive sunitinib, ramipril, sunitinib and ramipril, respectively, for ten days. Blood samples were collected at dif-ferent times after first-day and tenth-day administration. The concentrations of ramiprilat and sunitinib in rat plasma were determined by LC/MS/MS and the pharmacokinetic parameters were calculated and statistically analyzed. Compared with the administration of ramipril alone, after a single-dose combined administration, tmax of ramiprilat decreased significantly and t1/2 prolonged, while AUC0-∞ remained unchanged. These results indicated that the ab-sorption rate of ramiprilat increased and the elimination rate decreased, but total absorption degree was not changed. After multiple-dose administrations, CL of ramiprilat decreased and AUC0-∞ increased obviously. It sug-gested that accumulation of ramiprilat occurred in body and the drug elimination became slower. No obvious difference of sunitinib pharmacokinetic behavior was found when it was given in combination with ramipril after a single-dose administration or multiple-dose administration. Sunitinib decreased the elimination of ramiprilat after co-administration in company with drug accumulation in body after multiple-dose co-administration. The study showed that there were pharmacokinetic interactions between sunitinib and ramipril in SD rats.

Objective To detect the mutations of Von Hippel-Lindau (VHL) gene via analyzing the prevalence of family members of VHL syndrome,clinical diagnosis and treatment,and gene analysis of patients with hemangioblastoma.methods All members of the VHL syndrome family members improved all relevant tests and plotted the family map.5 ml peripheral blood was extracted for gene sequencing,and the sequencing Result s were compared with the reported mutations of VHL gene in NCBI database.Result s(1)Analysis of clinical data of four members of the family:Ⅰ-2,Ⅱ-1,Ⅱ-5 suffering from central nervous system hemangioblastoma, Ⅱ-3 with pancreatic,retinopathy and pheochromocytoma,and Ⅱ-5 also combined with kidney,pancreatic lesions.The second generation of patients in the family have been treated surgically.(2)Gene sequencing Result s showed that all subjects in the test had the same mutation:exon2 109 sequence ATATCACACTGCCA was deleted and termination codon UGA appeared in exon 502.Conclusion Through the mutations of the VHL syndrome family,it is found that the family mutation type is a new mutation.For patients with central nervous system hemangioblastoma-based should be suspected of the disease and improve the family history survey.Once the diagnosis of familial VHL syndrome patients are confirmed,it is necessary to inform the other members of the family for clinical screening,and carry out genetic testing to reduce the harm of the disease to the greatest extent.

BACKGROUND:Bismth-doped iron nanoparticles modified by hyaluronic acid (HA-BiIOPs) not only act as an effective MRI contrast agent, but also as a radiotherapy sensitizer.OBJECTIVE:To fabricate the HA-BiIOPs and to observe its effect to enhance the radiosensitivity of glioblastoma cells U87MG under X-ray radiation.METHODS:HA-BiIOPs were synthesized using hydrothermal polyol method. (1) Cytotoxicity: A cytotoxicity test was carried out on U87MG cells and rat vascular smooth muscle cells (VSMCs). Cell proliferation rate of two kinds of cells cultured with different concentrations of HA-BiIOPs (0, 12.5, 25, 50, 100, 200, 400 mg/L) at 24 hours after culture were determined by cell counting kit-8 assay. (2) Histological analysis: ICR mice were sacrificed after intravenous injection of HA-BiIOPs, and pathological changes of mouse visceral organs were observed under an optical microscope. (3) Cellular uptake: The HA-BiIOPs after entered into the cytoplasm were observed by Prussian blue staining. (4) Radiosensitization test: U87MG cells at Logarithmic growth stage were cultured in culture medium as control group, subjected to X-ray irradiation (0, 3, 6, 9 Gy) as radiotherapy group, cultured in HA-BiIOPs (0, 12.5, 25, 50, 100, 200 and 400 mg/L) as HA-BiIOPs group or subjected to HA-BiIOPs culture plus X-ray irradiation as combined therapy group. Then, the cell proliferation rate and cloning efficiency were measured at 24 hours after treatment.RESULTS AND CONCLUSION:(1) The HA-BiIOPs at different concentrations were non-cytotoxic for VSMC and U87MG cells. (2) After intravenous injection of HA-BiIOPs, there was no obvious toxicity to the mouse susceptible organs. (3) After 6 hours of culture, the HA-BiIOPs could be internalized by U87MG cells. (4) The proliferation rate of U87 cells was negatively correlated with the concentration of HA-BiIOPs (0-200 mg/L) and X-ray dose (0-9 Gy). Especialy, the combination of 6 Gy X-ray irradiation with 200 mg/L HA-BiIOPs dramatically decreased the cell viability that was decreased to (41±7)%. In the combined therapy group with 6 Gy X-ray and 100 mg/L HA-BiIOPs, the cells proliferation rate was significantly lower than that in the control and radiotherapy groups (P < 0.05). These results indicate that HA-BiIOPs have a radiosensitizative effect on glioblastoma cells U87MG.

Objective To investigate the compliance of secondary prevention and the relationship with the long-term outcomes in patients undergoing percutaneous coronary intervention(PCI).Methods 589 patients undergoing PCI were followed-up,and factors including major adverse cardiac events(MACE)),smoking status and the usage of antiplatelet agents,angiotensin converting enzyme inhibitor(ACEI)/angiotensin Ⅱ receptor blocker(ARB),statins,beta blocker,calcium channel blocker and nitrates were recorded.Results The average follow-up time was 18.92 months.At discharge,588 patients(99.83%)were prescribed clopidogrel for(7.89±4.96)months;there were 31 patients(5.26%)who completely discontinued antiplatelet therapy during follow-up.At discharge,the prescription rate of aspirin,ACEI/ARB,beta blocker,statins,calcium channel blocker and nitrates was 98.98%,41.94%,63.50%,83.02%,19.69%and 46.52%respectively,whereas at follow-up,these were decreased to 94.4%,35.99%,55.86%,65.89%,17.49%and 35.31%.At follow-up,there were still 105 current smokers(17.83%).Complete cessation of antiplatelet therapy and current smoking were related to the increased risk of non-fatal myocardial infarct(9.68%v.s.1.08%,P＜0.01);smoking(4.76%v.s.0.83%,P＜0.01)andMACE(19.35%v.s.6.45%,P＜0.01);smoking(11.43%v.s.6.20%,P＜0.05).Conclusion Most patients can adhere to secondary prevention during follow-up,however,the compliance with secondary prevention should be improved further.Cessation of antiplatelet therapy and current smoking contribute to poor prognosis.

Preeclampsia is a kind of idiopathic disease during pregnancy. Its pathogenesis may involve many factors, such as mother, placenta and fetus. The study found that the abnormal metabolism of blood glucose and blood lipid during pregnancy may be closely related to the onset of preeclampsia. This paper reviews the research progress of abnormal glycolipid metabolism in preeclampsia at home and abroad in order to better guide the management of related aspects during pregnancy.

BACKGROUND:Studies have shown that imbalance of bone metabolism during glucocorticoid-induced osteonecrosis of the femoral head necrosis is closely related to oxidative stress. OBJECTIVE:To investigate the pathological mechanism by which oxidative stress-induced ferroptosis promote apoptosis in osteoblasts involved in steroid-induced osteonecrosis of the femoral head. METHODS:General data and serum specimens were collected from 47 patients with steroid-induced osteonecrosis of the femoral head.In addition,six femoral head specimens were collected from these patients.According to the Association Research Circulation Osseous(ARCO)staging system,serum specimens were grouped into ARCO Ⅱ,Ⅲ,and IV,while femoral head specimens were classified into ARCO Ⅲ and IV.Serum levels of malondialdehyde and superoxide dismutase 1 were measured.The protein expression of superoxide dismutase 1,glutathione peroxidase 4,Bcl-2 in the femoral head was detected and verified by Data independent acquisition(DIA)for quantitative sequencing,western blot and alkaline phosphate detection. RESULTS AND CONCLUSION:The ARCO stage of patients with steroid-induced osteonecrosis of the femoral head was independent of age,sex and necrotic side.The serum levels of malondialdehyde and superoxide dismutase 1 were higher in patients with ARCO stage Ⅲ compared with those with ARCO stage Ⅱ and IV.The results of DIA protein quantification showed that the function of differential proteins was mainly related to redox.The levels of superoxide dismutase 1,glutathione peroxidase 4,and Bcl-2 in the necrotic region were lower than in the normal region,as well as lower in ARCO stage IV than in ARCO stage Ⅲ.Western blot verified the results of DIA protein quantification.The alkaline phosphatase activity was lower in the necrotic region than in the normal region,as well as lower in ARCO stage IV than in ARCO stage Ⅲ.In the necrotic and sclerotic regions,the function of differential proteins was also related to redox,and superoxide dismutase 1,glutathione peroxidase 4,Bcl-2 protein expression and alkaline phosphatase activity were lower in the necrotic area than in the sclerotic region,as well as lower in ARCO stage IV than in ARCO stage Ⅲ.To conclude,glucocorticoids can influence the progression of steroid-induced osteonecrosis of the femoral head by upregulating oxidative stress levels,inducing osteoblast ferroptosis,and inhibiting osteogenic function.

Objective:To explore the value of dilated Virchow-Robin spaces (dVRS) in the basal ganglia in predicting basal ganglia atrophy.Methods:A total of 120 patients accepted head MRI and conformed as having dVRS in the basal ganglia in our hospital from May 1, 2015 to April 30, 2016 were chosen in our study; these patients were followed up for 5 years. The basal ganglia volume was observed by 3.0T MRI; according to whether the basal ganglia had atrophy or not, these patients were divided into normal group ( n=82) and atrophy group ( n=38). The general data and dVRS grading between the normal group and the atrophy group were compared. The basal ganglia volume at baseline and 5 years later in patients with different dVRS grading and the difference value of basal ganglia volume at baseline and 5 years later (△basal ganglia volume) were recorded for comparative analysis. Spearman analysis was used to evaluate the correlation between △ basal ganglia volume and dVRS grading. Independent influencing factors for basal ganglia atrophy were analyzed by Logistics regression; receiver operating characteristic (ROC) curve was drawn to evaluate the predictive values of independent influencing factors and their combination in basal ganglia atrophy. Results:Patients in the atrophy group had significantly older age, significantly higher percentage of patients with diabetes history, and significantly higher dVRS grading in the basal ganglia than those in the normal group ( P<0.05). There were significant differences in basal ganglia volume and △ basal ganglia volume at baseline and 5 years later among patients with different dVRS grading ( P<0.05); △ basal ganglia volume gradually increased with the increase of dVRS grading. Correlation analysis showed that △ basal ganglia volume was positively correlated with dVRS grading in basal ganglia ( r s=0.695, P<0.001); after adjusting for age and history of diabetes, the correlation was still positive ( r s=0.667, P<0.001). Logistics regression showed that age ( OR=1.776, 95%CI: 1.372-2.141, P=0.008), diabetes history ( OR=1.513, 95%CI: 1.129-1.954, P=0.011) and dVRS grading in the basal ganglia ( OR=2.855, 95%CI: 2.367-3.283, P=0.006) were independent influencing factors for basal ganglia atrophy. The area under the ROC curve of dVRS grading for predicting the basal ganglia atrophy was 0.709 ( 95%CI: 0.611-0.792, P<0.001), with sensitivity of 61.89% and specificity of 83.59%; that of combined age, diabetes history and dVRS grading in the basal ganglia was 0.783 ( 95%CI: 0.687-0.878, P<0.001), with sensitivity of 73.68% and specificity of 85.19%. Conclusion:The dVRS in the basal ganglia has certain predictive value in basal ganglia atrophy after 5 years.

Hepatocellular carcinoma (HCC) accounts for approximately 75%-85% of primary liver cancer cases and is one of the most frequently diagnosed malignancies worldwide. Immunotherapy is currently considered to be the most promising treatment to prevent the progression and postoperative recurrence of HCC. At present, the treatment strategies of immunotherapy for HCC are classified as active immunotherapy and passive immunotherapy, including tumor vaccine therapy, immune checkpoint inhibitors, and adoptive cell therapy. Here we review the current clinical progression and discuss the future perspective on immune therapy for HCC.

Objective:To develop a deep transfer learning method for the differential diagnosis of osteonecrosis of the femoral head (ONFH) with other common hip diseases using anteroposterior hip radiographs.Methods:Patients suffering from ONFH, DDH, and other hip diseases including primary hip osteoarthritis, non-infectious inflammatory hip disease, and femoral neck fracture treated in the First Affiliated Hospital of Guangzhou University of Chinese Medicine from January 2018 to December 2020 were enrolled in the study. A clinical data set containing anteroposterior hip radiographs of the eligible patients was created. Data augmentation by rotating and flipping images was performed to enlarge the data set, then the data set was divided equally into a training data set and a testing data set. The ResNet-152, a deep neural network model, was used in the study, but the original Batch Normalization was replaced with Transferable Normalization to construct a novel deep transfer learning model. The model was trained to distinguish ONFH and DDH from other common hip diseases using anteroposterior hip radiographs on the training data set and its classification performance was evaluated on the testing data set.Results:The clinical data set was comprised of anteroposterior hip radiographs of 1024 hips, including 542 with ONFH, 296 with DDH, and 186 with other common hip diseases (56 hips with primary osteoarthritis, 85 hips with non-infectious inflammatory osteoarthritis, 45 hips with femoral neck fracture). After data augmentation, the size of the data set multiplied to 6144. The model was trained 100 050 times in each task. Accuracy was used as the representative parameter to evaluate the performance of the model. In the binary classification task to identify ONFH, the best accuracy was 95.80%. As for the multi-classification task for classification of ONFH and DDH from other hip diseases, the best accuracy was 91.40%. The plateau of the model was observed in each task after 50 000 times of training. The mean accuracy in plateaus was 95.35% (95% CI: 95.33%, 95.37%), and 90.85% (95% CI: 90.82%, 90.87%), respectively. Conclusion:The present study proves the encouraging performance of a deep transfer learning method for the first-visit classification of ONFH, DDH, and other hip diseases using the convenient and economical anteroposterior hip radiographs.

Objective: The heart contains a pool of c-kit+ progenitor cells which is believed to be able to regenerate. The differentiation of these progenitor cells is reliant on different physiological cues. Unraveling the underlying signals to direct differentiation of progenitor cells will be beneficial in controlling progenitor cell fate. In this regard, the role of the mitochondria in mediating cardiac progenitor cell fate remains unclear. Specifically, the association between changes in mitochondrial morphology with the differentiation status of c-kit+ CPCs remains elusive. In this study, we investigated the relationship between mitochondrial morphology and the differentiation status of c-kit+ progenitor cells. Methods: and Results: c-kit+ CPCs were isolated from 2-month-old male wild-type FVB mice. To activate differentiation, CPCs were incubated in α-minimal essential medium containing 10 nM dexamethasone for up to 7 days. To inhibit Drp1-mediated mitochondrial fragmentation, either 10 μM or 50 μM mdivi-1 was administered once at Day 0 and again at Day 2 of differentiation. To inhibit calcineurin, either 1 μM or 5 μM ciclosporin-A (CsA) was administered once at Day 0 and again at Day 2 of differentiation. Dexamethasone-induced differentiation of c-kit+ progenitor cells is aligned with fragmentation of the mitochondria via a calcineurin-Drp1 pathway. Pharmacologically inhibiting mitochondrial fragmentation retains the undifferentiated state of the c-kit+ progenitor cells. Conclusions The findings from this study provide an alternative view of the role of mitochondrial fusion-fission in the differentiation of cardiac progenitor cells and the potential of pharmacologically manipulating the mitochondria to direct progenitor cell fate.