Objective In this study,Knoevenagel derivatives of curcumin were synthesized,and their oil-water partition coefficient were determined.Our aim is to provide an experimental basis for further development of curcumin derivatives.Methods Two Knoevenagel derivatives of curcumin,including 4-(thiophen-2-ylidene)curcumin(3a)and 4-(pyridine-4-ylidene)curcumin(3b),were obtained by using the methylene group of curcumin as the modification site and purified by column chromatography.The structures of these derivatives were confirmed by nuclear magnetic resonance spectroscopy(NMR),infrared(IR)and high-resolution liquid mass spectrometry(HRLC-MS).The oil-water partition coefficient of the derivatives in n-octanol aqueous solution was determined by quantitative analysis using HPLC.Results Knoevenagel derivatives of curcumin were successfully synthesis.The oil-water partition coefficients(lgPap)of curcumin derivatives 3a and 3b are 0.96 and 0.82,respectively.Compared with the oil-water partition coefficient of curcumin(lgPap=3.85),it suggested that curcumin derivatives showed better water solubility than curcumin.Conclusion Compared to the curcumin prototype,Knoevenagel derivatives of curcumin increased water solubility and improved bioavailability.Thus,it may provide experimental basis for introducing heteroarylene moiety of the methylene position of curcumin to enhance pharmacological activity.

Hepatic stellate cells (HSCs) represent a significant component of hepatocellular carcinoma (HCC) microenvironments which play a critical role in tumor progression and drug resistance. Tumor-on-a-chip technology has provided a powerful in vitro platform to investigate the crosstalk between activated HSCs and HCC cells by mimicking physiological architecture with precise spatiotemporal control. Here we developed a tri-cell culture microfluidic chip to evaluate the impact of HSCs on HCC progression. On-chip analysis revealed activated HSCs contributed to endothelial invasion, HCC drug resistance and natural killer (NK) cell exhaustion. Cytokine array and RNA sequencing analysis were combined to indicate the iron-binding protein LIPOCALIN-2 (LCN-2) as a key factor in remodeling tumor microenvironments in the HCC-on-a-chip. LCN-2 targeted therapy demonstrated robust anti-tumor effects both in vitro 3D biomimetic chip and in vivo mouse model, including angiogenesis inhibition, sorafenib sensitivity promotion and NK-cell cytotoxicity enhancement. Taken together, the microfluidic platform exhibited obvious advantages in mimicking functional characteristics of tumor microenvironments and developing targeted therapies.

Objective To evaluate the differences in efficacy,safety and economics of vancomycin hydrochloride for injection between two manufacturers based on real-world data.Methods A total of 6 757 cases of intravenous use of vancomycin hydrochloride for injection from different manufacturers between January 1,2013 and December 31,2019 in the Affiliated Drum Tower Hospital of Nanjing University Medical School were retrospectively analyzed,and 5308 cases were matched by 1∶1 propensity score method,including 2 654 cases in the group A(domestic drug group)and 2 654 cases in group B(the innovator drug group).The differences in efficacy and safety between the two groups were compared.Cost-effectiveness analysis was used to compare the drug economics of the two groups.Results There were no significant differences in clinical cure rate,bacterial clearance rate,and incidence of adverse events between the two groups(P>0.05).In terms of economics,the average cost of vancomycin per capita,average daily cost of vancomycin and average cost of antibiotics per capita were significantly different between the two groups(P<0.05),and the cost of group B was higher than that of group A.Conclusion The efficacy and safety of vancomycin hydrochloride for injection were consistent between the two manufacturers.

BACKGROUND: Concerns exist regarding the potential development of tuberculosis in patients with rheumatoid arthritis (RA) treated with biological and targeted drugs. We assessed systematically whether biological therapy increased the risk of tuberculosis in patients with RA by meta-analysis of randomized controlled trials (RCTs). METHODS: A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and China Biology Medicine disc for RCTs evaluating biological therapy in patients with RA from inception through August 2021. Traditional meta-analysis and network meta-analysis were performed to compare the risk of tuberculosis for each biologics class in patients with RA. Peto odds ratio (Peto OR) and its 95% confidence interval (CI) were calculated as the primary effect measure. RESULTS: In total, 39 studies with 20,354 patients were included in this meta-analysis, and 82 patients developed tuberculosis. The risk of tuberculosis was increased in patients treated with biologics compared with non-biologics (Peto OR: 3.86, 95% CI: 2.36-6.32, P < 0.001). Also, tumor necrosis factor-α (TNF-α) inhibitors had a higher probability of developing tuberculosis than placebo (Peto OR: 3.98, 95% CI: 2.30-6.88, P < 0.001). However, network meta-analysis demonstrated that there was no significant difference in the risk of tuberculosis for each biologics class in patients with RA. Noticeably, tuberculosis was significantly more common in patients treated with a high dose compared with patients receiving a low dose of tofacitinib (Peto OR: 7.39, 95% CI: 2.00-27.31, P = 0.003). CONCLUSION This meta-analysis demonstrates the evidence of an elevated risk of tuberculosis in patients with RA treated with TNF-α inhibitors, and a dose-dependent elevated risk of tuberculosis in patients treated with tofacitinib.
Antirheumatic Agents/adverse effects* ; Arthritis, Rheumatoid/drug therapy* ; Humans ; Network Meta-Analysis ; Pharmaceutical Preparations ; Randomized Controlled Trials as Topic ; Tuberculosis/drug therapy*

Objective:To explore the value of contrast-enhanced ultrasound (CEUS) combined with Ovarian-Adnexal Reporting and Data System (O-RADS US) risk stratification and management system in differential diagnosis of ovarian-adnexal mass.Methods:Fifty-six patients with ovarian-adnexal mass who received transabdominal transvaginal ultrasound and CEUS in the Third People′s Hospital of Longgang District from September 2018 to January 2021 were enrolled. The images were classified by O-RADS US and diagnosed by CEUS by experienced and senior radiologist. On the basis of O-RADS US classification, the enhancement time, enhancement level and enhancement mode of CEUS were combined to upgrade or degrade the classification results of O-RADS US. The diagnostic accuracy was assessed using ROC curve analysis, the area under the ROC curve (AUC) was calculated. The reproducibility of O-RADS US was assessed by another senior radiologist.Results:The AUC of O-RADS US for diagnosing benign and malignant ovarian-adnexal masses was 0.844(0.722, 0.927), the AUC of CEUS was 0.833(0.710, 0.920), the AUC of O-RADS US combined with CEUS was 0.940(0.842, 0.986) (compared with O-RADS US, P=0.020; compared with CEUS, P=0.031). The intra-class correlation coefficient (ICC) was 0.897(0.824, 0.940) for O-RADS US. Conclusions:CEUS combined with O-RADS US classification can effectively improve the diagnostic efficiency for benign and malignant ovarian-adnexal masses.

Background::Concerns exist regarding the risk of infections in patients with spondyloarthritis (SpA) treated with biologics. We assessed the risk of infections of biological and targeted drugs in patients with SpA by performing a meta-analysis based on randomized controlled trials (RCTs).Methods::A systematic literature search was conducted in PubMed, Embase, Web of Science, the Cochrane Library, and China Biology Medicine Disc for RCTs evaluating the risk of infections of biological therapy in patients with SpA from inception through August 9, 2021. We calculated a pooled Peto odds ratio (OR) for infections in biologics-treated patients vs. placebo patients. The risk of bias on the included RCTs was assessed by using the Cochrane Risk of Bias Tool. Results::In total, 62 studies were included in this meta-analysis. Overall, the risk of infection (Peto OR: 1.16, 95% confidence interval [CI]: 1.07-1.26, P < 0.001), serious infection (Peto OR: 1.65, 95% CI: 1.26-2.17, P < 0.001), upper respiratory tract infection (URTI) (Peto OR: 1.17, 95% CI: 1.04-1.32, P = 0.008), nasopharyngitis (Peto OR: 1.25, 95% CI: 1.10-1.42, P < 0.001), and Candida infection (Peto OR: 2.64, 95% CI: 1.48-4.71, P = 0.001) were increased in SpA patients treated with biologics compared with placebo. Sensitivity analysis based on biologics classes was conducted, and results demonstrated that compared with placebo, there was a higher risk of infection for tumor necrosis factor (TNF)-α inhibitors (Peto OR: 1.38, 95% CI: 1.13-1.68, P = 0.001) and interleukin (IL)-17 inhibitors (Peto OR: 1.55, 95% CI: 1.08-2.22, P = 0.018) in axial SpA, and for Janus kinase inhibitors in peripheral SpA (Peto OR: 1.39, 95% CI: 1.14-1.69, P = 0.001); higher risk of serious infection for IL-17 inhibitors in peripheral SpA (Peto OR: 3.46, 95% CI: 1.26-9.55, P = 0.016) and axial SpA (Peto OR: 2.01, 95% CI: 1.38-2.91, P < 0.001); higher risk of URTI for TNF-α inhibitors in axial SpA (Peto OR: 1.37, 95% CI: 1.05-1.78, P= 0.019), and for apremilast in peripheral SpA (Peto OR: 1.60, 95% CI: 1.08-2.36, P = 0.018); higher risk of nasopharyngitis for TNF-α inhibitors in axial SpA (Peto OR: 1.41, 95% CI: 1.05-1.90, P = 0.022) and peripheral SpA (Peto OR: 1.49, 95% CI: 1.09-2.05, P = 0.013), and for IL-17 inhibitors in axial SpA (Peto OR: 1.35, 95% CI: 1.01-1.82, P = 0.044); higher risk of herpes zoster for Janus kinase inhibitors in peripheral SpA (Peto OR: 2.18, 95% CI: 1.03-4.62, P = 0.043); higher risk of Candida infection for IL-17 inhibitors in peripheral SpA (Peto OR: 2.52, 95% CI: 1.31-4.84, P= 0.006). Conclusions::This meta-analysis shows that biological therapy in patients with SpA may increase the risk of infections, including serious infections, URTI, nasopharyngitis, and Candida infection, which should be paid attention to in our clinical practice.

Currently, biomanufacturing technology and industry are receiving worldwide attention. However, there are still great challenges on bioprocess optimization and scale-up, including: lacing the process detection methods, which makes it difficult to meet the requirement of monitoring of key indicators and parameters; poor understanding of cell metabolism, which arouses problems to rationally achieve process optimization and regulation; the reactor environment is very different across the scales, resulting in low efficiency of stepwise scale-up. Considering the above key issues that need to be resolved, here we summarize the key technological innovations of the whole chain of fermentation process, i.e., real-time detection-dynamic regulation-rational scale-up, through case analysis. In the future, bioprocess design will be guided by a full lifecycle in-silico model integrating cellular physiology (spatiotemporal multiscale metabolic models) and fluid dynamics (CFD models). This will promote computer-aided design and development, accelerate the realization of large-scale intelligent production and serve to open a new era of green biomanufacturing.
Bioreactors ; Computer Simulation ; Fermentation ; Hydrodynamics

Abdominal aortic aneurysm (AAA) and atherosclerosis (AS) have considerable similarities in clinical risk factors and molecular pathogenesis. The aim of our study was to investigate the differences between AAA and AS from the perspective of metabolomics, and to explore the potential mechanisms of differential metabolites via integration analysis with transcriptomics. Plasma samples from 32 AAA and 32 AS patients were applied to characterize the metabolite profiles using untargeted liquid chromatography-mass spectrometry (LC-MS). A total of 18 remarkably different metabolites were identified, and a combination of seven metabolites could potentially serve as a biomarker to distinguish AAA and AS, with an area under the curve (AUC) of 0.93. Subsequently, we analyzed both the metabolomics and transcriptomics data and found that seven metabolites, especially 2'-deoxy-D-ribose (2dDR), were significantly correlated with differentially expressed genes. In conclusion, our study presents a comprehensive landscape of plasma metabolites in AAA and AS patients, and provides a research direction for pathogenetic mechanisms in atherosclerotic AAA.

Objective:To explore the value of pressure-strain loop (PSL) for non-invasive quantitative assessment of left ventricular myocardial work index (GWI), global work efficiency (GWE), global constructive work (GCW), global wasted work (GWW) in the evaluation of left ventricular myocardial work in patients with hypertrophic cardiomyopathy (HCM).Methods:Thirty-one HCM patients (HCM group) and 36 healthy volunteers (control group) from December 2018 to September 2019 in Henan Provincial People′s Hospital were selected. Relevant clinical data were collected, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), left ventricular end systolic diameter (LVEDs), left atrial diameter (LAD), the maximum wall thickness (MWT), left ventricular mass index (LVMI), the global longitudinal strain (GLS), the peak strain dispersion(PSD) and GWI, GWE, GCW and GWW between the two groups were compared.Results:Compared with the control group, MWT, LAD, E/e′, LVMI in HCM group were significantly increased (all P<0.05); left ventricular myocardial functional parameters of GLS, GWI, GWE, GCW were significantly decreased, and GWW and PSD were significantly increased (all P<0.05). Left ventricular GLS, PSD and GWI, GCW, GWW, GWE have better repeatability within the observer and between observers. ICC within the observer were 0.852, 0.707, 0.917, 0.955, 0.675, 0.618, respectively. And their ICC between observers were 0.837, 0.631, 0.927, 0.944, 0.555, 0.670, respectively. Correlation analysis showed that GLS was positively correlated with GWI, GWE, and GCW ( r=0.765, 0.737, 0.815; all P<0.001), and negatively correlated with GWW and PSD ( r=-0.517, -0.606; all P<0.001). Conclusions:The left ventricular GWI, GWE and GCW decreased in HCM patients, while the GWW increased. PSL can evaluate the damage of left ventricular myocardial work in HCM patients.

Objective:To compare the clinical efficacy of transjugular intrahepatic portosystemic shunt (TIPS) with expanded polytetrafluoroethylene (ePTFE)-covered stent and drug combined with gastroscopy as the secondary prevention of esophageal-gastric variceal bleeding in portal hypertension.Methods:Patients with esophageal-gastric variceal bleeding who received TIPS treatment (ePTFE covered stent) or gastroscopy for the first time as the secondary prevention for portal hypertension at Nanfang Hospital of Southern Medical University through March to July 2017 were selected. One year after the operation, liver function changes, ascites remission rates, incidence of hepatic encephalopathy, re-bleeding rate, average hospitalization frequency and expenses, survival time, as well as the TIPS patency conditions were analyzed in the two groups of patients. 2 test, Kaplan-Meier method and Mann-Whitney U test were used to analyze the data.Results:There were 74 and 66 cases in the TIPS and the drug combined gastroscopy group and the follow-up duration (14.57 ± 0.79) was 12-16 months. One year after surgery, the remission rate of ascites in the TIPS group was higher 57.1% (32/56) than that of the drug combined gastroscopy group (0), and the difference was statistically significant (χ 2 = 2 = 36.73, P < 0.01). The cumulative incidence of hepatic encephalopathy at 1, 3, 6, and 12 months after surgery in the TIPS group was 32.4% (24/74), 37.8% (28/74), 40.5% (30/74), and 40.5% (30/74), respectively. The cumulative incidence of hepatic encephalopathy in the drug combined gastroscopy group was 3.0% (2/66), 3.0% (2/66), 3.0% (2/66), and 6.1% (4/66), respectively. Kaplan-Meier analysis showed that the cumulative incidence of hepatic encephalopathy in the TIPS group was higher than that of the drug combined gastroscopy group (χ 2 = 11.29, P < 0.01). The incidence of severe hepatic encephalopathy ( grade III to IV) at 1, 3, 6, and 12 months after surgery in the TIPS group was 2.7% (2/74), 0, 0, and 0, respectively. The incidence of severe hepatic encephalopathy in drug combined gastroscopy group was 0, and there was no statistically significant difference in development of hepatic encephalopathy between the two groups ( P > 0.05). The re-bleeding rates of TIPS group and drug combined gastroscopy group were 0 and 27.3% (18/66), respectively, and the difference was statistically significant (χ 2 = 22.42, P < 0.01). There was no death reported during the follow-up period between both groups. The hospitalization frequency times (1.45 ± 0.80) in TIPS group was lower than that of the drug combined gastroscopy group times (3.24 ± 1.80), and the difference was statistically significant ( U = -4.52, P < 0.01). Conclusion:In the prevention of esophageal-gastric variceal bleeding, TIPS (ePTFE-covered stent) treatment has the advantages of reducing re-bleeding rate, high ascites remission rate and hospitalizations frequency. In addition, patients treated with TIPS have a higher incidence of hepatic encephalopathy than that of drugs combined with gastroscopy. However, TIPS did not exacerbate the incidence of hepatic encephalopathy, and there was no significant difference in the 1-year survival rate after TIPS and drugs combined with gastroscopy treatment.