Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).

ObjectiveTo explore the mechanism of Astragali Radix-Aconiti Lateralis Radix Praeparata in the treatment of heart failure and substance basis based on ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometer （UPLC-Q-TOF-MS） and network pharmacology. MethodThe chemical components of Astragali Radix-Aconiti Lateralis Radix Praeparata solution was analyzed by UPLC-Q-TOF-MS， and the active components and targets were screened out by the PubChem database. The targets related to heart failure disease were retrieved from Comparative Toxicogenomics Database（CTD）， Online Mendelian Inheritance in Man （OMIM）， and GeneCard databases， and the common targets were obtained by Venn analysis. The target protein-protein interactions （PPI） were analyzed using the STRING database. Gene ontology （GO） functional enrichment analysis and Kyoto encyclopedia of genes and genomes （KEGG） pathway enrichment analysis were performed using the Metascape database， and molecular docking verification of key targets and active components was performed using SYBYL-X 2.1.1. Experimental validation of key targets was carried out using the rat model of heart failure. ResultThere were 202 chemical components identified in Astragali Radix-Aconiti Lateralis Radix Praeparata solution， of which 64 active components were predicted to act on 183 targets for the treatment of heart failure. The important active components were caffeic acid， L-arginine， biochanin A， adenine， nicotinic acid， trans-ferulic acid， p-coumaric acid， riboflavin， calycosin， etc. The main targets were interleukin （IL）-6， cysteine aspartic acid specific protease （Caspase）-3， vascular endothelial growth factor A （VEGFA）， protein kinase B1 （Akt1）， tumor necrosis factor （TNF）， IL-1B， matrix metallopeptidase （MMP）-9， etc. The main signaling pathways involved hypoxia-inducible factor （HIF）-1 signaling pathway， TNF signaling pathway， phosphatidylinositol 3-kinase （PI3K）/Akt signaling pathway， Toll-like receptor signaling pathway， mitogen-activated protein kinase （MAPK） signaling pathway， forkhead box O （FoxO） signaling pathway， etc. The molecular docking results showed that the active components in Astragali Radix-Aconiti Lateralis Radix Praeparata solution had a good binding ability with HIF-1α， VEGFA， Akt1， Caspase-3， and IL-6， which were the key proteins in the HIF-1 signaling pathway. Animal experiments showed that Astragali Radix-Aconiti Lateralis Radix Praeparata solution significantly improved the hemodynamic indexes， reduced the serum atrial natriuretic peptide （ANP）， brain natriuretic peptide （BNP）， and IL-6 levels， improved the myocardial histopathological changes， protected the mitochondrial morphology of cardiomyocytes， down-regulated the expression of HIF-1α， VEGFA and phosphorylation（p）-Akt， and reduced the activation of Caspase-3 in the myocardial tissue of rats with heart failure. ConclusionAstragali Radix-Aconiti Lateralis Radix Praeparata treats heart failure in a multi-component， multi-target， and multi-pathway manner. The experimental validation indicates that it treats heart failure by improving myocardial histopathological changes and regulating HIF-1 signaling pathway， which provides references for the subsequent pharmacodynamic substance research.

Electronic tongue is one kind of bionic detection technologies, which can objectively reflect the taste of drugs based on electrochemical principle. In this paper, the development histories of electronic tongue both of potential type and voltammetry type were introduced, including their detection principles and key innovation technologies. In order to comprehensively improve the understanding of electronic tongue, its technological progresses, such as the study of dedicated sensors or biosensors for specific tastes, and the development of miniaturized or hybrid devices, were also discussed in detail. And the challenges and countermeasures in the application of electronic tongue were analyzed to provide some suggestions for its further technology promotion.

ObjectiveTo investigate the therapeutic effect of rhubarb decoction （RD） retention enema on a rat model of minimal hepatic encephalopathy （MHE） and its mechanism of action based on bile acid （BA） metabolomics. MethodsA total of 55 male Sprague－Dawley rats were randomly divided into blank group （NC group with 10 rats）， hepatic encephalopathy group （HE group with 15 rats）， MHE group with 15 rats， and MHE+rhubarb decoction treatment group （MHEY group with 15 rats）. Intraperitoneal injection of carbon tetrachloride （CCl₄） and thioacetamide （TAA） was performed to establish a rat model of MHE or HE， and the rats were sacrificed after 2 weeks of administration. The serum levels of aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， alkaline phosphatase （ALP）， total bilirubin （TBil）， and total bile acid （TBA） and the concentration of blood ammonia were measured； the colonic contents were collected to measure pH value； liver and brain tissue samples were collected， and HE staining was used to observe the histopathological changes of the liver； the bile was collected， and liquid chromatography－mass spectrometry was used to perform BA－targeted metabolomics analysis. Continuous data were expressed as mean±standard deviation； a one－way analysis of variance was used for comparison between multiple groups， and the least significant difference t－test was used for further comparison between two groups. ResultsCompared with the NC group， the HE group and the MHE group had a significant increase in searching platform latency （after modelling and after administration） and a significant reduction in the number of platform crossings （all P<0.05）； compared with the MHE group， the MHEY group had a significant reduction in searching platform latency （after administration） and a significant increase in the number of platform crossings， and the HE group had a significant increase in searching platform latency and a significant reduction in the number of platform crossings （all P<0.05）. Compared with the NC group， the HE group and the MHE group had significant increases in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）； compared with the MHE group， the MHEY group had significant reductions in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）， and the HE group had significant increases in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）. The MHE group had significantly lower TBA， primary BA， and secondary BA than the NC group （all P<0.05）； compared with the MHE group， the HE group had significantly lower TBA and primary BA （all P<0.05）， and the MHEY group had significantly higher TBA and primary BA （all P<0.05）. Compared with the NC group， the MHE group had significant reductions in GCDCA， GUDCA， GHDCA， TCDCA， TUDCA， GLCA， and TLCA （all P<0.05） and significant increases in γ－MCA， THCA， 7－KDCA， AlloLCA， and α－MCA （all P<0.05）， and compared with the MHE group， the MHEY group had significant increases in THDCA， TMCA， TCDCA， TUDCA， and TLCA （all P<0.05）. ConclusionRD retention enema can improve liver injury and cognitive function in a rat model of MHE induced by CCl₄ and TAA by regulating the enterohepatic circulation of BA， possibly by increasing the synthesis of taurine－binding BA.

Humans ; Magnetic Resonance Imaging ; Nocturnal Enuresis/diagnostic imaging*

Objective:To analyze clinical characteristics of ketosis-associated prurigo pigmentosa after ketogenic diet and bariatric surgery.Methods:Clinical data were collected from patients with ketosis-associated prurigo pigmentosa, who were diagnosed and treated in Department of Dermatology, Peking University People′s Hospital from September 2018 to September 2020. The clinical characteristics, sequelae and therapeutic effect of dietary modification were analyzed and summarized.Results:A total of 6 patients with ketosis-associated prurigo pigmentosa were collected, including 5 females who developed prurigo pigmentosa after ketogenic diet, and 1 male who developed prurigo pigmentosa after bariatric surgery. The skin lesions mainly involved the chest, back, waist and abdomen, and rarely involved the eyelids, axillae, elbows and mons pubis. Common skin lesions included urticaria-like erythema, papules and pigmentation arranged in a reticular distribution, and rare skin lesions included mung bean- to soybean-sized blisters, whose walls were liable to break. Among 5 patients undergoing routine urine analysis, 4 were positive (from + to ++++) for ketone bodies in the urine, and 3 were positive for urinary protein (+) . Pathological examination in 2 patients showed epidermal spongiosis, scattered necrotic keratinocytes, basal cell liquefaction, lymphocyte infiltration in the superficial dermis, and erythrocyte extravasation. The 6 patients were advised to eat staple foods. After dietary modification, 5 patients were nearly cured within 1 week; 1 patient, who continued ketogenic diet for weight loss, still received marked improvement after the treatment with minocycline at a dose of 100 mg/d in spite of restriction of carbohydrate intake. The levels of urinary ketone bodies and urinary protein in the 6 patients all returned to normal within 1 week after treatment.Conclusions:Ketosis plays an important role in the occurrence of prurigo pigmentosa. Dietary modification alone or adjuvant medical treatment such as minocycline is effective for the treatment of ketosis-related prurigo pigmentosa.

OBJECTIVE: To summarize and compare the clinical baseline characteristics of patients with monoclonal gammopathy of undetermined significance (MGUS), primary light chain amyloidosis (pAL), multiple myeloma (MM), or MM with concurrent amyloidosis, especially the differences in cytogenetic abnormalities. METHODS: The clinical data of 15 cases of MGUS, 34 cases of pAL, 842 cases of MM and 23 cases of MM with concurrent amyloidosis were analyzed and compared retrospectively. RESULTS: Cytogenetic statistics showed that the incidence of t (11; 14) in the four groups (MGUS vs pAL vs MM vs MM with concurrent amyloidosis) was 0%, 33.3%, 16.4%, and 15.8%, respectively (P=0.037); that of 13q deletion was 20.0%, 14.7%, 45.8% and 56.5%, respectively (P<0.001); gain of 1q21 was 50.0%, 12.5%, 47.4% and 40.9%, respectively (P=0.001). Proportion of pAL patients with 0, 1 and≥2 cytogenetic abnormalities (including 13q deletion, 17p deletion, 1q21 amplification and IgH translocation) accounted for 41.9%, 41.9% and 16.1%, respectively; while the proportion of the same category in MM was 17.6%, 27.3%, and 55.2% respectively; this ratio of MM with concurrent amyloidosis was more similar to MM. Subgroup analysis showed that genetic abnormalities (including 13q deletion, 17p deletion and 1q21 amplification) were comparable within t (11; 14) negative and positive groups. Compared with positive cases, t(11; 14) negative patients with MM or MGUS were more likely to have 13q deletions and multiple genetic abnormalities. CONCLUSION Clinical characteristics of pAL, especially cytogenetic abnormalities, are significantly different from MM with concurrent amyloidosis. It suggests that although the onset characteristics are similar, actually the two diseases belong to different disease subtypes which should be carefully predicted and identified.
Amyloidosis ; Humans ; In Situ Hybridization, Fluorescence ; Monoclonal Gammopathy of Undetermined Significance/complications* ; Multiple Myeloma ; Retrospective Studies

Background: Malignant pleural effusion (MPE) is a complicated condition of patients with advanced tumors. Further dissecting the microenvironment of infiltrated immune cells and malignant cells are warranted to understand the immune-evasion mechanisms of tumor development and progression. Methods: The possible involvement of microRNAs (miRNAs) in malignant pleural fluid was investigated using small RNA sequencing. Regulatory T cell (Treg) markers (CD4, CD25, forkhead box P3), and Helios (also known as IKAROS Family Zinc Finger 2 [IKZF2]) were detected using flow cytometry. The expression levels of IKZF2 and miR-4772-3p were measured using quantitative real-time reverse transcription polymerase chain reaction. The interaction between miR-4772-3p and Helios was determined using dual-luciferase reporter assays. The effects of miR-4772-3p on Helios expression were evaluated using an in vitro system. Correlation assays between miR-4772-3p and functional molecules of Tregs were performed. Results: Compared with non-malignant controls, patients with non-small cell lung cancer had an increased Tregs frequency with Helios expression in the MPE and peripheral blood mononuclear cells. The verified downregulation of miR-4772-3p was inversely related to the Helios⁺ Tregs frequency and Helios expression in the MPE. Overexpression of miR-4772-3p could inhibit Helios expression in in vitro experiments. However, ectopic expression of Helios in induced Tregs reversed the effects induced by miR-4772-3p overexpression. Additionally, miR-4772-3p could regulate Helios expression by directly targeting IKZF2 mRNA. Conclusion Downregulation of miR-4772-3p, by targeting Helios, contributes to enhanced Tregs activities in the MPE microenvironment.

Objective:To investigate whether human umbilical vein endothelial cell(HUVEC) vaccine combined with low dose docetaxel (DOC) could play a synergistic role in anti-breast cancer.Methods:BALB/c mice were randomly divided into normal saline group,HUVEC vaccine group,DOC group,and HUVEC vaccine combined with DOC treatment group (HUVEC-DOC) group.An experimental metastasis model by tail vein injection of EMT-6 breast cancer cells was employed to evaluate the anti-metastatic efficiency of the HUVEC-DOC combination treatment regime.Lymphocyte proliferation assay,cytotoxic T lymphocytes and an indirect enzyme-linked immunosorbent assay (ELISA) for detecting IFN-γ were used to investigate cellular immune responses elicited by the combination treatment regime.Results:Compared with HUVEC and DOC single drug group,the number of lung metastasis in HUVEC-DOC combination treatment group was significantly decreased(P<0.05).In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes(CTLs) with a lytic activity against activated endothelium.IFN-γ in the serum of im-munized mice of the HUVEC-DOC combination treatment group was significantly higher than that in the other three groups(P<0.05). Conclusion:HUVEC vaccine with low dose of DOC could display synergistic anti-breast cancer effect.