BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

This study investigates the effect of glycyrrhetinic acid(GA) combined with doxorubicin(DOX) on apoptosis in HepG2 cells and its possible mechanisms. HepG2 cells were cultured in vitro, and cell viability was assessed using the cell counting kit-8(CCK-8) method. Flow cytometry was used to measure apoptosis levels in HepG2 cells. The cells were divided into the following groups: control group(0 μmol·L~(-1)), DOX group(2 μmol·L~(-1)), GA group(150 μmol·L~(-1)), and DOX + GA combination group(2 μmol·L~(-1) DOX + 150 μmol·L~(-1) GA), with treatments given for 24 hours. The colocalization level between the endoplasmic reticulum(ER) and mitochondria was assessed by colocalization fluorescence imaging. Fluorescence probes were used to measure the Ca~(2+) content in the ER and mitochondria. The qRT-PCR and Western blot were used to determine the mRNA and protein expression of sirtuin-3(SIRT3). Co-immunoprecipitation(CO-IP) was applied to investigate the interactions between voltage-dependent anion channel 1(VDAC1) and SIRT3, as well as between VDAC1, glucose-regulated protein 75(GRP75), and inositol 1,4,5-trisphosphate receptor(IP3R). The results showed that the combination of DOX and GA promoted apoptosis in HepG2 liver cancer cells. The colocalization level between the ER and mitochondria was significantly reduced, the Ca~(2+) content in the ER was significantly increased, and the Ca~(2+) content in the mitochondria was significantly decreased. The relative expression of VDAC1, GRP75, and IP3R was significantly reduced, and interactions between VDAC1, GRP75, and IP3R were observed. SIRT3 mRNA and protein expression levels were significantly increased, and an interaction between SIRT3 and VDAC1 was detected. The acetylation level of VDAC1 was significantly decreased. In conclusion, GA combined with DOX induces apoptosis in HepG2 cells by mediating the deacetylation of VDAC1 through SIRT3, weakening the interactions among VDAC1, GRP75, and IP3R. This regulates the formation of endoplasmic reticulum-mitochondrial membrane domains(ERMMDs), affects Ca~(2+) transport between the ER and mitochondria, and ultimately triggers cell apoptosis.
Humans ; Apoptosis/drug effects* ; Hep G2 Cells ; Glycyrrhetinic Acid/pharmacology* ; Doxorubicin/pharmacology* ; Liver Neoplasms/genetics* ; Carcinoma, Hepatocellular/physiopathology* ; Mitochondria/metabolism* ; Endoplasmic Reticulum/metabolism* ; Cell Survival/drug effects* ; Membrane Proteins/genetics*

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Autologous ozonized blood transfusion(AOBT) is a therapy of re-transfusion of 100-200 mL of autologous blood after shaking and agitation with appropriate amount of oxygen-ozone in vitro. The oxidation of blood through the strong oxidation of ozone can enhance the non-specific immune response of the body, regulate the internal environment and promote health. This therapy has been increasingly applied in clinical practice, while no unified standard for the operation process in terms of ozone concentration, treatment frequency and treatment course had been established. This operation process of AOBT is primarily explored in order to standardize the operation process and ensure its safety and efficacy.

Recent studies have showed that thrombosis is closely related to leucocytes involved in immunity. Interfering with the binding of leukocyte integrin Mac-1 and platelet GPIbα can inhibit thrombosis without affecting physiological coagulation. Mac-1-GPIbα is proposed as a potential safety target for antithrombotic agents. Guanxinning tablet (GXNT) is an oral Chinese patent medicine used for the treatment of angina pectoris, which contains phenolic acid active ingredients, such as salvianolic acids, ferulic acid, chlorogenic acid, caffeic acid, rosmarinic acid, tanshinol, and protocatechualdehyde. Our previous studies demonstrated that GXN exhibited significant antithrombotic effects, and clinical studies suggested that it did not increase bleeding risk. In addition, GXN exerted a significantly regulatory effect on immune inflammation. In the current study, we intended to evaluate the effects of GXN on bleeding events and explore the safety antithrombotic mechanism of GXN based on leukocyte-platelet interaction. First, we established a gastric ulcer model induced by acetic acid in rats and found that GXN not only did not increase the degree of gastrointestinal bleeding when gastric ulcer occurred, but also had a certain promoting effect on the healing of gastric ulcer. Second, in vitroexperiments showed that after pretreatment with GXN and activation by phorbol 12-myristate-13-acetate (PMA), the adhesion and aggregation of leukocytes with human platelets were reduced. It was also found that GXN reduced the expression and activation of Mac-1 in leucocytes, and inhibited platelet activation due to leukocyte engagement via Mac-1. Overall, the results suggest that GXN may be a safe antithrombotic agent, and its low bleeding risk mechanism is probably related to inhibited leukocyte-platelet aggregation and its interaction target Mac-1-GPIbα.
Animals ; Fibrinolytic Agents ; Humans ; Integrins ; Leukocytes ; Macrophage-1 Antigen ; Rats ; Stomach Ulcer ; Tablets ; Thrombosis

In this paper, the low-field nuclear magnetic resonance technology CPMG (Carr-Purcell-Meiboom-Gill) echo method was used to determine the cross-linking degree and cross-linking density of crospovidone (PVPP) from different manufacturers. Based on the seven physical properties of PVPP, a fingerprint spectrum (radar chart) of twenty secondary quality indicators were obtained, and three compressibility evaluation indicators, index of the parameter (IP), index of parametric profile (IPP), index of good compression (IGC) were calculated by the fingerprint spectrum. It was found that the cross-linking degree and compressibility index IP of PVPP showed a strong correlation (r = 0.816) by the correlation analysis, indicating that the cross-linking degree is one of the key quality attributes for evaluating the compressibility of PVPP.

Dental pulp can initiate its damage repair after an injury of the pulp-dentin complex by rearrangement of odontoblasts and formation of newly differentiated odontoblast-like cells. Connexin 43 (Cx43) is one of the gap junction proteins that participates in multiple tissue repair processes. However, the role of Cx43 in the repair of the dental pulp remains unclear. This study aimed to determine the function of Cx43 in the odontoblast arrangement patterns and odontoblastic differentiation. Human teeth for in vitro experiments were acquired, and a pulp injury model in Sprague-Dawley rats was used for in vivo analysis. The odontoblast arrangement pattern and the expression of Cx43 and dentin sialophosphoprotein (DSPP) were assessed. To investigate the function of Cx43 in odontoblastic differentiation, we overexpressed or inhibited Cx43. The results indicated that polarized odontoblasts were arranged along the pulp-dentin interface and had high levels of Cx43 expression in the healthy teeth; however, the odontoblast arrangement pattern was slightly changed concomitant to an increase in the Cx43 expression in the carious teeth. Regularly arranged odontoblast-like cells had high levels of the Cx43 expression during the formation of mature dentin, but the odontoblast-like cells were not regularly arranged beneath immature osteodentin in the pulp injury models. Subsequent in vitro experiments demonstrated that Cx43 is upregulated during odontoblastic differentiation of the dental pulp cells, and inhibition or overexpression of Cx43 influence the odontoblastic differentiation. Thus, Cx43 may be involved in the maintenance of odontoblast arrangement patterns, and influence the pulp repair outcomes by the regulation of odontoblastic differentiation.
Animals ; Cell Differentiation ; Connexin 43 ; Dental Pulp ; Extracellular Matrix Proteins ; Odontoblasts ; Phosphoproteins ; Rats ; Rats, Sprague-Dawley

Objective To set up a time-resolved fluoroimmunoassay (TRFIA) method for human epidermal growth factor receptor 2 (HER2) detection and to evaluate its performance.Methods Each well of the 96-microwell plate was coated with monoclonal antibody of HER2(H7) and another monoclonal antibody of HER2(E5) was labeled by Eu3+.The sensitivity,stability,specificity,measurement range and reference value of this method were tested.The correlation between chemiluminescence (CLIA) method and TRFIA method was analyzed.Results The sensitivity of HER2-TRFIA method was 0.214 ng/ml.The measurement range was 0.214-1 000 ng/ml.The mean within-run CV and mean between-run CV were 3.48％ and 4.13％,respectively.HER2-TRFIA method had no cross-reaction with HER1 and its reference range was 0-13.20 ng/ml.The correlation coefficient between TRFIA and CLIA was 0.997.The same batch of reagents were found to be stable for more than 6 months at 4 ℃.Conclusions HER2-TRFIA method has high sensitivity,specificity,stability and wide detecting range.It might be suitable for clinical use.

Objective: To make long-term comparison of drug-eluting stent (DES) implantation betweenleft internal mammary artery (LIMA) graft and native vessel in patients with previous coronary artery bypass grafting (CABG).
Methods: A total of 151 patients with anterior wall ischemia because of previous CABG induced LIMA graft lesion who received percutaneous coronary intervention (PCI) in our hospital from 2004-07 to 2012-12 were retrospectively studied. The clinical, coronaryangiography (CAG) and follow-up conditions for DES implantation were analyzed;according to the target vessel, the patients were divided into 2 groups:LIMA group, n=40 and Native vessel (NV) group, which meant all segments of left main to left anterior descending arteries, n=111. Primary end points included target lesion revascularization (TLR), target lesion failure (TLF) as cardiac death, target vessel related non-fatal MI with the composition of TLR and major adverse cardiovascular events (MACE).
Results:The median follow-up time was 30 (10-100) months. The rates of TLR and TLF were similar between 2 groups:(15.0%vs 11.7%, log-rank P=0.65) and (17.5%vs 13.5%, log-rank P=0.63). MACE occurrence in LIMA group was higher than NV group (35.0%vs 18.0%, log-rank P=0.043) which was mainly presented by new non-target vessel revascularization as right coronary artery, left circumlfex and saphenous vein graft(17.5%vs 4.5%, log-rank P=0.014). Cox multivariate analysis indicated that target lesion stent length was the only independent predictor for both TLR (HR=1.03, 95%CI1.00-1.06, P=0.01) and TLF (HR=1.03, 95%CI1.00-1.05, P=0.02);whereas, LIMA-PCI was the only independent predictor for MACE occurrence (HR=3.09, 95%CI1.28-7.60, P=0.012).
Conclusion: The chances of TLR and TLF were similar inpatients with previous CABG by either LIMA or NV, while MACE occurrence was higher in LIMA patients which should be further investigated.

BACKGROUNDWhether final kissing balloon (FKB) dilatation after one-stent implantation at left-main (LM) bifurcation site remains unclear. Therefore, this large sample and long-term follow-up study comparatively assessed the impact of FKB in patients with unprotected LM disease treated with one-stent strategy.

METHODSTotal 1528 consecutive patients underwent LM percutaneous coronary intervention in one center from January 2004 to December 2010 were enrolled; among them, 790 patients treated with one drug-eluting stent crossover LM to left anterior descending (LAD) with FKB (n = 230) or no FKB (n = 560) were comparatively analyzed. Primary outcome was the rate of major adverse cardiovascular events, defined as a composite of death, myocardial infarction (MI) and target vessel revascularization (TVR).

RESULTSOverall, The prevalence of true bifurcation lesions, which included Medina classification (1,1,1), (1,0,1), or (0,1,1), was similar between-groups (non-FKB: 37.0% vs. FKB: 39.6%, P = 0.49). At mean 4 years follow-up, rates of major adverse cardiovascular events (non-FKB: 10.0% vs. FKB: 7.8%, P = 0.33), death, MI and TVR were not significantly different between-groups. In multivariate propensity-matched regression analysis, FKB was not an independent predictor of adverse outcomes.

CONCLUSIONSFor patients treated with one-stent crossover LM to LAD, clinical outcomes appear similar between FKB and non-FKB strategy.