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

[Objective] In view of the crucial role of indole propionic acid in the treatment of tumor immune checkpoint blockade and further revealing its mechanism, our study intended to design and synthesize 1-[¹⁸F]-fluoroethyl-indole propionic acid (1-[¹⁸F]-IPA), and evaluate it as a tumor PET imaging agent. [Methods] The precursor 1-(2-p-toluenesulfonic acid oxygen ethyl)-methyl indole propionate underwent nucleophilic substitution reaction with ¹⁸F^-. The crude product was separated and purified by high-performance liquid chromatography and the intermediates were collected. Finally, 1-[¹⁸F]-IPA was obtained by hydrolysis. The clarity of the product was measured by visual inspection, the pH value was determined by precision test paper, and the radiochemical purity and stability were determined by high-performance liquid chromatography. In order to determine the biodistribution of 1-[¹⁸F]-IPA in normal mice, ICR mice were intravenously injected with 1-[¹⁸F]-IPA (0.2 mL, 7 MBq), and sacrificed at 5, 15, 25, 45, 75 and 120 min and dissected. Micro-PET imaging was performed and analyzed in BxPC-3 tumor-bearing nude mice. Student t test was used to compare the biodistribution of tissues and organs at different time points. [Results] The total preparation time of 1-[¹⁸F]-IPA was 35-40 min, the radiochemical yield was (45±5)%, and the radiochemical purity was more than 95%. The product solution was clear without particles, and the pH value was 6.5, which had good stability in vitro and in vivo. The results of biodistribution in healthy ICR mice showed that except for the brain, 1-[¹⁸F]-IPA had a certain uptake in all major organs, with the most obvious uptake in the liver, gallbladder and kidneys. The radioactivity in the gallbladder gradually increased with time and reached (39.86±6.56)%ID/g at 120 min, but bone uptake did not change significantly with time. Micro-PET/CT showed that there was radioactive uptake at the tumor 30 min after injection of 1-[¹⁸F]-IPA in Dutch BxPC-3 nude mice, but it was not obvious. At this time, SUVmax was about 55.18±14.62. Consistent with the results of biodistribution, the brain uptake was low at each time point. [Conclusion] In summary, 1-[¹⁸F]-IPA with short preparation time and high yield is expected to be a tool to probe tryptophan indole metabolism pathway and further reveal tumor immune resistance.

Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived car-diomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a po-tential reagent for repairing damaged hearts.

Aim To explore the effect and mechanism of the artesunate(ART)on hepatocellular carcinoma(HCC).Methods The cell lines MHCC-97H and HCC-LM3 were used to be detected.MTT and clone formation were used to determine the cell proliferation;Wound healing was used to detect the cell migration;Transwell was used to test the cell invasion.Flow-cy-tometry was used to detect cell apoptosis and cell cy-cle.RNA-seq and qRT-PCR was used to detect the genes expression.Results The proliferation,migra-tion and invasion of treated cells were obviously inhibi-ted(P＜0.01).Moreover,the apoptosis rate in-creased significantly,so did the proportion of G2/M cells.Transcriptomic analysis identified GADD45A as a potential target of ART through RNA-sequencing da-ta,and suggested that ART might induce apoptosis and cell cycle arrest through regulating the expression of GADD45A.In addition,the results of mechanism studies and signaling analysis suggested that GADD45A had interaction with its upstream gene NACC1(nucle-us accumbens associated 1).Moreover,after ART treatment,the expressions of GADD45A and NACC1 were changed significantly.Conclusion ART may be a potential drug to resist HCC by affecting the expres-sion of GADD45A and its upstream gene NACC1,which provides a new drug,a new direction and a new method for the clinical treatment of HCC.

Methamphetamine abuse is a major public health problem in the world,and in recent years,methamphetamine is also the most abused synthetic drug in China.The neurotoxic or addiction mechanism of methamphetamine has not been fully clarified,and there is still a lack of specific withdrawal methods and drugs for methamphetamine abuse.Mitochondria are not on-ly the organelles to which methamphetamine directly produces toxic effects,but also participate in regulating the neurotoxic damage process of methamphetamine.Mitochondrial quality is the regulatory basis for maintaining mitochondrial homeostasis and is regulated by three main mechanisms,which are mitochon-drial biogenesis,mitochondrial dynamic,and mitophagy.This review summarizes the research progress of mitochondrial quality control in methamphetamine-induced neurotoxicity,which may provide theoretical support for further research on the mechanism of methamphetamine neurotoxicity and development the mito-chondria-targeting drugs.

Infectious bone defect is bone defect with infection or as a result of treatment of bone infection. It requires surgical intervention, and the treatment processes are complex and long, which include bone infection control,bone defect repair and even complex soft tissue reconstructions in some cases. Failure to achieve the goals in any step may lead to the failure of the overall treatment. Therefore, infectious bone defect has been a worldwide challenge in the field of orthopedics. Conventionally, sequestrectomy, bone grafting, bone transport, and systemic/local antibiotic treatment are standard therapies. Radical debridement remains one of the cornerstones for the management of bone infection. However, the scale of debridement and the timing and method of bone defect reconstruction remain controversial. With the clinical application of induced membrane technique, effective infection control and rapid bone reconstruction have been achieved in the management of infectious bone defect. The induced membrane technique has attracted more interests and attention, but the lack of understanding the basic principles of infection control and technical details may hamper the clinical outcomes of induced membrane technique and complications can possibly occur. Therefore, the Chinese Orthopedic Association organized domestic orthopedic experts to formulate An evidence-based clinical guideline for the treatment of infectious bone defect with induced membrane technique ( version 2023) according to the evidence-based method and put forward recommendations on infectious bone defect from the aspects of precise diagnosis, preoperative evaluation, operation procedure, postoperative management and rehabilitation, so as to provide useful references for the treatment of infectious bone defect with induced membrane technique.

The latest epidemiological data suggests that the situation of adult diabetes in China is severe, and metabolic diseases have become significant chronic illnesses that have a serious impact on public health and social development. After more than six years of practice, the National Metabolic Management Center(MMC) has developed distinctive approaches to manage metabolic patients and has achieved a series of positive outcomes, continuously advancing the standardized diagnosis and treatment model. In order to further improve the efficiency, based on the first edition, the second edition guideline was composed by incorporating experience of the past six years in conjunction with the latest international and domestic guidelines.

Objective　To investigate the drug resistance of Enterobacter cloacae isolated from blood samples in 75 member units of the Bacterial Drug Resistance Monitoring Network in Hebei, 2016- 2021, so as to provide a basis for rational drug use in clinic. Methods　WHONET 5.6 software was used to retrospectively analyze drug susceptibility of Enterobacter cloacae isolated from 32 secondary hospitals and 43 tertiary hospitals. SPSS19.0 software was used for statistical analysis. Results After removing the duplicate strains, 1 225 strains of E. cloacae were isolated from blood samples of 75 hospitals during 6 years, including 157 strains from secondary hospitals and 1 068 strains from tertiary hospitals. In this study, the resistance of Enterobacter cloacae to 16 kinds of antibiotics was analyzed. The drug resistance rates to cefuroxime (52.4%-67.8%), piperacillin (27.4%-31.2%), ceftazidime (27.8%-35.5%), ceftriaxone (29.5%-45.0%), aztreonam (22.2%-32.3%), cotrimoxazole (21.6%-28.7%) were higher; the resistance rates to amikacin and tobramycin were lower than 15.0%. The resistance rates to imipenem and meropenem were 3.6%-12.3% and 5.1%-11.4%, respectively. The resistance rate to ciprofloxacin in tertiary hospitals was 22.4%, and the resistance rate to cotrimoxazole was 23.9%. Except for these two antimicrobials, the resistance rates to other antimicrobial drugs in tertiary hospitals were higher than that in secondary hospitals. A total of 121 carbapenem-resistant Enterobacter cloacae strains were detected in the past 6 years, with an increasing detection rate (χ2trend=6.305, P=0.012). Conclusions　Enterobacter cloacae has great differences in antimicrobial resistance to different antibiotics, and is sensitive to carbapenems. The drug resistance in tertiary hospitals is generally higher than that in secondary hospitals. Drug resistance monitoring and drug resistance mechanism research should be strengthened to better guide clinical drug use and curb the rise of drug resistance.

Cell Differentiation ; Myeloid Differentiation Factor 88/metabolism* ; NF-kappa B/metabolism* ; Particulate Matter/toxicity* ; Signal Transduction ; Toll-Like Receptor 4/metabolism* ; RAW 264.7 Cells