As the number of patients with compromised immune function increases and fungal resistance develops, so does the risk of contracting deadly fungi in humans. Both fungi and humans are eukaryotes, so identifying unique targets for antifungal drug development is difficult. In addition, the existing antifungal drugs are limited by toxicity, drug interaction and drug resistance in practical application, which leads to the increasing incidence and fatal rate of fungal infections. Therefore, it is urgent to develop new antifungal drugs. The semi-synthetic technology using microbial fermentation products from natural sources as lead compounds has become the most used method in structural modification of antifungal drugs due to its advantages of few reaction steps and easy operation. This paper will introduce the current status of natural antifungal drugs in clinical use, as well as the latest progress in the research and development of new semi-synthetic antifungal drugs, and summarize their mechanism of action, structural modifications, advantages and disadvantages, so as to provide reference for the subsequent development of new antifungal drugs.

OBJECTIVE To analyze the characteristics of severe cutaneous adverse reactions （SCARs） induced by oral anticoagulants （OACs）， and provide a reference for clinical safety of drug use. METHODS Case reports of SCARs caused by OACs （warfarin， apixaban， rivaroxaban， edoxaban， dabigatran etexilate） were retrieved from PubMed， Embase， CNKI， Wanfang Data， VIP and other databases with search terms as “oral anticoagulants”“factor Ⅹa inhibitor”“direct thrombin inhibitor” and their Chinese equivalents. A descriptive statistical analysis was performed. RESULTS A total of 11 articles were included， involving 11 patients in total， among whom there were 5 males （45.5%） and 6 females （54.5%）， with an average age of （59.6±21.5） years. The primary underlying diseases were mainly atrial fibrillation， pulmonary embolism， joint replacement and valve replacement. The OACs involved included warfarin in 3 cases， rivaroxaban in 4 cases， apixaban in 2 cases， and dabigatran etexilate in 2 cases. SCARs occurred from 10 hours to 42 days after treatment， and 7 cases （63.6%） within 10 to 28 days. Among 11 patients， 5 cases were diagnosed as drug reaction with eosinophilia and systemic symptoms， 4 cases were diagnosed as Stevens-Johnson syndrome or toxic epidermal necrolysis， and 2 cases were diagnosed as acute generalized exanthematous pustulosis. The clinical manifestations mainly included rash， fever and mucosal damage， etc. Except for 1 patient who died of sepsis and diffuse intravascular coagulation， the rest of the patients improved or recovered after withdrawal and treatment with glucocorticoids. CONCLUSIONS SCARs are rare but serious adverse reactions caused by OACs， typically occurring 10 to 28 days after medication. Once SCARs are suspected to be caused by OACs， the medication should be discontinued immediately， and a treatment plan should be formulated based on the type of SCARs to ensure the safety of patients’ drug use.

Oral health is closely related to facial aesthetics, mastication, pronunciation, and systemic diseases. Flexible sensors can improve current deficiencies in clinical diagnosis and treatment through oral health monitoring. This paper reviews the research on and application of flexible sensors in oral health monitoring in recent years, providing a reference for the further development of flexible sensors in the oral field. The structural basis of flexible sensors includes a flexible substrate, stretchable electrodes, and an active layer, and each part is designed through material selection to adapt to the oral environment. The sensing mechanisms of sensors involve electricity, optics, electrochemistry, and immunology, among which electro-chemical, biological, and optical sensors are particularly prominent in the oral field. The monitored signals include physical signals such as orthodontic force, bite force, respiratory humidity, and implant temperature; chemical signals such as saliva metabolites and oral gases; and biological signals such as periodontal disease and oral cancer markers. At present, flexible sensors still face many challenges in this special oral environment. Future research directions include improving the biocompatibility, moisture resistance, and flexible fitting ability of sensors in the oral cavity; using temperature-insensitive materials and protective films to improve stability; and introducing artificial receptors and sensor arrays to improve factors such as selectivity. In addition, multi-disciplinary cooperation is crucial for breaking through current bottlenecks and achieving more accurate disease diagnosis and health monitoring. In the field of stomatology, finding specific biomarkers related to corresponding oral diseases is the key to sensor health monitoring. Through these efforts, flexible sensors are expected to gain more extensive applications in the field of oral health monitoring.

[摘 要] 目的：观察白细胞介素-37（IL-37）在乳腺癌患者的表达变化对CD8+ T细胞活性的影响。方法：纳入2020年7月至2022年9月在新乡医学院第一附属医院就诊的46例乳腺癌患者、24例乳腺良性肿瘤患者、20例对照者。采集外周血，分离血浆和外周血单个核细胞（PBMC），收集接受手术治疗的乳腺癌患者肿瘤组织和癌旁组织，分离组织中肿瘤浸润淋巴细胞（TIL），纯化CD8+ T细胞。ELISA法检测IL-37、可溶型单免疫球蛋白IL-1受体相关蛋白（SIGIRR）表达，实时定量PCR法检测组织中IL-37 mRNA，流式细胞术检测CD8+ T细胞中IL-18受体α链（IL-18Rα）和SIGIRR表达。外源性IL-37刺激纯化的CD8+ T细胞，与乳腺癌细胞系MCF-7共培养，通过测定乳酸脱氢酶水平计算靶细胞死亡比例，ELISA法检测上清中穿孔素、颗粒酶B、干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）水平。结果：乳腺癌患者血浆IL-37水平高于乳腺良性肿瘤患者[（554.17 ± 96.63）pg/mL vs （499.52 ± 78.66）pg/mL，P = 0.020]和对照者[（483.97 ± 47.23）pg/mL，P = 0.003]。乳腺癌患者肿瘤组织中IL-37 mRNA相对表达量高于癌旁组织[（1.88 ± 0.21） vs （1.00 ± 0.53）pg/mL，P < 0.001]。外周血IL-18Rα+ CD8+细胞比例、SIGIRR+ CD8+细胞比例、血浆可溶型SIGIRR水平在乳腺癌患者、乳腺良性肿瘤患者、对照者之间的差异无统计学意义（均P > 0.05）。CD8+ TIL表达IL-18Rα和SIGIRR的比例在肿瘤组织和癌旁组织之间的差异无统计学意义（P > 0.05）。重组人IL-37刺激后，CD8+ T细胞诱导靶细胞死亡比例、上清中IFN-γ和TNF-α水平在直接接触和间接接触共培养系统中均低于无刺激（均P < 0.05）。在直接接触共培养系统中，IL-37刺激后上清中穿孔素和颗粒酶B水平均低于无刺激（均P < 0.001），但在间接接触共培养系统中，上清中穿孔素和颗粒酶B水平在无刺激和IL-37刺激之间的差异无统计学意义（均P > 0.05）。结论：乳腺癌患者中IL-37水平升高可能参与诱导外周血和肿瘤微环境中CD8+ T细胞功能衰竭。

Aim To study the neuroprotective effects of Herba siegesbeckiae extract on cerebral ischemia/ reperfusion rats and its mechanism. Methods Sixty SD rats were randomly divided into model group, low, middle and high dose groups of Herba siegesbeckiae, and Sham operation group, and the drug was given continuously for seven days. The degree of neurologic impairment was evaluated by mNSS, and the infarct volume was measured by MRI. The number of Nissl-posi- tive cells was detected by Nissl staining, and the apop- tosis was accessed by Tunel staining. Furthermore, the expression of Bax, Bcl-2 and NeuN was observed by Western blot, and the expression of NeuN was detected by immunofluorescence staining. The expression of IL- 1β, TNF-α and IL-6 mRNA was performed by RT- qPCR. Results The mNSS score and the volume of ischemic cerebral infarction in the model group were significantly increased, and Herba siegesbeckiae extract treatment significantly decreased the mNSS score and infarct volume (P<0.05, P<0.01). Herba siegesbeckiae extract could increase the number of Nissl-pos- itive cells and the expression of NeuN (P<0.01), and reduce the number of Tunel-positive cells (P<0.01). Western blot showed that Herba siegesbeckiae extract inhibited the expression of Bax, increased Bcl-2 and NeuN in ischemic brain tissue (P<0.01). RT-qPCR showed that Herba siegesbeckiae extract inhibited the expression of IL-1 β, TNF-α and IL-6 mRNA in the is-chemic brain tissue (P<0.01). Conclusions Herba siegesbeckiae extract can reduce the cerebral infarction volume, improve the neurological function damage, inhibit the apoptosis of nerve cells and the expression of inflammatory factors and promote the expression of NeuN, there by exerting protective effects on MCAO rats.

OBJECTIVE To synthesize a polymer PEI-ss-PEG2000-DSPE containing disulfide bond and to prepare as cationic micelle(P-ss-PD) based on branched polyethyleneimine(PEI). To investigate the ability of P-ss-PD micelle to reduce cytotoxicity and improve the transfection efficiency of antisense oligonucleotide(ASO) in human breast cancer cell lines, and to study the anti-tumor effect of P-ss-PD micelle in nude mice. METHODS PEI-ss-PEG2000-DSPE was synthesized by grafting PEG2000-DSPE onto branched PEI with disulfide bond as a connecting arm. P-ss-PD micelle was prepared by ethanol injection method and P-ss-PD/ASO nanocomplex was obtained by combining P-ss-PD micelle with ASO. The particle size and zeta potential of P-ss-PD/ASO nanocomplex at various mass ratios were determined by laser particle size analyzer. Agarose gel retardation assay was used to investigate the binding degree of P-ss-PD/ASO nanocomplex and determine the optimal mass ratio. At the same time, the reduction responsive ability of P-ss-PD micelle was investigated. The cytotoxicity of P-ss-PD micelle was detected by CCK8 kit. The transfection efficiency of P-ss-PD micelle was investigated by flow cytometry and high content cell imaging analysis system in MDA-MB-231 cells. The anti-tumor effect of P-ss-PD micelle was investigated by tumor-bearing nude mice models. RESULTS When the mass ratio was 300∶1, the particle size of P-ss-PD/ASO nanocomplex was the smallest and had a good stability. The average particle size was (58.90 ± 4.08)nm, the average zeta potential was (16.80 ± 1.23)mV, and the morphology was uniform spherical. P-ss-PD/ASO nanocomplex had the reduction responsive ability and could release ASO under highly reductive conditions.In vitro, compared with unmodified branched PEI, the cytotoxicity of P-ss-PD micelle was significantly reduced and the transfection efficiency was significantly increased.In vivo, the tumor growth inhibition rate of P-ss-PD/ASO nanocomplex in tumor-bearing nude mice was more than 50%. CONCLUSION The P-ss-PD micelle prepared in this study is a kind of low toxicity and high transfection efficiency non-viral vector, which has the characteristics of reduction responsive releasing, and shows a promising application in ASO drug delivery.

OBJECTIVE To explore the anti-tumor effect and molecular mechanism prediction of rhein by network pharmacology and animal experiments, and provide experimental basis and theoretical guidance for further study of the molecular mechanism of rhein combined with doxorubicin in anti-breast cancer. METHODS The tumor xenograft in mouse model was constructed to investigate the anti-breast cancer effect of rhein combined with doxorubicin. And the Pubchem database, Swiss Target Prediction database, STITCH database, TCMSP database were used to obtain rhein components and action targets, the OMIM, TTD, Genecards and other databases was used to obtain breast cancer disease targets, the "component-disease-target" network and protein-protein interaction(PPI) network was constructed by Cytoscape 3.8.2 to perform topological analysis, and obtain potential targets; the Bioconductor bioinformatics package based on R software was used for GO functional annotation and KEGG enrichment analysis, to screen for possible mechanisms by which drugs act on diseases. RESULTS The pharmacodynamic results in vivo showed that rhein could enhance the anti-breast cancer effect of doxorubicin. Through database analysis, 64 targets of rhein components, 1 839 targets of breast cancer disease, and 31 targets of drug and disease intersection were obtained. PPI network analysis and KEGG pathway enrichment analysis showed that multiple key target proteins MMP9, CASP3, VEGFA, MAPK8, etc., as well as key signaling pathways such as interleukin-17, tumor necrosis factor, cell proliferation and apoptosis, were closely related to breast cancer. CONCLUSION Rhein can enhance the anti-breast cancer effect of doxorubicin by inhibiting tumor angiogenesis, down regulating estrogen receptor, inducing apoptosis, and participating in tumor extracellular matrix remodeling.

Objective To construct the competency of traditional Chinese medicine(TCM)rehabilitation based on World Health Or-ganization rehabilitation competency framework(RCF). Methods The competency requirements of TCM rehabilitation in higher TCM institutions were analyzed using RCF the-ory and method,through literature analysis and expert surveys, Results A comprehensive analysis was conducted to extract the practice,professionalism,learning and development,and research competency of TCM rehabilitation professionals,considering the characteristics of the educational envi-ronment in TCM institutions,the training orientation of TCM rehabilitation programs,core knowledge and ethi-cal requirements. Conclusion The adoption of the RCF to explore the competency of TCM rehabilitation professionals helps enhance the professionalism and applicability of the TCM rehabilitation field,providing ideas and methods for cultivating high-quality TCM rehabilitation professionals.

Therapeutic mRNA vaccine for tumors attracted much attention as a new type of tumor treatment,and most products are in the preclinical and clinical research stage,and there has not post-market drug.However,the non-clinical evaluation of therapeutic mRNA vaccines for tumors is more complicated,due to their target features,mechanisms,delivery patterns,and the cross-species differences of immune system.The choice of animal model is not only content of the clinical effectiveness,and it was a key factor of toxicity assessment.In this work,the challenges for non-clinical evaluation of therapeutic mRNA vaccines for tumors are discussed,and the compliant requirements are reviewed,and the general considerations are suggested.

Objective:To analyze the characteristics, change of injury death spectrum in children aged 0-14 years and its urban-rural difference in Tianjin.Methods:The incidence data of injury death in children aged 0-14 years in Tianjin from 1999 to 2021 were collected from the "Population Based Mortality Surveillance System in Tianjin". We calculated constituent ratio, crude and standardized mortality rates in different subgroups of the population and major injury subtypes, and compared the rural-urban differences. The Cochran-Armitage trend test was used to analyze temporal trends in cause-of-death component ratios. Joinpoint regression model was used to calculate average annual percent change (AAPC). Seasonal difference in injury mortality risk were expressed as mortality ratio and 95% confidence interval.Results:From 1999 to 2021, injury was the third cause of death in children aged 0-14 years in Tianjin. The percentage of children who died in health-care facilities in rural area was 31.08%, which was lower than 37.82% in urban area. There was a downward trend in the standardized mortality rate of injury in children (AAPC=-5.54%, P<0.001). The standardized mortality rates of drowning and road traffic injury declined in both urban area and rural area ( P<0.001). The mortality rate of accidental poisoning decreased in rural area (AAPC=-8.09%, P<0.001), but showed no significant change trend in urban area ( P>0.05). The standardized mortality rate of suicide showed no significant change trend in urban area, but there was an increasing trend in the standardized mortality rate of suicide in rural children aged 10-14 years (AAPC=4.58%). No significant change trend was observed in mortality rate of falls in urban and rural children ( P>0.05). The injury mortality rate showed obvious seasonality in children in Tianjin. Overall injury death risk and risk for drowning-caused death were highest in summer in both urban area and rural area. The risk for road traffic injury-related death was highest in autumn in urban area and in summer in rural area. The risk for death caused by accidental poisoning was highest in winter in both urban area and rural area. Conclusions:In recent decades, the injury mortality rate in children aged 0-14 years in Tianjin showed a decreasing trend. There is still a significant difference in the injury mortality level between urban area and rural area, to which close attention needs to be paid in the future policy development.