[摘 要] 自2017年以来，已有12款嵌合抗原受体基因修饰T淋巴细胞（CAR-T细胞）产品相继被批准用于血液系统恶性肿瘤的治疗，包括复发性/难治性急性B淋巴细胞白血病、特定亚型B细胞淋巴瘤和多发性骨髓瘤。然而，CAR-T细胞疗法在应用过程中面临诸多挑战，如在治疗血液系统肿瘤中的抵抗、生产周期长、个体化/价格昂贵，在实体瘤中的肿瘤异质性强/抗原逃逸、浸润能力不足、免疫抑制微环境和反应性差等问题。随着肿瘤免疫学研究的深入和基因工程技术的发展，尝试了众多新策略来提升CAR-T细胞疗法的疗效和普适性。作者根据自身对该领域研究的认知，针对CAR-T细胞疗法的临床关键问题及其应对解决策略进行述评，为未来CAR-T细胞疗法的基础研究和临床转化提供重要思路。

Lung cancer is the malignant tumor with the highest incidence and mortality rates globally. Current treatment methods for lung cancer primarily include surgery， chemotherapy， targeted therapy， and immunotherapy. However， the main limitations of these treatments are their side effects， the drug resistance， and the economic burden they impose. As a critical cancer pathway， the Janus kinase （JAK）/signal transducer and activator of transcription （STAT） signaling pathway regulates tumor occurrence and development through multiple mechanisms by influencing various downstream targets. Consequently， the JAK/STAT signaling pathway offers a promising avenue for lung cancer treatment research. Numerous studies have demonstrated that the JAK/STAT signaling pathway plays a key role in the proliferation and growth of lung cancer cells， angiogenesis， epithelial-mesenchymal transition （EMT）， metabolic alterations， remodeling of the immune microenvironment， and the development of treatment resistance. Traditional Chinese medicine （TCM） has garnered increasing attention due to its minimal side effects， low economic burden， and its potential to enhance efficacy and reduce toxicity when used in conjunction with Western medicine. In addition to traditional Chinese medicine compounds， a growing number of Chinese medicine monomers have come into the spotlight because of their more targeted effects. Numerous studies investigating the regulation of the JAK/STAT signaling pathway by TCM in the treatment of lung cancer have demonstrated that TCM can inhibit the proliferation and invasion of lung cancer cells， tumor angiogenesis， and EMT， improve the inflammatory and immunosuppressive microenvironments， and enhance treatment sensitivity by intervening in the JAK/STAT signaling pathway， thereby impeding the progression of lung cancer. In recent years， the research on the regulation of this pathway by TCM in the treatment of lung cancer has been updated rapidly. However， the summary of these studies has not been updated in time. This review summarizes and reflects on the recent research findings regarding the regulation of the JAK/STAT signaling pathway by TCM to intervene in lung cancer from three aspects， introducing the JAK/STAT pathway， elaborating the mechanism of this pathway in lung cancer， and exploring the intervention of TCM in the treatment of lung cancer through this pathway， to provide more reference for the treatment of lung cancer in the future.

Stroke is the main cause of death and disability among adults in China and is characterized by high incidence， disability， mortality， and recurrence rates. The combination of traditional Chinese and Western medicine has great potential in treating stroke and its sequelae. The classic traditional Chinese medicine prescription Da Chengqitang （DCQT） has a long history and proven efficacy in treating stroke. Clinically， DCQT is often used to treat stroke and its sequelae. However， the number and quality of clinical trials of DCQT in treating stroke need to be improved. Because of the insufficient basic research， the active ingredients and multi-target mechanism of action of DCQT remain unclear. Our research group has previously confirmed that DCQT can effectively reverse neurological damage， reduce iron deposition， and downregulate the levels of pro-inflammatory cytokines in the rat model of hemorrhagic stroke. The treatment mechanism is related to the nuclear factor erythroid 2-related factor 2 （Nrf2）-mediated signaling pathway and p38 mitogen-activated protein kinase （MAPK） signaling-mediated microglia activation. To clarify the pharmacodynamic basis and anti-stroke mechanism of DCQT， this article reviews the research progress in the treatment of stroke with DCQT in terms of clinical trials， pharmacodynamic material basis， safety evaluation， and mechanisms of absorbed components. This article summarizes 45 major phytochemical components of DCQT， 11 of which are currently confirmed absorbed components. Among them， emodin， rhein， chrysophanol， aloe-emodin， synephrine， hesperidin， naringin， magnolol， and honokiol can be used as quality markers （Q-markers） of DCQT. The mechanism of DCQT in treating stroke is complex， involving regulation of inflammatory responses， neuronal damage， oxidative stress， blood-brain barrier， brain-derived neurotrophic factor， and anti-platelet aggregation. This article helps to deeply understand the pharmacodynamic basis and mechanism of DCQT in treating stroke and provides a theoretical basis for the clinical application of DCQT in treating stroke and the development of stroke drugs.

Tumor cells adaptively reforge their metabolism to meet the demands of energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mtROS, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We expect to explore the core role of mitochondria in the dynamic interplay between the tumor and the host, in order to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Atherosclerosis(AS)is a common cardiovascular disease,and its treatment and prevention have been the focus of medical research.AS an emerging technology,nanotechnology has unique advantages and plays an important role in the prevention,diagnosis and treatment of AS.This paper reviews the latest research on the application of nanotechnology in AS diseases,systematically discusses the role of nanotechnology in the diag-nosis and treatment of AS,and comprehensively analyzes the effects of nano-drug carriers based on different sur-face trimmers,loading diagnostic and therapeutic drugs so as to monitordisease progression of AS and its targeted treatment.The aim is to provide new thought for the clinical treatment of AS.

Objective To explore the mechanism of Wumei pill on ulcerative colitis(UC)in mice based on the anti oxidative stress pathway of nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE).Methods Seventy SPF male C57BL/6 mice were randomly divided into the control group,the UC group,the mesalazine group(MES group,0.82 g/kg MES),the low dose Wumei pill group(WMW-L group,5 g/kg crude drug),the middle dose Wumei pill group(WMW-M group,10 g/kg crude drug),the high dose Wumei pill group(WMW-H group,20 g/kg crude drug)and the high dose Wumei pills+Nrf2 inhibitor ML-385 group(WMW-H+ML-385 group,Wumei pills crude drug 20 g/kg+20 mg/kg ML-385),with 10 rats in each group.The disease activity index(DAI)score and colonic mucosa injury score were performed in mice after the last administration.Pathological changes of colonic mucosa in mice were observed by HE staining.The levels of interleukin(IL)-1β,tumor necrosis factor-α(TNF-α)and IL-6 in serum and colon tissue of mice were measured by enzyme-linked immunosorbent assay(ELISA).The content of malondialdehyde(MDA)in serum and colon tissue of mice was determined by thiobarbituric acid colorimetry(TBA).The activity of superoxide dismutase(SOD)in serum and colon tissue of mice was measured by xanthine oxidase method.The activity of glutathione peroxidase(GSH-px)in serum and colon tissue of mice was determined by direct method with dithiodinitrobenzoic acid(DTNB).The positive expression of Nrf2 in colon tissue of mice was observed by immunohistochemistry.The expression of heme oxygenase-1(HO-1)and NAD(P)H:quinone oxidoreductase-1(NQO1)proteins in colon tissue of mice were detected by Western blot assay.Results Compared with the control group,the DAI score,colonic mucosa injury score,colonic histopathology score,levels of IL-1β,TNF-α,IL-6 and MDA in serum and colonic tissue,and expression levels of Nrf2,HO-1 and NQO1 protein in colonic tissue of mice were increased in the UC group,levels of SOD and GSH-px in serum and colon tissue decreased(P＜0.05),the colon mucosa of mice was seriously damaged.Compared with the UC group,changes of corresponding indexes were contrary to the above in the MES group,the WMW-M group and the WMW-H group.However,the expression levels of Nrf2,HO-1 and NQO1 proteins in colon tissue were increased(P＜0.05),and the damage of colon mucosa in mice was alleviated.Changes of the above indexes were dose-dependent in the WMW-L group,the WMW-M group and the WMW-H group.There were no significant differences in the above indexes between the WMW-H group and the MES group.ML-385 attenuated the improvement effect of high dose Wumei pill on colon mucosa injury.Conclusion Wumei pill may alleviate the colon mucosal damage of UC mice by activating Nrf2/ARE antioxidant stress pathway.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

Objective To evaluate the cost-effectiveness of edaravone dexborneol versus edaravone alone combined with conventional therapy in patients with acute ischemic stroke(AIS).Methods From the perspective of the healthcare systems,a decision tree model was constructed using the data from the randomized double-blind comparative trial of edaravone dexborneol in the treatment of acute ischemic stroke(TASTE trial).Cost-utility analysis was used to evaluate the health benefits of edaravone dexborneol at 1 month and 5 years.The robustness of the results was tested by single factor sensitivity analysis and probability sensitivity analysis.Results For AIS patients,the 1-month incremental cost-utility ratio was 53 212.89 yuan/quality-adjusted life-year(QALY),and the 5-year incremental cost-utility ratio was 49 631.25 yuan/QALY,both of which were smaller than China's per capita GDP in 2022(85 698 yuan).Univariate sensitivity analysis showed that the change of NIHSS score in 2 groups of improved patients,the probability of improvement in 2 groups and the probability of deterioration in edaravone group were the most influential factors on the outcome of incremental cost effectiveness.The results of probabilistic sensitivity analysis showed that edaravone dexcborneol was more economical when WTP was 1 times China's per capita GDP in 2022.Conclusion Edaravon dexborneol is a more effective and economical treatment for acute ischemic stroke patients than edaravone alone.

Objective To observe the feasibility of cardiac MR tissue tracking(CMR-TT)technique for quantitatively evaluating myocardial strain of patients with myocardial amyloidosis(CA).Methods Cardiac MRI were collected from 20 patients of immunoglobulin amyloid light-chain CA(AL-CA,group A),20 cases of transthyretin CA(ATTR-CA,group B)and 20 healthy subjects(group C),and myocardial strain parameters were obtained using CMR-TT technique.Left ventricular cardiac function parameters were compared among 3 groups,so were strain parameters of each myocardial segment of left ventricle and global myocardium,including 3D longitudinal strain(LS),3D radial strain(RS)and 3D circumferential strain(CS).Results Compared with those in group C,significant differences of left ventricular cardiac function parameters were found in both group A and B(all P＜0.01),while no statistical difference was found between group A and B(all P＞0.05).Except for apical segment RS(P=0.81),strain parameters in group A and B were both lower than those in group C(all P＜0.01),while no significant difference was detected between group A and B(all P＞0.05).Conclusion CMR-TT technique could be used to quantitatively evaluate left ventricular myocardial strain of CA patients.

Continuing medical education for general practitioners is an important measure to upgrade the quality of primary health care services in China, which is still facing various challenges and need to be further developed and improved. This article analyzes the status quo and existing problems of continuing medical education for general practitioners in China, and proposes suggestions based on the concept of people centered and integrated health care (PCIC), including faculty development, training contents, assessment methods, and experience learning, to provide references for the improvement of continuing medical education for general practitioners.