Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial-like tissue and is closely associated with pain and infertility. This review summarizes current evidence on immune dysregulation and emerging immunomodulatory therapies in endometriosis. Relevant clinical and mechanistic studies were identified through a structured literature review and qualitatively synthesized. Increasing evidence suggests that immune dysregulation plays a critical role in disease pathogenesis. Within the immune microenvironment, innate and adaptive immune cells—including macrophages, dendritic cells, neutrophils, mast cells, T cells, and B cells—collectively promote inflammation, angiogenesis, fibrosis, and immune evasion. Emerging immunotherapeutic strategies, including macrophage repolarization, NK cell restoration, dendritic cell modulation, neutrophil extracellular traps inhibition, immune checkpoint blockade, and cytokine/chemokine targeting, have shown promising preclinical and early clinical potential. However, disease heterogeneity, reproductive safety concerns, and the lack of validated biomarkers remain major barriers to clinical translation, highlighting the potential of immunomodulatory therapies as future non-hormonal treatment strategies.

The Astragalus membranaceus - Codonopsis pilosula decoction (ACD), is traditionally used as beverage to activate immunity. This study aimed to investigate the combined use of ACD and TP (paclitaxel and cisplatin) against non-small cell lung cancer (NSCLC) in a orthotopic mouse model. In this study, the anti-tumor and immunomodulation efficacies of ACD and TP were evaluated in an orthotopic lung cancer model. After treatment with ACD for one week, the luciferase-expressing Lewis cells were injected into the lungs of male C57 mice and treated with ACD and/or TP for about 2 weeks. Then, the flow cytometry, ELISA, IHC and WB were employed to assess immune cell populations, cytokine production and protein expression levels. Besides, in vitro cytotoxicity of ACD against NSCLC cells was performed using CCK-8 assays, while its immunomodulatory potential was evaluated using a co-culture system incorporating NSCLC cells and patient-derived PBMCs. Our results demonstrated that combination of ACD and TP had the most potent effects on tumor burden and immunity activation among treatment groups. ACD (1 g/kg) and TP (paclitaxel 22.5 mg/kg, cisplatin 12.5 mg/kg) treatment reduced tumor burden by 53.16%, as validated by IVIS imaging in the mouse model. Flow cytometry from mice spleens proved that the combined use of ACD and TP treatment significantly decreased Treg production and increased CD4+ and CD8+ T cell infiltration. Besides, ACD and TP treatment resulted in downregulation of FOXP3 and EZH2 expression, and suppression of PI3K/AKT phosphorylation in mice tumor. Furthermore, in vivo results showed that ACD had no direct cytotoxicity against NSCLC cells, which significantly enhanced PBMC-mediated tumor cell killing and promoted IFN-γ and TNF-α production in patient-derived co-culture systems. In conclusion, the combination of ACD plus TP demonstrated potent anti-tumor and immunomodulation effects against NSCLC in association with reduced Treg activity and increased CD8+ T cell infiltration. Our study provides compelling preclinical evidence supporting ACD as an immunomodulatory adjunct to conventional NSCLC therapies.

Multidrug resistance (MDR) remarkably hinders the success of clinical chemotherapy in carcinomas. The ATP-binding cassette (ABC) transporter as ABCB1, ABCG2, and ABCC1 are most crucial to drive MDR. Regrettably, no MDR modulators have been accepted in clinic. Herein, KSQ-4279, a first-in-class ubiquitin-specific peptidase 1 (USP1) inhibitor in clinical development, was found as a pan-MDR modulator. Our study showed that KSQ-4279 strikingly intensified the cytotoxicity of multiple classical chemotherapeutic drugs in ABCB1/ABCG2/ABCC1-induced MDR cancers independent of its own cytotoxicity in vitro, and remarkably improved chemotherapeutic efficacy not only in ABCB1/ABCG2/ABCC1-overexpressing tumor xenografts in vivo, but also in ABCB1-overexpressing clinical lung cancers ex vivo. Mechanistically, KSQ-4279 weakened ABCB1/ABCG2/ABCC1 efflux function, thus increasing drugs' reservation in cells; more specifically, it was achieved by KSQ-4279 activating the ATPase activity and competing for the substrate-binding pockets of ABCB1/ABCG2/ABCC1. Besides, at the effective reversal concentrations, KSQ-4279 neither altered expression and localization of ABCB1/ABCG2/ABCC1, nor affected USP1's potential downstream AKT or ERK1/2 signaling. This is the first study to investigate the combination of USP1 inhibitor (KSQ-4279) with traditional chemotherapeutic drugs in reversing MDR, which surprisingly hinted ABCB1, ABCG2, and ABCC1 as the new targets of KSQ-4279, and advocated this promising combination therapy in clinical refractory MDR cancers.

Gasdermin (GSDM) family proteins mediate inflammatory cell pyroptosis and exert critical contributions to the pathogenesis of gastrointestinal cancers, infections, and gut mucosal inflammation. Gasdermin C (GSDMC) is overexpressed in human colorectal cancer (CRC); however, the molecular mechanisms underlying GSDMC regulation of CRC tumorigenesis are largely elusive. Here, it is found that both GSDMC expression and activation are significantly elevated in human and mouse CRC tissues. Gsdmc2/3/4 deficiency attenuates tumor progression in both chemically induced CRC mouse model and spontaneous intestinal tumor model. Mechanistically, under hypoxia and low-glucose condition, GSDMC2/3/4 are directly activated by Caspase-6, but not by Caspase-8, as previously reported in other cancers. GSDMC2/3/4-mediated pyroptosis in tumor cells leads to the release of high mobility group protein B1 (HMGB1), which enhances the expression of chemokine attractant C-X-C motif chemokine 2 (CXCL2) in surrounding tumor cells. Subsequently, the elevated CXCL2 secretion from tumor cells promotes the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment (TME) through C-X-C chemokine receptor type 2 (CXCR2), thereby facilitating CRC progression. These findings reveal a mechanism by which Caspase-6/GSDMC-mediated tumor cell pyroptosis, in response to hypoxic and low-glucose conditions, remodels the immunosuppressive microenvironment through CXCL2-dependent recruitment of MDSCs. These results identify GSDMC as a potential drug target for CRC therapy.

ETHNOPHARMACOLOGY REVELANCE:Huangqi Si Jun Zi decoction (HSJZ), a modified traditional Chinese medicine formula, is known to enhance immunity. However, its immunomodulatory effects in non-small cell lung cancer (NSCLC) remain poorly understood. AIM OF STUDY:This study aimed to investigate the anti-tumor potential of HSJZ in NSCLC and elucidate its mechanisms of action. MATERIAL AND METHODS:In vitro studies assessed HSJZ cytotoxicity in 4 tumor cell lines and its ability to activate immune cells from NSCLC patients, followed by evaluating the cytotoxicity of these activated immune cells against NSCLC cell lines. An orthotopic lung cancer model in mice evaluated in vivo anti-tumor activity. Flow cytometry, immunohistochemistry, and Western blot analysis were conducted to analyze immune cell populations, cytokine production, and protein expression levels, including Tregs, CD8+ T cells, EZH2, and PI3K/AKT signaling pathways. RESULTS:While HSJZ alone exhibited no direct cytotoxicity on NSCLC cells in vitro, it significantly enhanced immune cell-mediated killing when co-cultured with patient-derived peripheral blood mononuclear cells (PBMCs), accompanied with increased IFN-γ and TNF-α production. In vivo, HSJZ (1 g/kg) treatment in a murine orthotopic lung cancer model resulted in a 54.2 % reduction in tumor burden, as assessed by IVIS spectrum imaging. Mechanistically, HSJZ suppressed regulatory T cells (Tregs) both in vivo and in vitro, as demonstrated by decreased Treg frequency and downregulation of phosphorylated PI3K/AKT signaling in mice bearing Lewis tumor. Moreover, HSJZ significantly inhibited the expression of EZH2, an epigenetic regulator crucial for Treg differentiation. CONCLUSION:These findings provide compelling evidence that HSJZ exerts anti-tumor effects in NSCLC by modulating the immune microenvironment, particularly through the inhibition of Tregs activity, as assessed by in vitro co-culture system, in vivo mouse orthotopic Lewis cancer model, immunohistochemistry, etc. Our results support the potential clinical application of HSJZ as an adjunct therapy for NSCLC patients.

The interplay between gut microbiota and host is crucial for maintaining host health. When this balance is broken, various diseases can arise, including colorectal cancer (CRC). However, the mechanism by which gut microbiota and host interactions mediate CRC development remains unclear. Here, we found that Gasdermin D (GSDMD), an inflammasome effector responsible for forming membrane pores to mediate cell pyroptosis, was upregulated in both human and mouse intestinal tumor samples. GSDMD deficiency significantly suppressed intestinal tumor development in Apcmin/+ mice, a spontaneous CRC mouse model. Apcmin/+Gsdmd−/− mice exhibited reduced IL-1β release in the intestine, and the administration of recombinant mouse IL-1β partially restored intestinal tumor development in Apcmin/+Gsdmd−/− mice. Moreover, 16s rRNA sequencing showed a substantial increase in Lactobacillus abundance in the feces of Apcmin/+Gsdmd−/− mice compared to Apcmin/+ mice. Concurrently, Kynurenine (Kyn), a metabolite derived from host tryptophan (Trp) metabolism, was significantly decreased in the feces of Apcmin/+Gsdmd−/− mice, as shown by metabolite analysis. Additionally, Kyn levels were inversely correlated with Lactobacillus abundance. Furthermore, the administration of exogenous Kyn also promoted intestinal tumor development in Apcmin/+Gsdmd−/− mice. Thus, GSDMD promotes spontaneous CRC development through increasing IL-1β release and Kyn production. Our data suggest an association between GSDMD, gut microbiota, the host Trp/Kyn pathway, and CRC development.

BACKGROUND:Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. METHODS:The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. RESULTS:We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity. CONCLUSIONS:This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.

Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. Moreover, TAMs promote tumor vascularization, and support the survival of tumor cells, causing an impact on tumor growth and patient prognosis. Numerous studies show that reducing the density of TAMs, or modulating the polarization of TAMs, can inhibit tumor growth, indicating that TAMs are a promising target for tumor immunotherapy. Recently, clinical trials have found that treatments targeting TAMs have achieved encouraging results, and the U.S. Food and Drug Administration has approved a number of drugs for use in cancer treatment. In this review, we summarize the origin, polarization, and function of TAMs, and emphasize the therapeutic strategies targeting TAMs in cancer treatment in clinical studies and scientific research, which demonstrate a broad prospect of TAMs-targeted therapies in tumor immunotherapy.

目的:应用网络药理学及分子对接技术探讨安子调冲方(ATF)中起和血作用的鸡血藤-蒲黄炭(JXT-PHT)对治疗免疫相关复发性流产(IRRPL)的作用机制,为进一步对ATF的拆方研究奠定基础.方法:利用.TCMSP和HERB数据库进行化合物成分检索,在Swiss Target Prediction数据库预测药物作用靶点.使用Genecards和ImmPort数据库获取IRRPL相关靶点.利用jvenn绘制韦恩图,得到潜在作用靶点.在STRING数据库构建蛋白互作(PPI)网络,并分析关键作用靶点.构建"和血作用中药-成分-靶点-疾病"网络,在Cytoscape3.10.0中可视化,并分析核心成分.应用DAVID(v2023q1)数据库,对潜在作用靶点进行基因本体(GO)和京都基因和基因组数据库(KEGG)功能富集分析.最后通过AutoDock-Vina(v1.2.5)对关键作用靶点和核心成分执行分子对接,在PyMOL 2.5进行可视化.结果:共筛选出ATF中起和血作用的JXT-PHT31个活性成分,预测靶点586个,IRRPL相关靶点226个,潜在作用靶点38个,构建PPI网络并分析后得到4个核心作用靶点.构建"和血作用中药-成分-靶点-疾病"网络并分析后得到3个核心成分.潜在作用靶点富集了 277条GO条目和86条KEGG条目.结论:ATF中的和血中药JXT-PHT可能与炎症反应、核糖核酸(RNA)聚合酶Ⅱ启动子的转录正调控、正调节细胞迁移及正向调控MAPK级联反应等密切相关,并通过PI3K-AKT、Th17细胞分化、白细胞介素-17(IL-17)、Rap1和肿瘤坏死因子(TNF)等信号通路发挥治疗IRRPL的作用.

Epigallocatechin (EGC) is one of the main bioactive polyphenols in green tea. This study aims to determine the anti-tumor effect of EGC against colorectal cancer. Our results revealed that treatment of EGC led to significant suppression of cell proliferation and apoptosis in three colorectal cancer cells. Western blot confirmed that EGC activated Caspase-3 and PARP, down-regulated the phosphorylation of STAT3 and decreased Bcl-2 expression. Luciferase-reporter-activity assay further determined that EGC suppressed the promoter activity of STAT3 and downregulated the transcription of STAT3. Besides, in vivo study proved that EGC (100 mg/kg) resulted in significant suppression of tumor volume and tumor weight (decreased by 63.7 %) in mice bearing SW620 tumors. Tumor organoid assays demonstrated the inhibitory efficacy of EGC in colorectal organoids. In conclusion, our study present evidence that EGC inhibited colon cancer cell proliferation both in vitro and in vivo by down-regulation phosphorylated STAT3 and activated downstreams.

The tumor microenvironment (TME) plays critical roles in immune modulation and tumor malignancies in the process of cancer development. Immune cells constitute a significant component of the TME and influence the migration and metastasis of tumor cells. Recently, a number of therapeutic approaches targeting immune cells have proven promising and have already been used to treat different types of cancer. In particular, PD-1 and PD-L1 inhibitors have been used in the first-line setting in non-small cell lung cancer (NSCLC) with PD-L1 expression ≥1%, as approved by the FDA. In this review, we provide an introduction to the immune cells in the TME and their efficacies, and then we discuss current immunotherapies in NSCLC and scientific research progress in this field.

目的 了解新型冠状病毒感染疫情(简称新冠疫情)期间深圳市医务人员的失眠、焦虑和抑郁情绪现状,并探讨其可能的影响因素.方法 于2022年5月10日—8月10日,采用分层抽样方法选择深圳市7家公立医院,再使用便利抽样法抽取符合条件的医务人员为研究对象.采用横断面研究方法,运用阿森斯失眠量表(Athens in-somnia scale,AIS)、7项广泛性焦虑问卷(generalized anxiety disorder questionnaire-7,GAD-7)和9项患者健康调查问卷(patient health questionnaire-9,PHQ-9)进行失眠、焦虑和抑郁情绪状况调查,利用SPSS 26.0软件对数据进行统计分析并建立多因素logistic回归模型.结果 共发放问卷1 050份,回收有效问卷1 007份.出现失眠、焦虑和抑郁的医务人员分别为552人(占54.8%)、555人(占55.1%)和541人(占53.7%).多因素logistic回归模型显示,本科学历(OR=1.733,95%CI:1.236～2.429)和连续1周、2周、2周以上未休(OR=1.789、1.883、2.928,95%CI:1.271～2.518、1.158～3.060、2.058～4.166)是发生失眠的危险因素;女性(OR=1.584,95%CI:1.165～2.154),本科、研究生及以上学历(OR=1.796、1.755,95%CI:1.270～2.539、1.075～2.865),工作年限≤10年(OR=1.759,95%CI:1.089～2.843),在抗疫一线(OR=1.474,95%CI:1.093～1.987)和连续1周、2周、2周以上未休(OR=1.730、1.879、2.481,95%CI:1.221～2.451、1.148～3.074、1.741～3.536)是发生焦虑的危险因素;本科、研究生及以上学历(OR=2.376、1.859,95%CI:1.688～3.343、1.164～2.969)和连续 1 周、2 周、2 周以上未休(OR=1.465、1.718、2.177,95%CI:1.040～2.063、1.054～2.803、1.539～3.079)是发生抑郁的危险因素.运动是医务人员发生失眠、焦虑和抑郁的保护因素(OR=0.760、0.783、0.572,95%CI:0.584～0.989、0.597～0.926、0.439～0.744).结论 新冠疫情期间深圳市医务人员出现失眠、焦虑和抑郁的概率较高,应采取综合性干预措施改善医务人员失眠和心理异常状况.

Stimulator of interferon gene (STING), an intracellular receptor in the endoplasmic reticulum, could induce the production of cytokines such as type I interferon (IFN) by activating the cGAS-STING signal pathway. In recent years, activation of STING has shown great potential to enhance anti-tumor immunity and reshape the tumor microenvironment, which is expected to be used in tumor immunotherapy. A number of STING agonists have demonstrated promising biological activity and showed excellent synergistic anti-tumor effects in combination with other cancer therapies in preclinical studies and some clinical trials. The combination of STING agonists and ICI also showed a potent effect in improving anti-tumor immunity. In this review, we introduce the cGAS-STING signaling pathway and its effect in tumor immunity and discuss the recent strategies of activation of the STING signaling pathway and its research progress in tumor immunotherapy.

摘要：为探索医院腹腔镜技能培训基地规范化教学培训考核管理体系，提升腹腔镜基地培训规范化和信息化管理水平，根据中国医师协会腹腔镜外科医师培训基地评审及授权专家委员会决议的目标合约要求，医院引入“智慧龙华”信息化项目匹配腔镜基地培训师资、培训考核课程、培训质控、档案管理等方面，构建一整套腹腔镜技能培训基地教学培训考核管理体系。该管理体系合理地将信息技术与腔镜培训教学培训考核相融合，更有利于学员顺利完成腔镜技能培训班，掌握腔镜技术，为真正走向临床腔镜手术奠定坚实基础。

基于腹腔镜模拟虚拟技术的规范化培训和标准化考核是进一步规范诊疗技术?强化人才培养和提高医疗安全的必经之路?目的:对腹腔镜模拟基础培训学员的培训效果进行研究?方法:以2019至2020年医院培训的十六期培训学员为研究对象，每期招募学员10人，共160人，每期学员按1∶1随机分两组，研究组由专业的腹腔镜带教老师现场指导，培训周期为2周，最低练习时数不低于50学时，对照组自由练习或不参加练习，培训前后分别对两组学员进行三个模块的测试和考核:抓持传递(30分)?缝合打结(40分)?精细剪切(30分)，共计100分

教学评价是教学管理的重要组成部分.教学医院由于评教理念落后、评教角色不清、结果反馈不畅等因素,致使评教工作的科学性及有效性常被质疑.为提升评教工作有效性、提高教学质量,本院构建了基于成果导向教育理念(OBE)的教学评价体—以学评教,成果导向,多手段持续改进的螺旋式上升评教体系.本院采用该体系对评教工作进行一系列尝试和探索,取得了较好的成效,以期为教学医院评教工作提供参考.

Background Green tea is a popular beverage worldwide and epigallocatechin-3-gallate (EGCG) is the most bioactive polyphenol in green tea. Our study aims to investigate the anti-proliferation and anti-migration effects of EGCG against colorectal-cancer SW480, SW620, and LS411N cells, and elucidate the underlying mechanism. Methods The in vitro anti-proliferation and anti-migration effects of EGCG against colon-cancer cells were evaluated using MTT, scratch-wound-healing, and transwell-migration assays. The effects of EGCG on apoptosis were assessed by Annexin V-FITC/PI double staining and JC-1 staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. Real-time qPCR and dual-luciferase reporter assay were adopted to determine the mRNA level and promoter activity. Results Our results demonstrated that treatment with EGCG resulted in significant inhibition of cell proliferation by the induction of apoptosis. EGCG also inhibited SW480 cell migration in a dose-dependent manner as assessed by wound-healing and transwell-migration assays. Western blot confirmed that EGCG induced apoptosis by the activation of Caspase-3 and PARP. In addition, both STAT3 and phosphorylated STAT3 (p-STAT3) were downregulated significantly by EGCG in three selected colorectal-cancer cell lines. EGCG treatment also resulted in a significant decrease in Bcl-2, MCL-1, and Vimentin, and an increase in E-cadherin. When STAT3 was inhibited, EGCG showed no obvious effect on cell proliferation and migration. Further investigation by luciferase-reporter-activity assay showed that EGCG suppressed the promoter activity of STAT3 and downregulated the transcription of STAT3. Conclusion Our study presents evidence on the anti-proliferation and anti-migration effects of EGCG against colorectal-cancer SW480, SW620, and LS411N cells by downregulating the expression of STAT3 and suggests that EGCG could be an effective and natural supplement for colon-cancer treatment.

Doxorubicin (DOX), the first-line chemotherapy for bladder cancer, usually induces side effects. We previously demonstrated that green tea polyphenol EGCG had potent anti-tumor effect in bladder cancer via down regulation of NF-κB. This study aimed to investigate the additive/synergistic effect EGCG and DOX against bladder cancer. Our results demonstrated that the combined use of DOX and EGCG inhibited T24 and SW780 cell proliferation. EGCG enhanced the apoptosis induction effect of DOX in both SW780 and T24 cells and resulted in significant differences. Besides, EGCG promoted the inhibitory effect of DOX against bladder cancer cell migration. In addition, the in vivo results demonstrated that DOX in combination with EGCG showed the most potent anti-tumor effects among DOX, EGCG and DOX+EGCG treatment groups. Further mechanistic studies determined that the combination of DOX and EGCG inhibited phosphorylated NF-κB and MDM2 expression, and up-regulated p53 expression in tumor, as assessed by western blot and immunohistochemistry. Western blot in SW780 cells also confirmed that the combined use of EGCG and DOX caused significant increase in p53, p21, and cleaved-PARP expression, and induced significant inhibition in phosphorylated NF-κB and MDM2. When NF-κB was inhibited, the expression of p53 and p-MDM2 were changed, and the combination of DOX and EGCG showed no obvious effect in transwell migration and cell viability. In conclusion, the novel application of chemotherapy DOX and EGCG demonstrated potent anti-tumor, anti-migration and anti-proliferation effects against bladder cancer. EGCG enhanced the anti-tumor effect of DOX in bladder cancer via NF-κB/MDM2/p53 pathway, suggesting the potential clinical application against bladder cancer patients.