[摘 要] 小细胞肺癌（SCLC）是肺癌中恶性程度最高的一种类型，其在全部肺癌病例中约占13%~15%。初治SCLC患者虽然对化疗和放疗具有较高的敏感性，但容易复发，导致患者生存率较低。2018年以来，随着IMpower133和CASPIAN研究相继成功，SCLC进入了免疫治疗时代，化疗联合免疫检查点抑制剂已成为广泛期SCLC的一线治疗标准方案。同时，免疫治疗在局限期SCLC中也取得了初步成功。SCLC的免疫治疗虽然取得了一些进展，但免疫治疗整体上带来的生存获益有限，缺乏有效的预测生物标志物，对复发/难治性SCLC缺少治疗手段，SCLC免疫治疗未来仍面临诸多挑战。本文回顾国内外SCLC免疫治疗临床研究的最新进展，分析不同类型的免疫治疗药物、生物标志物及新型免疫治疗靶点，探讨SCLC免疫治疗的联合策略和发展前景。

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

Objective To investigate the antigen presentation characteristics of dendritic cells(DC)and B cells in cardiac grafts.Methods The heart of BALB/c mice was transplanted into the abdominal cavity of C57BL/6J mice.CD45+cells in the heart graft were extracted and sorted by flow cytometry at postoperative 5 d,and single cell RNA sequencing was performed.Taking DC and B cell subsets in cardiac grafts as the main study cells,the changing trend,antigen presenting ability and intercellular communication with T cells after heart transplantation were analyzed by bioinformatics analysis and flow cytometry.Gene ontology(GO)function enrichment difference analysis was adopted to prove the specific function and the reliability annotation of cell subsets.Results Germinal center-like B cell(GC-L B)was the B cell subset with the largest increase in quantity during the acute rejection phase,accounting for 87％.Classical DC(cDC)2 was the only DC subset with a significant increase in quantity during acute rejection of heart transplantation,accounting for 44％of DC subset,and it occupied the highest communication intensity with T cells after heart transplantation.Mononucleated DC(moDC)and memory B cell(MBC)were the main transmitters of T cell input signals in non-transplanted hearts,whereas transformed into cDC2 and GC-L B during the acute rejection phase.Among them,MBC and GC-L B were the main sources of T cell input signals in non-transplanted hearts and heart grafts.Conclusions Compared with DC,B cells occupy a higher number and weight in the intercellular communication with T cells in non-transplanted hearts and heart grafts,prompting that the antigen presenting activity of B cells is more active and stronger than DC in the early stage of acute rejection of heart transplantation.

Background::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

Objective:The mouse kidney transplantation model presents challenges in terms of surgical difficulty and low success rate,making it difficult to master.This study aims to provide a crucial model for transplantation immunology research by modifying and developing novel techniques for mouse kidney transplantation. Methods:A total of 57 pairs of mice were used to establish and compare the modified and innovative surgical techniques for mouse kidney transplantation.Three different surgical models were established,including the abdominal suture technique for orthotopic kidney transplantation,the abdominal cuff technique for orthotopic kidney transplantation,and the cervical cuff technique for ectopic kidney transplantation.BALB/c or C57BL/6 male mice,aged 8 to 12 weeks and weighed 20 to 25 g with specified pathogen free-grade were served as the donor mice or the recipient mice.The surgical technique characteristics,key surgical times,complications,and pathological examination in the early postoperative period were summarized and compared. Results:Three different surgical models of mouse kidney transplantation were successfully established.The comparison of warm ischemic time for the 3 groups of mice showed no statistical significance(P=0.510 4).The abdominal suture group had the shortest total operation time of the donor compared with the abdominal cuff group and the cervical cuff group[(18.3±3.6)min vs(26.2±4.7)min and(22.8±2.5)min;both P<0.000 1].There was a significant difference in cold ischemia time among the 3 groups(all P<0.000 1),with(60.8±4.1)min in the cervical cuff group,(43.3±5.0)min in the abdominal suture group,and(88.8±6.7)min in the abdominal cuff group.Due to different anastomosis methods,the cervical cuff group had the shortest time[(17.6±2.7)min],whereas the abdominal cuff group had the longest time[(38.8±5.4)min].The total operation time for the recipients showed significant differences(P<0.000 1),with the abdominal suture group having the shortest time[(44.0±6.9)min],followed by the cervical cuff group[(64.1±5.2)min],and the abdominal cuff group[(80.0±6.0)min]being the longest.In the 32 mice of the abdominal suture group,there were 6 with intraoperative bleeding,including 1 arterial intimal injury bleeding and 5 with bleeding after vessel opening.Six mice had ureteral complications,including ureteral bladder anastomotic stenosis,necrosis,and renal pelvis dilation.Two mice had postoperative abdominal infections.In the abdominal cuff group,there was no intraoperative bleeding,but 6 mice showed mild arterial stenosis and 5 showed venous stenosis,4 arterial injury,4 arterial thrombosis,and 2 ureteral complications.No postoperative infections occurred in the mice.In the cervical cuff group,no intraoperative bleeding,arterial intimal injury,arterial/venous stenosis,or thrombosis were found in 13 mice.Five mice had ureteral complications,including ureteral necrosis and infection,which were the main complications in the cervical cuff group.The renal function in mice of the 3 groups remained stable 7 days after surgery.Hematoxylin and eosin staining and periodic acid-Schiff staining showed no significant differences in terms of acute rejection among the 3 surgical methods(all P>0.05). Conclusion:All 3 surgical methods are able to successfully establish mouse kidney transplantation models,with no significant differences observed in the short-term graft survival and acute rejection.The modified abdominal suture technique and abdominal cuff technique have their respective advantages in research applications.The novel cervical cuff technique for ectopic kidney transplantation model is relatively simple to be prepared and causes less trauma to the mice,providing more options for studies involving xenotransplantation,secondary transplantation,and local lymphatic drainage.However,the difficulty in harvesting the donor kidney and the high incidence of ureteral infections need further validation in long-term survival.This study holds important reference value for choosing the type of mouse kidney transplantation model for different research needs.

Objective:To explore the clinical efficacy of adult donor dual kidney transplantation.Methods:Retrospective analysis of case data of 13 adult donor kidney dual kidney transplantation (DKT) performed in the The Second Xiangya Hospital of Central South University from September 2016 to December 2020. For 13 donors, the average age and BMI were (53.5±12.4)years and (24.3±2.8) kg/m 2, respectively. Their mean Serum creatinine (SCr) at admission and before procurement was (132.9±54.1)and (228.7±112.4)μmol/L, respectively. 3 of them had diabetes mellitus history, and 8 had hypertension history. 11 met the United Network for Organ Sharing (UNOS) DKT criteria and 6 met Remuzzi score DKT criteria. For 13 recipients, the average age and BMI were (39.3±8.9)years and (20.2±2.4)kg/m 2, respectively. All of them received ABO blood type-matched kidney transplants. 2 of them had their grafts transplanted in the bilateral iliac. In 12 cases, the grafts filled rapidly and urinated immediately when opening blood flow. In 1 case, the grafts were dark in color and vascular showed weak pulsation after opening blood flow. The time to recovery of perioperative graft function (from the day of surgery to the natural reduction of SCr to the normal range 44-133μmol/L), the occurrence of delayed graft function (DGF), acute rejection (AR), ureteral and surgical incision complications, as well as the recipients’ final follow-up SCr, eGFR, urinary protein, and grafts outcome were observed. Risk factors affecting outcomes were assessed by univariate logistic regression analysis. Results:The SCr dropped to the normal range at discharge in 10 recipients, and the average recovery time was (13.8±13.0) days. In other 3 cases SCr at discharge were 300.0, 149.0, 152.5μmol/L. 4 cases had DGF, 4 had AR, 1 experienced urinary fistula, and 1 experienced incisional dehiscence, which were treated with anti-rejection, J-tube implantation, continuous catheterization to maintain bladder void, secondary suturing, respectively. The follow-up time ranged from 4 to 54 months, with a median of 28(15.5, 31.0) months. At the final follow-up time, 10 cases had good graft function, 2 suffered impaired kidney function, and 1 experienced graft failure. The average SCr and eGFR except for graft failure patient were (144.2±101.3)μmol/L and (52.9±21.2)ml/min, respectively. 4 had positive urine protein. Univariate logistic regression analysis showed that donor age, BMI, history of diabetes mellitus and hypertension, and SCr were not significantly correlated with recipients’ DGF and graft impairment ( P>0.05), and due to the small sample size, multifactorial logistic regression analysis was not performed. Conclusion:The short to medium-term effects of adult donor DKT coule be safe and feasible.

Objective:To investigate the clinical value of zoledronic acid in improving the prognosis of osteoporotic hip fracture and preventing its sequential contralateral hip fracture.Methods:A retrospective study of 206 patients diagnosed with hip fragile fractures in China Medical University Affiliated Shengjing Hospital and treated with anti-osteoporotic drugs after surgery was conducted. The prognosis of patients with hip fracture using survival rate analysis and the risk factors of acute febrile complications with multivariate analysis after zoledronic acid treatment were evaluated. Furthermore, chi-square test and multivariate analysis was used to explore whether zoledronic acid decreases the occurrence of the contralateral sequential fracture.Results:The 3-year survival rate of patients with overall hip fracture was higher in zoledronic acid treatment group compared with control group( P=0.026), with the incidence of fever at 53.3%. The age [ OR=0.786, P=0.027, the area under receiver operating characteristic (ROC) curve was 0.724] and cardiopulmonary complications ( OR=0.043, P=0.025, the area under ROC curve was 0.628) were significantly correlated with the occurrence of acute febrile response. The incidence of sequential contralateral fractures in zoledronic acid treatment group was significantly lower than that in control group ( χ2=4.356, P=0.037). The application of zoledronic acid ( OR=0.160, P=0.007, the area under ROC curve is 0.586) and the type of femoral neck fracture ( OR=0.196, P=0.001, the area under ROC curve is 0.607) were statistically associated with the occurrence of sequential fractures. Conclusion:Zoledronic acid treatment improves the outcome of patients with osteoporotic hip fracture and reduces the incidence of sequential hip fractures, especially femoral neck fracture. Senile age and cardiopulmonary complications might be associated with lower risk of acute febrile reactions after zoledronic acid treatment.

Objective:To assess the reliability, constructive validity and item characteristics of the general self-efficacy scale (GSES) among Chinese medical postgraduates using classical test theory and item response theory.Methods:A questionnaire survey was conducted among 1 021 medical postgraduates from 6 comprehensive level Ⅲ A hospitals in Beijing. Demographic characteristics and general self-efficacy were investigated. SPSS 24.0 software was used for statistical analysis. Internal consistency of the GSES was evaluated using Cronbach’s α coefficient and intraclass correlation coefficient. Factor analyses were implemented to test the structure of the scale. An item response theory (IRT) framework with a graded response model was performed to estimate the parameters of each item. Results:The overall Cronbach’s α coefficient of the GSES was 0.92. Parallel analysis and confirmatory factor analysis supported the unidimensional structure of the GSES. The discrimination parameter of the 10 items ranged from 1.82 to 3.65, and the difficulty parameter ranged from -3.51 to 1.66, with a monotonically increasing trend. The maximum test information of the scale among medical postgraduates was 19.16. Conclusion:The GSES has good reliability, validity and measurement precision, showing a good applicability in the survey of medical postgraduates. However, the difficulty of specific items is relatively low, and the scale may be further optimized and improved.

Objective:To investigate the correlation between the prognosis of patients infected with BK virus after renal transplantation and their peripheral blood related indexes.Methods:131 patients from the Renal Transplantation Department of the Second Xiangya Hospital of Central South University who underwent renal transplantation and firstly infected with BK virus after the surgery during the period from August 2018 to August 2021 were retrospectively analyzed. 93 males (71.0%) and 38 females (29.0%). The average age was (37.5±11.3) years old. 109 cases underwent cadaveric kidney transplant (83.2%) and 22 cases underwent relatives kidney transplant (16.8%). The onset time of the first infection with BK virus after renal transplantation was (188.7±16.6) days, and the serum creatinine was (127.5±39.5) μmol/L. 25 patients (19.1%)infected with BK virus were positive in blood and urine at the same time, and 106 patients (80.9%)infected with BK virus were positive only in urine. Among 131 patients infected with BK virus, 70 patients were treated by lowering the blood concentration of tacrolimus to enhance immunity, 12 patients were treated by switching tacrolimus to cyclosporine, and 49 patients had incomplete follow-up data. The DNA load of BK virus in 25 patients [5.6(2.4, 12.3)×10 3copies/ml] positive in blood, white blood cell count(WBC)(5.8±2.0)×10 9/L, hemoglobin(Hb)(122.0±22.4)g/L, platelet count(PLT)(187.1±63.1)×10 9/L, neutrophil count(NEUT)(3.9±1.7)×10 9/L, lymphocyte count(LYM)(1.5±0.8)×10 9/L, monocyte count(MONO)(0.4±0.2)×10 9/L, neutrophil to lymphocyte ratio(NLR)2.2(1.7, 3.5), derived neutrophil to lymphocyte ratio(dNLR)1.7(1.3, 2.6), platelet to lymphocyte ratio(PLR)121.3(86.3, 227.3), monocyte to lymphocyte ratio(MLR)0.2(0.1, 0.4) and lymphocyte to monocyte ratio(LMR)4.7±2.6. The DNA load of BK virus in 106 patients [20.4(0.4, 2 570.0)×10 5copies/ml] positive in urine, WBC 6.6(4.8, 9.1)×10 9/L, Hb(129.0±24.5)g/L, PLT 188.0(147.3, 226.5)×10 9/L, NEUT 4.6(3.0, 6.6)×10 9/L, LYM(1.7±0.8)×10 9/L, MONO 0.4(0.3, 0.5)×10 9/L, NLR 2.8(1.9, 3.9), dNLR 2.1(1.5, 3.0), PLR 120.5(87.0, 163.2), MLR 0.2(0.1, 0.4), LMR 4.5(2.8, 6.7). 70 patients infected with BK virus treated by lowering the blood concentration of tacrolimus were divided into BK virus rise group and BK virus decline group according to the change of BK virus DNA load in blood and urine before and after treatment (the grouping principle of this study gives priority to the change of BK virus DNA load in blood, followed by the change of BK virus DNA load in urine). The WBC, Hb, PLT, NEUT, LYM, MONO, NLR, dNLR, PLR, MLR, LMR, tacrolimus blood concentration and change difference, blood creatinine and change difference were analysed between two groups. Results:The BK virus DNA load in 25 patients positive in blood was correlated with NLR and dNLR ( r=0.5062, P=0.0098; r=0.5738, P=0.0027), and there was no correlation between the BK virus DNA load in blood with the WBC ( r=-0.0185, P=0.9302), Hb ( r=0.0912, P=0.6646), PLT ( r=-0.3931, P=0.0519), NEUT ( r=0.2438, P=0.2401), LYM ( r=-0.3035, P=0.1402), MONO ( r=-0.3279, P=0.1096), PLR( r=0.1054, P=0.6161), MLR( r=0.0738, P=0.7257), LMR( r=-0.0738, P=0.7257). There was no correlation between the BK virus DNA load in 106 patients positive in urine and WBC( r=0.0222, P=0.8209), Hb( r=-0.0323, P=0.7423), PLT( r=0.0847, P=0.3881), NEUT( r=0.0417, P=0.6713), LYM( r=0.0010, P=0.9916), MONO( r=0.0224, P=0.8196, NLR( r=0.0170, P=0.8623), dNLR ( r=-0.0013, P=0.9892), PLR( r=0.0387, P=0.6934), MLR( r=-0.0070, P=0.9433)and LMR( r=0.0070, P=0.9433). As for 70 patients infected with BK virus, there were 37 patients in the BK virus rise group and 33 patients in the BK virus decline group. In the two groups, age [(38.4±12.0)years old and(39.0±9.0)years old], gender [male /female: (23/14) cases and(27/6)cases], blood type [A+ /B+ /AB+ : (22/13/20)cases and (26/6/1)cases], donation type [relatives donnation/cadaveric donation: (29/8)cases and (27/60)cases], blood creatinine(after treatment)[123.0(98.4, 140.5)μmol/L and 132.0(107.1, 162.4)μmol/L] and change difference before and after treatment [0(-15.7, 10.5)μmol/L and -2.0(-9.1, 15.0)μmol/L], tacrolimus blood concentration (after treatment)[(6.7±2.0)ng/ml and(6.5±1.5)ng /ml] and tacrolimus concentration change difference [-1.4(-3.8, 0.6)ng/ml and -1.2(-2.2, 1.3)ng/ml] had no significant difference( P<0.05). The MONO of the two groups was statistically different [0.3(0.2, 0.5)×10 9/L and 0.4(0.3, 0.6)×10 9/L, P=0.033], and there was no difference between the two groups in WBC[6.6(4.1, 8.8)×10 9/L and 6.8(5.4, 8.9)×10 9/L], Hb[(133.2±25.3)g/L and(131.6±20.6)g/L], PLT[185.0(151.0, 231.5)×10 9/L and 196.0(149.0, 234.0)×10 9/L], NEUT[4.3(2.4, 6.4)× 10 9/L and 4.2(3.1, 5.5)×10 9/L], LYM[1.7(1.1, 2.2)×10 9/L and 1.8(1.1, 2.3)×10 9/L], NLR[2.5(1.9, 3.8)and 2.4(1.9, 3.7)], dNLR [2.0(1.5, 2.8)and 1.9(1.4, 2.5)], PLR [114.9(85.1, 159.4)and 111.3(77.1, 159.6)], LMR(4.6±2.6 and 5.2±2.4), MLR[0.2(0.2, 0.4)and 0.2(0.2, 0.4)]( P<0.05). Conclusions:There is a positive correlation between the blood BK virus DNA load and NLR, dNLR in renal transplant recipients infected with BK virus. The rise of MONO correlates with good prognosis of BK virus.