肝内胆管细胞癌（ICC）是发病率仅次于肝细胞癌的肝脏恶性肿瘤,它的恶性程度高、术后易复发,且早期无典型症状,大多数患者在确诊时已处于晚期。诊断主要依赖于增强CT、MRI和实验室检查。肝切除术是ICC首选的治疗方法,完整的切缘阴性切除和保留足够残留肝是影响手术预后的重要因素。淋巴结清扫、卡培他滨辅助化疗已被证实对患者有益。局部治疗、分子靶向治疗、免疫治疗等新疗法发展迅速,为晚期ICC患者带来了希望。传统疗法与新疗法的结合为ICC提供新的诊疗思路。

Intrahepatic cholangiocarcinoma（ICC）is the second most common liver malignancy after hepatocellular carcinoma．It is highly malignant,easy to recur after surgery,and has no typical symptoms in the early stage,and most patients are in the late stage when diagnosed．Diagnosis relies on enhanced CT,MRI and laboratory tests．Hepatectomy is the preferred treatment for intrahepatic cholangiocarcinoma．Complete resection with negative margin and adequate residual liver preservation are important factors affecting the prognosis of the operation．Lymph node dissection and adjuvant chemotherapy with capecitabine have been shown to be beneficial for patients．The rapid development of new therapies such as local therapy,molecular targeted therapy and immunotherapy has brought hope to patients with advanced intrahepatic cholangiocarcinoma．The combination of traditional therapy and new therapy provide a new idea for diagnosis and treatment of intrahepatic cholangiocarcinoma．

目的 探讨度普利尤单抗对瘙痒性皮肤病的效果及对嗜酸粒细胞（EOS）恢复和生活质量的影响。方法 选取2021年2月—2022年1月期间,我院收治的瘙痒性皮肤病患者96例。根据治疗方式不同分为对照组（48例）和观察组（48例）。对照组给予传统激素治疗,观察组给予度普利尤单抗治疗。比较治疗前后2组血清炎症因子、免疫球蛋白水平情况;比较治疗前后2组症状积分下降指数（SSRI 评分）、神经激肽/速激肽受体1（NK1R）及EOS情况。观察2组疗效情况。采用皮肤病生活质量问卷（DLQI）对2组生活质量进行评价,并观察2组复发率情况。结果 治疗后,2组血清IFN-γ（干扰素-γ）、IL-2（白介素2）、IgA、IgG、IgM、NK1R、EOS水平升高,IL-4、IL-13、IgE水平及SSRI 评分降低,且观察组更明显（P<0.05）。观察组治疗有效率高于对照组（P<0.05）。随访6个月,观察组DLQI评分及复发率低于对照组（P<0.05）。结论 度普利尤单抗可减轻瘙痒性皮肤病患者瘙痒症状,增强机体防御力,促进嗜酸粒细胞恢复,提高其生活质量,值得临床推广应用。

Objective To investigate the effect of Dupilumab on pruritic dermatosis,eosinophil（EOS）recovery and quality of life．Methods From February 2021 to January 2022,96 patients with pruritic dermatosis were selected．According to different treatment methods,they were divided into control group（48 cases）and observation group（48 cases）．The control group was treated with traditional hormone,and the observation group was treated with Dupilumab．The levels of serum inflammatory factors and immunoglobulin in the two groups were compared before and after treatment．The symptom score reduce index（SSRI score）,neurokinin/tachykinin receptor 1（NK1R）and EOS were compared between the two groups before and after treatment．The curative effect of the two groups was observed．The quality of life of the two groups was evaluated with Dermatology Quality of Life Questionnaire（DLQI）,and the recurrence rate of the two groups was observed．Results After treatment,levels of serum IFN-γ,IL-2,IgA,IgG,IgM,NK1R and EOS of two groups increased,while the levels of IL-4,IL-13,IgE and SSRI scores decreased,especially in the observation group（P<0.05）．The effective rate of the observation group was higher than that of the control group（P<0.05）．The DLQI score and recurrence rate in the observation group were lower than those in the control group（P<0.05）in 6 months follow-up．Conclusions Dupilumab can alleviate the itching symptoms of patients with pruritic dermatosis,enhance the body's defense,promote eosinophil recovery,and improve their quality of life,which is worthy of clinical application．

目的 探讨慢性淋巴细胞白血病（CLL）合并第二肿瘤临床特征和预后。方法 回顾性分析2015年8月—2021年10月我院收治的58例CLL患者,其中有11例合并第二肿瘤,47例无合并第二肿瘤,分析两组病例的临床特征及其对预后的影响。结果 CLL合并第二肿瘤和无合并第二肿瘤患者在年龄、性别、白细胞计数、血红蛋白水平、淋巴细胞计数、血小板计数、乳酸脱氢酶（LDH）、β₂-微球蛋白（β₂-MG）水平、分期、单个基因缺失类型之间比较差异无统计学意义,但CLL合并第二肿瘤患者基因缺失个数较无合并第二肿瘤CLL患者组高（χ²=11.17,P=0.03）,且总生存期较短。结论 CLL合并第二肿瘤患者常伴有多个基因缺失,且预后差,当CLL患者伴有多个基因缺失时,在诊治过程中需警惕有无合并第二肿瘤。

Objective To investigate the prognosis and clinical characteristics of chronic lymphocytic leukemia（CLL）patients with second tumor．Methods A retrospective analysis was performed on 58 cases of CLL patients who were diagnosed in our hospital from August 2015 to October 2021．The clinical data of 11 CLL patients with second cancer and 47 CLL patients without second cancer were compared and analyzed．Results There were no significant differences in age,sex,white blood cell count,lymphocyte count,platelet count,the level of serum β₂-microglobulin and lactate dehydrogenase between two groups．However,in CLL patients with second cancer,the incidence of multiple genetic deletions was higher than those without second cancer（χ² =11.17,P =0.03）．The overall survival time was shorter in CLL patients with second primary cancer．Conclusions CLL patients with second tumor have a frequent multiple gene deletions and poor prognosis．Physicians should pay attention to second cancers when diagnosing the CLL patients with multiple gene deletions．

目的 探讨非小细胞肺癌（NSCLC）组织中转化生长因子β激活激酶1（TAK-1）与T细胞因子-4（TCF-4）在 mRNA以及蛋白水平的表达情况及其相关性,并分析两者与NSCLC患者临床病理因素的关系。方法 收集NSCLC手术标本51例,每例均包含肺癌组织及配对癌旁组织,所有患者的术后诊断均经病理结果证实,通过RT-PCR以及Western blot法检测TAK1、TCF-4在癌组织及配对癌旁组织中的表达情况,并通过SPSS进一步分析两者的相关性及其与临床病理因素的关系。结果 TAK1与TCF-4 mRNA以及蛋白水平在NSCLC患者癌组织中均高表达,其中TAK1蛋白的表达与NSCLC的TNM分期（P=0.022）、淋巴结转移（P=0.014）相关,TCF-4蛋白的表达与NSCLC的TNM分期相关（P=0.045）。TAK1在NSCLC组织中的表达与TCF-4呈正相关（r=0.427,P=0.002）。结论 TAK1 mRNA及蛋白水平在NSCLC组织中均高表达,并与TCF-4呈正相关,TAK1有可能成为NSCLC诊断及预后的一个潜在靶标,并且TAK1与TCF-4的联合应用有可能成为一种更为理想的NSCLC辅助诊断及临床治疗方法。

Objective To investigate the mRNA and protein expressions of transforming growth factor β-activated kinase 1（TAK1）and T cell factor-4（TCF-4）in non-small cell lung cancer（NSCLC）tissues and their correlation,and to analyze the relationship between TAK1/TCF-4 and clinicopathological factors in NSCLC patients．Methods Cancer tissues and matched adjacent tissues of 51 NSCLC patients in our hospital were collected．The postoperative diagnosis of all patients was confirmed by pathological results．The expression of TAK1 and TCF-4 in cancer tissues and paired adjacent tissues were detected by RT-PCR and Western blot,then SPSS was used to further analyze the correlation between TAK1 and TCF-4 and clinicopathological factors．Results TAK1 and TCF-4 mRNA and protein were highly expressed in NSCLC tissues,and TAK1 protein expression was significantly correlated with TNM stage of NSCLC（P=0.022）and lymph node metastasis（P=0.014）;TCF-4 protein expression was significantly correlated with TNM stage of NSCLC（P=0.045）．TAK1 expression in NSCLC tissues was positively correlated with TCF-4（r=0.427,P=0.002）．Conclusions TAK1 mRNA and protein were highly expressed in NSCLC tissues and positively correlated with TCF-4．TAK1 may become a potential target for the diagnosis and prognosis of NSCLC,and the combined application of TAK1 and TCF-4 may become a more ideal method for the auxiliary diagnosis and clinical treatment of NSCLC．

目的 研究母代不同孕期巨细胞病毒（CMV）感染对自身精神及行为的影响。方法 72只BALB/c雌鼠随机分为12组（A1、A2、A3、B1、B2、B3、C1、C2、C3、D1、D2、D3,每组6只）,A为孕期再感染、B为既往感染、C为孕期原发感染、D为空白对照,1为孕早期、2为孕中期、3为孕晚期。母鼠腹腔注射小鼠CMV（murine CMV,MCMV）Smith株建立播散性感染模型,或注射无菌生理盐水建立对照模型。母鼠产仔后同笼合养,产后22 d分笼;母鼠做行为学试验。试验结束,每组随机处死3只母鼠;测量子宫、肝、脑脏器重量系数及唾液腺中MCMV含量。结果 A、B、C组母鼠产后次日体质量均低于D组（均P<0.05）,其中C2、C3组母鼠低体质量情况持续至产后22日（均P<0.05）。A、B、C组母鼠唾液腺组织均测出MCMV。与D组母鼠相比,A1、C1组母鼠活胎率降低（均P<0.05）,A、C组母鼠的子宫、肝、脑脏器系数升高（均P<0.05）且脑组织有病损表现。产后6天时,A3、B3、C组母鼠水平运动总距离和直立次数减少（均P<0.05）,糖水偏好量降低（均P<0.05）,悬尾不动时间延长（P<0.05）;其中,C2、C3组母鼠以上行为退缩情况至产后22天仍存在,且有逃避潜伏时间延长（均P<0.01）,穿越原平台位置次数减少（均P<0.01）情况。结论 孕期CMV感染损害母代身心健康,有可能增加子代不良抚养的风险。

Objective To investigate the effects of cytomegalovirus（CMV）infection in different stages of maternal pregnancy on its own spirit and behavior．Methods A total of 72 female BALB/c mice were randomly divided into 12 groups（each group had 6 mice）：A1-A3,B1-B3,C1-C3,D1-D3（group A had re-infection,group B had previous infection,group C had primary infection,group D was blank control,group 1 was in early pregnancy,group 2 was in middle pregnancy,group 3 was in late pregnancy）．The disseminative infection model was established by intraperitoneal inoculation of murine CMV（MCMV）Smith strain,and the blank control model was established by intraperitoneal inoculation of 0.9% sterile saline（NaCl）．After 21 days of parturition,the mothers and offspring were reared in separate cages,mothers were selected for the behavior experiments．At the end of all the behavior tests,3 mothers in each group were killed randomly．Weighed and calculated the organ coefficients of the uteri,livers and brains,and detected the expression levels of MCMV in salivary gland．Results On the first day after delivery,the weights of mothers in groups A,B and C were lower than those in group D（all P<0.05）,the low body weight of mice in C2 and C3 groups lasted to the 22th day（all P<0.05）．The MCMV in salivary gland tissue were found in groups A,B and C,but not in group D．The live fetus rates of groups A1 and C1 were significantly lower than that of group D．The organ coefficients of uteri,livers and brains in groups A and C were higher than those in group D（all P<0.05）．And the lesions of brain tissues in groups A and C were more serious than in the other groups．On the 6th day,compared with the other groups,the mothers of groups A3,B3 and C were significantly abnormal in the open field test,the tail suspension test and the sugar preference test（all P<0.05）．But on 22th day,only the mothers of groups C2 and C3 were significantly abnormal in those tests（all P<0.01）,and even in the water maze test（all P<0.01）．Conclusions Maternal CMV infection in different stages pregnancy have impacts on mother mice's physical and mental health．Those bad situations may bring poor parenting to the offspring．

目的 探讨鳞状上皮细胞抗原（SCCA）、人乳头瘤病毒（HPV）-DNA联合阴道镜检查在宫颈鳞状细胞癌（SCC）筛查中的应用价值。方法 选择2019年1月1日—2021年12月31日在中山市博爱医院就诊并确诊为SCC的妇女作为研究对象,共纳入100例SCC患者（SCC组）,同时选择200例经活检确诊为宫颈慢性炎症的患者（宫颈慢性炎症组）作为阴性对照。采用阴道镜观察研究对象的宫颈情况,并采集研究对象的宫颈组织标本进行HPV-DNA检测。采集研究对象的静脉血,采用化学发光免疫法测定研究对象SCCA的水平。以病理检查结果为金标准,分别对HPV-DNA检测、外周血SCCA两者联用以及阴道镜、HPV-DNA检测、外周血SCCA三者联用进行筛查效果的评价。结果 SCC组研究对象的年龄≥40岁者、出血者、性生活开始年龄≤20岁者比例均高于宫颈慢性炎症患者组;而宫颈慢性炎症患者组疼痛的比例高于SCC患者组,差异均有统计学意义（P<0.01）。χ²检验结果显示,SCC组研究对象的SCCA阳性率高于宫颈慢性炎症组（P<0.001）。阴道镜结合SCCA、HPV-DNA检测筛查SCC的灵敏度和特异度均高于单独使用SCCA和HPV-DNA,并取得较好的约登系数（75%）和Kappa值（0.730）。结论 采用阴道镜结合HPV-DNA、SCCA可有效提高SCC疾病的约登系数与Kappa值,其联合诊断的效能高于单独使用阴道镜、HPV-DNA或SCCA诊断SCC。

Objective To study the application value of squamus cell carcinoma antigen（SCCA）and human papillomavirus（HPV）-DNA combined with colposcope in cervical squamous cell carcinoma（SCC）screening．Methods Women diagnosed with SCC who visited Boai Hospital of Zhongshan city from January 1,2019 to December 31,2021 were selected as research subjects,including 100 patients with SCC（SCC group）and 200 patients with chronic cervical inflammation confirmed by biopsy（chronic cervical inflammation group）．The cervix of the subjects was observed by colposcope,and cervical tissue samples were collected for HPV-DNA testing．Venous blood of subjects was collected and SCCA levels were determined by chemiluminescence immunoassay．Using pathological examination results as the gold standard,the screening effect of combination HPV-DNA test and peripheral blood SCCA test,combination colposcope,HPV-DNA test and peripheral blood SCCA were evaluated respectively．Results In SCC group,the proportion of age≥40 years old,bleeding,sexual life age ≤20 years old were higher than those in chronic cervical inflammation group,but chronic cervical inflammation group had higher rate of pain than those in SCC group（P<0.01）by Chi-square test．SCCA positive rate in SCC group was higher than that in chronic cervical inflammation group（P<0.001）by Chi-square test．The sensitivity and specificity of colposcope combined with SCCA and HPV-DNA were higher than those of SCCA and HPV-DNA alone,and better Youden’s coefficient（75%）and Kappa value（0.730）were obtained．Conclusions Colposcope combined with HPV-DNA and SCCA can effectively improve the Youden’s coefficient and Kappa value of SCC disease,and its combined diagnosis efficiency was higher than that of colposcope,HPV-DNA and SCCA alone in the diagnosis of SCC,which has high clinical promotion significance．

肿瘤免疫治疗是指利用人体的免疫机制,通过主动或被动的方法增强患者免疫功能,达到杀伤肿瘤细胞的目的。嵌合抗原受体T细胞（CAR-T）作为肿瘤免疫治疗的新型精准靶向疗法,近几年通过优化和改良已成功应用于多种血液肿瘤的治疗,是目前恶性肿瘤治疗中最有潜力的疗法之一。但由于实体瘤中存在显著的异质性和复杂的肿瘤免疫微环境,CAR-T在实体瘤中的应用仍面临诸多挑战。本文将对目前 CAR-T 细胞治疗实体瘤的研究成果、现存挑战及相应的优化策略进行综述,以期为后续 CAR-T 细胞治疗实体肿瘤研究提供参考。

Tumor immunotherapy is the process of enhancing patients’ immune system through active or passive methods to achieve the goal of eliminating tumor cells．Through optimization and modification,chimeric antigen receptor T cells（CAR-T）,a novel precise targeted therapy of cancer immunotherapy,have been successfully used in the treatment of several hematological malignancies in recent years．CAR-T is considered as one of the most promising therapies for the treatment of malignant tumors at the moment．However,application of CAR-T in solid tumors still confronts several difficulties due to the high heterogeneity and intricate tumor immune microenvironment．To serve as a reference for future CAR-T cell therapy for solid tumors,the present research findings,current difficulties and associated optimization techniques are reviewed in this paper．

目的 分析早、中期肝细胞癌（HCC）切除术后早期（≤2年）复发的危险因素并探讨术前系统免疫炎症指数（SII）对早、中期HCC术后早期复发的预测价值。方法 回顾性研究2017年10月—2020年10月于我院接受肝癌根治性切除术的238例早中期HCC患者,收集基线资料,通过1∶1倾向性评分匹配（PSM）均衡组间协变量获取早期复发组及未复发组各69例;单因素和多因素Logistic回归分析影响术后早期HCC复发的相关因素,构建列线图模型,临床决策曲线（DCA）评估列线图预测模型在临床的应用效果;受试者操作特征（ROC）曲线评价预测效能,根据最高约登指数确定截断点。结果 单因素及多因素Logistic回归分析结果均提示微血管侵犯（MVI）及术前系统免疫炎症指数（SII）高水平是术后早期复发的独立危险因素;列线图模型有较好的预测效能;ROC曲线计算出SII最佳临界值为696.85×10⁹／L。结论 术前高水平SII可能对预测HCC患者术后早期复发具有潜在价值。

目的 采用体外试验的方法,研究弱酸性培养对人正常食管内皮细胞（HEEC）活力的影响及潜在的调控机制。方法 细胞培养液的pH值分别设为（6.0~6.5）和（7.0~7.4）。以中性培养组为对照。利用CCK8实验,检测弱酸培养条件下,不同时间点食管内皮细胞活力的变化。采用蛋白免疫印迹法检测p38和磷酸化p38（p-p38）的表达。利用酶联免疫吸附剂测定法检测培养基上清液中IL-1β和IL-8的表达水平,并检测加入p38激酶活性抑制剂SBS 203580后两者浓度的变化。结果 弱酸环境下,细胞活力下降。培养1 h时,弱酸组细胞活力为（96.4±8.0）%,培养3 h和6 h时分别为（88.7±6.2）%和（87.7±7.4）%。细胞中p38的水平与培养基的pH值无关。弱酸培养可以促使细胞内p-p38的含量增加。基线时,弱酸组p-p38的灰度值比值为（0.37±0.02）,在培养2 h和6 h时分别为（0.64±0.09）、（0.84±0.11）,差异显著（P<0.01）。弱酸刺激诱导食管内皮细胞表达更多的IL-8和IL-1β。基线时弱酸组上清液中IL-8和IL-1β的浓度分别为（8.64±1.31）pg/mL,（3.35±0.49）pg/mL。培养6 h后,二者的浓度分别上升至（36.85±2.02）pg/mL和（19.19±1.60）pg/mL,差异显著（P<0.01）。加入SBS 203580后,IL-8和IL-1β的浓度明显下降（P<0.05）。结论 弱酸刺激可以降低食管内皮细胞的活力。p38 MAPK可能通过调控IL-8和IL-1β的表达参与该调节过程。

Objective To study the effect of weak acidic culture on the viability of normal human esophageal endothelial cells(HEEC)and the potential regulatory mechanisms. Methods The pH values of cell culture medium were set at(6. 0-6. 5)and(7. 0-7. 4),respectively. The group in neutral medium was set as control. CCK8 experiment was used to detect the change of cell viability at different time points. The expressions of p38 and phosphorylated p38(p-p38)were detected by Western Blot experiment. Enzyme linked immunosorbent assay was used to detect IL-1β and IL-8 concentration in the medium supernatant before and after adding p38 activity inhibitor(SBS 203580). Results HEEC viability was decreased under weak acidic conditions. After 1 hour of cultivation,the HEEC viability was(96. 4±8. 0)%,after 3 and 6 hours,it decreased to(88. 7±6. 2)% and(87. 7±7. 4)%,respectively. The level of p38 in cells was independent of culture medium pH values. Weak acidic stimulation could promote an increase of p-p38 in HEEC. At baseline,the gray value ratio of p-p38 in the weak acidic group was(0. 37±0. 02),and after 2 and 6 hours of culturing,it increased to(0. 64±0. 09)and(0. 84±0. 11),respectively,which differences were significant(P<0. 01). More IL-8 and IL-1β were expressed after weak acidic stimulation. At baseline,the concentrations of IL-8 and IL-1β in the medium supernatant of weak acidic group were(8. 64±1. 31)pg/mL and(3. 35±0. 49)pg/mL. After 6 hours of culturing,they increased significantly to(36. 85±2. 02)pg/mL and(19. 19±1. 60)pg/mL(P<0. 01),while the concentrations were decreased after adding SBS 203580(P<0. 05). Conclusions The HEEC viability was reduced by weak acidic stimulation,p38 MAPK may participate in the process by regulating the expression of IL-8 and IL-1β.

目的 构建尺寸可变纳米递送系统PAMAM/DOX-pep并进行表征,检测其理化性质并评价其体外抗肿瘤效果与靶向性。方法 将阿霉素（DOX）物理包埋在阳离子聚合物PAMAM的疏水空腔内,以4-（N-马来酰亚胺基甲基）环己烷羧酸N-羟基琥珀酰亚胺酯（SMCC）作为交联剂,采用金属基质蛋白酶（MMP-2）敏感的多肽pep（CPLGVRGC）串联小粒径纳米颗粒形成大尺寸纳米递送系统（PAMAM/DOX-pep）,对各纳米颗粒的粒径、电位、理化性质以及对小鼠乳腺癌细胞（4T1）的抑制作用、细胞摄取效果和核靶向作用进行检测。结果 PAMAM/DOX粒径约为10 nm,载药率为23%,多肽pep交联后形成的PAMAM/DOX-pep粒径约为200 nm,可在低pH下缓释DOX,7天内体外保持稳定且溶血率低、安全无毒,其与MMP-2共孵育后细胞摄取量与核靶向性显著增加。结论 尺寸可变纳米颗粒有助于克服尺寸所引发的递送障碍,将药物靶向递送至乳腺癌细胞核内并发挥作用,为纳米递送系统的设计提供了新策略。

Objective To construct and characterize the size-variable nano-delivery system PAMAM/DOX-pep,examine its physicochemical properties and evaluate its antitumor and targeting effects in vitro. Methods Small particle size PAMAM/DOX was obtained by physically encapsulating DOX within the hydrophobic cavity of the cationic polymer PAMAM. The large size nano-delivery system(PAMAM/DOX-pep)was formed by tandem linking small size nanoparticles by MMP-2 sensitive peptide pep(CPLGVRGC)using SMCC as a cross-linker. The particle size,potential,physical and chemical properties,inhibitory effect,cell uptake and nuclear targeting effect of each nanoparticle on mouse breast cancer cells(4T1)were detected. Results The particle size of PAMAM/DOX was about 10 nm,and the drug loading rate was 23%. PAMAMAM/DOX-pep,formed after cross-linking of peptide,had a particle size of about 200 nm,which could release DOX slowly at low pH,and remained stable,safe and non-toxic in vitro for 7 days with low hemolysis rate,and its cellular uptake amount and nuclear targeting rate increased significantly after co-incubation with MMP. Conclusions Size-variable nanoparticles overcome size-induced delivery barriers to target and deliver drugs to the 4T1 nucleus,providing a new strategy for the design of nano delivery systems.