麻醉手术与自然杀伤细胞

麻醉诱导可使ＮＫ细胞活性增加，手术创伤后ＮＫ细胞进一步增加，术后３～６天活性下降且低于术前水平。其机理主要是应激性内分泌分应。麻醉药对ＮＫ细胞作用较小；但氟烷对Ｂ淋巴细胞有一定影响。     

肾癌的靶向治疗研究进展

进展期肾癌和转移性肾癌的预后差，系统治疗作用局限，分子靶向治疗是有希望的治疗手段。本文就肾癌靶向治疗的分子机制、临床试验及疗效等作一综述。     

索拉非尼治疗晚期肾癌临床观察

目的 评价索拉非尼治疗晚期肾癌的疗效及安全性.方法 使用索拉非尼治疗晚期肾癌85例,其中采用索拉非尼400 mg,2次/d治疗70例;索拉非尼剂量递增(400 mg,2次/d,服药1～4周,600 mg,2次/d,服药1～4周,如患者能耐受则增量至800 mg,2次/d)治疗10例;索拉非尼400 mg,2次/d联合干扰素α(IFN-α)300万U,皮下注射,5 d/周治疗5例,直至肿瘤进展或出现不可耐受的不良反应.评价客观反应率、临床获益率、不良反应发生率.结果 可评价疗效病例80例,中位随访时间72(4～108)周.完全缓解(CR)1例(1.2%)、部分缓解(PR)1 7例(21.2%)、疾病稳定(SD)50例(62.5%)、疾病进展(PD)12例(15.0%).客观反应率(CR+PR)为22.5%(18/80),临床获益率(CR+PR+SD)为85.0%(68/80).索拉非尼剂量递增或索拉非尼联合IFN-α方案与索拉非尼单药方案相比差异均无统计学意义(P值分别为0.78和0.95).随访截止至2009年5月,因肿瘤进展死亡18例(22.5%),无疾病进展生存和总生存时间尚未达到.常见不良反应为手足皮肤反应44例(55.0%)、牙龈黏膜出血42例(52.5%)、腹泻32例(40.0%)、疲乏28例(35.0%)、食欲下降18例(22.5%)、黏膜溃疡16例(20.0%)、高血压12例(15.0%)、脱发12例(15.0%)等,但多为1～2级,经相应对症处理均可缓解.结论 索拉非尼单药、索拉非尼增量或索拉非尼联合IFN-α 3种方案治疗晚期肾癌的近期疗效良好,患者耐受性良好.     

晚期肾癌靶向治疗的研究进展

肾癌是泌尿外科常见的恶性肿瘤,治疗以外科手术切除为主,对放、化疗均不敏感,这给晚期肾癌的治疗带来一定的困难.近年来随着对肾癌发病机理认识的逐渐深入,新的分子靶向治疗药物不断用于晚期肾癌的治疗.美国FDA(U.S.Food and Drug Administration)已经先后批准了6种靶向治疗药物用于晚期转移性肾癌的一、二线治疗.     

肾癌的树突状细胞治疗

肾癌是泌尿系最常见的恶性肿瘤之一,以往以手术治疗为主.但大多数患者就诊时肿瘤已发生转移,对这部分患者尽管采用手术治疗,往往不能取得满意的疗效.近年来,随着分子生物学、免疫学的研究进展,以树突状细胞为基础的免疫治疗在肾癌的治疗中发挥着重要的作用,本文就最近几年其在肾癌患者中的应用作一综述.     

肾癌肿瘤浸润淋巴细胞的研究进展和临床应用

肿瘤浸润淋巴细胞为治疗晚期肿瘤开辟了一个新的途径。本文就肾癌肿瘤浸润淋巴细胞的来源，制备、生物不和持性和临床应用的一些研究进展做一综述。     

经抗CD158单克隆抗体修饰的供者自然杀伤细胞对受者树突状细胞的杀伤作用

目的 研究应用抗CD158a和CD158b单克隆抗体封闭供者杀伤细胞免疫球蛋白样受体(KIR)的抑制性受体KIR2DL1及KIR2DL3后,供者自然杀伤细胞(NK细胞)对受者树突状细胞(DC)的杀伤作用,及其减少移植物抗宿主病(GVHD)的作用.方法 对15例异基因全相合造血干细胞移植的供、受者进行HLA及KIR高分辨基因分析,采集供者骨髓及受者外周血单个核细胞,培养受者DC作为靶细胞,使用磁珠负选高纯度供者NK细胞作为效应细胞,用抗CD158a和CD158b单抗封闭供者KIR抑制性受体,并采用四甲基偶氮唑盐比色法分别检测抑制性KIR封闭前后NK细胞对靶细胞的杀伤作用.结果 在效靶比为10∶1下,供者NK细胞抑制性受体经抗体封闭后,对受者DC的杀伤活性明显提高,随着封闭抗体浓度的增加而增高,各浓度间比较,差异均有统计学意义(P＜0.05).当供、受者KIR配体匹配模式为宿主抗移植物(HVG)模式时,供者NK细胞对受者成熟DC的杀伤效果明显高于供、受者KIR基因全相合或移植物抗宿主(GVH)模式,在用不同浓度单抗封闭KIR抗体后,随着封闭抗体浓度的增加,杀伤效果增高更明显(P＜0.05).结论 利用抗CD158单抗封闭KIR可以提高供者来源NK细胞对受者DC的杀伤活性,输注异源反应性NK细胞可能作为一种新的治疗GVHD的方法.     

肾移植受者血他克莫司浓度对外周血自然杀伤细胞及其受体的影响

目的 研究肾移植受者血他克莫司(Tac)浓度对外周血自然杀伤(NK)细胞及其受体的影响.方法 将2007年12月至2009年7月间的60例受者纳入研究,术后受者均采用以Tac为基础的免疫抑制方案.根据术后6个月监测到的血Tac浓度将受者分为低浓度组和高浓度组[各为30例,术后6个月时血Tac浓度分别为(6.84±1.72)和(11.88±2.59)μg/L],另以20名健康志愿者作为对照组.术前和术后6个月,采用流式细胞术检测NK细胞及其抑制性受体(CD85j和CD158d)和活化性受体( CD94、NKG2D)的表达情况,采用酶联免疫吸附试验法检测免疫耐受分子分泌型HLA-G5( sH LA-G5)的表达水平.结果 术前低浓度组和高浓度组受者外周血NK细胞绝对值均较对照组显著降低(P＜0.05),术后6个月时低浓度组和高浓度组NK细胞比例及绝对值较对照组均显著降低(P＜0.05),低浓度组NK细胞绝对值显著高于高浓度组(P＜0.05).术前两组间CD85j、CD158d、CD94、NKG2D表达的差异均无统计学意义(P＞0.05);术后6个月时低浓度组和高浓度组CD85j和CD158d的表达较术前升高,CD94和NKG2D的表达下降,而低浓度组CD85j和CD158d的表达显著高于高浓度组(P＜0.05).经Spearman系数统计,CD85j和CD158d与sHLA-G5呈正相关(P＜0.01),NKG2D与sHLA-G5呈负相关(P＜0.01).结论 肾移植受者血Tac浓度与外周血NK细胞数量及其受体的表达具有相关性,低血Tac浓度受者的NK细胞数量及其抑制性受体的表达升高,仍然能有效保护移植肾功能.     

肾癌生物治疗

分子生物学的飞速发展为肾癌的临床治疗谱写了新的篇章，目前常用的生物制品有细胞产品、蛋白质产品和核酸产品。本文主要从这三个方面进行综述。     

结直肠癌中CAR-T细胞免疫治疗的研究现状及展望

嵌合抗原受体T(CAR-T)细胞免疫疗法是一种通过基因工程修饰来招募T细胞对抗肿瘤的新方法。CAR-T细胞免疫疗法在血液系统恶性肿瘤中已取得巨大的进展,因此,许多研究者提出将其用于诸如结直肠癌(CRC)这类实体肿瘤。但是,由于肿瘤特异抗原的缺乏,肿瘤细胞间的紧密连接和免疫抑制性的肿瘤微环境,以及治疗不良反应等问题,限制...     

Sperm cell biology: current perspectives and future prospects

Major advances in biomolecular techniques as well as in the sensitivity and accuracy of mass spectrometers are transform-ing the scientific landscape by fuelin...     

Gene therapy for prostate cancer: current status and future prospects

PURPOSE: Locally advanced, relapsed and metastatic prostate cancer has a dismal prognosis with conventional therapies offering no more than palliation. In recent years advances achieved in understanding the molecular biology of cancer have afforded clinicians and scientists the opportunity to develop a range of novel genetic therapies for this disease. MATERIALS AND METHODS: We performed a detailed review of published reports of gene therapy for prostate cancer. Particular emphasis was placed on recent developments in the arena of nonviral (plasmid DNA, DNA coated gold particles, liposomes and polymer DNA complexes) and viral (adenovirus, retrovirus, adeno-associated virus, herpes virus and pox virus) vectors. Therapeutic strategies were categorized as corrective, cytoreductive and immunomodulatory gene therapy for the purpose of data analysis and comparison. RESULTS: Locoregional administration of nonviral and viral vectors can yield impressive local gene expression and therapeutic effects but to our knowledge no efficient systemically delivered vector is available to date. Corrective gene therapy to restore normal patterns of tumor suppressor gene (p53, Rb, p21 and p16) expression or negate the effect of mutated tumor promoting oncogenes (ras, myc, erbB2 and bcl-2) have efficacy in animal models but this approach suffers from the fact that each cancer cell must be targeted. A wide variety of cytoreductive strategies are under development, including suicide, anti-angiogenic, radioisotopic and pro-apoptotic gene therapies. Each approach has strengths and weaknesses, and may best be suited for use in combination. Immunomodulatory gene therapy seeks to generate an effective local immune response that translates to systemic antitumor activity. Currently most studies involve immunostimulatory cytokine genes, such as granulocyte-macrophage colony-stimulating factor, or interleukin-2 or 12. CONCLUSIONS: Various therapeutic genes have proved activity against prostate cancer in vitro and in vivo. However, the chief challenge facing clinical gene therapy strategies is the lack of efficient gene delivery by local and systemic routes. For the foreseeable future vector development may remain a major focus of ongoing research. Despite this caveat it is anticipated that gene therapy approaches may significantly contribute to the management of prostate cancer in the future.     

Levosimendan: current status and future prospects

PURPOSE OF REVIEW: While patients with acute heart failure typically receive diuretics and vasodilators, contractile dysfunction and peripheral hypoperfusion also leads to a widespread use of inotropic agents despite the lack of evidence for efficacy or safety. Levosimendan, a calcium sensitizer and vasodilator, has been proposed to be superior to standard inotropes. In addition, further possible indications for levosimendan have been described, such as perioperative use, cardioprotection, cardiogenic shock, sepsis, and right ventricular dysfunction. RECENT FINDINGS: The mortality benefit of levosimendan has not been confirmed in two recent trials but the substance improves symptoms, decreases brain natriuretic peptide and is effective during beta-blocker treatment. The use of levosimendan as an add-on therapy in acute heart failure has been encouraged as well as its perioperative use. Levosimendan may also be useful during right ventricular dysfunction and septic shock due to its favorable effects on splanchnic perfusion. SUMMARY: Levosimendan is an established substance in the treatment of acute heart failure in several countries despite disappointing findings concerning a possible survival benefit in two recent clinical trials. Owing to its alternative mechanisms of action as compared with traditional cardiotonic agents, several promising clinical applications have arisen. Available evidence for the use of levosimendan in settings other than decompensated heart failure is currently limited.     

Androgen deprivation therapy for prostate cancer: current status and future prospects

Androgens play a major role in promoting the development and progression of prostate cancer. As a result, androgen ablation or blockade of androgen action through the androgen receptor (AR) has been the cornerstone of treatment of advanced prostate cancer. Different strategies involving this hormonal therapy produce a significant clinical response in most of the patients, but most responders eventually lose dependency, resulting in mortality. Thus, whether hormonal therapy contributes to the improvement of overall survival rates, especially in patients with advanced prostate cancer, remains controversial. However, patients with advanced disease clearly have a benefit from androgen deprivation-based treatment for palliating their symptoms and for improving the quality of their lives. In order to improve overall survival, novel treatment strategies that prolong the androgen-dependent state and that are useful for androgen-independent disease based on specific molecular mechanisms need to be identified.     

Liver transplantation: current status and future prospects

The enormous progress that has been made in liver transplantation over the past two decades has culminated in survival approaching 90% at 12 months. The success of the procedure combined with the widening spectrum of disease processes deemed amenable to liver transplantation has meant that there are too few donors for those awaiting transplantation. This has extrapolated to many patients having such advanced disease by the time a suitable donor liver is available, that they are almost non-transplantable. The immediate options facing the transplant community are to decrease the number of patients listed or to increase the number of living donor transplants. Alternatives to liver transplantation such as hepatocyte transplantation, gene therapy, xenotransplantation and the bioartificial liver are being sought but, at best, are some way from clinical application. It is anticipated that a number of liver diseases that are indications for liver transplantation at this time will have progression arrested or will be cured by medical therapy in the future.     

Natural killer cell function predicts severe infection in kidney transplant recipients

The aim of this study was to determine if natural killer cell number (CD3^?/CD16^±/CD56^±) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty‐nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P = .018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.90; P < .0001) but not natural killer number (OR 0.96, 95% CI 0.93‐1.00; P = .051) remained significantly associated with a reduced likelihood of severe infection. Natural killer cell function predicts severe infection in kidney transplant recipients.     

Natural killer cells in patients with renal cell cancer

Cytotoxic activity of natural killer (NK) cells in peripheral blood was studied in 60 patients with renal cell carcinoma (RCC) by means of a 51Cr release assay against K 562 cells, homologous and autologous RCC. All patients were tested prior to surgery and thereafter followed up for 1 year. Immunostimulating agents as interferon, levamisole, OMPI, and various bacterial extracts were tested for their boosting capacity on NK cells. Patients with localized tumor showed increased activity in comparison to age-matched controls, whereas NK cell activity and interferon-boosted activity in patients with advanced disease and tumor spread was decreased. Augmentation of NK activity could only be achieved by interferon, while application of levamisole, OMPI, and bacterial extracts resulted rather in suppression of cytotoxic activity.     

Natural killer cell activity in patients with urologic cancer

Cell-mediated cytotoxicity in patients with urologic cancer was studied using the K562 cell line as target cell by a 4-hour chromium-51 release assay. Lysis of target cells by mononuclear cells of a healthy subject, over an 8-hour incubation period, demonstrated a linear function of incubation time and effector:target ratio. Natural killer (NK) cell activity was found decreased (mean 30.6%) in peripheral blood lymphocytes from 42 untreated patients with urologic cancer when compared to 20 healthy subjects (63.6%) and to 10 patients with varicocele, stone disease and benign prostatic hypertrophy (58.1%; p less than 0.05). There was no correlation between NK cell activity and the grade or stage status in bladder cancer patients. No age-dependent changes in NK cell activity could be found between young and aged groups of healthy subjects. Healthy male subjects have higher levels of NK cell activity (77.7%) than healthy female subjects (49.5%). Postoperative NK activity rose in 5 out of 6 cancer patients. It indicates that tumors may have an inhibitory effect on the surveillance activity of NK cells.     

Organ transplantation in mice: current status and future prospects

With the development of microsurgery and molecular biology in the 1990s, the mouse model for organ transplants has become increasingly popular. In the past 10 years, the number of studies using the mouse model has increased three-fold. All the organ transplants, originally done in the rat model, can now be performed in mice with high success rates. This article reviews the development, advantages, limitations, and unique immunology of the mouse model as well as future prospects.