Knockdown of the interleukin-6 receptor alpha chain of dendritic cell vaccines enhances the therapeutic potential against IL-6 producing tumors

Tumor microenvironment has emerged as one of the major obstacles against the clinical efficacy of dendritic cell (DC) vaccines. Tumor-derived IL-6 may inhibit the differentiation of hematopoietic progenitor cells into DCs and suppress DC maturation, rendering DCs tolerogenic. We hypothesized that silencing the IL-6 receptor alpha chain (IL-6Rα) would restore the functional competence of DC vaccines in mice with an IL-6-producing TC-1 tumor, and eventually give rise to protective immunity. We found that the IL-6Rα knockdown-DC vaccine significantly enhanced the frequency of tumor-specific CD8⁺ CTLs-producing effector molecules such as IFN-γ, TNF-α, FasL, perforin, and granzyme B, and generated more CD8⁺ memory T cells, leading to the substantially prolonged survival of TC-1 tumor-bearing mice.     

Vaxfectin enhances immunogenicity and protective efficacy of P. yoelii circumsporozoite DNA vaccines

We evaluated the capacity of the cationic lipid based formulation, Vaxfectin, to enhance the immunogenicity and protective efficacy of DNA-based vaccine regimens in the Plasmodium yoelii murine malaria model. We immunized Balb/c mice with varying doses (0.4-50 microg) of plasmid DNA (pDNA) encoding the P. yoelii circumsporozoite protein (PyCSP), either in a homologous DNA/DNA regimen (D-D) or a heterologous prime-boost DNA-poxvirus regimen (D-V). At the lowest pDNA doses, Vaxfectin substantially enhanced IFA titers, ELISPOT frequencies, and protective efficacy. Clinical trials of pDNA vaccines have often used low pDNA doses based on a per kilogram weight basis. Formulation of pDNA vaccines in Vaxfectin may improve their potency in human clinical trials.     

卵巢生殖细胞肿瘤的CT诊断

目的 探讨卵巢生殖细胞肿瘤的CT表现特点,提高CT诊断的准确性.方法 回顾性分析2009年1月-2011年1月以来经我院手术病理证实的55例62个卵巢生殖细胞肿瘤的CT影像资料,结合病理讨论其CT表现特点.结果 本组卵巢生殖细胞肿瘤中,畸胎瘤48例55个,内胚窦瘤7例7个.42例49个成熟囊性畸胎瘤,CT明确诊断42例49个,均含有脂肪密度区,7个见脂液平面,10个有浮球征,30个有钙化或牙齿状影.6个未成熟畸胎瘤呈囊性或实性为主肿块,肿块内均见多发斑点状钙化和少许小片状脂肪密度影.7个内胚窦瘤肿块以实质性为主,间杂有小片状低密度区.结论 卵巢畸胎瘤和内胚窦瘤的CT表现具有各自的特点,CT能作出正确诊断,尤其是对畸胎瘤,与B型超声相比,CT是更好的检查方法.     

不同流行性腮腺炎疫苗接种率及剂次保护效果比较

评估流行性腮腺炎疫苗的保护效果,为制定控制腮腺炎规划提供依据.方法 选择2008年7月-2010年6月学校暴发病例120例,采用1∶2配对的病例对照方法研究流行性腮腺炎疫苗保护效果.结果 暴发病例主要集中在7 ~14岁的学龄儿童,占78.33%.2组平均年龄、免疫史来源以及明确的接种年龄差异无统计学意义(P值均>0.05),但免疫史差异有统计学意义(P<0.01).以预防接种证(卡)记录统计,1剂次疫苗保护效果为61%,95% CI为11% ~83%;≥2剂次疫苗保护效果为83%,95% CI为37% ~ 96%.≥1剂次疫苗保护效果为69%,95%CI为40% ~84%.估计接种率分别为73.41%,32.01%和82.43%.结论 较低的疫苗接种率和/或较少的疫苗接种剂次是导致流行性腮腺炎暴发的主要原因.提高并维持高水平2剂次接种率是预防暴发的关键.     

Polynucleotide viral vaccines: codon optimisation and ubiquitin conjugation enhances prophylactic and therapeutic efficacy.

Papillomavirus infection is a major antecedent of anogenital malignancy. We have previously established that the L1 and L2 capsid genes of papillomavirus have suboptimal codon usage for expression in mammalian cells. We now show that the lack of immunogenicity of polynucleotide vaccines based on the L1 gene can be overcome with codon modified L1, which induces strong immune responses, including conformational virus neutralising antibody and delayed type hypersensitivity. Conjugation of a ubiquitin gene to a hybrid gene incorporating L1 and the E7 non-structural papillomavirus protein improved E7 specific CTL responses, and induced protection against an E7 expressing tumour, but induced little neutralising antibody. However, a mixture of ubiquitin conjugated and non-ubiquitin conjugated polynucleotides induced virus neutralising antibody and E7 specific CD8 T cells. An optimal combined prophylactic/therapeutic viral vaccine might therefore comprise ubiquitin conjugated and non-ubiquitinated genes, to induce prophylactic neutralising antibody and therapeutic cell mediated immune responses.     

两例青少年卵巢生殖细胞肿瘤治疗

2008年7月至2009年8月湖北省妇幼保健院收治两例比较特殊的生殖细胞肿瘤患者接受手术治疗,现将治疗结果报道如下.     

联合检测肿瘤标志物在卵巢肿瘤筛查中的意义

目的 探讨多项肿瘤标志物联合检测对卵巢肿瘤性质的诊断意义.方法 经病理确诊的卵巢肿瘤患者83例,采用磁化学发光法检测其多项肿瘤标志物:糖链多肽抗原(CA)125、CA19-9、甲胎蛋白(AFP)、癌胚抗原(CEA)、血清铁蛋白(FT),分析其结果与临床诊断的关系.结果 恶性卵巢肿瘤中任何一项肿瘤标志物的阳性率为83.87%(26/31),而良性卵巢肿瘤为36.54%(19/52),两者比较差异有统计学意义(P＜0.05).各项肿瘤标志物在恶性卵巢肿瘤、卵巢子宫内膜异位囊肿、良性卵巢肿瘤中的阳性率比较,差异均有统计学意义(P＜0.05),且在恶性卵巢肿瘤中的阳性率最高.CA125诊断恶性卵巢肿瘤灵敏度最高(74.2%),但特异度(55.8%)和阳性预测值(50.0%)低;CEA、AFP和Fr的特异度(均为98.1%)虽高,但灵敏度(分别为16.1%、3.2%、16.1%)低;CA125与其他肿瘤标志物联合检测可以提高其特异度和阳性预测值.结论 多项肿瘤标志物联合检测可以显著提高卵巢恶性肿瘤诊断的准确性,为处于亚临床期的卵巢癌患者和正常体检人群中卵巢肿瘤的筛查提供了可靠的检测方法.     

Development of therapeutic vaccines by direct modification of cell membranes from surgically removed human tumor tissue with immunostimulatory molecules

The addition of immunostimulatory molecules to tumor cells has been proposed as a potentially useful strategy to induce anti-tumor immunity. In this report we have investigated the application of using isolated tumor membranes modified by transfer of a glycosyl-phosphatidylinositol (GPI)-anchored form of the costimulatory molecule, B7-1 (CD80), as a cell free cancer vaccine for clinical use. Isolated tumor cell membranes were prepared from established tumor cell lines and the optimum conditions necessary for modification and clinical application were determined. GPI-B7-1 transferred optimally onto isolated human tumor membranes at physiological temperature (37 degrees C) in a dose dependent manner. Transfer of GPI-B7-1 to isolated membranes resulted in stable expression and costimulatory function. These modified membranes could be stored for repeated immunizations while retaining expression of GPI-B7-1. Critically, isolated tumor membranes, prepared directly from surgically removed human tumor tissue, could be modified by GPI-B7-1 and costimulate T cells. Finally, membranes isolated from tumor tissue expressed MHC class II, unlike the cell line established in vitro from the same patient. This novel approach to express immunostimulatory molecules on isolated membranes derived from a patient's tumor tissue will make the preparation of autologous therapeutic cancer vaccines available to patients from which tumor cell lines can not be established.     

Prospects and challenges for prophylactic and therapeutic HIV vaccines

The best strategy for controlling the HIV pandemic remains the development of an efficacious prophylactic vaccine. Efficacy trials performed during this decade will yield information on the protective ability of first-generation vaccines. Several novel mixed-modality vaccines capable of inducing high-frequency CD8(+) T-cell responses in macaques are being evaluated in humans. New hope has been raised with the prospect of therapeutic HIV vaccines. However, the development of HIV vaccines remains a formidable challenge to both the industry and the scientific community.     

妊娠期卵巢恶性生殖细胞肿瘤的治疗

卵巢恶性生殖细胞肿瘤多发生于年轻女性,甚至幼女。一般卵巢恶性生殖细胞肿瘤生长迅速,易早期转移,预后差。年轻女性正处于生育阶段,临床上常出现卵巢恶性生殖细胞肿瘤合并妊娠的情况。目前卵巢恶性生殖细胞肿瘤常采取单侧附件切除加术后辅助化疗,但妊娠期化疗对胎儿存在潜在威胁。目前卵巢恶性生殖细胞肿瘤合并妊娠的处理尚缺乏大样本的治疗学研究,相关文献比较分散,该综述总结这些分散的文献,希望找出治疗上的规律性,供临床处理上的参考。     

卵巢颗粒细胞瘤的超声表现及临床病理分析

目的 探讨卵巢颗粒细胞瘤(OGCT)的超声表现及临床病理特征.方法 回顾性分析广州市妇女儿童医疗中心15例经病理证实为卵巢颗粒细胞瘤的声像图表现及临床病理特点. 结果 15例肿块均为单侧发病,边界清楚、包膜完整、形态规则,肿块最大径为5.10~14.50cm(平均8.00± 2.70cm).15例颗粒细胞瘤声像图表现分为3种类型:Ⅰ实质型(2例)内部回声不均匀;Ⅱ多房囊型(2例)内部呈多分隔结构;Ⅲ囊实型(11例)内部不同程度囊性区域.15例肿块彩色多普勒显示少~中量血流信号.实性部分阻力指数(RI)为0.26~0.57,平均0.41±0.09.成人型颗粒细胞瘤(AGCT)9例;幼年型颗粒细胞瘤(JGCT)6例.AGCT平均发病年龄45岁,JGCT平均发病年龄3岁.临床主要表现为不规则阴道流血、腹痛、腹部包块、假性性早熟、腹水.成人型和幼年型卵巢颗粒细胞瘤均以囊实性超声表现为主.卵巢颗粒细胞瘤的超声表现与病理表现基本一致.结论 卵巢颗粒细胞瘤超声表现为大的不同程度囊变区的囊实性肿块为主,结合临床症状有助于正确诊断.     

宫颈癌治疗性疫苗的临床研究现状

人乳头瘤状病毒(human papillomavirus,HPV)是宫颈癌的主要致病因子,也是研制宫颈癌防治性疫苗的理想靶点。虽然现在针对HPV感染的宫颈癌预防性疫苗已成功上市,但是对于急需的治疗型疫苗的研发还在进行中。目前有多种类型的治疗性疫苗已用于临床前期及临床试验,并显示出很好的治疗效果。本文从活载体疫苗、多肽/蛋白疫苗、DNA疫苗和DC疫苗几个方面综述了目前国内外宫颈癌治疗性疫苗的研究现状及进展,特别是进入临床阶段的疫苗,从而为治疗性疫苗的研究提供参考。     

晚期卵巢癌选择初始肿瘤细胞减灭术还是间歇性肿瘤细胞减灭术探析

卵巢癌是致死率最高的妇科恶性肿瘤。晚期卵巢癌进行初始肿瘤细胞减灭术,随后给予铂类为基础的化疗,还是新辅助化疗后再行间歇性肿瘤细胞减灭术?两种方法各有优劣。需要结合诊治医院的水平、患者肿瘤的期别、转移部位,能否达到满意缩瘤效果等综合考虑。     

LAH4 enhances CD8+ T cell immunity of protein/peptide-based vaccines

It is now clear that CD8+ T cells are crucial for therapeutic immunity against chronic viral infections and/or tumors. We reason that a strategy capable of improving CD8+ T cell activation would improve the efficacy of protein-based vaccines, which predominantly generate CD4+ T cell-mediated responses. Herein, we explore the ability of a novel cell-penetrating peptide (CPP), LAH4, to facilitate intracellular delivery of protein-based vaccines adjuvanted with Toll-like receptor 9 agonist CpG oligonucleotide (CpG) to generate enhanced CD8+ T cell immune responses and antitumor effects. LAH4 was found to mediate the intracellular delivery of both protein and nucleotide cargo and facilitate protein internalization using mechanisms involving endosomal acidification and processing through the proteasome pathway, leading to enhanced cross presentation of protein antigen by dendritic cells to CD8+ T cells. LAH4 also improved the internalization of CpG, resulting in NFkB activation, thus potentiating the adjuvant effect of CpG. We found that protein-based vaccine comprised of LAH4 mixed with model antigen and CpG generated significantly improved antigen-specific CD8+ T cell immune responses and/or antitumor effects. Furthermore, we found that LAH4 was able to enhance the ability of a tyrosinase-related protein 2 (TRP-2) peptide-based vaccine to generate TRP2-specific CD8+ T cells and antitumor effects against TRP2-expressing tumors. Thus, our results suggest that CPP technology using LAH4 is able to enhance both protein-based and peptide-based vaccine potency to generate antigen-specific CD8+ T cells and antitumor effects. Our findings serve as an important foundation for future clinical applications of CPP technology to improve protein/peptide-based vaccine potency.     

卵巢恶性生殖细胞肿瘤的预后及影响因素分析

目的 了解卵巢恶性生殖细胞肿瘤的预后及其影响因素.方法 对29例卵巢恶性生殖细胞肿瘤患者的临床资料进行分析,设定变量因素,采用SPSS 16.0统计软件进行单因素及COX逐步回归分析,确定影响患者预后的因素.结果 患者的年龄、有无腹水、临床分期、有无正规化疗是影响预后的因素.结论 年轻、早期、合并腹水的患者预后较好,术后正规化疗是改善预后的重要措施.     

Formulation and evaluation of oral microparticulate ovarian cancer vaccines

Ovarian cancer is the fifth most leading cause of cancer related deaths in women in the US. Customized immunotherapeutic strategies may serve as an alternative method to control the recurrence or progression of ovarian cancer and to avoid severe adverse effects of chemotherapy. In this study, a microparticulate vaccine using whole cell lysate of a murine ovarian cancer cell line, ID8 was prepared with the use of a spray dryer. These particles were designed for oral delivery using enteric polymers such as methacrylic copolymer, Eudragit^® FS30D and hydroxyl propyl methyl cellulose acetate succinate. These particles were targeted for uptake via microfold cell (M-cell) in Peyer's patches of small intestine using M-cell targeting ligand, Aleuria aurantia lectin. The interleukins (ILs) such as IL-2 and IL-12 were added to the vaccine formulation to further enhance the immune response. The particles obtained were of 1.58 ± 0.62 μm size with a charge of 12.48 ± 2.32 mV. The vaccine efficacy was evaluated by administering the particles via oral route to C57BL/6 female mice. At the end of vaccination, mice were challenged with live tumor cells. Vaccinated mice showed significant (around six-fold) retardation of tumor volume in comparison to non-vaccinated animals for 3 weeks after the tumor challenge (p < 0.001). The serum IgG antibody levels were found to be elevated in case of vaccinated animals in comparison to non-vaccinated group (p < 0.05). Analysis of IgG1 titers (indicative of Th2 response) and IgG2a titers (indicative of Th1 response) showed a mixed Th1 and Th2 immune response in case vaccine alone and Th2 response in case of vaccine with interleukins group. Moreover, CD8+ T-cell, CD4+ T-cell and B-cell populations in different lymphatic organs were elevated in case of vaccinated mice. Thus, whole cell lysate vaccine microparticles formulated by spray drying could trigger humoral as well as cellular immune response when administered orally. Such vaccine could potentially be an effective treatment for patients with residual tumor or high tumor-relapse probability.