题名的的撰写规范

题名应简明、具体、确切,能概括论文的特定内容,有助于选定关键词,符合编制题录、索引和检索的有关原则。题名应该避免使用公式和不常见的缩略词、字符、代号等。必要时,可使用本行业通用缩写词。题名一般不宜超过20字。若题名语意未尽,可以用副题名补充说明论文中的特定内容。避免使用陈述句,因为题名主要起标示作用,而陈述句容易使题名具有判断式的语义,且不够精炼和醒目。少数情况（评述性、综述性和驳斥性）下可以用疑问句做题名,因为疑问句有探讨性语气,易引起读者兴趣。同一篇论文的英文题名与中文题名内容上应一致,尽量减少冠词的使用。     

药物的诱变作用和它的DNA的圆二色谱的影响

一个药物若与DNA反应则往往有诱变作用。因此分析药物与DNA的关系是一个重要的课题。已有多种方法,从不同的角度分析药物与DNA之间的相互作用,其中园二色谱(circular dichroism,CD)是一种可靠、灵敏、简便的方法。DNA分子有它特有的CD谱,若药物分子嵌入DNA分子或与之形成复合物,这将改变DNA的构型而导致CD谱的变化。我们试图探索药物的诱变作用和它对DNA的CD谱影响之间的关系。小     

多拉的梦：谁的声音——斯垂彻的、弗洛依德的或多拉的?

通过梦发掘潜意识为弗洛依德的重大贡献,他首次从科学的角度对梦进行了系统性的研究。弗洛依德在1900年出版的《梦的解析》(Die Traumdeutung)一书至今仍是许多心理学家教学和临床运用的范本。分析梦是我们考察潜意识的绝佳途径,它已经成为精神分析的基本技术之一。本文不仅详细地描述了如何分     

癌的光化学疗法的进展

1924年,有人发现血卟啉在动物及人的恶性肿瘤中聚集,并在光照后发生特异萤光。1960年Lipson研制成血卟啉衍生物(HPD)。1973年起Dougherty和早田义博等进行了大量基础理论研究工作。随着激光医学、光导纤维和纤维内窥镜的发展,已有效地应用于临床。     

肺癌的抗体治疗的研究进展

肺癌的传统疗法效果不够理想，用抗体治疗肺癌是一较为有效的方法。目前主要有5类抗体用于治疗肺癌：（1）西妥昔单抗(Cetuximab)、ABXEGF(Panitumumab)、Matuzumab（EMD72000）和曲妥珠单抗(Herceptin)等，这类抗体通过结合肿瘤细胞表面分子抑制细胞生长，具有较好的疗效，     

原发灶不明的黑色素瘤的治疗

本文报告1045例黑色素瘤中的64例原发灶不明的黑色素瘤的治疗与疗效。全组病例中,男性39例(59％),女性25例(38％),年龄2～73岁,平均44.5岁(中位年龄42.7岁)。34例仅有单部位的侵犯,其中位于腋窝区者10例(29％),位于腹股沟区者8例(23％),位于颈部者11例(32％),位于皮下组织者4例(12％),位于其他部位者1例(3％)。单部位侵犯限于一个淋巴结区者(腋窝、腹股沟、颈部)共计29例。另外30例有2个或2个以上部位的侵犯。     

温暖的陪伴 隽永的告别

1950年阿姨出生在安徽省一个山明水秀的小山村,她家有4个孩子,她排行老三,上有大她20岁的哥哥和大她18岁的姐姐,下有小她3岁的弟弟,父母的疼爱和哥哥姐姐的呵护使阿姨的童年无忧而快乐。     

特异的主动免疫疗法的新途径

肿瘤免疫学的主要目标是对肿瘤患者进行免疫接触,以对抗他自身的肿瘤。免疫疗法的途径是试图通过刺激免疫反应机构,增加患者对自身肿瘤的抵抗,以战胜恶性肿瘤。本文作者介绍了具有特异性的自动免疫刺激物,即病毒-溶瘤疫苗。     

Usefulness of immunomodulators for maturation of dendritic cells

Biological response modifiers (BRMs) augment the cytotoxic activity of various effector cells by the induction of multiple cytokines and suppression of immunosuppressive factors. BRMs are used extensively in adjuvant therapy for gastric cancer in Japan. In dendritic cell (DC)-based vaccine therapy, the quality of DCs is important in inducing strong antitumor immunity. A good manufacturing practice (GMP) grade agent for DCs maturation is desirable for safety. Here we report the effects of two BRMs, OK432 and PSK, which are GMP grade agents for the functional maturation of DCs. OK432 and PSK were examined in vitro, and compared with lipopolysaccharide (LPS) and a cytokine cocktail (IL-1beta, TNF-alpha, IL-6 and PGE2). In the immunophenotypical analysis, the expression of CD80 and CD83 of DCs stimulated with OK-432 increased significantly compared with PSK and medium, and this up-regulation was the same as levels of DCs stimulated with cytokine cocktail. DCs stimulated with OK-432 showed significantly higher production of IL-12 and Th1-type cytokines (IL-2 and IFN-gamma) compared with DCs stimulated with LPS or cytokine cocktail. OK-432 stimulated DCs could induce the significantly high level of cytotoxic T cell activity compared with PSK-stimulated or unstimulated DCs. These results suggest that OK432 is a GMP-grade reagent that promotes functional maturation of DCs and could be applied in DC-based vaccinations.     

Streptococcal preparation OK-432 promotes the capacity of dendritic cells (DCs) to prime carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte responses induced with genetically modified DCs that express CEA

Cancer immunotherapy using dendritic cells (DCs) adenovirally transduced with the whole tumor-associated antigen (TAA) gene is an effective approach. Streptococcal preparation OK-432 is useful for stimulating DCs in terms of maturation. In this study, we established carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes (CTLs) using in vitro stimulation with adenovirally modified human DCs that express CEA. We investigated whether OK-432 stimulation could be more effective in inducing CEA-specific CTLs compared with other typical stimuli. DCs adenovirally transduced with the CEA gene were cultured under various conditions with tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), or OK-432. A cytotoxicity assay using peripheral blood mononuclear cell (PBMC)-derived CTLs was performed in a 4 h-51Cr release assay. OK-432 stimulated immature DCs to acquire a mature phenotype and to produce significant amounts of T-helper 1 cytokines. In all groups (immature DCs, TNF-alpha/DCs, LPS/DCs, OK-432/DCs), CEA-specific CTLs were generated. OK-432-stimulated DCs (HLA-A24) induced the most potent cytotoxic activity against CEA-expressing targets (A24) but not against controls. OK-432/DCs were able to induce markedly potent CTLs specific to target cells pulsed with CEA652 peptide (HLA-A24-restricted peptide), although others failed to induce potent CTLs. In conclusion, the CTL induction protocol using adenovirally modified DCs that express CEA after maturation with OK-432 showed a potent antitumor activity against CEA-expressing target cells, and is therefore promising for clinical applications as a cancer vaccine therapy.     

Generation of mature dendritic cells fully capable of T helper type 1 polarization using OK-432 combined with prostaglandin E(2)

Dendritic cell (DC) administration appears to be a very promising approach for the immunotherapy of cancer. The results of clinical studies have suggested that the nature and the magnitude of antitumor immune responses are critically affected by DC functions, including production of T helper type 1 (Th1)-inducing cytokines, activation of T cell subsets and natural killer (NK) cells, and migration from peripheral tissues to the T cell area of the draining lymph nodes. Administration of immature DCs could fail to fully stimulate antigen-specific immune responses and might induce tolerance under some conditions. In this study, we developed a method to obtain fully mature DCs, and we compared in detail the DCs thus obtained with those obtained using a maturation stimulus termed monocyte-derived medium (MCM)-mimic, which is a mixture of recombinant cytokines and prostaglandin E₂ (PGE₂) mimicking the components of monocyte-conditioned medium. Using DCs derived from monocytes of advanced cancer patients in this study, we found that DCs stimulated with OK-432 alone showed phenotypes similar to those of mature DCs induced using MCM-mimic, though with better secretion of IL-6 and IL-12. However, these DCs were found to have poor migratory capacity associated with the marginal expression of CCR7. When OK-432 was combined with PGE₂, the CCR7 expression and migratory capacity of DCs were significantly improved without impairing other immuno-stimulatory functions. These results suggest that stimulation with the combination of OK-432 and PGE₂ could be applicable as an alternative to MCM-mimic in clinical trials which require fully matured DCs to induce Th1-type immune responses against tumor cells even in patients with advanced cancer.     

Oral administration of OK-432 (picibanil). (8th report) clinical application: its immunomodulatory effects on the patients with gastrointestinal cancers

A streptococcal preparation, OK-432 at a dose of 5 KE was orally administered to the patients with gastric or colorectal cancer for 7 approximately 14 days before operation, and its immunomodulatory effects on peripheral blood lymphocytes (PBL), regional lymph node lymphocytes (RLNL) and tumor infiltrating lymphocytes (TIL) were assessed. OK-432 treated group included 5 gastric and 6 colorectal cancers, and control group included 6 gastric and 8 colorectal cancers. After oral administration of OK-432 the proportion of Leu 7+ and Leu 11+ cells in PBL increased, and NK cell activity of PBL also was augmented. The proportion of OKT8+ cells increased in PBL and those of OKT3+ cells and OKT8+ cells decreased in RLNL after oral administration of OK-432. The responsiveness of TIL to autologous tumor extracts in the presence of interleukin-2 was enhanced in oral OK-432 group. These results indicate that oral OK-432 affects on NK and T cells and augments the antitumor immunity of the patients with gastrointestinal cancer.     

Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation

A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-gamma and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4(-/-)) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4(-/-) mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4(-/-) mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.     

A double blind study to evaluate the optimal dose and its frequency for oral administration of OK-432 (picibanil) by immunological parameters (the 2nd report)

The present study was designed to determine the optimal dose and frequency of oral administration of a biological response modifier, OK-432 (Picibanil), which has been used for cancer immunotherapy by injection. Ninety one stomach cancer patients were randomly assigned into 7 groups and were administered a placebo or OK-432 at a dose of 5, 20 or 40KE, once or 3 times a week before operation (5KE X 1/W, 20KE X 1/W, 40KE X 1/W, or X 3/W). Misregistration excluded 3 patients and the data of 88 patients were analysed. There was no significant difference in the background status of the patients in each group. In the 1st report, we already showed that 5KE X 3/W might be the optimal regimen to augment the natural killer (NK) activity of regional lymph node lymphocyte (RNL). In the 2nd report, we searched for the optimal regimen to augment the antitumor immunity of T lymphocytes. The proliferative response of RNL to SuPR (protein derived from OK-432) was augmented in all the groups administered OK-432. The responsiveness of PBL to autologous tumor extract enhanced by IL-2 was augmented by 5KE X 1/W, and that of RNL was augmented by 5KE X 3/W. The killer/suppressor (Leu2+15-/Leu2+15+) ratio in RNL increased in all the groups administered OK-432 especially in 20KE X 3/W group. Oral administration of OK-432 augmented both non-specific and the specific antitumor immunity of PBL as well as RNL, and 5KE X 3/W may be the optimal regimen to augment the antitumor immunity, especially of RNL.     

Hyperthermia improves cellular immune response to human hepatocellular carcinoma subsequent to co-culture with tumor lysate pulsed dendritic cells

Dendritic cells play a major role in cellular immunity. The crucial steps of antigen presentation and processing by DCs may be limiting factors for adoptive cellular immunotherapy. Here, we investigated whether hyperthermia of human hepatocellular carcinoma (HCC) cells induces enhanced cytotoxic cellular immune response. Peripheral blood mononuclear cell (PBMC)-derived DCs were pulsed with tumor cell lysate of the human HCC cell line HepG2, which had been heat shocked prior to incubation for 5 h. Subsequent to TNFalpha-induced maturation DCs were co-cultured with autologous CD4+ and/or CD8+ cells, and T cell mediated cytolysis of HepG2 cells was assessed. We observed enhanced CD4+/8+ cellular cytotoxicity against HepG2 cells subsequent to co-culture with the heat shocked tumor lysate pulsed DCs as compared to pulsing DCs with lysate of non-heat shocked tumor cells. The improved cellular immune response can be related to enhanced expression of HSP 70 and 90 in HepG2 cells upon hyperthermia.     

Dendritic cells stimulated with a bacterial product,OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide

Dendritic cells (DCs) are potent antigen-presenting cells, which have recently been applied for cancer immunotherapy using epitope peptides. Accumulating results of the clinical trials of such a strategy suggest that maturity of the applied DCs has a significant impact on the outcome of the vaccination. Here we examined the effects of penicillin-killed Streptococcus pyogenes (OK-432) on DC maturation and functions including induction of CTLs. DCs generated from peripheral blood using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 showed immunophenotypes consistent with immature DCs (iDCs). These iDCs were further incubated with medium alone, tumor necrosis factor alpha, lipopolysaccharide, or OK-432. The immunophenotypical analysis showed DCs stimulated with OK-432 (OK-DCs) possessed significantly higher expression of CD83 compared with unstimulated DCs. Furthermore, OK-DCs showed significantly higher production of IL-12 and IFN-gamma compared with DCs with other stimulations. These results indicate that OK-432 stimulates iDCs to have a mature phenotype and to produce a significant amount of T-helper 1-type cytokines. To examine the potency of OK-DCs on the induction of specific CTLs, the tumor rejection peptide derived from carcinoembryonic antigen was used as a model antigen. The HLA-tetramer assay showed that potent CTL was induced with OK-DCs at high frequency. These results indicate that OK-432 efficiently stimulates DCs without interfering with the presentation of pulsed peptide. Furthermore, OK-432 does not activate nuclear factor kappaB through Toll-like receptor 2 or Toll-like receptor 4 in the indicator cell system; however, it induces IL-12 production through the beta(2) integrin system on DCs. These results strongly suggest that OK-432 could be applied to develop an efficient cancer vaccine using DCs pulsed with tumor rejection peptides.     

Analysis of the immuno-activation mechanism of OK-432--phagocytosis, release of active components and TLR4 signaling

Although we have reported that Toll-like receptor (TLR) 4 is involved in OK-432-induced anti-cancer immunity, its detailed mechanism remained uncertain. We hypothesized that OK-432 may first be captured, dissolved by phagocytes, and then active components released from the cells may stimulate TLR4. This hypothesis was examined by the current in vitro experiments. We used TS-2 MoAb which recognizes OK-PSA, an active component of OK-432. First, we observed that OK-432-induced cytokine production by dendritic cells (DCs) and macrophages was significantly inhibited by cytochalasin B, a phagocytosis inhibitor. Immunofluorescence staining by using TS-2 clearly demonstrated that OK-432 was captured and dissolved by these cells. OK-PSA was detected in the supernatants derived from OK-432-treated DC culture by ELISA with TS-2. The supernatants from OK-432-treated DC culture, but not from untreated DC culture, increased NF-kappaB activity in TLR4-expressing cells. The increased NF-kappaB activity was inhibited by TS-2. These findings elucidated the mechanism mediated by phagocytosis and TLR4 signaling in the OK-432 action.