基于survivin的"模拟病毒"瘤苗对结肠癌免疫治疗的作用

背景与目的：结肠癌的免疫治疗在肿瘤的综合治疗中发挥了重要作用。本研究以结肠癌的survivin为靶分子，构建基于survivin的“模拟病毒”瘤苗，并探讨该瘤苗对结肠癌的免疫治疗作用。方法：制备基于survivin的“模拟病毒”瘤苗，用扫描电镜和免疫印迹（Western blot）进行鉴定。酶联免疫斑点试验（Enzyme linked immunospot assay,ELISPOT）和标准^51Cr释放试验分别检测瘤苗所诱导的特异性CTL活性，并对Babl／c小鼠荷瘤模型进行免疫学效应评价。结果：扫描电镜和免疫印迹证实“模拟病毒”瘤苗制备成功，并能有效介导“模拟病毒”瘤苗所携带基因的表达。ELISPOT和标准^51Cr释放试验显示体内有效激发抗原特异性CTL效应，可诱导CTL产生IFN-γ等细胞因子，对结肠癌细胞系CT26有明显的杀伤毒性，杀伤率为56．4％；肿瘤治疗实验证实“模拟病毒”瘤苗能有效抑制肿瘤的生长速度，提高荷瘤动物的生存率，与对照组相比差异显著（P〈0．05）。结论：基于survivin的“模拟病毒”瘤苗能有效激发出特异性CTL应答，并在荷瘤动物模型中有效抑制结肠癌细胞CT26的生长，提高荷瘤动物的生存率，为新型结肠癌治疗性疫苗的设计提供了新思路。     

表达VEGFR-2的减毒鼠伤寒沙门氏菌疫苗诱导特异性抗胶质瘤血管免疫应答

背景与目的:血管内皮生长因子(vascular endothelialgrowth factor,VEGF)及其主要受体血管内皮生长因子受体-2(vascular endothelialgrowth factorreceptor-2,VEGFR-2)在肿瘤新生血管和肿瘤基质形成过程中起着重要作用。本研究的目的是观察表达鼠VEGFR-2的重组减毒沙门氏疫苗菌诱导的抗血管特异性免疫应答及抗胶质瘤作用。方法:构建真核表达载体pcDNA3.1-VEGFR2,通过电转化法将pcDNA3.1-VEGFR2导入减毒鼠伤寒沙门氏菌SL7207中,经由胃管饲予C57BL/6J小鼠,对小鼠进行基因免疫。采用ELISA法检测免疫小鼠血清中特异性抗VEGFR2-IgG抗体,分离免疫小鼠的脾细胞,分析重组疫苗菌免疫后小鼠体内的特异性细胞毒性T细胞(cytotoxic T lym phocyte,CTL)应答。用携带pcDNA3.1-VEGFR2的重组沙门氏菌免疫治疗胶质瘤荷瘤小鼠,通过测量荷瘤小鼠肿瘤大小,检测肿瘤微血管密度及肿瘤细胞凋亡,评价重组疫苗菌的抗血管及肿瘤生长抑制作用。结果:重组疫苗菌免疫后小鼠产生了高水平的抗VEGFR2-IgG抗体,诱导小鼠脾淋巴细胞产生针对VEGFR2的特异性CTL活性。重组疫苗菌的免疫能够明显抑制胶质瘤的生长。NaH CO3对照组、载体对照组、重组疫苗菌组的平均微血管密度分别为26.5±5.8、27.2±4.5、8.8±1.9,平均凋亡细胞数分别为4.41.2、3.     

含IL-15基因佐剂的肿瘤疫苗对肿瘤特异性细胞毒性T淋巴细胞功能的影响

目的:研究含有小鼠IL-15基因佐剂的肿瘤疫苗对肿瘤特异性细胞毒性T淋巴细胞(CTL)的功能影响。方法:构建含有小鼠IL-15基因佐剂的肿瘤疫苗,免疫小鼠后,分离脾脏淋巴细胞,分析CTL的表面分子,分泌细胞因子能力,细胞毒功能和抗凋亡能力。结果:含有小鼠IL-15基因佐剂的肿瘤疫苗能上调CTL的CD8和CD44分子表达,促进IFN-γ分泌,增强细胞毒功能,提高抗凋亡能力。结论:IL-15能发挥很好的佐剂效应,增强CTL的功能,有望在抗肿瘤研究中得到很好的应用。     

4-1BBL修饰小鼠结肠癌疫苗体外诱导抗肿瘤免疫反应的研究

背景与目的:研究4-1BBL(4-1BB Ligand,即CD137配体)转基因小鼠结肠癌细胞瘤苗体外诱导细胞毒性T淋巴细胞(Cytotoxic T lymphocytes,CTL)特异性杀伤活性及刺激淋巴细胞产生细胞因子的作用.材料与方法:采用脂质体介导法将真核表达质粒pMKITneo/4-1BBL导入小鼠结肠癌colon26细胞,经G418筛选后获得4-1BBL高表达克隆,用丝裂霉素C(MMC)处理后,制成肿瘤细胞瘤苗,与经体外诱导的同系小鼠CTL共同培养,测定对CTL特异性杀伤活性及对脾细胞产生细胞因子(IL-2、IL.-4和IFN-γ)的影响.结果:转染4-1BBL的colon26细胞高表达4-1BBL蛋白,将该细胞经MMC处理后制成的瘤苗,与野生型colon26细胞相比,对CTL特异性杀伤亲本肿瘤细胞的作用明显增强(P＜0.01),但CTL对非亲本肿瘤细胞的杀伤作用无明显影响(P＞0.05);该瘤苗在体外能显著增强脾细胞分泌细胞因子(IL-2、IL-4和IFN-γ)的能力(P＜0.01).结论:4-1BBL转基因小鼠结肠癌细胞瘤苗能有效诱导抗结肠癌免疫反应.     

fat-1基因对乳腺癌细胞的增殖抑制作用

目的: 以胃癌特异性多肽抗原MG7为靶点研制胃癌特异性纳米疫苗,并观察其对小鼠的免疫效能.方法: 人工合成胃癌MG7-Ag的模拟表位多肽,用磁力超声法将其包封于纳米乳剂中,通过透析纯化,HPLC检测其包封效率.用包封有MG7抗原肽的纳米疫苗免疫健康Balb/c小鼠,以空白纳米疫苗和PBS作为对照,测定其免疫活性,通过ELISA测定血清中抗MG7抗体的效价;ELISPOT测定小鼠脾CTL活性.同时,用表达MG7-Ag的小鼠艾氏腹水瘤细胞进行肿瘤攻击2周,观察疫苗对小鼠的保护作用.结果: 成功制备了胃癌MG7-Ag的纳米疫苗,并具有较好的包封率和较好的稳定性,小鼠产生MG7抗体, ELISPOT检测包封组与对照组相比分泌IFN-γ的活性淋巴细胞数量明显增高.疫苗免疫组8只小鼠中有2只未见肿瘤形成, 而对照组8只小鼠则全部成瘤.结论: 胃癌MG7-Ag表位纳米疫苗具有免疫原性,可以诱导小鼠产生抗肿瘤免疫.     

猪endoglin胞外段DNA疫苗诱导抗小鼠结肠癌免疫反应

背景与目的:研究表明,endoglin是肿瘤血管生成的标志性分子,用抗endoglin单克隆抗体被动免疫治疗可以有效抑制肿瘤生长,而异种DNA疫苗可以打破自身同源分子的免疫耐受。因此,本研究用猪endoglin胞外段真核表达质粒(ppEDG)作为异种DNA疫苗,了解该DNA疫苗是否具有抑制小鼠结肠癌生长的作用,并探讨其作用的免疫学机理。方法:观察免疫治疗后的荷瘤小鼠肿瘤体积和生存情况,用免疫组化方法(抗CD31)观察肿瘤组织血管生长并计算肿瘤微血管密度,用Westernblot和ELISA方法检测荷瘤小鼠免疫治疗后的血清是否含有抗自身endoglin的抗体以及抗体亚型,用ELISPOT方法检测荷瘤小鼠脾脏中分泌抗自身endoglin抗体的B淋巴细胞。结果:肿瘤接种18天后,ppEDGDNA疫苗主动免疫治疗组肿瘤体积明显小于空质粒(e-p)对照组及生理盐水对照组(P<0.05),存活时间明显延长(P<0.001)。ppEDG组、e-p组和生理盐水组肿瘤组织微血管密度计数分别为19.2±4.5、76.9±14.4和81.4±16.9(P<0.001)。治疗组小鼠血清中含有抗自身endoglin的抗体,抗体亚型主要为IgG1和IgG2b。三组小鼠分泌抗自身endoglin抗体的B淋巴细胞数分别为82.5±14.1、3.6±1.3和4.7±2.0(P<0.001)。结论:ppEDGDNA疫苗诱导抗自身endoglin抗体产生,从而抑制肿瘤血管生成和肿瘤生长。     

重组腺病毒介导γ-干扰素基因对小鼠结肠癌腹腔转移模型的实验治疗作用

背景与目的：肿瘤细胞靶向的细胞因子基因治疗是肿瘤治疗领域的研究热点。γ干扰素通过多种机制发挥抗肿瘤免疫的作用。本研究探讨利用γ-干扰素（IFN-γ）基因治疗对大肠癌的预防和治疗作用。方法：利用BALB／C小鼠成瘤的小鼠结肠癌CT26细胞株制备小鼠结肠癌腹腔转移瘤模型，用携带鼠IFN-γ基因的重组缺陷型腺病毒AdIFN-γ进行治疗，同时利用携带LacZ（β—galactosidase）基因的腺病毒AdLacZ和PBS（phosphate—buffered saline）作空白对照，检测经基因治疗后小鼠体内IFN-γ基因的表达情况、脾脏的细胞毒性T淋巴细胞（CTL）活性变化、肝转移的发生及荷瘤小鼠的生存期。结果：经IFN-γ基因治疗后，与对照组相比，治疗组小鼠血清中IFN-γ表达量明显增加（P〈0．01），脾脏的CTL活性明显增强（P〈0．05），肿瘤生长受到抑制，肝转移的发生率明显下降，荷瘤小鼠的存活期明显延长。结论：利用IFN-γ基因治疗大肠癌具有明显的疗效，并对其肝转移具有一定的预防作用。     

重组人热休克蛋白70-抗原肽复合物对肿瘤的免疫治疗作用研究

目的：使用以毕赤酵母X-33为宿主菌，重组表达制备的rhHSP70与合成的HER2／neu抗原肽体外结合形成复合物，探讨其在肿瘤免疫治疗中的有效性。方法：在ADP存在的条件下．将rhHSP70与纯化的HER2／ueu抗原肽体外非共价结合形成复合物，并分次免疫BALB／c小鼠，通过ELISPOT和颗粒酶释放法，检测该复合物诱导特异性CTL的能力通过检测小鼠体内肿瘤的生长情况和肿瘤的组织切片，来观测该复合物对小鼠乳腺癌的免疫治疗作用结果：rhHSP70-HER2／neu抗原肽复合物免疫小鼠后，可以增加T细胞分泌IFN-γ的能力，诱导出肿瘤特异性CTL，并对小鼠的乳腺癌有明显的治疗作用结论：在毕赤酵母中重组表达的rhHSP70可以在体外与一定的抗原肽非共价结合形成复合物，该复合物具有较强的诱导特异性CTL的能力，可对实验鼠的乳腺癌起到明显的治疗作用。     

IFN-γ转基因治疗与重组IFN-γ注射对肝转移癌小鼠的治疗作用

转基因表达的IFN-γ可提高肿瘤细胞表面抗原的表达和激发宿主抗肿瘤免疫应答反应,这在肿瘤的基因免疫治疗中已得到人们的重视,但是对结肠癌肝转移模型的治疗作用鲜见报道.为了探讨转基因表达的IFN-γ和外源重组IFN-γ对结肠癌肝转移模型的作用,我们利用阳离子脂质体Lipofectamine将含huIFN-γ全长基因的真核表达质粒pcDNA3-huIFN-γ转染到小鼠结肠癌等细胞内,通过表达出的huIFN-γ发挥治疗作用并与外源重组的huIFN-γ作用进行比较.     

携带flk1的重组减毒沙门氏菌的构建及其抗肿瘤血管生成的研究

目的:观察携带鼠血管内皮生长因子受体-2(vascular endothelial growth factor receptor-2,flk1)的重组减毒鼠伤寒沙门氏菌诱导的flk1特异性免疫应答及抗肿瘤血管生成作用.方法:构建真核表达载体pcDNA3.1-flk1,并将其转化到减毒鼠伤寒沙门氏菌SL7207中,体外感染小鼠巨噬细胞,用Western印迹对表达产物进行鉴定,将重组菌口服免疫小鼠,分析免疫后小鼠体内的特异性CTL应答.采用藻酸盐微囊实验观察其对体内肿瘤血管生成的影响.结果:免疫印迹试验表明携带pcD-NA3.1-flk1表达载体的重组菌感染的小鼠巨噬细胞能表达flk1蛋白,免疫小鼠脾淋巴细胞产生针对flk1的特异性CTL活性.重组疫苗菌的免疫能够明显抑制小鼠体内肿瘤血管的形成.结论:携带flk1的重组减毒沙门氏菌经口服免疫,诱导小鼠产生抗flk1的特异性免疫反应,且能明显产生抗肿瘤血管生成作用.     

The medically important dematiaceous fungi and their identification

Dematiaceous fungi include a large group of organisms that are darkly pigmented (dark brown, olivaceous, or black). In most cases the pigment is melanin, and specifically, dihydroxynaphthalene melanin. The diseases produced include chromoblastomycosis, eumycotic mycetoma, and phaeohyphomycosis. Phaeohyphomycosis is a new classification for a diverse group of previously known entities grouped together on the basis of finding dematiaceous hyphal and/or yeast-like forms in tissue; tissue involvement may be superficial, cutaneous and corneal, subcutaneous, or systemic. Identification of these fungi is based mostly upon morphology. Important structures include annellides (Phaeoannellomyces, Exophiala), phialides (Phialophora, Wangiella), adelophialides (Phialemonium without collarettes, Lecythophora with collarettes), differentiation of conidiophores (Xylohypha versus Cladosporium) and conidial hilum, septation and germination (Bipolaris, Drechslera, Exserohilum). Useful laboratory tests include the 12% gelatin test (controversial), nitrate assimilation (W. dermatitidis is negative, most other species are positive), and determination of temperature maxima (especially 37 degrees C for E. jeanselmei, 40 degrees C for W. dermatitidis and B. spicifera, 42 degrees C for X. bantiana, and 45 degrees C for Dactylaria constricta var. gallopava and Scedosporium inflatum).     

Laboratory Techniques Alternative to In Vivo Experiments for Studying the Liberation, Penetration and Fungicidal Action of Topical Antimycotic Agents in the Skin, Including Ciclopiroxolamine

Summary: Short-term experiments on excised skin (human, pig) gave the following results: 1. In the tissue activity test with direct inoculation (D-TAT) commercial preparations of the non-azole antimycotics ciclopiroxolamine, tolnaftate and naftifine, produced higher inhibitory activity against Trichophyton mentagrophytes (standard strain) in various levels of the horny layer than were produced by the azole antimycotics econazole, miconazole, clotrimazole, oxiconazole and bifonazole. Fast drying solutions of antimycotics invariably gave higher inhibitory activities than creams. In the ultrafiltration tissue activity test (UFT- TAT) against Candida albicans (2 strains), antimycotic agents ranked in order of effectiveness as follows: ciclopiroxolamine – most of the azole antimycotics – bifonazole and naftifine. 2. In tests of fungicidal activity against T. mentagrophytes (2 strains) and Microsporum gypseum (1 strain) the first step was to inoculate the skin surface. After the horny layer had been penetrated by fungal mycelia, antimycotic agents of documented fungicidal potency, chiefly in the form of creams, were applied to the skin surface and left to act for up to 18 hours. The horny layer and epidermis were then scraped off and the concentration of viable fungi was determined. Ciclopiroxolamine cream and lotion produced by far the greatest diminution in viable fungi; creams containing oxiconazole and naftifine were moderately effective and those containing tioconazole and bifonazole produced a relatively small decrease in viable fungi. To avoid erroneous results it is important to homogenize and dilute the skin scrapings; if this is not done certain antimycotics will give misleadingly high fungal killing rates. At this early stage the scatter of results is still wide and minor differences in efficacy cannot as yet be detected with certainty. 3. From the results of various comparative tests it is evident that pig skin can be used as a substitute for human skin in the tests listed under 1. and 2. above. This discovery may make a valuable contribution towards limiting the need for experiments on living animals and trials on human beings. Zusammenfassung: In Kurzzeitversuchen an exzidierter Haut (Mensch, Schwein) wurde gefunden: 1. Im Gewebeaktivitätstest mit direkter Inokulation (D-GAT) wurde mit Handelspräparaten der Nichtazol-Antimykotika Ciclopiroxolamin, Tolnaftat und Naftifin in verschiedenen Hornschichtniveaus eine höhere Hemmaktivität gegenüber Trichophyton mentagrophytes (Standard-Stamm) erzielt als mit solchen der Azol-Antimykotika Econazol, Miconazol, Clotrimazol, Oxiconazol und Bifonazol. Rasch trocknende Lösungen von Antimykotika ergaben durchweg höhere Hemmaktivitäten als Cremes. Im Ultrafiltrations-Gewebeaktivitätstest (UFT-GAT) gegenüber Candida albicans (2 Stämme) ergab sich nach erzielter Wirksamkeit die Rangfolge Ciclopiroxolamine – Mehrzahl der Azolantimykotika – Bifonazol und Naftifin. 2. In Fungizidie-Testen gegenüber T. mentagrophytes (2 Stämme) und Microsporum gypseum (1 Stamm) wurde zunächst die Hautoberfläche inokuliert. Nach Durchdringung der Hornschicht mit Pilzmyzelien wirkten auf die Hautoberfläche bis zu 18 Stunden lang überwiegend Cremes von als fungizid publizierten Antimykotika ein. Während sich in abgeschabter Hornschicht und Epidermis der so bearbeiteten Hautoberflächen mit Ciclopiroxolamin-Creme und -Lotion die weitaus höchste Verminderung lebensfähiger Keime ergab, bewirkten Cremes mit Oxiconazol und Naftifin eine mittlere und solche mit Tioconazol und Bifonazol eine relativ niedrige Keimeliminierung. Zur Vermeidung von fehlerhaften Ergebuissen mußten Homogenisierung und Verdünnung der Hautschabsel erfolgen, anderenfalls bei mehreren Antimykotika eine zu hohe Keimabtötung vorgetäuscht worden wäre. Wegen der vorerst noch hohen Streuung der Ergebnisse können kleinere Wirksamkeitsunterschiede noch nicht sicher erfaßt werden. 3. Nach dem Ergebnis verschiedener Vergleichstests kann in den Testen zu 1. und 2. Schweinehaut als Ersatz für Haut vom Menschen dienen und dürfte damit wesentlich zur Einschränkung von Versuchen am lebenden Tier und von Prüfungen am Menschen beitragen.     

Efficiency of crude and purified fungal antigens in serodiagnosis to discriminate mycotic from other respiratory diseases

Mycotic immunodiagnosis was performed in 186 hospitalized patients with different respiratory diseases, mostly considered as tuberculosis and others with a doubtful diagnosis. Crude histoplasmin, coccidioidin, paracoccidioidin, blastomycin, candidin, aspergillin, and sporotrichin, as well as purified polysaccharide-protein complexes (PPC) of Histoplasma capsulatum, Coccidioides immitis, and Paracoccidioides brasiliensis were used as antigens. Immune tests used included skin test (ST), gel immunodiffusion (ID), counterimmunoelectrophoresis (CIE), complement fixation (CF), and ELISA. A possible association with candidosis was observed in 17% of patients with tuberculosis and diabetes; one presumptive paracoccidioidomycosis, one confirmed aspergillosis, and six cases of active histoplasmosis were determined. Candidin ST showed 29% of positive reactions with an increased frequency in patients between 31 and 55 years of age. CF test showed the highest positivity percentages with crude antigens, specially for Candida antigen (26.3%) and histoplasmin (18.2%). Cross reactions were evident with crude antigens but decreased when PPC's were used in ELISA.     

Isoconazole nitrate in the treatment of tropical dermatomycoses

Summary. A total of 54 patients with culturally proven tropical dermatomycoses, comprising 23 with various types of dermatophytoses, one with foot infection due to Trichosporon beigelii and one with foot infection due to Geotrichum candidum , two with candidoses of the groin and 27 with pityriasis versicolor, were included in a clinical trial of efficacy of 1% isoconazole cream (Travogen^R, Schering, Berlin, Germany). Five patients were not evaluable. A clinical and mycological cure was achieved in 29 cases in 3–4 weeks. In 15 (31%) of the remaining patients treatment was required for 5–6 weeks, while another three patients required treatment for 8 weeks. In two patients the disease proved to be resistant to treatment with the drug.
Zusammenfassung. Insgesamt 54 Patienten mit kulturell gesicherter Dermatomykose, (23 unterschiedliche Dermatophytosen, eine Trichosporon beigelii - und eine Geotrichum candidum -Fußinfektion, 2 Candidosen der Leistengegend und 27 Pityriasis versicolor) wurden in einer klinischen Wirksamkeits-studie mit 1% iger Isoconazol-Creme (Travogen^R, Schering, Berlin, Deutschland) behandelt. Fünf Patienten waren nicht auswertbar. Eine klinische und mykologische Heilung wurde bei 47 von 49 Patienten (96%) erreicht. Bei 29 patienten (59%) wurde die Heilung bereits nach 3–4 Wochen Behandlung erreicht. Weitere 15 Patienten (31%) benötigten 5–6 Wochen und drei Patienten 8 Wochen Behandlungsdauer. Zwei Mykosesituationen erwiesen sich als therapieresistent.     

Orale Langzeitbehandlung von Onychomykosen mit Ketoconazol

Zusammenfassung: An der Studie zur Wirksamkeit und Anwendungssicherheit von Ketoconazol nahmen 27 Männer im Alter von 20 bis 80 (Median: 57) Jahre, davon 18 mit Onychomykosen und 9 als KontroUen bei den Laborwertbestimmungen, teil. Während des ersten Behandlungsmonats erhielten je 9 Patienten 200 mg und 400 mg Ketoconazol täglich. Danach wurden beide Gruppen 6 Monate mit 200 mg/d weiterbehandelt. Die klinische Beurteilung sowie hämatologische, biochemische und Plasmaspiegeluntersu-chungen erfolgten mindestens monafich, mykologische Untersuchungen wurden vor Aufnahme und bei Beendigung der Therapie vorgenommen. Erne letzte klinische Unter-suchung erfolgte 1 Jahr nach Beginn der Studie. Nach 7 Monaten Behandlung wurden 23 von 30 Nägeln mit “gebessert” bis “stark gebessert” beurteilt, nach dem behandlungsfreien Intervall galt dies für 28 von 30 Nägeln. Die Plasmaspiegel waren mit 200 mg/d ausreichend und uber den Behandlungszeit-raum konstant. Dies spricht für gute orale Resorption und Abwesenheit von Enzyminduktion. Die Laborwerte zeigten im Vergleich zu den Kontrollen und den Werten vor Behandlung keine signifikanten Abweichungen, so daß myelo-, nephro- und hepatotoxische Wirkungen von 400 bzw. 200 mg/d ausgeschlossen werden können. Der Lipidhaushalt wurde nicht beeinfluat und es trat unter Therapie als Folge der Ketoconazolwirkung lediglich Lanosterin im Serum auf. Nach Beendigung der Therapie ging der Lanosteringehalt schnell zurück. Damit erweist sich Ketoconazol in den angewandten Dosen als ein gut verträgliches und zur Langzeitbehandlung von Onychomykosen geeignetes Antimykotikum. Summary: Twenty-seven males with a median age of 57 (range: 20 to 80) years took part in this study on the efficacy and safety of ketoconazole. Eighteen men suffered from onychomycosis; nine served as controls in the safety evaluation. During the first month of treatment, nine patients received 200 mg and the nine other 400 mg ketoconazole daily. Then the treatment was uniformly continued with 200 mg/d for 6 months. Clinical evaluation and haematological, biochemical and plasma level investigations were carried out at least at monthly intervals; mycological controls were performed at the start and end of therapy. A final clinical evaluation was carried out one year after the start of the study. After 7 months of treatment, moderate or definite clinical improvement was obtained in 23 out of 30 nails. After 5 more months without antimycotic treatment this was the case in 28 of 30 nails. Plasma levels obtained with 200 mg ketoconazole daily were adequate and constant during the entire treatment period. This indicates a good oral resorption as well as the absence of induction of hepatic enzymes. The laboratory values did not show significant deviations as compared with the controls or with the pretreatment values. This excludes myelo-, nephro- and hepatotoxic effects of 400 and 200 mg ketoconazole daily. The lipid metabolism was not influenced, the only difference was the occurrence of lanosterol in the serum, which is a result of the mechanism of action of ketoconazole. After the medication period the lanosterol levels subsided rapidly. In the applied doses ketoconazole is a well-tolerated and effective drug for the systemic long-term treatment of onychomycosis.     

Large-scale molecular characterization and analysis of gastric cancer

The recent effort by The Cancer Genome Atlas （TCGA） Network has revealed that gastric cancer, which is a leading cause of cancerrelated deaths worldwide with a 5-year survival rate less than 25%, is a much more heterogeneous disease than previously thought. And yet, conventional treatment approaches and clinical trials have assumed it is a single disease. Although it is well known that under the microscope, gastric cancer cells appear quite different, the current classification scheme recognizes two main categories of gastric cancer： diffuse and intestinal.     

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma''s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.     

Endometrial cancers and predisposition

As nearly 5% of all endometrial cancers occur because of a predisposition, this possibility has systematically to be explored. The hallmarks of predisposition, a young age at diagnosis, a personal or a familial history of cancer, have to be searched systematically. The identification of a predisposition in a family has a major impact on the management of the proband or his relatives. The endometrial cancer main predisposition is Lynch's syndrome. In this review, we will focus on this condition and describe its clinical manifestations, the underlying molecular mechanisms, the cancer risks and the management guidelines. We will also get onto some far less frequent other predispositions.