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Liver damage using suicide genes - A model for oval cell activation

AMERICAN JOURNAL OF PATHOLOGY 2000年第2期157卷 549-559页

作者： Bustos, M Sangro, B Alzuguren, P Gil, AG Ruiz, J Beraza, N Qian, C Garcia-Pardo, A Prieto, J Univ Navarra Sch Med Div Hepatol E-31080 Pamplona Spain Univ Navarra Clin Div Hepatol & Gene Therapy Pamplona Spain CSIC Ctr Invest Biol Madrid Spain

Liver regeneration from the facultative hepatic stem cells, the oval cells, takes place in situations in which liver regeneration from pre-existing hepatocytes is prevented. Different models have been used to stimulate oval cell response. Many of them involve the use of carcinogenic agents with or without partial hepatectomy, In this study we show that adenovirus-mediated gene transfer of the suicide gene thymidine kinase followed by ganciclovir administration caused hepatotoxicity of variable intensity. Rats with moderate elevation in serum transaminases recovered normal liver architecture few weeks after adenovirus injection. In contrast, rats with severe liver damage exhibited a marked and persisting activation of oval cells accompanied by ductular hyperplasia, In some rats, such lesion eventually evolved to cholangiofibrosis and in one rat to cholangiocarcinoma, Deposition of fibronectin and increased number of hepatic stellate cells were found in association with oval cells and cholangiofibrotic lesions. Hepatocyte growth factor was hyperexpressed in the livers with intense oval cell response or ductular proliferation, suggesting a participation of this factor in those lesions. In summary, our data demonstrate activation of oval cell response after gene transfer of thymidine kinase followed by ganciclovir administration. These findings indicate that high doses of this therapy causes liver damage together with an impairment in hepatocellular regeneration.

关键词：腺病毒科/遗传学抗病毒药/药理学细胞分裂疾病模型动物更昔洛韦/药理学遗传载体/投药和剂量遗传载体/遗传学肝细胞生长因子/遗传学肝细胞生长因子/生理学原位杂交肝/药物作用肝/代谢肝/病理学肝疾病/遗传学肝疾病/病理学肝疾病/治疗大鼠 Wistar 胸苷激酶/遗传学动物男(雄)性大鼠

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An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy

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NATURE MEDICINE 2000年第10期6卷 1134-1139页

作者： Heise, C Hermiston, T Johnson, L Brooks, G Sampson-Johannes, A Williams, A Hawkins, L Kirn, D Hammersmith Hosp Imperial Coll Sch Med Imperial Canc Res Fund Viral & Genet Therapy Programme London W12 0HS England Onyx Pharmaceut Richmond CA USA Berlex Biosci Richmond CA USA Chiron Corp Emeryville CA 94608 USA

Replication-selective oncolytic viruses constitute a rapidly evolving and new treatment platform for cancer. Gene-deleted viruses have been engineered for tumor selectivity, but these gene deletions also reduce the anti-cancer potency of the viruses. We have identified an E1A mutant adenovirus, dl922-947, that replicates in and lyses a broad range of cancer cells with abnormalities in cell-cycle checkpoints. This mutant demonstrated reduced S-phase induction and replication in non-proliferating normal cells, and superior in vivo potency relative to other gene-deleted adenoviruses. In some cancers, its potency was superior to even wild-type adenovirus. Intravenous administration reduced the incidence of metastases in a breast tumor xenograft model. dl922-947 holds promise as a potent, replication-selective virus for the local and systemic treatment of cancer.

关键词：腺病毒科/遗传学腺病毒E1A蛋白质类/遗传学抗肿瘤药/投药和剂量抗肿瘤药/药理学药物筛选试验抗肿瘤遗传载体/投药和剂量遗传载体/药理学注射病灶内注射静脉内小鼠裸肿瘤转移/药物疗法肿瘤/药物疗法肿瘤细胞培养的异种移植模型抗肿瘤试验动物女(雌)性人类小鼠

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Optimization of folate-conjugated liposomal vectors for folate receptor-mediated gene therapy

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第11期88卷 1112-1118页

作者： Reddy, JA Dean, D Kennedy, MD Low, PS Purdue Univ Dept Chem W Lafayette IN 47907 USA Univ S Alabama Coll Med Dept Microbiol & Immunol Mobile AL 36688 USA

A folate-targeted transfection complex that is internalized by certain cancer cells and displays several properties reminiscent of enveloped viruses has been developed. These liposomal vectors are comprised of a polycation-condensed DNA plasmid associated with a mixture of neutral and anionic lipids supplemented with folate-poly(ethylene glycol)-dioleylphosphatidylethanolamine for tumor cell-specific targeting. N-Citraconyl-dioleylphosphatidylethanolamine is also included for pH-dependent release of endosome-entrapped DNA into the cytoplasm, and a novel plasmid containing a 366-bp segment from SV40 DNA has been employed to facilitate transport of the plasmid into the nucleus. Because formation of the DNA core is an important step in the assembly of liposomal vectors, considerable effort was devoted to comparing the transfection efficiencies of various DNA condensing agents. It was found that complexation of plasmid DNA with high molecular weight polymers such as acylated-polylysine and cationic dendrimers leads to higher folate-mediated transfection efficiency than DNA complexed with unmodified polylysine. In contrast, compaction of plasmid DNA with small cationic molecules such as spermine, spermidine, or gramicidin S yields only weakly active folate-targeted liposomal vectors. Compared to analogous liposomal vector preparations lacking an optimally compacted DNA core, a cell-specific targeting ligand, a caged fusogenic lipid, and a nucleotide sequence that facilitates nuclear uptake, these modified liposomal vectors display greatly improved transfection efficiencies and target cell specificity.

关键词：阴离子/化学载体蛋白质类/生理学 DNA/投药和剂量 DNA/化学 DNA/遗传学叶酸盐受体 GPI锚连叶酸/投药和剂量叶酸/化学叶酸/代谢遗传载体/投药和剂量遗传载体/化学合成遗传载体/化学 KB细胞脂质体/化学合成脂质体/化学磷脂酰乙醇胺类/化学质粒/投药和剂量质粒/化学质粒/遗传学聚胺类/化学聚赖氨酸/化学受体细胞表面转染/方法人类

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Maintenance of CD8⁺ T-cell memory following infection with recombinant sindbis and vaccinia viruses

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VIROLOGY 2000年第1期270卷 54-64页

作者： Villacres, MC Zuo, J Bergmann, CC Univ So Calif Keck Sch Med Dept Neurol Los Angeles CA 90033 USA Univ So Calif Keck Sch Med Dept Mol Microbiol & Immunol Los Angeles CA 90033 USA

CD8(+) T-cell memory is critical for protection against pathogens poorly controlled by humoral immunity. To characterize two distinct vaccine vectors, the acute and memory CD8(+) T-cell responses to an HIV-1 epitope (p18) expressed by recombinant vaccinia (vp18) and Sindbis (SINp18) viruses were compared. Whereas 9 to 13% of CD8(+) splenocytes were p18 specific during the acute response to vp18, 4% were induced by SINp18 as revealed by class I tetramer staining. Increased T-cell activation by vp18 was confirmed by higher numbers of both p18-specific IFN-gamma-secreting splenocytes and activated CD8(+) and CD4(+) T cells. Although higher frequencies of p18-specific CD8(+) T cells during primary responses correlated with higher frequencies during memory, the overall decline was only two- to threefold during the transition to memory, demonstrating equally efficient maintenance of memory in SINp18- as in vp18-immune mice. Despite modest in vivo activation, SINp18-induced CD4(+) T cells secreted substantial amounts of IFN-gamma and IL-2, potentially contributing to sustained CD8(+) memory. Collectively the data indicate that Sindbis virus recombinants provide effective vaccines for inducing protective memory CD8(+) T cells in the absence of the extensive inflammation and replication associated with vaccinia virus. (C) 2000 Academic Press.

关键词：抗原病毒/遗传学抗原病毒/免疫学 CD4阳性T淋巴细胞/免疫学 CD8阳性T淋巴细胞/免疫学细胞因子类/免疫学酶联免疫吸附测定表位 T淋巴细胞/遗传学表位 T淋巴细胞/免疫学遗传载体/投药和剂量遗传载体/遗传学遗传载体/免疫学遗传载体/生理学 HIV包膜蛋白质gp120/遗传学 HIV包膜蛋白质gp120/免疫学免疫记忆/免疫学淋巴细胞活化/免疫学淋巴细胞计数小鼠近交BALBC Sindbis病毒/遗传学 Sindbis病毒/免疫学 Sindbis病毒/生理学疫苗合成/投药和剂量疫苗合成/遗传学疫苗合成/免疫学痘苗病毒/遗传学痘苗病毒/免疫学痘苗病毒/生理学病毒疫苗/投药和剂量病毒疫苗/遗传学病毒疫苗/免疫学病毒复制动物女(雌)性男(雄)性小鼠

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Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein

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GASTROENTEROLOGY 2000年第3期118卷 591-598页

作者： Forbes, SJ Themis, M Alison, MR Sarosi, I Coutelle, C Hodgson, HJF Univ London Imperial Coll Sci Technol & Med Sch Med Liver Grp Lab London England Univ London Imperial Coll Sci Technol & Med Sch Med Dept Histopathol London England Hammersmith Hosp London England Univ London Imperial Coll Sci Technol & Med Sch Med Gene Therapy Res Grp London England Amgen Inc Thousand Oaks CA 91320 USA

Background & Aims: Genetic diseases reflecting abnormal hepatocyte function are potentially curable through gene therapy. Retroviral vectors offer the potential for permanent correction of such conditions. These vectors generally require cell division to occur to allow provirus:entry into the nucleus, initiated in many experimental protocols by partial hepatectomy. We have explored methods to improve the efficiency of retroviral gene transfer that avoid the need for liver damage, Methods: Triiodothyronine (T3) and keratinocyte growth factor (KGF) were used to induce hepatic proliferation in rats. The effects of intraportal and peripheral administration of a modified retrovirus that encoded the Lac Z gene during growth factor-induced liver hyperplasia were analyzed. Results: T3 Initiated hepatocyte proliferation midzonally;after KGF, proliferation was more diffuse. Optimal concentrations of T3 and KGF acted synergistically to induce proliferation in 61% of hepatocytes in the intact liver. This enabled in vivo hepatocyte transduction, leading to gene expression by up to 7.3% of hepatocytes after intraportal retroviral vector administration and 7.1% after peripheral venous administration. Conclusions: T3 and KGF act synergistically to induce hepatocyte proliferation in undamaged liver. The liver can be simply transduced with integrating vectors via the peripheral venous system during a wave of growth factor-induced proliferation.

关键词：细胞分裂/药物作用药物协同作用成纤维细胞生长因子10 成纤维细胞生长因子7 成纤维细胞生长因子基因表达/生理学基因转移技术遗传载体/投药和剂量甘氨酸/类似物和衍生物甘氨酸/药理学生长物质/药理学注射静脉内肝/细胞学大鼠 Wistar 逆转录病毒科/遗传学精胺/类似物和衍生物精胺/药理学转导遗传/生理学三碘甲状腺原氨酸/药理学动物男(雄)性大鼠

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Gene transfer by adenovirus-mimetic peptides in the presence of a cationic lipid and/or adenovirus. Analysis of the contribution of the viral and nonviral components

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ARCHIVES OF VIROLOGY 2003年第1期148卷 1-18页

作者： Moritz, S Colin, M Keller, M Klonjkowski, B Capeau, J Coutelle, C Chroboczek, J Brahimi-Horn, MC Univ Paris 06 INSERM U402 Paris France Univ London Imperial Coll Sci Technol & Med Dept Chem London SW7 2AY England Univ London Imperial Coll Sci Technol & Med Genet Therapies Ctr London SW7 2AY England Univ London Imperial Coll Sci Technol & Med Mol Genet Sect Div Biomed Sci Sch Med London England Inst Biol Struct Grenoble France

Peptide and cationic lipid-based gene transfer vectors have shown promise for gene therapy but are still less efficient than viral gene transfer vectors. We have examined the mechanism of gene transfer of different adenovirus-mimetic peptides in the presence and absence of a cationic lipid, lipofectamine and/or adenovirus with the aim of improving the design of nonviral vectors for efficient gene transfer. Three polylysine-adenovirus-mimetic peptides were synthesised and examined for their efficacy for gene transfer. Transfection levels in four cell lines: adenovirus permissive human tracheal epithelial (56FHTE8o(-)), human lung carcinoma (A549), human colon carcinoma (Caco-2) cells, and adenovirus low-permissive Chinese hamster ovary (CHO) cells, were examined. The polylysine-adenovirus-mimetic peptides increased the level of transfection of a reporter transgene in all cell lines. Transfection was substantially increased when an adenovirus was added to cells after pre-incubation with the vector complexes. Formulation of the peptide vector complexes with lipofectamine increased their transfection efficacy and the subsequent addition of an adenovirus increased transfection levels even further but only in permissive cells. Pre-incubation of cells with lipofectamine-peptide vector complexes increased cell binding of the adenovirus but uptake was only increased in intermediate- or non-permissive cells. The addition of lipofectamine increased transgene expression of a recombinant adenovirus in non-permissive cells but not in permissive cells. Enhancement with an adenovirus of peptide vector gene transfer is probably due to more efficient endosome escape while enhancement of gene transfer by peptide vectors complexed to lipofectamine is due to an increase in cellular binding and/or internalisation of the adenovirus.

关键词：腺病毒科/遗传学 CHO细胞 Caco-2细胞阳离子交换树脂类/投药和剂量阳离子/化学细胞系仓鼠亚科 DNA 病毒基因转移技术遗传载体/投药和剂量遗传载体/遗传学脂类/投药和剂量肽碎片/化学肽碎片/遗传学肽类/化学肽类/遗传学肽类/药理学转染肿瘤细胞培养的动物人类

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Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with first-generation, but not with high-capacity, adenovirus vectors:: Toward realistic long-term neurological gene therapy for chronic diseases

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第13期97卷 7482-7487页

作者： Thomas, CE Schiedner, G Kochanek, S Castro, MG Löwenstein, PR Univ Manchester Sch Med Mol Med & Gene Therapy Unit Manchester M13 9PT Lancs England Univ Cologne Ctr Mol Med D-50931 Cologne Germany

Although adenoviral vectors provide prolonged gene expression in the brain by comparison to peripheral organs, expression is eliminated by a severe inflammatory infiltration (i.e,, activated macrophages/microglia and T-lymphocytes) after peripheral infection with adenovirus, Here, we demonstrate that high-capacity adenoviral (HC-Ad) vectors succeed in maintaining long-term transgene expression in the brain, even in the presence of an active peripheral immunization with adenovirus that completely eliminates expression from first-generation vectors within 60 days. Importantly, even 60 days after the peripheral infection, brains injected with first-generation vectors exhibited evidence of a chronic infiltration of CD8(+) cells, macrophage/microglial activation, and up-regulation of brain MHC-I expression. No inflammation was observed in the brains injected with the HC-Ad vector. Thus, these results demonstrate that HC-Ad vectors will allow safe, stable, and longterm transgene expression in the brain, even in the presence of peripheral infection with adenovirus, This markedly improves the prospects for the use of adenoviral vectors for long-term gene therapy of neurological disorders.

关键词：腺病毒科感染/病理生理学腺病毒科感染/病毒学慢性病脑炎/病理生理学脑炎/病毒学遗传载体/投药和剂量注射脑室内时间因素动物小鼠

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Intratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugates for cancer immunotherapy

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第16期97卷 9221-9225页

作者： Hu, ZW Garen, A Yale Univ Dept Mol Biophys & Biochem New Haven CT 06520 USA

The efficacy and safety of a new immunotherapy protocol for cancer were tested in a severe combined immunodeficient mouse model of human skin and metastatic lung melanoma, The protocol involves intratumoral injections of replication-incompetent adenoviral vectors encoding immunoconjugates composed of the Fc region of an IgG1 immunoglobulin conjugated to a tumor-targeting domain. One targeting domain is factor VII that binds to tissue factor expressed on endothelial cells lining the tumor neovasculature and on tumor cells;the active site of factor VII was mutated to inhibit the initiation of blood coagulation. Another targeting domain is a single-chain Fv antibody that binds to a cognate antigen expressed on human melanoma cells. The adenoviral vectors infect mainly the cells of the injected tumor, which synthesize and secrete the immunoconjugates. The bloodborne immunoconjugates induce a cytolytic immune response against the targeted neovasculature endothelial cells and tumor cells. The mouse model experiments showed that intratumoral delivery of the factor VII immunoconjugate, either alone or together with the single-chain Fv immunoconjugate, resulted in growth inhibition and regression of the injected tumor, and also of distant metastatic tumors, without evidence of damage to normal organs. There was extensive destruction of the tumor neovasculature, presumably mediated by the factor VII immunoconjugate bound to tissue factor on neovasculature endothelial cells. Because tissue factor is generally expressed on neovascular endothelial cells and tumor cells, a factor VII immunoconjugate could be used for immunotherapy against a broad range of human solid tumors.

关键词：腺病毒科/遗传学遗传载体/投药和剂量免疫轭合物/投药和剂量免疫疗法小鼠近交C57BL 小鼠 SCID 分子序列数据肿瘤/治疗肿瘤细胞培养的动物女(雌)性人类小鼠

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Politically correct gene therapy? A "clean environment" improves gene delivery to the brain!

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GENE THERAPY 1999年第4期6卷 463-464页

作者： Lowenstein, PR Thomas, CE Castro, MG Univ Manchester Sch Med Dept Med Mol Med Unit Manchester M13 9PT Lancs England

Comments on the factors that affect long-term transgene expression in the brain following infections of recombinant adenoviruses. Uncertainty on the reasons for variations in longevities; Important role of the environment in determining the outcome of gene transfer experiments in the brain; Theory on the role played by inflammation.

关键词：腺病毒科/免疫学脑/免疫学脑/生理学 CD4阳性T淋巴细胞/免疫学中枢神经系统疾病/治疗基因表达基因疗法/方法基因转移技术遗传载体/投药和剂量无特异性病原体有机物时间因素转基因动物人类

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Liposomal lipid and plasmid DNA delivery to B16/BL6 tumors after intraperitoneal administration of cationic liposome DNA aggregates

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期289卷 807-815页

作者： Reimer, DL Kong, S Monck, M Wyles, J Tam, P Wasan, EK Bally, MB British Columbia Canc Agcy Div Med Oncol Sect Adv Therapeut Vancouver BC V5Z 4E6 Canada Inex Pharmaceut Inc Burnaby BC Canada

The transfer of plasmid expression vectors to cells is essential for transfection after administration of lipid-based DNA formulations (lipoplexes). A murine i.p. B16/BL6 tumor model was used to characterize DNA delivery, liposomal lipid delivery, and gene transfer after regional (i.p.) administration of free plasmid DNA and DNA lipoplexes. DNA lipoplexes were prepared using cationic dioleoyldimethylammonium chloride/dioleoylphosphatidylethanolamine (50:50 mol ratio) liposomes mixed with plasmid DNA (1 mu g DNA/10 nmol lipid). The plasmid used contained the chloramphenicol acetyltransferase gene and chloramphenicol acetyltransferase expression (mU/g tumor) was measured to estimate transfection efficiency. Tumor-associated DNA and liposomal lipid levels were measured to estimate the efficiency of lipid-mediated DNA delivery to tumors. Plasmid DNA delivery was estimated using [3H]-labeled plasmid as a tracer, dot blot analysis, and/or Southern analysis. Liposomal lipid delivery was estimated using [C-14]-dioleoylphosphatidylethanolamine as a liposomal lipid marker. Gene expression in the B16/BL6 tumors was highly variable, with values ranging from greater than 2,000 mU/g tumor to less than 100 mU/g tumor. There was a tendency to observe enhanced transfection in small (<250 mg) tumors. Approximately 18% of the injected dose of DNA was associated with these small tumors 2 h after i.p. administration. Southern analysis of extracted tumor DNA indicated that plasmid DNA associated with tumors was intact 24 h after administration. DNA and associated liposomal lipid are efficiently bound to tumors after regional administration;however, it is unclear whether delivery is sufficient to abet internalization and appropriate subcellular localization of the expression vector.

关键词：印迹法 DNA 氯霉素O-乙酰转移酶/遗传学氯霉素O-乙酰转移酶/代谢大肠杆菌/酶学基因转移技术遗传载体/投药和剂量遗传载体/遗传学注射腹腔内脂类脂质体黑色素瘤实验性/酶学黑色素瘤实验性/遗传学黑色素瘤实验性/代谢小鼠近交C57BL 肿瘤移植磷脂酰乙醇胺类质粒/投药和剂量质粒/遗传学质粒/药代动力学季胺类化合物组织分布动物女(雌)性小鼠

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