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Expression liver-directed genes by employing synthetic transcriptional control units

World Journal of Gastroenterology 2005年第34期11卷 5295-5302页

作者： Marie-Luise Lemken Wolfgang A.Wybranietz Ulrike Schmidt Florian Graepler Sorin Armeanu michael bitzer Ulrich M.Lauer Department of Internal Medicine I University Clinic Tübingen D-72076 Tübingen Germany

AIM： To generate and characcerize the synthetic transoiptional control units for transcriptional targeting of the liver, thereby compensating for the lack of specificity of currently available gene therapeutic vector systems. METHODS： Synthetic transcriptional control unit constructs were generated and analyzed for transcriptional activities in different cell types by FACS quantification, semi-quantitative RT-PCR, and Western blotting. RESULTS： A new bifunctionally-enhanced green fluorescent protein （EGFP）/neor fusion gene cassette was generated, and could flexibly be used both for transcript quantification and for selection of stable cell clones. Then, numerous synthetic transcriptional control units consisting of a minimal promoter linked to “naturally” derived composite enhancer elements from liver-specific expressed genes or binding sites of liver-specific transcription factors were inserted upstream of this reporter cassette. Following liposome-mediated transfection, EGFP reporter protein quantification by FACS analysis identified constructs encoding multimerized composite elements of the apolipoprotein B100 （APOB） promoter or the ornithin transcarbamoylase （OTC） enhancer to exhibit maximum transcriptional activities in liver originating cell lines, but only background levels in non-liver originating cell lines. In contrast, constructs encoding only singular binding sites of liver-specific transcription factors, namely hepatocyte nuclear factor （HNF）, HNF3, HNF4, HNF5, or CAAT/enhancer binding protein （C/EBP） only achieved background levels of EGFP expression. Finally, both semi-quantitative RT-PCR and Western blotting analysis of Hep3B cells demonstrated maximum transcriptional activities for a multimeric 4xAPOB cassette construct, which fully complied with the dataobtained by initial FACS analysis CONCLUSION： Synthetic transcriptional control unit constructs not only exhibit a superb degree of structural compactness, but also provide new means for liver

关键词： Liver gene therapy Hepatoma gene therapy Liver-directed gene expression Synthetic liver-specific promoters

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Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model

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World Journal of Gastroenterology 2005年第44期11卷 6910-6919页

作者： Florian Graepler Marie-Luise Lemken Wolfgang A Wybranietz Ulrike Schmidt Irina Smirnow Christine D GroB Martin Spiegel Andrea Schenk Schenk Hansj(o|¨)rg Graf Ulrike A Lauer Reinhard Vonthein michael Gregor Sorin Armeanu michael bitzer Ulrich M.Lauer Department of Internal Medicine Ⅰ Section of Experimental Radiology Department of Medical Biometry

AIM： To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model. METHODS： To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine （5-FC）, we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase （YCD） and the yeast uracil phosphoribosyltransferase （YUPRT） gene. RESULTS： In vitro stably transduced Morris rat hepatoma cells （MH） expressing the bifunctional SuperCD suicide gene （MH SuperCD） showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with MH cells stably expressing YCD solely （MH YCD） or the cytosine deaminase gene of bacterial origin （MH BCD）, respectively. In vivo, MH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions （P〈0.01） under both high dose as well as low dose systemic 5-FC application, whereas MH tumors without transgene expression （MH naive） showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness （SuperCD〉〉 YCD〉〉BCD〉〉〉negative control） was defined as a result of a direct in vivo comparison of all three suicide genes. CONCLUSION： Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine.

关键词： YCD/YUPRT fusion Cytosine deaminase GDEPT Suicide gene therapy Hepatoma therapy

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Correlation of magnetic resonance signal characteristics and perfusion parameters assessed by volume perfusion computed tomography in hepatocellular carcinoma:Impact on lesion characterization

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World Journal of Radiology 2016年第7期8卷 683-692页

作者： Gerd Grozinger michael bitzer Roland Syha Dominik Ketelsen Konstantin Nikolaou Ulrich Lauer Marius Horger Department of Diagnostic and Interventional Radiology Eberhard Karls University Department of Hepatology and Gastroenterology Eberhard Karls University

AIM: To find out if magnetic resonance(MR)-signal characteristics of hepatocellular carcinomas(HCC) correlate with perfusion parameters assessed by volume perfusion computed tomography(VPCT).METHODS: From October 2009 to January 2014, 26(mean age, 69.3 years) patients with 36 HCC lesions who underwent both VPCT and MR liver imaging were analysed. We compared signal intensity in the T1 wand T2w-images and wash-in/wash-out kinetics on postcontrast MR images with mean values of blood flow(BF, mL/100 mL per minute), blood volume(BV, mL/100 mL), k-trans(mL/100 mL per minute), arterial liver perfusion(mL/100 mL per minute), portal venous perfusion and hepatic perfusion index(HPI, %) obtained by VPCT. Signal intensity on magnetic resonance imaging(MRI) was classified hyper/iso/hypointense compared with surrounding liver parenchyma. RESULTS: Signal intensity on native T1w- and T2 wimages was hyper/iso/hypo in 4/16/16 and 21/14/1 lesions, respectively. Wash-in and wash-out contrast kinetics were found on MRI in 33 of 36 lesions(91.7%) and 25 of 36 lesions(69.4%), respectively. The latter was observed significantly more often in higher graded lesions(P < 0.005). HPI was 94.7% ± 6.5%. There was no significant relationship between lesion's MRsignal intensity, MR signal combinations, size and any of the VPCT-perfusion parameters. However HPI was constantly high in all HCC ***: VPCT parameters add limited value to MR-lesion characterization. However in HCC lesions with atypical MR signal characteristics HPI can add a parameter to ensure HCC diagnosis.

关键词： Hepatocellular carcinoma Volume perfusion computed tomography Magnetic resonance imaging

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