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- Barash, Uri, et al.
(författare)
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Involvement of Heparanase in the Pathogenesis of Mesothelioma : Basic Aspects and Clinical Applications
- 2018
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Ingår i: Journal of the National Cancer Institute. - : OXFORD UNIV PRESS INC. - 0027-8874 .- 1460-2105. ; 110:10, s. 1102-1114
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy.Methods: The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non-small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided.Results: Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03).Conclusions: Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.
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| 4. |
- Jin, Haining, et al.
(författare)
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Influences on gene expression in vivo by a Shine-Dalgarno sequence.
- 2006
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Ingår i: Mol Microbiol. - : Wiley. - 0950-382X .- 1365-2958. ; 60:2, s. 480-92
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The Shine-Dalgarno (SD+: 5'-AAGGAGG-3') sequence anchors the mRNA by basepairing to the 16S rRNA in the small ribosomal subunit during translation initiation. We have here comparedhow an SD+ sequence influences gene expression, if located upstream or downstream of an initiation codon.The positive effect of an upstream SD+ is confirmed. A downstream SD+ gives decreased gene expression.This effect is also valid for appropriately modified natural Escherichia coli genes. If an SD+ is placedbetween two potential initiation codons, initiation takes place predominantly at the second start site.The first start site is activated if the distance between this site and the downstream SD+ is enlargedand/or if the second start site is weakened. Upstream initiation is eliminated if a stable stem-loopstructure is placed between this SD+ and the upstream start site. The results suggest that the two startsites compete for ribosomes that bind to an SD+ located between them. A minor positive contribution toupstream initiation resulting from 3' to 5' ribosomal diffusion along the mRNA is suggested. Analysisof the E. coli K12 genome suggests that the SD+ or SD-like sequences are systematically avoided in theearly coding region suggesting an evolutionary significance.
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| 6. |
- Wang, Shenqiu, et al.
(författare)
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Septate-Junction-Dependent Luminal Deposition of Chitin Deacetylases Restricts Tube Elongation in the Drosophila Trachea
- 2006
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Ingår i: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 16:2, s. 180-185
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Tidskriftsartikel (refereegranskat)abstract
- The function of tubular epithelial organs like the kidney and lung is critically dependent on the length and diameter of their constituting branches. Genetic analysis of tube size control during Drosophila tracheal development has revealed that epithelial septate junction (SJ) components and the dynamic chitinous luminal matrix coordinate tube growth. However, the underlying molecular mechanisms controlling tube expansion so far remained elusive. Here, we present the analysis of two luminal chitin binding proteins with predicted polysaccharide deacetylase activities (ChLDs). ChLDs are required to assemble the cable-like extracellular matrix (ECM) and restrict tracheal tube elongation. Overexpression of native, but not of mutated, ChLD versions also interferes with the structural integrity of the intraluminal ECM and causes aberrant tube elongation. Whereas ChLD mutants have normal SJ structure and function, the luminal deposition of the ChLD requires intact cellular SJs. This identifies a new molecular function for SJs in the apical secretion of ChLD and positions ChLD downstream of the SJs in tube length control. The deposition of the chitin luminal matrix first promotes and coordinates radial tube expansion. We propose that the subsequent structural modification of chitin by chitin binding deacetylases selectively instructs the termination of tube elongation to the underlying epithelium.
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