We have reported earlier the isolation and amino acid composition of bdellin A from medical leech, and characterised it as an inhibitor of trypsin, plasmin and acrosin [Fritz, H., Gebhardt, M., Meister, R. & Fink, E. (1971) in Proceedings of the international research conference on proteinase inhibitors (Fritz, H. & Tschesche, H., eds) pp. 271Ϫ280, Walter de Gruyter, Berlin]. In the present study, one of several chromatographic forms of this inhibitor was isolated from a semi-pure preparation. Elucidation of its amino acid sequence revealed that bdellin A is a member of the antistasin family. Therefore, it was renamed bdellastasin to avoid confusion with bdellin B, which is another trypsin-plasmin inhibitor from the medical leech, but of the Kazal type. Furthermore, a synthetic gene of bdellastasin was constructed, and the protein expressed in Saccharomyces cerevisiae with yields of 29 mg/l. The recombinant bdellastasin was purified by hydrophobic interaction and anion-exchange chromatography. Comparison by mass spectroscopy, far-ultraviolet circular dichroism studies, sequence determination, and inhibition characteristics demonstrated the identity of recombinant and native bdellastasin. The K i values of bdellastasin for inhibition of bovine trypsin and human plasmin are in the nanomolar range; no inhibition was detected for factor Xa, thrombin, tissue kallikrein, plasma kallikrein and chymotrypsin. Circular dichroism analyses indicated that bdellastasin is devoid of secondary-structural elements.Keywords : bdellastasin ; bdellin; gelin; leech; serine protease inhibitor.More than a century ago Haycraft (1884) reported on antico-tors from leeches was described by Seemüller et al. (1977Seemüller et al. ( , 1986. These so-called eglins inhibit strongly neutrophil elasagulant activity in the salivary secretion of the leech Hirudo medicinalis. Markwardt (1955) ascribed this activity to a protein, tase, cathepsin G, chymotrypsin and subtilisin. Shortly afterwards, antistasin, the first member of another group of leech which he called hirudin, and which turned out to be a specific and extremely potent inhibitor of thrombin. Later it was found protease inhibitors, was isolated from the Mexican leech Haementeria officinalis (Tuszynski et al., 1989). that leeches contain a variety of protease inhibitors. Fritz et al. (1969bFritz et al. ( , 1971 discovered that extracts of H. medicinalis contain Antistasin is a cysteine-rich 17-kDa protein with anticoagulant and antimetastatic properties. It exerts its anticoagulant eftwo groups of inhibitors directed against plasmin, trypsin and sperm acrosin. These two groups, named bdellins A and B, were fect by inhibiting highly selectively coagulation factor Xa in a competitive tight-binding manner with an inhibition constant distinguished by their elution behaviour on anion-exchange (K i ) of 0.5 nM (Dunwiddie et al., 1989). The molecule consists chromatography. Bdellins A were not characterised fully at that of 119 amino acid residues. Its primary structure features a twotime. Ami...
The article contains sections titled: 1. Polyols, General 1.1. Definition 1.2. Physical, Chemical, and Organoleptic Properties 1.3. Metabolism and Nutrition 1.3.1. Uptake, Digestion, and Tolerance 1.3.2. Nutritional Aspects 1.3.3. Oral Health and Hygiene 1.3.4. Oxidative Stress 1.3.5. Conclusion 1.4. Regulatory Aspects 2. Xylitol 2.1. Physical, Chemical, and Organoleptic Properties 2.2. Production 2.3. Specifications, Analysis, and Legal Aspects 2.4. Uses 2.5. Metabolism, Tolerance, and Safety 3. Sorbitol 3.1. Physical, Chemical, and Organoleptic Properties 3.2. Production 3.3. Regulatory and Quality Aspects 3.3.1. Purity Requirements 3.3.2. Analysis 3.4. Uses 3.5. Physiology, Tolerance, Toxicology 3.6. Economic Aspects 4. Mannitol 4.1. Physical, Chemical, and Organoleptic Properties 4.2. Production 4.3. Quality Aspects 4.4. Uses 4.5. Physiology, Tolerance, Toxicology 5. Isomaltulose and Trehalulose, Isomalt 5.1. Isomaltulose and Trehalulose 5.1.2. Physical and Chemical Properties 5.1.3. Production 5.1.4. Uses 5.1.5. Economic Aspects 5.2. Isomalt 5.2.1. Physical and Chemical Properties 5.2.2. Production 5.2.3. Uses 5.2.4. Economic Aspects 6. Lactitol 6.1. Physical, Chemical, and Physiological Properties 6.2. Production 6.3. Analysis and Regulatory Status 6.4. Uses 6.5. Economic Aspects 7. Maltitol and Maltitol‐Containing Syrups 7.1. Physical, Chemical, and Organoleptic Properties 7.2. Uses 7.3. Economic Aspects 8. Erythritol 8.1. Physical, Chemical, and Physiological Properties 8.2. Production 8.3. Analysis and Regulatory Status 8.4. Uses 8.5. Economic Aspects
ObjectiveTo investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation.Materials and MethodsColon carcinoma xenografts (HT-29) implanted subcutaneously in female athymic rats (n = 15) were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography). The therapy group (n = 7) received regorafenib daily (10 mg/kg bodyweight). Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31), tumor cell apoptosis (TUNEL), and proliferation (Ki-67).ResultsRegorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05) and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063). Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05). In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05) were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05) with microvascular density (CD-31; r = 0.84 and 0.66) and inversely with apoptosis (TUNEL; r = −0.66 and −0.71).ConclusionsRegorafenib significantly suppressed tumor vascularity (plasma volume) quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future approach to a more personalized and targeted cancer therapy.
RGD-USPIO MRI allows for the noninvasive assessment of αvß3-integrin expression in the investigated breast cancer model. RGD-USPIO MRI may be applicable for the in vivo monitoring of early antiangiogenic therapy effects in experimental breast cancer, generating possible complementary molecular imaging biomarkers to morphology-based tumor response assessments.
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