Multiple Beneficial Health Effects of Natural Alkylglycerols from Shark Liver Oil

Alkylglycerols (alkyl-Gro) are ether lipids abundant in the liver of some elasmobranch fish species such as ratfishes and some sharks. Shark liver oil from Centrophorus squamosus (SLO), or alkyl-Gro mix from this source, have several in vivo biological activities including stimulation of hematopoiesis and immunological defences, sperm quality improvement, or anti-tumor and anti-metastasis activities. Several mechanisms are suggested for these multiple activities, resulting from incorporation of alkyl-Gro into membrane phospholipids, and lipid signaling interactions. Natural alkyl-Gro mix from SLO contains several alkyl-Gro, varying by chain length and unsaturation. Six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0, 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro, were synthesized and tested for anti-tumor and anti-metastatic activities on a model of grafted tumor in mice (3LL cells). 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl- Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Multiple compounds and mechanisms are probably involved in the multiple activities of natural alkyl-Gro

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m(2 )of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects

Disentangling the complexity of groundwater dependent social-ecological systems

Groundwater resources are part of larger social-ecological systems. In this chapter, we review the various dimensions of these complex systems in order to uncover the diversity of elements at stake in the evolution of an aquifer and the loci for possible actions to control its dynamics. Two case studies illustrate how the state of an aquifer is embedded in a web of biophysical and sociopolitical processes. We propose here a holistic view through an IGM-scape that describes the various possible pathways of evolution for a groundwater related social-ecological system. Then we describe the elements of this IGM-scape starting with physical entities and processes, including relations with surface water and quality issues. Interactions with society bring an additional layer of considerations, including decisions on groundwater abstraction, land use changes and even energy related choices. Finally we point out the policy levers for groundwater management and their possible consequences for an aquifer, taking into account the complexity of pathways opened by these levers

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge

Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites

Ressourcenorientierte Planung von Kundenauftraegen Schlussbericht

Available from TIB Hannover: F03B569 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung, Berlin (Germany)DEGerman

Increased delivery of erucylphosphocholine to C6 gliomas by chemical opening of the blood-brain barrier using intracarotid pentylglycerol in rats

Background: Erucylphosphocholine (ErPC) has been shown to exert strong antineoplastic effects against various brain tumor cell lines in vitro. Since ErPC only enters the brain after long- term treatment, ineffective drug delivery to the tumor is considered to be the reason for the moderate responses to chemotherapy with ErPC observed in animal brain tumor models. We investigated a recently described method for chemically opening the blood-brain barrier (BBB) using intraarterial administration of alkylglycerols to increase the transfer of ErPC into the brain. Methods: ErPC (40 mg/kg) was given to C6 glioma-bearing rats either as a single intracarotid bolus injection in the presence or absence of 1-O-pentylglycerol (300 mM) or as an intracarotid infusion in conjunction with bradykinin. Brain tissue concentrations were analyzed and compared to values obtained after intravenous ErPC treatment over 14 and 30 days (cumulative ErPC doses of 210 and 350 mg/kg, respectively). Results: Pentylglycerol-induced BBB opening resulted in a significant increase in ErPC delivery to the tumor (17-fold) and, to a lesser extent, to the surrounding ipsilateral brain (7-fold) compared to intraarterial ErPC administration without alkylglycerol (P < 0.05). Furthermore, the resulting ErPC concentrations in the brain tumor exceeded those obtained in tumor and tumor-free brain after long-term intravenous ErPC administration. In contrast to this, intracarotid bradykinin did not increase the transfer of ErPC to the tumor or tumor-free brain. Conclusions: The intracarotid administration of pentylglycerol represents a novel and nontoxic method of overcoming the limited access of ErPC to both brain tumors and brain tissue adjacent to tumors. The present results provide further evidence that chemical opening of the BBB by intraarterial alkylglycerols is a promising new concept for improving delivery of chemotherapeutic agents to brain tumors