Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

Testing the bioaccumulation potential of manufactured nanomaterials in the freshwater amphipod Hyalella azteca

Standardized experimental approaches for the quantification of the bioaccumulation potential of nanomaterials in general and in (benthic) invertebrates in particular are currently lacking. We examined the suitability of the benthic freshwater amphipod Hyalella azteca for the examination of the bioaccumulation potential of nanomaterials. A flow-through test system that allows the generation of bioconcentration and biomagnification factors was applied. The feasibility of the system was confirmed in a 2-lab comparison study. By carrying out bioconcentration and biomagnification studies with gold, titanium dioxide and silver nanoparticles as well as dissolved silver (AgNO3) we were able to assess the bioaccumulation potential of different types of nanomaterials and their exposure pathways. For this, the animals were examined for their total metal body burden using inductively coupled mass spectroscopy (ICP-MS) and for the presence of nanoparticulate burdens using single-particle ICP-MS. The role of released ions was highlighted as being very important for the bioavailability and bioaccumulation of metals from nanoparticles for both examined uptake paths examined (bioconcentration and biomagnification). In 2018 a tiered testing strategy for engineered nanomaterials was proposed by Handy et al. that may allow a waiver of bioaccumulation fish studies using inter alia invertebrates. Data gained in studies carried out with invertebrates like the developed Hyalella azteca test may be included in this proposed tiered testing strategy.ISSN:0045-6535ISSN:1879-129

Bewertung der Umweltgefaehrlichkeit ausgewaehlter Altstoffe durch das Umweltbundesamt. T. 2

Von den hier vorgelegten 50 Risikobewertungen wurden 39 im Rahmen der Altstoffkonzeption der Bundesregierung im wesentlichen auf der Grundlage der in den BUA-Berichten enthaltenen Informationen erstellt. Bei den uebrigen 11 handelt es sich um Bewertungen von Stoffen, die als deutscher Beitrag fuer das OECD-Altstoffprogramm angefertigt wurden. Da in diesen Faellen die zugrundeliegenden Informationen nicht bereits in BUA-Berichten veroeffentlicht sind, wurden z.T. Daten zur Herstellung und Verwendung auf Wunsch der betroffenen Firmen anonymisiert. Die Vorgehensweise bei der Bewertung der Umweltgefaehrlichkeit besteht im wesentlichen darin, die Konzentration, mit der ein Stoff in der Umwelt vorkommt (Predicted Environmental Concentration, PEC) mit derjenigen zu vergleichen, bei der voraussichtlich noch keine biologischen Wirkungen auf Organismen oder Oekosysteme auftreten (Predicted No-Effect Concentration, PNEC). Es wird hierbei kompartimentspezifisch (Wasser, Sediment, Boden, Luft) vorgegangen, d.h. beispielsweise die Konzentration im Kompartiment Wasser mit der Wirkung auf aquatische Organismen verglichen. (orig./SR)Of the 50 risk assessments presented in this paper 39 were prepared as part of the Federal Government's used material plan and as such largely based on the information contained in the reports of the Federal Environmental Office (BUA). The remaining eleven were elaborated as a German contribution to the OECO used materials programme. As the information pertaining to these materials had not previously been published in the BUA reports, some of the data on the materials' manufacture and use have been made anonymous at the request of the companies concerned. The basic procedure of assessing the environmental hazard of a material is to compare the concentration at which it occurs in the environment (Predicted Environmental Concentration (PEC)) with the threshold concentration above which biological effects on organisms or ecosystems must be reckoned with. (Predicted No-Effect Concentration, PNEC). The procedure is compartment-specific (water, sediment, soil, air), which means, for example, that the concentration of a material in the water compartment is compared with that at which it affects aquatic organisms. (orig./SR)SIGLEAvailable from TIB Hannover: RN 8422(1996,38) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress

Background: Metabolic adaptations can allow cancer cells to survive DNA-damaging chemotherapy. This unmet clinical challenge is a potential vulnerability of cancer. Accordingly, there is an intense search for mechanisms that modulate cell metabolism during anti-tumor therapy. We set out to define how colorectal cancer CRC cells alter their metabolism upon DNA replication stress and whether this provides opportunities to eliminate such cells more efficiently. Methods: We incubated p53-positive and p53-negative permanent CRC cells and short-term cultured primary CRC cells with the topoisomerase-1 inhibitor irinotecan and other drugs that cause DNA replication stress and consequently DNA damage. We analyzed pro-apoptotic mitochondrial membrane depolarization and cell death with flow cytometry. We evaluated cellular metabolism with immunoblotting of electron transport chain (ETC) complex subunits, analysis of mitochondrial mRNA expression by qPCR, MTT assay, measurements of oxygen consumption and reactive oxygen species (ROS), and metabolic flux analysis with the Seahorse platform. Global metabolic alterations were assessed using targeted mass spectrometric analysis of extra- and intracellular metabolites. Results: Chemotherapeutics that cause DNA replication stress induce metabolic changes in p53-positive and p53-negative CRC cells. Irinotecan enhances glycolysis, oxygen consumption, mitochondrial ETC activation, and ROS production in CRC cells. This is connected to increased levels of electron transport chain complexes involving mitochondrial translation. Mass spectrometric analysis reveals global metabolic adaptations of CRC cells to irinotecan, including the glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways. P53-proficient CRC cells, however, have a more active metabolism upon DNA replication stress than their p53-deficient counterparts. This metabolic switch is a vulnerability of p53-positive cells to irinotecan-induced apoptosis under glucose-restricted conditions. Conclusion: Drugs that cause DNA replication stress increase the metabolism of CRC cells. Glucose restriction might improve the effectiveness of classical chemotherapy against p53-positive CRC cells

Unravelling Differences in Candidate Genes for Drought Tolerance in Potato (Solanum tuberosum L.) by Use of New Functional Microsatellite Markers

Potato is regarded as drought sensitive and most vulnerable to climate changes. Its cultivation in drought prone regions or under conditions of more frequent drought periods, especially in subtropical areas, requires intensive research to improve drought tolerance in order to guarantee high yields under limited water supplies. A candidate gene approach was used to develop functional simple sequence repeat (SSR) markers for association studies in potato with the aim to enhance breeding for drought tolerance. SSR primer combinations, mostly surrounding interrupted complex and compound repeats, were derived from 103 candidate genes for drought tolerance. Validation of the SSRs was performed in an association panel representing 34 mainly starch potato cultivars. Seventy-five out of 154 SSR primer combinations (49) resulted in polymorphic, highly reproducible banding patterns with polymorphic information content (PIC) values between 0.11 and 0.90. Five SSR markers identified allelic differences between the potato cultivars that showed significant associations with drought sensitivity. In all cases, the group of drought-sensitive cultivars showed predominantly an additional allele, indicating that selection against these alleles by marker-assisted breeding might confer drought tolerance. Further studies of these differences in the candidate genes will elucidate their role for an improved performance of potatoes under water-limited conditions