Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates

Computergestuurde circulatieregelingen : optimaal bewaarklimaat met minimaal energieverbruik

Bij het bewaren van bloembollen in kuubskisten gestapeld voor een systeemwand in een bewaarcel wordt voor de ventilatie met buitenlucht, en voor de circulatie met cellucht veel energie verbruikt. Door het ventilatiedebiet met de klimaatcomputer te sturen op basis van ethyleenmeting wordt bij het bewaren van tulpenbollen veel energie (gas) bespaard. Het energieverbruik bij de circulatie is uitsluitend voor de stroomvoorziening van de ventilatoren. Het circulatiedebiet wordt niet door de klimaatcomputer gestuurd, maar wordt handmatig via een frequentieregelaar ingesteld. Door ook de circulatie via de frequentieregelaar met de klimaatcomputer te sturen kan door het 3de>machtsverband tussen toerental en energieverbruik veel energie bespaard worden. In tegenstelling tot ethyleengestuurde ventilatie is computergestuurde circulatie niet alleen toepasbaar bij tulp, maar bij alle bolgewassen. Op sectorniveau kan hiermee dus heel veel energie bespaard worden. Doelstelling van dit project is het ontwikkelen van op sensoren gebaseerde computergestuurde regelingen voor de circulatie, waardoor bij een optimaal bewaarklimaat voor alle bolgewassen zeer fors op het elektraverbruik voor circulatie bespaard kan worden

A Novel Mechanism of Ataxia Telangiectasia Mutated Mediated Regulation of Chromatin Remodeling in Hypoxic Conditions

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-06-03, accepted 2021-08-31, epub 2021-09-21Publication status: PublishedThe effects of genotoxic stress can be mediated by activation of the Ataxia Telangiectasia Mutated (ATM) kinase, under both DNA damage-dependent (including ionizing radiation), and independent (including hypoxic stress) conditions. ATM activation is complex, and primarily mediated by the lysine acetyltransferase Tip60. Epigenetic changes can regulate this Tip60-dependent activation of ATM, requiring the interaction of Tip60 with tri-methylated histone 3 lysine 9 (H3K9me3). Under hypoxic stress, the role of Tip60 in DNA damage-independent ATM activation is unknown. However, epigenetic changes dependent on the methyltransferase Suv39H1, which generates H3K9me3, have been implicated. Our results demonstrate severe hypoxic stress (0.1% oxygen) caused ATM auto-phosphorylation and activation (pS1981), H3K9me3, and elevated both Suv39H1 and Tip60 protein levels in FTC133 and HCT116 cell lines. Exploring the mechanism of ATM activation under these hypoxic conditions, siRNA-mediated Suv39H1 depletion prevented H3K9me3 induction, and Tip60 inhibition (by TH1834) blocked ATM auto-phosphorylation. While MDM2 (Mouse double minute 2) can target Suv39H1 for degradation, it can be blocked by sirtuin-1 (Sirt1). Under severe hypoxia MDM2 protein levels were unchanged, and Sirt1 levels depleted. SiRNA-mediated depletion of MDM2 revealed MDM2 dependent regulation of Suv39H1 protein stability under these conditions. We describe a novel molecular circuit regulating the heterochromatic state (H3K9me3 positive) under severe hypoxic conditions, showing that severe hypoxia-induced ATM activation maintains H3K9me3 levels by downregulating MDM2 and preventing MDM2-mediated degradation of Suv39H1. This novel mechanism is a potential anti-cancer therapeutic opportunity, which if exploited could target the hypoxic tumor cells known to drive both tumor progression and treatment resistance

The medicinal treatment of COVID-19:a brief update

Much has changed in the medical treatment of COVID-19 after the first patient with an infection with SARS-CoV-2 in the Netherlands was diagnosed in February 2020. On the basis of limited data, at first only off-label use of (hydroxy)chloroquine seemed to be a treatment option. However, now based on the findings of several randomized studies, other medicines have been included in the Dutch guidelines about the treatment of COVID-19. In this article, we will briefly discuss the current state of affairs with regard to the drugs (hydroxy) chloroquine, remdesivir and corticosteroids. Again, it appears that only well-executed randomized clinical trials can determine the status of various supposedly effective drugs.</p

Chronic Allopurinol Treatment during the Last Trimester of Pregnancy in Sows: Effects on Low and Normal Birth Weight Offspring

Low-birth-weight (LBW) children are born with several risk factors for disease, morbidity and neonatal mortality, even if carried to term. Placental insufficiency leading to hypoxemia and reduced nutritional supply is the main cause for LBW. Brain damage and poor neurological outcome can be the consequence. LBW after being carried to term gives better chances for survival, but these children are still at risk for poor health and the development of cognitive impairments. Preventive therapies are not yet available. We studied the risk/efficacy of chronic prenatal treatment with the anti-oxidative drug allopurinol, as putative preventive treatment in piglets. LBW piglets served as a natural model for LBW. A cognitive holeboard test was applied to study the learning and memory abilities of these allopurinol treated piglets after weaning. Preliminary analysis of the plasma concentrations in sows and their piglets suggested that a daily dose of 15 mg.kg-1 resulted in effective plasma concentration of allopurinol in piglets. No adverse effects of chronic allopurinol treatment were found on farrowing, birth weight, open field behavior, learning abilities, relative brain, hippocampus and spleen weights. LBW piglets showed increased anxiety levels in an open field test, but cognitive performance was not affected by allopurinol treatment. LBW animals treated with allopurinol showed the largest postnatal compensatory body weight gain. In contrast to a previous study, no differences in learning abilities were found between LBW and normal-birth-weight piglets. This discrepancy might be attributable to experimental differences. Our results indicate that chronic prenatal allopurinol treatment during the third trimester of pregnancy is safe, as no adverse side effects were observed. Compensatory weight gain of treated piglets is a positive indication for the chronic prenatal use of allopurinol in these animals. Further studies are needed to assess the possible preventive effects of allopurinol on brain functions in LBW piglets

Ultra-energiezuinige kassystemen met Supertransparante Micro-V Gestructureerde materialen: Rapportage in het kader van het EOS-LT programma van Agentschap NL (Openbare versie)

Doel van het in dit rapport beschreven onderzoek is het gebruiken van micro- en nanostructuren uit de PV-industrie om te komen tot een diffuus kasdekmateriaal met een hoge hemisferische transmissie. Hierbij wordt gebruik gemaakt van de kennis die in het verleden is opgedaan in het ontwikkelen van het zigzag kasdekmateriaal. Met de ontwikkelde kennis kan energiebesparing gerealiseerd worden door het toepassen van de structuren op dubbel glas, waardoor materiaal gemaakt kan worden met een hoge hemisferische transmissie, diffuse eigenschappen en een hoge isolatiewaarde. Randvoorwaarde hierin is dat het ontwikkelde kasdekmateriaal toepasbaar is in een glastuinbouwmilieu. Dit betekent dat het materiaal niet mag verouderen, condensatie de transmissie niet mag verminderen en extra vervuiling niet mag optreden. Hierbij wordt de Nederlandse situatie als uitgangspunt genomen, maar interessante structuren voor andere klimaten zullen niet worden uitgesloten

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required