Continuation versus discontinuation of intravenous oxytocin in the active phase of labour.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of discontinuing intravenous oxytocin stimulation in pregnant women during the active phase of induced or augmented labour.

Targeting epigenetic regulation and post-translational modification with 5-Aza-2' deoxycytidine and SUMO E1 inhibition augments T-cell receptor therapy.

Background: Cellular immunotherapy using modified T cells offers new avenues for cancer treatment. T-cell receptor (TCR) engineering of CD8 T cells enables these cells to recognize tumor-associated antigens and tumor-specific neoantigens. Improving TCR T-cell therapy through increased potency and in vivo persistence will be critical for clinical success.

Analytical performance specifications for trace elements in biological fluids derived from six countries federated external quality assessment schemes over 10 years.

Objectives: This article defines analytical performance specifications (APS) for evaluating laboratory proficiency through an external quality assessment scheme.

Methods: Standard deviations for proficiency assessment were derived from Thompson's characteristic function applied to robust data calculated from participants' submissions in the Occupational and Environmental Laboratory Medicine (OELM) external quality assurance scheme for trace elements in serum, whole blood and urine. Characteristic function was based on two parameters: (1) β - the average coefficient of variation (CV) at high sample concentrations; (2) α - the average standard deviation (SD) at low sample concentrations.

Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.

poisonings account for the majority of fatal mushroom poisonings. Recently, we identified hematotoxicity as a relevant aspect of poisonings. In this study, we investigated the effects of the main toxins of , α- and β-amanitin, on hematopoietic cell viability in vitro.

Setting goals for agricultural nitrogen emission reduction to ensure safe air and groundwater quality: A case study of Quzhou, the North China Plain.

Setting nitrogen (N) emission targets for agricultural systems is crucial to prevent to air and groundwater pollution, yet such targets are rarely defined at the county level. In this study, we employed a forecasting-and-back casting approach to establish human health-based nitrogen targets for air and groundwater quality in Quzhou county, located in the North China Plain. By adopting the World Health Organization (WHO) phase I standard for PM concentration (35 μg m) and a standard of 11.

SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation.

The SUMO protease SENP6 maintains genomic stability, but mechanistic understanding of this process remains limited. We find that SENP6 deconjugates SUMO2/3 polymers on a group of DNA damage response proteins, including BRCA1-BARD1, 53BP1, BLM and ERCC1-XPF. SENP6 maintains these proteins in a hypo-SUMOylated state under unstressed conditions and counteracts their polySUMOylation after hydroxyurea-induced stress.

Child Neuropsychological Functioning and Interpersonal Callousness as Predictors of Externalising Behaviour in Early Adolescence: A Prospective Population-based Study.

Externalizing problems are a key predictor of individual functioning in adulthood. Therefore, identifying possible risk factors for externalising problems is valuable for optimising prevention and treatment programmes. Previous research has shown that (domains of) neuropsychological functioning predict externalising problems later in life.

Multicompartment Depletion Factors for Water Consumption on a Global Scale.

Balancing human communities' and ecosystems' need for freshwater is one of the major challenges of the 21 century as population growth and improved living conditions put increasing pressure on freshwater resources. While frameworks to assess the environmental impacts of freshwater consumption have been proposed at the regional scale, an operational method to evaluate the consequences of consumption on different compartments of the water system and account for their interdependence is missing at the global scale. Here, we develop depletion factors that simultaneously quantify the effects of water consumption on streamflow, groundwater storage, soil moisture, and evapotranspiration globally.

Inhibition of SUMOylation enhances DNA hypomethylating drug efficacy to reduce outgrowth of hematopoietic malignancies.

Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2'-deoxycytidine (5-Aza-2') enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1, yielding DNA-protein crosslinks. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1.

Disruption of vitamin A homeostasis by the biocide tetrakis(hydroxymethyl) phosphonium sulphate in pregnant rabbits.

The biocide tetrakis(hydroxymethyl)phosphonium sulphate (THPS) and other members of the tetrakis(hydroxymethyl) phosphonium salts (THPX) family are associated with liver toxicity in several mammalian species and teratogenicity in rabbits. Malformations include skeletal changes and abnormalities in eye development and are very similar to those seen with vitamin A deficiency or excess. For this reason, it was hypothesized that teratogenicity of THPS(X) might be attributed to disturbances in retinol availability and/or metabolism as a result of maternal toxicity, for example, either due to insufficient dietary intake by the mothers or due to liver toxicity.

Extending the viability of human precision-cut intestinal slice model for drug metabolism studies.

Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium.

Targeting pancreatic cancer by TAK-981: a SUMOylation inhibitor that activates the immune system and blocks cancer cell cycle progression in a preclinical model.

Objective: Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC.

Design: We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981.

Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices.

P-glycoprotein (ABCB1), an ATP-binding cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions. Drug-mediated induction of intestinal ABCB1 is a clinically relevant phenomenon associated with significantly decreased drug bioavailability. Currently, there are no well-established human models for evaluating its induction, so drug regulatory authorities provide no recommendations for / testing drugs' ABCB1-inducing activity.

Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding.

Mono-ubiquitination of Rabphilin 3A by UBE3A serves a non-degradative function.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by brain-specific loss of UBE3A, an E3 ubiquitin protein ligase. A substantial number of possible ubiquitination targets of UBE3A have been identified, although evidence of being direct UBE3A substrates is often lacking. Here we identified the synaptic protein Rabphilin-3a (RPH3A), an effector of the RAB3A small GTPase involved in axonal vesicle priming and docking, as a ubiquitination target of UBE3A.

Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Methylation.

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation.

Carbosilane Dendrimers Loaded with siRNA Targeting Nrf2 as a Tool to Overcome Cisplatin Chemoresistance in Bladder Cancer Cells.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as the master regulator of antioxidant and cytoprotective gene expressions. Moreover, it plays a pivotal role in cancer progression. Nrf2 mediates the adaptive response which contributes to the resistance to chemotherapeutic pro-oxidant drugs, such as cisplatin (CDDP), in various tumors, including bladder cancers.

Prenatal smoke exposure induces persistent methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring.

Prenatal smoke exposure (PSE) is a risk factor for nicotine dependence. One susceptibility gene for nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine and nicotine clearance in the liver. Higher activity of the CYP2A6 enzyme is associated with nicotine dependence, but no research has addressed the PSE effects on the gene or its mouse homologue .

toxicological evaluation of experimental anticancer gold(i) complexes with lansoprazole-type ligands.

Gold-based compounds are of great interest in the field of medicinal chemistry as novel therapeutic (anticancer) agents due to their peculiar reactivity and mechanisms of action with respect to organic drugs. Despite their promising pharmacological properties, the possible toxic effects of gold compounds need to be carefully evaluated in order to optimize their design and applicability. This study reports on the potential toxicity of three experimental gold-based anticancer compounds featuring lansoprazole ligands () studied in an model, using rat precision cut kidney and liver slices (PCKS and PCLS, respectively).

Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver.

The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo.

'She convinced me'- partner involvement in choosing a high risk birth setting against medical advice in the Netherlands: A qualitative analysis.

Home births in high risk pregnancies and unassisted childbirth seem to be increasing in the Netherlands. There is a lack of qualitative data on women's partners' involvement in these choices in the Dutch maternity care system, where integrated midwifery care and home birth are regular options in low risk pregnancies. The majority of available literature focuses on the women's motivations, while the partner's influence on these decisions is much less well understood.

External quality assessment schemes for inorganic elements in the clinical laboratory: Lessons from the OELM scheme.

Measurements of inorganic elements in clinical laboratories produce results used for the diagnosis, the treatment and the monitoring of deficiencies or overloads. The main objective of External Quality Assessment Schemes is to verify, on a regular frequency, that clinical laboratory results correspond to the quality requirement for patient care. Therefore, External Quality Assessment Schemes represent an essential component of a laboratory's quality management system.

Environmental flow limits to global groundwater pumping.

Groundwater is the world's largest freshwater resource and is critically important for irrigation, and hence for global food security. Already, unsustainable groundwater pumping exceeds recharge from precipitation and rivers, leading to substantial drops in the levels of groundwater and losses of groundwater from its storage, especially in intensively irrigated regions. When groundwater levels drop, discharges from groundwater to streams decline, reverse in direction or even stop completely, thereby decreasing streamflow, with potentially devastating effects on aquatic ecosystems.

Development of a Novel Ex-vivo 3D Model to Screen Amoebicidal Activity on Infected Tissue.

Amoebiasis is a parasitic disease that causes thousands of deaths every year, its adverse effects and resistance to conventional treatments have led to the search of new treatment options, as well as the development of novel screening methods. In this work, we implemented a 3D model of intestine and liver slices from hamsters that were infected ex vivo with virulent E. histolytica trophozoites.