Potential New Methods to Analyze Basal and Total Endogenous Protein Losses of Host and Bacterial Origin in Pigs.

Background: Current systems for assessing protein quality such as the Digestible Indispensable Amino Acid Score correct apparent amino acid (AA) digestibility for basal endogenous protein losses (bEPL), ignoring the potential influence of the diet on these losses. However, the quantification of total endogenous protein losses (tEPL) poses a challenge.

Objectives: To evaluate different methods for quantifying tEPL and bEPL, and to assess their potential in discriminating between tEPL originating from bacteria and host.

Transport of perfluoroalkyl substances across human induced pluripotent stem cell-derived intestinal epithelial cells in comparison with primary human intestinal epithelial cells and Caco-2 cells.

Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model.

Clinical Outcomes of Immune Checkpoint Inhibitors in Unique Cohorts Underrepresented in Clinical Trials.

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018.

Assessing seromuscular layer and serosa removal on intestinal permeability measurements in weaned piglet everted sac segments.

The integrity of the intestinal barrier is crucial for regulating the passage of pathogens and toxins, while facilitating nutrient absorption. The everted gut sac technique, an ex-vivo technique, can be used to study interventions on barrier function. This cost-effective approach utilizes relatively large gut segments to study specific intestinal regions.

Identification of plasminogen-binding sites in enolase that contribute to bacterial translocation across the blood-brain barrier.

is an emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, must cross the blood-brain barrier (BBB) comprising blood vessels that vascularize the central nervous system (CNS). The BBB is highly selective due to interactions with other cell types in the brain and the composition of the extracellular matrix (ECM).

Multi-country metabolic signature discovery for chicken health classification.

Introduction: To decrease antibiotic resistance, their use as growth promoters in the agricultural sector has been largely abandoned. This may lead to decreased health due to infectious disease or microbiome changes leading to gut inflammation.

Objectives: We aimed to generate a m/z signature classifying chicken health in blood, and obtain biological insights from the resulting m/z signature.

Microbial Regulation of Host Physiology by Short-chain Fatty Acids.

Our ancestral diet consisted of much more nondigestible fiber than that of many societies today. Thus, from an evolutionary perspective the human genome and its physiological and nutritional requirements are not well aligned to modern dietary habits. Fiber reaching the colon is anaerobically fermented by the gut bacteria, which produce short-chain fatty acids (SCFAs) as metabolic by-products.

Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers.

Purpose: Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed.

Methods: Open-label, parallel-group study (NCT03596567).

Impact of Fermentable Protein, by Feeding High Protein Diets, on Microbial Composition, Microbial Catabolic Activity, Gut Health and beyond in Pigs.

In pigs, high protein diets have been related to post-weaning diarrhoea, which may be due to the production of protein fermentation metabolites that were shown to have harmful effects on the intestinal epithelium in vitro. In this review, we discussed in vivo effects of protein fermentation on the microbial composition and their protein catabolic activity as well as gut and overall health. The reviewed studies applied different dietary protein levels, which was assumed to result in contrasting fermentable protein levels.

Clinical and Model-Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough QT Study.

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double-blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions.

Congruence of Transcription Programs in Adult Stem Cell-Derived Jejunum Organoids and Original Tissue During Long-Term Culture.

The emergence of intestinal organoids, as a stem cell-based self-renewable model system, has led to many studies on intestinal development and cell-cell signaling. However, potential issues regarding the phenotypic stability and reproducibility of the methodology during culture still needs to be addressed for different organoids. Here we investigated the transcriptomes of jejunum organoids derived from the same pig as well as batch-to-batch variation of organoids derived from different pigs over long-term passage.

Effects of undigested protein-rich ingredients on polarised small intestinal organoid monolayers.

Abstract: Here, we describe the use of monolayers of intestinal epithelial cells derived from intestinal organoids and transcriptomics to investigate the direct effects of dietary protein sources on epithelial function. Mechanically dissociated 3D organoids of mouse duodenum were used to generate a polarized epithelium containing all cell types found in the tissue of origin. The organoid-derived cell monolayers were exposed to 4% (w/v) of 'undigested (non-hydrolysed)-soluble' fraction of protein sources used as feed ingredients [soybean meal (SBM) and casein], or alternative protein sources (spray dried plasma protein, and yellow meal worm), or controls for 6 h prior to RNA isolation and transcriptomics.

High-level integration of murine intestinal transcriptomics data highlights the importance of the complement system in mucosal homeostasis.

Background: The mammalian intestine is a complex biological system that exhibits functional plasticity in its response to diverse stimuli to maintain homeostasis. To improve our understanding of this plasticity, we performed a high-level data integration of 14 whole-genome transcriptomics datasets from samples of intestinal mouse mucosa. We used the tool Centrality based Pathway Analysis (CePa), along with information from the Reactome database.

Absolute Oral Bioavailability of Glasdegib (PF-04449913), a Smoothened Inhibitor, in Randomized Healthy Volunteers.

Glasdegib (PF-04449913) is an oral small-molecule inhibitor of the Hedgehog signaling pathway under development for treating myeloid malignancies. This was an open-label phase 1, randomized, 2-sequence, 2-treatment, 2-period, crossover study evaluating the absolute bioavailability of glasdegib in healthy volunteers under fasting condition (NCT03270878). In period 1, 12 eligible subjects received either a single oral dose of glasdegib 100 mg (tablet) or a single intravenous (IV) dose of glasdegib 50 mg.

Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma.

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CL) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymphoma (NHL). Pharmacokinetic data included 8361 InO concentration-time observations that were modeled using nonlinear mixed-effects analysis.

Evaluation of the effects of formulation, food, or a proton-pump inhibitor on the pharmacokinetics of glasdegib (PF-04449913) in healthy volunteers: a randomized phase I study.

Purpose: To demonstrate the bioequivalence of the planned maleate salt-based commercial glasdegib tablet formulation [International Council for Harmonization (ICH) glasdegib] to the clinical di-hydrochloride (di-HCl) salt-based glasdegib formulation (di-HCl glasdegib). Additionally, to estimate the effects of a high-fat, high-calorie meal and proton-pump inhibitor (PPI) on the pharmacokinetics of ICH glasdegib.

Methods: This Phase I open-label study (ClinicalTrials.

Optimized procedures for generating an enhanced, near physiological 2D culture system from porcine intestinal organoids.

An important practical limitation of the three-dimensional geometry of stem-cell derived intestinal organoids is that it prevents easy access to the apical epithelium for testing food components, microorganisms, bioactive and toxic compounds. To this end, we here report on a new robust method for generating confluent intestinal cell monolayers from single-cell suspensions of enzymatically-dissociated porcine organoids using modified culture conditions. With this method, cell seeding densities can be standardised, overcoming problems with methods based on mechanical dissociation of organoids.

Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers.

Aims: This study aimed to evaluate the effect of a strong CYP3A inducer, rifampin, on glasdegib pharmacokinetics in healthy volunteers.

Methods: In an open-label, fixed-sequence, two-period Phase 1 study, subjects received a single 100-mg oral dose of glasdegib alone or following once-daily pre-treatment with 600 mg rifampin. Glasdegib pharmacokinetics were calculated using a noncompartmental analysis.

Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers.

Purpose: This phase I open-label study investigated the oral bioavailability of two novel maleate salt-based glasdegib (PF-04449913) tablet formulations (small- and large-particle size) relative to the current clinical formulation (diHCl salt-based). In addition, the effect of a gastric pH-altering agent (rabeprazole) and food on the pharmacokinetics of the large-particle size formulation of glasdegib were evaluated. The pharmacokinetics of glasdegib oral solution was also assessed.

Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet.

Scope: Metabolic flexibility is the ability to switch metabolism between carbohydrate oxidation (CHO) and fatty acid oxidation (FAO) and is a biomarker for metabolic health. The effect on metabolic health of nicotinamide riboside (NR) as an exclusive source of vitamin B3 is unknown and is examined here for a wide range of NR.

Design And Methods: Nine-week-old male C57BL/6JRcc mice received a semi-purified mildly obesogenic (40 en% fat) diet containing 0.

Metabolism, excretion and pharmacokinetics of [C]glasdegib (PF-04449913) in healthy volunteers following oral administration.

1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 μCi [C]glasdegib to six healthy male volunteers (NCT02110342). 2.

Pharmacokinetics, metabolism, and excretion of [14C]axitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in humans.

The disposition of a single oral dose of 5 mg (100 μCi) of [(14)C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.

Population pharmacokinetic analysis of axitinib in healthy volunteers.

Aims: Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers.

Methods: Plasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19).

Clinical pharmacology of axitinib.

Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that is approved in the US and several other countries for treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy. The recommended clinical starting dose of axitinib is 5 mg twice daily, taken with or without food. Dose increase (up to a maximum of 10 mg twice daily) or reduction is permitted based on individual tolerability.