First results of migoprotafib, a potent and highly selective Src homology-2 domain-containing phosphatase 2 (SHP2) inhibitor in patients with advanced solid tumors.

Src homology-2 domain-containing phosphatase 2 (SHP2) promotes RAS-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective SHP2 inhibitor designed for the treatment of RAS-MAPK driven cancers, particularly in combination with other targeted agents. Here we report first-in-human study results of single agent migoprotafib in advanced solid tumor patients.

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction: Evidence from Metabolomics.

Unlabelled: Epoxyeicosatrienoic acids (EETs) have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Heart failure with preserved ejection fraction (HFpEF) has shown an increased prevalence and worse prognosis over the decades. However, the role of sEH activity in HFpEF remains unclear.

Glimepiride Use is Associated with Reduced Cardiovascular Mortality in Patients with Type 2 Diabetes and Chronic Heart Failure: A Prospective Cohort Study.

Background: Glimepiride has good cardiovascular safety. However, whether glimepiride benefits clinical cardiovascular outcomes is unclear.

Methods: A total of 21,451 inpatients with type 2 diabetes (T2D) and chronic heart failure (CHF) were analyzed, including 638 who received glimepiride treatment and 20,813 who did not.

Differences in EAG Response and Behavioral Choices between Honey Bee and Bumble Bee to Tomato Flower Volatiles.

Bumble bees and honey bees are of vital importance for tomato pollination, although honey bees are less attracted to tomato flowers than bumble bees. Little is known about how tomato flower volatile compounds influence the foraging behaviors of honey bees and bumble bees. In this study, compounds of tomato flower volatiles were detected by gas chromatography-mass spectrometry.

Transporters and Toxicity: Insights From the International Transporter Consortium Workshop 4.

Over the last decade, significant progress been made in elucidating the role of membrane transporters in altering drug disposition, with important toxicological consequences due to changes in localized concentrations of compounds. The topic of "Transporters and Toxicity" was recently highlighted as a scientific session at the International Transporter Consortium (ITC) Workshop 4 in 2021. The current white paper is not intended to be an extensive review on the topic of transporters and toxicity but an opportunity to highlight aspects of the role of transporters in various toxicities with clinically relevant implications as covered during the session.

NADPH diaphorase detects S-nitrosylated proteins in aldehyde-treated biological tissues.

NADPH diaphorase is used as a histochemical marker of nitric oxide synthase (NOS) in aldehyde-treated tissues. It is thought that the catalytic activity of NOS promotes NADPH-dependent reduction of nitro-blue tetrazolium (NBT) to diformazan. However, it has been argued that a proteinaceous factor other than NOS is responsible for producing diformazan in aldehyde-treated tissues.

Changes in the gut microbiota of honey bees associated with jujube flower disease.

Honeybees are prone to poisoning after collecting jujube nectar during the jujube flowering period ('honeybee's jujube flower disease'). To explore the mechanism of honeybee poisoning, the gut microbiota of honeybees undergoing the disease were characterised based on amplicon sequencing of the 16 S rRNA gene. Our results showed that the composition and diversity of the gut microbiota were significantly altered in diseased honeybees.

A phase 2 study to evaluate the safety, efficacy and pharmacokinetics of DP2 antagonist GB001 and to explore biomarkers of airway inflammation in mild-to-moderate asthma.

Background: GB001 is an oral antagonist of the prostaglandin D2 receptor that may inhibit recruitment and activation of airway eosinophils, reducing airway inflammation.

Objective: To assess GB001 safety, efficacy and pharmacokinetics from a Phase 2 study and explore the association between type 2 biomarkers (fractional exhaled nitric oxide and blood eosinophils) and asthma control markers following GB001 administration.

Methods: A randomized, placebo-controlled, double-blind study evaluating 36 patients with mild-to-moderate atopic asthma.

Transcriptomic analysis reveals Apis mellifera adaptations to high temperature and high humidity.

Temperature and humidity are the most important factors affecting the growth, reproduction, and survival of bees. Apis mellifera are important pollinating bees that are widely used in agricultural systems. However, the higher temperatures and humidity in greenhouses are not conducive to the survival of bees.

High contamination, bioaccumulation and risk assessment of perfluoroalkyl substances in multiple environmental media at the Baiyangdian Lake.

The contamination of perfluoroalkyl substances (PFASs) in the Baiyangdian Lake has exacerbated readily since 2008. This study analyzed the perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) in the surface water, sediment, and fish of the Baiyangdian Lake. In the surface water, the total concentration of PFASs ranged in 1193-3462 ng L (mean 1734 ng L) in the rainy season and 469-1724 ng L (mean 876 ng L) in the dry season.

Tolerance and response of two honeybee species Apis cerana and Apis mellifera to high temperature and relative humidity.

The ambient temperature and relative humidity affect the metabolic and physiological responses of bees, thus affecting their life activities. However, the physiological changes in bee due to high temperature and high humidity remain poorly understood. In this study, we explored the effects of higher temperature and humidity on the epiphysiology of bees by evaluating the survival, tolerance and body water loss in two bee species (Apis cerana and Apis mellifera).

Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.

Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated.

Enhancing catalytic stability and cadaverine tolerance by whole-cell immobilization and the addition of cell protectant during cadaverine production.

A whole-cell (cadaverine-producing strain, Escherichia coli AST3) immobilization method was developed for improving catalytic activity and cadaverine tolerance during cadaverine production. Cell-immobilized beads were prepared by polyvinyl alcohol (PVA) and sodium alginate (SA) based on their advantages in biocatalyst activity recovery and mechanical strength. The following optimal immobilization conditions were established using response surface methodology: 3.

Expression Characterization and Localization of the foraging Gene in the Chinese Bee, Apis cerana cerana (Hymenoptera: Apidae).

In social insects, the foraging gene (for) regulates insect age- and task-based foraging behaviors. We studied the expression and localization of the for gene (Acfor) in Apis cerana cerana workers to explore whether the differential regulation of this gene is associated with the behaviors of nurses and foragers. The expression profiles of Acfor in different tissues and at different ages were examined using real-time quantitative reverse transcription polymerase chain reaction.

Pharmacokinetics, pharmacodynamics, and immunogenicity of belatacept in adult kidney transplant recipients.

Background And Objectives: Belatacept is a first-in-class, selective co-stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients. The objective of this study was to report the pharmacokinetics, pharmacodynamics, and immunogenicity of belatacept.

Methods: The pharmacokinetics, pharmacodynamics (CD86 receptor occupancy), and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies.

Five-year safety and efficacy of belatacept in renal transplantation.

Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept.