Quantitation of anacetrapib in human and animal adipose by liquid chromatography with mass spectrometric detection.

Cholesteryl ester transfer protein (CETP) inhibitor is a target for both lowering low-density lipoproteins and raising high-density lipoproteins. Anacetrapib was the lead compound in our cholesteryl ester transfer protein inhibitor program. Preclinical studies were initiated to support the safety of anacetrapib deposition in adipose tissue, followed by a clinical trial to evaluate the effects of anacetrapib in people with vascular disease.

Low-Temperature Reduction of NO by NH with Unity Conversion on Nanofilament MnO/Activated Semi-Coke Catalyst.

Selective catalytic reduction of nitrogen oxides with NH at low temperatures remains a crucial goal for industrial applications. However, effective catalysts operating at 70-90 °C are rarely reported, limiting SCR scenarios to high-temperature conditions. Herein, we report a unique MnO nanofilament catalyst grown on activated semi-coke synthesized via a one-step in situ hydrothermal approach, which exhibits a stable and marked 100 % conversion rate of NO to N with 100 % selectivity at 90 °C, superior to the other prepared structures (nanowires, nanorods, and nanotubes).

Quantification of clesrovimab, an investigational, half-life extended, anti-respiratory syncytial virus protein F human monoclonal antibody in the nasal epithelial lining fluid of healthy adults.

Background: Clesrovimab (MK-1654) is an investigational, half-life extended human monoclonal antibody (mAb) against RSV F glycoprotein in clinical trials as a prophylactic agent against RSV infection for infants.

Methods: This adult study measured clesrovimab concentrations in the serum and nasal epithelial lining fluid (ELF) to establish the partitioning of the antibody after dosing. Clesrovimab concentrations in the nasal ELF were normalized for sampling dilution using urea concentrations from ELF and serum.

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids.

Liver-specific androgen receptor knockout attenuates early liver tumor development in zebrafish.

Hepatocellular carcinoma (HCC) is one of the most severe cancer types and many genetic and environmental factors contribute to the development of HCC. Androgen receptor (AR) signaling is increasingly recognized as one of the important factors associated with HCC. Previously, we have developed an inducible HCC model in kras transgenic zebrafish.

Effects of sex hormones on liver tumor progression and regression in Myc/xmrk double oncogene transgenic zebrafish.

Hepatocellular carcinoma (HCC) shows clear sex disparity with men being more prone to developing HCC and having higher mortality than women. Previous studies have indicated that sex hormones play important roles in HCC initiation and development, but the effects of sex hormones on HCC in clinical trials remain inconsistent. Using zebrafish liver tumor model co-induced by oncogenes Myc and xmrk, we observed similar sex disparity between male and female zebrafish in liver tumor progression and regression; i.

Transcriptomic analyses of oncogenic hepatocytes reveal common and different molecular pathways of hepatocarcinogenesis in different developmental stages and genders in kras transgenic zebrafish.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is mainly due to genetic changes in hepatocytes. However, molecular expression in hepatocytes during hepatocarcinogenesis has not been characterized. In this study, using an inducible kras transgenic zebrafish models for HCC, transcriptomic profiles of oncogenic hepatocytes from larvae, male and female adult fish following a brief induction of oncogenic kras were investigated.

Transcriptomic profiles of tumor-associated neutrophils reveal prominent roles in enhancing angiogenesis in liver tumorigenesis in zebrafish.

We have previously demonstrated the pro-tumoral role of neutrophils using a kras-induced zebrafish hepatocarcinogenesis model. To further illustrate the molecular basis of the pro-tumoral role, Tumor-associated neutrophils (TANs) were isolated by fluorescence-activated cell sorting (FACS) and transcriptomic analyses were carried out by RNA-Seq. Differentially expressed gene profiles of TANs from larvae, male and female livers indicate great variations during liver tumorigenesis, but the common responsive canonical pathways included an immune pathway (Acute Phase Response Signaling), a liver metabolism-related pathway (LXR/RXR Activation) and Thrombin Signaling.

Immune response induced by major environmental pollutants through altering neutrophils in zebrafish larvae.

Environmental pollutants may cause adverse effects on the immune system of aquatic organisms. However, the cellular effects of pollutants on fish immune system are largely unknown. Here, we exploited the transgenic zebrafish Tg(lysC:DsRed2) larva as a preliminary screening system to evaluate the potential inflammatory effects of environmental pollutants.

Chemical inhibition reveals differential requirements of signaling pathways in kras- and Myc-induced liver tumors in transgenic zebrafish.

Previously we have generated inducible liver tumor models by transgenic expression of an oncogene and robust tumorigenesis can be rapidly induced by activation of the oncogene in both juvenile and adult fish. In the present study, we aimed at chemical intervention of tumorigenesis for understanding molecular pathways of tumorigenesis and for potential development of a chemical screening tool for anti-cancer drug discovery. Thus, we evaluated the roles of several major signaling pathways in kras- or Myc-induced liver tumors by using several small molecule inhibitors: SU5402 and SU6668 for VEGF/FGF signaling; IWR1 and cardionogen 1 for Wnt signaling; and cyclopamine and Gant61 for Hedgehog signaling.

Males develop faster and more severe hepatocellular carcinoma than females in kras transgenic zebrafish.

Hepatocellular carcinoma (HCC) is more prevalent in men than women, but the reason for this gender disparity is not well understood. To investigate whether zebrafish could be used to study the gender disparity of HCC, we compared the difference of liver tumorigenesis between female and male fish during early tumorigenesis and long-term tumor progression in our previously established inducible and reversible HCC model - the kras transgenic zebrafish. We found that male fish developed HCC faster than females.

Application of in vitro transmucosal permeability, dose number, and maximum absorbable dose for biopharmaceutics assessment during early drug development for intraoral delivery.

Intraoral (IO) administration is a unique route that takes advantage of transmucosal absorption in the oral cavity to deliver a drug substance locally or systemically. IO delivery can also enhance or enable oral administration, providing a better therapeutic benefit/safety risk profile for patient compliance. However, there are relatively few systematic biopharmaceutics assessments for IO delivery to date.

Synergistic Induction of Potential Warburg Effect in Zebrafish Hepatocellular Carcinoma by Co-Transgenic Expression of Myc and xmrk Oncogenes.

Previously we have generated inducible liver tumor models by transgenic expression of Myc or xmrk (activated EGFR homolog) oncogenes in zebrafish. To investigate the interaction of the two oncogenes, we crossed the two transgenic lines and observed more severe and faster hepatocarcinogenesis in Myc/xmrk double transgenic zebrafish than either single transgenic fish. RNA-Seq analyses revealed distinct changes in many molecular pathways among the three types of liver tumors.

Characterization and high cross-species transferability of microsatellite markers from the floral transcriptome of Aspidistra saxicola (Asparagaceae).

Recent studies utilizing transcriptome sequences generated by next-generation sequencing (NGS) technologies have demonstrated the ability to rapidly detect and characterize thousands of gene-based microsatellites from different plants. However, these simple sequence repeats (SSRs) were seldom used directly to test interspecific transferability in the populations of closely related species. Aspidistra Ker-Gawl.

Ultrasensitive liquid chromatography-tandem mass spectrometric methodologies for quantification of five HIV-1 integrase inhibitors in plasma for a microdose clinical trial.

HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds.

Metabolism and excretion of [14C]taranabant, a cannabinoid-1 inverse agonist, in humans.

Taranabant (N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 μCi [14C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (∼92%), with the majority of the dose (∼87%) excreted into faeces and a much smaller fraction (∼5%) into urine.

Development of a population pharmacokinetic model for taranabant, a cannibinoid-1 receptor inverse agonist.

Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.

Pharmacokinetics, safety, and tolerability of phentermine in healthy participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist.

This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.

Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers.

Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects.

Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers.

Taranabant is a novel cannabinoid CB-1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double-blind, randomized, placebo-controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5-600 mg) in 24 healthy male volunteers.