Chlamydial infections in free-ranging raptors presenting to a university veterinary medical teaching hospital (1993-2022).

Objective: To describe the prevalence, clinical findings, lesions, and risk factors associated with chlamydial infections in free-ranging raptors presented to a university veterinary medical teaching hospital.

Methods: Medical records retrospectively searched for raptors admitted from January 1993 through April 2022 were tested for Chlamydia spp infections using quantitative PCR (qPCR), immunohistochemistry, culture, and sequencing. Findings were collected and analyzed.

Role of Na1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries.

Na1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that Na1.7 blockers could be effective non-opioid analgesics.

Nonclinical pharmacokinetics, pharmacodynamics and safety assessment of a FLT3L-Fc molecule for cancer immunotherapy.

FLT3L-Fc is a cytokine-Fc fusion agonizing receptor-type tyrosine-protein kinase FLT3 (fms-related tyrosine kinase 3; CD135). FLT3 is expressed on dendritic cells (DCs) as well as myeloid and lymphoid progenitors. Nonclinical pharmacokinetics, pharmacodynamics and safety of FLT3L-Fc were investigated in rats and cynomolgus monkeys.

Preclinical development of ZED8, an Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.

Background: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1].

Methods: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function.

INVESTIGATION OF THE USE OF SERUM BIOMARKERS FOR THE DETECTION OF CARDIAC DISEASE IN MARINE MAMMALS.

Cardiac disease has been extensively documented in marine mammals; however, it remains difficult to diagnose antemortem. Assays measuring cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are used as sensitive and specific biomarkers of cardiac disease in many species, but have not been widely investigated in marine mammals. This study aimed to provide a set of reference values for cTnI and NT-proBNP in belugas (BW) (), sea otters (SO) (), Steller sea lions (SSL) (), and California sea lions (CSL) () with and without cardiac disease, and to determine if these biomarkers are useful indicators of cardiac disease in these species.

Nonclinical Pharmacokinetics and Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic Agent for B Cell Malignancies.

The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for preclinical characterization. To evaluate the impact of CD3 binding affinity on the TDB pharmacokinetics (PK), we utilized non-tumor-targeting bispecific anti-gD/CD3 antibodies composed of a low/high CD3 affinity arm along with a monospecific anti-gD arm as controls in monkeys and mice.

Establishment of baseline profiles of 50 bile acids in preclinical toxicity species: A comprehensive assessment of translational differences and study design considerations for biomarker development.

The use of bile acids as functional biomarkers for hepatobiliary injury and disease has been proposed for decades, but the utility has been generally limited due to lack of sensitivity in diagnosis and assay availability. However, recent advances in liquid chromatography and mass spectrometry have allowed for highly sensitive profiling of individual bile acids across several different matrices. In the current work, a panel of 54 bile acids were quantified in plasma by high resolution mass spectrometry in the common species used for preclinical toxicity studies, including rat (both Wistar and Sprague-Dawley strains), Beagle dog, Cynomolgus macaque monkey, and New Zealand White rabbit.

Polysorbate 80-Induced Anaphylactoid Reaction and the Effects on Cardiovascular Function: Dose Threshold and Species Comparison.

Polysorbate 80 (PS80) is commonly used in pre-clinical formulations. The dose threshold for cardiovascular (CV) changes and hypersensitivity reaction in the dog was assessed and compared to other species. PS80 was administered by intravenous (IV) bolus (.

Phase I/II Trial of Vemurafenib in Dogs with Naturally Occurring, -mutated Urothelial Carcinoma.

BRAF-targeted therapies including vemurafenib (Zelboraf) induce dramatic cancer remission; however, drug resistance commonly emerges. The purpose was to characterize a naturally occurring canine cancer model harboring complex features of human cancer, to complement experimental models to improve BRAF-targeted therapy. A phase I/II clinical trial of vemurafenib was performed in pet dogs with naturally occurring invasive urothelial carcinoma (InvUC) harboring the canine homologue of human The safety, MTD, pharmacokinetics, and antitumor activity were determined.

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research.

Discovery of Acyl-sulfonamide Na1.7 Inhibitors GDC-0276 and GDC-0310.

Na1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 () and GDC-0310 (), selective Na1.

The use of emerging safety biomarkers in nonclinical and clinical safety assessment - The current and future state: An IQ DruSafe industry survey.

Pharmaceutical and biotechnology companies rarely disclose their use of translational emerging safety biomarkers (ESBs) during drug development, and the impact of ESB use on the speed of drug development remains unclear. A cross-industry survey of 20 companies of varying size was conducted to understand current trends in ESB use and future use prospects. The objectives were to: (1) determine current ESB use in nonclinical and clinical drug development and impact on asset advancement; (2) identify opportunities, gaps, and challenges to greater ESB implementation; and (3) benchmark perspectives on regulatory acceptance.

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

Introduction: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP).

Methods: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays.

Results: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology.

Discovery of two highly divergent negative-sense RNA viruses associated with the parasitic nematode, , in wild from New York City.

Recent advances in high-throughput sequencing technology have led to a rapid expansion in the number of viral sequences associated with samples from vertebrates, invertebrates and environmental samples. Accurate host identification can be difficult in assays of complex samples that contain more than one potential host. Using unbiased metagenomic sequencing, we investigated wild house mice () and brown rats () from New York City to determine the aetiology of liver disease.

Considerations for an , Cell-Based Testing Platform for Detection of Adverse Drug-Induced Inotropic Effects in Early Drug Development. Part 1: General Considerations for Development of Novel Testing Platforms.

Drug-induced effects on cardiac contractility can be assessed through the measurement of the maximal rate of pressure increase in the left ventricle (LVdP/dt) in conscious animals, and such studies are often conducted at the late stage of preclinical drug development. Detection of such effects earlier in drug research using simpler, test systems would be a valuable addition to our strategies for identifying the best possible drug development candidates. Thus, testing platforms with reasonably high throughput, and affordable costs would be helpful for early screening purposes.

What evidence do we need for biomarker qualification?

Biomarkers can facilitate all aspects of the drug development process. However, biomarker qualification-the use of a biomarker that is accepted by the U.S.

Cardiotoxicity Associated with Nicotinamide Phosphoribosyltransferase Inhibitors in Rodents and in Rat and Human-Derived Cells Lines.

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein that functions as an enzyme, cytokine, growth factor and hormone. As a target for oncology, NAMPT is particularly attractive, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. Inhibition of NAMPT generally results in NAD depletion, followed by ATP reduction and loss of cell viability.

Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats.

Novel skeletal muscle (SKM) injury biomarkers that have recently been identified may outperform or add value to the conventional SKM injury biomarkers aspartate transaminase (AST) and creatine kinase (CK). The relative performance of these novel biomarkers of SKM injury including skeletal troponin I (sTnI), myosin light chain 3 (Myl3), CK M Isoform (Ckm), and fatty acid binding protein 3 (Fabp3) was assessed in 34 rat studies including both SKM toxicants and compounds with toxicities in tissues other than SKM. sTnI, Myl3, Ckm, and Fabp3 all outperformed CK or AST and/or added value for the diagnosis of drug-induced SKM injury (ie, myocyte degeneration/necrosis).

Preclinical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid.

Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in glycolysis and is a key molecule involved in maintaining cellular energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of an important salvage pathway in which nicotinamide is recycled into NAD. NAMPT is up-regulated in many types of cancer and NAMPT inhibitors (NAMPTi) have potential therapeutic benefit in cancer by impairing tumor metabolism.

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part I. Biotherapeutics.

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs.

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides.

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer.

NAD is a metabolite that is an important cofactor and second messenger for a number of cellular processes such as genomic stability and metabolism that are essential for survival. NAD is generated de novo from tryptophan or recycled from NAM through the NAMPT-dependent salvage pathway. Alternatively, cells can convert NA to NAD through the NAPRT1-dependent salvage pathway.

Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase.

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone. NAMPT is of interest for oncology, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), which is considered a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. This manuscript describes NAMPT inhibitor-induced retinal toxicity that was identified in rodent safety studies.