The erythrocyte sedimentation rate (ESR) in canine inflammation.

The clinical application of the erythrocyte sedimentation rate (ESR) assay is challenging due to its long processing time. However, in 2020 a new automated instrument for veterinary ESR was released and validated. This study sought: (1) to refine the proposed reference range (reference interval, RI) for canine ESR; (2) to compare the ESR values of healthy and sick dogs; and (3) to correlate ESR with other inflammatory markers such as C-reactive protein (CRP), fibrinogen, albumin:globulin ratio (A/G), and neutrophil-to-lymphocyte ratio (NLR); and also (4) to study ESR behavior across illnesses of varying durations. A prospective cohort study of 396 client-owned dogs (n = 120 healthy and n = 276 sick dogs) was conducted. Animals with a full clinical evaluation, complete hematobiochemical profile and a final diagnosis were included. ESR was performed according to manufacturer's instructions using the same 1 mL K3-EDTA tube used for the complete blood count. The RI was established at 1-8 mm/h in 14 min. Sick dogs had a significantly faster ESR (median 10 mm/h) than healthy dogs (median 1 mm/h; P < 0.0001). ESR was positively correlated with NLR (r = 0.36), CRP (r = 0.18) and fibrinogen (r = 0.56) and negatively correlated with A/G (r = -0.37). Dogs with an acute-on-chronic disease had the highest ESR values (median 17 mm/h) compared with either acute (median 11 mm/h; P < 0.001) or chronic diseases (median 7 mm/h; P = 0.001). ESR was confirmed as a reliable canine inflammatory marker, positively correlating with the main inflammatory markers in dogs and significantly different between sick and healthy dogs. The ESR assay appears useful especially in dogs with an acute clinical presentation, with or without an underlying chronic condition.

CXCR4 Antagonists: A Screening Strategy for Identification of Functionally Selective Ligands.

The CXC chemokine receptor 4 (CXCR4) is a widely expressed G protein-coupled receptor implicated in several diseases. In cancer, an increased number of surface CXCR4 receptors, in parallel with aberrant signaling, have been reported to influence several aspects of malignancy progression. CXCR4 activation by the specific ligand C-X-C motif chemokine 12 (CXCL12) induces several intracellular signaling pathways that have been selectively related to malignancy depending on the tissue or cell type. We developed a panel of CXCR4 screening assays investigating Gα(i)-mediated cyclic adenosine monophosphate modulation, ß-arrestin recruitment, and receptor internalization. All of the assays were set up in recombinant cells and were used to test four reported CXCR4 antagonists. Consequently, a set of hit compounds, deriving from a screening campaign of a 30,000-small-molecule internal library, was profiled with the different assays. We identified several compounds showing a pathway-selective activity: antagonists on a Gα(i)-dependent pathway; antagonists on both the ß-arrestin and Gα(i)-dependent pathways, some of which induce receptor internalization; and compounds with an antagonist behavior in all of the readouts. The identified biased antagonists induce different functional states on CXCR4 and preferentially affect specific downstream responses from the activated receptor, thus providing an improved therapeutic profile for correction of CXCR4 abnormal signaling.