Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling.

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling.

Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor Disrupts Serine Biosynthesis.

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of , a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD)-competitive PHGDH inhibitor , which has shown high selectivity against the majority of other dehydrogenase targets.

Feline panleukopenia virus in cerebral neurons of young and adult cats.

Background: Perinatal infections with feline panleukopenia virus (FPV) have long been known to be associated with cerebellar hypoplasia in kittens due to productive infection of dividing neuroblasts. FPV, like other parvoviruses, requires dividing cells to replicate which explains the usual tropism of the virus for the digestive tract, lymphoid tissues and bone marrow in older animals.

Results: In this study, the necropsy and histopathological analyses of a series of 28 cats which died from parvovirus infection in 2013 were performed.

Molecular evidence of Anaplasma phagocytophilum in wild boar (Sus scrofa) in Belgium.

Background: Anaplasma phagocytophilum is a tick-borne pathogen of veterinary and human importance. Both ticks as vectors and vertebrates as reservoir hosts are essential for the cycle maintenance of this bacterium. Currently, the whole range of animal species reservoirs for A.

Porcine CD18 mediates Actinobacillus pleuropneumoniae ApxIII species-specific toxicity.

Actinobacillus pleuropneumoniae, the causative agent of porcine pleuropneumonia, produces Apx toxins that are recognized as major virulence factors. Recently, we showed that ApxIIIA-cytotoxic activity specifically targets Sus scrofa leukocytes. Since both LtxA from Aggregatibacter actinomycetem comitans (aggressive periodontitis in humans) and LktA from Mannheimia haemolytica (pneumonia in ruminants) share this characteristic, respectively towards human and ruminant leukocytes, and because both use the CD18 subunit to interact with their respective LFA-1, we hypothesized that ApxIIIA was likely to bind porcine CD18 to exercise its deleterious effects on pig leukocytes.

Probing of Actinobacillus pleuropneumoniae ApxIIIA toxin-dependent cytotoxicity towards mammalian peripheral blood mononucleated cells.

Background: Actinobacillus pleuropneumoniae, the causative bacterial agent of porcine pleuropneumonia, produces Apx toxins which belong to RTX toxin family and are recognized as the major virulence factors. So far, their target receptor(s) has not been identified and the disease cytopathogenesis remains poorly understood. Production of an active Apx toxin and characterization of its toxic activity constitute the premises necessary to the description of its interaction with a potential receptor.

The wild boar (Sus scrofa) lymphocyte function-associated antigen-1 (CD11a/CD18) receptor: cDNA sequencing, structure analysis and comparison with homologues.

Background: The most predominant beta2-integrin lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2), expressed on all leukocytes, is essential for many adhesive functions of the immune system. Interestingly, RTX toxin-producing bacteria specifically target this leukocyte beta2-integrin which exacerbates lesions and disease development.

Results: This study reports the sequencing of the wild boar beta2-integrin CD11a and CD18 cDNAs.

Flow cytometric probing of mitochondrial function in equine peripheral blood mononuclear cells.

Background: The morphopathological picture of a subset of equine myopathies is compatible with a primary mitochondrial disease, but functional confirmation in vivo is still pending. The cationic dye JC-1 exhibits potential-dependent accumulation in mitochondria that is detectable by a fluorescence shift from green to orange. As a consequence, mitochondrial membrane potential can be optically measured by the orange/green fluorescence intensity ratio.

The CD11a partner in Sus scrofa lymphocyte function-associated antigen-1 (LFA-1): mRNA cloning, structure analysis and comparison with mammalian homologues.

Background: Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2), the most abundant and widely expressed beta2-integrin, is required for many cellular adhesive interactions during the immune response. Many studies have shown that LFA-1 is centrally involved in the pathogenesis of several diseases caused by Repeats-in-toxin (RTX)-producing bacteria.

Results: The porcine-LFA-1 CD11a (alpha) subunit coding sequence was cloned, sequenced and compared with the available mammalian homologues in this study.

Molecular characterisation of the caprine (Capra hircus) lymphocyte function-associated antigen-1 alpha subunit-encoding cDNA.

Background: Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alpha L beta 2) is required for many cellular adhesive interactions during the immune response.

Methods: We used SMART RACE technology to obtain caprine CD11a 5'- and 3'-ends and RT-PCR to amplify the full-length CDS.

Results: The Capra hircus CD11a-encoding cDNA was sequenced and compared with its human, murine, rat, bovine and ovine counterparts.

How Mannheimia haemolytica defeats host defence through a kiss of death mechanism.

Mannheimia haemolytica induced pneumonias are only observed in goats, sheep and cattle. The bacterium produces several virulence factors,whose principal ones are lipopolysaccharide and leukotoxin. The latter is cytotoxic only for ruminant leukocytes, a phenomenon that is correlated with its ability to bind and interact with the ruminant beta2-integrin Lymphocyte Function-associated Antigen 1.

Ground- and excited-state electronic structure of an emissive pyrazine-bridged ruthenium(II) dinuclear complex.

The synthesis, characterization, and electrochemical, photophysical, and photochemical properties of the binuclear compounds [(Ru(H8-bpy)2)2((Metr)2Pz)](PF6)2 (1) and [(Ru(D8-bpy)2)2((Metr)2Pz)](PF6)2 (2), where bpy is 2,2'-bipyridine and H2(Metr)2Pz is the planar ligand 2,5-bis(5'-methyl-4'H-[1,2,4]triaz-3'-yl)pyrazine, are reported. Electrochemical and spectro-electrochemical investigations indicate that the ground-state interaction between each metal center is predominantly electrostatic and in the mixed-valence form only a low level of ground-state delocalization is present. Resonance Raman, transient, and time-resolved spectroscopies enable a detailed assignment to be made of the excited-state photophysical properties of the complexes.