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Bruton’s tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

There are non-lymphocyte populations in joints which can produce and respond to IL-23.Therapeutic blockade of IL-23p19 subunit with a neutralizing monoclonal antibody can inhibit arthritic pain and disease.There can be an interdependence between IL-23 and the cytokines, TNF, GM-CSF and CCL17.

It is widely accepted that small-molecule drugs, despite their selectivity at primary targets, exert pharmacological effects (and safety liabilities) through a multiplicity of pathways. As such, it has proved extremely difficult to experimentally assess polypharmacology in an agnostic fashion. Profiling of metabolites produced as part of physiological responses to pharmacological stimuli provides a unique opportunity to explore drug pharmacology. A total of 122 eicosanoid lipids in human whole blood were monitored from 10 different donors upon stimulation with several inducers of immunological responses and treatment with modulators of prostaglandin (PG) and leukotriene biosynthesis, including clinical and investigational molecules. Such analysis revealed differentiation between drugs nominally targeting different eicosanoid biosynthetic enzymes, or even those designed to target the same enzyme. Profiled agents, some of them marketed products, affect eicosanoid biosynthesis in ways that cannot be predicted from information on their intended targets. As an example, we used this platform to discriminate drugs based on their ability to silence PG biosynthesis in response to bacterial lipopolysaccharide, resulting in differential pharmacological activity in an in vivo model of endotoxemia. Some of the observed effects are subject to variability among individuals, indicating a potential application of this methodology to the patient stratification, based on their responses to benchmark drugs and experimental compounds read on the eicosanome via a simple blood test.

Cytokine growth factors of the interleukin (IL)–6 family have recently been shown to play an important role in central nervous system (CNS) development, repair, and inflammation. These cytokines, which interact via specific membrane receptors, share a signal‐transducing receptor subunit, glycoprotein 130 (gp130). Gp130 is expressed by motoneurons in the gray matter of the rat spinal cord and by several brainstem nuclei that project to the spinal cord including the red, reticular, and vestibular nuclei. In this study, we examined whether stimulation of gp130 signaling, with the use of grafts of fibroblasts genetically modified to deliver the fusion protein, hyper‐IL‐6 (H‐IL‐6), which consists of the cytokine growth factor, IL‐6, and its α receptor, would elicit growth of injured spinal cord axons. Particular emphasis was placed on examining the potentially competing effects of growth factor versus proinflammatory influences of H‐IL‐6 in the context of spinal cord injury. Our results demonstrated that grafts delivering H‐IL‐6 induce a sixfold increase in the number of neutrophils (P< 0.05) and a twofold increase in the areas of spinal tissue occupied by macrophages and activated microglia (P< 0.01) at the site of the spinal cord injury when compared with control grafts. Of note, this augmentation in inflammatory cell infiltration correlated with a significant twofold increase in lesion size (P< 0.05) and a fourfold reduction in axonal growth (P< 0.01) at the lesion site. Thus, potential neurotrophic properties of this cytokine family of growth factors must be balanced against their inflammatory properties when considering therapeutic application to CNS injury. J. Comp. Neurol. 454:213–228, 2002. © 2002 Wiley‐Liss, Inc.

The article features the modern Chinese wood block prints. The author highlights the fact that reductive imagery and the blandishments of vibrant color and facile line perdure in the modern Chinese wood block print as in the tradition of nearly two millenia. Moreover, he also emphasizes that the invention of wood block printing contributed to the development of Chinese civilization.