Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors.

Purpose: JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493.

Patients And Methods: Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.

The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.

IL-17A and IL-17F, produced by the Th17 CD4(+) T cell lineage, have been linked to a variety of inflammatory and autoimmune conditions. We recently reported that activated human CD4(+) T cells produce not only IL-17A and IL-17F homodimers but also an IL-17F/IL-17A heterodimeric cytokine. All three cytokines can induce chemokine secretion from bronchial epithelial cells, albeit with different potencies.

Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone.

A preliminary expression profiling analysis of osteoblasts derived from tibia explants of the high bone mass LRP5 G171V transgenic mice demonstrated increased expression of canonical Wnt pathway and Wnt/beta-catenin target genes compared with non-transgenic explant derived osteoblasts. Therefore, expression of Wnt/beta-catenin target genes were monitored after in vivo loading of the tibia of LRP5 G171V transgenic mice compared with non-transgenic mice. Loading resulted in the increased expression of Wnt pathway and Wnt/beta-catenin target genes including Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43 in both genotypes; however, there was a further increased in transcriptional response with the LRP5 G171V transgenic mice.

From genome to phenome--RNAi library screening and hit characterization using signaling pathway analysis.

Comprehensive, high-throughput analysis of gene function using RNA interference (RNAi)-based screens is emerging as a significant step forward for preliminary drug-target identification. Until quite recently drug target identification depended heavily on the analysis of changes in gene expression, which in turn needed to be correlated with gene function. The promise of obtaining preliminary 'gene to phenotype' information using a single high-throughput platform is propelling major investment in this area by biotechnology and pharmaceutical companies.

Exploring the sounds of silence: RNAi-mediated gene silencing for target identification and validation.

Drug development begins with the identification and early preclinical validation of novel biological targets, a process often called 'target identification and validation'. This process usually uses various approaches, such as observations from literature and findings from animal or clinical studies, together with cutting edge molecular techniques that include analyses of gene and protein expression, interaction and function. The publication of the human genome has increased research in gene and protein expression analysis that, in combination with RNA interference technology, promises the evaluation of novel functions for known genes, as well as hitherto unknown or unstudied genes with functions relevant to disease.

Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation.

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated on tyrosine residue 705 in response to growth factors or cytokines to form activated homodimers that drive gene expression. Because the stat3 promoter has a binding site for STAT3 dimers, the amount of STAT3 protein increases when STAT3 is activated (e.g.

NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach.

Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine with pleiotropic immunological and biological activities. TNFalpha signaling is triggered by the engagement of soluble TNFalpha to two types of cell surface receptors, TNFR1 and TNFR2. This recruits cytosolic proteins to the intracellular domains of the receptors and initiates signaling to downstream effectors.

From differential gene expression to differential gene function and back.

Following the decoding of several plant and animal genomes, the identification of all corresponding transcripts and proteins and understanding how their expression corresponds to physiological and pathological states is the obvious next step. Nucleic acid quantification methods have become increasingly high-throughput and relatively low-cost, and moving ahead, combinations of technologies monitoring differential gene expression and those defining differential cellular function will yield maximum benefit in furthering biology and for drug target identification and validation.:

IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression.

Interleukin-1 (IL-1) induces the phosphorylation of Stat1 on serine 727 but not on tyrosine 701. Analyses of mutant I1A cells, which lack the IL-1 receptor-associated kinase (IRAK), and of I1A cells reconstituted with deletion mutants of IRAK show that the IL-1-mediated phosphorylation of Stat1 on serine requires the IRAK protein but not its kinase activity and does not involve phosphatidylinositol-3'-kinase (PI3K) or the mitogen-activated protein (MAP) kinases p38 or ERK. IRAK and Stat1 interact in vivo, and this interaction is increased in response to IL-1, suggesting that IRAK may serve to recruit the as yet unknown IL-1-induced Stat1 serine kinase.

Resistance to interferons in melanoma cells does not correlate with the expression or activation of signal transducer and activator of transcription 1 (Stat1).

Defects in expression or activation signal transducer and activator of transcription-1 (Stat1) in response to interferon-alpha2 (IFN-alpha2) have been implicated as a mechanism for IFN resistance in melanoma cells. To further determine the significance of this observation, 17 melanoma cell lines sensitive or resistant to the antiproliferative effects of IFN-alpha2 and IFN-beta, as well as 30 melanoma patient samples, were analyzed for Stat1 levels by either Western blot analysis or immunohistochemistry. Although the expression level varied between samples, all the cell lines except one and all melanoma biopsy specimens expressed Stat1.

Isolation and characterization of a human STAT1 gene regulatory element. Inducibility by interferon (IFN) types I and II and role of IFN regulatory factor-1.

The transcription factor STAT1 plays a pivotal role in signal transduction of type I and II interferons (IFNs). STAT1 activation leads to changes in expression of key regulatory genes encoding caspases and cell cycle inhibitors. Deficient STAT1 expression in human cancer cells and virally mediated inhibition of STAT1 function have been associated with cellular resistance to IFNs and mycobacterial infection in humans.