Temporal response of an injectable calcium phosphate material in a critical size defect.

Background: Calcium phosphate-based bone graft substitutes are used to facilitate healing in bony defects caused by trauma or created during surgery. Here, we present an injectable calcium phosphate-based bone void filler that has been purposefully formulated with hyaluronic acid to offer a longer working time for ease of injection into bony defects that are difficult to access during minimally invasive surgery.

Methods: The bone substitute material deliverability and physical properties were characterized, and in vivo response was evaluated in a critical size distal femur defect in skeletally mature rabbits to 26 weeks.

Using phospho-motif antibodies to determine kinase substrates.

Phosphorylation of substrates by protein kinases regulates a myriad of cellular processes, ranging from proliferation and migration to autophagy, senescence, and apoptosis. Kinase substrate selectivity is largely dependent on the amino acid sequence surrounding the phosphorylation site; therefore, substrate-directed, phosphorylation-state-sensitive, motif-specific ("phospho-motif") antibodies represent powerful tools to identify novel kinase substrates and to investigate mechanisms of substrate phosphorylation in many signaling pathways typically associated with human malignancies. Phospho-motif antibodies are engineered to recognize proteins that contain a phosphorylated residue in the context of a specific motif.

IQGAP1 and its binding proteins control diverse biological functions.

IQGAP proteins have been identified in a wide spectrum of organisms, ranging from yeast to humans. The most extensively studied family member is the ubiquitously expressed scaffold protein IQGAP1, which participates in multiple essential aspects of mammalian biology. IQGAP1 mediates these effects by binding to and regulating the function of numerous interacting proteins.

Salmonella enterica serotype Typhimurium usurps the scaffold protein IQGAP1 to manipulate Rac1 and MAPK signalling.

Salmonella enterica serotype Typhimurium invades eukaryotic cells by re-arranging the host-cell cytoskeleton. However, the precise mechanisms by which Salmonella induces cytoskeletal changes remain undefined. IQGAP1 (IQ motif-containing GTPase-activating protein 1) is a scaffold protein that binds multiple proteins including actin, the Rho GTPases Rac1 and Cdc42 (cell division cycle 42), and components of the MAPK (mitogen-activated protein kinase) pathway.

IQGAP1 protein binds human epidermal growth factor receptor 2 (HER2) and modulates trastuzumab resistance.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast cancers. Increased HER2 expression is an adverse prognostic factor and correlates with decreased patient survival. HER2-positive (HER2(+)) breast cancer is treated with trastuzumab.

MAPK scaffold IQGAP1 binds the EGF receptor and modulates its activation.

Cellular responses produced by EGF are mediated through the receptor (EGFR) and by various enzymes and scaffolds. Recent studies document IQGAP1 as a scaffold for the MAPK cascade, binding directly to B-Raf, MEK, and ERK and regulating their activation in response to EGF. We previously showed that EGF is unable to activate B-Raf in cells lacking IQGAP1.

IQGAP1 in microbial pathogenesis: Targeting the actin cytoskeleton.

Microbial pathogens cause widespread morbidity and mortality. Central to the pathogens' virulence is manipulation of the host cell's cytoskeleton, which facilitates microbial invasion, multiplication, and avoidance of the innate immune response. IQGAP1 is a ubiquitously expressed scaffold protein that integrates diverse signaling cascades.

Calmodulin binds HER2 and modulates HER2 signaling.

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of receptor tyrosine kinases, has defined roles in neoplastic transformation and tumor progression. Overexpression of HER2 is an adverse prognostic factor in several human neoplasms and, particularly in breast cancer, correlates strongly with a decrease in overall patient survival. HER2 stimulates breast tumorigenesis by forming protein-protein interactions with a diverse array of intracellular signaling molecules, and evidence suggests that manipulation of these associations holds therapeutic potential.

IQGAP1 and IQGAP2 are reciprocally altered in hepatocellular carcinoma.

Background: IQGAP1 and IQGAP2 are homologous members of the IQGAP family of scaffold proteins. Accumulating evidence implicates IQGAPs in tumorigenesis. We recently reported that IQGAP2 deficiency leads to the development of hepatocellular carcinoma (HCC) in mice.

Regulation of MAP kinase signaling by calcium.

Mitogen-activated protein kinase (MAPK) signaling influences a variety of cellular responses, ranging from stimulation of cell proliferation to induction of senescence and/or apoptosis. Ca(2+) is a ubiquitous intracellular signaling molecule that controls multiple processes in cells. Published evidence has identified both direct and indirect interactions between the Ca(2+) and MAPK signaling pathways.

IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis.

The IQGAP family comprises three proteins in humans. The best characterized is IQGAP1, which participates in protein-protein interactions and integrates diverse signaling pathways. IQGAP2 and IQGAP3 harbor all the domains identified in IQGAP1, but their biological roles are poorly defined.

A crucial role for Galphaq/11, but not Galphai/o or Galphas, in gonadotropin-releasing hormone receptor-mediated cell growth inhibition.

GnRH acts on its cognate receptor in pituitary gonadotropes to regulate the biosynthesis and secretion of gonadotropins. It may also have direct extrapituitary actions, including inhibition of cell growth in reproductive malignancies, in which GnRH activation of the MAPK cascades is thought to play a pivotal role. In extrapituitary tissues, GnRH receptor signaling has been postulated to involve coupling of the receptor to different G proteins.

Antiproliferative effects of GnRH agonists: prospects and problems for cancer therapy.

Gonadotropin-releasing hormone (GnRH) receptor activation has been demonstrated to inhibit cell proliferation in vitro and in vivo. These effects are dependent on the degree of receptor expression and the intracellular signaling protein milieu. The physiological and pathophysiological relevance is largely undefined, and its potential for exploitation in the treatment of specific malignancies is the subject of ongoing investigations.

Structural determinants for ligand-receptor conformational selection in a peptide G protein-coupled receptor.

G protein coupled receptors (GPCRs) modulate the majority of physiological processes through specific intermolecular interactions with structurally diverse ligands and activation of differential intracellular signaling. A key issue yet to be resolved is how GPCRs developed selectivity and diversity of ligand binding and intracellular signaling during evolution. We have explored the structural basis of selectivity of naturally occurring gonadotropin-releasing hormones (GnRHs) from different species in the single functional human GnRH receptor.

Making a difference: education and training retains and supports rural and remote doctors in Queensland.

Introduction: Access to appropriate continuing medical education (CME) opportunities has been identified by many researchers as a key factor in retaining medical practitioners in rural and remote communities. There has, however, been very little research that has measured the actual effectiveness of CME programs on retention. The purpose of this article is to provide some evidence as to the efficacy of rurally relevant CME programs in retaining medical practitioners in rural and remote communities.