Corticosteroids for sore throat: a clinical practice guideline.

What is the role of a single dose of oral corticosteroids for those with acute sore throat? Using the GRADE framework according to the BMJ Rapid Recommendation process, an expert panel make a weak recommendation in favour of corticosteroid use. The panel produced these recommendations based on a linked systematic review triggered by a large randomised trial published in April 2017. This trial reported that corticosteroids increased the proportion of patients with complete resolution of pain at 48 hours.

Highlights of the Fourth Canadian Symposium on Hepatitis C: Moving towards a National Action Plan.

Hepatitis C virus (HCV) affects at least 268,000 Canadians and causes greater disease burden than any other infectious disease in the country. The Canadian Institutes of Health Research (CIHR) and the Public Health Agency of Canada (PHAC) have identified HCV-related liver disease as a priority. In 2015, the release of well-tolerated, short course treatments (~12 weeks) able to cure the majority of treated HCV patients revolutionized HCV therapy.

Next Generation Vaccine Biomarkers workshop October 30-31, 2014--Ottawa, Canada.

Vaccine biomarkers are critical to many aspects of vaccine development and licensure, including bridging findings in pre-clinical studies to clinical studies, predicting potential adverse events, and predicting vaccine efficacy. Despite advances in our understanding of various biological pathways, and advances in systems analyses of the immune response, there remains much to learn about qualitative and quantitative aspects of the human host response to vaccination. To stimulate discussion and identify opportunities for collaborative ways to advance the field of vaccine biomarkers, A Next Generation Vaccine Biomarker workshop was held in Ottawa.

The 3rd Canadian Symposium on Hepatitis C Virus: expanding care in the interferon-free era.

Hepatitis C virus (HCV) currently infects approximately 250,000 individuals in Canada and causes more years of life lost than any other infectious disease in the country. In August 2011, new therapies were approved by Health Canada that have achieved higher response rates among those treated, but are poorly tolerated. By 2014⁄2015, short-course, well-tolerated treatments with cure rates >95% will be available.

The Second Canadian Symposium on hepatitis C virus: a call to action.

In Canada, hepatitis C virus (HCV) infection results in considerable morbidity, mortality and health-related costs. Within the next three to 10 years, it is expected that tolerable, short-duration (12 to 24 weeks) therapies capable of curing >90% of those who undergo treatment will be approved. Given that most of those already infected are aging and at risk for progressive liver disease, building research-based interdisciplinary prevention, care and treatment capacity is an urgent priority.

Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation.

The anti-tumor function of Stat1 as a regulator of innate immunity and tumor immune surveillance has been long studied and is well understood; however, less clear is its tumor-site specific role. Although Stat1 phosphorylated at tyrosine (Y) 701 and serine (S) 727 is essential for interferon (IFN) signalling, its function in signalling induced in breast cancer cells is not understood. Herein, we show that Stat1 Y701 phosphorylation is increased in human breast tumor cells with elevated levels of ErbB2/HER-2 and in cells transfected with ErbB2/Neu.

STAT1 represses Skp2 gene transcription to promote p27Kip1 stabilization in Ras-transformed cells.

The S-phase kinase-associated protein 2 (Skp2) is an F-box protein that serves as a subunit of the Skp1-Cullin-F-box ubiquitin protein ligase complex. Skp2 is overexpressed in many tumors and promotes tumor formation through its ability to induce the degradation of proteins with antiproliferative and tumor-suppressor functions, such as p27(Kip1). The signal transducer and activator of transcription 1 (STAT1) is a key regulator of the immune system through its capacity to act downstream of interferons.

A fusion of GMCSF and IL-21 initiates hypersignaling through the IL-21Ralpha chain with immune activating and tumoricidal effects in vivo.

We hypothesized that fusing granulocyte-macrophage colony-stimulation factor (GMCSF) and interleukin (IL)-21 as a single bifunctional cytokine (hereafter GIFT-21) would lead to synergistic anticancer immune effects because of their respective roles in mediating inflammation. Mechanistic analysis of GIFT-21 found that it leads to IL-21Ralpha-dependent STAT3 hyperactivation while also contemporaneously behaving as a dominant-negative inhibitor of GMCSF-driven STAT5 activation. GIFT-21's aberrant interactions with its cognate receptors on macrophages resulted in production of 30-fold greater amounts of IL-6, TNF-alpha, and MCP-1 when compared to controls.

Stat1 phosphorylation determines Ras oncogenicity by regulating p27 kip1.

Inactivation of p27 Kip1 is implicated in tumorigenesis and has both prognostic and treatment-predictive values for many types of human cancer. The transcription factor Stat1 is essential for innate immunity and tumor immunosurveillance through its ability to act downstream of interferons. Herein, we demonstrate that Stat1 functions as a suppressor of Ras transformation independently of an interferon response.

IRES-mediated translational control of AMAP1 expression during differentiation of monocyte U937 cells.

Global control of mRNA translation plays key roles in cell regulation, including growth, differentiation and apoptosis. Human monocyte-like U937 cells differentiate into macrophage-like cells upon 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, a process which is known to be accompanied with a large decrease in general protein synthesis. Here, we found that protein levels of AMAP1 (also called ASAP1 or DDEF1), a GTPase-activating protein for Arf GTPases, increase several fold during U937 cell differentiation.

The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.

Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG). PAP-1 activity is encoded by members of the lipin family, including lipin-1 (1alpha and 1beta), -2, and -3. We determined the effect of lipin-1 expression on the assembly and secretion of very low density lipoproteins (VLDL) using McA-RH7777 cells.

The eIF2alpha kinases inhibit vesicular stomatitis virus replication independently of eIF2alpha phosphorylation.

The eIF2alpha kinases have been involved in the inhibition of vesicular stomatatis virus replication but the contribution of each kinase to this process has not been fully investigated. Using mouse embryonic fibroblasts (MEFs) from knock-out mice we show that PKR and HRI have no effects on VSV replication as opposed to PERK and GCN2, which exhibit strong inhibitory effects. When MEFs containing the serine 51 to alanine mutation of eIF2alpha were used, we found that VSV replication is independent of eIF2alpha phosphorylation.

PERK and PKR: old kinases learn new tricks.

Regulating gene expression is an effective way for cells to deal with various stresses. The outcome of this regulation differs with the type of stress, and can promote either cell survival or cell death depending on the severity of the injury incurred. Gene expression can be controlled at several steps, including transcription, translation and degradation.

PKR and PKR-like endoplasmic reticulum kinase induce the proteasome-dependent degradation of cyclin D1 via a mechanism requiring eukaryotic initiation factor 2alpha phosphorylation.

Cyclin D1 plays a critical role in controlling the G(1)/S transition via the regulation of cyclin-dependent kinase activity. Several studies have indicated that cyclin D1 translation is decreased upon activation of the eukaryotic initiation factor 2alpha (eIF2alpha) kinases. We examined the effect of activation of the eIF2alpha kinases PKR and PKR-like endoplasmic reticulum kinase (PERK) on cyclin D1 protein levels and translation and determined that cyclin D1 protein levels decrease upon the induction of PKR and PERK catalytic activity but that this decrease is not due to translation.

A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway.

Phosphoinositide-3 kinase (PI3K) plays an important role in signal transduction in response to a wide range of cellular stimuli involved in cellular processes that promote cell proliferation and survival. Phosphorylation of the alpha subunit of the eukaryotic translation initiation factor eIF2 at Ser51 takes place in response to various types of environmental stress and is essential for regulation of translation initiation. Herein, we show that a conditionally active form of the eIF2alpha kinase PKR acts upstream of PI3K and turns on the Akt/PKB-FRAP/mTOR pathway leading to S6 and 4E-BP1 phosphorylation.

Interferons induce tyrosine phosphorylation of the eIF2alpha kinase PKR through activation of Jak1 and Tyk2.

The interferon (IFN)-inducible, double-stranded RNA activated protein kinase (PKR) is a dual-specificity kinase, which has an essential role in the regulation of protein synthesis by phosphorylating the translation eukaryotic initiation factor 2 (eIF2). Here, we show the tyrosine (Tyr) phosphorylation of PKR in response to type I or type II IFNs. We show that PKR physically interacts with either Jak1 or Tyk2 in unstimulated cells and that these interactions are increased in IFN-treated cells.

The catalytic activity of the eukaryotic initiation factor-2alpha kinase PKR is required to negatively regulate Stat1 and Stat3 via activation of the T-cell protein-tyrosine phosphatase.

Tyrosine phosphorylation of the transcription factors Stat1 and Stat3 is required for them to dimerize, translocate to the nucleus, and induce gene transcription. Nuclear Stat1 and Stat3 are dephosphorylated and deactivated by the T-cell protein-tyrosine phosphatase (TC-PTP), which facilitates the return of both proteins to the cytoplasm. The protein kinase PKR plays an important role in translational control through the modulation of eukaryotic initiation factor-2alpha phosphorylation.