The effects of anesthetic agents, commonly used in animal models, on blood glucose levels in fed and fasted rats were investigated. In fed Sprague-Dawley rats, ketamine (100 mg/kg)/xylazine (10 mg/kg) (KX) produced acute hyperglycemia (blood glucose 178.4 +/- 8.0 mg/dl) within 20 min. The baseline blood glucose levels (104.8 +/- 5.7 mg/dl) reached maximum levels (291.7 +/- 23.8 mg/dl) at 120 min. Ketamine alone did not elevate glucose levels in fed rats. Isoflurane also produced acute hyperglycemia similar to KX. Administration of pentobarbital sodium did not produce hyperglycemia in fed rats. In contrast, none of these anesthetic agents produced hyperglycemia in fasted rats. The acute hyperglycemic effect of KX in fed rats was associated with decreased plasma levels of insulin, adrenocorticotropic hormone (ACTH), and corticosterone and increased levels of glucagon and growth hormone (GH). The acute hyperglycemic response to KX was dose-dependently inhibited by the specific alpha2-adrenergic receptor antagonist yohimbine (1-4 mg/kg). KX-induced changes of glucoregulatory hormone levels such as insulin, GH, ACTH, and corticosterone were significantly altered by yohimbine, whereas the glucagon levels remained unaffected. In conclusion, the present study indicates that both KX and isoflurane produce acute hyperglycemia in fed rats. The effect of KX is mediated by modulation of the glucoregulatory hormones through stimulation of alpha2-adrenergic receptors. Pentobarbital sodium did not produce hyperglycemia in either fed or fasted rats. Based on these findings, it is suggested that caution needs to be taken when selecting anesthetic agents, and fed or fasted state of animals in studies of diabetic disease or other models where glucose and/or glucoregulatory hormone levels may influence outcome and thus interpretation. However, fed animals are of value when exploring the hyperglycemic response to anesthetic agents.
Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGFdependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGFresponsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (METamplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059-70. Ó2014 AACR.
Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1 receptor associated kinase 4 (IRAK4) is critical for IL-1/TLR signaling. We show here that inactivation of IRAK4 kinase in mice (IRAK4 KI) results in significant resistance to experimental autoimmune encephalomyelitis (EAE) due to a reduction in infiltrating inflammatory cells into the CNS and reduced antigen-specific CD4+ T cell-mediated IL-17 production. Adoptive transfer of MOG35-55-specific IRAK4 KI Th17 cells failed to induce EAE in either wild-type or IRAK4 KI recipient mice, indicating the lack of autoantigen-specific Th17 cell activities in the absence of IRAK4 kinase activity. Furthermore, the absence of IRAK4 kinase activity blocked induction of IL-23 receptor expression, STAT3 activation by IL-23, and Th17 cytokine expression in differentiated Th17 cells. Importantly, blockade of IL-1 signaling by IL-1RA inhibited Th17 differentiation and IL-23-induced cytokine expression in differentiated Th17 cells. The results of these studies demonstrate that IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23 receptor expression, Th17 differentiation, and autoimmune disease.
Sensitization to latex proteins can cause immediate IgE mast cell-mediated reactions. Health care workers have been found to be particularly at risk because of high exposure. Latex allergy can be produced in mice as demonstrated by IgE and eosinophil responses. Thus the mouse is a potential animal model for studying this disease, but the airway response to latex sensitization in mice has not been evaluated previously. In the present study, we immunized BALB/c mice intranasally with nonammoniated latex proteins. Animals were anesthetized, and lung mechanics were evaluated plethysmographically. Changes in pulmonary conductance (GL) and compliance (Cdyn) were measured in response to a nonspecific challenge with methacholine or to a direct challenge with intravenous latex antigen. Latex sensitization resulted in elevated levels of IgE and latex-specific IgG1 as well as interstitial infiltrates consistent with an allergic response. The methacholine dose-response ED50 for GL was 116.4 microg for the control mice and fell significantly to 20.9 microg for latex-sensitized mice. The ED50 calculated for Cdyn was also significantly lower after latex sensitization. The GL in latex-sensitized mice challenged with latex antigen fell significantly from a prechallenge value of 1.87 +/- 0.41 (S.E.) to 0. 198 +/- 0.03 ml x s-1 x cmH2O after latex antigen challenge. The results indicate that latex-sensitized mice did exhibit increased airway reactivity in the methacholine challenge test. The latex allergic response in mice is unique in that direct challenge with latex antigen itself also resulted in a significant airway response.
A rodent model of controlled acute hyperglycemia that is sensitive to glucose-lowering agents insulin and glucagon-like peptide-1 (GLP-1) analog has been developed. The studies show that anesthesia could be induced in fasted rats with ketamine (100 mg/kg) plus a low dose of xylazine (5 mg/kg) without inducing the acute hyperglycemia typically associated with these agents. Under these conditions, continuous infusion of glucose (10 and 20%) via the jugular vein for 30 to 150 min induced hyperglycemia in a time-dependent fashion. Administration of "loading" boluses of glucose (0.2-0.6 ml of a 20% solution) prior to continuous infusion of 10% glucose produced more immediate and sustained hyperglycemia. Plasma levels of a variety of glucoregulatory and stress hormones such as insulin, growth hormone, glucagon, and corticosterone were determined. Only glucagon levels changed significantly during induction and maintenance of hyperglycemia. The infusion of insulin (0.1 U/kg/h) or GLP-1 analog (10 g/kg/h) effectively lowered blood glucose from its elevated levels. Insulin produced a significant increase in glucagon levels, and GLP-1 analog produced a significant increase in insulin levels without any change in other glucoregulatory and stress hormone levels. In conclusion, the present studies identified a novel approach for the induction of anesthesia and surgical manipulations without inducing hyperglycemia and further defined an approach for producing acute hyperglycemia in a controlled fashion in rodents. This model will be beneficial to study the influence of hyperglycemia in acute models of critical illness where hyperglycemia develops following the precipitating event. This model was responsive to insulin and GLP-1 analog, both of which were effective in ameliorating hyperglycemia.
MET is involved in many mechanisms of cancer proliferation and metastasis. Inappropriate activation of MET can be induced by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional up-regulation, or by HGF-dependent autocrine or paracrine mechanisms. LY2875358 is a novel humanized bivalent MET antibody currently in phase I clinical testing (trial NCT01287546). LY2875358 has high neutralization and internalization activities against MET for inhibiting HGF-dependent and HGF-independent MET pathway activation and tumor growth. In HGF-dependent MET activation, LY2875358 blocks HGF binding to MET, HGF-induced MET phosphorylation and tumor growth both in cell culture and in mouse xenograft models, resembling activities of a humanized one-armed 5D5 MET antibody (monovalent antibody similar to Onartuzumab). In tumors with HGF-independent MET activation through MET gene amplification, LY2875358 induces internalization and degradation of MET, which results in decreased pMET and total MET, inhibition of cell proliferation and tumor growth in MKN45 and SNU5 gastric tumor lines and EBC-1 and H1993 NSCLC tumor lines. Moreover, LY2875358 enhances antitumor activity in combination with cisplatin or 5-FU in vitro and in vivo in MET amplified tumor cells. However, under the same ligand-independent conditions, the one-armed 5D5 antibody did not have anti-tumor activities. When HGF is added to tumor cells with high MET gene amplification, LY2875358 decreases cell proliferation, while the one-armed 5D5 antibody does not. In contrast to other bivalent MET antibodies, LY2875358 has no or otherwise negligible agonist activity and does not stimulate biological activities such as cell proliferation, scattering, invasion, tubulogenesis, apoptosis protection or angiogenesis in various HGF responsive cells. These findings indicate that LY2875358 has a different mechanism of action from the humanized one-armed 5D5 MET antibody. LY2875358 may be a promising therapy for treatment of patients whose tumors are driven by HGF-dependent and HGF-independent MET activation. Citation Format: Wei Zeng, Victoria Peek, Mark Wortinger, Jonathan Tetreault, Jinqi Xia, Jennifer Stephens, Kelly Credille, Darryl Ballard, Trish Brown-Augsburger, Jirong Lu, Chi-Kin Chow, Peter Vaillancourt, Ying Tang, Sau-Chi B. Yan, Ling Liu. LY2875358, a bivalent MET antibody with anti-tumor activity through blocking HGF as well as inducing degradation of MET, differentiates from a one-armed 5D5 MET antibody. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5465. doi:10.1158/1538-7445.AM2013-5465
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