Search

Copyright of Canadian Journal of Forest Research is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Although knee inflammation is thought to adversely affect joint function in patients with knee osteoarthritis (OA), the effects of reducing knee inflammation on gait biomechanics and strength are unknown. Our objectives were to compare ultrasound (US) measures of knee inflammation, gait biomechanics, knee extension and flexion strength, and pain before and after knee aspiration and glucocorticoid injection, and to explore associations among changes. Methods: Forty‐nine patients (69 knees) with symptomatic knee OA and synovitis were tested before and 3–4 weeks after US‐guided knee aspiration and glucocorticoid injection. At each visit, participants completed US assessments for inflammatory features of knee OA, 3D gait analysis, isokinetic knee extension and flexion strength tests, and Knee Osteoarthritis Outcome Score (KOOS) pain subscales. Linear and polynomial mixed‐effects regression models were used to investigate changes and their associations. Results: Changes were observed for the synovitis score (unstandardized β [post‐injection minus pre‐injection] –0.55/9 [95% confidence interval (95% CI) –0.97, –0.12]), effusion depth (–1.05 mm [95% CI –1.07, –0.39]), KOOS pain (unstandardized β 5.91/100 [95% CI 1.86, 9.97]), peak external knee flexion and extension moments (KFM; 3.33 Nm [95% CI 0.45, 6.22]), KEM (–2.99 Nm [95% CI –5.93, –0.05]), and knee extension strength (4.70 Nm [95% CI 0.39, 9.00]) and flexion strength (3.91 Nm [95% CI 1.50, 6.81]). The external KFM increased during 13–38% and 76–89% of stance post‐injection. When controlled for time, greater synovitis was associated with lower knee extension strength, while lower pain was associated with increased knee extension and flexion strength. Conclusion: In patients with knee OA and synovitis, reduced inflammation and pain after aspiration and glucocorticoid injection are associated with changes in knee gait biomechanics and strength. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is strongly associated with malignant progression such as increased cell invasion and metastasis. Although the invasion-related genes affected by hypoxia have been well described, the contribution of post-transcriptional mechanisms such as protein trafficking and proprotein processing associated with the hypoxic response remains poorly understood. The proprotein convertase furin, the major processing enzyme of the secretory pathway, resides in the trans-Golgi network and most studies support a model where endogenous substrates are processed by furin within this compartment. Here, we report that hypoxia triggered an unexpected relocalization of furin from the trans-Golgi network to endosomomal compartments and the cell surface in cancer cells. Exposing these cells back to normoxic conditions reversed furin redistribution, suggesting that the tumor microenvironment modulates furin trafficking in a highly regulated manner. Assessment of the mechanisms involved revealed that both Rab4GTPase-dependent recycling and interaction of furin with the cytoskeletal anchoring protein, filamin-A, are essential for the cell surface relocalization of furin. Interference with the association of furin with filamin-A, prevented cell surface relocalization of furin and abolished the ability of cancer cells to migrate in response to hypoxia. Our observations support the notion that hypoxia promotes the formation of a peripheral processing compartment where furin translocates for enhanced processing of proproteins involved in tumorigenesis. J. Cell. Physiol. 227: 789-800, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: CGS 35601 is a potent triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin-converting enzyme (ECE). The aim of the study was to determine the effects of this VPI on the hemodynamic profile of conscious, instrumented, unrestrained spontaneously hypertensive rats (SHR), in comparison to selective inhibitors of ACE and ACE + NEP, than +ECE combined. Circulating plasma concentrations of vasoactive mediators and reactive oxygen species were measured. Methods: Old SHR male were instrumented (arterial catheter) and placed in a metabolic cage for daily hemodynamic measurements and blood samplings. Seven days after surgery, SHR received 1) saline vehicle; 2) increasing doses of the triple CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/d, intra-arterially (i.a.) infusion for 5 d/dose) followed by a 5-day washout period; 3) benazepril (ACE inhibitor), ACE inhibitor + CGS 24592 (NEP inhibitor) and ACE inhibitor + NEP inhibitor + CGS 35066 (ECE inhibitor) (1 or 5 mg/kg/d i.a. infusion for 5 d/combination) followed by a 5-day washout period. Results: The lowest dose of CGS 35601 had no effect. Doses at 0.1, 1, and 5 mg/kg/d reduced mean arterial blood pressure by 10%, 22%, and 40%, respectively. Heart rate was unaffected in all groups. CGS 35601 decreased concentrations of angiotensin II (Ang II), endothelin-1 (ET-1), and pro-atrial natriuretic peptide (proANP), and increased those of big ET-1, atrial natriuretic peptide (ANP), bradykinin (BK), and hydrogen peroxide (H2O2) dose dependently. Conclusions: The blood pressure-lowering effect of this triple VPI was superior to that of the other VPI in this preclinical rat model of hypertension. Further experiments are needed to assess triple VPI to other combinations in other models with regard to efficacy and angioedema. Only then it may constitute a first-in-class approach for the treatment of hypertension and other cardiovascular disorders. [Copyright &y& Elsevier]

Colorectal cancer (CRC) is a progressive disorder associated with an accumulation of multiple heterogeneous genetic alterations in intestinal epithelial cells (IEC). However, when these cells undergo neoplastic transformation and become cancerous and metastatic, they invariably acquire hallmarks conferring them the ability to hyperproliferate, escape growth-inhibitory and death-inducing cues, and promote angiogenesis as well as epithelial-to-mesenchymal transformation (EMT), fostering their invasive dissemination from primary tumor into distant tissues. Compelling clinical and experimental evidence suggest that aberrant engagement of cell surface growth factor receptor tyrosine kinase (RTK) signaling, like that of the hepatocyte growth factor (HGF)/MET receptor, underlies CRC metastatic progression by promoting these cancer hallmarks. To date, though, the use of RTK-targeting agents has been viewed as a promising approach for the treatment of metastatic CRC, clinical success has been modest.Our vision is that the prospect of designing RTK-based, improved and innovative CRC therapies and prognostic markers likely rests on a comprehensive understanding of the biological processes and underlying regulatory molecular mechanisms by which deregulation of RTK signaling governs IEC's neoplastic transformation and their transition from noninvasive to metastatic and malignant cells. Herein, we describe our scheme for defining the full scope of oncogenic MET-driven cancer biological processes, in cellulo and in vivo, as well as the individual contribution of MET-binding effectors in a nontransformed IEC model, the IEC-6 cell line.