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Author (up) Akhurst, R.J.; Hata, A. file  url
openurl 
  Title Targeting the TGFbeta signalling pathway in disease Type Journal Article
  Year 2012 Publication Nature Reviews. Drug Discovery Abbreviated Journal Nat Rev Drug Discov  
  Volume 11 Issue 10 Pages 790-811  
  Keywords Animals; Drug Delivery Systems/*methods; Humans; Protein Binding/physiology; Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism; Signal Transduction/drug effects/*physiology; Transforming Growth Factor beta/*antagonists & inhibitors/*physiology  
  Abstract Many drugs that target transforming growth factor-beta (TGFbeta) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFbeta signalling pathway is a drug target, the potential clinical applications of TGFbeta inhibition, the issues arising with anti-TGFbeta therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.  
  Call Number Serial 1548  
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Author (up) Atherton, P.J.; Babraj, J.; Smith, K.; Singh, J.; Rennie, M.J.; Wackerhage, H. file  url
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  Title Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation Type Journal Article
  Year 2005 Publication FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology Abbreviated Journal Faseb J  
  Volume 19 Issue 7 Pages 786-788  
  Keywords Adaptation, Physiological; Adenylate Kinase/*metabolism; Animals; Electric Stimulation; Enzyme Activation; Male; Mitogen-Activated Protein Kinases/metabolism; Muscle Contraction; Muscle Proteins/biosynthesis; Muscle, Skeletal/*physiology; Myofibrils/metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Physical Conditioning, Animal; Physical Endurance/physiology; Physical Exertion; Protein Kinases/*metabolism; Proto-Oncogene Proteins c-akt/*metabolism; RNA-Binding Proteins/*metabolism; Rats; Rats, Wistar; Sarcoplasmic Reticulum/metabolism; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors/*metabolism; Tumor Suppressor Proteins/*metabolism  
  Abstract Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the “AMPK-PKB switch.” We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.  
  Call Number Serial 2075  
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Author (up) Blair, J.M.A.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J.V. file  url
doi  openurl
  Title Molecular mechanisms of antibiotic resistance Type Journal Article
  Year 2015 Publication Nature Reviews. Microbiology Abbreviated Journal Nat Rev Microbiol  
  Volume 13 Issue 1 Pages 42-51  
  Keywords *Anti-Bacterial Agents/metabolism/pharmacology; *Bacteria/drug effects/metabolism/pathogenicity; *Drug Resistance, Bacterial; Signal Transduction  
  Abstract Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.  
  Call Number Serial 1136  
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Author (up) Bonello, T.T.; Stehn, J.R.; Gunning, P.W. file  url
openurl 
  Title New approaches to targeting the actin cytoskeleton for chemotherapy Type Journal Article
  Year 2009 Publication Future Medicinal Chemistry Abbreviated Journal Future Med Chem  
  Volume 1 Issue 7 Pages 1311-1331  
  Keywords Actin Cytoskeleton/chemistry/*drug effects/physiology; Actin-Related Protein 2-3 Complex/genetics/metabolism; Cortactin/genetics/metabolism; Destrin/genetics/metabolism; Gelsolin/genetics/metabolism; Humans; Microfilament Proteins/*antagonists & inhibitors/chemistry; Myosin Type II/genetics/metabolism; Neoplasms/drug therapy/metabolism; Signal Transduction; Tropomyosin/genetics/metabolism; Wiskott-Aldrich Syndrome Protein Family/genetics/metabolism  
  Abstract The actin cytoskeleton is indispensable for normal cellular function. In particular, several actin-based structures coordinate cellular motility, a process hijacked by tumor cells in order to facilitate their propagation to distant sites. The actin cytoskeleton, therefore, represents a point for chemotherapeutic intervention. The challenge in disrupting the actin cytoskeleton is in preserving actin-driven contraction of cardiac and skeletal muscle. By targeting actin-binding proteins with altered expression in malignancy, it may be possible to achieve tumor-specific toxicity. A number of actin-binding proteins act cooperatively and synergistically to regulate actin structures required for motility. The actin cytoskeleton is characterized by a significant degree of plasticity. Targeting specific actin-binding proteins for chemotherapy will only be successful if no other compensatory mechanisms exist.  
  Call Number Serial 1054  
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Author (up) Bonello, T.T.; Stehn, J.R.; Gunning, P.W. file  url
doi  openurl
  Title New approaches to targeting the actin cytoskeleton for chemotherapy Type Journal Article
  Year 2009 Publication Future Medicinal Chemistry Abbreviated Journal Future Med Chem  
  Volume 1 Issue 7 Pages 1311-1331  
  Keywords Actin Cytoskeleton/chemistry/*drug effects/physiology; Actin-Related Protein 2-3 Complex/genetics/metabolism; Cortactin/genetics/metabolism; Destrin/genetics/metabolism; Gelsolin/genetics/metabolism; Humans; Microfilament Proteins/*antagonists & inhibitors/chemistry; Myosin Type II/genetics/metabolism; Neoplasms/drug therapy/metabolism; Signal Transduction; Tropomyosin/genetics/metabolism; Wiskott-Aldrich Syndrome Protein Family/genetics/metabolism  
  Abstract The actin cytoskeleton is indispensable for normal cellular function. In particular, several actin-based structures coordinate cellular motility, a process hijacked by tumor cells in order to facilitate their propagation to distant sites. The actin cytoskeleton, therefore, represents a point for chemotherapeutic intervention. The challenge in disrupting the actin cytoskeleton is in preserving actin-driven contraction of cardiac and skeletal muscle. By targeting actin-binding proteins with altered expression in malignancy, it may be possible to achieve tumor-specific toxicity. A number of actin-binding proteins act cooperatively and synergistically to regulate actin structures required for motility. The actin cytoskeleton is characterized by a significant degree of plasticity. Targeting specific actin-binding proteins for chemotherapy will only be successful if no other compensatory mechanisms exist.  
  Call Number Serial 1081  
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