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Malcolm R. Clench - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate Protein Induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein Induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of Protein Induction following treatment could yield insights into resistance mechanisms. The distribution of a number of Proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in Proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-Protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified Proteins to their functional partners.
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Investigation of Protein Induction in tumour vascular targeted strategies by MALDI MSI.
Methods (San Diego Calif.), 2011Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Emmanuelle Claude, M-c Djidja, Malcolm R. ClenchAbstract:Characterising the Protein signatures in tumours following vascular-targeted therapy will help determine both treatment response and resistance mechanisms. Here, mass spectrometry imaging and MS/MS with and without ion mobility separation have been used for this purpose in a mouse fibrosarcoma model following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P). Characterisation of peptides after in situ tissue tryptic digestion was carried out using Matrix-Assisted Laser Desorption/Ionisation-Mass Spectrometry (MALDI-MS) and Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Mass Spectrometry Imaging (MALDI IMS-MSI) to observe the spatial distribution of peptides. Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Tandem Mass Spectrometry (MALDI-IMS-MS/MS) of peaks was performed to elucidate any pharmacological responses and potential biomarkers. By taking tumour samples at a number of time points after treatment gross changes in the tissue were indicated by changes in the signal levels of certain peptides. These were identified as arising from haemoglobin and indicated the disruption of the tumour vasculature. It was hoped that the use of PCA-DA would reveal more subtle changes taking place in the tumour samples however these are masked by the dominance of the changes in the haemoglobin signals.
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Investigation of Protein Induction in tumour vascular targeted strategies
2011Co-Authors: Joanne E. Bluff, Martyn N.j. Paley, Emmanuelle Claude, Malcolm R. ClenchAbstract:Characterising the Protein signatures in tumours following vascular-targeted therapy will help determine both treatment response and resistance mechanisms. Here, mass spectrometry imaging and MS/MS with and without ion mobility separation have been used for this purpose in a mouse fibrosarcoma model following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P). Characterisation of peptides after in situ tissue tryptic digestion was carried out using Matrix-Assisted Laser Desorption/Ionisation-Mass Spectrometry (MALDI-MS) and Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Mass Spectrometry Imaging (MALDI IMS-MSI) to observe the spatial distribution of peptides. Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility SeparationTandem Mass Spectrometry (MALDI-IMS-MS/MS) of peaks was performed to elucidate any pharmacological responses and potential biomarkers. By taking tumour samples at a number of time points after treatment gross changes in the tissue were indicated by changes in the signal levels of certain peptides. These were identified as arising from haemoglobin and indicated the disruption of the tumour vasculature. It was hoped that the use of PCA-DA would reveal more subtle changes taking place in the tumour samples however these are masked by the dominance of the changes in the haemoglobin signals.
Laura M. Cole - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate Protein Induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein Induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of Protein Induction following treatment could yield insights into resistance mechanisms. The distribution of a number of Proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in Proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-Protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified Proteins to their functional partners.
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Investigation of Protein Induction in vascular-targeted strategies
2013Co-Authors: Laura M. ColeAbstract:The aims of the study reported in this thesis were to develop and utilise mass spectrometry imaging techniques (MALDI-MSI), in combination with conventional proteomic methodologies, to investigate Protein Induction in vascular-targeted strategies. Proteins thought to be involved in tumourigenesis and drug treatment resistance were observed along with the responses from Proteins identified via the techniques used, in this global analysis study. MALDI-MSI, LC-ESI-MS/MS, LC-MALDI-MS/MS with iTRAQ labelling and immunohistochemistry intended to provide cross validation of the effects post administration of vascular disrupting agent CA-4-P. Two mouse fibrosarcoma models (expressing VEGF120/ VEGF188 isoforms only) following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P) have been studied. The gross haemorrhagic pharmacological response elicited by CA-4-P was visible by MALDI-MSI throughout the fibrosarcoma 120 time course. The latter encouraged the prospect that other Proteins could potentially be observed induced via a dose response relationship. The haemoglobin time course using the resistant 188 tumour model gave quite different results to those previously seen in the MALDI-MSI of the fibrosarcoma 120 data set. The first indication of the 'switch back to tissue viability' concept was revealed. The experimental work using LC-ESI-MS/MS revealed many Proteins connected with necrosis, apoptosis, cell structural reorganisation, polymerisation, tumour survival and stress induced molecular chaperones. The inverse correlation of structural Proteins, haemoglobin and heat shock molecular chaperones gave the required validation and identification to relate these responses to those seen in MALDI-MSI. The relationship pathways generated by using STRING 9.0 proteomic network software gave an invaluable insight into the activity of the active tumour milieu and provided a means of linking the identified Proteins to their functional partners. Protein-Protein interactions could be observed to help interpretation of the MALDI-MSI, LC-ESI-MS/MS and iTRAQ LC-ESI-MS/MS response graphs. Overall, the dose relationships observed in the iTRAQ data by the Proteins involved in haemorrhaging, structural remodelling, were in good agreement with the other techniques employed here.It could be said that MALDI-MSI could potentially forge a place in the workflow of clinical diagnostics. Targeted approaches for the observation of disease biomarkers could be visualised using MALDI-MSI and serve as a complimentary technique to standard clinical imaging. A novel method reported here using a multi-peptide recombinant standard could prove an important diagnostic tool for the analysis of patient biopsies and tissue micro-arrays. The exciting prospect is the diversity of a multi-peptide recombinant standard, an artificial construct that can be engineered to include any prospective biomarkers for both research and diagnostic screening applications.
Joanne E. Bluff - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate Protein Induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein Induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of Protein Induction following treatment could yield insights into resistance mechanisms. The distribution of a number of Proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in Proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-Protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified Proteins to their functional partners.
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Investigation of Protein Induction in tumour vascular targeted strategies by MALDI MSI.
Methods (San Diego Calif.), 2011Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Emmanuelle Claude, M-c Djidja, Malcolm R. ClenchAbstract:Characterising the Protein signatures in tumours following vascular-targeted therapy will help determine both treatment response and resistance mechanisms. Here, mass spectrometry imaging and MS/MS with and without ion mobility separation have been used for this purpose in a mouse fibrosarcoma model following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P). Characterisation of peptides after in situ tissue tryptic digestion was carried out using Matrix-Assisted Laser Desorption/Ionisation-Mass Spectrometry (MALDI-MS) and Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Mass Spectrometry Imaging (MALDI IMS-MSI) to observe the spatial distribution of peptides. Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Tandem Mass Spectrometry (MALDI-IMS-MS/MS) of peaks was performed to elucidate any pharmacological responses and potential biomarkers. By taking tumour samples at a number of time points after treatment gross changes in the tissue were indicated by changes in the signal levels of certain peptides. These were identified as arising from haemoglobin and indicated the disruption of the tumour vasculature. It was hoped that the use of PCA-DA would reveal more subtle changes taking place in the tumour samples however these are masked by the dominance of the changes in the haemoglobin signals.
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Investigation of Protein Induction in tumour vascular targeted strategies
2011Co-Authors: Joanne E. Bluff, Martyn N.j. Paley, Emmanuelle Claude, Malcolm R. ClenchAbstract:Characterising the Protein signatures in tumours following vascular-targeted therapy will help determine both treatment response and resistance mechanisms. Here, mass spectrometry imaging and MS/MS with and without ion mobility separation have been used for this purpose in a mouse fibrosarcoma model following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P). Characterisation of peptides after in situ tissue tryptic digestion was carried out using Matrix-Assisted Laser Desorption/Ionisation-Mass Spectrometry (MALDI-MS) and Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Mass Spectrometry Imaging (MALDI IMS-MSI) to observe the spatial distribution of peptides. Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility SeparationTandem Mass Spectrometry (MALDI-IMS-MS/MS) of peaks was performed to elucidate any pharmacological responses and potential biomarkers. By taking tumour samples at a number of time points after treatment gross changes in the tissue were indicated by changes in the signal levels of certain peptides. These were identified as arising from haemoglobin and indicated the disruption of the tumour vasculature. It was hoped that the use of PCA-DA would reveal more subtle changes taking place in the tumour samples however these are masked by the dominance of the changes in the haemoglobin signals.
Ki Churl Chang - One of the best experts on this subject based on the ideXlab platform.
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regulation of lipopolysaccharide induced inducible nitric oxide synthase expression through the nuclear factor κb pathway and interferon β tyrosine kinase 2 janus tyrosine kinase 2 signal transducer and activator of transcription 1 signaling cascades
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Konstantin Tsoyi, Youngjin Kang, Min Kyu Park, Hye Sook Yunchoi, Ki Churl ChangAbstract:The effects of 2-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), on nitric oxide (NO) production and inducible nitric-oxide synthase (iNOS) Protein Induction by lipopolysaccharide (LPS) were investigated in RAW 264.7 cells and mice. In cells, THI 53 concentration dependently reduced NO production and iNOS Protein Induction by LPS. In addition, THI 53 inhibited NO production and iNOS Protein Induction in LPS-treated mice. LPS-mediated iNOS Protein Induction was inhibited significantly by the specific tyrosine kinase inhibitor α-cyano-(3-hydroxy-4-nitro)cinnamonitrile (AG126) as well as by THI 53. In addition, a c-Jun NH2-terminal kinase (JNK) inhibitor anthra[1,9- cd ]pyrazole-6 (2 H )-one) (SP600125) but not an extracellular regulated kinase inhibitor [2-(2-amino-3-methoxyphenyl)-4 H -1-benzopyran-4-one (PD98029)] or a p38 inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1 H -imidazole (SB230580)] reduced the iNOS Protein level induced by LPS. Moreover, a Janus kinase 2 (JAK2) inhibitor α-cyano-(3,4-dihydroxy)- N -benzylcinnamide (AG490) dose-dependently prevented LPS-mediated iNOS Protein Induction. LPS activated phosphorylations of tyrosine kinases, especially tyrosine kinase 2 (Tyk2) and signal transducer and activator of transcription-1 (STAT-1); these were reduced by THI 53. LPS also phosphorylated the JNK pathway; however, this phosphorylation was unaffected by THI 53. Interestingly, a JNK inhibitor (SP600125) and another tyrosine kinase inhibitor (genistein) significantly inhibited STAT-1 phosphorylation, suggesting that the LPS-activated JNK pathway and a tyrosine kinase pathway (especially Tyk2) may link to the STAT-1 pathway, which is involved in iNOS Induction. However, THI 53 regulates LPS-mediated iNOS Protein Induction by affecting the Tyk2/JAK2-STAT-1 pathway, not the JNK pathway. The inhibition by THI 53 of LPS-induced NO production was recovered by a tyrosine phosphatase inhibitor (Na3VO4), which supports the possibility that THI 53 inhibits the LPS-induced inflammatory response through regulation of tyrosine kinase pathways. THI 53 also inhibited LPS-mediated interferon (IFN)-β production and nuclear factor-κB (NF-κB) activation. Thus, THI 53 may regulate LPS-mediated inflammatory response through both the NF-κB and IFN-β/Tyk2/JAK2-STAT-1 pathways.
Martyn N.j. Paley - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate Protein Induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein Induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of Protein Induction following treatment could yield insights into resistance mechanisms. The distribution of a number of Proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in Proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-Protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified Proteins to their functional partners.
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Investigation of Protein Induction in tumour vascular targeted strategies by MALDI MSI.
Methods (San Diego Calif.), 2011Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Emmanuelle Claude, M-c Djidja, Malcolm R. ClenchAbstract:Characterising the Protein signatures in tumours following vascular-targeted therapy will help determine both treatment response and resistance mechanisms. Here, mass spectrometry imaging and MS/MS with and without ion mobility separation have been used for this purpose in a mouse fibrosarcoma model following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P). Characterisation of peptides after in situ tissue tryptic digestion was carried out using Matrix-Assisted Laser Desorption/Ionisation-Mass Spectrometry (MALDI-MS) and Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Mass Spectrometry Imaging (MALDI IMS-MSI) to observe the spatial distribution of peptides. Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Tandem Mass Spectrometry (MALDI-IMS-MS/MS) of peaks was performed to elucidate any pharmacological responses and potential biomarkers. By taking tumour samples at a number of time points after treatment gross changes in the tissue were indicated by changes in the signal levels of certain peptides. These were identified as arising from haemoglobin and indicated the disruption of the tumour vasculature. It was hoped that the use of PCA-DA would reveal more subtle changes taking place in the tumour samples however these are masked by the dominance of the changes in the haemoglobin signals.
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Investigation of Protein Induction in tumour vascular targeted strategies
2011Co-Authors: Joanne E. Bluff, Martyn N.j. Paley, Emmanuelle Claude, Malcolm R. ClenchAbstract:Characterising the Protein signatures in tumours following vascular-targeted therapy will help determine both treatment response and resistance mechanisms. Here, mass spectrometry imaging and MS/MS with and without ion mobility separation have been used for this purpose in a mouse fibrosarcoma model following treatment with the tubulin-binding tumour vascular disrupting agent, combretastatin A-4-phosphate (CA-4-P). Characterisation of peptides after in situ tissue tryptic digestion was carried out using Matrix-Assisted Laser Desorption/Ionisation-Mass Spectrometry (MALDI-MS) and Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility Separation-Mass Spectrometry Imaging (MALDI IMS-MSI) to observe the spatial distribution of peptides. Matrix-Assisted Laser Desorption/Ionisation-Ion Mobility SeparationTandem Mass Spectrometry (MALDI-IMS-MS/MS) of peaks was performed to elucidate any pharmacological responses and potential biomarkers. By taking tumour samples at a number of time points after treatment gross changes in the tissue were indicated by changes in the signal levels of certain peptides. These were identified as arising from haemoglobin and indicated the disruption of the tumour vasculature. It was hoped that the use of PCA-DA would reveal more subtle changes taking place in the tumour samples however these are masked by the dominance of the changes in the haemoglobin signals.
