The Experts below are selected from a list of 15603 Experts worldwide ranked by ideXlab platform
Andrew Wilcock - One of the best experts on this subject based on the ideXlab platform.
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Short-term integrated rehabilitation for people with newly diagnosed Thoracic Cancer: a multi-centre randomized controlled feasibility trial:
Clinical Rehabilitation, 2019Co-Authors: Joanne Bayly, Andrew Wilcock, Lucy Fettes, Eleanor Douglas, Maria J Teixiera, Nicola Peat, India Tunnard, Vishit Patel, Wei Gao, Irene J HigginsonAbstract:Objectives:The main objective of this study is to determine the feasibility of recruiting and retaining patients recently diagnosed with Thoracic Cancer to a trial of short-term integrated rehabili...
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Holistic Needs of People with Thoracic Cancer Identified by the Sheffield Profile for Assessment and Referral to Care Questionnaire
Journal of Palliative Medicine, 2019Co-Authors: Andrew Wilcock, Asmah Hussain, Matthew MaddocksAbstract:Abstract Background: A holistic needs assessment is recommended in people with Cancer at key stages, including soon after diagnosis. For people with Thoracic Cancer, there is a lack of data obtaine...
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Developing an integrated rehabilitation model for Thoracic Cancer services: views of patients, informal carers and clinicians.
Pilot and Feasibility Studies, 2018Co-Authors: Joanne Bayly, Andrew Wilcock, Nicola Peat, Irene J Higginson, Bethany Mary Edwards, Geoffrey Warwick, I. Hennig, Arvind Arora, Matthew MaddocksAbstract:Access to rehabilitation to prevent disability and optimise function is recommended for patients with Cancer, including following Cancer diagnosis. Models to integrate rehabilitation within oncology services as Cancer treatment commences are required, but must be informed by those they are intended to support. We aimed to identify views of patients, carers and clinicians to develop and refine a rehabilitation model to be tested in a feasibility trial for people newly diagnosed with lung Cancer or mesothelioma. We conducted a focus group study with people affected by lung Cancer or mesothelioma, their carers and clinicians providing their care to identify priorities for rehabilitation in this period. We sought views on core intervention components, processes and outcomes and integration with oncology services. Data were analysed using thematic analysis. Fifteen clinicians (oncologists, nurse specialists, physiotherapists and occupational therapists), nine patients and five carers participated. A proposed outline rehabilitation model was perceived as highly relevant for this population. Participants recommended prompt and brief rehabilitation input, delivered whilst people attend for hospital appointments or at home to maximise accessibility and acceptability. Participants recognised variation in need and all prioritised tailored support for symptom self-management, daily activities and the involvement of carers. Clinicians also prioritised achieving fitness for oncology treatment. Patients and carers prioritised a sensitive manner of approach, positivity and giving hope for the future. Participant’s recommendations for outcome measurement related to confidence in usual daily activities, symptom control and oncology treatment completion rates over objective measures of cardiorespiratory fitness. The importance of providing tailored rehabilitation around the time of diagnosis for people with lung Cancer or mesothelioma was affirmed by all participants. The refined model of rehabilitation recommended for testing in a feasibility trial is flexible, tailored and short-term. It aims to support people to self-manage symptoms, tolerate Cancer treatments and to remain active and independent in daily life. It is delivered alongside scheduled hospital appointments or at home by an expert practitioner sensitive to the psycho-social sequelae that follow a diagnosis of Thoracic Cancer.
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Changing health behaviour with rehabilitation in Thoracic Cancer: A systematic review and synthesis.
Psycho-Oncology, 2018Co-Authors: Joanne Bayly, Andrew Wilcock, Irene J Higginson, Dominique Wakefield, Nilay Hepgul, Matthew MaddocksAbstract:Objectives: International guidelines recommend that rehabilitation be offered to people with Thoracic Cancer to improve symptoms, function and quality of life. When rehabilitation interventions require a change in behaviour, the use of theory and behaviour change techniques (BCTs) enhance participation. Our objective was to systematically identify BCTs and examine their use in relation to the Capability,Opportunity,Motivation-Behaviour model and known enablers and barriers to engagement in this population. Method: Bibliographic databases and grey literature were searched for controlled trials of rehabilitation interventions for adults with lung Cancer or mesothelioma, with no limits on language or date. Data on the application of behavioural change theory and BCTs were extracted, categorized using the BCT Taxonomy (v1) and described according to the ‘Capability, Opportunity, Motivation-Behaviour' model. Results: Twenty-seven studies of exercise (n=15) and symptom self-management (n=12) interventions were identified. Four studies reported use of behavioural change theory, one study used symptom theory. Across studies, a mean (range) of 7 (1-18) BCTs were used, representing 26 of 93 possible BCTs included in the taxonomy. Most frequent enabling BCTs were ‘instructions on how to perform behaviours' (74%), ‘behavioural practice' (74%) and ‘action planning' (70%). BCTs to address barriers were less frequent and included ‘information about health consequences' (22%), and ‘verbal persuasion about capability' (7%) to change perceptions about benefits, burden and harms. Conclusion: The application of behavioural change tools appears sub-optimal in this group of patients. Explicit use of BCTs targeting behavioural components upon which outcomes depend may improve the uptake and effectiveness of rehabilitation interventions.
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Changing health behaviour with rehabilitation in Thoracic Cancer: A systematic review and synthesis.
Psycho-oncology, 2018Co-Authors: Joanne Bayly, Andrew Wilcock, Irene J Higginson, Dominique Wakefield, Nilay Hepgul, Matthew MaddocksAbstract:International guidelines recommend that rehabilitation be offered to people with Thoracic Cancer to improve symptoms, function, and quality of life. When rehabilitation interventions require a change in behaviour, the use of theory and behaviour change techniques (BCTs) enhance participation. Our objective was to systematically identify BCTs and examine their use in relation to the Capability, Opportunity, Motivation-Behaviour model and known enablers and barriers to engagement in this population. Bibliographic databases and grey literature were searched for controlled trials of rehabilitation interventions for adults with lung Cancer or mesothelioma, with no limits on language or date. Data on the application of behavioural change theory and BCTs were extracted, categorised using the BCT Taxonomy (v1) and described according to the "Capability, Opportunity, Motivation-Behaviour" model. Twenty-seven studies of exercise (n = 15) and symptom self-management (n = 12) interventions were identified. Four studies reported use of behavioural change theory; one study used symptom theory. Across studies, a mean (range) of 7 (1-18) BCTs were used, representing 26 of 93 possible BCTs included in the taxonomy. Most frequent enabling BCTs were "instructions on how to perform behaviours" (74%), "behavioural practice" (74%), and "action planning" (70%). BCTs to address barriers were less frequent and included "information about health consequences" (22%) and "verbal persuasion about capability" (7%) to change perceptions about benefits, burden, and harms. The application of behavioural change tools appears sub-optimal in this group of patients. Explicit use of BCTs targeting behavioural components upon which outcomes depend may improve the uptake and effectiveness of rehabilitation interventions. Copyright © 2018 John Wiley & Sons, Ltd.
Matthew Maddocks - One of the best experts on this subject based on the ideXlab platform.
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Holistic Needs of People with Thoracic Cancer Identified by the Sheffield Profile for Assessment and Referral to Care Questionnaire
Journal of Palliative Medicine, 2019Co-Authors: Andrew Wilcock, Asmah Hussain, Matthew MaddocksAbstract:Abstract Background: A holistic needs assessment is recommended in people with Cancer at key stages, including soon after diagnosis. For people with Thoracic Cancer, there is a lack of data obtaine...
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Developing an integrated rehabilitation model for Thoracic Cancer services: views of patients, informal carers and clinicians.
Pilot and Feasibility Studies, 2018Co-Authors: Joanne Bayly, Andrew Wilcock, Nicola Peat, Irene J Higginson, Bethany Mary Edwards, Geoffrey Warwick, I. Hennig, Arvind Arora, Matthew MaddocksAbstract:Access to rehabilitation to prevent disability and optimise function is recommended for patients with Cancer, including following Cancer diagnosis. Models to integrate rehabilitation within oncology services as Cancer treatment commences are required, but must be informed by those they are intended to support. We aimed to identify views of patients, carers and clinicians to develop and refine a rehabilitation model to be tested in a feasibility trial for people newly diagnosed with lung Cancer or mesothelioma. We conducted a focus group study with people affected by lung Cancer or mesothelioma, their carers and clinicians providing their care to identify priorities for rehabilitation in this period. We sought views on core intervention components, processes and outcomes and integration with oncology services. Data were analysed using thematic analysis. Fifteen clinicians (oncologists, nurse specialists, physiotherapists and occupational therapists), nine patients and five carers participated. A proposed outline rehabilitation model was perceived as highly relevant for this population. Participants recommended prompt and brief rehabilitation input, delivered whilst people attend for hospital appointments or at home to maximise accessibility and acceptability. Participants recognised variation in need and all prioritised tailored support for symptom self-management, daily activities and the involvement of carers. Clinicians also prioritised achieving fitness for oncology treatment. Patients and carers prioritised a sensitive manner of approach, positivity and giving hope for the future. Participant’s recommendations for outcome measurement related to confidence in usual daily activities, symptom control and oncology treatment completion rates over objective measures of cardiorespiratory fitness. The importance of providing tailored rehabilitation around the time of diagnosis for people with lung Cancer or mesothelioma was affirmed by all participants. The refined model of rehabilitation recommended for testing in a feasibility trial is flexible, tailored and short-term. It aims to support people to self-manage symptoms, tolerate Cancer treatments and to remain active and independent in daily life. It is delivered alongside scheduled hospital appointments or at home by an expert practitioner sensitive to the psycho-social sequelae that follow a diagnosis of Thoracic Cancer.
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Changing health behaviour with rehabilitation in Thoracic Cancer: A systematic review and synthesis.
Psycho-Oncology, 2018Co-Authors: Joanne Bayly, Andrew Wilcock, Irene J Higginson, Dominique Wakefield, Nilay Hepgul, Matthew MaddocksAbstract:Objectives: International guidelines recommend that rehabilitation be offered to people with Thoracic Cancer to improve symptoms, function and quality of life. When rehabilitation interventions require a change in behaviour, the use of theory and behaviour change techniques (BCTs) enhance participation. Our objective was to systematically identify BCTs and examine their use in relation to the Capability,Opportunity,Motivation-Behaviour model and known enablers and barriers to engagement in this population. Method: Bibliographic databases and grey literature were searched for controlled trials of rehabilitation interventions for adults with lung Cancer or mesothelioma, with no limits on language or date. Data on the application of behavioural change theory and BCTs were extracted, categorized using the BCT Taxonomy (v1) and described according to the ‘Capability, Opportunity, Motivation-Behaviour' model. Results: Twenty-seven studies of exercise (n=15) and symptom self-management (n=12) interventions were identified. Four studies reported use of behavioural change theory, one study used symptom theory. Across studies, a mean (range) of 7 (1-18) BCTs were used, representing 26 of 93 possible BCTs included in the taxonomy. Most frequent enabling BCTs were ‘instructions on how to perform behaviours' (74%), ‘behavioural practice' (74%) and ‘action planning' (70%). BCTs to address barriers were less frequent and included ‘information about health consequences' (22%), and ‘verbal persuasion about capability' (7%) to change perceptions about benefits, burden and harms. Conclusion: The application of behavioural change tools appears sub-optimal in this group of patients. Explicit use of BCTs targeting behavioural components upon which outcomes depend may improve the uptake and effectiveness of rehabilitation interventions.
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Changing health behaviour with rehabilitation in Thoracic Cancer: A systematic review and synthesis.
Psycho-oncology, 2018Co-Authors: Joanne Bayly, Andrew Wilcock, Irene J Higginson, Dominique Wakefield, Nilay Hepgul, Matthew MaddocksAbstract:International guidelines recommend that rehabilitation be offered to people with Thoracic Cancer to improve symptoms, function, and quality of life. When rehabilitation interventions require a change in behaviour, the use of theory and behaviour change techniques (BCTs) enhance participation. Our objective was to systematically identify BCTs and examine their use in relation to the Capability, Opportunity, Motivation-Behaviour model and known enablers and barriers to engagement in this population. Bibliographic databases and grey literature were searched for controlled trials of rehabilitation interventions for adults with lung Cancer or mesothelioma, with no limits on language or date. Data on the application of behavioural change theory and BCTs were extracted, categorised using the BCT Taxonomy (v1) and described according to the "Capability, Opportunity, Motivation-Behaviour" model. Twenty-seven studies of exercise (n = 15) and symptom self-management (n = 12) interventions were identified. Four studies reported use of behavioural change theory; one study used symptom theory. Across studies, a mean (range) of 7 (1-18) BCTs were used, representing 26 of 93 possible BCTs included in the taxonomy. Most frequent enabling BCTs were "instructions on how to perform behaviours" (74%), "behavioural practice" (74%), and "action planning" (70%). BCTs to address barriers were less frequent and included "information about health consequences" (22%) and "verbal persuasion about capability" (7%) to change perceptions about benefits, burden, and harms. The application of behavioural change tools appears sub-optimal in this group of patients. Explicit use of BCTs targeting behavioural components upon which outcomes depend may improve the uptake and effectiveness of rehabilitation interventions. Copyright © 2018 John Wiley & Sons, Ltd.
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Within and between day repeatability of the incremental shuttle walking test in patients with Thoracic Cancer
Respiratory Medicine, 2018Co-Authors: Andrew Wilcock, Cathann Manderson, Sim Koon, Vicky Taylor, Matthew MaddocksAbstract:Abstract Background Breathlessness is common in patients with Thoracic Cancer but difficult to manage. The Incremental Shuttle Walking Test (ISWT) can help assess new treatments, but its repeatability has not been described in this group. Aim To examine within and between day repeatability of the ISWT in this setting. Methods Patients with incurable Thoracic Cancer were recruited from outpatient clinics at a University Hospital. Two ISWTs were completed one hour apart on two consecutive days, with the first test for familiarization purposes only. Repeatability of distance walked was examined using Bland and Altman plots and assessed as the single determination (within subject) standard deviation of the difference between tests and its 95% range. Results Forty-one patients participated and completed all tests. Mean (SD) distance walked was 333 (134), 349 (129) and 353 (130) m over the three tests, with the mean difference significantly different from zero between days (16 m, 95% CI 8–24 m, P = 0.043) but not within days (5 m, 95% CI –2 to 12 m, P = 0.47). Within and between day single determination SD and 95% ranges were 30 (−31 to 91) m and 36 (−37 to 109) m respectively. Conclusions These data help inform the design of studies making use of the ISWT and the interpretation of their findings.
Duc M. Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Rapid and profound potentiation of Apo2L/TRAIL-mediated cytotoxicity and apoptosis in Thoracic Cancer cells by the histone deacetylase inhibitor Trichostatin A: the essential role of the mitochondria-mediated caspase activation cascade.
Apoptosis, 2006Co-Authors: Rishindra M Reddy, Wen Shuz Yeow, Aris Baras, Alex Chua, Duc M. Nguyen, David S. Schrump, Justin B Maxhimer, M. Firdos Ziauddin, Susan Shamimi-nooriAbstract:Apo2L/TRAIL is actively investigated as a novel targeted agent to directly induce apoptosis of susceptible Cancer cells. Apo2L/TRAIL-refractory cells can be sensitized to the cytotoxic effect of this ligand by cytotoxic chemotherapeutics. The aim of this study was to evaluate the in vitro tumoricidal activity of the Apo2L/TRAIL + Trichostatin A in cultured Thoracic Cancer cells and to elucidate the molecular basis of the synergistic cytotoxicity of this combination. Concurrent exposure of cultured Cancer cells to sublethal concentrations of Apo2L/TRAIL and Trichostatin A resulted in profound enhancement of Apo2L/TRAIL-mediated cytotoxicity in all cell lines regardless of their intrinsic susceptibility to this ligand. This combination was not toxic to primary normal cells. While Apo2L/TRAIL alone or Trichostatin A alone mediated < 20% cell death, 60 to 90% of Cancer cells were apoptotic following treatment with TSA + Apo2L/TRAIL combinations. Complete translocation of Bax from the cytosol to the mitochondria compartment was mainly observed in combination-treated cells and this was correlated with robust elevation of caspase 9 proteolytic activity indicative of activation of the mitochondria apoptogenic effect. Profound TSA + Apo2L/TRAIL–mediated cytotoxicity and apoptosis were completely abrogated by either Bcl2 over-expression or by the selective caspase 9 inhibitor, highlighting the essential role of mitochondria-dependent apoptosis signaling cascade in this process. Moreover, increased caspase 8 activity observed in cells treated with the TSA + Apo2L/TRAIL combination was completely suppressed by Bcl-2 over-expression or by the selective caspase 9 inhibitor indicating that the elevated caspase 8 activity in combination-treated cells was secondary to a mitochondria-mediated amplification feedback loop of caspase activation. These finding form the basis for further development of HDAC inhibitors + Apo2L/TRAIL combination as novel targeted therapy for Thoracic malignancies.
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valproic acid an antiepileptic drug with histone deacetylase inhibitory activity potentiates the cytotoxic effect of apo2l trail on cultured Thoracic Cancer cells through mitochondria dependent caspase activation
Neoplasia, 2006Co-Authors: Firdos M Ziauddin, Wen Shuz Yeow, Aris Baras, Alex Chua, David S. Schrump, Justin B Maxhimer, Rishindra M Reddy, Wilson Tsai, George W Cole, Duc M. NguyenAbstract:Inhibitors of histone deacetylases have been shown to enhance the sensitivity of Cancer cells to tumor necrosis factor–related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL–mediated cytotoxicity in cultured Thoracic Cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured Thoracic Cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5–5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of Cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for Thoracic Cancers. Neoplasia (2006) 8, 446–457
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Gossypol, a phytochemical with BH3-mimetic property, sensitizes cultured Thoracic Cancer cells to Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand.
The Journal of Thoracic and Cardiovascular Surgery, 2006Co-Authors: Wen Shuz Yeow, Aris Baras, Alex Chua, Duc M. Nguyen, Shailen S. Sehgal, David S. SchrumpAbstract:Objectives Chemotherapeutic agents sensitize Cancer cells to Apo2 ligand/tumor necrosis factor–related apoptosis-inducing ligand (Apo2L/TRAIL) via recruitment of the mitochondria-dependent activation of caspase and induction of apoptosis. This study was designed to evaluate whether gossypol, a phytochemical compound with BH3-mimetic property that functions as an inhibitor of Bcl2/BclXL, would sensitize cultured Thoracic Cancer cells to this death-inducing ligand. Methods Cancer cell lines from the lung (H460, H322), the esophagus (TE2, TE12), and the pleura (H290, H211) or primary normal cells were treated with gossypol+Apo2L/TRAIL combinations. Cell viability and apoptosis were evaluated by (4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) assays, respectively. Caspase 9 and 3 specific proteolytic activity in combination-treated cells was determined by fluorometric enzymatic assay. Results Gossypol, selectively cytotoxic to Cancer cells and not primary normal cells, significantly sensitized Thoracic Cancer cells to Apo2L/TRAIL as indicated by 1.5- to more than 10-fold reduction of Apo2L/TRAIL 50% inhibitory concentration values in cells treated with gossypol+Apo2L/TRAIL combinations. Whereas less than 20% of Cancer cells exposed to either gossypol (5 μmol/L) or Apo2L/TRAIL (20 ng/mL) were dead, more than 90% of cells treated with the drug combinations were apoptotic. Combination-induced cytotoxicity and apoptosis was completely abrogated either by overexpression of Bcl2 or by the selective caspase 9 inhibitor. This combination was not toxic to normal cells. Conclusion Gossypol profoundly sensitizes Thoracic Cancer cells to the cytotoxic effect of Apo2L/TRAIL via activation of the mitochondria-dependent death signaling pathway. This study provides evidence for the profound antiCancer activity of this drug combination and should be further evaluated as a novel targeted molecular therapeutic for Thoracic Cancers.
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Valproic Acid, an Antiepileptic Drug with Histone Deacetylase Inhibitory Activity, Potentiates the Cytotoxic Effect of Apo2L/TRAIL on Cultured Thoracic Cancer Cells through Mitochondria-Dependent Caspase Activation
Neoplasia, 2006Co-Authors: M. Firdos Ziauddin, Wen Shuz Yeow, Aris Baras, Alex Chua, David S. Schrump, Justin B Maxhimer, Rishindra M Reddy, George W Cole, Wilson S. Tsai, Duc M. NguyenAbstract:Inhibitors of histone deacetylases have been shown to enhance the sensitivity of Cancer cells to tumor necrosis factor–related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL–mediated cytotoxicity in cultured Thoracic Cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured Thoracic Cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5–5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of Cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for Thoracic Cancers. Neoplasia (2006) 8, 446–457
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The essential role of the mitochondria-dependent death-signaling cascade in chemotherapy-induced potentiation of Apo2L/TRAIL cytotoxicity in cultured Thoracic Cancer cells: amplified caspase 8 is indispensable for combination-mediated massive cell de
The Cancer Journal, 2006Co-Authors: Duc M. Nguyen, Wen Shuz Yeow, Aris Baras, Alex Chua, Rishindra M Reddy, George W Cole, M. Firdos Ziauddin, Wilson S. Tsai, David S. SchrumpAbstract:PURPOSE Despite adequately expressing functional receptors for tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL), many cultured tumor cells are refractory to the cy-totoxic effect of this ligand. Cytotoxic chemotherapeutic drugs have been shown to synergize with Apo2L/TRAIL to mediate apoptosis in Cancer cells. The main goal of this study was to evaluate the effect of either cisplatin or paclitaxel, two common used chemotherapeutic agents for solid tumors, on enhancing Apo2L/TRAIL cytotoxicity in a panel-cultured Thoracic Cancer cells and to examine the role of the mitochondria-dependent caspase activation cascade in mediating apoptosis of combination-treated cells. METHODS Cultured Thoracic Cancer cells were treated with cisplatin/ Apo2L/TRAIL or paclitaxel/Apo2L/TRAIL sequential combinations in vitro. Cell viability and apoptosis were determined by 4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. Stable transfectants expressing high levels of Bcl-2 were created by retroviral gene transfer. Specific proteolytic activity of caspases 3, 6, 8, and 9 were measured by commercially available kits using fluorescent substrates. RESULTS All cell lines preferentially expressed high levels of DR4 and/or DR5 and low levels of DcR1/DcR2; all of which were not altered by chemotherapeutic drug treatments. Pretreatment of these Cancer cells with sublethal concentrations of either cisplatin or paclitaxel increased their susceptibility to Apo2L/TRAIL by twofold to > 20-fold. Profound synergistic induction of apoptosis was observed in combination-treated cells. Viability of primary normal cells was affected by neither Apo2L/TRAIL nor the combinations of chemotherapy and Apo2L/TRAIL. Overexpression of Bcl-2 or inhibition of caspase 9 activity completely abrogated combination-induced cytotoxicity and apoptosis, indicating the essential role of the mitochondria-dependent death signaling cascade in this process. Robust activation of caspase 8 in combination-treated cells was completely suppressed either by Bcl-2 overexpression or by blocking of the activity of the mitochondria-regulated caspase 9, thus identifying the amplification feedback loop as the source of elevated caspase 8 activity. Finally, mitochondria-mediated amplification of caspase 8 activity was indispensable for complete caspase activation and full execution of apoptosis, because suppression of its activity using the selective caspase 6 inhibitor (located downstream of the caspase 3 but upstream of the caspase 8 in the feedback loop) resulted in profound suppression of not only caspase 8 activity but also those of caspases 9 and 3, as well as complete protection of Cancer cells from combination-induced cytotoxicity. CONCLUSION Cisplatin or paclitaxel synergistically interacts with Apo2L/ TRAIL to mediate profound induction of apoptosis. The mitochondria-dependent caspase activation cascade and the amplification feedback loop are essential for the complete execution of the cell death program. Furthermore, our data identify mitochondria as the direct target for the development of more refined strategies to enhance the therapeutic effect of Apo2L/TRAIL as an antiCancer agent.
Vera Pancaldi - One of the best experts on this subject based on the ideXlab platform.
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Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.
Cancer cell, 2020Co-Authors: Annalisa Trama, Jan P. Van Meerbeeck, Claudia Proto, Jennifer G. Whisenant, Valter Torri, Alessio Cortellini, Olivier Michielin, Fabrice Barlesi, Anne Marie C. Dingemans, Vera PancaldiAbstract:To understand the real impact of COVID-19 on Cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in Thoracic Cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in Thoracic Cancer during the SARS-CoV-2 pandemic.
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Supporting Clinical Decision-Making, during the SARS-CoV-f2 Pandemic through a Global Research Commitment: The TERAVOLT Experience
Cancer Cell, 2020Co-Authors: Annalisa Trama, Jan P. Van Meerbeeck, Claudia Proto, Jennifer G. Whisenant, Valter Torri, Alessio Cortellini, Olivier Michielin, Fabrice Barlesi, Anne Marie C. Dingemans, Vera PancaldiAbstract:Abstract To understand the real impact of COVID-19 on Cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in Thoracic Cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in Thoracic Cancer during the SARS-CoV-2 pandemic.
Yasumasa Nishimura - One of the best experts on this subject based on the ideXlab platform.
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Correction: Evaluation of lung toxicity risk with computed tomography ventilation image for Thoracic Cancer patients.
PLOS ONE, 2019Co-Authors: Masakazu Otsuka, Hajime Monzen, Kenji Matsumoto, Mikoto Tamura, Masahiro Inada, Noriyuki Kadoya, Yasumasa NishimuraAbstract:Background Four-dimensional computed tomography (4D-CT) ventilation is an emerging imaging modality. Functional avoidance of regions according to 4D-CT ventilation may reduce lung toxicity after radiation therapy. This study evaluated associations between 4D-CT ventilation-based dosimetric parameters and clinical outcomes. Methods Pre-treatment 4D-CT data were used to retrospectively construct ventilation images for 40 Thoracic Cancer patients retrospectively. Fifteen patients were treated with conventional radiation therapy, 6 patients with hyperfractionated radiation therapy and 19 patients with stereotactic body radiation therapy (SBRT). Ventilation images were calculated from 4D-CT data using a deformable image registration and Jacobian-based algorithm. Each ventilation map was normalized by converting it to percentile images. Ventilation-based dosimetric parameters (Mean Dose, V5 [percent lung volume receiving ≥5 Gy], and V20 [percent lung volume receiving ≥20 Gy]) were calculated for highly and poorly ventilated regions. To test whether the ventilation-based dosimetric parameters could be used predict radiation pneumonitis of ≥Grade 2, the area under the curve (AUC) was determined from the receiver operating characteristic analysis. Results For Mean Dose, poorly ventilated lung regions in the 0–30% range showed the highest AUC value (0.809; 95% confidence interval [CI], 0.663–0.955). For V20, poorly ventilated lung regions in the 0–20% range had the highest AUC value (0.774; 95% [CI], 0.598–0.915), and for V5, poorly ventilated lung regions in the 0–30% range had the highest AUC value (0.843; 95% [CI], 0.732–0.954). The highest AUC values for Mean Dose, V20, and V5 were obtained in poorly ventilated regions. There were significant differences in all dosimetric parameters between radiation pneumonitis of Grade 1 and Grade ≥2. Conclusions Poorly ventilated lung regions identified on 4D-CT had higher AUC values than highly ventilated regions, suggesting that functional planning based on poorly ventilated regions may reduce the risk of lung toxicity in radiation therapy.
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Evaluation of lung toxicity risk with computed tomography ventilation image for Thoracic Cancer patients.
PLOS ONE, 2018Co-Authors: Masakazu Otsuka, Hajime Monzen, Kenji Matsumoto, Mikoto Tamura, Masahiro Inada, Noriyuki Kadoya, Yasumasa NishimuraAbstract:Four-dimensional computed tomography (4D-CT) ventilation is an emerging imaging modality. Functional avoidance of regions according to 4D-CT ventilation may reduce lung toxicity after radiation therapy. This study evaluated associations between 4D-CT ventilation-based dosimetric parameters and clinical outcomes. Pre-treatment 4D-CT data were used to retrospectively construct ventilation images for 40 Thoracic Cancer patients retrospectively. Fifteen patients were treated with conventional radiation therapy, 6 patients with hyperfractionated radiation therapy and 19 patients with stereotactic body radiation therapy (SBRT). Ventilation images were calculated from 4D-CT data using a deformable image registration and Jacobian-based algorithm. Each ventilation map was normalized by converting it to percentile images. Ventilation-based dosimetric parameters (Mean Dose, V5 [percent lung volume receiving ≥5 Gy], and V20 [percent lung volume receiving ≥20 Gy]) were calculated for highly and poorly ventilated regions. To test whether the ventilation-based dosimetric parameters could be used predict radiation pneumonitis of ≥Grade 2, the area under the curve (AUC) was determined from the receiver operating characteristic analysis. For Mean Dose, poorly ventilated lung regions in the 0-30% range showed the highest AUC value (0.809; 95% confidence interval [CI], 0.663-0.955). For V20, poorly ventilated lung regions in the 0-20% range had the highest AUC value (0.774; 95% [CI], 0.598-0.915), and for V5, poorly ventilated lung regions in the 0-30% range had the highest AUC value (0.843; 95% [CI], 0.732-0.954). The highest AUC values for Mean Dose, V20, and V5 were obtained in poorly ventilated regions. There were significant differences in all dosimetric parameters between radiation pneumonitis of Grade 1 and Grade ≥2. Poorly ventilated lung regions identified on 4D-CT had higher AUC values than highly ventilated regions, suggesting that functional planning based on poorly ventilated regions may reduce the risk of lung toxicity in radiation therapy.
