14 results on '"Selfridge, Andrew"'
Search Results
2. Efficacy and safety of etrasimod, a sphingosine 1‐phosphate receptor modulator, in adults with moderate‐to‐severe atopic dermatitis (ADVISE).
- Author
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Silverberg, Jonathan I., Bissonnette, Robert, Kircik, Leon, Murrell, Dedee F., Selfridge, Andrew, Liu, Kris, Ahluwalia, Gurpreet, and Guttman‐Yassky, Emma
- Subjects
ATOPIC dermatitis ,SPHINGOSINE ,BODY surface area - Abstract
Background: Etrasimod is an oral, selective, sphingosine 1‐phosphate (S1P) receptor1,4,5 modulator in development for immune‐mediated inflammatory disorders. Efficacy and safety of orally administered S1P receptor modulation in atopic dermatitis (AD) have not yet been examined. Objective: To assess the efficacy and safety of etrasimod monotherapy in adults with moderate‐to‐severe AD. Methods: In this phase 2, randomized, double‐blind, placebo‐controlled trial, participants (≥18 years) with moderate‐to‐severe AD defined as baseline validated Investigator's Global Assessment (vIGA‐AD) score ≥ 3, Eczema Area and Severity Index (EASI) score ≥ 16, and body surface area involvement ≥10% were randomized 1:1:1 to once‐daily oral etrasimod 1 mg, 2 mg or placebo for 12 weeks. The primary outcome was percent change in EASI score from baseline at week 12, assessed in the Full Analysis Set (all randomized participants). Key secondary outcomes were achievement of a vIGA‐AD score of 0 or 1 with a ≥2‐point improvement from baseline and EASI‐75 response at Week 12. Safety was assessed during the double‐blind period. Results: One hundred and forty participants were randomized to etrasimod 2 mg (n = 47), 1 mg (n = 47) or placebo (n = 46). At Week 12, percent change in EASI score was −57.2% in the etrasimod 2‐mg group versus −48.4% in the placebo group (p = 0.18). A significantly greater proportion of participants receiving etrasimod 2 mg achieved vIGA‐AD scores of 0 or 1 with a ≥2‐point improvement at Week 12 versus placebo (29.8% vs. 13.0%; p = 0.045); however, EASI‐75 response was not statistically significant versus placebo. Treatment‐emergent adverse events (AEs) occurred in 59.6%, 40.4% and 47.8% of participants receiving etrasimod 2 mg, 1 mg and placebo, respectively. There were no serious AEs or deaths. Conclusions: The primary outcome was not met, although efficacy was observed for etrasimod 2 mg on several clinician‐ and patient‐assessed measures, and both 1‐ and 2‐mg doses were well tolerated, warranting further clinical investigation in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD
- Author
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Van Welden, Sophie, Selfridge, Andrew C., and Hindryckx, Pieter
- Published
- 2017
- Full Text
- View/download PDF
4. Carbon dioxide-sensing in organisms and its implications for human disease
- Author
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Cummins, Eoin P., Selfridge, Andrew C., Sporn, Peter H., Sznajder, Jacob I., and Taylor, Cormac T.
- Published
- 2014
- Full Text
- View/download PDF
5. Validation of the skin pain numerical rating scale of the Pruritus and Symptoms Assessment for Atopic Dermatitis for adults and adolescents with moderate-to-severe atopic dermatitis.
- Author
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Silverberg, Jonathan I., Ständer, Sonja, Kim, Brian S., Bewley, Anthony, Misery, Laurent, Vestergaard, Christian, Gooderham, Melinda J., Bushmakin, Andrew G., Cappelleri, Joseph C., Güler, Erman, Alderfer, Justine, Watkins, Melissa, Selfridge, Andrew, and Myers, Daniela E.
- Subjects
ATOPIC dermatitis ,CUMULATIVE distribution function ,CLINICAL trials ,ITCHING ,INTRACLASS correlation - Abstract
Background Skin pain is a common and burdensome symptom of atopic dermatitis (AD), and its severity increases with disease progression. The Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) is a validated 11-item patient-reported instrument developed in accordance with regulatory agency guidance for assessment of the daily symptoms of patients with AD, including skin pain. Objective To establish content validity and evaluate the psychometric properties of the skin pain numerical rating scale (NRS) item of the PSAAD. Methods: The skin pain NRS is a single-item measure from the PSAAD and is used to assess skin pain severity over the past 24 hours with the question "How painful was your skin over the past 24 hours?" on a 10-point scale from 0 (not painful) to 10 (extremely painful). A qualitative validation analysis consisting of concept elicitation (CE) interviews; electronic completion of the PSAAD measure, including the skin pain NRS; and cognitive debriefing (CD) interviews was conducted for adults and adolescents with mild-to-severe AD. Evaluation of psychometric properties of the skin pain NRS--including test-retest reliability, estimation of meaningful within-patient change (MWPC), known-group validity, ability to detect change, construct validity, quality of completion, and ceiling and floor effects--was conducted based on a post hoc qualitative and quantitative analysis of pooled data, with skin pain NRS as part of the PSAAD in the abrocitinib monotherapy phase 3 trials JADE MONO-1 (NCT03349060) and JADE MONO-2 (NCT03575871). Data from patients (≥12 years of age) with moderate-to-severe AD were pooled across all treatment arms. Results: Among 30 CE interviews (adolescents [12-17 years], n=15; adults [≥18 years], n=15) conducted over 2 rounds of testing, 20 of 30 (67%) patients reported skin pain. During CD interviews (n=30), 100% of patients interpreted the skin pain NRS item as intended, and 73% reported it as relevant. The psychometric validation analysis included 736 patients (JADE MONO-1, N=347; JADE MONO-2, N=389). The test-retest reliability of the skin pain NRS was evidenced by large intraclass correlation coefficients (ICC; 0.76 and 0.72 in JADE MONO-1 and MONO-2, respectively) for a single daily skin pain score, which increased to 0.93 and 0.91 for a measurement averaging at least 4 scores per week. Convergent validity was demonstrated by correlations between skin pain and other clinician- and patient-reported AD measures (median correlation >0.4 starting at week 4). The skin pain NRS distinguished between "clear" and "severe" disease severity groups, assessed using the Patient Global Assessment (PtGA) and Investigator's Global Assessment (IGA) as continuous and categorical anchors (P<0.0001); differences were also significant among other disease severity groups using the PtGA and IGA as continuous anchors (P<0.0001). Based on the PtGA and IGA anchor analysis, the estimated MWPC was 1.9 and ranged from 2.7 to 3.9 points using the empirical cumulative distribution function analysis. Ability to detect change was demonstrated by linear relationships between disease severity measures and skin pain scores (correlation of ≥0.5 between the skin pain NRS and the PtGA). More than 90% of patients provided at least 4 daily skin pain scores each week. No floor or ceiling effects were observed. Conclusions: The qualitative and quantitative data from initial PSAAD development and psychometric evaluation of the skin pain NRS from the PSAAD support its content validity, reliability, construct validity, and ability to detect change. These findings corroborate the 4-point improvement in skin pain as the adequate and meaningful cut-off to define a skin pain responder in JADE MONO-1 and MONO-2. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. REST is a hypoxia-responsive transcriptional repressor
- Author
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Cavadas, Miguel A. S., Mesnieres, Marion, Crifo, Bianca, Manresa, Mario C., Selfridge, Andrew C., Keogh, Ciara E., Fabian, Zsolt, Scholz, Carsten C., Nolan, Karen A., Rocha, Liliane M. A., Tambuwala, Murtaza M., Brown, Stuart, Wdowicz, Anita, Corbett, Danielle, Murphy, Keith J., Godson, Catherine, Cummins, Eoin P., Taylor, Cormac T., Cheong, Alex, University of Zurich, and Cheong, Alex
- Subjects
1000 Multidisciplinary ,HEK293 ,REST ,Transcriptional regulatory elements ,Gene silencing ,610 Medicine & health ,A300 ,Hypoxia-inducible factor ,10052 Institute of Physiology ,Hypoxia-responsive ,10076 Center for Integrative Human Physiology ,HIF ,570 Life sciences ,biology ,Hypoxia - Abstract
Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia. Science Foundation Ireland grant: (06/CE/B1129).
- Published
- 2016
7. Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.
- Author
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Selfridge, Andrew C., Cavadas, Miguel A. S., Scholz, Carsten C., Campbell, Eric L., Welch, Lynn C., Lecuona, Emilia, Colgan, Sean P., Barrett, Kim E., Sporn, Peter H. S., Sznajder, Jacob I., Cummins, Eoin P., and Taylor, Cormac T.
- Subjects
- *
HYPERCAPNIA , *HYPOXIA-inducible factor 1 , *CARBON dioxide , *HYPOXEMIA , *GENE regulatory networks , *PROTEIN stability - Abstract
Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
8. Hypoxia Modulates Infection of Epithelial Cells by Pseudomonas aeruginosa.
- Author
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Schaible, Bettina, McClean, Siobhán, Selfridge, Andrew, Broquet, Alexis, Asehnoune, Karim, Taylor, Cormac T., and Schaffer, Kirsten
- Subjects
PSEUDOMONAS aeruginosa infections ,HYPOXIA-inducible factors ,EPITHELIAL cells ,NF-kappa B ,GENE expression ,HOST-parasite relationships ,PNEUMONIA-related mortality ,BACTERIAL adhesion - Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen commonly associated with lung and wound infections. Hypoxia is a frequent feature of the microenvironment of infected tissues which induces the expression of genes associated with innate immunity and inflammation in host cells primarily through the activation of the hypoxia-inducible factor (HIF) and Nuclear factor kappaB (NF-κB) pathways which are regulated by oxygen-dependent prolyl-hydroxylases. Hypoxia also affects virulence and antibiotic resistance in bacterial pathogens. However, less is known about the impact of hypoxia on host-pathogen interactions such as bacterial adhesion and infection. In the current study, we demonstrate that hypoxia decreases the internalization of P. aeruginosa into cultured epithelial cells resulting in decreased host cell death. This response can also be elicited by the hydroxylase inhibitor Dimethyloxallyl Glycine (DMOG). Reducing HIF-2α expression or Rho kinase activity diminished the effects of hypoxia on P. aeruginosa infection. Furthermore, in an in vivo pneumonia infection model, application of DMOG 48 h before infection with P. aeruginosa significantly reduced mortality. Thus, hypoxia reduces P. aeruginosa internalization into epithelial cells and pharmacologic manipulation of the host pathways involved may represent new therapeutic targets in the treatment of P. aeruginosa infection. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
9. REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia.
- Author
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Cavadas, Miguel A. S., Mesnieres, Marion, Crifo, Bianca, Manresa, Mario C., Selfridge, Andrew C., Scholz, Carsten C., Cummins, Eoin P., Cheong, Alex, and Taylor, Cormac T.
- Published
- 2015
- Full Text
- View/download PDF
10. Hypoxia Modulates Infection of Epithelial Cells by Pseudomonas aeruginosa.
- Author
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Schaible, Bettina, McClean, Siobhán, Selfridge, Andrew, Broquet, Alexis, Asehnoune, Karim, Taylor, Cormac T., and Schaffer, Kirsten
- Subjects
- *
PSEUDOMONAS aeruginosa infections , *HYPOXIA-inducible factors , *EPITHELIAL cells , *NF-kappa B , *GENE expression , *HOST-parasite relationships , *PNEUMONIA-related mortality , *BACTERIAL adhesion - Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen commonly associated with lung and wound infections. Hypoxia is a frequent feature of the microenvironment of infected tissues which induces the expression of genes associated with innate immunity and inflammation in host cells primarily through the activation of the hypoxia-inducible factor (HIF) and Nuclear factor kappaB (NF-κB) pathways which are regulated by oxygen-dependent prolyl-hydroxylases. Hypoxia also affects virulence and antibiotic resistance in bacterial pathogens. However, less is known about the impact of hypoxia on host-pathogen interactions such as bacterial adhesion and infection. In the current study, we demonstrate that hypoxia decreases the internalization of P. aeruginosa into cultured epithelial cells resulting in decreased host cell death. This response can also be elicited by the hydroxylase inhibitor Dimethyloxallyl Glycine (DMOG). Reducing HIF-2α expression or Rho kinase activity diminished the effects of hypoxia on P. aeruginosa infection. Furthermore, in an in vivo pneumonia infection model, application of DMOG 48 h before infection with P. aeruginosa significantly reduced mortality. Thus, hypoxia reduces P. aeruginosa internalization into epithelial cells and pharmacologic manipulation of the host pathways involved may represent new therapeutic targets in the treatment of P. aeruginosa infection. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
11. Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO2-dependent immune regulation.
- Author
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Keogh, Ciara E., Scholz, Carsten C., Rodriguez, Javier, Selfridge, Andrew C., von Kriegsheim, Alexander, and Cummins, Eoin P.
- Subjects
- *
IMMUNOREGULATION , *HYPERCAPNIA , *PROTEIN-protein interactions , *BACTERIAL diseases , *CHROMOSOMAL translocation , *OXYGEN , *CARBON dioxide - Abstract
CO2 is a physiological gas normally produced in the body during aerobic respiration. Hypercapnia (elevated blood pCO2 > ≈50 mm Hg) is a feature of several lung pathologies, e.g. chronic obstructive pulmonary disease. Hypercapnia is associated with increased susceptibility to bacterial infections and suppression of inflammatory signaling. The NF-κB pathway has been implicated in these effects; however, the molecular mechanisms underpinning cellular sensitivity of the NF-κB pathway to CO2 are not fully elucidated. Here, we identify several novel CO2-dependent changes in the NF-κB pathway. NF-κB family members p100 and RelB translocate to the nucleus in response to CO2. A cohort of RelB protein-protein interactions (e.g. with Raf-1 and IκBα) are altered by CO2 exposure, although others are maintained (e.g. with p100). RelB is processed by CO2 in a manner dependent on a key C-terminal domain located in its transactivation domain. Loss of the RelB transactivation domain alters NF-κB-dependent transcriptional activity, and loss of p100 alters sensitivity of RelB to CO2. Thus, we provide molecular insight into theCO2 sensitivity of the NF-κB pathway and implicate altered RelB/p100-dependent signaling in the CO2-dependent regulation of inflammatory signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
12. Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO 2 -dependent immune regulation.
- Author
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Keogh CE, Scholz CC, Rodriguez J, Selfridge AC, von Kriegsheim A, and Cummins EP
- Subjects
- A549 Cells, Animals, Humans, Hypercapnia genetics, Hypercapnia pathology, Mice, NF-kappa B p52 Subunit genetics, Protein Domains, Signal Transduction genetics, Transcription Factor RelB genetics, Transcription, Genetic genetics, Transcription, Genetic immunology, Carbon Dioxide immunology, Hypercapnia immunology, NF-kappa B p52 Subunit immunology, Signal Transduction immunology, Transcription Factor RelB immunology
- Abstract
CO
2 is a physiological gas normally produced in the body during aerobic respiration. Hypercapnia (elevated blood pCO2 >≈50 mm Hg) is a feature of several lung pathologies, e.g. chronic obstructive pulmonary disease. Hypercapnia is associated with increased susceptibility to bacterial infections and suppression of inflammatory signaling. The NF-κB pathway has been implicated in these effects; however, the molecular mechanisms underpinning cellular sensitivity of the NF-κB pathway to CO2 are not fully elucidated. Here, we identify several novel CO2 -dependent changes in the NF-κB pathway. NF-κB family members p100 and RelB translocate to the nucleus in response to CO2 A cohort of RelB protein-protein interactions ( e.g. with Raf-1 and IκBα) are altered by CO2 exposure, although others are maintained ( e.g. with p100). RelB is processed by CO2 in a manner dependent on a key C-terminal domain located in its transactivation domain. Loss of the RelB transactivation domain alters NF-κB-dependent transcriptional activity, and loss of p100 alters sensitivity of RelB to CO2 Thus, we provide molecular insight into the CO2 sensitivity of the NF-κB pathway and implicate altered RelB/p100-dependent signaling in the CO2 -dependent regulation of inflammatory signaling., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)- Published
- 2017
- Full Text
- View/download PDF
13. REST is a hypoxia-responsive transcriptional repressor.
- Author
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Cavadas MA, Mesnieres M, Crifo B, Manresa MC, Selfridge AC, Keogh CE, Fabian Z, Scholz CC, Nolan KA, Rocha LM, Tambuwala MM, Brown S, Wdowicz A, Corbett D, Murphy KJ, Godson C, Cummins EP, Taylor CT, and Cheong A
- Subjects
- Cell Hypoxia, Cell Line, Cell Nucleus genetics, Cell Nucleus metabolism, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, HEK293 Cells, Humans, Promoter Regions, Genetic, Signal Transduction, Repressor Proteins genetics, Repressor Proteins metabolism, Sequence Analysis, RNA methods, Transcription, Genetic
- Abstract
Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.
- Published
- 2016
- Full Text
- View/download PDF
14. Hypoxia modulates infection of epithelial cells by Pseudomonas aeruginosa.
- Author
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Schaible B, McClean S, Selfridge A, Broquet A, Asehnoune K, Taylor CT, and Schaffer K
- Subjects
- Amides pharmacology, Amino Acids, Dicarboxylic pharmacology, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors immunology, Basic Helix-Loop-Helix Transcription Factors metabolism, Blotting, Western, Caco-2 Cells, Cell Hypoxia, Cell Line, Cell Line, Tumor, Cells, Cultured, Endocytosis drug effects, Endocytosis immunology, Epithelial Cells metabolism, Epithelial Cells microbiology, Hep G2 Cells, Host-Pathogen Interactions drug effects, Host-Pathogen Interactions immunology, Humans, Lung drug effects, Lung immunology, Lung metabolism, Mice, Pneumonia microbiology, Pneumonia prevention & control, Pseudomonas Infections microbiology, Pseudomonas Infections prevention & control, Pseudomonas aeruginosa physiology, Pyridines pharmacology, RNA Interference, Survival Analysis, rho GTP-Binding Proteins antagonists & inhibitors, rho GTP-Binding Proteins immunology, rho GTP-Binding Proteins metabolism, Epithelial Cells immunology, Pneumonia immunology, Pseudomonas Infections immunology, Pseudomonas aeruginosa immunology
- Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen commonly associated with lung and wound infections. Hypoxia is a frequent feature of the microenvironment of infected tissues which induces the expression of genes associated with innate immunity and inflammation in host cells primarily through the activation of the hypoxia-inducible factor (HIF) and Nuclear factor kappaB (NF-κB) pathways which are regulated by oxygen-dependent prolyl-hydroxylases. Hypoxia also affects virulence and antibiotic resistance in bacterial pathogens. However, less is known about the impact of hypoxia on host-pathogen interactions such as bacterial adhesion and infection. In the current study, we demonstrate that hypoxia decreases the internalization of P. aeruginosa into cultured epithelial cells resulting in decreased host cell death. This response can also be elicited by the hydroxylase inhibitor Dimethyloxallyl Glycine (DMOG). Reducing HIF-2α expression or Rho kinase activity diminished the effects of hypoxia on P. aeruginosa infection. Furthermore, in an in vivo pneumonia infection model, application of DMOG 48 h before infection with P. aeruginosa significantly reduced mortality. Thus, hypoxia reduces P. aeruginosa internalization into epithelial cells and pharmacologic manipulation of the host pathways involved may represent new therapeutic targets in the treatment of P. aeruginosa infection.
- Published
- 2013
- Full Text
- View/download PDF
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