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Author  |
Zapotoczna, M.; Forde, E.; Hogan, S.; Humphreys, H.; O'Gara, J.P.; Fitzgerald-Hughes, D.; Devocelle, M.; O'Neill, E. |
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Title |
Eradication of Staphylococcus aureus Biofilm Infections Using Synthetic Antimicrobial Peptides |
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Journal Article |
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Year |
2017 |
Publication |
The Journal of Infectious Diseases |
Abbreviated Journal |
J Infect Dis |
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Volume |
215 |
Issue |
6 |
Pages |
975-983 |
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Keywords |
Animals; Anti-Bacterial Agents/*pharmacology; Biofilms/*drug effects; Catheter-Related Infections/*drug therapy; Cytokines/blood; Disease Models, Animal; Humans; Methicillin-Resistant Staphylococcus aureus/*drug effects; Microbial Sensitivity Tests; Peptides/*pharmacology; Peptides, Cyclic/pharmacology; Rats; Rats, Sprague-Dawley; Staphylococcal Infections/*drug therapy; Vancomycin/administration & dosage; *Staphylococcus aureus; *antimicrobial peptides (AMPs); *biofilm; *catheter lock solution (CLS) |
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Abstract |
Here, we demonstrate that antimicrobial peptides (AMPs) are an effective antibiofilm treatment when applied as catheter lock solutions (CLSs) against S. aureus biofilm infections. The activity of synthetic AMPs (Bac8c, HB43, P18, Omiganan, WMR, Ranalexin, and Polyphemusin) was measured against early and mature biofilms produced by methicillin-resistant S. aureus and methicillin-susceptible S. aureus isolates from patients with device-related infections grown under in vivo-relevant biofilm conditions. The cytotoxic and hemolytic activities of the AMPs against human cells and their immunomodulatory potential in human blood were also characterized. The D-Bac8c2,5Leu variant emerged as the most effective AMP during in vitro studies and was also highly effective in eradicating S. aureus biofilm infection when used in a CLS rat central venous catheter infection model. These data support the potential use of D-Bac8c2,5Leu, alone or in combination with other AMPs, in the treatment of S. aureus intravenous catheter infections. |
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Department of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland |
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0022-1899 |
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PMID:28453851 |
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Call Number |
ref @ user @ |
Serial |
99511 |
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Author |
Zapotoczna, M.; Forde, E.; Hogan, S.; Humphreys, H.; O'Gara, J.P.; Fitzgerald-Hughes, D.; Devocelle, M.; O'Neill, E. |
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Title |
Eradication of Staphylococcus aureus Biofilm Infections Using Synthetic Antimicrobial Peptides |
Type |
Journal Article |
| |
Year |
2017 |
Publication |
The Journal of Infectious Diseases |
Abbreviated Journal |
J Infect Dis |
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| |
Volume |
215 |
Issue |
6 |
Pages |
975-983 |
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Keywords |
Animals; Anti-Bacterial Agents/*pharmacology; Biofilms/*drug effects; Catheter-Related Infections/*drug therapy; Cytokines/blood; Disease Models, Animal; Humans; Methicillin-Resistant Staphylococcus aureus/*drug effects; Microbial Sensitivity Tests; Peptides/*pharmacology; Peptides, Cyclic/pharmacology; Rats; Rats, Sprague-Dawley; Staphylococcal Infections/*drug therapy; Vancomycin/administration & dosage; *Staphylococcus aureus; *antimicrobial peptides (AMPs); *biofilm; *catheter lock solution (CLS) |
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Abstract |
Here, we demonstrate that antimicrobial peptides (AMPs) are an effective antibiofilm treatment when applied as catheter lock solutions (CLSs) against S. aureus biofilm infections. The activity of synthetic AMPs (Bac8c, HB43, P18, Omiganan, WMR, Ranalexin, and Polyphemusin) was measured against early and mature biofilms produced by methicillin-resistant S. aureus and methicillin-susceptible S. aureus isolates from patients with device-related infections grown under in vivo-relevant biofilm conditions. The cytotoxic and hemolytic activities of the AMPs against human cells and their immunomodulatory potential in human blood were also characterized. The D-Bac8c2,5Leu variant emerged as the most effective AMP during in vitro studies and was also highly effective in eradicating S. aureus biofilm infection when used in a CLS rat central venous catheter infection model. These data support the potential use of D-Bac8c2,5Leu, alone or in combination with other AMPs, in the treatment of S. aureus intravenous catheter infections. |
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Department of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland |
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0022-1899 |
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Notes |
PMID:28453851 |
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Call Number |
ref @ user @ |
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100541 |
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Author |
Yu, W.-L.; Lee, M.-F.; Chen, C.-C.; Tang, H.-J.; Ho, C.-H.; Chuang, Y.-C. |
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Title |
Impacts of Hypervirulence Determinants on Clinical Features and Outcomes of Bacteremia Caused by Extended-Spectrum beta-Lactamase-Producing Klebsiella pneumoniae |
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Journal Article |
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Year |
2017 |
Publication |
Microbial Drug Resistance (Larchmont, N.Y.) |
Abbreviated Journal |
Microb Drug Resist |
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23 |
Issue |
3 |
Pages |
376-383 |
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Keywords |
Aged; Anti-Bacterial Agents/therapeutic use; Bacteremia/drug therapy/*microbiology; Bacterial Proteins/genetics; Cross Infection/drug therapy/microbiology; Female; Hospital Mortality; Humans; Klebsiella Infections/drug therapy/*microbiology; Klebsiella pneumoniae/*genetics; Male; Middle Aged; Serogroup; Urinary Tract Infections/drug therapy/microbiology; Virulence Factors/*genetics; beta-Lactamases/*genetics; Esbl; Klebsiella pneumoniae; hypermucoviscosity; hypervirulence; rmpA; virulence |
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We investigated the implications of hypervirulence determinants on clinical features of 48 adult patients with bacteremia caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Isolates in the hypervirulence group included any of the following virulence determinants: K1/K2 capsule serotypes, hypermucoviscosity phenotype, rmpA gene, or rmpA2 gene. Nonhypervirulence group isolates were negative for all of the above virulence factors. In this study, all isolates used were non-K1/K2 strains. Statistically significant differences were observed in clinical features of patients between the two groups. The hypervirulent isolates (n = 19), including 11 isolates with the hypermucoviscosity phenotype, 15 with the rmpA gene, and 16 with the rmpA2 gene, were more commonly recovered from diabetic patients and mainly manifested as secondary bacteremia (such as pneumonia, urinary tract infections, or other localized infections). The nonhypervirulent isolates (n = 29) were more commonly recovered from patients after prolonged hospital stays (>30 days) and mostly manifested as primary bacteremia. The overall in-hospital mortality was 56.3%. Hazard ratio (HR) analysis revealed the following positive predictors for mortality: nosocomial infection, stay in an intensive care unit, no removal of the central venous catheter, Charlson comorbidity score, and APACHE II score (>==15). The negative predictors were initial appropriate antibiotic therapy (HR 0.42) and urinary tract infection (HR 0.19). Charlson score was an independent confounder based on multivariate analysis (HR 1.43, 95% confidence interval 1.04-1.99). In conclusion, hypervirulence determinants played a role in causing secondary infections in diabetic patients; however, the presence of morbidity cofactors could themselves influence mortality, despite the absence of hypervirulence determinants. |
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6 Department of Internal Medicine, Chi Mei Medical Center-Liou Ying , Tainan City, Taiwan |
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1076-6294 |
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Notes |
PMID:27380450 |
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Call Number |
ref @ user @ |
Serial |
99505 |
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Author |
Yu, W.-L.; Lee, M.-F.; Chen, C.-C.; Tang, H.-J.; Ho, C.-H.; Chuang, Y.-C. |
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Title |
Impacts of Hypervirulence Determinants on Clinical Features and Outcomes of Bacteremia Caused by Extended-Spectrum beta-Lactamase-Producing Klebsiella pneumoniae |
Type |
Journal Article |
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Year |
2017 |
Publication |
Microbial Drug Resistance (Larchmont, N.Y.) |
Abbreviated Journal |
Microb Drug Resist |
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Volume |
23 |
Issue |
3 |
Pages |
376-383 |
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Keywords |
Aged; Anti-Bacterial Agents/therapeutic use; Bacteremia/drug therapy/*microbiology; Bacterial Proteins/genetics; Cross Infection/drug therapy/microbiology; Female; Hospital Mortality; Humans; Klebsiella Infections/drug therapy/*microbiology; Klebsiella pneumoniae/*genetics; Male; Middle Aged; Serogroup; Urinary Tract Infections/drug therapy/microbiology; Virulence Factors/*genetics; beta-Lactamases/*genetics; Esbl; Klebsiella pneumoniae; hypermucoviscosity; hypervirulence; rmpA; virulence |
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Abstract |
We investigated the implications of hypervirulence determinants on clinical features of 48 adult patients with bacteremia caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Isolates in the hypervirulence group included any of the following virulence determinants: K1/K2 capsule serotypes, hypermucoviscosity phenotype, rmpA gene, or rmpA2 gene. Nonhypervirulence group isolates were negative for all of the above virulence factors. In this study, all isolates used were non-K1/K2 strains. Statistically significant differences were observed in clinical features of patients between the two groups. The hypervirulent isolates (n = 19), including 11 isolates with the hypermucoviscosity phenotype, 15 with the rmpA gene, and 16 with the rmpA2 gene, were more commonly recovered from diabetic patients and mainly manifested as secondary bacteremia (such as pneumonia, urinary tract infections, or other localized infections). The nonhypervirulent isolates (n = 29) were more commonly recovered from patients after prolonged hospital stays (>30 days) and mostly manifested as primary bacteremia. The overall in-hospital mortality was 56.3%. Hazard ratio (HR) analysis revealed the following positive predictors for mortality: nosocomial infection, stay in an intensive care unit, no removal of the central venous catheter, Charlson comorbidity score, and APACHE II score (>==15). The negative predictors were initial appropriate antibiotic therapy (HR 0.42) and urinary tract infection (HR 0.19). Charlson score was an independent confounder based on multivariate analysis (HR 1.43, 95% confidence interval 1.04-1.99). In conclusion, hypervirulence determinants played a role in causing secondary infections in diabetic patients; however, the presence of morbidity cofactors could themselves influence mortality, despite the absence of hypervirulence determinants. |
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6 Department of Internal Medicine, Chi Mei Medical Center-Liou Ying , Tainan City, Taiwan |
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Summary Language |
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Abbreviated Series Title |
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1076-6294 |
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Notes |
PMID:27380450 |
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no |
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Call Number |
ref @ user @ |
Serial |
100535 |
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Author |
Yin, J.; Oh, Y.T.; Kim, J.-Y.; Kim, S.S.; Choi, E.; Kim, T.H.; Hong, J.H.; Chang, N.; Cho, H.J.; Sa, J.K.; Kim, J.C.; Kwon, H.J.; Park, S.; Lin, W.; Nakano, I.; Gwak, H.-S.; Yoo, H.; Lee, S.-H.; Lee, J.; Kim, J.H.; Kim, S.-Y.; Nam, D.-H.; Park, M.-J.; Park, J.B. |
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Title |
Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPbeta Signaling |
Type |
Journal Article |
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Year |
2017 |
Publication |
Cancer Research |
Abbreviated Journal |
Cancer Res |
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Volume |
77 |
Issue |
18 |
Pages |
4973-4984 |
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Abstract |
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPbeta, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-kappaB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPbeta expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. (c)2017 AACR. |
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Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea |
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0008-5472 |
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Notes |
PMID:28754668 |
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Call Number |
ref @ user @ |
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96575 |
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