Kuei-Pin Chung

NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages

Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.

Arrival of Klebsiella pneumoniae carbapenemase (KPC)-2 in Taiwan

Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

Clinical Outcomes in Non–Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR

Purpose: Several deletions in exon 19 of epidermal growth factor receptor (EGFR) gene have been reported in non–small cell lung cancer (NSCLC). It is unknown if deletions occurring at different amino acid positions or of different sizes are associated with different clinical outcome to EGFR tyrosine kinase inhibitors (TKI). Experimental Design: This study enrolled NSCLC patients with deletions in EGFR exon 19. Patients who had received EGFR TKIs for advanced NSCLC were further evaluated for response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: In 308 patients with deletions in EGFR exon 19, 298 had deletions encompassing the entire amino acid string from L747 through E749 (LRE deletions). EGFR TKIs were used in 204 patients with advanced NSCLC. Patients with non-LRE deletions had the least RR, compared with those with deletions from E746 or L747 (42.9%, 68.2%, and 79.6%, respectively; P = 0.022). Patients with non-LRE deletions had relatively short median PFS, though not significantly different from those with deletions from E746 or L747 (5.9, 9.8, and 10.5 months, respectively; P = 0.665). The OS was not different among patients with deletions occurring at different amino acid positions (P = 0.776). Deletions in exon 19 of different sizes were not associated with different RR, PFS, or OS. Conclusions: Non-LRE deletions in exon 19 were associated with worse response to EGFR TKIs, compared with LRE deletions. Therefore, the expected clinical outcome under EGFR TKIs depends on not only the existence but also the types of deletions in exon 19. Clin Cancer Res; 18(12); 3470–7. ©2012 AACR.

Trends and predictors of changes in pulmonary function after treatment for pulmonary tuberculosis

OBJECTIVES: The present study aimed to investigate the trends in changes in pulmonary function and the risk factors for pulmonary function deterioration in patients with pulmonary tuberculosis after completing treatment. INTRODUCTION: Patients usually have pulmonary function abnormalities after completing treatment for pulmonary tuberculosis. The time course for changes in pulmonary function and the risk factors for deterioration have not been well studied. METHODS: A total of 115 patients with 162 pulmonary function results were analyzed. We retrieved demographic and clinical data, radiographic scores, bacteriological data, and pulmonary function data. A generalized additive model with a locally weighted scatterplot smoothing technique was used to evaluate the trends in changes in pulmonary function. A generalized estimating equation model was used to determine the risk factors associated with deterioration of pulmonary function. RESULTS: The median interval between the end of anti-tuberculosis treatment and the pulmonary function test was 16 months (range: 0 to 112 months). The nadir of pulmonary function occurred approximately 18 months after the completion of the treatment. The risk factors associated with pulmonary function deterioration included smear-positive disease, extensive pulmonary involvement prior to anti-tuberculosis treatment, prolonged anti-tuberculosis treatment, and reduced radiographic improvement after treatment. CONCLUSIONS: After the completion of anti-tuberculosis TB treatment, several risk factors predicted pulmonary function deterioration. For patients with significant respiratory symptoms and multiple risk factors, the pulmonary function test should be followed up to monitor the progression of functional impairment, especially within the first 18 months after the completion of anti-tuberculosis treatment.

Clinical Significance of Thyroid Transcription Factor-1 in Advanced Lung Adenocarcinoma Under Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment

BACKGROUND Thyroid transcription factor 1 (TTF-1) positivity correlates with a higher prevalence of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma. It is unknown whether TTF-1 expression affects the clinical outcome of patients with advanced lung adenocarcinoma, who have received EGFR tyrosine kinase inhibitors (TKIs) during the treatment course. METHODS This study enrolled patients with advanced lung adenocarcinoma who had results of EGFR mutation analysis and TTF-1 immunostaining. The impact of TTF-1 expression on overall survival (OS) and progression-free survival (PFS) under EGFR TKI treatment was evaluated. Multivariate analyses were done to examine the independent predictors of OS and PFS. RESULTS Of 496 patients with advanced lung adenocarcinoma, 443 had TTF-1-positive adenocarcinoma. Patients with TTF-1-positive lung adenocarcinoma had longer OS than did those with TTF-1-negative lung adenocarcinoma (median survival, 27.4 vs 11.8 months, P = .001). In patients with EGFR TKI treatment, those with TTF-1-positive lung adenocarcinoma and mutant EGFR had longer OS. In patients with EGFR mutation, those with TTF-1-positive lung adenocarcinoma had longer PFS than did those with TTF-1-negative lung adenocarcinoma (median survival, 8.7 vs 5.7 months, P = .043). Multivariate analysis showed that negative TTF-1 expression is a predictor for shorter OS, and a predictor for shorter PFS under EGFR TKI treatment. CONCLUSIONS TTF-1 shows independent prognostic significance in advanced lung adenocarcinoma. Patients with TTF-1-negative lung adenocarcinoma have not only shorter OS, but also shorter PFS under EGFR TKI treatment, despite the existence of mutant EGFR. Further studies are needed to investigate the optimal treatment of patients with TTF-1-negative lung adenocarcinoma.

High levels of serum macrophage migration inhibitory factor and interleukin 10 are associated with a rapidly fatal outcome in patients with severe sepsis

OBJECTIVES The aim of this study was to delineate the association between high macrophage migration inhibitory factor (MIF) and interleukin 10 (IL-10) levels in the early phase of sepsis and rapidly fatal outcome. METHODS One hundred and fifty-three adult subjects with the main diagnosis of severe sepsis (including septic shock) admitted directly from the emergency department of two tertiary medical centers and one regional teaching hospital between January 2009 and December 2011, were included prospectively. MIF and IL-10 levels were measured and outcomes were analyzed by Cox regression analysis according to the following outcomes: rapidly fatal outcome (RFO, death within 48 h), late fatal outcome (LFO, death between 48 h and 28 days), and survival at 28 days. RESULTS Among the three outcome groups, IL-10 levels were significantly higher in the RFO group (p < 0.001) and no significant differences were seen between the LFO and survivor groups. After Cox regression analysis, each incremental elevation of 1000 pg/ml in both IL-10 and MIF was independently associated with RFO in patients with severe sepsis. Each incremental elevation of 1000 pg/ml in IL-10 increased the RFO risk by a factor of 1.312 (95% confidence interval 1.094-1.575; p=0.003); this was the most significant factor leading to RFO in patients with severe sepsis. CONCLUSIONS Patients with RFO exhibited simultaneously high MIF and IL-10 levels in the early phase of severe sepsis. Incremental increases in both IL-10 and MIF levels were associated with RFO in this patient group, and of the two, IL-10 was the most significant factor linked to RFO.

Infections caused by unusual Methylobacterium species

ABSTRACT We describe six patients with hospital-acquired bacteremia caused by Methylobacterium species, including M. radiotolerans (n = 2), M. thiocyanatum (n = 2), M. aminovorans (n = 1), and M. lusitanum (n = 1), which were confirmed to species level by 16S rRNA gene sequence analysis. Among these patients, five had catheter-related bacteremia and all had favorable outcomes.

Antifungal Susceptibilities of Candida Isolates Causing Bloodstream Infections at a Medical Center in Taiwan, 2009-2010

ABSTRACT We used the Sensititre YeastOne (SYO) method (Trek Diagnostic Systems) to determine the MICs of nine antifungal agents against 474 nonduplicate blood Candida isolates. The MIC results were interpreted according to updated clinical breakpoints (CBPs) recommended by the Clinical and Laboratory Standards Institute (CLSI; document M27-S4) or epidemiology cutoff values (ECVs). The rates of fluconazole susceptibility were 99.2% (234/236) in Candida albicans, 86.7% (85/98) in C. tropicalis, and 97.7% (42/43) in C. parapsilosis. Among the 77 isolates of C. glabrata, 90.9% showed dose-dependent susceptibility (S-DD) to fluconazole. Nearly all isolates of C. albicans, C. parapsilosis, and C. krusei were susceptible to voriconazole; however, rates of voriconazole susceptibility were 78.6% in C. tropicalis. Few isolates of C. albicans (n = 5; 2.1%) and C. glabrata (n = 3; 3.9%), no isolates of C. parapsilosis, C. krusei, and C. guilliermondii, but 62.2% (n = 51) of C. tropicalis isolates were non-wild type for posaconazole susceptibility. For itraconazole susceptibility, 98.3% of C. albicans isolates were wild type, and 3.9% (n = 3) of C. glabrata isolates were non-wild type. Almost all of the isolates tested (>97% for all species) were susceptible to both micafungin and anidulafungin. All isolates tested were found to be wild type for amphotericin B susceptibility, with MICs of <1μg/ml. Further evaluation is needed to establish CBPs of antifungal agents by the 24-h SYO method for the management of patients with candidemia or other invasive candida infections.

Differences in drug resistance profiles of Mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in a medical centre in Taiwan, 2000–2010

Few studies have investigated the drug resistance profiles of Mycobacterium tuberculosis (MTB) isolates recovered from different sites of infection. A total of 4521 non-duplicate MTB isolates, including 3723 (82.3%) from respiratory specimens and 798 (17.7%) from non-respiratory sources, were recovered from patients treated at a medical centre in Taiwan from 2000 to 2010. Trend analysis showed a significant decrease (P<0.05) in the rates of resistance to isoniazid, rifampicin and ethambutol, a decrease in resistance to any one of four agents, namely isoniazid, rifampicin, ethambutol or streptomycin, and a decrease in resistance to both isoniazid and rifampicin (multidrug resistance) amongst pulmonary MTB isolates. A similar decrease in resistance to isoniazid and ethambutol was noted amongst non-pulmonary isolates. Rates of drug resistance were significantly higher amongst MTB isolates recovered from respiratory specimens than amongst those from non-respiratory specimens to 0.2 μg/mL isoniazid (15.3% vs. 9.4%; P<0.0001), 1 μg/mL rifampicin (5.5% vs. 3.3%; P=0.0108), 5 μg/mL ethambutol (7.3% vs. 3.8%; P=0.0004), and both isoniazid and rifampicin (4.8% vs. 2.5%; P=0.0051). Resistance rates amongst isolates causing tuberculous lymphadenitis were significantly lower than amongst those causing genitourinary tuberculosis (TB) to isoniazid (3.5% vs. 19.4%, P=0.0012) and to isoniazid, rifampicin, ethambutol or streptomycin (9.6% vs. 22.6%, P=0.0003). In conclusion, the rates of resistance to first-line anti-TB agents and to multiple agents differed amongst MTB isolates obtained from different infectious sources. Continuous monitoring of resistance of MTB isolates from various sites is necessary in order to establish an effective TB surveillance programme.

Severe lymphopenia is associated with elevated plasma interleukin-15 levels and increased mortality during severe sepsis.

ABSTRACT Sepsis-related mortality has been found increased in RAG-1 knockout mice. However, in patients admitted to medical intensive care units, it is unknown whether severe lymphocyte depletion at admission is associated with increased interleukin (IL)-7 and IL-15 levels in circulation, and increased mortality. We prospectively enrolled 92 patients who were admitted to medical intensive care units for severe sepsis or septic shock. At admission, 24 patients (26.1%) had severe lymphopenia, defined as lymphocyte counts of less than 0.5 × 103/&mgr;L. Severe lymphopenia was associated with significantly higher plasma levels of tumor necrosis factor &agr;, IL-6, IL-8, and IL-10 and was also independently associated with 28-day mortality (adjusted hazard ratio, 3.532; 95% confidence interval, 1.482−8.416; P = 0.004). The levels of plasma IL-15, but not IL-7, were increased modestly in patients with severe lymphopenia compared with those without (median, 12.2 vs. 6.4 pg/mL; P = 0.005). The elevated plasma IL-15 levels were contrarily associated with significantly decreased B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells. In conclusion, severe lymphopenia was associated with increased mortality in patients with severe sepsis. We found that patients with sepsis with severe lymphopenia had down-regulated B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells, despite increased plasma IL-15 concentrations. Whether IL-7 and IL-15 are insufficient in patients with severe lymphopenia during severe sepsis warrants further investigations.