National Cheng Kung University

About: National Cheng Kung University is a education organization based out in Tainan City, Taiwan. It is known for research contribution in the topics: Population & Thin film. The organization has 49723 authors who have published 69799 publications receiving 1437420 citations. The organization is also known as: NCKU.

Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

Abstract: Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133(+) cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133(+) cells has not been investigated methodically. In this study, we revealed that CD133(+) lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC(20)) was sufficient to enrich CD133(+) cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133(+) cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133(+) cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133(+) cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133(+) cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133(+) cell number. Together, our results showed that cisplatin induces the enrichment of CD133(+) cells, leading to multidrug resistance by the activation of Notch signaling.

Clinical implications of hypermucoviscosity phenotype in Klebsiella pneumoniae isolates: association with invasive syndrome in patients with community-acquired bacteraemia.

Abstract: . Background. Klebsiella pneumoniae, a Gram-negative bacillus usually forming glistening mucoid colonies with viscid consistency on the culture plate, is a common pathogen causing various clinical infection patterns. However, little is known about the clinical implications of this mucoid character. Objective. The purposes of this study, therefore, were to investigate the frequency of hypermucoviscosity (HV) in bacteraemic isolates of K. pneumoniae, and determine the significance of any association between HV and various clinical manifestations. Design. Retrospective observational study. Patients. Patients diagnosed with K. pneumoniae bacteraemia at a community-based university hospital between June 1999 and June 2001 were enrolled in this analysis. Measurements. Clinical data concerning comorbid diseases and infection patterns was collected. K. pneumoniae bacteraemic isolates were examined for the presence of HV using a modified string test. The clinical impact of HV and risk factors for the invasive syndrome were assessed using statistical analysis. Polymerase chain reaction (PCR) was performed to detect magA, a gene related to HV phenotype. Results. Overall, 200 (64.9%) of the 308 cases of K. pneumoniae bacteraemia were community-acquired infections. Compared with hospital-acquired K. pneumoniae bacteraemia (HA-KpB), community-acquired K. pneumoniae bacteraemia (CA-KpB) was more likely to be monomicrobial in nature (83.5% vs. 64.8%; P < 0.001) and caused by HV strains (41.5% vs. 14.8%; P < 0.001). The prevalence rate of magA among HV phenotypical K. pneumoniae strains was 24.1%. Patients infected with HV-positive strains were more likely to have the distinctive invasive syndrome (i.e. liver abscess, meningitis, pleural empyaema or endophthalmitis) than those infected with HV-negative variants (37.3% vs. 6.8%; P < 0.001). Multivariate logistic regression analysis, adjusted for age, showed that HV phenotype in K. pneumoniae strains (OR 8.86; 95% CI, 3.70–21.25; P < 0.001) was positively associated with the development of the invasive syndrome in CA-KpB cases. Conclusions. The HV phenotype of K. pneumoniae bacteraemic isolates was associated with the development of a distinctive invasive syndrome. Identification of the HV phenotype should prompt clinicians to initiate aggressive investigations for invasive diseases.