Correction to: CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

Following publication of their article "CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation", the authors reported an error in Fig.6b. α-Tubulin image of rCCN2 treatment  (upper panel in CL1-5) only showed eight lanes, when there should be nine.

Cost Analysis and Determinants of Living Donor Liver Transplantation in Taiwan.

BACKGROUND: Liver transplantation (LT) has become established therapy for end-stage liver disease and small-cell hepatocellular carcinoma (HCC), relying mainly on living donor LT (LDLT) in Taiwan. The cost of LDLT varies in different countries depending on the insurance system, the costs of the facility, and staff. In this study we aimed to investigate cost outcomes and determinants of LDLT in Taiwan. METHODS: From January 2014 to December 2015, 184 LDLT patients were enrolled in a study performed at the Kaohsiung Chang Gung Memorial Hospital. Patients' transplantation costs were defined as expense from immediately after surgery to discharge during hospitalization for LDLT. Antiviral therapy and hepatitis B immunoglobulin (HBIG) for prevention of hepatitis B virus (HBV) were included, but direct-acting antiviral (DAA) therapy for hepatitis C (HCV) was excluded. RESULTS: The median total, intensive care unit (ICU), and ward costs of LT were US$64,250, $43,357, and $16,138 (currency ratio 1:30), respectively. HBV significantly increased the total cost of LT, followed by postoperative reintubation and bile duct complications. CONCLUSION: The charges associated with anti-HBV viral therapy and HBIG increase the cost of LDLT. Disease severity of liver cirrhosis showed less importance in predicting cost. Postoperative complications such as reintubation or bile duct complications should be avoided to reduce the cost of LT.

A composite of exhaled LTB4 , LXA4 , FeNO, and FEV1 as an "asthma classification ratio" characterizes childhood asthma.

BACKGROUND: Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma. METHODS: Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases. RESULTS: Exhaled LTB4 , LTE4 , PGE2, and LXA4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB4 , LXA4 , together with FeNO and FEV1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as "asthma classification ratio" was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively. CONCLUSIONS: In a pediatric study population in Taiwan, the levels of exhaled LTB4 , LTE4 , LXA4, and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4 , together with FeNO and FEV1 , best characterized childhood asthma.

Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association.

This corrects the article DOI: 10.1038/onc.2015.397.

Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association.

Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs.

Impaired phagocytosis and susceptibility to infection in pediatric-onset systemic lupus erythematosus.

OBJECTIVES: Impaired function of polymorphonuclear cells (PMNs) in systemic lupus erythematosus (SLE) leads to severe gram-positive and gram-negative bacterial infection, and to major morbidity and mortality. Few studies have focused on the association of impaired function of PMNs and SLE patients' susceptibility to infection. This study aimed to analyze function of PMNs in peroxidase production, chemotaxis, and phagocytosis in pediatric-onset SLE with severe infection. METHODS: This study compared function of PMNs among pediatric-onset SLE patients with and without histories of severe infection and in normal control subjects. Human peripheral blood PMNs were isolated from patients and controls. Function of PMNs was measured by analyzing peroxidase, chemotaxis, and phagocytic activities. Different disease activity and severity, and drug use in newly diagnosed SLE patients were also compared. RESULTS: In total, 34 SLE patients (12 patients with severe infection, 22 patients without infection) and 25 healthy controls were analyzed. There were no differences in function of PMNs between SLE patients with or without severe infection. Regardless of infection status, medication, and disease activity, SLE patients had impaired phagocytic ability against Salmonella-specific lipopolysaccharides (LPS) compared with normal controls (p < 0.01). The use of immunosuppressants did not influence phagocytic ability against Salmonella-derived LPS. CONCLUSIONS: Immunosuppressant agents do not influence phagocytic ability against Salmonella in SLE subjects. Impaired phagocytosis against Salmonella is prominent in pediatric-onset SLE subjects, which may result in the high prevalence of Salmonella infection. There is no deficiency of peroxidase production and chemotaxis activity among SLE subjects.

CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the ß-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer.

MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol.

Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.

Connective tissue growth factor modulates oral squamous cell carcinoma invasion by activating a miR-504/FOXP1 signalling.

Connective tissue growth factor (CTGF) is a multi-functional secreted protein, and it has been shown either to promote or suppress tumor progression among different kinds of cancers. Here, we investigated the role of CTGF in oral squamous cell carcinoma (OSCC) invasion and metastasis. In five OSCC cell lines, endogenous CTGF negatively correlated with invasiveness. Exogenous CTGF protein or forced expression of CTGF gene in the oral cancer cell line SAS significantly decreased their invasive and migratory abilities. MicroRNA (miRNA) microarray analysis was performed in CTGF-overexpressed SAS cells (SAS/CTGF-M3) versus control cells to investigate the mechanism of CTGF-mediated inhibition of OSCC invasion. Among the miRNAs regulated by CTGF, miR-504 and miR-346 were the top two miRNAs downregulated in CTGF transfectants, and the result was confirmed by quantitative reverse transcriptase-PCR. Ectopic miR-504 increased migration and invasion in SAS/CTGF-M3, however, miR-346 did not have such impact on migration/invasion. Furthermore, we identified FOXP1, a member of forkhead transcription factors, as a target gene that takes part in the miR-504-induced cellular invasion. Knockdown of FOXP1 increased invasiveness in SAS/CTGF-M3, confirming the signal axis of CTGF/miR-504/FOXP1 in OSCC. Animal experiments showed that SAS/CTGF-M3-formed orthotopic tumors were associated with a lesser invasive phenotype than control cells. Expression of miR-504 in SAS/CTGF-M3 increased lymph node metastasis, and co-expression of FOXP1 in miR-504-transfected SAS/CTGF-M3 alleviated miR-504-induced metastasis. In OSCC samples, high CTGF was associated with a lower clinical stage and a better outcome. A reverse correlation between CTGF and miR-504, miR-504 and FOXP1, and a positive correlation between CTGF and FOXP1 were shown. Our study discovers a novel signal pathway involving the regulation of miRNA machinery by a secreted cytokine, which will be beneficial for developing therapeutic strategy against advanced OSCC.

Lack of association of mannose-binding lectin gene polymorphisms with development and clinical manifestations of systemic lupus erythematosus in Chinese children.

Mannose-binding lectin (MBL) gene polymorphisms may be associated with adult-onset systemic lupus erythematosus (SLE), but studies in children with SLE are rare. This study tested the genetic association between MBL polymorphisms and paediatric-onset SLE in a cohort of Chinese children in Taiwan. In all 150 children with SLE and 100 healthy controls of comparable age were genotyped for codon 52, 54 and 57 mutations of the MBL gene using a polymerase chain reaction-based assay. Clinical manifestations, organ involvement, disease activity, laboratory characteristics and outcome were recorded and compared between patients with different MBL genotypes. Codon 54 mutation was fairly common in both SLE patients and controls, whereas codon 52 and codon 57 mutations were not detected in our study subjects. No statistically significant differences were found in allele frequencies of the codon 54 mutation between SLE and control groups. Moreover, no association was found between this MBL polymorphism and clinical manifestations, organ involvement, disease activity, laboratory characteristics or outcome of SLE. These results suggest that MBL polymorphisms do not influence susceptibility to paediatric-onset SLE and do not influence clinical manifestations of SLE in Chinese children.

Characterization of interleukin 8 in woodchucks with chronic hepatitis B and hepatocellular carcinoma.

The eastern woodchuck, Marmota monax, represents a useful animal model to study hepatitis B virus infection in humans. However, immunological studies in this model have been impeded by a lack of basic information about the components of the immune system such as cytokines and chemokines. To clarify the role(s) of interleukin 8 (IL-8) in chronic hepatitis B and hepatocellular carcinoma (HCC) in the woodchuck model, we cloned and characterized the woodchuck IL-8 cDNA and genomic DNA. Sequence analysis revealed that the organization of the wk-IL-8 gene is similar to that of the human IL-8 gene and consists of four exons and three introns. Woodchuck IL-8 protein exhibits the conserved ELRCXC motif of IL-8 and shows 87, 82, 82 and 79% similarity with rabbit, ovine, bovine and human IL-8 proteins, respectively. The biological activity of wk-IL-8 was demonstrated using neutrophil chemotaxis assays. Wk-IL-8 could be readily detected in both tumor and non-tumor tissues with higher expression in the non-tumor tissues in most cases. The results from this study will facilitate the investigation of IL-8 in the immunopathogenesis of hepadnavirus-related diseases by the woodchuck model.

Effect of cyclosporin A on interleukin-15-activated umbilical cord blood natural killer cell function.

BACKGROUND: Interleukin (IL)-15-activated natural killer (NK) cells may provide a graft-versus-leukemia (GvL) effect post-umbilical cord blood (CB) transplantation. The effect of cyclosporin A (CsA), a calcineurin-inhibitor used for prophylaxis of graft-versus-host disease (GvHD), on IL-15-mediated activation, cytotoxic function and target-induced apoptosis of CB NK cells, was examined in comparison with adult peripheral blood (APB) NK cells. METHODS: CsA was added to anti-CD3+/-IL-15-stimulated CB and APB mononuclear cells (MNC) for a 5-day incubation. CD3- CD56+ NK cell recovery was determined by flow cytometric analysis. Magnetic bead-purified CB and APB NK cells were stimulated with IL-15 for 18 h under the influence of CsA. NK activation (CD69), K562 cytotoxicity and NK-K562 interactions (CD54, perforin and annexin-V expression 4 h following contact with K562 cells) were assessed by flow cytometry. RESULTS: CsA decreased CD3- CD56+ NK cell recovery in anti-CD3-stimulated CB MNC 5-day cultures, an effect that could be counteracted by IL-15; comparable effects were observed with APB. Short-term (18-h) experiments revealed that CsA down-regulated K562 cytotoxicity of IL-15-activated (P=0.018) but not resting (P=0.268) purified CB NK cells. IL-15-induced CB NK CD69 expression showed increased CsA sensitivity over APB (P=0.012). CsA down-regulated K562 cell-induced CD54 (P=0.028) but not perforin (P=0.416) expression of IL-15-activated CB NK cells. Target-induced apoptosis of IL-15-activated CB (P=0.043) but not APB (P=0.144) NK cells was decreased by CsA. DISCUSSION: We have demonstrated differential CsA sensitivity of IL-15-activated CB and APB NK cells. These results may be used to improve the design of IL-15-activated NK cell adoptive immunotherapy in cancer patients receiving CsA post-CB transplantation.

The role of the VEGF-C/VEGFR-3 axis in cancer progression.

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) (also called VEGFR-3) is activated by its specific ligand, VEGF-C, which promotes cancer progression. The VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumours. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, activation of the VEGF-C/VEGFR-3 axis in several types of solid tumours enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis. In this review, we discuss the novel function and molecular mechanism of the VEGF-C/VEGFR-3 axis in cancer progression.

Involvement of matrix metalloproteinase-13 in stromal-cell-derived factor 1 alpha-directed invasion of human basal cell carcinoma cells.

Basal cell carcinoma (BCC) is one of the most common skin neoplasms in humans and is usually characterized by local aggressiveness with little metastatic potential, although deep invasion, recurrence, and regional and distant metastases may occur. Here, we studied the mechanism of BCC invasion. We found that human BCC tissues and a BCC cell line had significant expression of CXCR4, which was higher in invasive than non-invasive BCC types. Further, of 19 recurrent tumors among 390 BCCs diagnosed during the past 12 years, 17/19 (89.5%) had high CXCR4 expression. We found that the CXCR4 ligand, stromal-cell-derived factor 1alpha (SDF-1alpha), directed BCC invasion and that this was mediated by time-dependent upregulation of mRNA expression and gelatinase activity of matrix metalloproteinase-13 (MMP-13). The transcriptional regulation of MMP-13 by SDF-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the AP-1 component c-Jun. Finally, CXCR4-transfected BCC cells injected into nude mice induced aggressive BCCs that co-expressed CXCR4 and MMP-13. The identification of SDF-1alpha/CXCR4 as an important factor in BCC invasiveness may contribute insight into mechanisms involved in the aggressive potential of human BCC and may improve therapy for invasive BCCs.

Attenuated Salmonella typhimurium reduces ovalbumin-induced airway inflammation and T-helper type 2 responses in mice.

Cytokines produced by Th2 cells are responsible for the pathogenesis of asthma. Th1-biased immune responses caused by attenuated salmonella have the potential to relieve asthmatic symptoms. We evaluated whether oral administration of attenuated salmonella could modulate allergic responses in a chicken ovalbumin (OVA)-induced asthmatic murine model. Mice were fed with attenuated salmonella SL7207 one dose before and three doses during the induction of an allergic response. Lung histology, percentages of eosinophil in bronchoalveolar lavage fluid, serum levels of OVA-specific antibodies and cytokine production by OVA-activated splenocytes were evaluated in mice with or without the administration of SL7207. A significant reduction in pulmonary eosinophilic infiltration was observed in mice receiving attenuated salmonella. Lower levels of OVA-specific IgG1 but higher titres of OVA-IgG2a in serum were also detected in this group. Splenocytes from salmonella-fed mice produced lower levels of Th2 cytokines upon OVA stimulation. The administration of attenuated salmonella significantly suppressed immunopathological symptoms in OVA-sensitized mice. Inhibition of Th2 responses might explain the potential mechanisms. This study provides some evidence for the feasibility of attenuated salmonella as an effective vaccine for allergic diseases.

Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway.

This study is to investigate the molecular mechanism of radiation-enhanced cell invasiveness of hepatocellular carcinoma (HCC) correlating with clinical patients undergoing radiotherapy and subsequently developing metastasis. Three HCC cell lines (HepG2, Hep3B and Huh7) and normal hepatocyte cell line (CL-48) were irradiated with different doses. The effect of radiation on cell invasiveness was determined using the Boyden chamber assay. Radiation-enhanced invasion capability was evident in HCC cells but not in normal hepatocytes. Invasion was observed in gelatin-coated but not fibronectin-coated or type I collagen-coated membranes. Radiation upregulated matrix metalloproteinase-9 (MMP-9) mRNA level, MMP-9 protein level and MMP-9 activity. MMP-9 antisense oligonucleotides inhibited radiation-induced MMP-9 expression and thereby significantly inhibited radiation-induced HCC invasion. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt chemical inhibitors LY294002 and wortmannin suppressed radiation-induced MMP-9 mRNA expression. Transient transfection with dominant-negative Akt plasmid also showed that the PI3K/Akt-signaling pathway was involved in this radiation-induced MMP-9 expression. Moreover, nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide suppressed radiation enhanced MMP-9 promoter activity completely. PI3K/Akt chemical inhibitors inhibited radiation-induced NF-kappaB-driven luciferase promoter activity. Taken together, our results indicated that sublethal dose of radiation could enhance HCC cell invasiveness by MMP-9 expression through the PI3K/Akt/NF-kappaB signal transduction pathway.

Calreticulin expression in neuroblastoma--a novel independent prognostic factor.

BACKGROUND: Calreticulin (CRT), an endoplasmic reticulum protein, has been reported to be essential for the differentiation of neuroblastoma (NB) cells, suggesting that CRT may affect the tumor behavior of neuroblastoma. The aim of this study was to evaluate the association of clinicopathologic factors and patient survival with the expression of CRT in patients with NB. PATIENTS AND METHODS: Sixty-eight NBs were investigated by immunohistochemical staining against CRT, and were divided into positive and negative immunostaining groups. Correlations between calreticulin expression, various clinicopathologic and biologic factors, and patient survival were studied. In seven tumor samples, CRT mRNAs and proteins were evaluated with real-time PCR and western blot, respectively, and correlated with immunohistochemical findings. RESULTS: Among 68 NBs, 32 (47.1%) showed positive CRT expression. Positive CRT immunostaining strongly correlated with differentiated histologies, as well as known favorable prognostic factors such as detected from mass screening, younger age (< or =1 year) at diagnosis and early clinical stages, but inversely correlated with MYCN amplification. Kaplan-Meier analysis revealed that NB patients with CRT expression did have better survival. Multivariate analysis demonstrated CRT expression to be an independent prognostic factor. Moreover, CRT expression also predicted better survival in patients with advanced-stage NBs, and its absence predicted poorer survival in patients whose tumor had no MYCN amplification. The amount of CRT mRNAs and proteins in NB tumor samples tested correlated well with the immunohistochemical expressions. CONCLUSIONS: CRT expression correlates with the differentiation of NB and predicts favorable survival, thereby suggesting CRT to be a useful indicator for planning treatment of NB.

p53-Dependent and -independent functions of the Arf tumor suppressor.

The Ink4a-Arf locus encodes two closely wedded tumor suppressor proteins (p16(Ink4a) and p19(Arf)) that inhibit cell proliferation by activating Rb and p53, respectively. With few exceptions, the Arf gene is repressed during mouse embryonic development, thereby helping to limit p53 expression during organogenesis. However, in adult mice, sustained hyperproliferative signals conveyed by somatically activated oncogenes can induce Arf gene expression and trigger a p53 response that eliminates incipient cancer cells. Disruption of this tumor surveillance pathway predisposes to cancer, and inactivation of INK4a- ARF by deletion, silencing, or mutation has been frequently observed in many forms of human cancer. Although it is accepted that much of Arf's tumor-suppressive activity is mediated by p53, more recent genetic evidence has pointed to additional p53- independent functions of Arf, including its ability to inhibit gene expression by a number of other transcription factors. Surprisingly, the enforced expression of Arf in mammalian cells promotes the sumoylation of several Arf-interacting proteins, implying that Arf has an associated catalytic activity. We speculate that transcriptional down-regulation in response to Arf-induced sumoylation may account for Arf's p53-independent functions.

HLA-DRB1 genotyping in patients with juvenile idiopathic arthritis in Taiwan.

The object of this study was to investigate whether there is an association between HLA-DRB1 alleles and the development of juvenile idiopathic arthritis (JIA) in Taiwan. HLA-DRB1 alleles were studied in 60 patients with JIA and 200 healthy controls using polymerase chain reaction (PCR)/sequence-specific oligonucleotide probes (SSO). The frequency of HLA-DRB1*0405 in patients with JIA was found to be significantly higher than that in healthy controls [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.01-6.91]. The DRB1*0405 allele was significantly associated with the development of both polyarthritis (OR 4.30, 95% CI 1.34-13.80) and oligoarthritis (OR 3.27, 95% CI 1.01-10.58). The frequency of HLA-DRB1*1502 was higher in Taiwanese JIA patients with systemic arthritis than in controls (OR 18.09, 95% CI 2.25-145.73). We conclude that, in Taiwan, HLA-DRB1*0405 is associated with the development of polyarthritis and oligoarthritis in children, and HLA-DRB1*1502 is associated with the development of systemic arthritis.

MCP-1 gene regulatory region polymorphism in Chinese children with mild, moderate and near-fatal asthma.

BACKGROUND: A polymorphism in the monocyte chemoattractant protein 1 (MCP-1) gene regulatory region has been associated with asthma in Caucasians. This polymorphism is possibly endemic to the Asian region, but its impact on Asian populations is unclear. In addition, the relationship of this marker with life-threatening asthma has not been clarified. The aim of this study was to test the genetic association between the MCP-1 -2518A/G polymorphism and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 mild-to-moderate asthmatics, 69 allergic-disorder cases without asthma, and 107 nonasthmatic, nonatopic control children were genotyped by a polymerase chain reaction-based assay. RESULTS: Comparison of the four groups of children (n = 358) revealed no detectable differences in genotype or allele frequencies of the MCP-1 -2518A/G polymorphism. There was no evidence of association between the polymorphism and any of the outcomes of interest including clinical severity, blood eosinophil count, atopy, total serum IgE levels, and degree of bronchial hyper-responsiveness. CONCLUSION: These results suggest that the MCP-1 -2518A/G polymorphism is not a risk factor for near-fatal asthma. Furthermore, this polymorphism seems to play no role in the development of asthma or atopy in Chinese subjects, possibly as a result of the genetic heterogeneity between Asian and Caucasian populations with respect to regulation of MCP-1 expression. Our results underscore the necessity of accounting for ethnic background in the investigation of asthma-predisposition genes.