A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer.

Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin-binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells. We observed that, upon HB-EGF induction, CITED4 was induced through a signal transducer and activator of transcription 3 (STAT3)-dependent pathway, regulating cell proliferation. CITED4 interacted with MYC and potentiated MYC-mediated transactivation of the CCND1 promoter, leading to cell cycle progression. Correlation analysis revealed that HB-EGF and CITED4 were significantly positively associated in primary lung tumors, and expression of HB-EGF predicted a poor survival outcome in patients. In vitro and in vivo experiments revealed that pharmacological inhibition of HB-EGF with CRM197 significantly attenuated tumor cell growth. Thus, CITED4 functions as a molecular switch in HB-EGF-induced growth control, and HB-EGF provides a novel therapeutic target for lung cancer intervention.

Multidetector computed tomography assessment on tumor size and nodal status in patients with locally advanced breast cancer before and after neoadjuvant chemotherapy.

AIMS: To evaluate the utility of multidetector computed tomography (MCT) in assessing tumor size and nodal status in patients with advanced breast cancers before and after the neoadjuvant chemotherapy. METHODS: Twenty-eight proven locally advanced breast cancer patients with 30 tumors were enrolled in this study. MCT was used to assess tumor size and axillary lymph nodes before and after the neoadjuvant chemotherapy. The correlation between tumor size on MCT and gross tumor size was tested. RESULTS: The MCT measurements documented complete response in 3, partial response in 18, non-response in 8 and progressed in 1. The mean tumor diameters on pathology and post-chemotherapy MCT were 3.6cm (S.D.=+/-2.9cm) and 3.1cm (S.D.=+/-2.6cm), respectively. The Pearson correlation coefficient was 0.76 (p<0.001). The sensitivity, specificity, positive predictive valve, negative predictive valve and accuracy of MCT in diagnosing the axillary lymph node metastases after pre-operative neoadjuvant chemotherapy were counted, respectively, to 72%, 40%, 85.7%, 22.2% and 66.7%. All the 5 downstaged axillary nodal statuses from node-positive to node-negative on MCT had micrometastases. CONCLUSION: MCT can be used to evaluate tumor size and nodal status in patients with advanced breast cancer. As there is a baseline MCT before chemotherapy for comparison, we are potentially aware of the possibility of false negative nodal micrometastases on the post-chemotherapy MCT.

An outbreak of enterovirus 71 infection in Taiwan, 1998. II. Laboratory diagnosis and genetic analysis.

BACKGROUND: An epidemic of enterovirus 71 (EV71) occurred in Taiwan from April to December of 1998, with two peaks, one in June and the other in October. Many enteroviruses were isolated in our laboratory from 258 cases during this outbreak. Approximately half of the enteroviruses isolated were EV71 and one fifth were coxsackievirus A16. OBJECTIVES: To analyze laboratory findings in the EV71 epidemic of 1998 in Taiwan, various EV71 specimens in different cell lines were examined. In addition, genetic analysis of 5' non-coding region (NCR) was performed to analyze the strain variation in this outbreak. RESULTS: The cytopathic effect induced by EV71 was observed 2-13 (mean of 4.5) days post-inoculation in Vero cells and 4-15 (mean of 6.6) days in green monkey kidney (GMK) cells inoculated with throat swabs. Of the total positive EV71 cases, virus was most frequently obtained from throat swabs (91.7%), less from stools (64.8%), and none from cerebral spinal fluid (CSF). Molecular analyses of EV71 by sequencing the 5' NCR of 34 strains obtained from different clinical categories and various geographic areas showed that their sequences differed (0-13 bp in 681 bp sequenced) by approximately 0-2%. The sequences of these isolates differed from EV71 prototype BrCr or MS strain by 17.5-19%, with the exception of two samples which exhibited nucleotide variation by only 8.9 and 8.2%, when compared to the MS strain. CONCLUSION: EV71 was most frequently isolated from throat swab specimens in Vero cells. The molecular analyses of the 5' NCR of EV71 revealed that most isolates from this epidemic belonged to a group of closely related clones and only two were in a different group which was clustered with the EV71 MS strain.

Respiratory viral infections among pediatric inpatients and outpatients in Taiwan from 1997 to 1999.

The present study examined the association of specific virus infections with acute respiratory tract conditions among hospitalized and outpatient children in a subtropical country. A total of 2,295 virus infections were detected in 6,986 patients between 1997 and 1999, including infections caused by respiratory syncytial virus (RSV) (1.7%), parainfluenza virus (2.0%), influenza B virus (2.6%), adenovirus (4.0%), herpes simplex virus type 1 (4. 4%), influenza A virus (5.5%), and enterovirus (12.7%). There were 61 mixed infections, and no consistent seasonal variation was found. One or more viruses were detected among 24.8% of hospitalized patients and 35.0% of outpatients. The frequencies and profiles of detection of various viruses among in- and outpatients were different. The occurrence of enterovirus infections exceeded that of other viral infections detected in 1998 and 1999 due to outbreaks of enterovirus 71 and coxsackievirus A10. RSV was the most prevalent virus detected among hospitalized children, whereas influenza virus was the most frequently isolated virus in the outpatient group. Most respiratory viral infections (39.3%) occurred in children between 1 and 3 years old. RSV (P < 0.025) and influenza A virus (P < 0.05) infections were dominant in the male inpatient group. In addition, most pneumonia and bronchiolitis (48.4%) was caused by RSV among hospitalized children less than 6 months old. Adenovirus was the most common agent associated with pharyngitis and tonsilitis (45.5%). These data expand our understanding of the etiology of acute respiratory tract viral infections among in- and outpatients in a subtropical country and may contribute to the prevention and control of viral respiratory tract infections.

Clinicopathologic factors influencing long-term survival after resection for hepatocellular carcinoma.

BACKGROUND: The purpose of this study is to investigate the clinicopathologic factors that influence a survival longer than 5 years with no recurrence in patients after resection for hepatocellular carcinoma (HCC). METHODS: Between January 1992 and December 1994, 64 patients with complete viral markers study underwent curative hepatic resection for HCC. Four patients who died of surgical morbidity (hospital mortality, 6.3%) were excluded from this study. Among the 60 patients who survived, 10 patients (16.7%) survived over 5 years without recurrence. The clinicopathologic features and surgical procedures of the patients with long-term survival (> or = 5 years) without recurrence (n = 10) were compared with those of less than 5 years survival or with tumor recurrence (n = 50). The median follow-up was 64.8 months, ranging from 61.1 to 76.7 months. RESULTS: Six of the 10 patients were men with an age ranging from 35 to 75 years (mean, 57.6 +/- 9.7). Using univariate analysis, long-term survival without recurrence was significantly associated with a lower amount of perioperative blood transfusion (less than 7 units, p = 0.036) and an existence of tumor capsule (p = 0.031). But in multivariate analysis, only the presence of tumor capsule was statistically significant. CONCLUSIONS: Long-term survival without recurrence was related to a lower amount of perioperative blood transfusion, and an existence of tumor capsule in univariate analysis. But in multivariate analysis, only the existence of tumor capsule plays a significant role.

Potential dengue virus-triggered apoptotic pathway in human neuroblastoma cells: arachidonic acid, superoxide anion, and NF-kappaB are sequentially involved.

Direct in vivo evidence for the susceptibility of human neuronal cells to dengue virus has not been reported. In this study, we demonstrated that type 2 dengue (DEN-2) virus infection induced extensive apoptosis in the human neuroblastoma cell line SK-N-SH. Phospholipase A(2) (PLA(2)) was activated by DEN-2 infection, which led to the generation of arachidonic acid (AA). Inhibition of PLA(2) activity by the PLA(2) inhibitors, AACOCF(3) and ONO-RS-082, diminished DEN-2 virus-induced apoptosis. In contrast, the cyclooxygenase inhibitors aspirin and indomethacin, thought to increase AA accumulation by blocking AA catabolism, enhanced apoptosis. Exogenous AA induced apoptosis in a dose-dependent manner. Superoxide anion, which is thought to be generated through the AA-activated NADPH oxidase, was increased after infection. Pretreatment with superoxide dismutase (SOD) protected cells against DEN-2 virus-induced apoptosis. Furthermore, generation of superoxide anion was blocked by AACOCF(3). In addition, the transcription factors, NF-kappaB and c-Jun, were found to be activated after DEN-2 virus infection. However, pretreatment of cells with oligodeoxynucleotides containing NF-kappaB, but not c-Jun, binding sites (transcription factor decoy) strongly prevented dengue virus-induced apoptosis. The finding that AACOCF(3) and SOD significantly block activation of NF-kappaB suggests that this activation is derived from the AA-superoxide anion pathway. Our results indicate that DEN-2 virus infection of human neuroblastoma cells triggers an apoptotic pathway through PLA(2) activation to superoxide anion generation and subsequently to NF-kappaB activation. This apoptotic effect can be either directly derived from the action of AA and superoxide anion on mitochondria or indirectly derived from the products of apoptosis-related genes activated by NF-kappaB.