Tegafur-Uracil Plus Gemcitabine Combination Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with Platinum

BackgroundAn open-label, single-arm prospective study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine and tegafur-uracil (UFT) in patients with advanced nonsmall-cell lung cancer (NSCLC) after the failure of previous platinum-containing regimens.Patients and MethodsPatients with advanced NSCLC received 200 mg/m2 of UFT twice daily from day 1 through 14 plus 900 mg/m2 of gemcitabine per day via intravenous injection on days 8 and 15. This regimen was repeated every 3 or 4 weeks.ResultsA total of 40 patients were enrolled. Eleven patients (28%; 95% confidence interval [CI], 15–44%) achieved a partial response. The median progression-free survival, median overall survival, and 1-year survival rate were 4.0 months (95% CI, 3.3–6.7 months), 12.6 months (95% CI, 7.0–22.3 months), and 51% (95% CI, 33–66%), respectively. The most common grade 3 or 4 toxicity was neutropenia (38%; 95% CI, 23–54%) and the rate of grade 3 or 4 nonhematologic toxicity remained at less than 5%. A multivariate Cox model showed that adenocarcinoma, nonsmoking history, and good performance status predicted better survival.ConclusionsCombination chemotherapy with UFT and gemcitabine showed a promising effectiveness and acceptable toxicity for patients with platinum-resistant NSCLC

Efficacy of Wnt-1 monoclonal antibody in sarcoma cells

BACKGROUND: Sarcomas are one of the most refractory diseases among malignant tumors. More effective therapies based on an increased understanding of the molecular biology of sarcomas are needed as current forms of therapy remain inadequate. Recently, it has been reported that Wnt-1/β-catenin signaling inhibits apoptosis in several cancers. In this study, we investigated the efficacy of a monoclonal anti-Wnt-1 antibody in sarcoma cells. METHODS: We treated cell lines A-204, SJSA-1, and fresh primary cultures of lung metastasis of sarcoma with a monoclonal anti-Wnt-1 antibody. Wnt-1 siRNA treatment was carried out in A-204. We assessed cell death using Crystal Violet staining. Apoptosis induction was estimated by flow cytometry analysis (Annexin V and PI staining). Cell signaling changes were determined by western blotting analysis. RESULTS: We detected Wnt-1 expression in all tissue samples and cell lines. Significant apoptosis induction was found in monoclonal anti-Wnt-1 antibody treated cells compared to control monoclonal antibody treated cells (p < 0.02). Similarly, we observed increased apoptosis in Wnt-1 siRNA treated cells. Blockade of Wnt-1 signaling in both experiments was confirmed by analyzing intracellular levels of Dishevelled-3 and of cytosolic β-catenin. Furthermore, the monoclonal anti-Wnt-1 antibody also induced cell death in fresh primary cultures of metastatic sarcoma in which Wnt-1 signaling was active. CONCLUSION: Our results indicate that Wnt-1 blockade by either monoclonal antibody or siRNA induces cell death in sarcoma cells. These data suggest that Wnt-1 may be a novel therapeutic target for the treatment of a subset of sarcoma cells in which Wnt-1/β-catenin signaling is active

Risk Factors for a Second Episode of Hemoptysis

Objectives Hemoptysis is an alarming symptom of underlying lung disease. Clinicians are often unsure how to deal with and follow up patients who have had a single episode of hemoptysis, especially if the cause remains unknown despite thorough examination, because a second, more severe episode of hemoptysis might occur despite an apparently stable condition. Investigations were done, using multivariate analyses, to see whether several clinical factors present during an initial episode of hemoptysis could be used to predict a second episode. Subjects and Methods Eighty patients with an initial episode of hemoptysis who underwent both computed tomographic and bronchoscopic examinations from 2003 through 2005 were reviewed. Results The isolation of bacteria from bronchial lavage fluid (odds ratio 13.5, P = 0.001) and the failure to determine the cause of the initial episode of hemoptysis (odds ratio 7.0, P = 0.014) were significant independent predictors of a second episode of hemoptysis. Subset analysis showed that isolation of either Pseudomonas aeruginosa or Haemophilus influenzae increased the likelihood of a second episode of hemoptysis (P = 0.077), even if colonization, representing host-bacterial equilibrium, had occurred. Furthermore, the failure to determine the etiology of an initial episode of hemoptysis was associated with an increased risk of a massive second episode (P = 0.042), regardless of the volume of the initial episode. Conclusions In patients with bacterial colonization of the respiratory tract or an initial episode of hemoptysis of unknown etiology, there is an increased possibility of a second episode of hemoptysis

A Monoclonal Antibody against Wnt-1 Induces Apoptosis in Human Cancer Cells

Aberrant activation of the Wingless-type (Wnt)/β-catenin signaling pathway is associated with a variety of human cancers. Little is known regarding the role that Wnt ligands play in human carcinogenesis. To test whether a Wnt-1 signal is a survival factor in human cancer cells and thus may serve as a potential cancer therapeutic target, we investigated the effect of inhibition of Wnt-1 signaling in a variety of human cancer cell lines, including non small cell lung cancer, breast cancer, mesothelioma, and sarcoma. Both monoclonal antibody and RNA interference (RNAi) were used to inhibit Wnt-1 signaling. We found that incubation of a monoclonal anti-Wnt-1 antibody induced apoptosis and caused downstream protein changes in cancer cells overexpressing Wnt-1. In contrast, apoptosis was not detected in cells lacking or having minimal Wnt-1 expression after the antibody incubation. RNAi targeting of Wnt-1 in cancer cells overexpressing Wnt-1 demonstrated similar downstream protein changes and induction of apoptosis. The antibody also suppressed tumor growth in vivo. Our results indicate that both monoclonal anti-Wnt-1 antibody and Wnt-1 siRNA inhibit Wnt-1 signaling and can induce apoptosis in human cancer cells. These findings hold promise as a novel therapeutic strategy for cancer

Efficacy of Wnt-1 monoclonal antibody in sarcoma cells

Abstract Background Sarcomas are one of the most refractory diseases among malignant tumors. More effective therapies based on an increased understanding of the molecular biology of sarcomas are needed as current forms of therapy remain inadequate. Recently, it has been reported that Wnt-1/β-catenin signaling inhibits apoptosis in several cancers. In this study, we investigated the efficacy of a monoclonal anti-Wnt-1 antibody in sarcoma cells. Methods We treated cell lines A-204, SJSA-1, and fresh primary cultures of lung metastasis of sarcoma with a monoclonal anti-Wnt-1 antibody. Wnt-1 siRNA treatment was carried out in A-204. We assessed cell death using Crystal Violet staining. Apoptosis induction was estimated by flow cytometry analysis (Annexin V and PI staining). Cell signaling changes were determined by western blotting analysis. Results We detected Wnt-1 expression in all tissue samples and cell lines. Significant apoptosis induction was found in monoclonal anti-Wnt-1 antibody treated cells compared to control monoclonal antibody treated cells (p Conclusion Our results indicate that Wnt-1 blockade by either monoclonal antibody or siRNA induces cell death in sarcoma cells. These data suggest that Wnt-1 may be a novel therapeutic target for the treatment of a subset of sarcoma cells in which Wnt-1/β-catenin signaling is active.</p

A novel isoform of Homeodomain-interacting protein kinase-2 promotes YAP/TEAD transcriptional activity in NSCLC cells.

Homeodomain-interacting protein kinase-2 (HIPK2) can either promote or inhibit transcription depending on cellular context. In this study, we show that a new HIPK2 isoform increases TEAD reporter activity in NSCLC cells. We detected HIPK2 copy number gain in 5/6 (83.3%) NSCLC cell lines. In NSCLC patients with high HIPK2 mRNA expression in the Human Protein Atlas, the five-year survival rate is significantly lower than in patients with low expression (38% vs 47%; p = 0.047). We also found that 70/78 (89.7%) of NSCLC tissues have moderate to strong expression of the N-terminal HIPK2 protein. We detected and cloned a novel HIPK2 isoform 3 and found that its forced overexpression promotes TEAD reporter activity in NSCLC cells. Expressing HIPK2 isoform 3_K228A kinase-dead plasmid failed to increase TEAD reporter activity in NSCLC cells. Next, we showed that two siRNAs targeting HIPK2 decreased HIPK2 isoform 3 and YAP protein levels in NSCLC cells. Degradation of the YAP protein was accelerated after HIPK2 knockdown in NSCLC cells. Inhibition of HIPK2 isoform 3 decreased the mRNA expression of YAP downstream gene CTGF. The specific HIPK2 kinase inhibitor TBID decreased TEAD reporter activity, reduced cancer side populations, and inhibited tumorsphere formation of NSCLC cells. In summary, this study indicates that HIPK2 isoform 3, the main HIPK2 isoform expressed in NSCLC, promotes YAP/TEAD transcriptional activity in NSCLC cells. Our results suggest that HIPK2 isoform 3 may be a potential therapeutic target for NSCLC