Functional microRNA high throughput screening reveals miR-9 as a central regulator of liver oncogenesis by affecting the PPARA-CDH1 pathway

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths, reflecting the aggressiveness of this type of cancer and the absence of effective therapeutic regimens. MicroRNAs have been involved in the pathogenesis of different types of cancers, including liver cancer. Our aim was to identify microRNAs that have both functional and clinical relevance in HCC and examine their downstream signaling effectors. Methods: MicroRNA and gene expression levels were measured by quantitative real-time PCR in HCC tumors and controls. A TargetScan algorithm was used to identify miR-9 downstream direct targets. Results: A high-throughput screen of the human microRNAome revealed 28 microRNAs as regulators of liver cancer cell invasiveness. MiR-9, miR-21 and miR-224 were the top inducers of HCC invasiveness and also their expression was increased in HCC relative to control liver tissues. Integration of the microRNA screen and expression data revealed miR-9 as the top microRNA, having both functional and clinical significance. MiR-9 levels correlated with HCC tumor stage and miR-9 overexpression induced SNU-449 and HepG2 cell growth, invasiveness and their ability to form colonies in soft agar. Bioinformatics and 3’UTR luciferase analyses identified E-cadherin (CDH1) and peroxisome proliferator-activated receptor alpha (PPARA) as direct downstream effectors of miR-9 activity. Inhibition of PPARA suppressed CDH1 mRNA levels, suggesting that miR-9 regulates CDH1 expression directly through binding in its 3’UTR and indirectly through PPARA. On the other hand, miR-9 inhibition of overexpression suppressed HCC tumorigenicity and invasiveness. PPARA and CDH1 mRNA levels were decreased in HCC relative to controls and were inversely correlated with miR-9 levels. Conclusions: Taken together, this study revealed the involvement of the miR-9/PPARA/CDH1 signaling pathway in HCC oncogenesis

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>To compare the activity and toxicity of docetaxel/carboplatin (DC) doublet vs single agent docetaxel (D) as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>Patients pre-treated with front-line platinum-free regimens, were randomized to receive either docetaxel/carboplatin (DC), (docetaxel 50 mg/m²; carboplatin AUC4; both drugs administered on days 1 and 15) or docetaxel single-agent (D), (docetaxel 50 mg/m²on days 1 and 15).</p> <p>Results</p> <p>Response rate was similar between the two arms (DC vs D: 10.4% vs 7.7%; p = 0.764). After a median follow-up time of 28.0 months for DC arm and 34.5 months for D arm, progression free survival (PFS) was significantly higher in the DC arm (DC vs D:3.33 months vs 2.60 months; p-value = 0.012), while no significant difference was observed in terms of overall survival (OS) (DC vs D: 10.3 months vs 7.70 months; p-value = 0.550). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed.</p> <p>Conclusions</p> <p>This study has not achieved its primary objective of significant OS prolongation with docetaxel/carboplatin combination over single-agent docetaxel in patients who had not received front-line docetaxel; however, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS.</p

A Phase II Study of Docetaxel and Epirubicin in Advanced Adult Soft Tissue Sarcomas (STS)

Purpose: The aim of this study was to determine the efficacy and safety of docetaxel plus epirubicin combination as first-line chemotherapy in patients with locally advanced and/or metastatic adult STS

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

Ribonucleotide reductase subunits M1 (RRM1) and M2 (RRM2) are involved in the metabolism of gemcitabine (2′,2′-difluorodeoxycytidine), which is used for the treatment of nonsmall cell lung cancer. The mRNA expression of RRM1 and RRM2 in tumours from lung adenocarcinoma patients treated with docetaxel/gemcitabine was assessed and the results correlated with clinical outcome. RMM1 and RMM2 mRNA levels were determined by quantitative real-time PCR in primary tumours of previously untreated patients with advanced lung adenocarcinoma who were subsequently treated with docetaxel/gemcitabine. Amplification was successful in 42 (79%) of 53 enrolled patients. Low levels of RRM2 mRNA were associated with response to treatment (P< 0.001). Patients with the lowest expression levels of RRM1 had a significantly longer time to progression (P=0.044) and overall survival (P=0.02) than patients with the highest levels. Patients with low levels of both RRM1 and RRM2 had a significantly higher response rate (60 vs 14.2%; P=0.049), time to progression (9.9 vs 2.3 months; P=0.003) and overall survival (15.4 vs 3.6; P=0.031) than patients with high levels of both RRM1 and RRM2. Ribonucleotide reductase subunit M1 and RRM2 mRNA expression in lung adenocarcinoma tumours is associated with clinical outcome to docetaxel/gemcitabine. Prospective studies are warranted to evaluate the role of these markers in tailoring chemotherapy

A global atmospheric electricity monitoring network for climate and geophysical research

The Global atmospheric Electric Circuit (GEC) is a fundamental coupling network of the climate system connecting electrically disturbed weather regions with fair weather regions across the planet. The GEC sustains the fair weather electric field (or potential gradient, PG) which is present globally and can be measured routinely at the surface using durable instrumentation such as modern electric field mills, which are now widely deployed internationally. In contrast to lightning or magnetic fields, fair weather PG cannot be measured remotely. Despite the existence of many PG datasets (both contemporary and historical), few attempts have been made to coordinate and integrate these fragmented surface measurements within a global framework. Such a synthesis is important elvinin order to fully study major influences on the GEC such as climate variations and space weather effects, as well as more local atmospheric electrical processes such as cloud electrification, lightning initiation, and dust and aerosol charging. The GloCAEM (Global Coordination of Atmospheric Electricity Measurements) project has brought together experts in atmospheric electricity to make the first steps towards an effective global network for atmospheric electricity monitoring, which will provide data in near real time. Data from all sites are available in identically-formatted files, at both one second and one minute temporal resolution, along with meteorological data (wherever available) for ease of interpretation of electrical measurements. This work describes the details of the GloCAEM database and presents what is likely to be the largest single analysis of PG data performed from multiple datasets at geographically distinct locations. Analysis of the diurnal variation in PG from all 17 GloCAEM sites demonstrates that the majority of sites show two daily maxima, characteristic of local influences on the PG, such as the sunrise effect. Data analysis methods to minimise such effects are presented and recommendations provided on the most suitable GloCAEM sites for the study of various scientific phenomena. The use of the dataset for a further understanding of the GEC is also demonstrated, in particular for more detailed characterization of day-to-day global circuit variability. Such coordinated effort enables deeper insight into PG phenomenology which goes beyond single-location PG measurements, providing a simple measurement of global thunderstorm variability on a day-to-day timescale. The creation of the GloCAEM database is likely to enable much more effective study of atmospheric electricity variables than has ever been possible before, which will improve our understanding of the role of atmospheric electricity in the complex processes underlying weather and climate

Quantitative RT-PCR luminometric hybridization assay with an RNA-internal standard for cytokeratin-19 mRNA in peripheral blood of patients with breast cancer. Clin Biochem

6 normal PBMC and is highly specific as none of the 26 healthy controls tested had detectable CK-19 mRNA levels, while 10 out of 14 (71.4%) and 9 out of 37 (24.3%) patients with stage IV and stage I/II breast cancer, respectively, were tested positive. Conclusion: The developed quantitative RT-PCR hybridization assay for CK-19 is reproducible, highly sensitive and specific, and can be used for a large-scale prospective evaluation of clinical samples

Second-line treatment with irinotecan plus cisplatin vs cisplatin of patients with advanced non-small-cell lung cancer pretreated with taxanes and gemcitabine: a multicenter randomised phase II study

The aim of this study was to compare the irinotecan/cisplatin regimen with cisplatin as second-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) pretreated with a taxane/gemcitabine regimen. Patients (n=147) with stage IV NSCLC pretreated with a taxane/gemcitabine regimen were randomly assigned to receive either irinotecan (110 mg m−2, day 1 and 100 mg m−2, day 8) and cisplatin (80 mg m−2, day 8) (IC; n=74) or CDDP (80 mg m−2, day 1) (C; n=73) every 3 weeks. Patients treated with IC and C had a median survival of 7.8 and 8.8 months, respectively (P=0.933). The 1-year survival rate was 34.3% for IC-treated patients and 31.7% for C-treated patients. Cox's regression analysis revealed that response to treatment (hazard ratio (HR)=2.787; 95% confidence interval (CI): 1.1578–4.922) and performance status (HR=1.865; 95% CI: 1.199–2.872) was independent prognostic factors for survival. Overall response rate was 22.5% (95% CI: 12.8–32.2%) for IC-treated patients and 7.0% (95% CI: 1.15–13.6%) for C-treated patients (P=0.012); tumour growth control (partial remission (PR)+stable disease (SD)) was observed in 26 (38%) IC and 25 (36%) C patients (P=0.878). There was no difference in terms of quality of life between the two chemotherapy arms. The incidence of febrile neutropenia, grade 3 and 4 neutropenia and grade 3 and 4 diarrhoea was significantly higher in the IC- than the C-treated patients. Other toxicities were mild. There were no treatment-related deaths in either arm. The IC regimen did not confer a survival benefit compared with C as second-line treatment of patients with advanced NSCLC pretreated with a taxane/gemcitabine regimen, despite its better efficacy in terms of response rate