Explore the vast range of titles available.

Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment.

Background Within the class Enoplea, the earliest-branching lineages in the phylum Nematoda, the relatively highly conserved ancestral mitochondrial architecture of Trichinellida is in stark contrast to the rapidly evolving architecture of Dorylaimida and Mermithida. To better understand the evolution of mitogenomic architecture in this lineage, we sequenced the mitogenome of a fish parasite Pseudocapillaria tomentosa (Trichinellida: Capillariidae) and compared it to all available enoplean mitogenomes. Results P. tomentosa exhibited highly reduced noncoding regions (the largest was 98 bp), and a unique base composition among the Enoplea. We attributed the latter to the inverted GC skew (0.08) in comparison to the ancestral skew in Trichinellidae (-0.43 to -0.37). Capillariidae, Trichuridae and Longidoridae (Dorylaimida) generally exhibited low negative or low positive skews (-0.1 to 0.1), whereas Mermithidae exhibited fully inverted low skews (0 to 0.05). This is indicative of inversions in the strand replication order or otherwise disrupted replication mechanism in the lineages with reduced/inverted skews. Among the Trichinellida, Trichinellidae and Trichuridae have almost perfectly conserved architecture, whereas Capillariidae exhibit multiple rearrangements of tRNA genes. In contrast, Mermithidae (Mermithida) and Longidoridae (Dorylaimida) exhibit almost no similarity to the ancestral architecture. Conclusions Longidoridae exhibited more rearranged mitogenomic architecture than the hypervariable Mermithidae. Similar to the Chromadorea, the evolution of mitochondrial architecture in enoplean nematodes exhibits a strong discontinuity: lineages possessing a mostly conserved architecture over tens of millions of years are interspersed with lineages exhibiting architectural hypervariability. As Longidoridae also have some of the smallest metazoan mitochondrial genomes, they contradict the prediction that compact mitogenomes should be structurally stable. Lineages exhibiting inverted skews appear to represent the intermediate phase between the Trichinellidae (ancestral) and fully derived skews in Chromadorean mitogenomes (GC skews = 0.18 to 0.64). Multiple lines of evidence (CAT-GTR analysis in our study, a majority of previous mitogenomic results, and skew disruption scenarios) support the Dorylaimia split into two sister-clades: Dorylaimida + Mermithida and Trichinellida. However, skew inversions produce strong base composition biases, which can hamper phylogenetic and other evolutionary studies, so enoplean mitogenomes have to be used with utmost care in evolutionary studies.

Background Influenza A virus (IAV) evolves strategies to counteract the host antiviral defense for establishing infection. The influenza A virus (IAV) non-structural protein 1 (NS1) is a key viral factor shown to counteract type I IFN antiviral response mainly through targeting RIG-I signaling. Growing evidence suggests that viral RNA sensors RIG-I, TLR3, and TLR7 function to detect IAV RNA in different cell types to induce type I IFN antiviral response to IAV infection. Yet, it remains unclear if IAV NS1 can exploit a common mechanism to counteract these RNA sensing pathways to type I IFN production at once, then promoting viral propagation in the host. Methods Luciferase reporter assays were conducted to determine the effect of NS1 and its mutants on the RIG-I and TLR3 pathways to the activation of the IFN-β and NF-κB promoters. Coimmunoprecipitation and confocal microscopic analyses were used to the interaction and colocalization between NS1 and TRAF3. Ubiquitination assays were performed to study the effect of NS1 and its mutants on TRAF3 ubiquitination. A recombinant mutant virus carrying NS1 E152A/E153A mutations was generated by reverse genetics for biochemical, ex vivo, and in vivo analyses to explore the importance of NS1 E152/E153 residues in targeting the RNA sensing-TRAF3-type I IFN axis and IAV pathogenicity. Results Here we report that NS1 subverts the RIG-I, TLR3, and TLR7 pathways to type I IFN production through targeting TRAF3 E3 ubiquitin ligase. NS1 harbors a conserved FTEE motif (a.a. 150-153), in which the E152/E153 residues are critical for binding TRAF3 to block TRAF3 ubiquitination and type I IFN production by these RNA sensing pathways. A recombinant mutant virus carrying NS1 E152A/E153A mutations induces higher type I IFN production ex vivo and in vivo, and exhibits the attenuated phenotype in infected mice, indicating the importance of E152/E153 residues in IAV pathogenicity. Conclusions Together our work uncovers a novel mechanism of IAV NS1-mediated immune evasion to promote viral infection through targeting the RNA sensing-TRAF3-type I IFN axis.

Cholangiocarcinoma (CCA) is a malignant neoplasm of the bile ducts, being the second most common type of cancer in the liver, and most patients are diagnosed at a late stage with poor prognosis. Targeted therapy aiming at receptors tyrosine kinases (RTKs) such as c-Met or EGFR have been developed but with unsatisfactory outcomes. In our recent report, we found several oncogenic molecules downstream of RTKs, including hydrogen peroxide clone-5 (Hic-5), Src, AKT and JNK, were elevated in tissues of a significant portion of metastatic CCAs. By inhibitor studies and a knockdown approach, these molecules were found to be within the same signal cascade responsible for the migration of HuCCT1 cells, a conventionally used CCA cell line. Herein, we also found Src inhibitor dasatinib and Hic-5 siRNA corporately suppressed HuCCT1 cell invasion. Moreover, dasatinib inhibited the progression of the HuCCT1 tumor on SCID mice skin coupled with decreasing the expression of Hic-5 and EGFR and the activities of Src, AKT and JNK. In addition, we found a glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and several cytoskeletal molecules such as tubulin and cofilin were dramatically decreased after a long-term treatment of the HuCCT1 tumor with a high dose of dasatinib. Specifically, GAPDH was shown to be a downstream effector of the Hic-5/Src/AKT cascade involved in HuCCT1 cell migration. On the other hand, TFK1, another CCA cell line without Hic-5 expression, exhibited very low motility, whereas an ectopic Hic-5 expression enhanced the activation of Src and AKT and marginally increased TFK1 migration. In the future, it is tempting to investigate whether cotargeting Src, Hic-5 and/or GAPDH is efficient for preventing CCA progression in future clinical trials.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer with poor prognosis. The deregulation of a lot of oncogenic signaling molecules, such as receptor tyrosine kinases (RTKs), has been found to be associated with CCA progression. However, RTKs-based target therapy showed limited improvement suggesting a need to search for alternative targets for preventing CCA progression. To address this issue, we screened the oncogenic signal molecules upregulated in surgical tissues of CCAs. Interestingly, over-expression of hydrogen peroxide inducible clone-5 (Hic-5) coupled with over-activation of Src, AKT, JNK were observed in 50% of the cholangiocarcinoma with metastatic potential. To investigate whether these molecules may work together to trigger metastatic signaling, their up-and-down relationship was examined in a well-established cholangiocarcinoma cell line, HuCCT1. Src inhibitors PP1 (IC50, 13.4 μM) and dasatinib (IC50, 0.1 μM) significantly decreased both phosphorylated AKT (phosphor-AKT Thr450) and Hic-5 in HuCCT1. In addition, a knockdown of Hic-5 effectively suppressed activation of Src, JNK, and AKT. These implicated a positive cross-talk occurred between Hic-5 and Src for triggering AKT activation. Further, depletion of Hic-5 and inhibition of Src suppressed HuccT1 cell migration in a dose-dependent manner. Remarkably, prior transfection of Hic-5 siRNA for 24 h followed by treatment with PP1 or dasatinib for 24 h resulted in additive suppression of HuCCT1 migration. This suggested that a promising combinatory efficacy can be achieved by depletion of Hic-5 coupled with inhibition of Src. In the future, target therapy against CCA progression by co-targeting Hic-5 and Src may be successfully developed in vivo.

There is increasing evidence that cancer stem cells contribute to the initiation and propagation of many tumor. Therefore, to find out and identify the metastatic tumor stem-like cells in Lewis lung cancer cell line (LLC), the expression of CXCR4 was measured in LLC by flow cytometry and observed by laser scanning confocal microscope (LSCM). After the CXCR4 + LLC cell was isolated from LLC by magnetic cell sorting, its properties were evaluated by their tumorigenic and metastatic potentials. CXCR4 + cells were counted for 0.18% of the total number of LLC, and immunofluorescent staining cells were identified by LSCM. CXCR4 + LLC suspension cultured in a serum-free medium, cell spheres expressed a high level of Sca-1. The chemotherapy sensitivity to cisplatin of CXCR4 + LLC was lower than that of CXCR4 − LLC. The expression of ABCG2 and IGF1R mRNA in CXCR4 + LLC was higher than that in CXCR4 − LLC ( P  < 0.01). Most of CXCR4 + LLC cells were close to vascular endothelial cells, aberrant vasculature around it was forming. The expression of VEGF and MMP9 mRNA in CXCR4 + LLC was higher than that in CXCR4 − LLC ( P  < 0.05), the microvessel density (MVD) of CXCR4 + subsets growing were higher than that of CXCR4 − subsets growing tumor tissue ( P  < 0.01). The tumor size, volume, and metastatic foci in the lungs of CXCR4 + LLC was significantly higher than that in CXCR4 − LLC ( P  < 0.001). Similarly, elevated expression of MMP9 and VEGF was also positively associated with CXCR4 + LLC. Our results demonstrated that CXCR4 + cells from Lewis lung carcinoma cell line exhibit cancer metastatic stem cell characteristics.

Background This study aimed to determine the miRNA profile in breast cancer stem cells (BCSCs) and to explore the functions of characteristic BCSC miRNAs. Methods We isolated ESA + CD44 + CD24 -/low BCSCs from MCF-7 cells using fluorescence-activated cell sorting (FACS). A human breast cancer xenograft assay was performed to validate the stem cell properties of the isolated cells, and microarray analysis was performed to screen for BCSC-related miRNAs. These BCSC-related miRNAs were selected for bioinformatic analysis and target prediction using online software programs. Results The ESA + CD44 + CD24 -/low cells had up to 100- to 1000-fold greater tumor-initiating capability than the MCF-7 cells. Tumors initiated from the ESA + CD44 + CD24 -/low cells were included of luminal epithelial and myoepithelial cells, indicating stem cell properties. We also obtained miRNA profiles of ESA + CD44 + CD24 -/low BCSCs. Most of the possible targets of potential tumorigenesis-related miRNAs were oncogenes, anti-oncogenes or regulatory genes. Conclusions We identified a subset of miRNAs that were differentially expressed in BCSCs, providing a starting point to explore the functions of these miRNAs. Evaluating characteristic BCSC miRNAs represents a new method for studying breast cancer-initiating cells and developing therapeutic strategies aimed at eradicating the tumorigenic subpopulation of cells in breast cancer.

Conflicting results using the combination of ezetimibe and statins to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS) have been reported. The aim of this work was to assess the effectiveness of ezetimibe coadministered with statins in reducing cardiovascular events in patients with ACS. A retrospective cohort study of patients discharged after hospitalization with ACS was conducted from January 1, 2006, to December 31, 2007, and included those who were prescribed statins alone (n = 37,753) and those who received ezetimibe plus statins (n = 1001) within 365 days after the hospitalization, based on patient data obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. The propensity score method was used to identify a 1:1 matched cohort (n = 2002). Risk of rehospitalization for ACS was analyzed by a multivariable Cox proportional hazards regression model. The crude event rate of rehospitalization due to ACS in the original cohort was 13.4 per 100 person-years (268 events) in the combination group and 22.6 per 100 person-years (12,724 events) in the statins-alone group (adjusted hazard ratio [HR] 0.69; 95% CI, 0.62–0.78). The crude event rates of rehospitalization due to ACS in the matched cohort were 13.4 and 20.0 per 100 person-years in the combination group and statins-alone group, respectively (HR 0.62; 95% CI, 0.53–0.73). Compared with statins alone, the adjusted HRs for rehospitalization for percutaneous transluminal coronary angioplasty without stent, with stent, and revascularization for the combination group in the matched cohort were 0.61 (0.50–0.75), 0.62 (0.48–0.81), and 0.62 (0.51–0.76), respectively. Based on the data of Taiwan's NHIRD, our findings suggest that patients with ACS on ezetimibe combined with statins had a significantly lower risk of rehospitalization due to ACS, percutaneous transluminal coronary angioplasty, and revascularization than those on statins alone. The generalization of the results is limited because of using claims data of a specific population as the data source.

Background Polypharmacy is common in outpatients and has been identified as a major risk factor for drug-drug interactions (DDIs), which are an important cause of adverse drug reactions. There has been a rapid increase in the number of elderly patients worldwide. However, there have been few studies quantifying the impact of both patient age and the number of concomitant drugs prescribed on the probability of potential DDIs per person in general outpatients. Objective To assess the extent to which polypharmacy and aging are associated with potential DDIs in outpatients at a medical centre in Taiwan. Methods The medications of 81 650 outpatients who visited a medical centre in Taiwan between January 2004 and March 2004 were retrospectively screened for potential DDIs using a computerized drug-interaction program. The main inclusion criteria were a minimum of two drug prescriptions and duration of use of 14 or more days. We also analysed the DDI pattern, which included severity, level of documentation and onset of potential DDIs, and assessed the impact of the number of drugs prescribed and of aging on the prevalence of potential DDIs per person. Results The prevalence of potential DDIs was 25.6% (20 902 of 81 650). The mean±SD age of the 20 902 patients with potential DDIs was 57.5±16.5 years, and 47.6% of these patients were male. The mean±SD number of prescribed drugs in patients with potential DDIs was 5.8±2.4, and 67.7% of these patients were prescribed more than four drugs. The majority (55.7%) of DDIs were of the C2 pattern (severity: moderate; documentation: probable). The prevalence of potential DDIs increased in a linear mode with increasing age (p <0.001) and with the number of drugs prescribed (p <0.001); furthermore, in addition to being independently associated with potential DDIs, these two factors interacted to increase the risk further. Conclusions This study showed that approximately one-quarter of 81 650 outpatients who visited a medical centre in Taiwan over a period of 3 months in 2004 had potential DDIs. We observed independent increases in potential DDIs per person in association with aging and increasing number of prescribed drugs. Furthermore, a significant interaction between these two factors was observed: the effect of aging on the prevalence of potential DDIs increased as the number of prescribed drugs increased. Potential DDIs in outpatients can be reduced by minimizing the number of drugs prescribed following careful consideration of both their benefits and risks, particularly in the aging population.