An Integrative Meta-analysis of MicroRNAs in Hepatocellular Carcinoma

We aimed to shed new light on the roles of microRNAs （miRNAs） in liver cancer using an integrative in silico bioinformatics analysis. A new protocol for target prediction and functional analysis is presented and applied to the 26 highly differentially deregulated miRNAs in hepatocellular carcinoma. This framework comprises： （1） the overlap of prediction results by four out of five target prediction tools, including TargetScan, PicTar, miRanda, DIANA-microT and miRDB （combining machine-learning, alignment, interaction energy and statistical tests in order to minimize false positives）, （2） evidence from previous microarray analysis on the expression of these targets, （3） gene ontology （GO） and pathway enrichment analysis of the miRNA targets and their pathways and （4） linking these results to oncogenesis and cancer hallmarks. This yielded new insights into the roles of miRNAs in cancer hallmarks. Here we presented several key targets and hundreds of new targets that are significantly enriched in many new cancer-related hallmarks. In addition, we also revealed some known and new oncogenic pathways for liver cancer. These included the famous MAPK, TGFβ and cell cycle pathways. New insights were also provided into Wnt signaling, prostate cancer, axon guidance and oocyte meiosis pathways. These signaling and developmental pathways crosstalk to regulate stem cell transformation and implicate a role of miRNAs in hepatic stem cell deregulation and cancer development. By analyzing their complete interactome, we proposed new categorization for some of these miRNAs as either tumor-suppressors or oncomiRs with dual roles. Therefore some of these miRNAs may be addressed as therapeutic targets or used as therapeutic agents. Such dual roles thus expand the view of miRNAs as active maintainers of cellular homeostasis.     

Correction to: Stress impact of liposomes loaded with ciprofloxacin on the expression level of MepA and NorB efflux pumps of methicillin‑resistant Staphylococcus aureus

International Microbiology -     

Synthesis,Characterization, and Biological Evaluation of Cu(II) Complexes Containing Triflupromazine with Glycine and Histidine

Two novel copper (II) complexes [Cu(TFP)(Gly)Cl] ⋅ 2H₂O complex ( 1 ) and [Cu(TFP)(His)Cl] ⋅ 2H₂O complex ( 2 ) are synthesized, where TFP stands for trifluropromazine, Gly. represents glycine, and His. is histidine. Chemical composition, IR, mass spectra, and magnetic susceptibility tests are performed. Complex binding with macromolecules was investigated using UV-vis, viscosity, gel electrophoresis, and fluorescence quenching. Fluorescence spectroscopy revealed that each complex could replace ethidium bromide (EB). These complexes exhibit grooved, non-covalent, and electrostatic interactions with CT-DNA. Spectroscopy analysis of the BSA interaction showed that complexes bind to protein (K_b values for ( 1 ) is 5.89×10³ M⁻¹ and for ( 2 ) is 9.08×10³ M⁻¹) more strongly than CT-DNA (K_b values for ( 1 ) is 5.43×10³ M⁻¹ and for ( 2 ) is 7.17×10³ M⁻¹). Molecular docking analysis and spectral absorption measurements showed high agreement. Antimicrobial, antioxidant, and anti-inflammatory properties were tested in vitro. The druggability of complex ( 2 ) should be tested in vivo as it is more biologically active.     

Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner

Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified the Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the antiapoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of apoptotic regulators that bind to SMAC and LATS1. Mechanistic analysis shows that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results in apoptosis. Importantly, we show that the oncogenic BRAF^V600E mutant prevents the proapoptotic signal mediated by the LATS1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes the formation of this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAF^V600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant, which requires C-IAP1 inhibition and the degradation of XIAP, suggesting that the MST2 pathway is part of the mechanism of action of Birinapant. Overall, the current work shows that SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the ERK pathway.Subject terms: Protein-protein interaction networks, Extracellular signalling molecules     

Chronic hypoxia alters the physiological and morphological trajectories of developing chicken embryos

Chicken embryos were chronically exposed to hypoxia (P(O(2)) approximately 110 mmHg) during development, and assessed for detrimental metabolic and morphological effects. Eggs were incubated in one of four groups: control (i.e. 151 mmHg), or treated with continuous 110 mmHg (15% O(2)) during days 1-6 (H1-6), 6-12 (H6-12), or 12-18 (H12-18) with normoxia during the remaining incubation. Metabolism (V(O(2))), body mass, hemoglobin (Hb) and hematocrit (Hct) were measured in embryos on days 12 and 18 of incubation and in day-old hatchlings. Ability to maintain V(O(2)) was acutely measured during a step-wise decrease in P(O(2)) from normoxia to hypoxia (55 mmHg). On day 12, V(O(2)) of H1-6 eggs were significantly lower than in the control and H6-12 eggs. P(crit) in H6-12 eggs was lower than in control and H1-6 eggs. Body mass of H1-6 and H6-12 embryos on day 12 was significantly lower than in control embryos, while in H6-12 embryos, Hct and Hb were higher. On day 18, H6-12 embryos had significantly lower V(O(2)) than control eggs. Body mass of H6-12 and H12-18 embryos was significantly lower than control embryos. Hct and Hb did not differ between treatments. In hatchlings, mass, Hb and Hct had returned to values statistically identical to controls. However, H6-12 embryos had significantly lower V(O(2)). Long-term hypoxia altered V(O(2)) when hypoxic incubation occurred during the middle third of incubation, but not during earlier or later incubation. Thus, chronic hypoxic exposure during critical periods in development altered the developmental physiological trajectories and modified the phenotypes of the developing embryos.     

Stress impact of liposomes loaded with ciprofloxacin on the expression level of MepA and NorB efflux pumps of methicillin-resistant Staphylococcus aureus

International Microbiology - One mechanism of ciprofloxacin resistance is attributed to chromosomal DNA-encoded efflux pumps such as the MepA and NorB proteins. The goal of this research is to find...     

GDdom: An Online Tool for Calculation of Dominant Marker Gene Diversity

Gene diversity (GD), also called polymorphism information content, is a commonly used measure of molecular marker polymorphism. Calculation of GD for dominant markers such as AFLP, RAPD, and multilocus SSRs is valuable for researchers. To meet this need, we developed a free online computer program, GDdom, which provides easy, quick, and accurate calculation of dominant marker GD with a commonly used formula. Results are presented in tabular form for quick interpretation.