There is an urgent need to discover new drug entities due to the increased incidence of severe diseases as cancer and neurodegenerative pathologies, and reducing efficacy of existing antibiotics. ...Recently, there is a renewed interest in exploring the marine habitat for new pharmaceuticals also thanks to the advancement in cultivation technologies and in molecular biology techniques. Microorganisms represent a still poorly explored resource for drug discovery. The possibility of obtaining a continuous source of bioactives from marine microorganisms, more amenable to culturing compared to macro-organisms, may be able to meet the challenging demands of pharmaceutical industries. This would enable a more environmentally-friendly approach to drug discovery and overcome the over-utilization of marine resources and the use of destructive collection practices. The importance of the topic is underlined by the number of EU projects funded aimed at improving the exploitation of marine organisms for drug discovery.
•Marine microorganisms are a new and poorly explored source for the discovery of novel bioactives.•Advances in cultivation and molecular biology contribute to marine drug discovery.•Omics tools allow the identification of bioactives in uncultivable species.•Novel ocean medicines represent the most exciting new directions of marine science.
miRNAs are small non-coding RNAs of ~24 nt that can block mRNA translation and/or negatively regulate its stability. There is a large body of evidence that dysregulation of miRNAs is a hallmark of ...cancer. miRNAs are often aberrantly expressed and their function is linked to the regulation of oncogenes and/or tumor suppressor genes involved in cell signaling pathway. miR-221 and miR-222 are two highly homologous microRNAs, whose upregulation has been recently described in several types of human tumors. miR-221/222 have been considered to act as oncogenes or tumor suppressors, depending on tumor system. Silencing oncomiRs or gene therapy approaches, based on re-expression of miRNAs that are down-regulated in cancer cells, could represent a novel anti-tumor approach for integrated cancer therapy. Here we will review the role of miR-221/222 in cancer progression and their use as prognostic and therapeutic tools in cancer.
•Production of maps of spatial distribution of land suitability integrating Geographical Information Systems and Multi-Criteria Analysis.•The spatial distribution of suitable areas is linked to the ...capability of the WLC and OWA methods in varying both risk and tradeoff parameters.•The AHP method and the pairwise comparison matrix have been used for the criteria prioritization based on a participatory approach.•The OWA procedure shows higher potentialities in performing the territorial evaluation.•Identification of similarities and differences between the maps produced by OWA and WLC method have been carried out performing the cross tabulation method.
Selection of suitable areas for territorial planning is a complex process and needs many diverse indications on the basis of which a decision may be assumed. This paper focuses on the integration of Geographical Information Systems (GIS) and Multi-Criteria Decision Analysis (MCDA) to evaluate the potential of a rural coastal area, located in northern Puglia (Southern Italy), to improve its sustainable development through the restoration of manor farms. Comparing the results obtained using the Weighted Linear Combination (WLC) and the Ordered Weighted Averaging (OWA) procedures, suitable sites where the restoration could be implemented were identified. In order to consider the stakeholders’ judgments and to reach a shared decision in selecting the preferred alternatives, the Analytical Hierarchy Process (AHP) approach was used for prioritization, due to its relative ease in handling multiple criteria and compensating both qualitative and quantitative data. The results highlight how the spatial distribution of suitable areas is closely linked to the risk assumed and, consequently, to the capability of the methods in varying both risk and tradeoff parameters. Particularly, the OWA procedure shows higher potentialities in performing, with greater detail, the territorial evaluation and generating a wide range of decision strategies. The methodologies described and their application procedures can be extended to similar territorial contexts, in issues in which a notable number of territorial factors should be taken into account.
•We perform measurements on turbulent jet flows using PIV.•Jets have different nozzles: rectangular, elliptic, triangular and square.•The boundary condition is sharp-edged orifice with vena ...contracta.•Two classes: square–triangular and elliptic–rectangular related to axis-switching.
An experimental study using Particle Image Velocimetry (PIV) on free jets issuing from different orifice plate (OP) nozzles is reported. Mean velocity, turbulence intensity and higher order profiles relevant for large and small scale mixing are considered in the near field and interaction zone (0<X/D<20). This is done to determine mixing enhancement due to rectangular, squared, elliptic and triangular nozzles in comparison to circular nozzle results in two orthogonal planes. The effect of Reynolds number on the differences among the nozzle shapes is also considered by performing measurements just after laminar–turbulent transition (Re=8000) and in the fully turbulent regime (Re=35,000). The results at low Reynolds number show two classes of jets, i.e. at one side, those closer to axial-symmetric conditions, as circular, square and triangular jets, whereas on the other side those with elongated nozzles as rectangular and elliptic. The reason for the different behavior of the latter is connected to the phenomenon of axis-switching which allows a rearrangement of turbulence over the different velocity components and directions. However, for the highest Reynolds number investigated, all nozzles show similar behavior especially in the jet far field (X/D>10), thus suggesting a significant Reynolds number dependence of the results.
Antithrombotic therapy for intracranial arterial stenosis was recently evaluated in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. A prespecified aim of WASID was to ...identify patients at highest risk for stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy.
WASID was a randomized, double-blinded, multicenter trial involving 569 patients with transient ischemic attack or ischemic stroke due to 50% to 99% stenosis of a major intracranial artery. Median time from qualifying event to randomization was 17 days, and mean follow-up was 1.8 years. Multivariable Cox proportional hazards models were used to identify factors associated with subsequent ischemic stroke in the territory of the stenotic artery. Subsequent ischemic stroke occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery. Risk of stroke in the territory of the stenotic artery was highest with severe stenosis > or =70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (< or =17 days) after the qualifying event (hazard ratio 1.69; 95% confidence interval 1.06 to 2.72; P=0.028). Women were also at increased risk, although this was of borderline significance (hazard ratio 1.59; 95% confidence interval 1.00 to 2.55; P=0.051). Location of stenosis, type of qualifying event, and prior use of antithrombotic medications were not associated with increased risk.
Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis > or =70%, after recent symptoms, and in women.
Non-small cell lung cancer (NSCLC) accounts for ∼80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 ...and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.
MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that negatively regulate the expression of their target genes. They are involved in many biological processes, including cell ...proliferation, apoptosis and differentiation, and are considered as promising new therapeutic targets for cancer. However, the identity of miRNAs involved in apoptosis and their respective targets remain largely unknown. Given the elevated complexity of miRNA regulation of gene expression, we performed a functional screening as an alternative strategy to identify those miRNAs that in lung cancer cells may interfere with the apoptotic process. To this aim, we generated a derivative of the non-small cell lung carcinoma A549 cell line in which caspase-8, a critical upstream initiator of apoptosis, can be activated by administration of the small dimerizer drug AP20187. We found a number of miRNAs that may rescue cell viability from caspase-8 activation. They included miRNAs already described as oncogenic such as miR-17, miR-135 and miR-520, but also some miRNAs such as miR-124-1 and miR-34c for which a tumor-suppressive role has instead been described or expected. Among them, miR-34c-5p markedly increased resistance to paclitaxel-induced apoptosis. We demonstrate that Bmf (Bcl-2-modifying factor) is a target of miR-34c-5p, and that its silencing, together with that of c-myc, a known target of miR-34c-5p, contributes to resistance to apoptosis induced by paclitaxel through p53 downregulation.
Atherosclerotic intracranial arterial stenosis is an important cause of stroke. Warfarin is commonly used in preference to aspirin for this disorder, but these therapies have not been compared in a ...randomized trial.
We randomly assigned patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery to receive warfarin (target international normalized ratio, 2.0 to 3.0) or aspirin (1300 mg per day) in a double-blind, multicenter clinical trial. The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.
After 569 patients had undergone randomization, enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin. During a mean follow-up period of 1.8 years, adverse events in the two groups included death (4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group; hazard ratio for aspirin relative to warfarin, 0.46; 95 percent confidence interval, 0.23 to 0.90; P=0.02), major hemorrhage (3.2 percent vs. 8.3 percent, respectively; hazard ratio, 0.39; 95 percent confidence interval, 0.18 to 0.84; P=0.01), and myocardial infarction or sudden death (2.9 percent vs. 7.3 percent, respectively; hazard ratio, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P=0.16); the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P=0.05). The primary end point occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group (hazard ratio, 1.04; 95 percent confidence interval, 0.73 to 1.48; P=0.83).
Warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin in this trial. Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.
To define novel pathways that regulate susceptibility to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in non-small cell lung cancer (NSCLC), we have performed genome-wide ...expression profiling of microRNAs (miRs). We show that in TRAIL-resistant NSCLC cells, levels of different miRs are increased, and in particular, miR-221 and -222. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. Indeed, transfection with anti-miR-221 and -222 rendered CALU-1-resistant cells sensitive to TRAIL. Conversely, H460-sensitive cells treated with -221 and -222 pre-miRs become resistant to TRAIL. miR-221 and -222 target the 3'-UTR of Kit and p27(kip1) mRNAs, but interfere with TRAIL signaling mainly through p27(kip1). In conclusion, we show that high expression levels of miR-221 and -222 are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets or diagnostic tool for TRAIL resistance in NSCLC.
Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. To define novel ...pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant glioma cells, levels of different miRs are increased, and in particular, miR-30b/c and -21. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. T98G-sensitive cells treated with miR-21 or -30b/c become resistant to TRAIL. Furthermore, we demonstrate that miR-30b/c and miR-21 target respectively the 3' untranslated region of caspase-3 and TAp63 mRNAs, and that those proteins mediate some of the effects of miR-30 and -21 on TRAIL resistance, even in human glioblastoma primary cells and in lung cancer cells. In conclusion, we show that high expression levels of miR-21 and -30b/c are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets for TRAIL resistance in glioma.
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