MicroRNAs in Brain Metastases: Potential Role as Diagnostics and Therapeutics

Brain metastases remain a daunting adversary that negatively impact patient survival. Metastatic brain tumors affect up to 45% of all cancer patients with systemic cancer and account for ~20% of all cancer-related deaths. A complex network of non-coding RNA molecules, microRNAs (miRNAs), regulate tumor metastasis. The brain micro-environment modulates metastatic tumor growth; however, defining the precise genetic events that promote metastasis in the brain niche represents an important, unresolved problem. Understanding these events will reveal disease-based targets and offer effective strategies to treat brain metastases. Effective therapeutic strategies based upon the biology of brain metastases represent an urgent, unmet need with immediate potential for clinical impact. Studies have demonstrated the ability of miRNAs to distinguish normal from cancerous cells, primary from secondary brain tumors, and correctly categorize metastatic brain tumor tissue of origin based solely on miRNA profiles. Interestingly, manipulation of miRNAs has proven effective in cancer treatment. With the promise of reduced toxicity, increased efficacy and individually directed personalized anti-cancer therapy, using miRNA in the treatment of metastatic brain tumors may prove very useful and improve patient outcome. In this review, we focus on the potential of miRNAs as diagnostic and therapeutic targets for the treatment of metastatic brain lesions.     

The cost optimal solution of the multi-constrained multicast routing problem

In this paper, we define the cost optimal solution of the multi-constrained multicast routing problem. This problem consists in finding a multicast structure that spans a source node and a set of destinations with respect to a set of constraints, while minimizing a cost function. This optimization is particularly interesting for multicast network communications that require Quality of Service (QoS) guarantees. Finding such a structure that satisfies the set of constraints is an NP-hard problem. To solve the addressed routing problem, most of the proposed algorithms focus on multicast trees. In some cases, the optimal spanning structure (i.e. the optimal multicast route) is neither a tree nor a set of trees nor a set of optimal QoS paths. The main result of our study is the exact identification of this optimal solution. We demonstrate that the optimal connected partial spanning structure that solves the multi-constrained multicast routing problem always corresponds to a hierarchy, a recently proposed generalization of the tree concept. We define the directed partial minimum spanning hierarchies as optimal solutions for the multi-constrained multicast routing problem and analyze their relevant properties. To our knowledge, our paper is the first study that exactly describes the cost optimal solution of this NP-hard problem.     

Graphene oxide‐ellagic acid nanocomposite as effective anticancer and antimicrobial agent

In this study, ellagic acid (ELA), a skin anticancer drug, is capped on the surface(s) of functionalised graphene oxide (GO) nano‐sheets through electrostatic and π–π staking interactions. The prepared ELA‐GO nanocomposite have been thoroughly characterised by using eight techniques: Fourier‐transform infrared spectroscopy (FTIR), zeta potential, X‐ray diffraction (XRD), thermogravimetric analysis (TGA), Raman spectroscopy, atomic force microscopy (AFM) topographic imaging, transmission electron microscopy (TEM), and surface morphology via scanning electron microscopy (SEM). Furthermore, ELA drug loading and release behaviours from ELA‐GO nanocomposite were studied. The ELA‐GO nanocomposite has a uniform size distribution averaging 88 nm and high drug loading capacity of 30 wt.%. The in vitro drug release behaviour of ELA from the nanocomposite was investigated by UV–Vis spectrometry at a wavelength of λ _max 257 nm. The data confirmed prolonged ELA release over 5000 min at physiological pH (7.4). Finally, the IC ₅₀ of this ELA‐GO nanocomposite was found to be 6.16 µg/ml against B16 cell line; ELA and GO did not show any cytotoxic effects up to 50 µg/ml on the same cell lines.     

Morphology selective construction of β-cyclodextrin functionalized Fe3O4-Bi2WO6 nanocomposite with superior adsorptivity and visible-light-driven catalytic activity

Controlled growth of Bi₂WO₆ nanorods with exposed [0 0 1] facets and the fabrication of an Fe₃O₄-Bi₂WO₆ magnetic composite by a microwave-assisted polyol process, were achieved in this study. The adsorptivity and photocatalytic performance of the composite toward sunset yellow dye degradation were greatly enhanced by the β-cyclodextrin cavities on its surface, firmly anchored through a cetyltrimethylammonium bromide linkage. A series of examinations and characterizations were carried out to determine the influence of various factors on the morphological modulation-photocatalytic behavior of the pure Bi₂WO₆ prior to final functionalization. Changing the pH of the precursor solution impacted the formation of 0D, 2D, and 3D structures; however, the presence of hexamethylenetetramine surfactant induced the development of 1D nanorod structure. A reasonable crystal growth mechanism was proposed to elucidate the formation process. Conversely, the mechanism of the activity enhancement of β-cyclodextrin functionalized Fe₃O₄-Bi₂WO₆, compared to that of the non-functionalized samples, could be realized with the assistance of chemical trapping experiments on sunset yellow, and was confirmed on the colorless antibiotic (sulfamethoxazole). The high performance and durability of this composite can be attributed to the facet-dependent activity, large adsorption capacity due to inclusion interactions, enhanced visible light absorption, and efficient charge separation.     

The Plant Sesquiterpene Nootkatone Efficiently Reduces Heterodera schachtii Parasitism by Activating Plant Defense

Plant parasitic nematodes, including the beet cyst nematode Heterodera schachtii, constitute a devastating problem for crops worldwide. The limited availability of sustainable management options illustrates the need for new eco-friendly control means. Plant metabolites represent an invaluable source of active compounds for the discovery of such novel antagonistic agents. Here, we evaluated the impact of eight plant terpenoids on the H. schachtii parasitism of Arabidopsis thaliana. None of the metabolites affected the plant development (5 or 10 ppm). Nootkatone decreased the number of adult nematodes on A. thaliana to 50%, with the female nematodes being smaller compared to the control. In contrast, three other terpenoids increased the parasitism and/or female size. We discovered that nootkatone considerably decreased the number of nematodes that penetrated A. thaliana roots, but neither affected the nematode viability or attraction to plant roots, nor triggered the production of plant reactive oxygen species or changed the plant’s sesquiterpene profile. However, we demonstrated that nootkatone led to a significant upregulation of defense-related genes involved in salicylic and jasmonic acid pathways. Our results indicate that nootkatone is a promising candidate to be developed into a novel plant protection agent acting as a stimulator of plant immunity against parasitic nematodes.     

A Structure-Activity Relationship Study of Bimodal BODIPY-Labeled PSMA-Targeting Bioconjugates

The aim of this study was to identify a high-affinity BODIPY peptidomimetic that targets the prostate-specific membrane antigen (PSMA) as a potential bimodal imaging probe for prostate cancer. For the structure-activity study, several BODIPY (difluoroboron dipyrromethene) derivatives with varying spacers between the BODIPY dye and the PSMA Glu-CO-Lys binding motif were prepared. Corresponding affinities were determined by competitive binding assays in PSMA-positive LNCaP cells. One compound was identified with comparable affinity (IC₅₀=21.5±0.1 nM) to Glu-CO-Lys-Ahx-HBED-CC (PSMA-11) (IC₅₀=18.4±0.2 nM). Radiolabeling was achieved by Lewis-acid-mediated ¹⁹F/¹⁸F exchange in moderate molar activities (∼0.7 MBq nmol⁻¹) and high radiochemical purities (>99 %) with mean radiochemical yields of 20–30 %. Cell internalization of the ¹⁸F-labeled high-affinity conjugate was demonstrated in LNCaP cells showing gradual increasing PSMA-mediated internalization over time. By fluorescence microscopy, localization of the high-affinity BODIPY-PSMA conjugate was found in the cell membrane at early time points and also in subcellular compartments at later time points. In summary, a high-affinity BODIPY-PSMA conjugate has been identified as a suitable candidate for the development of PSMA-specific dual-imaging agents.     

Dispute Review Boards: Expected Application on Egyptian Large-Scale Construction Projects

The construction industry is heavily affected by the troubles arising out of construction disputes, especially when it comes to large-scale projects, as a direct result of the inherent complexity of such projects. This paper seeks the most suitable dispute-resolution mechanism for large-scale construction projects in Egypt, which is a developing country in the Middle East with an emerging reformed economical policy, a population in excess of 70 million people, and an increasing need for infrastructure and industrial development. This dispute-resolution mechanism was attained through a multistep methodology that (1) started with the study of the Arbitration process in relation to an Egyptian construction project with an initial contract price of 85 million; (2) continued with interviews of five senior experts in the field of construction disputes in Egypt about their views pertaining to the most efficient dispute-resolution methodology for Egyptian megaprojects; (3) developed a tailored questionnaire to assess the perceptions of 35 professionals toward the issue of construction disputes and dispute resolution mechanisms, including DRB; (5) concluded by carrying out a what-if scenario for the arbitration case of the large-scale construction project using DRB instead of arbitration. On basis of the analysis of the methodology, the authors concluded that despite the wide range of current dispute-resolution methodologies, the employment of DRBs in accordance with a set of 13 regulatory guidelines should mitigate the negative effects of disputes in Egyptian large-scale construction projects. Accordingly, this paper is both timely and valuable for all owners, contractors, and professionals who are acquainted with Egyptian megaprojects.     

Some new formulae for posterior expectations and Bartlett corrections

Some new accurate approximations for posterior expectations and Bartlett corrections are derived. These approximations are modifications of formulae based on signed root log-likelihood ratios obtained in Sweeting (1996) and are designed to address two problems that arise in the practical application of these formulae in the multiparameter case. The first problem is a computational one associated with inversion of signed root log-likelihood ratios. The second concerns the form of the posterior expectation formula, which is not in a particularly convenient form for the computation of predictive densities. The theory is illustrated by two examples.