N6-Isopentenyladenosine Hinders the Vasculogenic Mimicry in Human Glioblastoma Cells through Src-120 Catenin Pathway Modulation and RhoA Activity Inhibition

Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry represents a means whereby GBM can escape anti-angiogenic therapies. Methods: Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of N6-isopentenyladenosine (iPA) to interfere with vasculogenic mimicry (VM). RhoA activity was assessed using a pull-down assay, while the modulation of the adherens junctions proteins was analyzed by Western blot analysis. Results: We found that iPA at sublethal doses inhibited the formation of capillary-like structures suppressing cell migration and invasion of U87MG, U343MG, and U251MG cells, of patient-derived human GBM cells and GBM stem cells. iPA reduces the vascular endothelial cadherin (VE-cadherin) expression levels in a dose-dependent manner, impairs the vasculogenic mimicry network by modulation of the Src/p120-catenin pathway and inhibition of RhoA-GTPase activity. Conclusions: Taken together, our results revealed iPA as a promising novel anti-VM drug in GBM clinical therapeutics.     

Multiblock copolymers based on segments of poly (D,L‐lactic‐glycolic acid) and poly(ethylene glycol) or poly(ϵ‐caprolactone): A comparison of their thermal properties and degradation behavior

A comparison of the thermal properties of two classes of poly(D,L ‐lactic‐glycolic acid) multiblock copolymers is reported. In particular, the results of differential scanning calorimetry, and thermogravimetric analysis of copolymers containing poly(ethylene glycol) (PEG) or diol‐terminated poly(ϵ‐caprolactone) (PCDT) segments are described. The influence of the chemical structure and the length of PEG and PCDT on thermal stability, degree of crystallinity and glass transition temperature (T_g ) is discussed. Finally, an evaluation of the hydrolytic behavior in conditions mimicking the physiological environment is reported. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 78: 1721–1728, 2000     

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.     

CD93 Signaling via Rho Proteins Drives Cytoskeletal Remodeling in Spreading Endothelial Cells

During angiogenesis, cell adhesion molecules expressed on the endothelial cell surface promote the growth and survival of newly forming vessels. Hence, elucidation of the signaling pathways activated by cell-to-matrix adhesion may assist in the discovery of new targets to be used in antiangiogenic therapy. In proliferating endothelial cells, the single-pass transmembrane glycoprotein CD93 has recently emerged as an important endothelial cell adhesion molecule regulating vascular maturation. In this study, we unveil a signaling pathway triggered by CD93 that regulates actin cytoskeletal dynamics responsible of endothelial cell adhesion. We show that the Src-dependent phosphorylation of CD93 and the adaptor protein Cbl leads to the recruitment of Crk, which works as a downstream integrator in the CD93-mediated signaling. Moreover, confocal microscopy analysis of FRET-based biosensors shows that CD93 drives the coordinated activation of Rac1 and RhoA at the cell edge of spreading cells, thus promoting the establishment of cell polarity and adhesion required for cell motility.     

Monte Carlo simulation approach for a modified FMECA in a power plant

This paper presents a new tool for failure mode and effect analysis developed for a new Integrated Gasification and Combined Cycle plant in an important Italian oil refinery. The methodology is based on the integration between a modified Failure Mode Effect and Criticality Analysis (FMECA) and a Monte Carlo simulation as a method for testing the weights assigned to the measure of the risk priority numbers (RPNs). The RPN proposed consists of a weighted sum of six parameters (safety, machine importance for the process, maintenance costs, failure frequency, downtime length, and operating conditions) multiplied by a seventh factor (the machine access difficulty). Adopting this tool and considering the budget constraints, the best maintenance policy has been selected for each plant facility (about 140 in total). Copyright © 2000 John Wiley & Sons, Ltd.     

On the ability of chromatographic mass balance to predict solute diffusivity in drug delivery systems

The ability to predict the drug diffusion coefficient within hydrogel-based drug delivery devices has a pivotal role in the design of these materials. In the last years, many mathematical models have been developed, but they often rely on fitted parameters with a consequent limitation in terms of prediction. Indeed, they are mainly centered on the pure Fickian diffusion together with degradation and swelling contributions. However, especially with a drug concentration typical of pharmacological treatments, several other mechanisms such as drug–polymer and drug–drug interactions cannot be neglected. In this work, we checked the ability of a simple mathematical model to estimate diffusion coefficients of drugs loaded within hydrogel considered as a chromatographic stationary phase. Mathematical modeling satisfactorily matched with different sets of literature data proving that our assumptions are able to describe the key phenomena governing the device's behavior.     

Telechelic ionomeric poly(butylene terephthalate): Synthesis,characterization and comparison with random ionomers

Telechelic poly(butylene terephthalate) (PBT) ionomers have been prepared by melt synthesis using a new polycondensation process that involves a pre-reaction of sulfobenzoic acid sodium salt with butanediol. No side reaction occurs and the incorporation of the ionic groups is quantitative. The addition of a buffer agent, such as Na₃PO₄, to the catalyst reduces the THF formation and improves the polycondensation rate. The comparison of the thermo-mechanical and physical properties between random and telechelic ionomers is also reported. The ionic groups act as chain-extension reversible electrostatic links for telechelic ionomers while act as cross-links in random ionomers. Therefore, random ionomers present a consistently higher melt viscosity compared to telechelic ionomers and to PBT and for this reason high molecular weight random ionomers cannot be obtained by melt polycondensation. Thermal and hydrolytic stabilities of telechelic ionomers are comparable with those of commercial PBT and consistently higher respect to those of random ionomers. The presence of ionic groups decreases the translation mobility of the polymer chains thus lowering the crystallization rate.     

Role of Lipids in the Onset,Progression and Treatment of Periodontal Disease. A Systematic Review of Studies in Humans

The risk of different oral problems (root caries, tooth mobility, and tooth loss) can be increased by the presence of periodontal disease, which has also been associated with a growing list of systemic diseases. The presence of some bacteria is the primary etiology of this disease; a susceptible host is also necessary for disease initiation. In this respect, the progression of periodontal disease and healing of the periodontal tissues can be modulated by nutritional status. To clarify the role of lipids in the establishment, progression, and/or treatment of this pathology, a systematic review was conducted of English-written literature in PubMed until May 2016, which included research on the relationship of these dietary components with the onset and progression of periodontal disease. According to publication type, randomized-controlled trials, cohort, case-control and cross-sectional studies were included. Among all the analyzed components, those that have any effect on oxidative stress and/or inflammation seem to be the most interesting according to current evidence. On one hand, there is quite a lot of information in favor of a positive role of n-3 fatty acids, due to their antioxidant and immunomodulatory effects. On the other hand, saturated fat-rich diets increase oxidative stress as well the as intensity and duration of inflammatory processes, so they must be avoided.