How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: “Activating Invasion and Metastasis” and the “Avoiding Immune Destruction”, with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.     

Probabilistic Strength Estimates and Reliability of Damaged Parallel Wire Cables

Cable reliability analysis involves the combined evaluation of cable capacity and cable load in a probabilistic manner. Assessment of cable capacity is only possible through visual inspections of the wires, field sampling, laboratory analysis of the degraded wire populations, and analytical techniques. In addition to a brief presentation of cable mechanics and deterministic models that approximate cable strength, this paper discusses inspection methodologies and statistical methods of estimation of the sizes of the degraded wire populations, and wire properties, leading to cable capacities. These capacities are described by probability distributions. The paper also discusses fundamentals of reliability analysis as they apply to bridge cables. Load criteria of present standard specifications (such as AASHTO or other international codes) are not applicable to long-span suspension bridges. The paper discusses criteria of bridge loading and reliability indices for bridge cables. More work is needed in the evaluation of loading for long-span bridges.     

Lonidamine solid dispersions: in vitro and in vivo evaluation

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Inclusion of Methoxybutropate in β-and Hydroxypropyl β-Cyclodextrins: Comparison of Preparation Methods

Interactions between methoxybutropate and β-cyclodextrin or hydroxypropyl β-cyclodextrin and the possibility of obtaining inclusion complexes have been evaluated by phase solubility diagram, HPLC, DSC, and x-ray diffractometry. Solid inclusion complexes were prepared by spray drying, kneading, and solid dispersion. The dissolution profiles of the obtained powders were studied in order to define the most appropriate cyclodextrin preparation method and molar ratio to use in the production of methoxybutropate inclusion complexes     

Measurements of the auto-ignition of n-heptane/toluene mixtures using a rapid compression machine

Ignition delay times of undiluted stoichiometric n-heptane/toluene mixtures have been measured in a rapid compression machine (RCM) for pure n-heptane and for an increasing concentration of toluene by liquid volume (25–100%) in the mixture, mainly at two different molar densities (150 and 180 mol/m³). Initial pressures and temperatures were varied respectively in the 0226–0298 bar range and in the 299–352 K range, in order to allow compressed pressures and temperatures respectively in the 7.95–10.38 bar range and in the 710–814 K range.No ignition was observed for pure toluene due most probably to the variation of the final temperature and pressure in the combustion chamber during the very long ignition times of pure toluene at the experimental conditions considered in this work. The ignition delay variation at fixed temperature and the relative variation of the two-stage ignition times are reported. It is shown how the mixture behavior seems to be governed by the n-heptane chemistry for low toluene amount, while an increase of toluene concentration causes longer ignition delay times.Numerical modeling of the experiments with a recent Lawrence Livermore chemical mechanism for surrogate fuels shows that the results agree fairly well in the case of low and mid proportion of toluene by liquid volume. The single-zone model has allowed to extend the temperature range of investigation, showing that the low temperature range is the most influenced by the presence of toluene.     

Influence of Metronidazole Particle Properties on Granules Prepared in a High-Shear Mixer-Granulator

ABSTRACT

Metronidazole is a good example of high-dose drug substance with poor granulating and tableting properties. Tablets are generally produced by liquid granulation; however, the technological process failure is quite frequent. In order to verify how the metronidazole particle characteristics can influence granule properties, three metronidazole batches differing for crystal habit, mean particle size, BET surface area and wettability were selected, primarily designed according to their different elongation ratio: needle-shaped, stick-shaped, and isodimensional. In the presence of lactose monohydrate and pregelatinized maize starch, respectively as diluent and binder, they were included in a formula for wet granulation in a high-shear mixer-granulator. In order to render the process comparable as far as possible, all parameters and experimental conditions were maintained constant. Four granule batches were obtained: granules from placebo (G-placebo), granules from needle-shaped crystals (G-needle-shaped), granules from stick-shaped crystals (G-stick-shaped), and granules from isodimensional crystals (G-isodimensional). Different granule properties were considered, in particular concerning porosity, friability, loss on drying (LOD), and flowability. In order to study their tabletability and compressibility, the different granules obtained were then compressed in a rotary press. The best tabletability was obtained with the isodimensional batch, while the poorest was exhibited by the stick-shaped one. Differences in tabletability are in good accordance with compressibility results: to a better tabletability corresponds an important granule ability to undergo a volume reduction as a result of an applied pressure. In particular, it was proposed that the greatest compressibility of the G-isodimensional must be related to the greatest granule porosity percentage.     

Sorption of humic acids by a zeolite-feldspar-bearing tuff in batch and fixed-bed column

The sorption of humic acids (HA) on zeolite-feldspar-bearing Phlegraean Yellow Tuff enriched with calcium ions has been investigated at neutral pH both on fixed-bed columns and in batch. A two-step sorption kinetics and a relatively long time to reach the equilibrium were observed in batch. In line with this behaviour, the breakthrough curves and shipping curves from exhaust columns showed distinctive properties that cannot be easily modelled by the common mass balance equations; noteworthy, the breakthrough curves were dependent on the space velocity also for very slow processes and the bed sorption capacity decreased linearly with the space velocity. Moreover, after an initial high-rate burst, HA desorption from exhausted columns proceeded at a very slow rate, particularly so for columns loaded with higher amounts of HA.