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.     

Strategic sensemaking and organizational performance: linkages among scanning, interpretation, action, and outcomes.

This study investigated the strategic "sensemaking" processes of scanning, interpretation, and action and how those activities are linked to organizational performance. Using path analyses on data from 156 hospitals, we tested the direct and indirect effects among these sensemaking processes and performance outcomes and developed a model of their relationships. In a more general sense, the research represents an attempt to provide insight not only into relationships between cognition and action, but also into the links between those fundamental processes and organizational performance outcomes.     

Molecular basis of open-angle glaucoma in Italy

Glaucoma is a group of ocular diseases characterized by an optic neuropathy in which degeneration of retinal ganglion cells leads to a characteristic excavation of the optic nerve head. Primary open-angle glaucoma (POAG) can be subdivided into two groups according to age of onset:- 1. the more common middle- to late-age onset, chronic open-angle glaucoma (COAG) diagnosed after the age of 40 years; 2. the rarer juvenile open-angle glaucoma (JOAG), which is diagnosed between the age of 3 years and early adulthood. Recently, the gene coding for the trabecular meshwork-induced glucocorticoid response protein (TIGR), located in chromosome 1 (1q23-25), was found mutated in patients affected by POAG. In this work we describe the clinical and molecular genetic features of several Italian families affected by autosomal dominant POAG, collected in various regions of Italy.     

Polymer Encapsulated Liposomes for Oral Co-Delivery of Curcumin and Hydroxytyrosol

Curcumin (Cur) is a hydrophobic polyphenol from the rhizome of Curcuma spp., while hydroxytyrosol (HT) is a water-soluble polyphenol from Olea europaea. Both show outstanding antioxidant properties but suffer from scarce bioavailability and low stability in biological fluids. In this work, the co-encapsulation of Cur and HT into liposomes was realized, and the liposomal formulation was improved using polymers to increase their survival in the gastrointestinal tract. Liposomes with different compositions were formulated: Type 1, composed of phospholipids and cholesterol; Type 2, also with a PEG coating; and Type 3 providing an additional shell of Eudragit^® S100, a gastro-resistant polymer. Samples were characterized in terms of size, morphology, ζ-potential, encapsulation efficiency, and loading capacity. All samples were subjected to a simulated in vitro digestion and their stability was investigated. The Eudragit^®S100 coating demonstrated prevention of early releases of HT in the mouth and gastric phases, while the PEG shell reduced bile salts and pancreatin effects during the intestinal digestion. In vitro antioxidant activity showed a cumulative effect for Cur and HT loaded in vesicles. Finally, liposomes with HT concentrations up to 40 μM and Cur up to 4.7 μM, alone or in combination, did not show cytotoxicity against Caco-2 cells.     

Novel rifamycins. I-Synthesis and antibacterial activity of 3-hydrazinorifamycin derivatives

A number of semisynthetic rifamycin derivatives, modified at position 3, belonging to general structures (II), (III), (IV), (V), (VI), (VII) and (VIII) (see Scheme), have been prepared. The synthesis, structure, and antimicrobial evaluation of the new compounds are described. All the derivatives have in vitro antibacterial activities comparable with that of rifampicin.     

Towards biomimetic models of the reduced [FeFe]-hydrogenase that preserve the key structural features of the enzyme active site; a DFT investigation

[FeFe]-hydrogenases are the most efficient biological catalysts available for the H₂ evolution reaction. Their active site – the H-cluster – features a diiron subsite which has the peculiar characteristic of bearing cyanide groups hydrogen-bonded to the apoprotein as well as carbonyl ligands. Notably, one of the CO ligands is disposed in bridging position between the metal centers. This allows one of the Fe ions to retain a square pyramidal coordination – which determines the assumption of the so-called “rotated structure” – with a vacant coordination site in trans to the μ-CO group, ready to bind protons when the active site is in the Fe^IFe^I state. Many Fe^IFe^I biomimetic models have been synthesized and characterized so far, but most of them fail to reproduce the orientation of the diatomic ligands that is observed in the enzyme active site.     

Does the organ of Corti attempt to differentiate new hair cells after antibiotic intoxication in rat pups?

In the adult mammalian cochlea, post-injury hair cell losses are considered to be irreversible. Recent studies in cochlear explants of embryonic rodents show that the organ of Corti can replace lost hair cells after injury. We have investigated this topic in vivo during the period of cochlear development. Rat pups were treated with a daily subcutaneous injection of 500 mg/kg amikacin for eight consecutive days between postnatal day 9 (PND 9) and PND 16. During this period the organ of Corti is not fully mature, but hair cells are hyper-sensitive to aminoglycoside antibiotics. Scanning and transmission electron microscopy was used to evaluate morphological changes in the organs of Corti during the treatment and at different post-treatment periods, up until PND 90. A massive loss in outer and inner hair cells was observed at least as early as PND 14. A prominent feature in the apical part of cochleas at PND 21 and 35 was the transient presence of small atypical cells in the region of pre-existing outer hair cells. These atypical cells had tufts of microvilli reminiscent of nascent stereociliary bundles. A second striking observation was the replacement of degenerating inner hair cells by pear-shaped supporting cells throughout the cochlea. These cells were covered with long microvilli, and their basal pole was contacted by both afferent and efferent fibers, as in the early stages of inner hair cell maturation. At PND 55 and 90, these features were not clearly observed due to further cytological changes in the organ of Corti. It is possible that an attempt at hair cell neodifferentiation could occur in vivo after an amikacin treatment in the rat during the period of cochlear hyper-sensitivity to antibiotic.     

Effects of estradiol and medroxyprogesterone-acetate treatment on erythrocyte antioxidant enzyme activities and malondialdehyde plasma levels in amenorrhoic women

Plasma levels of 17 beta-estradiol (E2) and malondialdehyde and erythrocyte antioxidant enzyme [superoxide dismutase, catalase, and glutathione-peroxidase (GSH-Px)] activities were evaluated in 20 healthy eumenorrhoic women (EW) on day 7 of the menstrual cycle and in 48 secondary hypothalamic amenorrhea patients (AP) (time 0). The AP were randomly divided into four subgroups of 12 subjects and treated with transdermal E2 for 30 days (subgroup A), oral medroxyprogesterone-acetate for 30 days (subgroup B), and transdermal E2 plus medroxyprogesterone-acetate for 30 days (subgroup C). The fourth subgroup acted as control. E2 and malondialdehyde plasma levels and superoxide dismutase, catalase, and GSH-Px activities were evaluated in subgroups A, B, and C on day 30 of therapy and in the control subgroup. GSH-Px activity was significantly higher in EW than in AP at time 0. A statistically significant increase in E2 plasma levels and GSH-Px activity was observed in subgroups A and C on day 30 of treatment, and there was a significant positive correlation between E2 plasma levels and GSH-Px activity in both subgroups. After a month of treatment, erythrocyte GSH-Px activity in subgroups A and C was not significantly different from that observed in EW. After a month of treatment, no significant variation was found in subgroup B nor in the control group. These results strongly suggest that when plasma E2 is restored to physiological levels in AP, it stimulates erythrocyte GSH-Px activity. Progesterone therapy did not induce significant modifications.     

Combined Nano‐ and Micro‐Scale Topographic Cues for Engineered Vascular Constructs by Electrospinning and Imprinted Micro‐Patterns

The major cause of synthetic vessel failure is thrombus and neointima formation. To prevent these problems the creation of a continuous and elongated endothelium inside lumen vascular grafts might be a promising solution for tissue engineering. Different micro‐ and nano‐surface topographic cues including grooved micro‐patterns and electrospun fibers have been previously demonstrated to guide the uniform alignment of endothelial cells (ECs). Here, with a very simple and highly versatile approach we combined electrospinning with soft lithography to fabricate nanofibrous scaffolds with oriented fibers modulated by different micro‐grooved topographies. The effect of these scaffolds on the behavior of the ECs are analyzed, including their elongation, spreading, proliferation, and functioning using unpatterned random and aligned nanofibers (NFs) as controls. It is demonstrated that both aligned NFs and micro‐patterns effectively influence the cellular response, and that a proper combination of topographic parameters, exploiting the synergistic effects of micro‐scale and sub‐micrometer features, can promote EC elongation, allowing the creation of a confluent ECs monolayer in analogy with the natural endothelium as assessed by the positive expression of vinculin. Combining different micro‐ and nano‐topographic cues by complementary soft patterning and spinning technologies could open interesting perspectives for engineered vascular replacement constructions.