Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Review

Glioblastoma (GBM) is the most common and malignant tumour of the central nervous system. Recent appreciation of the heterogeneity amongst these tumours not only changed the WHO classification approach, but also created the need for developing novel and personalised therapies. This systematic review aims to highlight recent advancements in understanding the molecular pathogenesis of the GBM and discuss related novel treatment targets. A systematic search of the literature in the PubMed library was performed following the PRISMA guidelines for molecular pathogenesis and therapeutic advances. Original and meta-analyses studies from the last ten years were reviewed using pre-determined search terms. The results included articles relevant to GBM development focusing on the aberrancy in cell signaling pathways and intracellular events. Theragnostic targets and vaccination to treat GBM were also explored. The molecular pathophysiology of GBM is complex. Our systematic review suggests targeting therapy at the stemness, p53 mediated pathways and immune modulation. Exciting novel immune therapy involving dendritic cell vaccines, B-cell vaccines and viral vectors may be the future of treating GBM.     

Biological Effects of Cyclin-Dependent Kinase Inhibitors Ribociclib,Palbociclib and Abemaciclib on Breast Cancer Bone Microenvironment

The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice.     

Targeting Endothelial Connexin37 Reduces Angiogenesis and Decreases Tumor Growth

Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37−/− mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37−/− mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments.     

Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways

Prevention of cancer through dietary intervention recently has received an increasing interest, and dietary polyphenols have become not only important potential chemopreventive, but also therapeutic, natural agents. Polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. They might lead to the modulation of proteins in diverse pathways and require the integration of different signals for the final chemopreventive or therapeutic effect. Polyphenols have been demonstrated to act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis; however, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of potential chemopreventive and therapeutic activities of dietary polyphenols with emphasis in their ability to control intracellular signalling cascades considered as relevant targets in a cancer preventive approach.     

Characterization of PAX‐21 Insensitive Munition Detonation Residues

Insensitive high explosives are being used in military munitions to counteract unintended detonations during storage and transportation. These formulations contain compounds such as 2,4‐dinitroanisole (DNAN) and 3‐nitro‐1,2,4‐triazol‐5‐one (NTO), which are less sensitive to shock and heat than conventional explosives. We conducted a series of four tests on snow‐covered ice utilizing 60‐mm mortar cartridges filled with 358 g of PAX‐21, a mixture of RDX, DNAN, and ammonium perchlorate. Rounds were detonated high‐ and low‐order using a fuze simulator to initiate detonation. Blow‐in‐place (BIP) operations were conducted on fuzed rounds using an external donor charge or a shaped‐charge initiator. Results indicate that 0.001 % of the original mass of RDX and DNAN were deposited during high‐order detonations, but up to 28 % of the perchlorate remained. For the donor block BIPs, 1 % of the RDX and DNAN remained. Residues masses for these operations were significantly higher than for conventional munitions. Low‐order detonations deposited 10–15 % of their original explosive filler in friable chunks up to 5.2 g in mass. Shaped‐charge BIPs scattered 15 % of the filler and produced chunks up to 15 g. Ammonium perchlorate residue masses were extremely high because of the presence of large AP crystals, up to 400 μm in the recovered particles.     

Air exposure time of olive pastes during the extraction process and phenolic and volatile composition of virgin olive oil

The time of exposure of olive pastes to air contact (TEOPAC) during malaxation was studied as a processing parameter that could be used to control endogenous oxidoreductases, such as polyphenoloxidase, peroxidase, and lipoxygenase, which affect virgin olive oil quality. Phenolic and volatile compounds were analyzed in the oils obtained using progressive TEOPAC at three ripening stages of olives. Multivariate statistical analysis was applied to the raw data. The phenolic concentration of virgin olive oil progressively decreased with increasing IEOPAC. On the contrary, a positive relationship was found with the concentration of several volatile compounds responsible for virgin olive oil aroma. The effect of TEOPAC, however, was strictly related to fruit ripening.     

Interlaboratory study on lipid oxidation during accelerated storage trials with rapeseed and sunflower oil analyzed by conjugated dienes as primary oxidation products

Accelerated storage tests are frequently used to assess the oxidative stability of foods and related systems due to its reproducibility. Various methods and experimental conditions are used to measure lipid oxidation. Differences between laboratories make it necessary to determine the repeatability and reproducibility of oxidation tests performed under the same conditions. The objective of the present interlaboratory study was to evaluate the outcome of a storage test for two different bulk oils, sunflower oil (SFO) and rapeseed oil (RSO), during a period of 9 weeks at 20°C, 30°C, 40°C, and 60°C. Sixteen laboratories were provided with bottled oils and conducted the storage tests according to a detailed protocol. Lipid oxidation was monitored by the formation of conjugated dienes (CD) and the activation energy (E_a) was determined for comparative purposes and statistically evaluated. An increase in CD formation was observed for both oils when the storage temperature was increased in all laboratories. The E_a,1 ranged from 47.9 to 73.3 kJ mol⁻¹ in RSO and from 27.8 to 62.6 kJ mol⁻¹ in SFO, with average values of 58.2 and 46.8 kJ mol⁻¹, respectively. The reproducibility coefficients were 10.9% and 18.2% for RSO and SFO, respectively. Practical applications: In order to compare results on oxidative stability of foods derived from different studies, the reproducibility of storage tests and methods employed to evaluate the oxidation level should be considered. This study provides fundamental data on the reproducibility of lipid oxidation under accelerated storage conditions and defines important parameters to be considered for the conduction of experiments.     

Transport properties of sulfonated poly (styrene‐isobutylene‐styrene) membranes with counter‐ion substitution

In this study, the transport properties of poly(styrene‐isobutylene‐styrene) (SIBS) were determined as a function of sulfonation level (0–94.9%) and counter‐ion substitution (Ba⁺², Ca⁺², Mg⁺², Mn⁺², Cu⁺², K⁺¹) for fuel cell applications. Increasing the sulfonation level improved the ion exchange capacity (IEC) of the membranes up a maximum (1.71 mequiv/g), suggesting a complex three‐dimensional network at high sulfonation levels. Results show that proton conductivity increases with IEC and is very sensitive to hydration levels. Methanol permeability, although also sensitive to IEC, shows a different behavior than proton conductivity, suggesting fundamental differences in their transport mechanism. The incorporation of counter‐ion substitution decreases both methanol and proton transport. Methanol permeability seems to be related to the size of the counter‐ion studied, while proton conductivity is more sensitive to water content, which is also reduced upon the incorporation of counter‐ions. To complement the studies, selectivity (i.e., proton conductivity/methanol permeability) of the studied membranes was determined and compared to Nafion® 117. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Crystallization and melting properties of extra virgin olive oil studied by synchrotron XRD and DSC

Crystallization and melting properties of triacylglycerols in extra virgin olive oil were studied by using synchrotron X‐ray diffraction (XRD) and differential scanning calorimetry (DSC). The phase transitions were monitored by cooling and heating the samples at 2°C/min from 60 to ?60°C and vice versa. Upon cooling, a first DSC endothermic peak was recorded at ?9.6°C followed by one at ?33.5°C. These thermal events were associated to the formation of two different structures: a triple‐chain length (3L) having a c parameter of about 58.38 Å and a quadruple chain length structure (4L) with a c parameter of about 89.99 Å, respectively. Both structures evidenced a cell packing arrangement ascribable to a β′ form. During heating, part of the metastable β′ crystals rearranged into the more thermodynamically stable β form. Then, upon further heating, the sequential melting of the two crystal structures was observed. The melting was completed at 10.7°C. Beside this interpretation of XRD data, a model considering a cell with a c parameter of about 170 Å and a hexagonal crystal system was proposed. Even if more research is needed to validate this approach, it allowed all XRD events recorded during the experiments to be described. See commentary by Chiavaro [p. 267–269], http://dx.doi.org/10.1002/ejlt.201200415     

Impact of Particle Generation Method on the Apparent Hygroscopicity of Insoluble Mineral Particles

Calcite (CaCO ₃ ) mineral particles are commonly generated by atomization techniques to study their heterogeneous chemistry, hygroscopicity, and cloud nucleation properties. Here we investigate the significant artifact introduced in generating calcium mineral particles through the atomization of a saturated suspension of the powder in water, by measuring particle hygroscopicity via CCN activation curves. Particles produced from atomization displayed hygroscopicities as large as κ_app > 0.1, 100 times more hygroscopic than that obtained for dry-generated calcite, κ_app = 0.0011. The hygroscopicity of the wet-generated particles increased as a function of time the calcite powder spent in water, and with decreasing particle size. Wet-generated calcium oxalate was more hygroscopic through wet- (κ_app = 0.34) versus dry-generation (κ_app = 0.048). Atomized calcium sulfate particles, however, were only slightly more hygroscopic (κ_app = 0.0045) than those generated dry (κ_app = 0.0016). Single-particle analysis by ATOFMS and SEM/EDX, and bulk analysis of the calcite powders by ICP-MS and IC revealed no significant soluble contaminants. The atomized particles were likely composed of components that dissolved from the powder and then re-precipitated, and appeared to contain little of the original mineral powder. The increased hygroscopicity of atomized calcite may have been caused by aqueous carbonate chemistry producing Ca(OH) ₂ , Ca(HCO ₃ ) ₂ , and metastable hydrates with increased solubility. Surface water adsorption may have also played a role, in addition to uncharacterized soluble components produced by wet-generation, and the precipitation of amorphous phases including glassy states. This study suggests that using wet-generation methods to suspend mineral dust samples will not produce particles with the correct physicochemical properties in laboratory studies, a finding which has important implications for past and future laboratory studies focusing on understanding relationships between the hygroscopicity and chemistry of mineral dust particles.