On the effects of HV/MV stations on global grounding systems

The METERGLOB project has faced the issue of the identification of Global Grounding Systems. One of the main point of the problem is to define if an interconnection of single grounding systems gives place to a Global Grounding System in any condition and for every kind of ground fault. This paper focuses the attention on what happens in the case of single line to ground fault inside a HV/MV station whose ground electrode is connected to the cable' shields of the MV lines outgoing the station and supplying the secondary substations of a given area

Histone deacetylase (HDAC) inhibition modulates intracellular deoxynucleotides (dNTP) pools and potentiates the antitumor effects of the ribonucleotide reductase (RR) inhibitor 3’-Methyl-adenosine (3’-Me-Ado) in promyelocitic leukaemia cell lines.

HDAC inhibitors are a new class of antitumor agents that were reported to enhance the cytotoxic effects of a number of classical anticancer drugs through multiple mechanisms. In particular, they are capable of modulating the expression of a series of key cellular genes leading to significant antiproliferative and apoptotic effects. However, which of the possible drug combinations would be the most effective and clinically useful is still to be determined. We treated the HL60 and NB4 promyelocitic leukaemia cells with a combination of the RR inhibitor 3’-Me-Ado and several hydroxamic acid–derived HDAC inhibitors, including the two recently synthesized molecules, MC1864 and MC1879, and the reference compound Trichostatin A (TSA). Initial results showed significant antiproliferative and apoptotic synergistic effects with the combinations. To investigate the molecular basis of this finding, we evaluated the effects of the combinations on cell cycle distribution and on the level of some proteins involved in the apoptotic process (p21, caspase-3, Bcl-2, Bax, AIF). Since HDAC inhibitors seemed to increase the G1-S transition block induced by 3’-Me-Ado, an effect on RR activity was hypothesized. Indeed, the HPLC evaluation of intracellular dNTP pools showed that both TSA and MC1864 induced a significant perturbation in dNTP pools, even if with a somewhat different pattern, suggesting that RR modulation could contribute to the observed synergism. Furthermore, while TSA was shown to activate the intrinsic apoptotic pathway, MC1864 induced a significant dose-dependent increase in ROS generation and the activation of an AIF-dependent apoptotic mechanism. Finally, cell exposure to the radical scavenger N-acetylcysteine determined a significant inhibition of MC1864- but not TSA-mediated synergistic effects. Hence, our findings are consistent with a possible role of HDAC inhibitor mediated-ROS induction in RR inhibition and in the potentiation of RR inhibitors-mediated apoptosis induction

The synergistic apoptotic effects of thiophenfurin, an inosine monophosphate dehydrogenase inhibitor, in combination with retinoids in HL60 cells.

New effective cytotoxic agents and combinations are urgently needed in cancer treatment. The enzyme inosine monophosphate dehydrogenase is a potentially useful target for drug development, since its activity has been shown to be amplified in malignant cells. Thiophenfurin, an inhibitor of the enzyme synthesized by us, is endowed with a significant apoptotic activity in promyelocytic leukaemia HL60 cells. Since retinoids were successfully employed in the treatment of patients with leukaemia, demonstrating significant differentiation-inducing and apoptotic effects, we carried out this study to evaluate the effects of the combination of thiophenfurin and several retinoid molecules, acting in different phases of the cell cycle in vitro. The results show that thiophenfurin is capable of eliciting significant S phase-specific antiproliferative effects in different sensitive and resistant cell lines with the IC50s ranging from 6.7 to 26 microM. When HL60 cells were treated with thiophenfurin in combination with retinoids, the effects on cell growth were additive or synergistic, depending on the kind of retinoid used and the sequence of treatment. In particular, we observed additive effects when the cells were exposed to thiophenfurin and all-transretinoic acid either simultaneously or sequentially. Instead, when the new heterocyclic retinoid isoxazole benzoic acid was used, synergism was obtained in the cells treated sequentially. The combination of thiophenfurin and isoxazole benzoic acid determined synergistic apoptotic effects through a mitochondrion-dependent mechanism, suggesting the possible usefulness of this combination in the treatment of leukaemia

Epigenetic agents as an adjunct to active chemotherapy in hematological tumor cell lines

Epigenetic therapy is a new promising area in cancer research that is based on the use of a series of molecules capable of affecting tumor cell growth, differentiation and death by modifying the cellular mechanisms underlying the control of gene expression. Significant enhancement of traditional anticancer drug effects has been also reported by several authors. Our recent research focused on the identification of new epigenetic agent-containing drug combinations to be employed in the therapy of leukemia. The results showed that the new combination of an histone deacetylase (HDAC) inhibitor and the ribonucleotide reductase (RR) inhibitor 3’-methyl-adenosine (3’-Me-Ado) is endowed with a significant antitumor activity against promyelocytic leukemia cells. This effect was dependent not only by the HDAC inhibitors-mediated enhancement of drug-induced apoptosis, but also by the ability of these pleiotropic agents to inhibit the activity of the RR enzyme. Studies are ongoing to verify the feasibility of creating new bifunctional agents containing both an RR and an HDAC inhibitor within the same molecule, so that they can reproduce the effects of this combination and furnish an easier and effective therapeutic modality in view of a possible future use in the clinics

Expression of IAPs (Inhibitory of Apoptosis Proteins) and of their alternative splice variants in hepatocellular carcinoma tissues and cells

IAPs (inhibitors of apoptosis proteins) might have a major role in the apoptotic resistance that marks many cancers. The studies on IAPs in human HCC have focused on survivin or XIAP, indicating that their new or increased expression in this tumor is associated with a more unfavorable prognosis. The present results corroborate these findings, emphasizing the role that the coordinated expression of different IAPs and alternative splice variants might play in the adverse biology of hepatocellular carcinoma

On the Interconnections of HV-MV Stations to Global Grounding Systems

The interconnection of grounding systems of HV-MV stations via the armors of medium voltage cables, is herein analyzed to verify the effects on touch voltages in ground-fault conditions. The major contributions of this paper are two: the analysis of the impact of an HV ground-fault on a global grounding system (GGS), and the analysis of the parameters that may affect safety due to the interconnection between HV-MV stations and the GGS. The authors have analyzed cases when the connection of an HV-MV station to a GGS improves safety, and then may introduce hazards under ground-fault conditions. Two main issues are herein discussed: 1) the transfer of dangerous voltages to substations, due to ground-faults occurring at the HV-MV station; and 2) the reduction in the magnitude of the ground potential rise caused by ground-fault conditions at substations, due to the connection of their ground grids to the HV-MV station's grounding system. This paper, by examining various grid configurations, demonstrates that in some instances the inclusion of HV-MV stations in the GGS may reduce the level of protection against touch voltages, and that this depends on the following elements: the number of MV lines fed by the faulted station, the number of MV-LV substations per line, the value of the ground resistance of the substations, and the distance between the substations. This paper has practical relevance for both utilities distribution systems and industrial facilities supplied by the MV power grid