Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma.

Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/brain barrier

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Technical and technological progress in malt production

Postęp techniczny jest głównym czynnikiem wpływającym na racjonalizację i intensyfikację procesów produkcyjnych, a także unowocześnienie produkowanych wyrobów. Dzięki temu można go uznać za zasadnicze narzędzie rozwoju konkurencyjności firm. W artykule przedstawiono pojęcia postępu technicznego i technologicznego oraz opisano jego wdrożenie w branży słodowniczej na przykładzie małej lokalnej słodowni. Postęp techniczny i technologiczny w produkcji słodu znalazł się obecnie w martwym punkcie. Inwestycje w urządzenia powodują niewspółmierny przyrost osiąganej wydajności w stosunku do poniesionych kosztów, natomiast postęp technologiczny w produkcji słodu opiera się głównie na stosowaniu dodatków wspomagających proces słodowania i podnoszących jakość słodu.Technical progress is a key factor influencing the rationalization and intensification of production processes, as well as the modernization of manufactured products. Thanks to that, it can be acknowledged as a tool for developing competitiveness of companies. Changes in a company, that are conditioned by technical progress, can be related to technological processes, applied machines or manufactured products, what can result in the reduction of outlay of production factors. By dint of technical progress, process of manufacturing activity can be facilitated even if it generates additional costs. In this paper the idea of technical and technological process was presented and described considering malting branch based on the example of a small local malt house. Both technical and technological progress in the field of malting has currently reached a standstill. Investments in machines cause disproportionate growth of efficiency when comparing to incurred costs, whereas technological progress in malting bases mainly on changes not affecting the ways of conducting unit processes or operations, but in applied additions aiding in the process of malting and increasing malt quality

Modulo N Backoff Scheme for Effective QoS Differentiation and Increased Bandwidth Utilization in IEEE 802.11 Networks

The paper presents a new modulo N channel access scheme for wireless local area networks (WLANs). The novel solution derives from the distributed coordination function (DCF) of the IEEE 802.11 standard, further elaborated as enhanced distribution channel access (EDCA) by the 802.11e draft specification. The main innovation concerns improvement of the binary exponential backoff scheme used for collision avoidance in 802.11 networks. The most appealing feature of the new modulo N backoff scheme is that it outperforms the original 802.11 solution in terms of channel utilization ratio under any traffic conditions. Furthermore, the modulo N proposal can be naturally augmented with QoS differentiation mechanisms like 802.11e extensions. The prioritized modulo N scheme achieves better throughput-delay characteristics for multimedia traffic when compared with the original 802.11e proposal. At the same time, the new solution retains backward compatibility and includes all features which have made IEEE 802.11 networks extremely popular nowadays

Preserved global histone H4 acetylation linked to ETV6-RUNX1 fusion and PAX5 deletions is associated with favorable outcome in pediatric B-cell progenitor acute lymphoblastic leukemia.

Epigenetic dysregulation is a hallmark of cancer executed by a number of complex processes the most important of which converge on DNA methylation and histone protein modifications. Epigenetic marks are potentially reversible and thus promising drug targets. In the setting of acute lymphoblastic leukemia (ALL) they have been associated with clinicopathological features including risk of relapse or molecular subgroups of the disease. Here, using immunocytochemistry of bone marrow smears from diagnosis, we studied global histone H4 acetylation, whose loss was previously linked to treatment failure in adults with ALL, in pediatric patients. We demonstrate that preserved global histone H4 acetylation is significantly associated with favorable outcome (RFS, EFS, OS) in children with B cell progenitor (BCP) ALL, recapitulating the findings from adult populations. Further, for the first time we demonstrate differential histone H4 acetylation in molecular subclasses of BCP-ALL including cases with ETV6-RUNX1 fusion gene or PAX5 deletion or deletions in genes linked to B cell development. We conclude global histone H4 acetylation is a prognostic marker and a potential therapeutic target in ALL