The advantages of using a Geographic Information System to evaluate risk in highly contaminated sites

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Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis

Abstract Based on promising results in preclinical models, clinical trials have been performed to evaluate the efficacy of the first-in-class proteasome inhibitor bortezomib towards malignant pleural mesothelioma (MPM), an aggressive cancer arising from the mesothelium of the serous cavities following exposure to asbestos. Unexpectedly, only minimal therapeutic benefits were observed, thus implicating that MPM harbors inherent resistance mechanisms. Identifying the molecular bases of this primary resistance is crucial to develop novel pharmacologic strategies aimed at increasing the vulnerability of MPM to bortezomib. Therefore, we assessed a panel of four human MPM lines with different sensitivity to bortezomib, for functional proteasome activity and levels of free and polymerized ubiquitin. We found that highly sensitive MPM lines display lower proteasome activity than more bortezomib-resistant clones, suggesting that reduced proteasomal capacity might contribute to the intrinsic susceptibility of mesothelioma cells to proteasome inhibitors-induced apoptosis. Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein. Taken together, our data suggest that an unfavorable load-versus-capacity balance represents a critical determinant of primary apoptotic sensitivity to bortezomib in MPM

Relationship between Antibody Susceptibility and Lipopolysaccharide O-Antigen Characteristics of Invasive and Gastrointestinal Nontyphoidal Salmonellae Isolates from Kenya

Background: Nontyphoidal Salmonellae (NTS) cause a large burden of invasive and gastrointestinal disease among young children in sub-Saharan Africa. No vaccine is currently available. Previous reports indicate the importance of the O-antigen of Salmonella lipopolysaccharide for virulence and resistance to antibody-mediated killing. We hypothesised that isolates with more O-antigen have increased resistance to antibody-mediated killing and are more likely to be invasive than gastrointestinal. Methodology/Principal findings: We studied 192 NTS isolates (114 Typhimurium, 78 Enteritidis) from blood and stools, mostly from paediatric admissions in Kenya 2000-2011. Isolates were tested for susceptibility to antibody-mediated killing, using whole adult serum. O-antigen structural characteristics, including O-acetylation and glucosylation, were investigated. Overall, isolates were susceptible to antibody-mediated killing, but S. Enteritidis were less susceptible and expressed more O-antigen than Typhimurium (p\u3c0.0001 for both comparisons). For S. Typhimurium, but not Enteritidis, O-antigen expression correlated with reduced sensitivity to killing (r = 0.29, 95% CI = 0.10-0.45, p = 0.002). Both serovars expressed O-antigen populations ranging 21-33 kDa average molecular weight. O-antigen from most Typhimurium were O-acetylated on rhamnose and abequose residues, while Enteritidis O-antigen had low or no O-acetylation. Both Typhimurium and Enteritidis O-antigen were approximately 20%-50% glucosylated. Amount of S. Typhimurium O-antigen and O-antigen glucosylation level were inversely related. There was no clear association between clinical presentation and antibody susceptibility, O-antigen level or other O-antigen features. Conclusion/Significance: Kenyan S. Typhimurium and Enteritidis clinical isolates are susceptible to antibody-mediated killing, with degree of susceptibility varying with level of O-antigen for S. Typhimurium. This supports the development of an antibody-inducing vaccine against NTS for Africa. No clear differences were found in the phenotype of isolates from blood and stool, suggesting that the same isolates can cause invasive disease and gastroenteritis. Genome studies are required to understand whether invasive and gastrointestinal isolates differ at the genotypic level

I fondi patrimoniali e la loro contabilizzazione. Dal pensiero di Fabio Besta a talune prassi del settore pubblico nord americano

Gli studi storici possono inizialmente rispondere a mera curiosit\ue0 circa accadimenti che, per essere del passato, possono oggi apparirci curiosi e stimolanti. In tale ottica, curiosit\ue0 scientifica destano talune affinit\ue0 immediate che \ue8 possibile percepire tra la \u201cfund accounting\u201d anglosassone, utilizzata, per quanto qui pi\uf9 interessa, nel settore pubblico USA e il concetto di \u201cfondo\u201d, tipico della dottrina ragionieristica prezappiana, particolarmente sviluppato da Fabio Besta. Ci si chiede allora se possa essere utile interrogarsi circa possibili relazioni intercorse tra pensiero e prassi di tempi e luoghi successivi. In tale direzione, il confronto longitudinale tra pensiero antico e prassi attuali sar\ue0 volto a ricercare significative somiglianze e diversit\ue0 e se il primo possa mostrare capacit\ue0 esplicative di fenomenologie economiche contemporanee

I fondi patrimoniali e la loro contabilizzazione. Dal pensiero di Fabio Besta a talune prassi del settore pubblico nord americano

Gli studi storici possono inizialmente rispondere a mera curiosità circa accadimenti che, per essere del passato, possono oggi apparirci curiosi e stimolanti. In tale ottica, curiosità scientifica destano talune affinità immediate che è possibile percepire tra la “fund accounting” anglosassone, utilizzata, per quanto qui più interessa, nel settore pubblico USA e il concetto di “fondo”, tipico della dottrina ragionieristica prezappiana, particolarmente sviluppato da Fabio Besta. Ci si chiede allora se possa essere utile interrogarsi circa possibili relazioni intercorse tra pensiero e prassi di tempi e luoghi successivi. In tale direzione, il confronto longitudinale tra pensiero antico e prassi attuali sarà volto a ricercare significative somiglianze e diversità e se il primo possa mostrare capacità esplicative di fenomenologie economiche contemporanee

2(3)-aryl-thio(oxy)-methylquinoxaline derivatives: a new class of P-glycoprotein-mediated drug efflux inhibitor

A series of quinoxalines variously substituted, namely 3-arylthiomethyl-1,6-dimethylquinoxalin-2-ones (6a-f), 3-arylthiomethyl-1-benzyl-7-trifluoromethylquinoxalin-2-ones (8a-g) and 2-arylthiomethyl-3-benzyloxy-6-trifluoro-methylquinoxalines (10a,b,e-h), were synthesized and compared with previous arylphenoxymethylquinoxalines (1a-f, 2a-f and 3a-b). The purpose was to verify whether the replacement of oxygen with sulphur atom and the insertion of different substituents on the phenyl side chain were able to improve the capability to inhibit the Pgp pump and restore the antiproliferative activity of clinically useful drugs, such as doxorubicin (Doxo), vincristine (VCR) and etoposide (VP16), in drug-resistant human nasopharyngeal carcinoma KB cells (KB(wt), KB(MDR), KB(7D) and KB(V20C)). Furthermore, 2,3-bis(aryloxy-methyl)-6-trifluoromethylquinoxalines (13a-c) were designed with the objective to evaluate the capability of the double side chain to potentiate the antiproliferative activity of the drugs tested. Biological assays showed that title compounds were, in general, endowed with good activity as Pgp inhibitors. In particular compound 3a, bearing 2-CONHPh substituent on phenoxymethyl side chain, resulted the most effective, while the double side chain (compound 13c) gives the ability to inhibit a different MRP pump (a membrane glycoprotein named mrp). Furthermore, we can conclude that replacement of oxygen with sulphur atom did not improve the biological activity