Pain after stroke is more frequent in the subacute and chronic phase than in the acute phase, but it is still largely undertreated.

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.

Objectives-To assess and quantify the occurrence of pleural malignant mesotheliomas in people who neither experienced occupational exposure to asbestos nor were married to (or known to live with) workers exposed to asbestos in the workplace. The study was con-

The study investigates mortality from cancer and other diseases in a cohort of wives of asbestos cement workers in Casale Monferrato (northwest Italy). After the exclusion of women with an occupational record in the asbestos cement industry, the cohort comprised 1964 women. Their domestic exposure was estimated according to their husbands' periods of employment in the plant: 1740 had a period of domestic exposure whereas the remaining 224 married an asbestos cement worker only after he definitely stopped his activity in the asbestos cement plant; these have, therefore, been considered as unexposed. The cohort of wives was constructed entirely through official records in the town offices and is both exhaustive and unaffected by recall bias. At the end of follow up (1988) 1669 women were alive, 270 were dead and 25 (1.2%) were untraced. Main mortality analyses were only up to age 79 to reduce the misclassification of causes of death. Expected mortality was based on local rates. Mortality analyses were limited to the period due to the availability of local rates: in that period 210 deaths occurred among women with domestic exposure v 229-1 expected. There were four deaths from pleural tumours (one diagnosed as mesothelioma at necropsis) and six from lung cancer v. 0.5 and 4-0 expected respectively. Two further cases of mesothelioma were diagnosed by histological examination after the end of follow up. None of the three wives with histologically diagnosed mesothelioma had been engaged in

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood–brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.

Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gramnegative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.

Cystic fibrosis (CF) is a multi-organ protein misfolding disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses, bacteria and their co-infections are recognized triggers of acute pulmonary exacerbations, accelerating disease progression, and increasing hospitalization and mortality rate. Treatment complexity increases with the age of patients, as do the number and severity of side effects, drug-drug interactions and costs. Simplifying the therapeutic regimen represents therefore one of the key priorities of CF treatment. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as mild correctors and broad-spectrum picornavirus inhibitors. Starting from the previously identified multitarget hits, we report herein the synthesis and biological profiling of new bithiazole derivatives to elucidate the structural requirements to improve F508del-CFTR correction and antiviral potencies. The most promising compound 23a inhibited PI4KIIIβ and selected picornaviruses (EV71, CVB3, hRV02), showed good F508del-CFTR correction potency, additivity and possible synergy with lumacaftor (VX809) at low micromolar concentration. In addition, it was well tolerated in vivo by C57BL/6 mice with no sign of acute toxicity and histological alterations in key biodistribution organs.

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