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We identified a discrete number of microRNAs differentially expressed in benign or malignant mesothelial tissues. We focused on mir-145 whose levels were significantly downregulated in malignant mesothelial tissues and malignant pleural mesothelioma (MPM) cell lines as compared to benign tissues (pleura, peritoneum or cysts). We show that promoter hyper-methylation caused very low levels in MPM cell lines and specimens. Treatment of MPM cell lines with mir-145 agonists negatively modulated some protumorigenic properties of MPM cells, such as clonogenicity, cell migration and resistance to pemetrexed treatment. The main effector mechanism of the clonogenic death induced by mir-145 was that of accelerated senescence. We found that mir-145 targeted OCT4 via specific binding to its 3′-UTR. Increased intracellular levels of mir-145 decreased the levels of OCT4 and its target gene ZEB1, thereby counteracting the increase of OCT4 induced by pemetrexed treatment which is known to favor the development of chemoresistant cells. In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence. This further supports the relevance of the mir-145-OCT4 interaction for the survival of MPM cells. The potential use of mir-145 expression levels to classify benign vs malignant mesothelial tissues and the differences between pemetrexed-induced senescence and that induced by the re-expression of mir-145 are discussed.

The purpose of this study is the evaluation of the histological effects of a new-generation superpulsed CO2 laser through an “ex vivo” study. A CO2 (λ = 10,600 nm) ultra-speed laser (SmartUS20D, DEKA, Florence, Italy) has been used at different parameters from 2 to 4 watt in Continuous Wave (CW) and Pulsed Wave (PW, 50 Hz) to obtain 30 samples from pig cadaver tongues. All the specimens have been subdivided into 6 groups (from A to F) and each group consisted of 5 samples. A final specimen has been taken by scalpel and used as control group. Histological analysis has been performed using an optical microscope (Leica DM 2000) at a magnification of ×40. Results showed that histological readability was optimal in all the samples. The thermal damage has been negligible in all the groups. Furthermore, the average of thermal damage was 0,095 mm in the epithelial, while it was 0.245 mm in the connective tissue. Statistical analysis using Graphpad Prism 5 software showed no significant differences among the groups. CO2 laser demonstrated a good surgical effectiveness provoking little peripheral damage onto the cut edges and allowing a safe histological diagnosis.

Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFR tyr1068 ) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFR tyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFR tyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFR tyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.

The molecular epidemiology and the genetic basis of carbapenem resistance was investigated in 185 Acinetobacter baumannii isolates obtained from 13 centers of northern Croatia and Istria during 2009–2010. All isolates were multidrug-resistant, and 35 % ( n  = 64) were resistant to both imipenem and meropenem. IS Aba1 -driven overexpression of the intrinsic bla OXA-51-like gene was observed in all carbapenem resistant isolates, and 69 % of these ( n  = 44) also produced acquired OXA-type carbapenemases. The presence of bla OXA-58-like , bla OXA-24/40-like , and bla OXA-23-like genes was demonstrated in 33 % ( n  = 21), 27 % ( n  = 17) and 9 % ( n  = 6) of carbapenem-resistant isolates, respectively. None of the isolates harbored the bla IMP , bla VIM , bla SIM , bla NDM or bla PER β-lactamase genes, while bla TEM-1 was detected in five carbapenem- and ampicillin/sulbactam-resistant isolates. Sequence group determination showed a high prevalence (81 %) of isolates belonging to the International clonal lineage (ICL)-I, although the majority (80 %) of isolates carrying acquired carbapenemase genes belonged to the ICL-II. Random amplified polymorphic DNA analysis and multilocus-sequence typing of a subset of carbapenem-resistant isolates revealed a low degree of genetic variability within both ICL-I and ICL-II populations, irrespective of the genetic basis of carbapenem resistance. Overall, an increasing trend toward carbapenem resistance was observed for A. baumannii in Croatia, and the emergence of ICL-II strains producing a variety of acquired carbapenemases.

The siderophore pyoverdine (PVD) is a primary virulence factor of the human pathogenic bacterium Pseudomonas aeruginosa, acting as both an iron carrier and a virulence-related signal molecule. By exploring a number of P. aeruginosa candidate systems for PVD secretion, we identified a tripartite ATP-binding cassette efflux transporter, here named PvdRT-OpmQ, which translocates PVD from the periplasmic space to the extracellular milieu. We show this system to be responsible for recycling of PVD upon internalization by the cognate outer-membrane receptor FpvA, thus making PVD virtually available for new cycles of iron uptake. Our data exclude the involvement of PvdRT-OpmQ in secretion of de novo synthesized PVD, indicating alternative pathways for PVD export and recycling. The PvdRT-OpmQ transporter is one of the few secretion systems for which substrate recognition and extrusion occur in the periplasm. Homologs of the PvdRT-OpmQ system are present in genomes of all fluorescent pseudomonads sequenced so far, suggesting that PVD recycling represents a general energy-saving strategy adopted by natural Pseudomonas populations.

Although antibiotic resistance represents a public health emergency, the pipeline of new antibiotics is running dry. Repurposing of old drugs for new clinical applications is an attractive strategy for drug development. We used the bacterial pathogen Pseudomonas aeruginosa as a target for the screening of antivirulence activity among marketed drugs. We found that the antimycotic agent flucytosine inhibits the expression of the iron-starvation σ-factor PvdS, thereby repressing the production of major P. aeruginosa virulence factors, namely pyoverdine, PrpL protease, and exotoxin A. Flucytosine administration at clinically meaningful dosing regimens suppressed P. aeruginosa pathogenicity in a mouse model of lung infection. The in vitro and in vivo activity of flucytosine against P. aeruginosa, combined with its desirable pharmacological properties, paves the way for clinical trials on the anti- P. aeruginosa efficacy of flucytosine in humans.

The seroprevalence of antibodies to Borrelia burgdorferi and tick-borne encephalitis (TBE) virus was evaluated in a group of forestry rangers in the Lazio region of Italy. One hundred and forty-five forestry rangers and 282 blood donors were examined by two-tiered serological tests for B. burgdorferi and TBE virus. Information on occupation, residence, tick bites, outdoor leisure activities and other risk factors was obtained. The prevalence of IgG/IgM antibodies to B. burgdorferi showed no statistical difference between the two groups, but there was a higher occurrence of IgM antibodies. There were significant differences between indoor and outdoor, urban and rural workplaces among the 145 exposed workers (χ² test: p < 0.001), and a higher risk for outdoor rural than urban tasks was detected among the ten Western blot-tested forestry rangers positive to B. burgdorferi (χ² test: p < 0.1). No seropositivity was observed for the TBE virus. Forestry rangers from the Lazio region did not have a higher risk of Borrelia infection than the blood donors, though an increase in the risk for outdoor tasks in a rural environment was observed.

The utility of amplified fragment length polymorphism (AFLP) analysis as a genotyping method for the epidemiological typing of Legionella pneumophila serogroup 1 has been previously demonstrated. This study (i). reports recommendations for the designation of the European Working Group on Legionella Infections (EWGLI) AFLP types, (ii). describes the EWGLI AFLP types identified for the 130 strains in the EWGLI culture collection, and (iii). reports the results of a newly introduced international programme of proficiency testing. Following preliminary analysis of 20 epidemiologically unrelated isolates, 16 major AFLP types were identified. A coded proficiency panel, comprising 12 additional isolates representing 9 of these 16 AFLP types, was sent to 17 centres in 14 European countries where it was analysed following a previously determined standard protocol. The identity of each coded strain (recorded as AFLP type 001-016 or untypeable) was determined by participants with reference to these 16 AFLP types, either visually or using gel analysis software where available, and reported to the coordinating centre. Nine of the 12 strains, including an epidemiologically related pair and two pairs of unrelated isolates of the same type, were correctly identified to the correct AFLP type by all or all but one of the participants. Seven laboratories correctly identified all 12 isolates, and a further seven laboratories correctly identified 11. Type identification scores ranged from 75% (1 centre), 83% (2 centres), and 92% (7 centres) to 100% (7 centres). The AFLP method as described is robust and rapid and allows the genotypic comparison of isolates of Legionella pneumophila between different testing centres without the need for exchange of the strains studied.

The purpose of this study is the evaluation of the histological effects of a new-generation superpulsed C[O.sub.2] laser through an \"ex vivo\" study A C[O.sub.2] (λ = 10,600 nm) ultra-speed laser (SmartUS20D, DEKA, Florence, Italy) has been used at different parameters from 2 to 4 watt in Continuous Wave (CW) and Pulsed Wave (PW, 50 Hz) to obtain 30 samples from pig cadaver tongues. All the specimens have been subdivided into 6 groups (from A to F) and each group consisted of 5 samples. A final specimen has been taken by scalpel and used as control group. Histological analysis has been performed using an optical microscope (Leica DM 2000) at a magnification of x40. Results showed that histological readability was optimal in all the samples. The thermal damage has been negligible in all the groups. Furthermore, the average of thermal damage was 0,095 mm in the epithelial, while it was 0.245 mm in the connective tissue. Statistical analysis using Graphpad Prism 5 software showed no significant differences among the groups. C[O.sub.2] laser demonstrated a good surgical effectiveness provoking little peripheral damage onto the cut edges and allowing a safe histological diagnosis.

In September 1997, a 25-year-old Italian woman with cystic fibrosis (CF) spent 3 weeks in Thailand. In August 1998, her pulmonary function rapidly declined, with productive cough and intermittent fever. Chest x-ray films revealed diffuse, small, patchy opacities in the upper lobes. Burkholderia pseudomallei (BP) was isolated from specimens of the patient's sputum and was identified by means of 16S rDNA sequencing. The diagnosis of melioidosis was serologically confirmed. Continuous therapy with ceftazidime and co-trimoxazole and maintenance with co-trimoxazole, doxycycline, and chloramphenicol resulted in eradication of BP. We present the issue of whether patients with CF represent a population particularly at risk for melioidosis.