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SummaryThis study offers a methodology for monitoring the conformity of monofloral honeys by using a descriptive profile method, which should be considered as an extension of the research on this topic previously carried out by Piana et al., (2004). The five major monofloral Italian honeys have been studied and characterized. They are: chestnut honey (Castanea sativa Miller); citrus honey (Citrus spp.); eucalyptus honey (Eucalyptus spp.); black locust honey (Robinia pseudoacacia L.); and honeydew honey. The aim of the present study is to develop a modern sensory profile method able to supply objective, reliable and reproducible data on monofloral honeys.

Introduction: Although risk-adapted therapy improved the prognosis of pediatric T-ALL in the last decades, patients with T-ALL still have a worse outcome compared to B Cell Precursor (BCP)-ALL, and therefore they would benefit from the identification of new prognostic markers for a better treatment stratification and novel strategies to complement current chemotherapy regimens. Among newly reported genomic abnormalities, a subset of BCP-ALL patients is characterized by the over-expression of the Cytokine Receptor-like Factor 2 (CRLF2) gene, due to either an intra-chromosomal deletion causing the P2RY8-CRLF2 fusion or the IGH@-CRLF2 translocation. These two CRLF2 rearrangements were shown to correlate with poor outcome in BCP-ALL patients. In T-ALL, alterations of CRLF2 were not reported yet, but recently, mutations in its partner IL7Rα have been identified in about 10% of T-ALL patients. Aim: To estimate the incidence of CRLF2 aberrations and their prognostic value in pediatric T-ALL. Methods: We analyzed CRLF2 gene expression in 120 T-ALL patients, consecutively enrolled in the AIEOP-BFM ALL2000 study in Italian centers (AIEOP) from September 2000 to July 2005, and, as a validation cohort, in 92 consecutive patients treated with the same protocol in German centers (BFM-G), from July 1999 to December 2004. CRLF2 transcript levels were analyzed by RQ-PCR. Relative gene expression of CRLF2 was quantified by the 2-DDCt method. The DDCt for AIEOP and BFM-G samples was referred to the median DCt of their respective cohort. Results: An heterogeneous expression of CRLF2 was observed among AIEOP T-ALL patients (range: 0.06 to 82 fold change). Seventeen patients (14.2%) presented an expression 5 times higher than the median (‘CRLF2-high’). Interestingly, none of the CRLF2-high cases resulted to be positive for P2RY8-CRLF2 fusion, 1/5 was positive for the IGH@ translocation and 1/7 showed a supernumerary X chromosome. JAK2 and CRLF2 mutations were absent in all 120 cases, while IL7R mutations were detected in 5/107 patients (4.7%), but unexpectedly they were not associated to CRLF2 over-expression. CRLF2-high patients had a significantly inferior 5-y EFS (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and an increased, although not statistically significant, cumulative incidence of relapse (CIR) compared to CRLF2-low patients (41.2%±11.9 vs. 26.3%±4.3, p=0.17). The prognostic value of CRLF2 over-expression was confirmed in the BFM-G cohort (5-y EFS in 12 CRLF2-high patients was 50.0%±14.4 vs 83.8%±4.1, p-=0.008; CIR: 33.3%±13.6 vs. 11.3%±3.5, p= 0.06). Interestingly, CRLF2-high patients were more frequently allocated to the high risk (HR) T-ALL subgroup (20.9% in HR vs.8.3% in no-HR in the two cohorts analyzed together). In this subgroup, CRLF2 over-expression was significantly associated to a poor prognosis (5-y EFS: 31.6%±10.7 vs. 62.5%±5.7, p-value=0.008; CIR: 47.4%±11.5 vs. 29.2%±5.4, p=0.14). When analyzed according to prednisone (PDN) response, 17/28 (61%) were prednisone poor responders (PPR), and in the ‘PPR-only’ subgroup (non-HR by other features) 4/9 (44%) CRLF2-high patients relapsed versus 4/36 (11%) CRLF2-low. Cox model analysis adjusted by risk group showed that CRLF2-high expression had a relevant prognostic impact with a 2-fold increased risk of relapse (Hazard ratio 2.12; 95% CI 1.07-4.21; p=0.03). The mechanisms responsible for CRLF2 over-expression in T-ALL and its contribution to the pathogenesis of the disease is still being investigated. Notably, gene set enrichment analysis (GSEA) showed an inverse correlation between the expression of CRLF2 and positive cell cycle regulators, thus suggesting that CRLF2-high blasts have a low proliferating activity and may therefore be less sensitive to conventional chemotherapy. Conclusions: CRLF2 over-expression is a poor prognostic marker not only in BCP-ALL patients, but also in T-ALL, identifying a subset of HR T-ALL patients with extremely severe outcome. Specifically, this marker would allow identifying T-ALL patients that could benefit from alternative therapy, potentially targetting the CRLF2 pathway. Disclosures No relevant conflicts of interest to declare.

A series of quinolone- and 1,8-naphthyridone-3-carboxylic acids, designed by previous QSAR studies and characterized by an amino group at the C-6 position instead of the usual fluorine atom, were synthesized for the first time and evaluated for in vitro antibacterial activity. All of the synthesized compounds maintain good activity against Gram-negative bacteria (Pseudomonas aeruginosa excluded), and those compounds having a thiomorpholine group as the C-7 substituent also have good activity against Gram-positive bacteria. Some aspects of structure-activity relationships associated with the C-1, C-5, C-7, and C-8 substituents are also discussed. Derivatives 18g and 38g displayed the best activity with geometric mean MICs of 0.45 and 0.66-0.76 micrograms/mL against Gram-negative and Gram-positive bacteria, respectively. This antimicrobial activity reflects their ability to inhibit bacterial DNA-gyrase. The results of this study show that, while the C-6 fluorine is still the preferred substituent, good activity can still be obtained by replacing it with an amino group.

A chemometric approach based on multivariate calibration and design in latent variables permits one to rationalize the antibacterial activity of quinolones against gram negative bacteria, ranking the relative importance of individual structural features, and suggesting a new active structure.

Some pathologic and epidemiologic evidence suggests that benign fibrous plaques may form in the pleura as a reaction to inspired asbestos. The ferruginous bodies formed in reaction to asbestos and other respirable fibers have virtually never been demonstrated in these lesions by study of tissue sections. Using a tissue digestion and microfiltration technic the authors identified small numbers of typical ferruginous bodies in three of eight specimens studied. Also found was another type of iron-coated structure which was designated an “atypical ferruginous body.” These may be endogenous or exogenous in origin. Ferruginous bodies probably are of little significance in the genesis of fibrous pleural plaques.

A series of 2-substituted-7-oxo-2,3-dihydro-1H-pyrido [1,2,3-de] [1,4] benzothiazine-6-carboxylic acids has been prepared and evaluated for in vitro antibacterial activity. These derivatives were less active than corresponding desmethylated analogues. Among these derivatives, the most active compound 9-fluoro-2-methyl-10-(4-methyl-1-piperazinyl)-7-oxo- 2,3-dihydro-1H-pyrido [1,2,3-de] [1,4] benzothiazine-6-carboxylic acid (22a) was selected for preliminary pharmacokinetics in rats. The pharmacokinetic data indicated that (22a) was rapidly absorbed and induced lasting plasma and urinary levels. In comparison with rufloxacin, it was excreted in low quantity in urine; a significant amount of desmethylated piperazinyl urinary metabolite was observed