Haemophilus influenzae is a major pathogen of the respiratory tract in humans that has developed the capability to exploit host NAD(P) for its nicotinamide dinucleotide requirement. This strategy is organized around a periplasmic enzyme termed NadN (NAD nucleotidase), which plays a central role by degrading NAD into adenosine and NR (nicotinamide riboside), the latter being subsequently internalized by a specific permease. We performed a biochemical and structural investigation on H. influenzae NadN which determined that the enzyme is a Zn2+-dependent 5'-nucleotidase also endowed with NAD(P) pyrophosphatase activity. A 1.3 Å resolution structural analysis revealed a remarkable conformational change that occurs during catalysis between the open and closed forms of the enzyme. NadN showed a broad substrate specificity, recognizing either mono- or di-nucleotide nicotinamides and different adenosine phosphates with a maximal activity on 5'-adenosine monophosphate. Sequence and structural analysis of H. influenzae NadN led us to discover that human CD73 is capable of processing both NAD and NMN, therefore disclosing a possible novel function of human CD73 in systemic NAD metabolism. Our data may prove to be useful for inhibitor design and disclosed unanticipated fascinating evolutionary relationships.

The aim of the present study was to evaluate the effect of iron overload on gene expression in HepG2 cells by differential display. Iron-treated cells showed a 50% decrease in apolipoprotein B100 (Apo B100) and a 2-and 3-fold increase in semaphorin cd100 and aldose reductase mRNA, respectively, with parallel variations in Apo B100 and aldose reductase proteins. These effects were time-dependent. Vitamin E prevented the increase in aldose reductase expression, but had no effect on Apo B100 and semaphorin cd100. Treatment with hydrogen peroxide and 4-hydroxy-2,3-nonenal increased only aldose reductase mRNA. These data suggest that iron can affect mRNA levels by lipid peroxidation-dependent and -independent pathways.z 2000 Federation of European Biochemical Societies.

In the last decades, the catabolic intermediates arising from the main pathway for tryptophan oxidative degradation, collectively known as kynurenines, have received great attention on account of their roles in the physiological tuning of the central nervous system and in the etiogenesis and progression of several human neurodegenerative diseases (reviewed in [1][2][3][4]). One of the most powerful cytotoxic metabolites of the kynurenine pathway is the 3-hydroxykynurenine (3-HK), which is generated in the third step of the catabolic cascade, through the hydroxylation of the central common precursor l-kynurenine (L-KYN) [5][6][7]. Spontaneous oxidation of the 3-HK induces free radical generation and apoptosis as shown both in vitro and in animal models [8,9]. Mammals can scavenge the potentially toxic 3-HK excess either by converting 3-HK to xanthurenic acid (XA) by direct transamination or by hydrolysing the molecule to produce alanine and 3-hydroxyanthranilic acid (3-HAA); this metabolic intermediate is then fluxed into the central branch of the catabolic cascade, resulting in the de novo synthesis of the essential cofactor NAD [10]. 3-Hydroxykynurenine detoxification is a metabolic priority also for the vast majority of other living species that depend on

6020 Background: Palliative chemotherapy is the standard of care for RMSGCs. However its activity is usually poor especially in adenoid cystic carcinoma (ACC), while in histotypes other than ACC (non ACC) the response, if any, is of short duration. Some preclinical and clinical evidence suggest a rationale for the employment of anti-angiogenetic agents in RMSGCs, such as sorafenib. Methods: Subjects withproven RMSGC not amenable to surgery and/or radiotherapy were enrolled to receive sorafenib at 400 mg BID q28 days until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was response rate (RR) (CR+PR) according to RECIST; secondary objectives included RR according to CHOI criteria, disease control rate (DCR) and toxicity. 37 subjects were required to test the null hypothesis that RR will be ≤ 5% versus the alternative that RR ≥ 20% within a two stage Simon design. At least 4 responders were necessary to reject the null hypothesis. Results: 19 ACC and 18 non ACC subjects were accrued from September 2010 to September 2012. 21 patients had received at least one chemotherapy regimen for RMSGC. Overall 6 PRs according to RECIST were recorded corresponding to a RR of 16% (95% CI 6,2-32,0) (11% in ACC and 22% in non ACC). PR according to CHOI was observed in 10 cases (of which only 2 were concordant with RECIST); no response was reported in 15 cases while CHOI response was not evaluable in 12 patients. A dramatic necrotic evolution of the disease, which resulted in cavitation of metastatic lesions in one case, was observed in two patients with mucoepidermoid cancer (MEC). SD was 57% lasting a median of 7 months (range 2-15+ months). At a median follow up of 10 months (range 3-28+ months): 5 patients are still receiving sorafenib; 15 are no longer being treated and 17 have died. AEs were generally consistent with previous sorafenib studies, except for one G5 toxicity due to meningitis (probably related to necrosis of a local relapse) and one G3 aspergillus abscess. Conclusions: Sorafenib is the first anti-angiogenetic agent to demonstrate some activity in RMSGCs, particularly in MEC. Molecular analyses, typifying MEC and ACC are ongoing. Clinical trial information: NCT01703455.

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