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Introduction:Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently being evaluated as potential anticancer medicines at both preclinical and clinical levels. They have the peculiarity to increase the efficacy of DNA-damaging agents and to selectively target tumor cells with specific DNA repair defects. This later development of these drugs should make it possible, in principle, to selectively target neoplastic vs healthy cells, thus realizing the Ehrlich's magic bullet concept of a personalized and tailored cure of diseases.Areas covered:This review is designed to provide the readers with a brief summary and an update on PARP inhibitors in the oncology field, by covering the recent patent literature (2010 – 2012: and Questel Intellectual Property Portal [QPat] database search).Expert opinion:Presently, along with a number of preclinical candidates, there are eight PARP inhibitors in the clinic as either single agents or in combination with various chemotherapy and radiotherapy regimens. The tremendous efforts underneath those results testify the high interest on the target. The investigation and understanding of the cross-reactivity among members of the PARPs family as well as a deeper knowledge of their biological functions may lead to a more profound characterization of the PARP inhibitor's profile. This, in turn, will cast additional light on this exciting approach in treating cancer.

Background. Fumes and vapours released during laying of hot asphalt mix have been recognised as a major source of exposure for asphalt workers. Objectives. We investigated the relationships between inhalation exposure to asphalt emissions and urinary biomarkers of polycyclic aromatic hydrocarbons (PAHs) in asphalt workers (AW, n=75) and in ground construction workers (CW, n=37). Methods. Total polyaromatic compounds (PAC) and 15 priority PAHs in inhaled air were measured by personal sampling. Hydroxylated PAH metabolites (OH-PAHs) (2-naphthol, 2-hydroxyfluorene, 3-hydroxyphenanthrene, 1-hydroxypyrene, 6-hydroxychrysene and 3-hydroxybenzo[a]pyrene) were determined in urine spot samples collected in three different times during the work week. Results. Median vapour-phase PAC (5.5 µg m-3), PAHs (≤50 ng m-3) and OH-PAHs (0.08-1.11 µg l-1) were significantly higher in AW than in CW, except in the cases of air naphthalene and 2-naphthol. Airborne levels of particle-phase contaminants were similar in the two groups and much lower than vapour-phase levels; metabolites of particulate PAHs were never found in quantifiable amounts. An appreciable increase in OH-PAH levels during the work day and work week was found in AW; median levels for 2-hydroxyfluorene, 3-hydroxyphenanthrene and 1-hydroxypyrene were, respectively, 0.29, 0.08 and 0.18 at baseline; 0.50, 0.18 and 0.29, pre-shift; 1.11, 0.44 and 0.44 µg l-1, post-shift. Each OH-PAH exhibited a characteristic profile of increase, reflecting differences in half-lives of the parent compounds. In non-smoking subjects, positive correlations were found between vapour-phase PAC or PAHs and OH-PAHs both in pre- and post-shift samples (0.34 ≤ r≤69). Smokers exhibited 2-5-fold higher OH-PAHs than non-smokers, at any time and at both workplaces. Conclusions. Our results suggest that OH-PAHs are useful biomarkers for monitoring exposure to asphalt emissions. The work-related exposure to PAC and PAHs was low in all AW, but urinary metabolites reflected exposure satisfactorily.

Covering: 1989 to September 2003

Covering: 1989 to September 2003 The combretastatins are a group of anti-mitotic agents isolated from the bark of the South African tree Combretum caffrum. The most potent member is combretastatin A-4, and this compound together with a phosphate pro-drug form have already progressed through into clinical trails for the treatment of solid tumours. What makes this class of compounds rather more interesting than other anti-mitotic agents is that they are also angiogenesis inhibitors, and are being evaluated for their efficacy in the treatment of diabetic retinopathy which is the biggest single cause of blindness. They are thus of considerable contemporary interest.

17 workers in a thermometer factory exposed to mercury for periods ranging from 1 to 40 years all had high urine and blood mercury levels on undergoing electromyographic examination. All were clinically free from central and peripheral nervous symptoms. 88% had subclinical neuropathy, mainly distal and axonal. There was no correlation between severity of the neuropathy and blood and urine mercury levels or between severity of neuropathy and duration of exposure to mercury. The presence of a subclinical neuropathy in symptomless workers exposed to mercury is perhaps the most reliable index for the detection of the early toxic effects of mercury on the peripheral nerve fiber when it is probably still reversible.

A group of 182 workers exposed to diisocyanates (varnishers, carpenters, producers of polyurethane resins and expanded plastic) were examined to study the immunogenic capacity of these substances. The skin tests, particularly the intradermal tests, revealed reactions of the immediate, accelerated and/or delayed types due to the presence of IgE and IgG, in addition to responses of the cellular type. This was confirmed by passive transfer in guinea-pigs and man and immunohaematological tests such as passive haemagglutination and lymphocyte transformation. In 4 cases it was possible to demonstrate thermoresistant, homocytotropic immunoglobulins, that were not dependent on complement and behaved like reagins (i.e. short-term anaphylactic IgG). Exposure tests were performed on 45 cases; the results are analyzed and compared with those of the skin tests. It is concluded that both these groups of tests are of value in investigating the aetiopathogenesis of the pathology of the isocyanates: the skin tests for initial screening, and then the exposure tests for resolving doubtful diagnoses. Cross-reactions were also demonstrated between toluenediisocyanate and methylene-diisocyanate. Two phases could be considered in the pathogenesis; in the first phase, signs of inflammation appeared at the primary sites of contact with the irritant, then the ability of the diisocyanates to form a conjugate with organic proteins results in the production of a complete antigen and consequent sensitization of the exposed person. The appearance of symptoms naturally depends on subsequent exposure and the immunogenic capacity of the patient: the response is mainly of the reagin type in atopic patients and of type 3 in non-atopic patients.

Abstract: Objective: The aim of this study was to evaluate the outcome of the specific inhalation challenge test (SIC) in 160 subjects with suspected baker's asthma and to assess its relation to total flour dust levels and to personal characteristics such as specific skin sensitisation, non-specific bronchial hyper-responsiveness (NSBH) and atopy. Methods: We investigated the outcome of SIC tests performed with wheat flour in six Italian laboratories. For each subject, data was available regarding skin sensitisation to wheat flour, NSBH, atopy, forced expiratory volume at 1 s (FEV1) monitoring and airborne flour dust in the challenge chamber measured by the gravimetric method (total dust in mg/m3). Results: The SIC test was positive for early asthma in 42 subjects (26%) and for late/dual asthma in 18 (11%). Positive outcome to SIC was significantly associated with NBSH (odds ratio, OR: 3.5, 95% CI: 1.6–7.7) and skin sensitisation to wheat flour (OR: 3.1, 95% CI: 1.3–7.0). Exposure level to wheat flour was less than or equal to 10 mg/m3 in 12% of individuals, ranged between 11 and 30 mg/m3 in 43% and exceeded 30 mg/m3 in 45%. The outcome of SIC was always negative among workers not skin sensitised to wheat flour and without NSBH and atopy. An increasing prevalence of positive SIC was observed among workers with one or more of the above-mentioned personal characteristics whose challenge exposure was greater than 10 mg/m3 (P < 0.001). Conclusion: Procedures currently adopted for wheat flour dust exposure during SIC need to be better standardised in order to avoid excessive airborne dust exposure. Over-exposure seems to be of no use for the diagnosis and risks making the asthmatic reaction worse, particularly in patients who are both sensitised to wheat allergens and have NSBH and/or atopy.

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