Comparison of regulations on occupational carcinogens in several industrialized countries

Regulations controlling the manufacture and use of carcinogens in the industrial setting of various countries are examined. In addition, the occupational exposure limits (OEL) of chemicals known or suspected to be carcinogenic in humans are listed, and criteria for the establishment of OELs are discussed. It is also stressed that control measures should not be confined to a few developed countries, and it is hoped that attracting attention to their unevenness will contribute to the implementation of a more efficient primary prevention of cancer.     

Effect of interferon-alpha therapy on epitope-specific cytotoxic T lymphocyte responses in hepatitis C virus-infected individuals.

The majority of hepatitis C virus (HCV)-infected individuals fail to resolve the infection and become chronically infected despite the presence of HCV-specific CTL responses directed to different HCV-derived peptide antigens. Only a minority of individuals is able to clear the virus by mounting efficient CTL responses early after acute infection, but at present it is not clear whether viral clearance is associated with CTL responses of defined specificity. To elucidate those responses associated with improvement of the disease, we analyzed CTL responses to 16 different HLA-A2-presented, HCV-derived epitopes in 12 chronically infected patients, 14 chronically infected patients treated with interferon-alpha, and in one patient with acute symptomatic disease. We show here that the majority of chronically infected individuals present CTL responses directed to an NS4-derived peptide antigen (amino acids 1789-1797). Treated patients presented stronger HCV-specific CTL responses and therapy-induced changes in CTL target choice. In particular, 13 out of 14 individuals responded to an NS3-derived epitope (amino acids 1073-1081). By longitudinal analysis we show that five individuals responding to IFN-alpha therapy with decreases in alanine aminotransferase levels presented a strong CTL activity directed to the NS3-derived epitope. One patient that spontaneously resolved the infection presented a generally strong CTL activity specific for HCV-derived epitopes with a dominant response to the NS3-derived peptide antigen. This suggests that CTL responses directed to this NS3-derived antigen may be beneficial for the control of HCV infection. Improvement of these responses may represent a therapeutic intervention in chronic HCV infection.     

Monte Carlo simulation of light fluence in tissue in a cylindrical diffusing fibre geometry

The propagation of light emitted by a linear light diffuser in a cylindrical hollow organ was investigated by means of the Monte Carlo (MC) method. The height and radius of the cavity, scattering (mu(s)) (or reduced scattering, mu'(s)) and absorption (mu(a)) coefficients, anisotropy (g), and refractive indices of the media involved (n1, n2) are required as input data by the MC code, as are characteristics of the light diffuser (length, delivered power and emission profile). Results of our MC model were tested by measuring the light fluence rate in a tissue-simulating phantom (mu(a) = 0.5 cm(-1), mu(s) = 23 cm(-1) and g = 0.75) irradiated at 633 nm with a cylindrical diffuser. Since geometric and optical parameters determine the behaviour of light propagation in tissue, MC simulations with different sets of input parameters were carried out to provide qualitative as well as quantitative data useful in planning photodynamic therapy. Data are reported on light penetration and fluence rate build-up at mu(a) and mu'(s) values ranging between 0.1 and 5 cm(-1) and 2.5 and 50 cm(-1), respectively. Furthermore, results suggest that a shift and spread could occur in the isofluence curves along the symmetry axis, which depend on the diameter of the treated lumen as well as on the emission profile of the light diffuser. Using our data it is possible to estimate how inaccuracy in knowledge of the optical coefficients can affect (i.e. usually by increasing) the light dose scheduled at a certain depth into tissue.     

Chemotactic response of human monocytes to pentapeptide analog derived from immunodeficiency virus protein gp 120

The octapeptide sequence of peptide T is contained within the envelope of HIV and seems to mediate the viral binding to CD4 expressing cells, including monocytes. The biological activity of the -aminobutyric acid pentapeptide derived from the C-terminal sequence of peptide T, in which the polar side chain of threonine in position 4 is substituted by a hydrophilic group, is measured by the monocyte chemotaxis assay. The ehemotactic activity of human monocytes is assessed by determining the concentration at which the pentapeptide analog is maximally active and the effectiveness at that concentration, in comparison with peptide T and two shorter homologs, the pentapeptide and tetrapeptide. These experiments suggest that the synthetic analog is a potent ehemotactic factor active at picomolar concentrations and that it competes with peptide T for the monocyte binding site.     

Opioid deltorphin C analogues containing cis- or trans-2- or 3- or 4-aminocyclohexanecarboxylic acid residues

The solid phase synthesis, based on the Fmoc chemical protocol, was used to prepare ten deltorphin C (Del-C; H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) analogues containing cis- and trans- 2 or 3- or 4- aminocyclohexanecarboxylic acid (ACCA) residues at position 2. ACCA-peptides showed high resistance to degradation by plasma or brain enzymes, negligible affinity for the kappa-binding site and modest delta- and/or mu-receptor affinities. Both [cis-3-ACCA2]Del-C analogues and one trans isomer are the only deltorphin analogues of this series exhibiting an appreciable delta-affinity and selectivity. These data suggest that the presence of a conformationally constrained ACCA residue in position 2 of the "message" sequence of deltorphin C is slightly tolerated.     

Multispectral imaging and artificial neural network: mimicking the management decision of the clinician facing pigmented skin lesions

Various instruments based on acquisition and elaboration of images of pigmented skin lesions have been developed in an attempt to in vivo establish whether a lesion is a melanoma or not. Although encouraging, the response of these instruments, e.g. epiluminescence microscopy, reflectance spectrophotometry and fluorescence imaging, cannot currently replace the well-established diagnostic procedures. However, in place of the approach to instrumentally assess the diagnosis of the lesion, recent studies suggest that instruments should rather reproduce the assessment by an expert clinician of whether a lesion has to be excised or not. The aim of this study was to evaluate the performance of a spectrophotometric system to mimic such a decision. The study involved 1794 consecutively recruited patients with 1966 doubtful cutaneous pigmented lesions excised for histopathological diagnosis and 348 patients with 1940 non-excised lesions because clinically reassuring. Images of all these lesions were acquired in vivo with a multispectral imaging system. The data set was randomly divided into a train (802 reassuring and 1003 excision-needing lesions, including 139 melanomas), a verify (464 reassuring and 439 excision-needing lesions, including 72 melanomas) and a test set (674 reassuring and 524 excision-needing lesions, including 76 melanomas). An artificial neural network (ANN(1)) was set up to perform the classification of the lesions as excision-needing or reassuring, according to the expert clinicians' decision on how to manage each examined lesion. In the independent test set, the system was able to emulate the clinicians with a sensitivity of 88% and a specificity of 80%. Of the 462 correctly classified as excision-needing lesions, 72 (95%) were melanomas. No major variations in receiver operating characteristic curves were found between the test and the train/verify sets. On the same data set, a further artificial neural network (ANN(2)) was then architected to perform classification of the lesions as melanoma or non-melanoma, according to the histological diagnosis. Having set the sensitivity in recognizing melanoma to 95%, ANN(1) resulted to be significantly better in the classification of reassuring lesions than ANN(2). This study suggests that multispectral image analysis and artificial neural networks could be used to support primary care physicians or general practitioners in identifying pigmented skin lesions that require further investigations.     

Mimicking natural evolution in metallo-beta-lactamases through second-shell ligand mutations

Metallo-beta-lactamases (MBLs) represent the latest generation of beta-lactamases. The structural diversity and broad substrate profile of MBLs allow them to confer resistance to most beta-lactam antibiotics. To explore the evolutionary potential of these enzymes, we have subjected the Bacillus cereus MBL (BcII) to a directed evolution scheme, which resulted in an increased hydrolytic efficiency toward cephalexin. A systematic study of the hydrolytic profile, substrate binding, and active-site features of the evolved lactamase reveal that directed evolution has shaped the active site by means of remote mutations to better hydrolyze cephalosporins with small, uncharged C-3 substituents. One of these mutations is found in related enzymes from pathogenic bacteria and is responsible for the increase in that enzyme's hydrolytic profile. The mutations lowered the activation energy of the rate-limiting step rather than improved the affinity of the enzyme toward these substrates. The following conclusions can be made: (i) MBLs are able to expand their substrate spectrum without sacrificing their inherent hydrolytic capabilities; (ii) directed evolution is able to mimic mutations that occur in nature; (iii) the metal-ligand strength is tuned by second-shell mutations, thereby influencing the catalytic efficiency; and (iv) changes in the position of the second Zn(II) ion in MBLs affect the substrate positioning in the active site. Overall, these results show that the evolution of enzymatic catalysis can take place by remote mutations controlling reactivity.     

The IARC monographs program: changing attitudes towards public health

From its outset, the International Agency for Research on Cancer's (IARC's) program for the evaluation of carcinogenic risks for humans had to resist strong direct and indirect pressures from various sources to protect its independence. External experts for Monographs working groups were selected on the basis of competence and the absence of conflicts of interest. The IARC did not use unpublished or confidential data, so readers could access the original information and thus follow the groups' reasoning. The strength of the original program lay in its scientific integrity and its transparency. Since 1994, however, the IARC appears to have attributed less importance to public health-oriented research and primary prevention, and the Monographs program seems to have lost some of its independence. Criteria for evaluating carcinogenicity related to mechanism(s) of action are not necessarily used as originally intended, to ensure better protection of public health. Evidence for carcinogenicity provided by the results of experimental bioassays has been disregarded on the basis of only suggested mechanistic hypotheses. If tests show those hypotheses to be incorrect, or if they do not account adequately for the wide range of susceptibility in humans, serious consequences for public health may follow.