RESUMO
Skin sensitisation potential is an endpoint that needs to be assessed within the framework of existing and forthcoming legislation. At present, skin sensitisation hazard is normally identified using in vivo test methods, the favoured approach being the local lymph node assay (LLNA). This method can also provide a measure of relative skin sensitising potency which is essential for assessing and managing human health risks. One potential alternative approach to skin sensitisation hazard identification is the use of (Quantitative) structure activity relationships ((Q)SARs) coupled with appropriate documentation and performance characteristics. This represents a major challenge. Current thinking is that (Q)SARs might best be employed as part of a battery of approaches that collectively provide information on skin sensitisation hazard. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here we focus on three models (TOPKAT, Derek for Windows and TOPS-MODE), and evaluate their performance against a recently published dataset of 211 chemicals. The current strengths and limitations of one of these models is highlighted, together with modifications that could be made to improve its performance. Of the models/expert systems evaluated, none performed sufficiently well to act as a standalone tool for hazard identification.
Assuntos
Ensaio Local de Linfonodo , Relação Quantitativa Estrutura-Atividade , Alcanos/química , Alcanos/toxicidade , Simulação por Computador , Humanos , Cetonas/química , Cetonas/toxicidade , Modelos Biológicos , Modelos Químicos , Medição de Risco/métodos , Sensibilidade e Especificidade , Testes Cutâneos , SoftwareRESUMO
Using NMR spectroscopy, we determined the solution structure of a single-chain T-cell receptor (scTCR) derived from the major histocompatibility complex (MHC) class II-restricted D10 TCR. The conformations of complementarity-determining regions (CDRs) 3beta and 1alpha and surface properties of 2alpha are different from those of related class I-restricted TCRs. We infer a conserved orientation for TCR V(alpha) domains in complexes with both class I and II MHC-peptide ligands, which implies that small structural variations in V(alpha) confer MHC class preference. High mobility of CDR3 residues relative to other CDR or framework residues (picosecond time scale) provides insight into immune recognition and selection mechanisms.
Assuntos
Antígenos de Histocompatibilidade Classe II/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Cinética , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , Solubilidade , TermodinâmicaRESUMO
The crystal structure of the two immunoglobulin variable-like domains of the murine CD8alphaalpha homodimer complexed to the class I MHC H-2Kb molecule at 2.8 A resolution shows that CD8alphaalpha binds to the protruding MHC alpha3 domain loop in an antibody-like manner. Comparison of mouse CD8alphaalpha/H-2Kb and human CD8alphaalpha/HLA-A2 complexes reveals shared as well as species-specific recognition features. In both species, coreceptor function apparently involves the participation of CD8 dimer in a bidentate attachment to an MHC class I molecule in conjunction with a T cell receptor without discernable conformational alteration of the peptide or MHC antigen-presenting platform.
Assuntos
Antígenos CD8/química , Antígenos H-2/química , Sequência de Aminoácidos , Animais , Antígenos CD8/genética , Cristalografia por Raios X , Dimerização , Antígenos H-2/genética , Antígeno HLA-A2/química , Antígeno HLA-A2/genética , Humanos , Substâncias Macromoleculares , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genéticaRESUMO
This study was developed to test whether prospective dietician counseling could abrogate the unwanted weight gain seen among women receiving adjuvant chemotherapy for resected breast cancer. It was also designed to examine predictive factors for weight gain in an exploratory manner. Premenopausal women starting adjuvant chemotherapy for primary breast cancer were recruited for this trial. After appropriate stratification, they were randomized to a group which received monthly dietician counseling primarily aimed at weight maintenance versus a control group (whose attending physicians and nurses told them about possible weight gain but provided no formalized dietician counseling). One hundred and seven evaluable women were equally divided between the two protocol arms. The median weight changes 6 months after start of chemotherapy were gains of 2.0 kg in the dietician counseling group versus 3.5 kg in the control group. The median changes in average calorie consumption were reductions of 120 versus 46 cal/day on weekdays and 196 versus 20 cal/day on weekends for the counseling and control groups, respectively. Study data suggest that more weight was gained by patients with higher Quetelet's indices (p = 0.01) and patients who had been on a diet in the preceding 6 months (p = 0.02). Routine prospective dietician counseling aimed at weight maintenance appeared to produce small but statistically insignificant reductions in both calorie consumption and weight gain in this group of patients.