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1.
Eur J Cancer ; 41(18): 2904-10, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16243516

ABSTRACT

Melanoma is a severe skin cancer related to sun exposure. Whether this malignancy is linked to exposure to ionising radiation during adulthood is still controversial. This case-control study examined the risk of melanoma following treatment for an adulthood first malignant neoplasm (FMN). Cases were patients who presented with cutaneous melanoma after a first cancer in adulthood. Controls (3 per case) were patients free of melanoma, matched for age, duration of follow-up since the FMN, type of FMN, and followed in the same institution. A total of 57 cases and 171 controls were included. In the final multivariate analysis, no risk of melanoma was associated with radiotherapy (odds ratio (OR) for 1 Gy = 1.01, 95% confidence interval (95%CI) 0.96-1.07) nor hormonotherapy, whereas chemotherapy use (OR = 2.3, 95%CI 0.93-5.6) and having a history of familial cancer (OR = 2.8, 95%CI 1.3-5.9) exhibited a nearly significant risk. In conclusion, unlike the evidence for risk of exposure to ionising radiation during childhood, we did not substantiate a risk for association of melanoma with exposure to ionising radiation during adulthood. The risk associated with chemotherapy should justify the implementation of skin surveillance for early detection of melanoma in these patients.


Subject(s)
Melanoma/etiology , Neoplasms, Radiation-Induced/etiology , Neoplasms, Second Primary/etiology , Neoplasms/radiotherapy , Skin Neoplasms/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Epidemiologic Methods , Female , Humans , Male , Melanoma/drug therapy , Middle Aged , Radiotherapy/adverse effects , Skin Neoplasms/drug therapy
2.
Eur J Cancer ; 39(16): 2379-86, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14556931

ABSTRACT

The aim of this study was to determine therapy-related risk factors for the development of melanoma after childhood cancer. Among 4401 3-year survivors of a childhood cancer in eight French and British centres and 25120 patients younger than 20 years old at first malignant neoplasm (FMN) extracted from the Nordic Cancer Registries, 16 patients developed a melanoma as a second malignant neoplasm (SMN). A cohort study of the French and British cohorts was performed. In a nested case-control study, the 16 patients who developed a melanoma as a SMN (cases) were matched with 3-5 controls in their respective cohort according to gender, age at the first cancer, the calendar year of occurrence of the first cancer and follow-up. Radiotherapy appeared to increase the risk of melanoma for local doses >15 Gy, Odds Ratio (OR)=13 (95% Confidence Interval (CI): 0.94-174). Regarding chemotherapy, we observed an increased OR for both alkylating agents and spindle inhibitors, OR=2.7 (95% CI: 0.5-14). Children treated for a gonadal tumour as a FMN were found to be at a higher risk of melanoma, OR=8.7 (95% CI: 0.9-86). The adjusted OR for the local radiation dose was 1.07 (95% CI: 1.00-1.15). In conclusion, radiotherapy may contribute to an increased risk of melanoma as a SMN, but only at very high doses of low linear energy transfer radiation. Common genetic origins between gonadal tumours and malignant melanomas are likely.


Subject(s)
Neoplasms, Radiation-Induced/etiology , Neoplasms/radiotherapy , Radiotherapy/adverse effects , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Follow-Up Studies , Humans , Infant , Infant, Newborn , Melanoma/etiology , Middle Aged , Neoplasms, Second Primary/etiology , Radiotherapy Dosage , Risk Factors , Skin Neoplasms/etiology , Survivors
3.
J Am Chem Soc ; 123(1): 8-17, 2001 Jan 10.
Article in English | MEDLINE | ID: mdl-11273595

ABSTRACT

The N-Boc O-tert-butyldimethysilyl-substituted hexa-beta-peptide methyl ester 18 was constructed from the O-TBS ether of (-)-(2R, 3S)-phenylisoserine. By NMR, it was determined that this homo beta-peptide adopts a highly stable beta-strand-type secondary structure in chloroform solution, which is stabilized by both hydrophobic interactions involving the OTBS methyl groups of residues i and i + 2, and inter-(five-membered)/intra (six-membered)-residue H-bonding interactions. These interactions are systematically repeated along the peptide chain and, thereby, operate in concert to stabilize the observed conformation of 18.


Subject(s)
Peptides/chemical synthesis , Protein Structure, Secondary , Serine/chemistry , Circular Dichroism , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Peptides/chemistry , Protein Conformation , Serine/analogs & derivatives , Surface Properties
4.
J Magn Reson ; 143(1): 229-32, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10698665

ABSTRACT

In the study of protein dynamics by (13)C or (15)N relaxation measurements different models from the Lipari-Szabo formalism are used in order to determine the motion parameters. The global rotational correlation time tau(R) of the molecule must be estimated prior to the analysis. In this Communication, the authors propose a new approach in determining an accurate value for tau(R) in order to realize the best fit of R(2) for the whole sequence of the protein, regardless of the different type of motions atoms may experience. The method first determines the highly structured regions of the sequence. For each corresponding site, the Lipari-Szabo parameters are calculated for R(1) and NOE, using an arbitrary value for tau(R). The chi(2) for R(2), summed over the selected sites, shows a clear minimum, as a function of tau(R). This minimum is used to better estimate a proper value for tau(R).


Subject(s)
Magnetic Resonance Spectroscopy/methods , Proteins/chemistry , Carbon Isotopes , Nitrogen Isotopes
5.
Eur J Biochem ; 246(1): 218-27, 1997 May 15.
Article in English | MEDLINE | ID: mdl-9210487

ABSTRACT

Lqh-8/6 is a minor fraction isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus. Here we describe the purification, amino acid sequencing and solution structure determination by NMR and molecular modeling of this peptide. Lqh-8/6 is a small polypeptide (38 residues) which contains 8 half-cystines and is highly similar to another venom component, chlorotoxin. Standard homonuclear methods were used to sequentially assign the proton NMR spectra and to collect spatial restraints for structure determination. Two populations, identified early in the assignment step, are in slow interconversion on the NMR timescale. The two conformers were shown to originate from a cis/trans peptidyl-prolyl isomerization. Using a distance geometry program and simulated annealing protocol under the NMR restraints we obtained 10 final structures for the major conformation (trans isomer). None of the structures showed NOE violations larger than 0.05 nm, and the rmsd value relative to the mean structure (considering the main chain atoms in well-defined secondary structure) is 0.07 nm. The three-dimensional structure contains a short alpha-helix strapped on a small antiparallel beta-strand and an N-terminal extended fragment. The sequence/structure and structure/function relationships of the new scorpion toxin-like peptide are discussed in the context of the present structure determination. This toxin shows a stable, highly populated cis conformer of a peptidyl-prolyl peptide bond.


Subject(s)
Neurotoxins , Protein Conformation , Scorpion Venoms/chemistry , Amino Acid Sequence , Insect Proteins , Isomerism , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Sequence Data , Proline/chemistry , Protein Structure, Secondary , Protein Structure, Tertiary , Scorpion Venoms/isolation & purification , Sequence Homology, Amino Acid , Structure-Activity Relationship
6.
J Biomol NMR ; 5(3): 233-44, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7787421

ABSTRACT

Dynamics of the backbone and some side chains of apo-neocarzinostatin, a 10.7 kDa carrier protein, have been studied from 13C relaxation rates R1, R2 and steady-state 13C-(1H) NOEs, measured at natural abundance. Relaxation data were obtained for 79 nonoverlapping C alpha resonances and for 11 threonine C beta single resonances. Except for three C alpha relaxation rates, all data were analysed from a simple two-parameter spectral density function using the model-free approach of Lipari and Szabo. The corresponding C-H fragments exhibit fast (tau e < 40 ps) restricted libration motions (S2 = 0.73 to 0.95). Global examination of the microdynamical parameters S2 and tau e along the amino acid sequence gives no immediate correlation with structural elements. However, different trends for the three loops involved in the binding site are revealed. The beta-ribbon comprising residues 37 to 47 is spatially restricted, with relatively large tau e values in its hairpin region. The other beta-ribbon (residues 72 to 87) and the large disordered loop ranging between residues 97-107 experience small-amplitude motions on a much faster (picosecond) time scale. The two N-terminal residues, Ala1 and Ala2, and the C-terminal residue Asn113, exhibit an additional slow motion on a subnanosecond time scale (400-500 ps). Similarly, the relaxation data for eight threonine side-chain C beta must be interpreted in terms of a three-parameter spectral density function. They exhibit slower motions, on the nanosecond time scale (500-3000 ps). Three threonine (Thr65, Thr68, Thr81) side chains do not display a slow component, but an exchange contribution to the observed transverse relaxation rate R2 could no be excluded at these sites. The microdynamical parameter (S2, tau e and R2ex) or (S(slow)2, S(fast)2 and tauslow) were obtained from a straightforward solution of the equations describing the relaxation data. They were calculated assuming an overall isotropic rotational correlation time tau c for the protein of 5.7 ns, determined using standard procedures from R2/R1 ratios. However, it is shown that the product (1-S2) x tau e is nearly independent of tau c for residues not exhibiting slow motions on the nanosecond time scale. In addition, this parameter very closely follows the heteronuclear NOEs, which therefore could be good indices for local fast motions on the picosecond time scale.


Subject(s)
Apoproteins/chemistry , Zinostatin/chemistry , Carbon Isotopes , Computer Simulation , Magnetic Resonance Spectroscopy , Protein Conformation
7.
J Biomol NMR ; 4(5): 689-702, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7919954

ABSTRACT

Nearly complete assignment of the protonated carbon resonances of apo-neocarzinostatin, a 113-amino acid antitumor antibiotic carrier protein, has been achieved at natural 13C abundance using heteronuclear 2D experiments. Most of the cross peaks in the proton-carbon correlation map were identified by the combined use of HMQC, HMQC-RELAY and HMQC-NOESY spectra, using already published proton chemical shifts. However, double-DEPT and triple-quantum experiments had to be performed for the edition of CH and CH2 side-chain groups, respectively, which were hardly visible on HMQC-type maps. The triple-quantum pulse sequence was adapted from its original scheme to be applicable to a natural abundance sample. The correlation between carbon chemical shifts and the apo-neocarzinostatin structure is discussed. In particular, 13C alpha secondary shifts correlate well with the backbone conformation. These shifts also yield information about the main-chain flexibility of the protein. Assignments reported herein will be used further for interpretation of carbon relaxation times in a study of the internal dynamics of apo-neocarzinostatin.


Subject(s)
Apoproteins/chemistry , Magnetic Resonance Spectroscopy/methods , Zinostatin/chemistry , Amino Acid Sequence , Carbon Isotopes , Molecular Sequence Data , Protons
8.
Eur J Biochem ; 220(2): 415-25, 1994 Mar 01.
Article in English | MEDLINE | ID: mdl-8125099

ABSTRACT

Circular dichroic and nuclear magnetic resonance spectroscopies were used to evaluate the conformational properties in solution of a series of 20-amino-acid peptides derived from the primary structure of an antigen from Echinococcus granulosus. The linear peptide corresponding to the sequence 93-112 in the antigen was found to populate in a significant proportion the alpha-helix conformational state. In the presence of 2,2,2-trifluoroethanol, a cosolvent known to stabilize peptide secondary structure, the helical population, estimated from circular dichroic spectra, increases up to 60-70%. Two-dimensional nuclear magnetic resonance studies under these conditions showed that the segment K96-K108 meets all the criteria of an alpha-helix at 281 K and 298 K. Three different variants were synthesized with the same or similar primary structure but containing a lactam-bridged (>) side chain: D107 > K110, D97 > K100 and K94 > E98. Generally, the observed helical content in these variants was lower than in the parent molecule and the stability of the helical conformation decreased in the order D107, K110, K94, E98, D97, K100. Analysis of chemical shift and nuclear Overhauser enhancement data suggested that the lactam rings induce significant distortions of the local features of helix secondary structure. The possible factors of helix destabilization induced by lactam bridges, observed in the studied peptides are discussed in relation to the stabilizing effect of ion pairs in model compounds.


Subject(s)
Antigens, Helminth/chemistry , Echinococcus/immunology , Peptides/chemistry , Protein Conformation , Protein Structure, Secondary , Amino Acid Sequence , Animals , Circular Dichroism , Magnetic Resonance Spectroscopy/methods , Models, Molecular , Molecular Sequence Data , Peptides/chemical synthesis , Spectrophotometry, Ultraviolet/methods
9.
Biochimie ; 74(9-10): 853-8, 1992.
Article in English | MEDLINE | ID: mdl-1334698

ABSTRACT

The three-dimensional structure of apo-NCS, as revealed by proton NMR, is based on an antiparallel seven-stranded beta-barrel. This fold is frequently encountered in protein structures, especially for immunoglobulin domains. The strands forming the barrel are joined by flexible loops of which three are implicated in the ligand binding site of these proteins. In this paper a preliminary comparison is given with respect to the static and dynamic properties of both the constant beta-barrel and the active loops for apo-NCS and the variable VH domain of an immunoglobulin Fab' fragment.


Subject(s)
Immunoglobulins/chemistry , Magnetic Resonance Spectroscopy , Protein Structure, Tertiary , Zinostatin/chemistry , Amino Acid Sequence , Binding Sites/physiology , Models, Chemical , Molecular Sequence Data , Protons , X-Ray Diffraction
10.
Eur J Biochem ; 203(3): 505-11, 1992 Feb 01.
Article in English | MEDLINE | ID: mdl-1531194

ABSTRACT

The three-dimensional solution structure of apo-neocarzinostatin has been resolved from nuclear magnetic resonance spectroscopy data. Up to 1034 constraints were used to generate an initial set of 45 structures using a distance geometry algorithm (DSPACE). From this set, ten structures were subjected to refinement by restrained energy minimization and molecular dynamics. The average atomic root mean square deviations between the final ten structures and the mean structure obtained by averaging their coordinates run from 0.085 nm for the best defined beta-sheet regions of the protein to 0.227 nm for the side chains of the most flexible loops. The solution structure of apo-neocarzinostatin is closely similar to that of the related proteins, macromomycin and actinoxanthin. It contains a seven-stranded antiparallel beta-barrel which forms, together with two external loops, a deep cavity that is the chromophore binding site. It is noteworthy that aromatic side chains extend into the binding cleft. They may be responsible for the stabilization of the holo-protein complex and for the chromophore specificity within the antitumoral family.


Subject(s)
Streptomyces/metabolism , Zinostatin/chemistry , Amino Acid Sequence , Computer Simulation , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Protein Conformation , Sequence Homology, Nucleic Acid , Solutions , Zinostatin/metabolism
12.
Eur J Biochem ; 190(2): 263-71, 1990 Jun 20.
Article in English | MEDLINE | ID: mdl-2142075

ABSTRACT

The sequence-specific resonance assignment of apo-neocarzinostatin from Streptomyces carzinostaticus was carried out from two-dimensional proton-NMR spectra. The assignments were obtained for the backbone protons of 111 of the 113 residues of the protein, missing the two C alpha H of one glycine but including 3 of the 4 prolines. The majority of side chain protons were also assigned. The secondary structure derived from the analysis of sequential connections corresponds to ten beta-strands separated by clearly identified loops and turns. Inter-strand connectivities and slowly exchanging amide protons confirm the presence of the two disulfide bridges from Cys37 to Cys47 and from Cys88 to Cys93 and indicate a global folding similar to that of the similar proteins, actinoxanthin and macromomycin, for which crystallographic data are available.


Subject(s)
Antibiotics, Antineoplastic/isolation & purification , Streptomyces/analysis , Zinostatin/isolation & purification , Alanine , Amino Acid Sequence , Amino Acids/analysis , Glycine , Leucine , Magnetic Resonance Spectroscopy/methods , Molecular Sequence Data , Protein Conformation , Solutions , Threonine , Valine
13.
Ann Med Psychol (Paris) ; 145(6): 469-82, 1987 Jun.
Article in French | MEDLINE | ID: mdl-3688702

ABSTRACT

The problem of the hospitalization of patients with severe mental disorders. In relating three clinical cases, the author's purpose is to show that sometimes an hospitalization of long duration is necessary and that the psychiatrist has to be able to assume that decision for the patient's sake. In the first two cases, suicide was the issue, each time after a too-short period of hospitalization, given the antecedents in the first case, and in the second, not allowing that an efficient treatment be set up and accepted. The third case shows how a sufficiently long hospitalization (about 2 months) could enable the setting of a long-duration treatment which led to a sensible improvement of the patient's state.


Subject(s)
Hospitalization , Length of Stay , Mental Disorders/therapy , Suicide Prevention , Adult , Female , Humans , Male , Patient Acceptance of Health Care
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