Biomedical subjects
Publications and source records attributed to J Lebeau.
Three newly synthesised lipid peroxidation inhibitors (7, 11, 14) were evaluated for their effects on myocardial functional recovery during reperfusion after 30 min global ischemia in isolated rat hearts. The flavonoid compounds (7, 11, 14, rutin) reduce ischemia/reperfusion-induced cardiac dysfunction.
Epidemiological evidence suggests an inverse relationship between dietary intake of flavonoids and cardiovascular risk. The biological activities of flavonoids are related to their antioxidative effects, but they also can be mutagenic, due to the prooxidant activity of the catechol pattern. To prevent these problems, we synthesized new flavonoids where one or two di-tert-butylhydroxyphenyl (DBHP) groups replaced catechol moiety at position 2 of the benzopyrane heterocycle. Two DBHP moieties can also be arranged in an arylidene structure or one DBHP fixed on a chalcone structure. Position 7 on the flavone and arylidene or position 4 on the chalcone was substituted by H, OCH(3), or OH. New structures were compared with quercetin and BHT in an LDL oxidation system induced by Cu(II) ions. Arylidenes and chalcones had the best activities (ED(50) = 0.86 and 0.21) compared with vitamin E, BHT, and quercetin (ED(50) = 10.0, 7. 4, and 2.3 microM). Activity towards stable free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) was measured by log Z and ECR(50) parameters. Synthesized flavones proved to be poor DPPH radical scavengers, the activity increasing with the number of DBHP units. In contrast, arylidenes and chalcones were stronger DPPH radical scavengers (log Z > 3, 0.3 < ECR(50) < 2.12) than BHT (log Z = 0.75, ECR(50) = 12.56) or quercetin (log Z = 2.76, ECR(50) = 0.43). Unlike quercetin, synthesized compounds neither chelated nor reduced copper, proving that these new flavonoids had no prooxidant activity in vitro.
Since defects in molecular mechanisms controlling DNA repair, cell cycle checkpoint and apoptosis could modify cellular sensitivity to DNA damaging agents, we have conducted a multiparametric molecular analysis for better understanding the regulation pathways leading to cell survival or cell death after irradiation. Using a human lymphoblastoid cell line, we have analysed, following gamma irradiation (0.5, 1, 2, 4, 8, 16 and 32 Gy, at 0.5, 24, 48 and 72 h after treatment), the correlation between proliferation, cell cycle analysis, apoptosis and micronuclei frequency with the expression of TP53, WAF1, DNA LIGASE 1, PCNA, BAX, BLC-2, BAK, DAD1, ICH1-Long and -Short forms mRNAs. We have found that whereas TP53, BAK, ICH1-Short form, and DAD1 were expressed at constant levels, WAF1, PCNA, BAX were up-regulated, ICH1-Long form, DNA LIGASE 1, and BCL-2 were down-regulated. These modifications of expression were significantly correlated with doses, survival, proliferation, cell cycle delays, and apoptosis. A positive correlation of WAF1 and BAX, and a borderline negative correlation with BCL-2 expressions were observed with micronuclei frequency for doses ranging from 0.5 to 4 Gy. In conclusion, our data clearly demonstrate that gene expression profiling, which is easier and more rapid to conduct than the assessments of classical phenotypic responses, could be useful to improve knowledge concerning pathways involved in cellular response to irradiation, knowing that such biomarkers could constitute tools to assess radio-sensitivity/radio-resistance. Oncogene (2000) 19, 916 - 923.
Functional tests are needed to assess the quality of reconstructive surgery after treatment of intraoral cancers. Quality of Life tests are subjective and Cinefluoroscopy is a demanding and non-comparative procedure. We develop here a method to test the capacity of patients to maximize use of their articulatory space. We recorded a corpus of sounds. These sounds were analyzed with classical signal processing procedures. By comparison with a non-distorded sound database, it was possible to evaluate speech disorders, localize the defect, and provide a guide for rehabilitation. This method is an objective, reproductible, and comparative measurement tool.
Why initially normal wound healing sometimes shifts toward an impaired cicatrization is poorly understood. Collagen gels with incorporated fibroblasts constitute valuable in vitro models to study mechanisms of connective tissue reorganization. Such 1-week-old, partially contracted normal dermal equivalents were treated with concentrations of TGF-beta1 ranging from 1 to 10 ng/ml. The cytokine was applied in a single dose or four times at regular intervals, over a 2-week period. Dose-dependent activation of fibroblasts was observed after treatment. The cytokine induced a myofibroblastic transformation of dermal cells, significantly enhanced the process of dermal contraction, and stimulated synthesis of such proteins as cellular fibronectin, tenascin and smooth-muscle actin. Our approach is more informative than models using pathological or pretreated dermal cells, since it demonstrates newly induced modulation of fibrotic transformation in an initially normal dermal equivalent. This in vitro assay will enable us to study mechanisms involved in the shift between normal and impaired fibrotic transformation during wound healing.
Pregnant females appear to have an increased chromosomal sensitivity to gamma-irradiation. This hypersensitivity was found to parallel the increase of gestation hormone amounts [M. Ricoul, L. Sabatier, B. Dutrillaux, Increased chromosome radiosensitivity during pregnancy, Mutat. Res. 374(1997) 73-78]. An in vitro experiment was developed to study the effect of progesterone. We performed irradiations of whole blood from normal human donors and chromosome were analysed in first generation metaphases. By comparison to untreated controls, all cultures in which progesterone was added around the 24th h of culture exhibited an increased frequency of chromosome rearrangements, principally dicentrics and rings, which confirms the role of progesterone in the results of in vivo studies. BrdU incorporation studies suggested that progesterone was particularly efficient just before the entry into S-phase, which corresponds to the G1/S transition period. Cultures with an increased frequency of chromosome breakage had a slightly higher mitotic index than controls. It is suggested that progesterone may stimulate DNA repair in cells which reached the end of G1-phase with unrepaired breaks. This would allow the cells to enter the S-phase and survive, although some illegitimate repair leads to chromosome rearrangements, visible at the following metaphase.
The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT-PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no significant difference was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identified a single base substitution in each of the three cases: two transversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type profile. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney.
OBJECTIVE: The authors report the case of an 83-year-old patient with a benign oncocytoma of the inferior eyelid. DESIGN: INTERVENTIONal case report. INTERVENTION: Treatment consisted of a large orbital exenteration followed by reconstruction with a pedicled temporalis muscle flap. MAIN OUTCOME MEASURES: Histologic evaluation and clinical follow-up were measured. RESULTS: After a year of follow-up, there was no sign of local recurrence. CONCLUSIONS: Oncocytomas, even if benign, must be considered as very aggressive tumors and treated accordingly.
A local wound infection developed in a 42-year-old female patient after replacement of ascending aorta, aortic arch and supra-aortic vessels, following aortic dissection. Because of the high risk of infection due to the vascular prosthesis and its location at the upper part of the sternum, a right pectoral muscular flap, detached from the humerus and vascularized by medial perforators originating from the internal mammary artery, was isolated. The postoperative course was uneventful and the patient remains well 16 months after the operation.
For pituitary adenomas surgery, rhinoseptal transsphenoidal approach is used in 98 to 99% of the cases. Although this approach is fitting for microadenomas and the majority of macroadenomas, some of them develop extensions in the nasal fossas, the posterior cranial fossa, the suprasellar region, or into the cavernous sinus and will require other approaches. For the superior routes, the frontopterional approach gives good control of the suprasellar region, the anterior and middle base of the skull. The tumor dissection is performed inside the concavity of the chiasm and between the internal carotid artery and the optic nerve (optico-carotid approach). The frontopterional approach is used for superolateral extensions, especially in the lateral fissure. The bifrontal basal inter hemispheric approach, through a medial frontal bone flap tangential to the base, gives a good route to the suprasellar region and behind the dorsum, and also for tumors extended in the third ventricle in case of prefixed chiasm. For the inferior routes, the participation of ENT or craniofacial surgeons is a great help. The transfacial or transethmoidal approach performs a hollowing of the nasal fossas and gives a large interorbital tunnel adapted for tumors extended in the rhinopharynx and the ethmoid. The Le Fort I maxillary osteotomy offers also a large approach for adenomas extending in the rhinopharynx. The transcavernous approach from Dolenc, for adenomas progressing in the cavernous sinus requires a long and difficult procedure. The progression of some adenomas in many directions may require a combined approach in one or two procedures.
Telomeres are complex protein-DNA structures located at the ends of eukaryotic chromosomes. In a normal cell, telomere DNA shortens with cell divisions. Such a telomere loss may act as a mitotic clock to eventually signal cell cycling exit and cellular senescence. In a transversal study, we found a marked decrease in telomere length of peripheral blood mononuclear cells in HIV-infected patients with advanced immunodeficiency. This telomere reduction concerns T4, T8, and B lymphocytes, providing evidence of high turnover of these cells in the course of HIV infection. These data suggest that replicative senescence could be involved in the final immunosuppression and may have important therapeutical implications.
The prognosis of locally advanced cancers of the head and the neck is pejorative, particularly when nodal involvement is present. In order to improve local control and to reduce distant failures, we have treated stages III and IV patients with induction chemotherapy. From May 1986 to November 1992, 125 patients with squamous cell carcinoma of the head and neck were treated by induction chemotherapy: cisplatine (100 mg/m2 at J1) and 5FU (1 g/m2 from J1 to J5 in continuous infusion) every 21 days subsequent local therapy consisted of surgery for patients with resectable disease, and/or radiotherapy. One hundred and nineteen patients were assessable (110 men and 9 women) with a median age of 57 years (range: 36-78). All patients had performance status inferior or equal to 2. According to the TNM of UICC classification 50 patients were stage IV (42%), 61 stage III (51%), 7 stage II (6%) and a stage I (1%). One hundred (84%) patients have received at least 3 cycles of chemotherapy. Seventy-four patients (62%, IC: 60.4-63.5) had clinical objective response (complete response (CR) or partial response (PR)) with 24 patients (20%) CR and 50 patients (42%) PR. Local therapy included surgery in 81 patients (68%) and radiotherapy alone in 42 patients (35%). Overall, 103 patients (87%) were rendered clinically disease-free by treatment on this protocol. The toxicities of cisplatine and 5-FU chemotherapy consisted predominantly of myelosuppression (5%) and renal toxicities (4%) and were moderate as described for this combination. At a median follow-up of 32 months, the median survival is 38 months (CI 95%, 18-54 months), and the median time to progression is 62 months. The oropharynx localization reached statistical significance for survival rates (Log-rank test, p = 0.02).
The maxilla and mandible give the face its proportions and equilibrium, while remaining indissociable from the skull. The harmony of these structures is established according to two planes of reference: the base of the skull in a relationship of cranio-facial interdependence, the dental arch making the occlusal relationship a decisive factor in the concept of facial equilibrium. This occlusal obligation, criterion of normality and stability, confers all of the originality of orthognatic surgery, which must also take into account the periods of cranio-facial growth and oro-facial functions. The authors describe the modern concept of this surgery, the essential place of orthodontic preparation, and technical innovations such as computer-assisted simulation.
We investigated the interrelationship between p53 gene alterations, MDR1 gene expression, and S-phase fraction (SPF) in breast carcinomas treated primarily with chemotherapy or radiotherapy and correlated the results with patient outcome to determine the potential clinical significance of these factors. In a consecutive series of 64 fine-needle samplings of breast cancer patients who underwent either neoadjuvant chemotherapy (n = 53) or radiotherapy (n = 11), p53 (exons 5-9) gene alterations by denaturating gradient gel electrophoresis and subsequent direct sequencing, MDR1 gene expression by semiquantitative reverse transcription-PCR, and SPF by DNA flow cytometry were determined. Our results show that p53 mutations (n = 20) were significantly associated (P = 0.01) with high SPF but not with de novo MDR1 gene expression. Most patients with wild-type p53 tumors were found to be resistant to neoadjuvant chemotherapy. No correlation was observed between p53 mutations and the induction of MDR1 gene expression during treatment. Although a significant correlation between shorter distant disease-free survival and high (>/=5%) SPF (P = 0.016) was found, no correlation between distant disease-free survival and p53 status or intrinsic MDR1 gene expression was found. Poor overall survival was observed in patients with tumors with high SPF (P < 0.0004) or lacking MDR1 gene expression (P = 0.03) before treatment, but not with p53 alterations. These data suggest that SPF remains the most relevant biological factor for breast cancer patients treated by primary chemotherapy or radiotherapy and that p53 and MDR1 status may identify a small subset of patients that may resist therapy or pursue an aggressive course.
Craniofacial growth has been the subject of numerous studies in which different techniques have been elaborated aiming to model this dynamic phenomenon in a rational manner. One of the methods employed is cephalometric analysis applied to the fetus. Generally, however, these studies are confined to the exploration of a single spatial plane (sagittal plane), whose orientation is never defined in a rigorous and perfectly reproducible manner. Thus, none of these analyses offers a formal growth model. This has led us to propose a new method of fetal cephalometric study taking into account criteria for proper reproducible analysis: spatial exploration of the head performed through three-dimensional tomodensitometric images and precise location of landmarks and reproducibility of the orientation of each image, which is assured by reference to the vestibular orientation (based on the external semicircular canals), as has been described by Girard and Perez and further developed by Fenart. When the labyrinth is developed, this orientation does not change during the growth stages of the head, even with craniofacial deformities. This permits application of this orientation on fetuses and the superposition of images of different subjects. The methodology is presented using two normal human fetuses, and the advantages of this computerized tool are discussed.
After immortalization of human normal mammary epithelial cells by replication-defective SV40 genome integration, 2 cultures were developed independently. Both had the same integration site, in band 9q21, but rapidly diverged karyotypically. After a few passages, one, designated SC2T2, exhibited near-diploid (a) and the other, designated SL2T2, near-tetraploid (b) karyotypes. The simplest formulas were 44, X, -X, der(3;22) (q10;q10), der(4) t(4;9)(q34;q12), +8, +9, add(13)(p1), der(19) t(8;19)(q21;p13.3), add(22)(p1) for karyotype (a) and 93, XXXX, add(1)(q12), add(11)(q13), +20 for karyotype (b). A number of alterations were further acquired with passages. Both cell cultures were tumorigenic, but their efficiency of grafting in nude mice largely differed: it was low for SL2T2 and high for SC2T2 cultures. All cultures of the xenografted tumors, obtained from either SL2T2 or SC2T2, exhibited the same clonal anomalies as those characterizing karyotype (a). It was concluded that only cells with karyotype (a) were tumorigenic, and that the difference in the tumorigenic potential of cultures SC2T2 and SL2T2 was related to their richness in cells with this karyotype. The comparison of the various karyotypes, together with data obtained in other cell types transformed by SV40, suggests that the acquisition of tumorigenicity in S2T2 mammary epithelial cells may be related to the loss of chromosome 3p arm.
The outcome of stent implantation for children with pulmonary venous obstruction has been characterized by late reocclusion associated with a marked vessel neointimal proliferation. The purpose of this study was to compare the responses of the systemic vein and pulmonary vein to the presence of an intravascular stent, using a Yorkshire swine (N = 10) model. Under cardiopulmonary bypass, a single Palmaz stent was placed in the inferior vena cava (IVC) and right lower pulmonary vein (PV) with sacrifice at 4.9-6.1 months. Angiography and hemodynamic data were determined at 1 and 3 months post-stent implant and prior to euthanasia. All stents were found to be patent, with no difference in degree of thrombosis or neointimal formation. No statistical difference was found in the initial and final stent diameter for both inferior vena cava and pulmonary vein stents (PV initial 6.8 +/- 0.9; final 7.1 +/- 0.6) (IVC initial 10.4 +/- 1.2; final 10.4 +/- 1.2). Electron microscopy demonstrated smooth endothelialization of both pulmonary and systemic venous stent devices. No thrombosis was found on gross morphology. The data indicate that there is no intrinsic difference in the response of the pulmonary vein to the presence of a stent device. The clinical experience of restenosis following stent implantation for pulmonary vein stenosis appears to be more related to variables of final stent diameter combined with the marked intrinsic abnormal vessel architecture, as seen with this condition.
In spite of a well-known relationship between exposure to radiation and increased risk for cancer development, the biological mechanisms involved in radiation-induced carcinogenesis remain poorly documented. Various hypotheses are discussed in this paper. It appears that radiation cannot be directly responsible for the numerous genetic alterations of cancer cells. Most of them occur during tumor progression. Only one or a very limited number of them was induced by radiation many years before tumor growth. This long delay is a major difficulty for experimental research and raises many questions. Recently, it has been shown that a genomic instability occurs after many generations in cells descending from irradiated cells. This instability leads to multiple genetic alterations and, preferentially, affects some chromosome structures, particularly telomeres. This kind of telomeric instability - related to the shortening of telomeric DNA sequences - has also been observed in senescent cells as well as in non-senescent cells from patients predisposed to cancer, and this process may possibly also occur in the progeny of irradiated cells.