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Philippe Bertrand

Publications and source records attributed to Philippe Bertrand.

16 recordsLinked to original sources
PubMed2006

Synthesis of rigid trichostatin A analogs as HDAC inhibitors.

New inhibitors of histone deacetylase (HDAC) have been synthesized and evaluated for their activity toward non small lung cancer cell line H661. Their design is based on indanone (or tetralone) systems leading to trichostatin A (TSA) analogs with limited conformational mobility. Molecular modelization at the AM1 level revealed that the conformations of indane-based analogs and TSA bound to HDAC like protein are similar. The synthesis of these new analogs was achieved by alkylation of an appropriate indanone (or tetralone) to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. Hydroxamic acids with the TSA side chain were found to be the most active compounds and the presence of the dimethylamino group on the phenyl ring turned out to be essential to achieve low micromolar activities against H661 cancer cells.

Antineoplastic Agents↗
PubMed2006

The logistic organ dysfunction score as a tool for making ethical decisions.

PURPOSE: We examined whether the change of the logistic organ dysfunction score (LOD) between the first and the fourth day in the intensive care unit (ICU) could be predictive of death in the ICU. The LOD could then be used to help make decisions concerning therapeutic limitations (TL). METHODS: One hundred fifty-four patients were included. Exclusion criteria were: discharge from the ICU or TL before the 72nd hr. Ninety-three patients remained for evaluation. The LOD was calculated on the day of admission (LOD1) and between the 72nd and 96th hr (LOD4). The DeltaLOD = LOD4-LOD1 index was calculated for survivors and non-survivors; sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Sixteen patients died in the ICU, they had a higher DeltaLOD (0 vs -2; P = 0.0046) than the survivors. After logistic regression, a high DeltaLOD was associated with a higher risk of death in the ICU independent of the initial severity of disease. The PPV concerning death in the ICU was 0.66 for a DeltaLOD > or = 4 cut-off. The NPV was 0.89 for a cut-off of > or = 1. CONCLUSION: DeltaLOD appears to be a predictor of death in the ICU, independent of the initial severity of disease. The PPV is not high enough to assist with making individual TL decisions. The NPV can help to identify patients at low risk of death. The DeltaLOD deserves to be evaluated in a population exhibiting greater severity of disease.

APACHE↗
PubMed2006

Polyethylene glycol and prevalence of colorectal adenomas.

BACKGROUND AND AIM: Dietary polyethylene glycol (PEG) is extraordinarily potent in the chemoprevention of experimental colon carcinogenesis. PEG is used to treat constipation in France and in the USA. French laxatives include Forlax (PEG4000), Movicol and Transipeg (PEG3350), and Idrocol (pluronic F68). This study tests the hypothesis that use of a PEG-based laxative might reduce the prevalence of colorectal tumors. METHODS: In this population-based study, consecutive patients attending for routine total colonoscopy were enrolled during four months by the gastroenterologists of Indre-et-Loire. They were asked if they had previously taken a laxative or a NSAID. Age, gender, previous polyps, family history of colorectal cancer, constipation, digestive symptoms were also recorded. Tumors found during colonoscopy were categorized histologically. RESULTS: Records from 1165 patients fulfilled the inclusion criteria, 607 women and 498 men, mean age 58.3. Among those, 813 had no tumor, 329 had adenomas, and 23 had carcinomas. In a univariate analysis, older age, male gender, lack of digestive symptom, and previous polyps were more common in patients with colorectal tumors. In contrast, previous Forlax intake was more common in tumor-free patients (odds ratio (OR) any use/no use, 0.52; 95% confidence interval, 0.27-0.94). More people used Forlax, which contains a higher dose of PEG than the other PEG-laxatives, whose ORs were smaller than one, but did not reach significance. In multivariate analysis, older age and male gender were associated with higher risk, and NSAIDs use with lower risk, of colorectal tumors. CONCLUSION: Forlax users had a halved risk of colorectal tumors in univariate analysis, which suggests that PEG may prevent carcinogenesis.

Adenoma↗
PubMed2005

p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death.

In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducible p25 expression. In this system, no sign of apoptosis was seen before 24 hours of p25 induction. Thus, at that time, cell-cycle-regulatory proteins were analysed by immunoblotting and some of them showed a significant deregulation. Interestingly, after time-course experiments, the earliest feature correlated with p25 expression was the phosphorylation of the retinoblastoma protein (Rb). Indeed, this phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a Cdk5 inhibitor, roscovitine, which does not inhibit the usual Rb cyclin-D kinases Cdk4 and Cdk6. Furthermore, analyses of levels and subcellular localization of Cdk-related cyclins did not reveal any change following Cdk5 activation, arguing for a direct effect of Cdk5 activity on Rb protein. This latter result was clearly demonstrated by in vitro kinase assays showing that the p25-Cdk5 complex in our cell system phosphorylates Rb directly without the need for any intermediary kinase activity. Hence, Rb might be an appropriate candidate that connects Cdk5 to cell-cycle deregulation during neuronal cell death.

Apoptosis↗
PubMed2005

High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS.

Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.

Adult↗
PubMed2005

Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness.

Hyaluronidases and their substrate, hyaluronan (HA), were mainly explored in solid tumors but rarely in hematologic malignancies. While HA involvement was demonstrated in invasion and metastasis in most cases of solid tumors, the role of hyaluronidases in cancer progression remains controversial. One of the hyaluronidases, HYAL2, is suspected to be involved in the first step of HA degradation. In this work, HYAL2 mRNA, HA and total hyaluronidases expression were examined in lymphoma tissue extracts and correlated to the lymphoma subtype. Real-time RT-PCR was performed to evaluate HYAL2 mRNA. HA and hyaluronidase were assayed by enzyme-linked sorbent assay. Our results showed that HYAL2 mRNA expression was correlated to lymphoma diagnosis (p = 6 x 10(-3)) and was significantly lower in high-grade lymphoma, i.e., diffuse large B-cell diffuse lymphomas (DLBCLs). Several forms of hyaluronidase were detected by zymography and total hyaluronidase activity detected in tissue extracts was not significantly different according to tumor grade. HA levels also correlated to lymphoma subtype (p = 1 x 10(-5)) and were higher in DLBCLs. Moreover, HYAL2 mRNA and HA expressions were inversely correlated (p = 0.035). HYAL2 gene is localized on chromosome 3p21, which contains candidates tumor suppressor genes. Our results suggest that HYAL2 may have a prognostic significance in lymphomas and an antioncogenic activity. Conversely, HA overexpression in high-grade lymphomas is in favor of its involvement in tumor development and could provide a useful target for lymphoma therapy using HA-binding peptides.

Cell Adhesion Molecules↗
PubMed2005

Hui and Walter's latent-class reference-free approach may be more useful in assessing agreement than diagnostic performance.

BACKGROUND AND OBJECTIVE: Hui and Walter developed a latent class approach to assess the accuracy of a diagnostic procedure when no reference test is available. Our objective was to compare sensitivity and specificity estimates obtained with this reference-free approach and standard approaches, and to examine how and why they differed on a computerized tomography (CT) scan case study. STUDY DESIGN AND SETTING: We compared two sets of sensitivity and specificity estimates from four radiologists independently assessing tumoral and lymph node extension of 85 lung cancer patients with preoperative thoracic CT scan, those obtained relative to pathology findings from surgical specimens (reference set), and those derived from Hui and Walter's approach. RESULTS: The two sets of estimates significantly and markedly differed from each other. From simulations, we found that small-sample bias in Hui and Walter's estimates could be a major factor in explaining this difference. Furthermore, errors in pathology findings could account for part of this difference. Finally, our analyses revealed that the latent classes may differ intrinsically from the reference classes as defined from pathology findings and may have a different interpretation. CONCLUSION: Diagnostic parameters estimated with respect to latent classes may be more useful in providing a complete assessment of interobserver agreement than in assessing diagnostic performance.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

Mitotic-like tau phosphorylation by p25-Cdk5 kinase complex.

Among tau phosphorylation sites, some phosphoepitopes referred to as abnormal ones are exclusively found on tau aggregated into filaments in Alzheimer's disease. Recent data suggested that molecular mechanisms similar to those encountered during mitosis may play a role in abnormal tau phosphorylation. In particular, TG-3 phosphoepitope is associated with early stages of neurofibrillary tangles (NFTs). In this study, we reported a suitable cell model consisting of SH-SY5Y cells stably transfected with an inducible p25 expression vector. It allows investigation of tau phosphorylation by p25-Cdk5 kinase complex in a neuronal context and avoiding p25-induced cytotoxicity. Immunoblotting analyses showed that p25-Cdk5 strongly phosphorylates tau protein not only at the AT8 epitope but also at the AT180 epitope and at the Alzheimer's mitotic epitope TG-3. Further biochemical analyses showed that abnormal phosphorylated tau accumulated in cytosol as a microtubule-free form, suggesting its impact on tau biological activity. Since tau abnormal phosphorylation occurred in dividing cells, TG-3 immunoreactivity was also investigated in differentiated neuronal ones, and both TG-3-immunoreactive tau and nucleolin, another early marker for NFT, were also generated. These data suggest that p25-Cdk5 is responsible for the mitotic-like phosphoepitopes present in NFT and argue for a critical role of Cdk5 in neurodegenerative mechanisms.

Blotting, Western↗
PubMed2003

Intracranial aneurysms treated with Guglielmi detachable coils: is contrast material necessary in the follow-up with 3D time-of-flight MR angiography?

BACKGROUND AND PURPOSE: Three-dimensional time-of-flight (TOF) MR angiography has been evaluated in the follow-up of intracranial aneurysms treated with Guglielmi detachable coils (GDCs) with good results. Some of the studies used contrast material in addition to the 3D TOF MR technique and others did not. We assessed the usefulness of contrast material with 3D TOF MR angiography by comparing this sequence before and after contrast material injection. METHODS: Fifty-eight patients harboring a total of 71 cerebral aneurysms previously treated with GDCs were included in the prospective study. MR angiography (at 1.5 T) was performed with a 3D TOF sequence before and after injection of gadolinium-based contrast material. Features evaluated were presence and size of a neck remnant, parent and adjacent vessel patency, and venous overlap. Digital subtraction angiography was the standard of reference. RESULTS: Comparison of the techniques showed a good agreement in the detection of residual flow. Six cases of small residual neck were not detected with either the 3D TOF or the contrast-enhanced 3D TOF sequence. In one case of giant aneurysm, the extent of recanalization was more evident after contrast material administration. The use of contrast material did not help to show the parent and adjacent arteries. Venous overlap on contrast-enhanced 3D TOF angiograms did not affect image interpretation. CONCLUSION: In this series, the use of intravenous contrast material did not improve the ability of 3D TOF MR angiography to depict the presence of residual or recurrent aneurysms previously treated with endovascular coiling. In one giant aneurysm, use of intravenous contrast material did result in improved visualization of a residual aneurysm.

Angiography, Digital Subtraction↗
PubMed2002

Importance of hyaluronan length in a hyaladherin-based assay for hyaluronan.

Specific hyaladherin-based assays have been set up to measure the concentration of hyaluronan in biological fluids. Hyaluronectin (HN; a hyaladherin extracted from ovine brain) binds to hyaluronan (HA) that must be 10 units (HA10) or more long. It was therefore of interest to determine whether HN would continue to bind to HA10 in full-length HA since conformational changes might mask potential binding sites. We used the enzyme-linked sorbent assay (ELSA) to assay HA and hyaluronan-derived oligosaccharides, with different standard HAs, and the results were compared to results obtained with the carbazole technique. Oligosaccharide length was calculated from the ratio glucuronic acid/reducing N-acetylglucosamine in fractions of hyaluronidase-digested macromolecular hyaluronan prepared by chromatography; the size of the HA12 oligosaccharide was confirmed by matrix-assisted laser desorption ionization mass spectrometry. During the digestion of macromolecular HA with hyaluronidase, the binding of HN to HA first increased and then decreased as shown using the ELSA. The concentration of HA fragments of HA60 and below was overestimated when intact macromolecular HA was used as the reference for the ELSA, while the concentration of HA100 and above was underestimated when HA10 was used as the reference. The binding of HN to HA20, HA40, and HA60 saccharides was consistent with binding to multiples of HA10 sites. In conclusion, the level of HN binding is determined by the conformation of HA, which may mask binding sites. Hence, calibration HA used in the ELSA must be adapted to the size of HA to assay.

Binding Sites↗
PubMed2002

Human monocytes synthesize hyaluronidase.

The involvement of hyaluronic acid (HA) oligosaccharides and blood-derived mononuclear cells in inflammatory processes prompted us to determine whether peripheral blood mononuclear cells (PBMC) possess hyaluronidase activity. PBMC were incubated with macromolecular-tritiated HA at pH 3.8 and supernatants were analysed by size exclusion chromatography to reveal digestion of HA. This digestion was due to the CD14-positive (CD14+), adherent, non-specific esterase-positive, subpopulation of PBMC. Hyaluronidase activity (72 kDa) was found in aqueous and non-ionic detergent PBMC extracts but not in the medium in which the cells had been cultured. These results indicate that hyaluronidase is, at least in part, linked to the membrane rather than excreted. Hence, monocytes have one or more hyaluronidases that can generate a pool of active HA fragments within tissues. Hyaluronidase activity was also found in 3/3 myelomonocytic lineage leukaemias but not in 3/3 lymphoblastic leukaemias.

Humans↗
PubMed2002

[Prevalence and risk factors of urinary incontinence in young women].

OBJECTIVE: Urinary incontinence is a very common disease among women but only few studies have been published in young adult and middle-aged population. We studied urinary incontinence prevalence and risk factors in this young and middle-aged population. MATERIAL AND METHODS: We studied during the year 1998 the prevalence of global incontinence and stress, urge and mixed urinary incontinence in 1700 women working in a French academic hospital (n = 2800). Women received the questionnaire at the same time than their convocation for their yearly visit in occupational medicine. Usual risk factors of constitutional events (increasing âge, obesity defined by a Body Mass Index > or = 25); obstetric events (pregnancy, previous caesarean delivery, previous vaginal delivery, post-partum incontinence) and gynaecological event (hysterectomy) were evaluated. RESULTS: 177 women (mean âge 40.0 years) returned the questionnaire. 467 women (27.5% 95% CI = 25.4-29.7) reported urinary incontinence, 210 (12.4% 95% CI = 10.8-14.0) stress urinary incontinence, 28 (1.6% 95% CI = 1.1-2.4) urge urinary incontinence and 229 (13.5% 995% CI = 11.9-15.2) mixed urinary incontinence. 38 women (8.1%) suffered from frequent urinary leakage corresponding to 1 (0.5%), 4 (14.3%) and 33 (14.4%) stress, urge and mixed urinary incontinence. The prevalence of urinary incontinence increased significantly with âge > or = 40 years (RR = 2.16 95% CI = 1.86-2.57) pregnancy (RR = 2.22 95% CI = 1.71-2.87), previous vaginal delivery (RR = 2.15 95% CI = 1.72-2.69), post-partum incontinence (RR = 2.57 95% CI = 2.22-2.97, hysterectomy (RR = 1.52 95% CI = 1.11-2.08). Obesity (RR = 1.14 95% CI = 0.99-1.32) and previous caesarean delivery (RR = 2.15 95% CI = 1.72-2.69) did not increase the risk of urinary incontinence. The risk factors for stress urinary incontinence were âge > or = 40 years (RR = 2.18 95% CI = 1.66-2.87), pregnancy (RR = 2.36 95% CI = 1.55-3.58), previous vaginal delivery (RR = 2.47 95% CI = 1.70-3.59), post-partum incontinence (RR = 2.78 95% CI = 2.14-3.61) and hysterectomy (RR = 2.83 95% CI = 1.93-4.15). No relationship was found between stress urinary incontinence and obesity (RR = 1.25 95% CI = 0.96-1.64) and previous caesarean delivery (RR = 1.02 95% CI = 0.45-2.32). CONCLUSION: A high prevalence of urinary incontinence was observed among young adult and middle-aged female hospital workers with an easy access to medical resources. Gynaecological and obstetric event (pregnancy particularly previous vaginal delivery and hysterectomy) were the most prominent risk factors, especially for stress urinary incontinence.

Adult↗
PubMedDate not supplied

Hyaluronidase in sera of tumour-bearing nude mice.

Cancer cell lines often secrete hyaluronidase, suggesting that this enzyme could be used as a marker of growing tumours. We have measured hyaluronidase in the sera of non-grafted mice and mice grafted with human tumour-derived hyaluronidase-secreting H460M and SA87 cells or non-secreting CB 193 cells. Mouse serum hyaluronidase was measured at pH 3.8 using the enzyme-linked sorbent assay (ELSA) technique by reference to human serum whose activity at pH 3.8 was determined by the Reissig technique. The serum hyaluronidase in non-grafted mice ranged from 310-520 mU l(-1) (mean+/-SD 432+/-70 mU l(-1), median 440 mU l(-1)). Hyaluronidase increased in the sera of tumour-bearing mice grafted with H460M cells or with SA87 cells, but not in the sera of mice grafted with CB 193 cells. Serum hyaluronidase activity in H460M or SA87 tumour-bearing mice correlated with the tumour mass, increased with time, and decreased after tumour removal. Zymography detected two different hyaluronidase forms in the sera of non-grafted mice: type 1 had only one hyaluronidase band and type 2 had five different bands. In both types, enzyme augmentation in tumour-bearing mice correlated with the presence of an additional enzyme band that was not seen in normal sera and that migrated as the cancer cell enzyme did; there was no augmentation of the normal isoform(s). These results show that serum hyaluronidase can be used to follow the development of tumours in mice grafted with hyaluronidase-secreting cells.

Animals↗
PubMedDate not supplied

Hyaluronidase is more elevated in human brain metastases than in primary brain tumours.

BACKGROUND: Hyaluronidase is hypothesised to play a role in cancer invasion and metastasis formation. MATERIALS AND METHODS: Hyaluronidase activity was investigated at pH 3.8 in extracts of 30 human brain tumours (17 glioblastomas and 13 brain metastases of carcinomas) and in cancer cell cultures with the ELSA method and zymography. RESULTS: In brain metastases, hyaluronidase activities were significantly higher than in glioma extracts (9.16 +/- 4.48 mU/g vs 4.25 +/- 5.74) which was not explained by serum hyaluronidase contamination. Serum hyaluronidase of tumour patients' sera was within the normal values determined in 28 matched blood donors'sera (33.8 +/- 11 U/l). The maximum hyaluronidase/albumin (U/g) ratio was 0.9, below which the hyaluronidase content of tumours was below the maximum value calculated from the albumin content of the tumour extract and could not be considered as local production by tumour cells. The hyaluronidase content and hyaluronidase/albumin ratio of metastasis extracts was significantly higher than in glioma extracts and patients' sera, whereas no significant difference was found between the ratios of glioma extracts and sera. The production of hyaluronidase was studied in cell extracts and in culture media of 3 human glioma-derived cell lines and of the brain metastasis-derived cell line SA87. Hyaluronidase activity of the metastasis-derived cell line SA87 was 100 to 1000-fold that of glioma cell lines. CONCLUSION: These results suggest that hyaluronidase is associated with the more aggressive cancer cells and is directly or indirectly involved in brain metastasis phenotype.

Adolescent↗
PubMedDate not supplied

Biodistribution of injected tritiated hyaluronic acid in mice: a comparison between macromolecules and hyaluronic acid-derived oligosaccharides.

BACKGROUND: Hyaluronan (HA) has been reported to bind specifically and with high affinity to various cell types and to directly modify cell behaviour. In a previous report we demonstrated that both high molecular weight molecules (HA(H)) and HA-derived oligosaccharides were efficient at triggering terminal differentiation of acute myeloid leukemia (AML) blasts, in vitro, through CD44 ligation. MATERIALS AND METHODS: To explore the possibility of using HA for a differentiation therapy in AML, we investigated whether intravenous injection of tritiated HA(H) and/or HA-derived oligosaccharides (HA10-20) into mice accumulated in bone marrow, the main site of AML cell proliferation. RESULTS: The present work showed that the level of HA in bone marrow: 1) was maximum 5 hours after injection of either HA(H) or HA10-20; 2) was about 40 times higher after HA(H) than after HA10-20 injection. The amount of HA in bone marrow (5.8% ID/g) was two-fold higher than in serum, indicating that it was not due to circulating blood. Finally, using chromatographic analysis, we showed that about 34% of tritiated HA present in bone marrow 5 hours after HA(H) injection displayed a size higher or equal to HA10. CONCLUSION: After a single injection of macromolecular hyaluronan in mouse bone marrow we obtained a concentration of oligosaccharides close to the one shown to trigger AML cell differentiation in vitro. A part of the oligosaccharides had a size higher than or equal to the minimal one required to interact with HA receptors.

Animals↗