Biomedical subjects

F Robert

Publications and source records attributed to F Robert.

At least 37 records · Page 2Linked to original sources

PubMed2000

Genome-wide location and function of DNA binding proteins.

Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding of gene-specific transcription activators in yeast. A combination of location and expression profiles was used to identify genes whose expression is directly controlled by Gal4 and Ste12 as cells respond to changes in carbon source and mating pheromone, respectively. The results identify pathways that are coordinately regulated by each of the two activators and reveal previously unknown functions for Gal4 and Ste12. Genome-wide location analysis will facilitate investigation of gene regulatory networks, gene function, and genome maintenance.

Binding Sites↗

PubMed2000

Solar wind record on the moon: deciphering presolar from planetary nitrogen.

Ion microprobe analyses show that solar wind nitrogen associated with solar wind hydrogen implanted in the first tens of nanometers of lunar regolith grains is depleted in 15N by at least 24% relative to terrestrial atmosphere, whereas a nonsolar component associated with deuterium-rich hydrogen, detected in silicon-bearing coatings at the surface of some ilmenite grains, is enriched in 15N. Systematic enrichment of 15N in terrestrial planets and bulk meteorites relative to the protosolar gas cannot be explained by isotopic fractionation in nebular or planetary environments but requires the contribution of 15N-rich compounds to the total nitrogen in planetary materials. Most of these compounds are possibly of an interstellar origin and never equilibrated with the 15N-depleted protosolar nebula.

Argon↗

PubMed2000

Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers.

PURPOSE: Epidermal growth factor receptor (EGFr) is overexpressed in a majority of head and neck squamous cell carcinomas, and this overexpression is associated with a poor prognosis. Therefore, EGFr has become the target of investigations aimed at disabling the receptor to determine whether this process leads to improved tumor kill with conventional treatment. MATERIALS AND METHODS: C225 is an anti-EGFr monoclonal antibody that inhibits receptor activity by blocking the ligand binding site. A panel of human head and neck squamous cell carcinoma cell lines was used to study the combination of C225 and radiation. RESULTS: It was determined that the combination of C225 (5 microgram/mL) delivered simultaneously with radiation (3 Gy) resulted in a greater decrement in cellular proliferation than either treatment alone. This reduction in proliferation correlated with reduced EGFr tyrosine phosphorylation and a reduction in phosphorylated signal transducer and activator of transcription-3 (STAT-3) protein (known to protect cells from apoptosis). Also, the decrement in proliferation correlated with increased apoptotic events, thereby indirectly linking C225/radiation-induced regulation of STAT-3 protein to apoptosis. CONCLUSION: This preclinical work serves as important support for the ongoing clinical investigation of C225 and radiotherapy for patients with head and neck carcinomas. The initial results of these clinical studies have been promising.

Antibodies, Monoclonal↗

PubMed2000

Incorporation of short-lived (10)Be in a calcium-aluminum-rich inclusion from the allende meteorite

Enrichments in boron-10/boron-11 in a calcium-aluminum-rich inclusion from the Allende carbonaceous chondrite are correlated with beryllium/boron in a manner indicative of the in situ decay of short-lived beryllium-10. Because this radionuclide is produced only by nuclear spallation reactions, its existence in early solar system materials attests to intense irradiation processes in the solar nebula. The particle fluence inferred from the initial beryllium-10/beryllium-9 is sufficient to produce other short-lived nuclides, calcium-41 and manganese-53, found in meteorites, but the high canonical abundance of aluminum-26 may still require seeding of the solar system by radioactive stellar debris.

Journal Article↗

PubMed2000

A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer.

PURPOSE: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. METHODS: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. RESULTS: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. CONCLUSION: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.

Adenocarcinoma↗

PubMed2000

Rapid access to synthetic lysobisphosphatidic acids using P(III) chemistry.

An expeditious route to synthetic lysobisphosphatidic acid S,S-1, its enantiomer, and regioisomers is reported. Synthetic difficulties concerning lipid stability and stereochemistry are bypassed using a phosphite triester approach in combination with multiple silyl protection. Spectroscopic studies evidence that acyl group migration in S,S-1 is accelerated by nonpolar solvents and inhibited by pyridine.

Biochemistry↗

PubMed2000

[Primary parvovirus B19 infection in immunocompetent adults: clinical and biological manifestations. Retrospective study of 16 patients].

PURPOSE: The spectrum of clinical and biological expressions of parvovirus B19 infection is incompletely described. METHODS: We report 16 retrospective cases of primary parvovirus B19 infection that occurred in immunocompetent adults and were diagnosed by serology. RESULTS AND CONCLUSION: Most cases conformed to the classical descriptions of parvovirus-induced arthropathy (transient polyarthritis often accompanied by erythema, dysesthesia and pruritus). However, the diagnosis of primary parvovirus B19 infection should also be considered in other clinical and biological situations such as edema, acute anemia or cytopenia, vascular purpura, neuro-ophthalmologic manifestations, and hepatitis. Parvovirus infection may mimic diseases such as lupus erythematosus or systemic necrotizing vasculitis. The risk for confusion with both diseases is increased, as immunological abnormalities such as hypocomplementemia, when they are systematically searched for, prove to be common.

Adult↗

PubMed2000

Mapping of the RNA recognition site of Escherichia coli ribosomal protein S7.

Bacterial ribosomal protein S7 initiates the folding of the 3' major domain of 16S ribosomal RNA by binding to its lower half. The X-ray structure of protein S7 from thermophilic bacteria was recently solved and found to be a modular structure, consisting of an alpha-helical domain with a beta-ribbon extension. To gain further insights into its interaction with rRNA, we cloned the S7 gene from Escherichia coli K12 into a pET expression vector and introduced 4 deletions and 12 amino acid substitutions in the protein sequence. The binding of each mutant to the lower half of the 3' major domain of 16S rRNA was assessed by filtration on nitrocellulose membranes. Deletion of the N-terminal 17 residues or deletion of the B hairpins (residues 72-89) severely decreased S7 affinity for the rRNA. Truncation of the C-terminal portion (residues 138-178), which includes part of the terminal alpha-helix, significantly affected S7 binding, whereas a shorter truncation (residues 148-178) only marginally influenced its binding. Severe effects were also observed with several strategic point mutations located throughout the protein, including Q8A and F17G in the N-terminal region, and K35Q, G54S, K113Q, and M115G in loops connecting the alpha-helices. Our results are consistent with the occurrence of several sites of contact between S7 and the 16S rRNA, in line with its role in the folding of the 3' major domain.

Amino Acid Sequence↗

PubMed2000

Synthesis of multiply substituted, ion channel forming octi(p-phenylene)s: theme and variations.

[reaction: see text] To facilitate the access to unique models for biological processes, we examined six different synthetic routes to octi(p-phenylene) rods with lateral and terminal substituents R(L) and R(T). This systematic study allowed us to increase to overall yield for the synthesis of a new class of oligo(p-phenylene) ionophores about 20 times and to provide general insights into the practicability of synthetic routes to multiply substituted molecular rods.

Anti-Infective Agents↗

PubMed1999

Genomic and membrane actions of progesterone: implications for reproductive physiology and behavior.

Progesterone, produced by the ovaries and adrenal glands, regulates reproductive behavior and the surge of luteinizing hormone which precedes ovulation by acting on neurons located in different parts of the hypothalamus. The study of the activation of these reproductive functions in female rats has allowed to explore the different mechanisms of progesterone action in the brain. It has allowed to demonstrate that new actions of the hormone, which have been observed in particular in vitro systems, are also operational in vivo, and may thus be biologically relevant. This mainly concerns the direct actions of progesterone on receptors of neurotransmitters such as oxytocin and GABA. Activation of the progesterone receptor in the absence of ligand by phosphorylation may also play a role.

Animals↗

PubMed1999

[Agenesis of the vas deferens in male infertility. A tentative classification based on 39 cases].

OBJECTIVES: We attempted to establish a classification of vas deferens agenesia observed in male infertility to better ascertain the pathophysiology involved and help guide genetic counselling. PATIENTS AND METHODS: Among 387 men consulting for infertility, agenesia of the vas deferens was confirmed by transrectal ultrasonography in 39. A search for 13 different cystic fibrosis mutations was performed in subjects without associated renal agenesia. RESULTS: Among the 39 cases, we identified 4 ultrasonographic categories: unique bilateral agenesia (25 cases), bilateral agenesia associated with renal agenesia (1 case), unique unilateral agenesia (6 cases) and unilateral agenesia with renal agenesia (7 cases). Presence or absence of a seminal vesicle was variable. A cystic fibrosis mutation was observed in 64% of the bilateral cases and in none of the unilateral cases. The delta F 508 mutation accounted for 62% of the mutations. Phenotypically, there was not distinction between patients with and without a mutation. In cases of unilateral agenesia of the vas deferens, azoospermia was more frequent in unique forms than in forms with associated renal agenesia. CONCLUSION: Presence or absence of a mutation does not affect the pathophysiology of vas deferens agenesia in cases without associated renal agenesia. Genetic counselling should however take into account the presence of an associated mutation. Vas deferens agenesia associated with renal agenesia is not associated with cystic fibrosis mutations and results from a different pathogenic mechanism.

Adult↗

PubMed1999

The various MRI patterns of pituitary apoplexy.

The aim of this study was to describe the various MRI features, in correlation to surgical and pathological findings, in patients who presented with pituitary apoplexy (PA). Eleven patients presenting with PA, were evaluated with various MR protocols including spin-echo (SE) T1-weighted sequences in 9 of 11 patients, post gadolinium SE T1-weighted sequences in only 8 of 11 patients, and with T2-weighted SE sequences in 2 of 11 patients. All patients had transsphenoidal pituitary surgery after MR studies. The severity of presenting symptoms ranged from headaches to coma. Ten patients had pituitary macroadenoma; one had a non-hemorrhagic metastatic lesion into a non-adenomatous pituitary gland. Of the 11 patients, one was studied at the acute stage of PA (1 day after onset), 9 at the subacute period (3-15 days after onset), and one at the late stage (5 months after onset). Images compatible with intratumoral hemorrhage were found in all macroadenomas, whereas the metastatic pituitary lesion did not show evidence of bleeding. All gadolinium-enhanced studies showed partial tumoral enhancement. The SE T2-weighted studies demonstrated areas of low and high signal intensities in keeping with the presence of blood degradation contents. Pituitary apoplexy present with different MR features, including hemorrhagic and non-hemorrhagic characteristics on T1-weighted images. Gadolinium-enhanced images do not provide complementary diagnostic information when the presence of blood is assessed on plain images.

Adult↗

PubMed1999

Monoclonal antibodies as potentiators of radiotherapy and chemotherapy in the management of head and neck cancer.

The overall survival of patients with squamous cell cancer of the head and neck has not significantly improved over the past 2 decades. Preclinical studies suggest that combining a monoclonal antibody to the epidermal growth factor receptor with irradiation or chemotherapy agents active in squamous cell cancer of the head and neck could increase treatment efficacy. Completed phase I studies have shown these combinations to be both feasible and tolerable. Phase III studies are now beginning to establish firmly the efficacy of this innovative new approach.

Antibodies, Monoclonal↗

PubMed1999

Phase I/IIa study of concurrent paclitaxel and cisplatin with radiation therapy in locally advanced non-small cell lung cancer: analysis of early and late pulmonary morbidity.

Recent efforts to improve survival outcome in patients with locally advanced non-small cell lung cancer have focused on the use of chemoradiotherapy regimens containing vinblastine/cisplatin or etoposide/cisplatin. However, the overall treatment outcome with these regimens remains poor, emphasizing the need for new therapeutic options. Based on the activity of paclitaxel in advanced non-small cell lung cancer, its additive cytotoxicity with cisplatin, and the radiation-sensitizing effect of both agents, a phase I/IIa study was designed to examine the feasibility of paclitaxel/cisplatin concurrently with conventional thoracic irradiation in patients with locally advanced tumors. One major concern regarding combined modality therapy has been the enhancement of pulmonary toxicity. This report describes the incidence and severity of pulmonary toxicities observed in this trial according to the Radiation Therapy Oncology Group scoring criteria. A literature-based review was performed in an attempt to determine the impact of paclitaxel-based versus non-paclitaxel-based chemoradiotherapy regimens on the early and late pulmonary morbidity. Twenty-four evaluable patients died and 14 (37%) are still alive without evidence of disease. The 1- and 2-year survival rates are 62% and 40%, respectively, with a median survival of 17 months. Pulmonary toxicity >/=grade 2 was more frequently manifested as late toxicity in approximately 70% of the patients. In most, prompt symptomatic and radiologic improvement was observed with the early administration of corticosteroids. There were three late grade 5 toxicities characterized by diffuse (bilateral) rapidly progressive interstitial infiltrates. Protracted lymphocytopenia was noted in the great majority of patients, and its role in the pathogenesis of this complication remains to be determined. There were minor changes in pulmonary function parameters, except in the forced vital capacity and diffusion capacity to carbon monoxide. In a univariate analysis, no relationship was noted between paclitaxel dose level, degree of lymphocytopenia, changes in pulmonary function indices, and incidence of pulmonary toxicity. However, there was a significant dose-volume relationship (using conventional dose-volume histograms) with late pulmonary toxicity at radiation doses between 15 Gy and 30 Gy. Based on a literature review, paclitaxel-based chemotherapy regimens seem to be associated with a slightly higher risk of pulmonary toxicity; however, comparison of such toxicity between trials has many limitations that require that the conclusion reached be viewed with caution.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

UFT/oral calcium folinate plus radiation in pancreatic cancer.

A phase I, single-center, open-label, dose-escalation study (University of Alabama [UAB] 9614) has been undertaken to evaluate the feasibility and safety of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus oral calcium folinate (Orzel) plus radiotherapy in patients with pancreatic cancer. A total of 11 patients with a median age of 59 years have been treated for 35 days with 150 mg/m2/day of UFT and 90 mg/day of oral calcium folinate, divided into three daily doses. Radiotherapy began on day 1, to a total dose of 45 Gy at 1.8 Gy per day (for approximately 5 weeks). Dose escalation of UFT will be performed until the maximum tolerated dose is defined. Overall, therapy has been well tolerated and the maximum tolerated dose has not yet been reached.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

[Neurosteroids: trophic effects in the nervous system].

Some steroids, named "neurosteroïds", can be synthesized from cholesterol within both the central and peripheral nervous systems. Thus, pregnenolone and progesterone persist in the brain and in peripheral nerves long after removal of the steroidogenic endocrine glands by castration and adrenalectomy. The role of neurosteroids during the development of the nervous system is not well known, although they are synthesized by glial cells and some populations of neurons already during embryonic life. Cell culture experiments suggest that neurosteroids may influence the survival and differentiation of neurons and glial cells. In the adult nervous system, neurosteroids play an important role during regeneration. Progesterone is indeed synthesized by Schwann cells in peripheral nerves, where it plays an important role in the formation of new myelin sheaths after lesion. This is the first demonstration of a vital role for a neurosteroid in the nervous system.

Adrenalectomy↗

PubMed1998

Coupling on-line brain microdialysis, precolumn derivatization and capillary electrophoresis for routine minute sampling of O-phosphoethanolamine and excitatory amino acids.

In previous papers, we described the analysis of excitatory amino acids (EAAs) and catecholamines in microdialysis samples using capillary electrophoresis with laser-induced fluorescence detection (CE-LIFD). In the present paper, we report that an automated analysis of such samples can be easily achieved by on-line coupling of the microdialysis probe with a continuous flow derivatization system and a commercially available CE-LIFD apparatus. Because of the short analysis time (less than 2 min) and high separation efficiency (100-200,000 theoretical plates), high temporal resolution of microdialysis (minute range) is preserved as compared to off-line systems, while both EAAs and O-phosphoethanolamine (PEA) can be simultaneously detected. This new method has been applied to the measurement of these compounds in microdialysis samples from hippocampal slice cultures and striatum of anesthetized rats. Extracellular concentrations of EAAs, but not PEA, increased during perfusion of a solution containing high K+ or a glutamate uptake inhibitor. However, after in vitro ischemia on hippocampal slices, both EAAs and PEA concentrations increased, but with different temporal patterns.

Animals↗

PubMed1998

An in vitro blood-brain barrier model: cocultures between endothelial cells and organotypic brain slice cultures.

This communication describes a novel in vitro blood-brain barrier (BBB) model: organotypic slice cultures from the central nervous system were overlaid on endothelial cell monolayers grown on permeable membranes. Morphological, electrophysiological, and microdialysis approaches were carried out to characterize and validate this model. After 10 days in coculture, morphological studies reveal the presence of tight junctions. Electrophysiological recordings of neuronal activity performed on organotypic cultures with or without an endothelial cell monolayer show that amplitude of evoked responses were comparable, indicating good viability of cocultures after 2 weeks. Perfusion of known BBB permeable or nonpermeable molecules was used to test the coculture tightness in conjunction with electrophysiological or microdialysis approaches: application of glutamate (Glu), which doesn't easily cross the BBB, triggers off rhythmic activity only in control cultures, whereas epileptogenic activity was observed in both control cultures and cocultures during perfusions with picrotoxin, a molecule that can diffuse through the BBB. Finally, the microdialysis technique was used to determine the permeability of molecules coming from the perfusion chamber: L-dopa, dopamine, and Glu were employed to assess the selective permeability of the coculture model. Thus, these results indicate that the in vitro model described possesses characteristics similar to those of the BBB in situ and that cocultures of organotypic slices and endothelial cell monolayers have potential as a powerful tool for studying biochemical mechanisms regulating BBB function and drug delivery to the central nervous system.

Animals↗