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Biomedical subjects

A Bergeron

Publications and source records attributed to A Bergeron.

At least 19 recordsLinked to original sources
PubMed2006

Characterisation of dendritic cell subsets in lung cancer micro-environments.

The aim of the current study was to seek evidence for a correlation between mediators present in lung cancer micro-environments and subsets of dendritic cells (DCs) infiltrating these tumours. Immunohistochemistry and recently available antibodies were used to define the phenotype of DCs present in surgical biopsies from 12 patients with lung carcinomas, and the local expression of chemokines potentially involved in the recruitment of these cells was evaluated, both at mRNA and protein levels. Real-time PCR was used to analyse the expression of mRNA coding for cytokines known to influence the maturation of DCs in vitro. Different subsets of myeloid DCs were present in lung cancers, but no plasmocytoid DCs were identified. Both Langerhans cells and CD1a+/Langerin cells were interspersed among tumour cells, in numbers that were correlated to the amounts of CC chemokine ligand 20 produced in these tumours. In most specimens, DC-specific intercellular adhesion molecule-grabbing nonintegrin-positive DCs were also present at the periphery of the tumour beds. No DC-lysosomal associated membrane protein-positive DCs were identified and CD83+ DCs were rarely present in the tumour stroma. All tumours expressed interleukin (IL)-10, transforming growth factor-beta and vascular endothelial growth factor, whereas IL-12 was virtually absent. Thus, various types of dendritic cells infiltrate lung carcinomas and display an immature phenotype, presumably because of the inhibitory cytokine micro-environment.

Adenocarcinoma↗
PubMed2005

Cancer-testis antigen expression in bladder cancer.

PURPOSE: To evaluate the potential of cCancer-t/Testis antigens (CTAs) as targets for immunotherapy of bladder cancer, we evaluated the expression of 9 CTA genes or families of genes in normal urothelia, bladder tumours and bladder cancer human bladder tissuescell lines. As expression of most CTAs is controlled by epigenetic mechanisms, we also evaluated the effect of the DNA methylase inhibitor 5-aza-2'-deoxycytidine (5-AZA-DC), and/or theand histone deacetylase inhibitors Trichostatin A (TSA) on their expression in bladder cancer cell lines. MATERIAL AND METHODS: Expression of NY-ESO-1/LAGE-1, MAGE-A, MAGE-C1, BAGE, HOM-TES-85, SCP-1, SSX-1, SSX-2 and SSX-4 was analyzed by semi-quantitative RT-PCR and Western blotting on 10 normal urothelia, 23 24 superficial and 223 invasive tumours and on 10 cell lines treated with 5-aza-2'-deoxycytidine (5-AZA-DC) and/or Trichostatin A (TSA). RESULTS: Expression of all CTA genes could be observed in at least 1 tumour except for HOM-TES-85 for which mRNA was never detected. MAGE-A, BAGE and NY-ESO-1/LAGE-1 mRNAs were the most frequently detected, respectively in 5677%, 212% and 89% of superficial and in 6461%, 4139% and 276% of invasive tumours. With the exception of MAGE-A, CTA transcripts were rarely detected in the cell lines. However, expression of all CTA genes, except SCP-1, could be induced at various levels by the drugs and 5-AZA-DC was a much more potent inducer than TSA. CONCLUSION: These data suggest that immunotherapy of bladder cancer could target CTAs, especially those expressed at higher frequency such as MAGE-A, BAGE and NY-ESO-1/LAGE-1. Moreover, their induction by chemotherapeutic agents such as 5-AZA-DC, provides a potential pretreatment aimed at inducing the immunogenicity of the tumours.

Antigens, Neoplasm↗
PubMed2003

Platelet FcgammaRIIA His131Arg polymorphism and platelet function: antibodies to platelet-bound fibrinogen induce platelet activation.

The His131Arg polymorphism of platelet FcgammaRIIA affects the binding affinity of certain IgG subclasses. The Arg131 allele has been associated with (auto)immune thrombocytopenia and heparin-induced thrombocytopenia in some studies. Because FcgammaRIIA can transmit platelet activation signals, we studied platelet responsiveness from 73 healthy donors to determine if this polymorphism modulated platelet function. Platelet function was studied by agonist and shear-induced activation, and standard aggregation. FcgammaRIIA was genotyped by allele-specific PCR. Compared with His131, the Arg131 allele was associated with significantly greater binding of activation-dependent antibodies. This effect was most prominent for the receptor-induced binding site (RIBS) antibodies F26 (P < 0.0001) and RIBS1 (P = 0.0057), and the ligand-induced binding site antibody LIBS1 (P = 0.0367). Unexpectedly, Arg131-positive platelets did not show greater fibrinogen binding, platelet aggregation or shear-induced platelet activation. We considered whether enhanced Fc binding and FcgammaRIIA cross-linking were responsible for those discrepancies. The increased binding of the two RIBS antibodies to the Arg131 isoform was abolished by blocking FcgammaRIIA, and the FcgammaRIIA genotype effect on F26 IgG binding was lost when F26 F(ab')2 fragments were used. Furthermore, intact F26 and RIBS1 IgG directly and specifically induced P-selectin expression, and this effect was greatest in Arg131-positive platelets. We concluded that (a) the His131Arg polymorphism of FcgammaRIIA does not affect intrinsic platelet reactivity; (b) RIBS antibodies are able to cross-link FcgammaRIIA and activate platelets, and this activation has a modest effect on Arg131 platelets; and (c) flow cytometric based platelet assays may need to compensate for this FcgammaRIIA His131Arg effect on platelet activation.

Adult↗
PubMed2003

Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10.

Modulation of cytokine expression represents a potentially useful approach for the treatment of idiopathic pulmonary fibrosis (IPF). To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids (mRNAs) coding for 17 cytokines in lung tissue obtained from patients with IPF at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques. mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor (TGF)-beta and interleukin (IL)-10 mRNAs were quantitatively increased in lung biopsies from patients with IPF compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor (PDGF)-BB and keratinocyte growth factor (KGF) were expressed in similar amounts in lungs from patients with IPF and controls, localised accumulation of both factors was also observed in IPF. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where IL-10, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed (PDGF-BB, TGF-beta). These results offer new insights into the cytokines produced in the lung in idiopathic pulmonary fibrosis and suggest that modulation of the production of transforming growth factor-beta and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.

Female↗
PubMed2002

Common intervals and sorting by reversals: a marriage of necessity.

This paper revisits the problem of sorting by reversals with tools developed in the context of detecting common intervals. Mixing the two approaches yields new definitions and algorithms for the reversal distance computations, that apply directly on the original permutation. Traditional constructions such as recasting the signed permutation as a positive permutation, or traversing the overlap graph to analyze its connected components, are replaced by elementary definitions in terms of intervals of the permutation. This yields simple linear time algorithms that identify the essential features in a single pass over the permutation and use only simple data structures like arrays and stacks.

Algorithms↗
PubMed2001

A missense mutation (Q279R) in the fumarylacetoacetate hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation.

BACKGROUND: Tyrosinemia type I, the most severe disease of the tyrosine catabolic pathway is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). A patient showing few of the symptoms associated with the disease, was found to be a compound heterozygote for a splice mutation, IVS6-1g->t, and a putative missense mutation, Q279R. Analysis of FAH expression in liver sections obtained after resection for hepatocellular carcinoma revealed a mosaic pattern of expression. No FAH was found in tumor regions while a healthy region contained enzyme-expressing nodules. RESULTS: Analysis of DNA from a FAH expressing region showed that the expression of the protein was due to correction of the Q279R mutation. RT-PCR was used to assess if Q279R RNA was produced in the liver cells and in fibroblasts from the patient. Normal mRNA was found in the liver region where the mutation had reverted while splicing intermediates were found in non-expressing regions suggesting that the Q279R mutation acted as a splicing mutation in vivo. Sequence of transcripts showed skipping of exon 8 alone or together with exon 9. Using minigenes in transfection assays, the Q279R mutation was shown to induce skipping of exon 9 when placed in a constitutive splicing environment. CONCLUSION: These data suggest that the putative missense mutation Q279R in the FAH gene acts as a splicing mutation in vivo. Moreover FAH expression can be partially restored in certain liver cells as a result of a reversion of the Q279R mutation and expansion of the corrected cells.

DNA Mutational Analysis↗
PubMed2001

Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in hereditary tyrosinemia type 1.

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by a deficiency of the enzyme involved in the last step of tyrosine degradation, fumarylacetoacetate hydrolase (FAH). Thus far, 34 mutations in the FAH gene have been reported in various HT1 patients. Site-directed mutagenesis of the FAH cDNA was used to investigate the effects of eight missense mutations found in HTI patients on the structure and activity of FAH. Mutated FAH proteins were expressed in Escherichia coli and in mammalian CV-1 cells. Mutations N16I, F62C, A134D, C193R, D233V, and W234G lead to enzymatically inactive FAH proteins. Two mutations (R341W, associated with the pseudo-deficiency phenotype, and Q279R) produced proteins with a level of activity comparable to the wild-type enzyme. The N16I, F62C, C193R, and W234G variants were enriched in an insoluble cellular fraction, suggesting that these amino acid substitutions interfere with the proper folding of the enzyme. Based on the tertiary structure of FAH, on circular dichroism data, and on solubility measurements, we propose that the studied missense mutations cause three types of structural effects on the enzyme: 1) gross structural perturbations, 2) limited conformational changes in the active site, and 3) conformational modifications with no significant effect on enzymatic activity.

Animals↗
PubMed2001

The superior colliculus and its control of fixation behavior via projections to brainstem omnipause neurons.

Evidence, obtained in the animal whose head is unrestrained, has shown that the superior colliculus (SC) controls, not specifically eye-in-head motion, but rather saccadic shifts of the visual axis (gaze) composed of coordinated eye and head movements. The SC has also been implicated in fixation control. In a current hypothesis, activity on the SC motor map reflects two conflictual behavioral states: 'Orient!' versus 'Don't orient!' The latter behavior is thought to be commanded from a 'fixation zone' in the rostral SC that includes the foveal representation of the retinotopic map. 'Fixation neurons' (SCFNs) in this zone project to brainstem 'omnipause neurons' (OPNs) that inhibit the gaze-saccade generating circuits. It has been proposed that activity in SCFNs during active fixation, drives OPNs which in turn inhibit the gaze saccade generator, thereby maintaining the visual axis stable on a target of interest. Cats with head unrestrained frequently orient in the dark, to a briefly visible target, using multiple-step gaze shifts with a variable number of gaze saccades interspersed with periods of steady fixation. We found that SCFNs are not always active during the inter-step fixation periods when the visual axis is immobile--whereas OPNs are tonically active--thereby implying that activity in FNs and OPNs can be decoupled. In cats with head unrestrained, SCFNs encode the error between desired and actual gaze positions, not necessarily that the visual axis is immobile. By comparison, OPNs are tonically active when the visual axis is immobile, but some also encode gaze position error. Thus, the discharge of an OPN may reflect combined inputs from SCFNs combined with a steady bias.

Animals↗
PubMed2001

Computed tomography of pulmonary sarcoid-like granulomas induced by complete Freund's adjuvant in rats.

Intravenous injection of complete Freund's adjuvant (CFA) in rats has been proposed as an experimental model for pulmonary sarcoidosis, but only some animals develop granulomas. Because the detection of the presence of granulomas and evaluation of the extent of the reaction has required histological evaluation, this model has been of limited use in following the evolution of the granulomatous process. The present study evaluated the ability of lung computed tomography (CT) scanning to identify in vivo pulmonary granulomas induced by CFA in rats. Wistar rats were injected with CFA to induce pulmonary sarcoid-like granulomas, and the presence and extent of pulmonary abnormalities, as detected by spiral CT and histopathological analysis, were compared. Spiral CT had a high sensitivity and specificity for the detection of sarcoid-like granulomas in rats injected with CFA. The extent of the pulmonary granulomatous reaction as assessed by the two techniques strongly correlated (r=0.93, p<0.01). In contrast, the mean density of lungs containing granulomas was not significantly different from that of lungs with no granulomatous reaction. Thus, lung computed tomography appears to be a valuable tool for the in vivo evaluation of the pulmonary granulomatous reaction induced by complete Freund's adjuvant in rats. With the help of computed tomography, this experimental model should be suitable for the sequential study of pulmonary sarcoid-like granulomas, particularly in response to various therapeutic strategies.

Adjuvants, Immunologic↗
PubMed2000

Fixation neurons in the superior colliculus encode distance between current and desired gaze positions.

A visual scene is scrutinized during sequential periods of steady fixation, connected by saccades that shift the visual axis (gaze) to new positions. During such exploratory scan paths, gaze frequently strays from and then returns to salient features. How the brain keeps track of major end-goals and intermediate subgoals is not understood. We studied the discharge of fixation neurons of the brainstem's superior colliculus during multiple-step gaze shifts composed of a sequence of saccades made in the dark and separated by short periods of steady fixation. Cells were initially silent. As sequential gaze saccades approached the goal, firing began; its frequency increased progressively and peaked when gaze was on the remembered target location. We conclude that these fixation neurons encode the error between desired and actual gaze positions, irrespective of trajectory characteristics.

Action Potentials↗
PubMed2000

Chemosensory signal transduction in paramecium.

Paramecia are ciliated single-cell eukaryotic organisms that can respond to chemical cues in their environment. Glutamate is among those cues, which attract cells. We describe briefly here the following attributes of glutamate chemoresponse: 1) Cells are attracted to L-glutamate relative to KCl at high concentrations of glutamate. 2) There are at least two specific, relatively low affinity glutamate binding sites on the cell surface. Glutamate can be displaced from only one of the binding sites by inosine monophosphate (IMP), and quisqualate displaces glutamate from the second site, which is likely to be the glutamate receptor involved in attraction to glutamate. 3) IMP is a repellent and does not act synergistically with glutamate, whereas guanosine monophosphate (GMP) does. 4) Similarly, glutathione is an attractant, but glutamate and glutathione appear to use different transduction pathways. 5) Glutamate hyperpolarizes the cell. The ionic mechanism is not yet verified, but is likely to involve a K conductance. 6) Glutamate induces a rapid and robust increase in cAMP in the cell. Protein kinase A (PKA) is possibly involved in the transduction pathway because kinase inhibitors such as H7 and H8 inhibit glutamate response, but do not affect responses to other attractants, such as acetate and ammonium. Activation of PKA by the rapid rise in cAMP may sustain the hyperpolarization phosphorylation and activation of the plasma membrane calcium pump. 7) Candidate glutamate binding proteins are being identified among the cell surface proteins with the use of affinity chromatography.

Animals↗
PubMed2000

Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis?

High-resolution computed tomography (HRCT) has proved to be very useful in the diagnosis and follow-up of pulmonary Langerhans cell histiocytosis (PLCH), but the precise relationships between nodules and thin-wall cysts observed by HRCT, and granulomatous or cystic lesions present in lung tissue, remain to be established. The aim of this study was to compare quantitative data obtained by HRCT and those obtained by histopathological examination of corresponding lung tissue specimens in patients with biopsy-proven PLCH. The results demonstrated that the extent of nodular abnormalities was strongly correlated with the density of florid granulomatous lesions in lung tissue. A strong correlation was also found between the extent of cystic abnormalities and the density of cavitary lesions, but the latter included both still inflammatory cavitary granulomas and cicatricial fibrous cysts. Interestingly, small isolated florid granulomas were found in lung tissue from most patients with a predominant cystic CT scan pattern. Taken together, these results demonstrate that HRCT has to be considered with caution to evaluate the histopathological activity of PLCH. Patients presenting with predominant HRCT cystic abnormalities should benefit from a long-term follow-up. Because these patients are susceptible to developing severe respiratory insufficiency, they should also be considered for treatment as soon as an effective therapy for LCH is available.

Adult↗
PubMed1999

Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment.

Because Langerhans cells (LC) in peripheral tissues are generally "immature" cells with poor lymphostimulatory activity, the contribution of immune responses initiated by LC to the pathogenesis of pulmonary LC histiocytosis (LCH) has been uncertain. In this study we demonstrate that LC accumulating in LCH granulomas are phenotypically similar to mature lymphostimulatory dendritic cells present in lymphoid organs. LC in LCH granulomas intensely expressed B7-1 and B7-2 molecules, whereas normal pulmonary LC and LC accumulating in other pathologic lung disorders did not express these costimulatory molecules. The presence of B7+ LC in LCH granulomas was associated with the expression in these lesions, but not at other sites in the lung, of a unique profile of cytokines (presence of GM-CSF, TNF-alpha, and IL-1beta and the absence of IL-10) that is known to promote the in vitro differentiation of LC into cells expressing a lymphostimulatory phenotype. Finally, LCH granulomas were the only site where CD154-positive T cells could be identified in close contact with LC intensely expressing CD40 Ags. Taken together, these results strongly support the idea that an abnormal immune response initiated by LC may participate in the pathogenesis of pulmonary LCH, and suggest that therapeutic strategies aimed at modifying the lymphostimulatory phenotype of LC may be useful in the treatment of this disorder.

Adult↗
PubMed1999

In situ expression of B7 and CD40 costimulatory molecules by normal human lung macrophages and epithelioid cells in tuberculoid granulomas.

Normal alveolar macrophages (AM) are not efficient in inducing the proliferation of resting T lymphocytes, and, rather, tend to inhibit pulmonary immune responses. In contrast, epithelioid cells (EC), activated macrophages that play an essential role in the course of granulomatous responses, appear to stimulate T cell proliferation efficiently. The inability of macrophages to deliver potent costimulatory signals through the B7/CD28 and CD40/CD40L pathways could explain their weak accessory cell activity. Using MoAbs and immunohistochemical techniques, however, we found that essentially all AM in normal human lung tissue expressed B7-1, B7-2 and CD40 molecules, and most of these cells were strongly positive. Pulmonary macrophages in other compartments also expressed these costimulatory molecules; no differences in expression were observed comparing macrophages from smokers and non-smokers. Most AM recovered by bronchoalveolar lavage from normal lung segments also strongly expressed B7-1, B7-2 and CD40 molecules. In comparison, resting blood monocytes were B7-1- and only moderately positive for B7-2. Activation of monocytes with lipopolysaccharide (LPS) induced expression of these costimulatory molecules to levels similar to that of AM from the control subjects. EC in granulomatous lesions also expressed easily detectable levels of B7-1, B7-2 and CD40. T lymphocytes within and surrounding the granulomas expressed CD28, the counter-receptor for B7, and many of these T cells also expressed B7-1 and B7-2. These findings suggest that both AM and EC can deliver costimulatory signals through B7-1, B7-2 and CD40 molecules, and indicate that the impairment in accessory cell activity observed for normal AM cannot be attributed to the absence of expression of these costimulatory molecules.

Adult↗