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Biomedical subjects

Pierre Validire

Publications and source records attributed to Pierre Validire.

7 recordsLinked to original sources
PubMed2003

A three-dimensional tumor cell defect in activating autologous CTLs is associated with inefficient antigen presentation correlated with heat shock protein-70 down-regulation.

We described previously a CTL clone able to lyse the autologous carcinoma cell line IGR-Heu after specific recognition of an HLA-A2/mutated alpha-actinin-4 peptide complex. Here, we used IGR-Heu, cultured either as standard two-dimensional monolayers or as three-dimensional spheroids, to further analyze the influence of target architecture on CTL reactivity. Interestingly, we found that changes in the tumor structure from two- to three-dimensional induced a dramatic decrease in its capacity to activate autologous CTL, as measured by IFN-gamma and tumor necrosis factor-alpha secretion. These functional alterations were attributable neither to MHC class I expression nor to tumor antigen (Ag) down-regulation, because IGR-Heu, cultured as two- or three-dimensional, expressed similar levels of HLA-A2 and alpha-actinin-4. More importantly, incubation of three-dimensional cells with synthetic epitope completely restored cytokine release by CTL. This defective Ag presentation correlated with a decrease in heat shock protein (hsp)70 expression by three-dimensional tumors compared with two-dimensional cells. Furthermore, transfection of the tumor cells with hsp70 cDNA completely restored the Ag-presenting potential of spheroids and, therefore, cytokine production by T cells. These data strongly suggest that hsp70 down-regulation in three-dimensional cells may result in tumor resistance to the immune response.

Antigen Presentation↗
PubMed2003

The zinc finger protein OZF (ZNF146) is overexpressed in colorectal cancer.

Overexpression of the OZF gene has previously been demonstrated in the majority of pancreatic cancers. However, because the stages of tumour progression in this disease are poorly defined, no conclusion could be drawn concerning the relationship between OZF overexpression and the course of tumour progression. In contrast, initiation and progression steps are well defined in colorectal cancer. Most colon cancers are believed to arise from polypoid adenomas as a result of the gradual accumulation of genetic alterations, allowing the study of genetic events in the early stages of neoplasia. Accordingly, we wanted to assess the frequency of OZF overexpression in this tumour type and the relationship between overexpression and disease stage. Twenty-five colon carcinoma specimens from different sites and at various stages were analysed by immunoblotting using a highly specific mouse monoclonal antibody. Each sample was compared with adjacent normal colonic mucosa. Complementary immunohistochemical analysis was also carried out on a commercially available tissue array to identify cells expressing OZF. Of the 25 tumours analysed by immunoblotting, 20 expressed higher levels of OZF protein than their adjacent normal mucosa. Immunohistochemistry revealed OZF expression in tumour cells of 56/59 carcinomas and occasionally in infiltrating lymphocytes but at lower levels. Little or no staining was observed in cells taken from normal or inflammatory colon specimens. In both immunoblot and immunohistochemistry experiments, no correlation was found between OZF expression and clinical parameters such as TNM classification, stage, localization and age. Immunostaining was observed in low-grade adenomas, indicating that OZF expression occurs very early in the course of tumour progression. OZF expression, infrequent or absent in normal colonic mucosa, is present in more than 80% of colorectal cancers. Dysregulation of the OZF gene is an early event that may be implicated in the genesis of colonic carcinoma and may therefore provide a potential therapeutic target.

Adenoma↗
PubMed2002

Impact of human bladder cancer cell architecture on autologous T-lymphocyte activation.

To investigate the influence of tumor cell architecture on T-cell activation, we used an autologous human model based on 2 bladder tumor cell lines as targets for cytotoxic tumor-infiltrating lymphocytes (TILs). These tumor cell lines were grown in vitro as either standard 2-dimensional (2D) monolayers or 3-dimensional (3D) spheroids. T-cell activation was determined by measuring the production of three major cytokines (tumor necrosis factor, granulocyte/macrophage colony-stimulating factor and interferon-gamma), known to be secreted by most activated TILs. Changes in the architecture of target cells from 2D to 3D induced a dramatic decrease in their capacity for stimulating TILs. Interestingly, neither TIL infiltration nor MHC class I, B7.1 costimulatory or lymphocyte function-associated factor-3 adhesion molecule downregulation played a major role in this decrease. These findings demonstrate that tumor architecture has a major impact on T-cell activation and might be implicated in the escape of tumor cells from the immune system.

CD58 Antigens↗
PubMed2002

Full thoracoscopic approach for surgical management of invasive pulmonary aspergillosis.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a frequent and serious infection occurring in patients with hematologic malignancies and allogenic stem cell transplant (SCT) recipients, causing a high mortality rate. We report the use of full thoracoscopic management in 19 patients. METHODS: Nineteen patients (mean age 27 years) with diagnosed or probable IPA were operated on. Seventeen had an hematologic malignancy and 2 had a refractory aplastic anemia. Nine patients had undergone an allogenic SCT that was complicated by a graft-versus-host disease in 5 patients. In 3 patients, SCT was pending. All patients had preoperative systemic antifungal therapy for at least 2 weeks. Fifteen patients had only one lesion, whereas 4 had two lesions. Eight patients had an absolute neutrophil count less than 3,000 and 2 less than 1,000, and 9 were thrombopenic (platelet count <60,000) at the day of surgery. Wedge resections were performed in 7 patients and lobectomies were performed for the other 12. For the latter, an open approach via posterolateral thoracotomy was decided upon in only 1 patient. For the other 11 lobectomies, a mini-thoracotomy was needed in 3 cases for intraoperative difficulties. Conversion to conventional thoracotomy was necessary for 2 of these patients. In total, out of the 19 patients, 15 had a total endoscopic approach, 3 had a thoracotomy, and 1 had a video-assisted approach. RESULTS: There was no intraoperative mortality. In the group of wedge resections, no intraoperative or postoperative complication occurred. In the lobectomy group, three hemorrhages occurred during dissection of the pulmonary artery in the fissure, leading to conversion to a mini-thoracotomy in 2 patients and to a classic posterolateral thoracotomy in 1 patient. There were two minor complications: one pneumothorax and one mild pleural effusion. CONCLUSIONS: In these debilitated and immunocompromised patients, a full thoracoscopic resection of fungal infection is feasible, even for lobectomies. It allows a simpler postoperative course and minimizes sequelae.

Adolescent↗
PubMed2002

Laparoscopic radical prostatectomy. preliminary pathologic evaluation.

OBJECTIVES: Although there is increasing evidence of the interest in the laparoscopic approach for radical prostatectomy, carcinologic data, including surgical margin status, remain to be described. METHODS: We analyzed the oncologic results of laparoscopic prostatectomies performed during 2000. The data were compared with retropubic prostatectomies performed between 1994 and 1997 by the same two senior urologists. After matching for preoperative prostate-specific antigen level, the final analysis included 139 patients in both groups, with similar data for age, biopsy Gleason score, and number of positive biopsies. All specimens were processed with the same method of pathologic evaluation. The results were compared using either the chi-square test or Student t test. RESULTS: The mean prostate weight and rate of positive lymph nodes were similar in both groups. No statistical difference was observed in the distribution of either the radical prostatectomy Gleason score or the pathologic stage between the laparoscopic and retropubic groups. In contrast, the decrease in the rate of positive surgical margins was statistically significant in the laparoscopic approach compared with the retropubic approach (P <0.02), particularly in localized cancers (pT2). No difference was observed in either the length or the distribution of the margin location. The rate of positive apical margins in organ-confined disease was significantly decreased in the laparoscopic group. CONCLUSIONS: These results suggest that laparoscopic prostatectomy performed by trained surgeons does not lead to an increased risk of positive margins compared with the retropubic approach.

Adenocarcinoma↗
PubMedDate not supplied

Expression of genes involved in chemoresistance, proliferation and apoptosis in clinical samples of renal cell carcinoma and correlation with clinical outcome.

This study investigated the multidrug resistance, proliferation and apoptosis expression in renal cell carcinomas compared to adjacent normal kidney (ANK) tissues. Multidrug resistance (MDR1), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi), Topoisomerase-II alpha (TOPO-IIalpha), thymidylate synthase (TS), thymidine kinase (TK), Ki67, BAX and BCL-2 genes were analysed in a series of 30 renal cell carcinomas (RCC) and 16 biopsies from adjacent normal kidney (ANK) tissue using reverse-transcription-PCR (rt-PCR). The mean MDR1 expression was significantly lower in RCC than that of ANK (0.4 +/- 0.2 sd versus 0.75 +/- 0.19, p = 0.0008). The expression of MRP, GST-pi and TOPO-IIalpha was not significantly different in RCC as compared with ANK. The mean TK expression in RCC was significantly higher than in ANK (0.31 +/- 0.15 versus 0.09 +/- 0.08, p = 0.002). The TS and Ki67 expression in RCC was significantly higher than in ANK (87.5%, IC95% 71-100% versus 0%, p = 0.001; 56% IC95% 32-81% versus 0%, p = 0.004, respectively). BAX and BCL-2 expression in RCC was significantly higher than that of ANK (0.51 +/- 0.08 versus 0.18 +/- 0.12, p = 0.0001; 0.73 +/- 0.16 versus 0.5 +/- 0.22, p = 0.01, respectively). No significant correlation was found between MDR1, MRP, GST-pi, TOPO-IIalpha, TS, TK and BAX expression with the grade and the clinical stage in RCC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗