FGFR1 and WT1 are markers of human prostate cancer progression

BACKGROUND: Androgen-independent prostate adenocarcinomas are responsible for about 6% of overall cancer deaths in men. METHODS: We used DNA microarrays to identify genes related to the transition between androgen-dependent and androgen-independent stages in the LuCaP 23.1 xenograft model of prostate adenocarcinoma. The expression of the proteins encoded by these genes was then assessed by immunohistochemistry on tissue microarrays (TMA) including human prostate carcinoma samples issued from 85 patients who had undergone radical prostatectomy. RESULTS: FGFR1, TACC1 and WT1 gene expression levels were associated with the androgen-independent stage in xenografts and human prostate carcinoma samples. MART1 protein expression was correlated with pT2 tumor stages. CONCLUSION: Our results suggest that each of these four genes may play a role, or at least reflect a stage of prostate carcinoma growth/development/progression

Recherche de facteurs pronostiques des lymphomes malins non hodgkiniens par la technique des "tissue arrays"

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Identification de marqueurs pronostiques et de cibles thérapeutiques potentielles dans le domaine des lymphomes malins non hodgkiniens

Alors que certaines entités de lymphomes non hodgkiniens (LNH) restent mal définies, d'autres, a priori mieux définies, manquent de marqueurs pronostiques capables de dépister les patients de mauvais pronostic. Des techniques dites " à grande échelle " appliquées à la recherche de marqueurs biologiques et pronostiques se sont récemment développées. Nous avons appliqué ces techniques " à grande échelle " aux LNH, et identifié des signatures moléculaires pronostiques pour le lymphome B diffus à grandes cellules (LBDGC) et le lymphome folliculaire (LF). Pour le LBDGC, nous avons validé l'impact pronostique de TCL1A par immunohistochimie sur tissue microarray et tenté d'évaluer l'intérêt de l'IL-18 dans un modèle murin de LBDGC. Nos résultats montraient l'impact pronostique des réactions immunitaires sur le LF. Enfin, nous avons démembré les lymphomes T périphériques-sans autre indication en trois classes moléculaires. Ces travaux illustrent comment ces techniques " à grande échelle " ont modifié l'appréhension de la biologie des LNH, même si nos résultats restent à valider.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Effets tardifs des radiations sur le foie

Until recently, the liver was classified as a radioresistant organ, although it is in fact highly radiosensitive. The realization that the whole liver could be treated safely only with low doses of radiation led to the conclusion that radiation therapy had an extremely limited role in the treatment of intrahepatic malignancies. A resurgence of interest has been observed with the advent of conformal radiotherapy and the introduction of bone marrow transplantation with total body irradiation. The radiation- induced liver disease, often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites, approximately 2 weeks to 4 months after hepatic irradiation. Immediate tolerance is generally surprisingly good, and the subacute radiation injury is followed by a complete asymptomatic healing, although the late lesions may be associated with signs of chronic radiation hepatitis. Radiation hepatitis must be distinguished from chemoradiation-induced-hepatitis occuring in patients undergoing bone marrow transplantation and total body irradiation. Both syndromes demonstrate the same pathological lesion: veno-occlusive disease. The main treatment for radiation hepatitis is diuretics, although soma advocate steroids for severe cases.SCOPUS: re.jinfo:eu-repo/semantics/publishe

New mechanistic insights of integrin β1 in breast cancer bone colonization

Bone metastasis is a frequent and life-threatening complication of breast cancer. The molecular mechanisms supporting the establishment of breast cancer cells in the skeleton are still not fully understood, which may be attributed to the lack of suitable models that interrogate interactions between human breast cancer cells and the bone microenvironment. Although it is well-known that integrins mediate adhesion of malignant cells to bone extracellular matrix, their role during bone colonization remains unclear. Here, the role of β1 integrins in bone colonization was investigated using tissue-engineered humanized in vitro and in vivo bone models. In vitro, bone-metastatic breast cancer cells with suppressed integrin β1 expression showed reduced attachment, spreading, and migration within human bone matrix compared to control cells. Cell proliferation in vitro was not affected by β1 integrin knockdown, yet tumor growth in vivo within humanized bone microenvironments was significantly inhibited upon β1 integrin suppression, as revealed by quantitative in/ex vivo fluorescence imaging and histological analysis. Tumor cells invaded bone marrow spaces in the humanized bone and formed osteolytic lesions; osteoclastic bone resorption was, however, not reduced by β1 integrin knockdown. Taken together, we demonstrate that β1 integrins have a pivotal role in bone colonization using unique tissue-engineered humanized bone models

Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly expresses EBNA3A with conserved CD8+ T-cell epitopes

Post-transplantation lymphoproliferative disorders (PTLD) arise in the immunosuppressed and are frequently Epstein-Barr virus (EBV) associated. The most common PTLD histological sub-type is diffuse large B-cell lymphoma (EBV+DLBCL-PTLD). Restoration of EBV-specific T-cell immunity can induce EBV+DLBCL-PTLD regression. The most frequent B-cell lymphoma in the immunocompetent is also DLBCL. ‘EBV-positive DLBCL of the elderly’ (EBV+DLBCL) is a rare but well-recognized DLBCL entity that occurs in the overtly immunocompetent, that has an adverse outcome relative to EBV-negative DLBCL. Unlike PTLD (which is classified as viral latency III), literature suggests EBV+DLBCL is typically latency II, i.e. expression is limited to the immuno-subdominant EBNA1, LMP1 and LMP2 EBV-proteins. If correct, this would be a major impediment for T-cell immunotherapeutic strategies. Unexpectedly we observed EBV+DLBCL-PTLD and EBV+DLBCL both shared features consistent with type III EBV-latency, including expression of the immuno-dominant EBNA3A protein. Extensive analysis showed frequent polymorphisms in EB-NA1 and LMP1 functionally defined CD8+ T-cell epitope encoding regions, whereas EBNA3A polymorphisms were very rare making this an attractive immunotherapy target. As with EBV+DLBCL-PTLD, the antigen presenting machinery within lymphomatous nodes was intact. EBV+DLBCL express EBNA3A suggesting it is amenable to immunotherapeutic strategies

Epstein-Barr virus-positive diffuse large B-cell lymphoma of\ud the elderly expresses EBNA3A with conserved CD8+ T-cell\ud epitopes

Post-transplantation lymphoproliferative disorders (PTLD) arise in the immunosuppressed and are frequently\ud Epstein-Barr virus (EBV) associated. The most common PTLD histological sub-type is diffuse large B-cell lymphoma\ud (EBV+DLBCL-PTLD). Restoration of EBV-specific T-cell immunity can induce EBV+DLBCL-PTLD regression. The\ud most frequent B-cell lymphoma in the immunocompetent is also DLBCL. ‘EBV-positive DLBCL of the elderly’\ud (EBV+DLBCL) is a rare but well-recognized DLBCL entity that occurs in the overtly immunocompetent, that has\ud an adverse outcome relative to EBV-negative DLBCL. Unlike PTLD (which is classified as viral latency III), literature\ud suggests EBV+DLBCL is typically latency II, i.e. expression is limited to the immuno-subdominant EBNA1, LMP1 and\ud LMP2 EBV-proteins. If correct, this would be a major impediment for T-cell immunotherapeutic strategies. Unexpectedly\ud we observed EBV+DLBCL-PTLD and EBV+DLBCL both shared features consistent with type III EBV-latency, including\ud expression of the immuno-dominant EBNA3A protein. Extensive analysis showed frequent polymorphisms in EBNA1\ud and LMP1 functionally defined CD8+ T-cell epitope encoding regions, whereas EBNA3A polymorphisms were very\ud rare making this an attractive immunotherapy target. As with EBV+DLBCL-PTLD, the antigen presenting machinery\ud within lymphomatous nodes was intact. EBV+DLBCL express EBNA3A suggesting it is amenable to immunotherapeutic\ud strategies

Constitutive nuclear localization and initial cytoplasmic apoptotic activation of endogenous caspase-3 evidenced by confocal microscopy

The localization of caspases and their substrates in different cellular compartments may be one way to regulate apoptosis. Caspase-3-dependent proteolysis of inhibitor caspase-activated deoxyribonuclease (ICAD) activates caspase-activated deoxyribonuclease (CAD), which induces apoptotic internucleosomal DNA degradation. The nuclear localization of ICAD, pro- and active-caspase-3 molecules remains a controversial issue. Using a combination of immunodetection of endogenous molecules and confocal microscopy, we analysed the kinetics of the procaspase-3 and CAD activation induced by FAS triggering in Jurkat cells. Through a semi-quantitative image analysis, we showed a constitutive nuclear localization of pro-caspase 3 and ICAD in non-apoptotic cells. FAS stimulation induced 7A6 apoptotic antigen expression, which could be related to three different sequential patterns of nuclear chromatin organization. Active-caspase-3 first appeared in the cytoplasm and was next observed in the nucleus. Simultaneously, the amount of ICAD located in the nucleus decreased, whereas the amount of ICAD located in the cytoplasm remained unchanged. Thus, our experiments using in situ immunodetection of endogenous molecules show that the ICAD cleavage by the active-caspase-3 probably takes place in the nucleus. These results provide new perspectives about the subcellular compartmentation and traffic of caspases during the apoptotic process