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Casablanca, Morocco

Lessard L.,McGill University | Labbe D.P.,McGill University | Deblois G.,McGill University | Begin L.R.,Service danatomopathologie | And 8 more authors.
Cancer Research | Year: 2012

The androgen receptor (AR) signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that the protein tyrosine phosphatase PTP1B, a well-established regulator of metabolic signaling, was induced after androgen stimulation of AR-expressing prostate cancer cells. PTP1B induction by androgen occurred at the mRNA and protein levels to increase PTP1B activity. High-resolution chromosome mapping revealed AR recruitment to two response elements within the first intron of the PTP1B encoding gene PTPN1, correlating with an AR-mediated increase in RNA polymerase II recruitment to the PTPN1 transcriptional start site. We found that PTPN1 and AR genes were coamplified in metastatic tumors and that PTPN1 amplification was associated with a subset of high-risk primary tumors. Functionally, PTP1B depletion delayed the growth of androgen-dependent human prostate tumors and impaired androgen-induced cell migration and invasion in vitro. However, PTP1B was also required for optimal cell migration of androgen-independent cells. Collectively, our results established the AR as a transcriptional regulator of PTPN1 transcription and implicated PTP1B in a tumor-promoting role in prostate cancer. Our findings support the preclinical testing of PTP1B inhibitors for prostate cancer treatment. ©2012 AACR.

Thervet E.,University of Paris Descartes | Aouizerate J.,Service de Transplantation | Noel L.H.,Laboratoire danatomopathologie | Brocheriou I.,Service danatomopathologie | And 3 more authors.
Transplantation | Year: 2011

Background. Henoch-Schonlein Purpura nephropathy (HSPN) recurrence in renal transplant recipients (RTRs) has been reported in 35% of patients, leading in 11% of these patients to graft loss at 5 years. However, its true incidence is unknown. The aim of this study was to investigate this recurrence incidence using routine allograft biopsies (RBs). Methods. All RTRs with biopsy-proven HSP initial nephropathy were included (13 RTRs and 18 renal transplantations). At transplantation, the median age was 34 years, and 85% of RTRs were men. Overall, we analyzed 66 RBs that were routinely performed at 3 and 12 months after RT and when clinically indicated. Histologic recurrence was defined as the presence of IgA deposits within the mesangium and along the glomerular capillary walls. Results. After a median follow-up of 83 months (range, 13-232 months; interquartile range, 26-235 months), histologic recurrence was detected in 69% of patients and in 61% of grafts after a mean period of 24 months (range, 1-156 months). Clinical or biological signs were absent in all but one. Patient survival was 92.8%. Graft loss occurred in five cases, never were related to recurrence. At the last follow-up, the mean glomerular filtration rate was 48±14.2 mL/min/1.73 m; in patients with and without recurrence, the mean rates were 52.1±17.5 and 42.4±5.3 mL/min/1.73 m, respectively (P=0.27). Conclusion. Histologic recurrence of HSPN after RT is frequently observed on routine RBs but is not associated with clinical consequences. The short-term prognosis of recurrence is good, but its long-term prognosis remains to be determined. © 2011 by Lippincott Williams & Wilkins.

Wantz M.,Service de dermatologie | Spanoudi-Kitrimi I.,Service de dermatologie | Lasek A.,Service de dermatologie | Lebas D.,Service de dermatologie | And 2 more authors.
Annales de Dermatologie et de Venereologie | Year: 2014

Background Herein we report the first case of toxic epidermal necrolysis (TEN) occurring with use of vemurafenib. Patients and methods A 75-year-old female patient was being treated with vemurafenib for stage IV melanoma with BRAF V600E mutation. She suddenly presented fever, diffuse pruriginous maculopapular erythema, palpebral edema, palmar bulla, conjunctivitis, cheilitis and mucosal ulceration. The condition progressed towards detachment affecting 50% of the skin area. Cutaneous biopsy revealed lichenoid dermatosis, chiefly vesicular with numerous eosinophils. Direct immunofluorescence (IFD) was negative. Vemurafenib was the only drug to which the reaction was ascribable and we concluded on vemurafenib-induced TEN. Discussion To our knowledge, this is the first reported case of vemurafenib-induced TEN, but this adverse effect, although already described in the BRIM-3 study, appears rare in clinical practice. Other severe skin reactions have been described in the literature. These include a case of Stevens-Johnson syndrome in a female patient treated with vemurafenib and previously receiving ipilimumab. A more common occurrence is cutaneous reactions involving efflorescence of benign hyperkeratotic lesions, occasionally accompanied by authentic epidermal carcinoma or keratoacanthoma, and requiring regular dermatological monitoring of patients treated with vemurafenib. Conclusion If maculopapular exanthema occurs under vemurafenib, continuation of this treatment should be reassessed since the risk of progression to a more serious condition such as TEN, as seen in the present case, cannot be ruled out. © 2013 Elsevier Masson SAS.

Hardy S.,McGill University | Uetani N.,McGill University | Wong N.,McGill University | Kostantin E.,McGill University | And 5 more authors.
Oncogene | Year: 2015

The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.

Camdessanche J.-P.,Jean Monnet University | Streichenberger N.,Service danatomopathologie | Cavillon G.,Pres de Lyon 1 | Rogemond V.,Pres de Lyon 1 | And 4 more authors.
European Journal of Neurology | Year: 2011

Background and purpose: Anti-N-methyl-d-asparate (NMDA) receptor encephalitis is thought to be antibody-mediated. To perform an immunohistopathological study of the inflammatory reaction in a brain biopsy performed before immunomodulatory treatments in a patient with anti-NMDA receptor encephalitis. Methods: An immunohistochemical study was performed using CD3, CD68, CD20, CD138 and CD1a antibodies. Results: Prominent B-cell cuffing was present around brain vessels accompanied by some plasma cells, while macrophages and T cells were scattered throughout the brain parenchyma. Conclusion: These findings suggest that the B cells interact with the T cells and are involved in antibody secretion by the plasma cells. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

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