The ARF ru mor suppressor: structure, functions ans status in cancer

International audienc

P14 ARF inhibits the growth of lung adenocarcinoma cells harboring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway

International audienc

Contrôle de la signalisation oncogénique du mutant L858R de l'EGFR par la protéine suppresseur de tumeur p14ARF dans les adénocarcinomes pulmonaires

Contrôle de la signalisation oncogénique du mutant L858R de l'EGFR par la protéine suppresseur de tumeur p14ARF dans les adénocarcinomes pulmonaires. Le récepteur à l'EGF (EGFR) est un oncogène puissant impliqué dans le développement des cancers du poumon. Dans ces cancers, la présence de mutations activatrices de l'EGFR (majoritairement L858R et Del19) est un facteur prédictif de réponse aux agents pharmacologiques qui ciblent spécifiquement ce récepteur (EGFR-TKI). Cependant, l'association entre réponse thérapeutique et mutation est plus complexe que prévue, soulignant la nécessité d'approfondir la compréhension des mécanismes moléculaires impliqués dans développement de ces cancers. Nous avons précédemment montré que la quasi-totalité des tumeurs pulmonaires avec des mutations activatrices de l'EGFR présente une expression faible ou indétectable de la protéine suppressive de tumeur p14ARF. Ces résultats nous ont conduites à émettre l'hypothèse que l'expression de p14ARF était un frein essentiel à l'expansion clonale de ces cellules. Nous décrivons pour la première fois une relation fonctionnelle entre p14ARF et du mutant L858R de l'EGFR dans laquelle p14ARF inhibe la croissance de cellules exprimant ce mutant en induisant leur apoptose. Les effets suppresseurs de tumeur de p14ARF impliquent une fonction pro-apoptotique originale de STAT3 qui conduit à l'inhibition de l'expression de la protéine anti-apoptotique Bcl-2. De plus, nous montrons que les cellules EGFR-L858R maintiennent leur avantage de croissance en inhibant l'expression de p14ARF et la signalisation pro-apoptotique STAT3/Bcl-2 qui en découle. Nos résultats identifient également p14ARF comme une nouvelle cible transcriptionnelle de STAT3, mettant ainsi en évidence une boucle de rétrocontrôle positif entre ces deux protéines qui pourrait entretenir la signalisation pro-apoptotique médiée par STAT3. Sur la base de ces résultats, nous suggérons que la réactivation de la voie p14ARF/STAT3/Bcl-2 pourrait être une nouvelle stratégie thérapeutique dans le traitement de ces cancers.Control of EGFR-L858R oncogenic signaling pathway by the p14ARF tumor suppressor in lung adenocarcinoma. The EGF receptor (EGFR) is a strong oncogene involved in lung carcinogenesis. In these cancers, sensitivity to inhibitors of the EGFR tyrosine kinase activity (EGFR-TKI) has been shown to be related to the presence of activating mutations in the TK domain of EGFR (mainly L858R and Del19). However, the association between mutations and responsiveness to EGFR-TKI based treatment is more complex than previously envisioned, underlying the pressing need to study thoroughly the molecular mechanisms of lung cancer growth. We previously showed that almost all lung cancer with EGFR activated mutations has very low or undetectable levels of the p14ARF tumor suppressor protein. These results led us to postulate that expression of p14ARF is an efficient break against clonal proliferation of these cells. We report for the first time a relationship between p14ARF and mutant EGFR-L858R in which p14ARF inhibits the growth of EGFR-L858R expressing cells by inducing apoptosis. The p14ARF tumor suppressor effects involve an original STAT3 pro-apoptotic function that drives the inhibition of the anti-apoptotic Bcl-2 protein. Moreover, we show that the EGFR-L858R mutant maintains their survival and proliferation characteristics by inhibiting p14ARF expression and consequently the STAT3/Bcl-2 pro-apoptotic pathway. Our results also identify p14ARF as a new transcriptional target of STAT3, therefore providing evidence of a positive feed-back loop that could maintain STAT3 pro-apoptotic pathway. Based on these data, we suggest that manipulation of this pathway could be a therapeutic strategy for lung cancer treatment.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

asociacion entre angioma cavernoso y glioma cerebral reporte de dos casos y revision de la literatura acerca de los llamados angiogliomas

La asociacion entre las malformaciones vasculares y los gliomas cerebrales es inusual. Mientras que la asociacion entre angioma cavernoso con lesiones gliomatosas es aun mas rara, es por esto considerado por algunos autores como una entidad patologica particular llamada angioglioma. Los autores reportan dos casos de asociacion de un angioma cavernoso con una ganglioglioma y un oligodendroglioma, respectivamente. Ademas se realizo una revision de la literatura sobre los llamados angiogliomas. En opinion de los autores, la entidad de los angiogliomas se presenta dentro de un espectro general de neoplasias angiomatosas, que incluyen tumores cerebrales, en su mayoria gliomas de bajo grado, asociados a su vez, con un componente vascular importante

Next generation of ventricular catheters for hydrocephalus based on parametric design

Background The flow pattern of the cerebrospinal fluid is probably the most important factor related to obstruction of ventricular catheters during the normal treatment of hydro cephalus. To better comprehend the flow pattern, we have carried out a parametric study via numerical models of ven tricular catheters. In previous studies, the flow was studied under steady and, recently, in pulsatile boundary conditions by means of computational fluid dynamics (CFD) in three dimensional catheter models. Objective This study aimed to bring in prototype models of catheter CFD flow solutions as well to introduce the theory behind parametric development of ventricular catheters. Methods A preceding study allowed deriving basic principles which lead to designs with improved flow patterns of ventric ular catheters. The parameters chosen were the number of drainage segments, the distances between them, the number and diameter of the holes on each segment, as well as their relative angular position. Results CFD results of previously unreleased models of ven tricular catheter flow solutions are presented in this study. Parametric development guided new designs with better flow distribution while lowering the shear stress of the catheters holes. High-resolution 3D printed catheter solutions of three models and basic benchmark testing are introduced as well. Conclusions The next generation of catheter with homoge neous flow patterns based on parametric designs may repre sent a step forward for the treatment of hydrocephalus, by possibly broadening their lifespan

Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

International audienc

p14 ARF activates a Tip60-dependent ATM/ATR/CHK pathway in response to genotoxic stresses 2 Running title: ARF activates a Tip60-dependent DNA damage checkpoint 3

International audienc

A Case Report of "Spinal Cord Apoplexy" Elicited by Metastatic Intramedullary Thyroid Carcinoma

A 31-year-old man presented with acute onset of paraplegia. The patient's history was significant for thyroid carcinoma that had been treated 2 years earlier by thyroidectomy. A magnetic resonance imaging scan showed an enhancing intramedullary lesion at T7-8. Patient underwent surgical treatment and a tumor with hematoma was resected via posterior midline myelotomy. Postoperatively, the patient's motor weakness was improved to grade 3. The lesion showed typical histologic features consistent with papillary thyroid carcinoma. Early diagnosis and microsurgical resection can result in improvement in neurological deficits and quality of life of patients with an ISCM

A cervical ligamentum flavum cyst in an 82-year-old woman presenting with spinal cord compression: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>We report on a very rare case of a cervical ligamentum flavum cyst, which presented with progressive myelopathy and radiculopathy. The cyst was radically extirpated and our patient showed significant recovery. A review of the relevant literature yielded seven cases.</p> <p>Case presentation</p> <p>An 82-year-old Greek woman presented with progressive bilateral weakness of her upper extremities and causalgia, cervical pain, episodes of upper extremity numbness and significant walking difficulties. Her neurological examination showed diffusely decreased motor strength in both her upper and lower extremities. Magnetic resonance imaging of her cervical spine demonstrated a large, well-demarcated cystic lesion on the dorsal aspect of her spinal cord at the C3 to C4 level, significantly compressing the spinal cord at this level, in close proximity to the yellow ligament and the C3 left lamina. The largest diameter of this lesion was 1.4 cm, and there was no lesion enhancement after the intravenous administration of a paramagnetic contrast. The lesion was surgically removed after a bilateral C3 laminectomy. The thick cystic wall was yellow and fibro-elastic in consistency, while its content was gelatinous and yellow-brownish. A postoperative cervical-spine magnetic resonance image was obtained before her discharge, demonstrating decompression of her spinal cord and dural expansion. Her six-month follow-up evaluation revealed complete resolution of her walking difficulties, improvement in the muscle strength of her arms (4+/5 in all the affected muscle groups), no causalgia and a significant decrease in her preoperative upper extremity numbness.</p> <p>Conclusion</p> <p>Cervical ligamentum flavum cysts are rare benign lesions, which should be included in the list of differential diagnosis of spinal cystic lesions. They can be differentiated from other intracanalicular lesions by their hypointense appearance on T₁-weighted and hyperintense appearance on T₂-weighted magnetic resonance images, with contrast enhancement of the cystic wall. Surgical extirpation of the cyst is required for symptom alleviation and decompression of the spinal cord. The outcome of these cysts is excellent with no risk of recurrence.</p