MET: a promising anticancer therapeutic target.

The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.

Low-grade and high-grade mammary carcinomas in WAP-T transgenic mice are independent entities distinguished by Met expression.

Mammary carcinomas developing in SV40 transgenic WAP-T mice arise in two distinct histological phenotypes: as differentiated low-grade and undifferentiated high-grade tumors. We integrated different types of information such as histological grading, analysis of aCGH-based gene copy number and gene expression profiling to provide a comprehensive molecular description of mammary tumors in WAP-T mice. Applying a novel procedure for the correlation of gene copy number with gene expression on a global scale, we observed in tumor samples a global coherence between genotype and transcription. This coherence can be interpreted as a matched transcriptional regulation inherited from the cells of tumor origin and determined by the activity of cancer driver genes. Despite common recurrent genomic aberrations, e.g. gain of chr. 15 in most WAP-T tumors, loss of chr. 19 frequently occurs only in low-grade tumors. These tumors show features of "basal-like" epithelial differentiation, particularly expression of keratin 14. The high-grade tumors are clearly separated from the low-grade tumors by strong expression of the Met gene and by coexpression of epithelial (e.g. keratin 18) and mesenchymal (e.g. vimentin) markers. In high-grade tumors, the expression of the nonmutated Met protein is associated with Met-locus amplification and Met activity. The role of Met as a cancer driver gene is supported by the contribution of active Met signaling to motility and growth of mammary tumor-derived cells. Finally, we discuss the independent origin of low- and high-grade tumors from distinct cells of tumor origin, possibly luminal progenitors, distinguished by Met gene expression and Met signaling.

Quand la liturgie met en jeu des attitudes empruntées à la Bible

(Résumé de l'ouvrage) Quelle place pour la Bible dans la célébration liturgique? Catholiques et protestants sont marqués par des traditions différentes, biblistes et liturgistes divergent sur la question, les attentes des fidèles sont pratiques. Ce livre réunit des études dans différentes disciplines théologiques: Des exégètes exposent les découvertes sur la naissance de la Bible tant juive que chrétienne au début de notre ère, des historiens montrent l'utilisation de la Bible dans l'histoire de l'Église, des liturgistes comparent et évaluent les systèmes de lecture mis en vigueur par les récentes réformes liturgiques. Il en va de la réception de la divine Parole dans l'Eglise d'aujourd'hui. Le rituel de la proclamation a son importance. Informations et réflexions à ce propos se côtoient dans le présent volume. Une vingtaine d'auteur(e)s interpellent ceux et celles qui au culte ou à la messe reçoivent la Parole vivante.

Distinct sets of alphabeta TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues.

Naturally acquired immune responses against human cancers often include CD8(+) T cells specific for the cancer testis antigen NY-ESO-1. Here, we studied T cell receptor (TCR) primary structure and function of 605 HLA-A*0201/NY-ESO-1(157-165)-specific CD8 T cell clones derived from five melanoma patients. We show that an important proportion of tumor-reactive T cells preferentially use TCR AV3S1/BV8S2 chains, with remarkably conserved CDR3 amino acid motifs and lengths in both chains. All remaining T cell clones belong to two additional sets expressing BV1 or BV13 TCRs, associated with alpha-chains with highly diverse VJ usage, CDR3 amino acid sequence, and length. Yet, all T cell clonotypes recognize tumor antigen with similar functional avidity. Two residues, Met-160 and Trp-161, located in the middle region of the NY-ESO-1(157-165) peptide, are critical for recognition by most of the T cell clonotypes. Collectively, our data show that a large number of alphabeta TCRs, belonging to three distinct sets (AVx/BV1, AV3/BV8, AVx/BV13) bind pMHC with equal antigen sensitivity and recognize the same peptide motif. Finally, this in-depth study of recognition of a self-antigen suggests that in part similar biophysical mechanisms shape TCR repertoires toward foreign and self-antigens.

Quand le sociologue se met le doigt dans l'oeil. L'observation ethnographique et la photographie à l'épreuve des compétences visuelles policières

Cet article propose un retour méthodologique sur une enquête de terrain parmi les policiers de la ville de Lausanne (Suisse). En plus des observations conduites, des photographies ont été prises durant les patrouilles. Les images produites par le chercheur ont alors fait l'objet d'une présentation systématique aux enquêtés. Cet échange in situ autour des photographies a ouvert des pistes pour documenter empiriquement l'organisation professionnelle des regards, ainsi que les « compétences visuelles » à l'oeuvre dans le contexte du travail policier.

Evidence for different expression profiles for c-Met, EGFR, PTEN and the mTOR pathway in low and high grade endometrial carcinomas in a cohort of consecutive women. Occurrence of PIK3CA and K-Ras mutations and microsatellite instability.

Molecular and genetic investigations in endometrial carcinogenesis may have prognostic and therapeutic implications. We studied the expression of EGFR, c-Met, PTEN and the mTOR signalling pathway (phospho-AKT/phospho-mTOR/phospho-RPS6) in 69 consecutive tumours and 16 tissue microarrays. We also analysed PIK3CA, K-Ras mutations and microsatellite instability (MSI). We distinguished two groups: group 1 (grade 1 and 2 endometrioid cancers) and group 2 (grade 3 endometrioid and type II clear and serous cell cancers). We hypothesised that these histological groups might have different features. We found that a) survival was higher in group 1 with less aggressive tumours (P⟨0.03); b) EGFR (P=0.01), PTEN and the AKT/mTOR/RPS6 signalling pathway were increased in group 1 versus group 2 (P=0.05 for phospho-mTOR); c) conversely, c-Met was higher (P⟨0.03) in group 2 than in group 1; d) In group 1, EGFR was correlated with c-Met, phospho-mTOR, phospho-RPS6 and the global activity of the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway. In group 2, EGFR was correlated only with the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway, whereas c-Met was correlated with PTEN; e) survival was higher for tumours with more than 50% PTEN-positive cells; f) K-RAS and PIK3CA mutations occurred in 10-12% of the available tumours and MSI in 40.4%, with a loss of MLH1 and PMS2 expression. Our results for endometrial cancers provide the first evidence for a difference in status between groups 1 and 2. The patients may benefit from different targeted treatments, anti-EGFR agents and rapamycin derivatives (anti-mTOR) for group 1 and an anti c-MET/ligand complex for group 2.

A role for septins in the interaction between the Listeria monocytogenes INVASION PROTEIN InlB and the Met receptor.

Septins are conserved GTPases that form filaments and are required for cell division. During interphase, septin filaments associate with cellular membrane and cytoskeleton networks, yet the functional significance of these associations have, to our knowledge, remained unknown. We recently discovered that different septins, SEPT2 and SEPT11, regulate the InlB-mediated entry of Listeria monocytogenes into host cells. Here we address the role of SEPT2 and SEPT11 in the InlB-Met interactions underlying Listeria invasion to explore how septins modulate surface receptor function. We observed that differences in InlB-mediated Listeria entry correlated with differences in Met surface expression caused by septin depletion. Using atomic force microscopy on living cells, we show that septin depletion significantly reduced the unbinding force of InlB-Met interaction and the viscosity of membrane tethers at locations where the InlB-Met interaction occurs. Strikingly, the same order of difference was observed for cells in which the actin cytoskeleton was disrupted. Consistent with a proposed role of septins in association with the actin cytoskeleton, we show that cell elasticity is decreased upon septin or actin inactivation. Septins are therefore likely to participate in anchorage of the Met receptor to the actin cytoskeleton, and represent a critical determinant in surface receptor function.

High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis.

AIMS: c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting. METHODS AND RESULTS: c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis. CONCLUSIONS: Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.

Testi volgari della seconda metà del sec. XIV attorno ai Visconti

Oggetto della tesi è la poesia volgare prodotta nell'orbita della corte viscontea nel corso del Trecento e del primo Quattrocento. La presente ricerca si propone di illustrare il contesto culturale lombardo e correggere alcuni giudizi di colore avanzati dagli studi positivistici di fine Ottocento e inizio Novecento, attraverso un'indagine rigorosa sui testi scritti attorno ai Visconti, dei quali si propone un'edizione filologicamente sorvegliata, accompagnata da uno studio sulla tradizione manoscritta, da cappelli introduttivi, apparati critici e note di commento. Una prima sezione ospita il corpus di rime dell'aretino Braccio Bracci: tre canzoni {Silenzio posto aveva al dire in rima-, O aspettato dalla giusta verga e lo scambio epistolare fittizio Soldan di Bambilonia et ceterà-Illustri e serenissimo, alto e vero) e quindici sonetti (O tesorier, che 7 bel tesor d'Omero-, Antonio mio, tua fama era inmortale; Deh, non guastare il popol cristiano; O santo Pietro, per Dio, non restare; El tempio tuo, che tu edificasti-, Veggio l'antica, dritta e ferma Scala-, Messer Luigi, vostra nobil fama-, Volse Traian, quando la vedovella-, Firenze, or ti rallegra, or ti conforta-, O infamato da ' lucenti raggi-, Sette sorelle sono a mme venute-, Sempre son stato con gran signoria; Se Ile cose terrene al possesore; Sia con voi pace, signor' fiorentini). La seconda sezione accoglie dodici sonetti attribuiti al fiorentino Marchionne di Matteo Arrighi {Deh, quant 'egli è in villa un bello stare; Omé, e ' mi par che Ila mia rota torca; Acciò che veggi chiaro il mio sonetto; Tu non potrai più bere alle stagioni; O Iscatizza di vii condizione; Se mille volte il dì tu m'uccidessi; Io n'ò 'n dispetto il Sole e Ila Luna; Tanto mi piace l'angelico sono; Lasso, tapino a mme, quando riguardo; Era venuta nella mente mia; Io ti ricordo, caro amico fino; Solo soletto ma non di pensieri). Nella terza sezione si propongono due canzoni viscontee del magister Giovanni da Modena, La mia gravosa e disformata vita e Ne l'ora che la caligin nocturna . La quarta e ultima sezione è dedicata ad alcune poesie anonime viscontee: sei sonetti (Egli è gran tempo, dolce Signor mio; Quela dolce saeta che nel core; Stan le cita lombarde co le chiave; Cesere in arme fu feroce e franco; l'pensava stancar la destra mano; Poniam silenzio a tutti i gran Signori), due ballate (Chi troppo al fuoco si lassa apressare e Io udii già cantare), due Lamenti di Bernabò Visconti in ottava rima (Novo lamento con doglioxo pianto e l'prego Idio eh 'è Signore e Padre, quest'ultimo pronunciato da un tal Matteo da Milano) e una canzone in morte del duca Gian Galeazzo {Fortuna c 'ogni ben mundan remuti).

Prevalence and clinical outcomes for patients with MET protein expression in patients with non-small cell lung cancer in Europe: Results from the European Thoracic Oncology Platform Lungscape Project.

Aim The reported prevalence of MET overexpression varies from 25-55% in non-small cell lung cancer (NSCLC) and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the Lungscape program, we explore the epidemiology, the natural history of IHC MET positivity and its association to OS, RFS and TTR. Methods Resected stage I-III NSCLC identified based on the quality of clinical data and FFPE tissue availability were assessed for MET expression using immunohistochemistry (IHC) on TMAs (CONFIRM anti total c-MET assay, clone SP44, Ventana BenchMark platform). All cases were analysed at participating pathology laboratories using the same protocol, after passing an external quality assurance program. MET positive status is defined as ≥ 50% of tumor cells staining with 2+ or 3+ intensity. Results A total of 2709 cases are included in the iBiobank and will be analysed. IHC MET expression is currently available for 1552 patients, with positive MET IHC staining in 380 cases [24.5%; IHC 3+ in 157 cases (41.3%) and 2+ in 223 cases (58.7%)]. The cohort of 1552 patients includes 48.2%, 44.7% and 4.4% cases of adenocarcinoma, squamous and large cell histologies, respectively. IHC MET status was independent of stage, age and smoking history. Significant differences in MET positivity were associated with gender (32% vs. 21% for female vs. male, p < 0.001), with performance status (25% vs. 18% for 0 vs. 1-3, p = 0.006), and histology (34%, 14% and 24% for adenocarcinoma, squamous and large cell carcinoma, p < 0.001). IHC MET positivity was independent of the IHC ALK status (p = 0.08). At last FU, 52% of patients were still alive, with a median FU of 4.8 yrs. No association of IHC MET was found with OS, RFS or TTR. Conclusions The preliminary results for this large multicentre European cohort describe a prevalence of MET overexpression that seems lower than previous observations in NSCLC, such as reported for the OAM4971g trial, suggesting potential biological differences between surgically resected and metastatic disease. Analysis for the full cohort is ongoing and results will be presented. Disclosure L. Bubendorf: Disclosures: Stock ownership: Roche Advisory boards: Roche, Pfizer Research support: Roche; K. Schulze: Full time employee of Roche; A. Das-Gupta: I am a full time employee of Roche. All other authors have declared no conflicts of interest.

Simenon, un auteur et ses lecteurs : une économie de la grandeur

En invitant à se pencher sur les modalités concrètes de la réception d'un écrivain, l'étude des lettres de lecteurs à Simenon met en lumière ce que ce dernier fait à et pour eux, et ce, dans l'enchevêtrement de la personne réelle, du personnage de fiction (Maigret) et de la vedette. Les traits marquants de la relation auteurs-lecteurs sont examinés, en tenant compte de la tension spécifique engendrée par les valeurs marchandes et symboliques portées ensemble par un auteur présent sur plus d'un terrain : commercial, médiatique et littéraire. Au final, il s'agit de décrire les formes d'un « attachement aux grands singuliers » (Heinich) qu'illustre la correspondance « ordinaire » à Simenon.