Pas-kaart van Europa met een gedeelte van de kust van Africa tot aen Cabo verde - [Yleisnäkymä - Overview]

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Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-β-Induced oxidative stress and apoptosis.

We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met−/− oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Metflx/flx), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Metflx/flx and Met−/− oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met-/- oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met−/− oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Metflx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met−/− oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Metflx/flx oval cells, whereas no effect was observed in Met−/− oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

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.

Estudi tècnic-econòmic de l'adaptació a la Llei de Benestar Animal d'una explotació porcina de la comarca d'Osona i posterior valoració de la seva implementació

Des de la publicació de la Llei de Benestar Animal RD 1135/ 2002, de 31 d’octubre que regula els tres aspectes clau de la producció porcina‐ sistemes d’estabulació i construccions permeses; formació obligatòria dels ramaders i maneig dels animals‐ totes les granges de nova construcció han estat projectades seguint els seus preceptes. Mentre que les granges existents han hagut d’adaptar‐hi les seves instal∙lacions sota amenaça de tancament si no es complien els requisits. L’objectiu d’aquest treball ha estat l’elaboració de l’estudi tècnic‐ econòmic per a l’adaptació a la Llei de Benestar Animal d’una explotació porcina de la comarca d’Osona. Després d’avaluar la situació inicial de les instal∙lacions, establir les línies de previsió de creixement i analitzar els avantatges i inconvenients de cada sistema i model, s’opta pel sistema d’alimentació electrònic model Nedap en grup dinàmic de truges sobre sòl amb jaç de palla. Una decisió no massa extesa en granges del sud d’Europa on se sol preferir l’slat de formigó i/o superfície pavimentada, però imprescindible perquè aquesta explotació pogués aconseguir una millor gestió de les dejeccions ramaderes i assegurar una millora agronòmica de les terres de conreu. El treball conclou amb el seguiment del desenvolupament de l’alternativa escollida i una valoració dels canvis derivats de l’adaptació al Benestar Animal després del primer any i mig en ús. Les millores obtingudes en termes de maneig, funcionament de la granja, salut dels animals i índex productius són remarcables. D’una banda, cal destacar el fet de tenir un nombre de coixeres molt menor respecte les granges amb superfície dura, així com la facilitat i rapidesa en els parts degut al benestar. De l’altra,la reducció del volum de purí, l’increment de la fracció sòlida i la disponibilitat de compost per al camp. Per això, no és exagerat observar el jaç amb palla com una de les solucions més adequades i equilibrades per aquesta explotació que combina boví, porcí i terra per a la producció de cultius.

Synthesis of a tetrahydroimidazo-[2',1':2,3]thiazolo[5,4-c]pyridine derivative with Met inhibitory activity

A straightforward synthesis of the Met antagonist JLK1360 involving an alkylationcyclocondensation process using aminothiazole 1 and nitrophenacyl bromide 2, reduction of the nitro group, and coupling of the resulting tetracyclic aniline 5 with an appropriate N-acyl alanine derivative, is reported.

Synthesis of a tetrahydroimidazo-[2',1':2,3]thiazolo[5,4-c]pyridine derivative with Met inhibitory activity

A straightforward synthesis of the Met antagonist JLK1360 involving an alkylationcyclocondensation process using aminothiazole 1 and nitrophenacyl bromide 2, reduction of the nitro group, and coupling of the resulting tetracyclic aniline 5 with an appropriate N-acyl alanine derivative, is reported.

Waarachtige en aen-merkens-waardige historie van Lapland: ofte een Beschrijving van desselfs oorspronk, landschappen, geberchten, gewassen, gedierten, metalen, steenen, wateren, en voornaemste geschiedenissen. Benessens der inwoonderen zeden, regeering, godtsdiensten, oorlogen, drachten, koophandel, gebouwen, van tenten, schepen, sleden, &c. Als ook van hare tover-trommelen, en wind-koopery. Met noch een kort bericht van den toestand der Finnen. Nieuwelijks uit het frans van den Heer Scheffer vertaalt. Met kurieuse kopere Plaaten

Added engraved title page: Waragtige en aanmerkenswaardige historie van Lapland en Finland.

Mäet pois

kuv., 13 x 19 cm

Hb Köln [a2b298(FG5) val-met] identified by DNA analysis in a Brazilian family

Hb Köln was identified by DNA analysis in a Brazilian patient. A four-year old Brazilian female, with jaundice since birth, presented an abnormal band, between A2 and S, in hemoglobin electrophoresis on a cellulose acetate membrane, and a band with electrophoretic migration similar to Hb C on agar gel. Thermic instability and isopropanol precipitation tests were positive. Heinz bodies were observed in the patient’s peripheral blood. Sequencing of the three exons of the b globin gene detected a transition from G to A in the first position of codon 98. This alteration does not create or abolish any known restriction site. In this case, confirmation of the mutation was accomplished by allele-specific oligonucleotide hybridization, which is a simple and fast identification method when the clinical data and hematological and electrophoretic patterns are suggestive of Hb Köln.

Die custe va Lijfflandt met de eijlanden daer beneffens ... tot Sijburgs ness tho : tractus littoralis Livoniae ab Ekeholmis ad Siburghnessam ... diligentissima descriptio

Julkaisussa: Speculum nauticum super navigatione maris Occidentalis confectum. - Vol. II: Pars altera speculi marini, integram cum borealis tum orientalis oceani navigationem