Verordeningen voor het Nederlandsch-Israëlietisch Kerkgenootschap : Verzameling uitg. op last der Centrale Commissie ... . Met aanteekeningen en alphabetisch register

door D. M. Sluys

Keur van grafsteenen op de Nederl.-Portug.-Israe͏̈l. begraafplaats te Ouderkerk aan den Amstel met beschrijving en biographische aanteekeningen : tot inleiding een en ander over deze en de vroegere begraafplaats der Nederl.-Portug.-Israe͏̈l. gemeente te Amsterdam ; eerste bundel

von D. Henriques de Castro

Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation

Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2/M cell cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1/S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1/S and G2/M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wildtype p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell cycle distribution profiling indicates constantly lower G1 and higher G2/M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared to the parental counterpart. IMPLICATIONS The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, since p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA damaging agents for MET positive/p53 negative tumors.

KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells.

The MET receptor tyrosine kinase is often deregulated in human cancers and several MET inhibitors are evaluated in clinical trials. Similarly to EGFR, MET signals through the RAS-RAF-ERK/MAPK pathway which plays key roles in cell proliferation and survival. Mutations of genes encoding for RAS proteins, particularly in KRAS, are commonly found in various tumors and are associated with constitutive activation of the MAPK pathway. It was shown for EGFR, that KRAS mutations render upstream EGFR inhibition ineffective in EGFR-positive colorectal cancers. Currently, there are no clinical studies evaluating MET inhibition impairment due to RAS mutations. To test the impact of RAS mutations on MET targeting, we generated tumor cells responsive to the MET inhibitor EMD1214063 that express KRAS G12V, G12D, G13D and HRAS G12V variants. We demonstrate that these MAPK-activating RAS mutations differentially interfere with MET-mediated biological effects of MET inhibition. We report increased residual ERK1/2 phosphorylation indicating that the downstream pathway remains active in presence of MET inhibition. Consequently, RAS variants counteracted MET inhibition-induced morphological changes as well as anti-proliferative and anchorage-independent growth effects. The effect of RAS mutants was reversed when MET inhibition was combined with MEK inhibitors AZD6244 and UO126. In an in vivo mouse xenograft model, MET-driven tumors harboring mutated RAS displayed resistance to MET inhibition. Taken together, our results demonstrate for the first time in details the role of KRAS and HRAS mutations in resistance to MET inhibition and suggest targeting both MET and MEK as an effective strategy when both oncogenic drivers are expressed.

Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting MET-associated angiogenesis as a major biological determinant for liver tumor growth control.

Gebeden der Nederlandsche Israelieten : ... Hebreeuwsch en Nederduitsch, met een historisch overzigt

bewerkt door G.I. Polak en M.L. van Ameringen

Metamorphosis Insectorum Surinamensium Ofte Verandering Der Surinaamsche Insecten : Waar in de Surinaamsche Rupsen en Wormen met alle des zelfs Veranderingen na het leven afgebeeld en beschreeven worden, zynde elk geplaast ob die Gewassen, Bloemen en Vruchten, daar sy op gevonden zyn ...

door Maria Sibylla Merian. [J. Mulder Sculp. ; P. Sluyter Sculp.]

De Europische Insecten : Naauwkeurig onderzogt, na't leven geschildert, en in print gebragt door Maria Sibilla Merian; Met een korte Beschryving, waar in door haar gehandelt word van der Rupsen begin, Voedzel en wonderbare Verandering; En Ook Vertoont Word De Oorspronk, Spys en Gestalt-verwisseling, de Tyd, Plaats en Eigenschappen der Rupzen, Uiltjes, Vliegen en andere diergelyke bloedeloose Beesjes; Hier Is Nog Bygevoegt Een naauwkeurige Beschryving van de Planten, in dit Werk voorkomende; ... In't Frans beschreven door J. Marret, Medicinæ Doctor, En door een voornaam Liefhebber in't Nederduits vertaalt

Die Illustrationen sind Kupferstiche

Mus Hs 7 - Psalmboek : voor orgel en clavicimbel, behelzende de CL psalmen, en gewoone lofzangen, op de ordinaire & sleute gesteld, en met een bas daar egens, en een bas continuo daar booven geteekent, met noch een twééde loopende bas, ofte bas obligato, dienende tot een variatio ; alsmede ider Psalm in zyn toon getransponeert, waar in dezelve moet gespeelt, en gezongen werden, voor't orgel, clavecimbel, en andre instrumenten

door Hk: Radeker

Catalogus van de tentoonstelling van Joodsche oorlogslitteratuur : gehouden te Amsterdam in de bibliotheek van het Portugeesch Israelietisch Seminarium "Ets Haim" ... van zondag 23 Nissan 5677 (15 April 1917) tot en met vrijdag 28 Nissan 5677 (20 April 1917) ten bate van het inzamelingswerk voor de Joodsche oorlogsslachtoffers

[bewerkt door J.S. Da Silva Rosa]

The survival role and the potential therapeutic targeting of MET in multiple myeloma

Multiple myeloma (MM) is a debilitating and incurable B-cell malignancy. Previous studies have documented that the hepatocyte growth factor (HGF) plays a role in the pathobiology of MM. The receptor tyrosine kinase MET induced signaling initiates when its ligand HGF binds to the MET receptor. However, the direct importance of MET in MM has not been elucidated. The present work used three different but complementary approaches to reduce MET protein levels or its activity to demonstrate the importance of MET in MM. ^ In the first approach, MET transcript and protein levels were reduced by directly targeting the cellular MET transcripts using shRNA retroviral infection techniques. This direct reduction of MET mRNA leads to a reduction of MET protein levels, which caused an inhibition of growth and induction of cell death. ^ In the second approach, a global transcription inhibitor flavopiridol was used as a potential pharmacological tool to reduce MET levels. MET has a short half-life of 30 min for mRNA and 4 hours for protein; therefore using a RNA pol II inhibitor such as flavopiridol would be a viable option to reduce MET levels. When using flavopiridol in MM cell lines, there was a reduction of MET transcript and protein levels, which was associated with the induction of cell death. ^ Finally in the last strategy, MET kinase activity was suppressed by MP470, a small molecule inhibitor that binds to the ATP binding pocket in the kinase domain. At concentrations where phosphorylation of MET was inhibited there was induction of cell death in MM cell lines and primary cells from patients. In addition, in MM cell lines there was a decrease in phosphorylation of AKT (ser473) and caspase-9 (ser196); downstream of MET, suggesting that the mechanism of action for survival may be through these cascade of events. ^ Overall, this study provides a proof-of-principle that MET is important for the survival of MM cell lines as well as primary plasma cells obtained from patients. Therefore, targeting MET therapeutically may be a possible strategy to treat patients with this debilitating disease of MM. ^