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Macropinocytotic uptake and infection of human epithelial cells with species B2 adenovirus type 35

Kälin, S. (author), Amstutz, B. (author), Gastaldelli, M. (author), Wolfrum, N. (author), Boucke, K. (author), Havenga, M. (author), DiGennaro, F. (author), Liska, N. (author), Hemmi, S. (author), Greber, U.F. (author), TNO Kwaliteit van Leven (author)

Human adenovirus serotype 35 (HAdV-35; here referred to as Ad35) causes kidney and urinary tract infections and infects respiratory organs of immunocompromised individuals. Unlike other adenoviruses, Ad35 has a low seroprevalence, which makes Ad35-based vectors promising candidates for gene therapy. Ad35 utilizes CD46 and integrins as receptors...

article 2010

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Effect of neutralizing sera on factor X-mediated adenovirus serotype 5 gene transfer

Parker, A.L. (author), Waddington, S.N. (author), Buckley, S.M.K. (author), Custers, J. (author), Havenga, M.J.E. (author), van Rooijen, N. (author), Goudsmit, J. (author), McVey, J.H. (author), Nicklin, S.A. (author), Baker, A.H. (author), TNO Kwaliteit van Leven (author)

The deployment of adenovirus serotype 5 (Ad5)-based vectors is hampered by preexisting immunity. When such vectors are delivered intravenously, hepatocyte transduction is mediated by the hexon-coagulation factor X (FX) interaction. Here, we demonstrate that human sera efficiently block FX-mediated cellular binding and transduction of Ad5-based...

article 2009

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Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys

Liu, J. (author), O'Brien, K.L. (author), Lynch, D.M. (author), Simmons, N.L. (author), La Porte, A. (author), Riggs, A.M. (author), Abbink, P. (author), Coffey, R.T. (author), Grandpre, L.E. (author), Seaman, M.S. (author), Landucci, G. (author), Forthal, D.N. (author), Montefiori, D.C. (author), Carville, A. (author), Mansfield, K.G. (author), Havenga, M.J. (author), Pau, M.G. (author), Goudsmit, J. (author), Barouch, D.H. (author), TNO Kwaliteit van Leven (author)

A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus...

article 2009

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Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

Kuhlmann, K.F.D. (author), van Geer, M.A. (author), Bakker, C.T. (author), Dekker, J.E.M. (author), Havenga, M.J.E. (author), Oude Elferink, R.P.J. (author), Gouma, D.J. (author), Bosma, P.J. (author), Wesseling, J.G. (author), TNO Kwaliteit van Leven (author)

Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved gene transfer, a library of Ad vectors based on...

article 2009

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Apolipoprotein CI inhibits scavenger receptor BI and increases plasma HDL levels in vivo

de Haan, W. (author), Out, R. (author), Berbée, J.F.P. (author), van der Hoogt, C.C. (author), Dijk, K.W.v. (author), van Berkel, T.J.C. (author), Romijn, J.A. (author), Wouter Jukema, J. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), TNO Kwaliteit van Leven (author)

Apolipoprotein CI (apoCI) has been suggested to influence HDL metabolism by activation of LCAT and inhibition of HL and CETP. However, the effect of apoCI on scavenger receptor BI (SR-BI)-mediated uptake of HDL-cholesteryl esters (CE), as well as the net effect of apoCI on HDL metabolism in vivo is unknown. Therefore, we evaluated the effect of...

article 2008

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Vascular Growth in Ischemic Limbs: A Review of Mechanisms and Possible Therapeutic Stimulation

van Weel, V. (author), van Tongeren, R.B. (author), van Hinsbergh, V.W.M. (author), van Bockel, J.H. (author), Quax, P.H.A. (author), TNO Kwaliteit van Leven (author)

Stimulation of vascular growth to treat limb ischemia is promising, and early results obtained from uncontrolled clinical trials using angiogenic agents, e.g., vascular endothelial growth factor, led to high expectations. However, negative results from recent placebo-controlled trials warrant further research. Here, current insights into...

article 2008

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Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

Pols, T.W.H. (author), Ottenhoff, R. (author), Vos, M. (author), Levels, J.H.M. (author), Quax, P.H.A. (author), Meijers, J.C.M. (author), Pannekoek, H. (author), Groen, A.K. (author), de Vries, C.J.M. (author), TNO Kwaliteit van Leven (author)

NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a...

article 2008

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The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI

TNO Kwaliteit van Leven (author), Hu, L. (author), van der Hoogt, C.C. (author), Espirito Santo, S.M.S. (author), Out, R. (author), Kypreos, K.E. (author), van Vlijmen, B.J.M. (author), van Berkel, T.J.C. (author), Romijn, J.A. (author), Havekes, L.M. (author), van Dijk, K.W. (author), Rensen, P.C.N. (author)

LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance...

article 2008

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ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoA-V but unaffected by apoC-III deficiency

TNO Kwaliteit van Leven (author), Gerritsen, G. (author), van der Hoogt, C.C. (author), Schaap, F.G. (author), Voshol, P.J. (author), Kypreos, K.E. (author), Maeda, N. (author), Groen, A.K. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), van Dijk, K.W. (author)

Apolipoprotein E2 (apoE2)-associated hyperlipidemia is characterized by a disturbed clearance of apoE2-enriched VLDL remnants. Because excess apoE2 inhibits LPL-mediated triglyceride (TG) hydrolysis in vitro, we in vestigated whether direct or indirect stimulation of LPL activity in vivo reduces the apoE2-associated hypertriglyc-eridemia. Here,...

article 2008

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Plasma plasminogen activator inhibitor-1 level is not regulated by the hepatic low-density lipoprotein receptor-related protein [2]

Hu, L. (author), Bovenschen, N. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Tamsma, J.T. (author), TNO Kwaliteit van Leven (author)

article 2007

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Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors

Verhaagh, S. (author), de Jong, E. (author), Goudsmit, J. (author), Lecollinet, S. (author), Gillissen, G. (author), de Vries, M. (author), van Leuven, K. (author), Que, I. (author), Ouwehand, K. (author), Mintardjo, R. (author), Weverling, G.J. (author), Radošević, K. (author), Richardson, J. (author), Eloit, M. (author), Lowik, C. (author), Quax, P. (author), Havenga, M. (author), TNO Kwaliteit van Leven (author)

Wild-type strains of mice do not express CD46, a high-affinity receptor for human group B adenoviruses including type 35. Therefore, studies performed to date in mice using replication-incompetent Ad35 (rAd35) vaccine carriers may underestimate potency or result in altered vector distribution. Here, it is reported that CD46 transgenic mice (MYII...

article 2006

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Generation of a novel replication-incompetent adenoviral vector derived from human adenovirus type 49: Manufacture on PER.C6 cells, tropism and immunogenicity

TNO Kwaliteit van Leven (author), Lemckert, A.A.C. (author), Grimbergen, J. (author), Smits, S. (author), Hartkoorn, E. (author), Holterman, L. (author), Berkhout, B. (author), Barouch, D.H. (author), Vogels, R. (author), Quax, P. (author), Goudsmit, J. (author), Havenga, M.J.E. (author)

Recombinant adenoviral vectors based on type 5 (rAd5) show great promise as a vaccine carrier. However, neutralizing activity against Ad5 is prevalent and high-titred among human populations, and significantly dampens Ad5-based vaccine modalities. The generation of alternative adenoviral vectors with low seroprevalence thus receives much...

article 2006

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Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma

Lamfers, M.L.M. (author), Gianni, D. (author), Tung, C.H. (author), Idema, S. (author), Schagen, F.H.E. (author), Carette, J.E. (author), Quax, P.H.A. (author), van Beusechem, V.W. (author), van der Top, W.P. (author), Dirven, C.M.F. (author), Chiocca, E.A. (author), Gerritsen, W.R. (author), TNO Kwaliteit van Leven (author)

Oncolytic adenoviruses exhibiting tumor-selective replication are promising anticancer agents. Insertion and expression of a transgene encoding tissue inhibitor of metalloproteinase-3 (TIMP-3), which has been reported to inhibit angiogenesis and tumor cell infiltration and induce apoptosis, may improve the antitumor activity of these agents. To...

article 2005

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Efficient targeting of adenoviral vectors to integrin positive vascular cells utilizing a CAR-cyclic RGD linker protein

Krom, Y.D. (author), Gras, J.C.E. (author), Frants, R.R. (author), Havekes, L.M. (author), van Berkel, T.J. (author), Biessen, E.A.L. (author), van Dijk, K.W. (author), TNO Kwaliteit van Leven (author)

Vascular smooth muscle (VSMC) and endothelial cells (EC) are particularly resistant to infection by type 5 adenovirus (Ad) vectors. To overcome this limitation and target Ad vectors to ubiquitously expressed α Vβ3/5 integrins, we have generated a linker protein consisting of the extracellular domain of the coxsackie adenovirus receptor (CAR)...

article 2005

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ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

TNO Kwaliteit van Leven (author), Gerritsen, G. (author), Rensen, P.C.N. (author), Kypreos, K.E. (author), Zannis, V.I. (author), Havekes, L.M. (author), van Dijk, K.W. (author)

Adenovirus-mediated overexpression of human apolipoprotein E (apoE) induces hyperlipidemia by stimulating the VLDL-triglyceride (TG) production rate and inhibiting the LPL-mediated VLDL-TG hydrolysis rate. Because apoC-III is a strong inhibitor of TG hydrolysis, we questioned whether Apoc3 deficiency might prevent the hyperlipidemia induced by...

article 2005

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Generation of a recombinant apolipoprotein E variant with improved biological functions: Hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia

TNO Kwaliteit van Leven (author), Kypreos, K.E. (author), van Dijk, K.W. (author), Havekes, L.M. (author), Zannis, V.I. (author)

To identify the residues in the carboxyl-terminal region 260-299 of human apolipoprotein E (apoE) that contribute to hypertriglyceridemia, two sets of conserved, hydrophobic amino acids between residues 261 and 283 were mutated to alanines, and recombinant adenoviruses expressing these apoE mutants were generated. Adenovirus-mediated gene...

article 2005

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Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo

van Weel, V. (author), Deckers, M.M.L. (author), Grimbergen, J.M. (author), van Leuven, K.J.M. (author), Lardenoye, J.W.H.P. (author), Schlingemann, R.O. (author), van Nieuw Amerongen, G.P. (author), van Bockel, J.H. (author), van Hinsbergh, V.W.M. (author), Quax, P.H.A. (author), Gaubius Instituut TNO (author)

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography...

article 2004

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Involvement of Membrane-Type Matrix Metalloproteinases (MT-MMPs) in capillary tube formation by human endometrial microvascular endothelial Cells: Role of MT3-MMP

Plaisier, M. (author), Kapiteijn, K. (author), Koolwijk, P. (author), Fijten, C. (author), Hanemaaijer, R. (author), Grimbergen, J.M. (author), Mulder-Stapel, A. (author), Quax, P.H.A. (author), Helmerhorst, F.M. (author), van Hinsbergh, V.W.M. (author), Gaubius Instituut TNO (author)

In the endometrium, angiogenesis is a physiological process, whereas in most adult tissues neovascularization is initiated only during tissue repair or pathological conditions. Pericellular proteolysis plays an important role in angiogenesis being required for endothelial cell migration, invasion, and tube formation. We studied the expression of...

article 2004

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GIT1 Mediates Thrombin Signaling in Endothelial Cells: Role in Turnover of RhoA-Type Focal Adhesions

van Nieuw Amerongen, G.P. (author), Natarajan, K. (author), Yin, G. (author), Hoefen, R.J. (author), Osawa, M. (author), Haendeler, J. (author), Ridley, A.J. (author), Fujiwara, K. (author), van Hinsbergh, V.W.M. (author), Berk, B.C. (author), Gaubius Instituut TNO (author)

Thrombin mediates changes in endothelial barrier function and increases endothelial permeability. A feature of thrombin-enhanced endothelial hyperpermeability is contraction of endothelial cells (ECs), accompanied by formation of focal adhesions (FAs). Recently, a G protein-coupled receptor kinase-interacting protein, GIT1, was shown to regulate...

article 2004

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TR3 orphan receptor is expressed in vascular endothelial cells and mediates cell cycle arrest

Arkenbout, E.K. (author), van Bragt, M. (author), Eldering, E. (author), van Bree, C. (author), Grimbergen, J.M. (author), Quax, P.H.A. (author), Pannekoek, H. (author), de Vries, C.J.M. (author), Gaubius Instituut TNO (author)

Objective - Endothelial cells play a pivotal role in vascular homeostasis. In this study, we investigated the function of the nerve growth factor-induced protein-B (NGFI-B) subfamily of nuclear receptors comprising the TR3 orphan receptor (TR3), mitogen-induced nuclear orphan receptor (MINOR), and nuclear orphan receptor of T cells (NOT) in...

article 2003