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1. The assessment of Pseudomonas aeruginosa lectin LecA binding characteristics of divalent galactosides using multiple techniques

Author

Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, Pieters, Roland J, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, and Pieters, Roland J

Abstract

Pseudomonas aeruginosa is a widespread opportunistic pathogen that is capable of colonizing various human tissues and is resistant to many antibiotics. LecA is a galactose binding tetrameric lectin involved in adhesion, infection and biofilm formation. This study reports on the binding characteristics of mono- and divalent (chelating) ligands to LecA using different techniques. These techniques include Affinity Capillary Electrophoresis (ACE), Bio Layer Interferometry (BLI), Native Mass Spectrometry and a Thermal Shift Assay. Aspects of focus include: affinity, selectivity, binding kinetics and residence time. The affinity of a divalent ligand was determined to be in the low nanomolar range for all of the used techniques and with a ligand residence time of approximately 7 hours, while no strong binding was seen to related lectin tetramers. Each of the used techniques provides a unique and complementary insight into the chelation based binding mode of the divalent ligand to the LecA tetramer.

Published
2021

2. Bioanalysis of erlotinib, its O-demethylated metabolites OSI-413 and OSI-420, and other metabolites by liquid chromatography-tandem mass spectrometry with additional ion mobility identification

Author

Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., Sparidans, Rolf W., Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., and Sparidans, Rolf W.

Abstract

Erlotinib is a first-generation epithelial growth factor receptor inhibitor used in the treatment of non-small cellular lung cancers. Our previously published method on a Thermo TSQ Quantum Ultra triple quadrupole mass spectrometer for the quantitation of erlotinib, OSI-420, and OSI-413 and some other kinase inhibitors was transferred to a more sensitive Sciex QTRAP5500 system. Both methods showed comparable performance in the previous range (5–5000 and 1–1000 ng/mL for erlotinib and OSI-420) with comparable accuracies and precisions (98.9–106.2 vs 98.7.0–104.0, and 3.7–13.4 vs 4.6–13.2), and a high level of agreement between the methods (R2 = 0.9984 and 0.9951) for the quality control samples. The new system however was also capable of quantifying lower concentrations of both erlotinib and OSI-420 (0.5 and 0.1 ng/mL) with sufficient accuracy and precision. Along with the increased sensitivity we included the semi-quantitative determination of additional erlotinib metabolites M2, M3, M5, M6, M7, M8, M9, M10, M11, M12, M16 (hydroxy-erlotinib), M17, M18, M19, M20, M21 in a 0.1–1000 ng/mL range to the method. With a simple crash, dilute, and shoot sample preparation with acetonitrile and a 4.5 min analytical run time the method outperformed most other published methods in speed and simplicity and was suitable for TDM. Further, enhancement of the understanding of the pharmacokinetics of erlotinib and its metabolites was demonstrated.

Published
2021

3. The assessment of Pseudomonas aeruginosa lectin LecA binding characteristics of divalent galactosides using multiple techniques

Author

Afd Chemical Biology and Drug Discovery, Virologie, dI&I I&I-1, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, Pieters, Roland J, Afd Chemical Biology and Drug Discovery, Virologie, dI&I I&I-1, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, and Pieters, Roland J

Published
2021

4. Bioanalysis of erlotinib, its O-demethylated metabolites OSI-413 and OSI-420, and other metabolites by liquid chromatography-tandem mass spectrometry with additional ion mobility identification

Author

Afd Pharmacoepi & Clinical Pharmacology, Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Chemical Biology and Drug Discovery, Pharmacology, Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., Sparidans, Rolf W., Afd Pharmacoepi & Clinical Pharmacology, Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Chemical Biology and Drug Discovery, Pharmacology, Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., and Sparidans, Rolf W.

Published
2021

5. The assessment of Pseudomonas aeruginosa lectin LecA binding characteristics of divalent galactosides using multiple techniques

Author

Afd Chemical Biology and Drug Discovery, Virologie, dI&I I&I-1, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, Pieters, Roland J, Afd Chemical Biology and Drug Discovery, Virologie, dI&I I&I-1, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, and Pieters, Roland J

Published
2021

6. Bioanalysis of erlotinib, its O-demethylated metabolites OSI-413 and OSI-420, and other metabolites by liquid chromatography-tandem mass spectrometry with additional ion mobility identification

Author

Afd Pharmacoepi & Clinical Pharmacology, Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Chemical Biology and Drug Discovery, Pharmacology, Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., Sparidans, Rolf W., Afd Pharmacoepi & Clinical Pharmacology, Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Chemical Biology and Drug Discovery, Pharmacology, Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., and Sparidans, Rolf W.

Published
2021

7. The assessment of Pseudomonas aeruginosa lectin LecA binding characteristics of divalent galactosides using multiple techniques

Author

Afd Chemical Biology and Drug Discovery, Virologie, dI&I I&I-1, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, Pieters, Roland J, Afd Chemical Biology and Drug Discovery, Virologie, dI&I I&I-1, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Zaree, Pouya, Torano, Javier Sastre, de Haan, Cornelis A M, Scheltma, Richard A, Barendregt, Arjan, Thijssen, Vito, Yu, Guangyun, Flesch, Frits, and Pieters, Roland J

Published
2021

8. Bioanalysis of erlotinib, its O-demethylated metabolites OSI-413 and OSI-420, and other metabolites by liquid chromatography-tandem mass spectrometry with additional ion mobility identification

Author

Afd Pharmacoepi & Clinical Pharmacology, Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Chemical Biology and Drug Discovery, Pharmacology, Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., Sparidans, Rolf W., Afd Pharmacoepi & Clinical Pharmacology, Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Chemical Biology and Drug Discovery, Pharmacology, Rood, Johannes J.M., Toraño, Javier Sastre, Somovilla, Victor J., Beijnen, Jos H., and Sparidans, Rolf W.

Published
2021

9. Azolla ferns testify: seed plants and ferns share a common ancestor for leucoanthocyanidin reductase enzymes

Author

Güngör, Erbil, Brouwer, Paul, Dijkhuizen, Laura W., Chaerul Shaffar, Dally, Nierop, Klaas G.J., de Vos, C.H., Toraño, Javier Sastre, van der Meer, Ingrid M., Schluepmann, Henriette, Güngör, Erbil, Brouwer, Paul, Dijkhuizen, Laura W., Chaerul Shaffar, Dally, Nierop, Klaas G.J., de Vos, C.H., Toraño, Javier Sastre, van der Meer, Ingrid M., and Schluepmann, Henriette

Abstract

Questions about in vivo substrates for proanthocyanidin (PA) biosynthesis and condensation have not been resolved and wide gaps in the understanding of transport and biogenesis in ‘tannosomes’ persist. Here we examined the evolution of PA biosynthesis in ferns not previously reported, asking what PAs are synthesised and how.Chemical and gene‐expression analyses were combined to characterise PA biosynthesis, leveraging genome annotation from the floating fern Azolla filiculoides. In vitro assay and phylogenomics of PIP‐dehydrogenases served to infer the evolution of leucoanthocyanidin reductase (LAR).Sporophyte‐synthesised (epi)catechin polymers, averaging only seven subunits, accumulated to 5.3% in A. filiculoides, and 8% in A. pinnata biomass dry weight. Consistently, a LAR active in vitro was highly expressed in A. filiculoides. LAR, and paralogous fern WLAR‐enzymes with differing substrate binding sites, represent an evolutionary innovation of the common ancestor of fern and seed plants.The specific ecological niche of Azolla ferns, a floating plant–microbe mat massively fixing CO2 and N2, shaped their metabolism in which PA biosynthesis predominates and employs novel fern LAR enzymes. Characterisation of in vivo substrates of these LAR, will help to shed light on the recently assigned and surprising dual catalysis of LAR from seed plants.

Published
2021

10. Nanobody-Targeted Photodynamic Therapy Selectively Kills Viral GPCR-Expressing Glioblastoma Cells

Author

De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., Oliveira, Sabrina, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., and Oliveira, Sabrina

Abstract

Photodynamic therapy (PDT) eradicates tumors by the local activation of a photosensitizer with near-infrared light. One of the aspects hampering the clinical use of PDT is the poor selectivity of the photosensitizer. To improve this, we have recently introduced a new approach for targeted PDT by conjugating photosensitizers to nanobodies. Diverse G protein-coupled receptors (GPCRs) show aberrant overexpression in tumors and are therefore interesting targets in cancer therapy. Here we show that GPCR-targeting nanobodies can be used in targeted PDT. We have developed a nanobody binding the extracellular side of the viral GPCR US28, which is detected in tumors like glioblastoma. The nanobody was site-directionally conjugated to the water-soluble photosensitizer IRDye700DX. This nanobody-photosensitizer conjugate selectively killed US28-expressing glioblastoma cells both in 2D and 3D cultures upon illumination with near-infrared light. This is the first example employing a GPCR as target for nanobody-directed PDT. With the emerging role of GPCRs in cancer, this data provides a new angle for exploiting this large family of receptors for targeted therapies.

Published
2019

11. Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys

Author

Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, Kok, Robbert Jan, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, and Kok, Robbert Jan

Abstract

The aim of the present study was to develop folic acid (FA) conjugates which can deliver the kinase inhibitor dactolisib to the kidneys via folate receptor-mediated uptake in tubular epithelial cells. Dactolisib is a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) and is considered an attractive agent for treatment of polycystic kidney disease. The ethylenediamine platinum(II) linker, herein called Lx, was employed to couple dactolisib via coordination chemistry to thiol-containing FA-spacer adducts to yield FA-Lx-dactolisib conjugates. The dye lissamine was coupled via similar linker chemistry to folate to yield fluorescent FA-Lx-lissamine conjugates. Three different spacers (PEG5-Cys, PEG27-Cys or an Asp-Arg-Asp-Asp-Cys peptide spacer) were used to compare the influence of hydrophilicity and charged groups in the spacer on interaction with target cells and in vivo organ distribution of the final conjugates. The purity and identity of the final products were confirmed by UPLC and LC-MS analysis, respectively. FA-Lx-dactolisib conjugates were stable in serum and culture medium, while dactolisib was released from the conjugates in the presence of glutathione. All three type of conjugates were internalized efficiently by HK-2 cells and uptake could be blocked by an excess of folic acid in the medium, demonstrating FR mediated uptake. FA-Lx-dactolisib conjugates showed nanomolar inhibition of the PI3K pathway (Akt phosphorylation) and mTOR pathway (S6 phosphorylation) in cultured kidney epithelial cells (HK-2 cells). After intraperitoneal administration, all three types conjugates accumulated extensively in kidneys of iKsp-Pkd1del mice with polycystic kidney disease. In conclusion, folate conjugates were successfully prepared by platinum(II) coordination chemistry and accumulated in a target-specific manner in kidney cells and polycystic kidneys. The folate conjugate of dactolisib thus may have potential for targeted t

Published
2019

12. Quantitative Translation of Microfluidic Transporter in Vitro Data to in Vivo Reveals Impaired Albumin-Facilitated Indoxyl Sulfate Secretion in Chronic Kidney Disease

Author

Made, Thomas K. van der, Fedecostante, Michele, Scotcher, Daniel, Rostami-Hodjegan, Amin, Torano, Javier Sastre, Middel, Igor, Hoenderop, J.G.J., Masereeuw, Rosalinde, Galetin, Aleksandra, Made, Thomas K. van der, Fedecostante, Michele, Scotcher, Daniel, Rostami-Hodjegan, Amin, Torano, Javier Sastre, Middel, Igor, Hoenderop, J.G.J., Masereeuw, Rosalinde, and Galetin, Aleksandra

Abstract

Contains fulltext : 210092.pdf (publisher's version ) (Closed access)

Published
2019

13. Nanobody-Targeted Photodynamic Therapy Selectively Kills Viral GPCR-Expressing Glioblastoma Cells

Author

Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Afd Pharmaceutics, Chemical Biology and Drug Discovery, Pharmaceutics, Celbiologie, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., Oliveira, Sabrina, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Afd Pharmaceutics, Chemical Biology and Drug Discovery, Pharmaceutics, Celbiologie, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., and Oliveira, Sabrina

Published
2019

14. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Author

Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, Masereeuw, Rosalinde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, and Masereeuw, Rosalinde

Published
2019

15. Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys

Author

Afd Pharmaceutics, Afd Chemical Biology and Drug Discovery, Pharmaceutics, Chemical Biology and Drug Discovery, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, Kok, Robbert Jan, Afd Pharmaceutics, Afd Chemical Biology and Drug Discovery, Pharmaceutics, Chemical Biology and Drug Discovery, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, and Kok, Robbert Jan

Published
2019

16. Quantitative Translation of Microfluidic Transporter in Vitro Data to in Vivo Reveals Impaired Albumin-Facilitated Indoxyl Sulfate Secretion in Chronic Kidney Disease

Author

Made, Thomas K. van der, Fedecostante, Michele, Scotcher, Daniel, Rostami-Hodjegan, Amin, Torano, Javier Sastre, Middel, Igor, Hoenderop, J.G.J., Masereeuw, Rosalinde, Galetin, Aleksandra, Made, Thomas K. van der, Fedecostante, Michele, Scotcher, Daniel, Rostami-Hodjegan, Amin, Torano, Javier Sastre, Middel, Igor, Hoenderop, J.G.J., Masereeuw, Rosalinde, and Galetin, Aleksandra

Abstract

Contains fulltext : 210092.pdf (publisher's version ) (Closed access)

Published
2019

17. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Author

Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, Masereeuw, Rosalinde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, and Masereeuw, Rosalinde

Published
2019

18. Nanobody-Targeted Photodynamic Therapy Selectively Kills Viral GPCR-Expressing Glioblastoma Cells

Author

Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Afd Pharmaceutics, Chemical Biology and Drug Discovery, Pharmaceutics, Celbiologie, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., Oliveira, Sabrina, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Afd Pharmaceutics, Chemical Biology and Drug Discovery, Pharmaceutics, Celbiologie, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., and Oliveira, Sabrina

Published
2019

19. Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys

Author

Afd Pharmaceutics, Afd Chemical Biology and Drug Discovery, Pharmaceutics, Chemical Biology and Drug Discovery, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, Kok, Robbert Jan, Afd Pharmaceutics, Afd Chemical Biology and Drug Discovery, Pharmaceutics, Chemical Biology and Drug Discovery, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, and Kok, Robbert Jan

Published
2019

20. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Author

Researchbureau DHL, Experimentele Afd. Cardiologie 2, Onderzoek Cardiovasculair Reg. Med., Circulatory Health, Regenerative Medicine and Stem Cells, CDL Rode cel, Nefro Vasculaire Geneeskunde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, Masereeuw, Rosalinde, Researchbureau DHL, Experimentele Afd. Cardiologie 2, Onderzoek Cardiovasculair Reg. Med., Circulatory Health, Regenerative Medicine and Stem Cells, CDL Rode cel, Nefro Vasculaire Geneeskunde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, and Masereeuw, Rosalinde

Published
2019

21. Nanobody-Targeted Photodynamic Therapy Selectively Kills Viral GPCR-Expressing Glioblastoma Cells

Author

Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Afd Pharmaceutics, Chemical Biology and Drug Discovery, Pharmaceutics, Cell Biology, Neurobiology and Biophysics, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., Oliveira, Sabrina, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Afd Pharmaceutics, Chemical Biology and Drug Discovery, Pharmaceutics, Cell Biology, Neurobiology and Biophysics, De Groof, Timo W.M., Mashayekhi, Vida, Fan, Tian Shu, Bergkamp, Nick D., Toraño, Javier Sastre, Van Senten, Jeffrey R., Heukers, Raimond, Smit, Martine J., and Oliveira, Sabrina

Published
2019

22. Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys

Author

Afd Pharmaceutics, Afd Chemical Biology and Drug Discovery, Pharmaceutics, Chemical Biology and Drug Discovery, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, Kok, Robbert Jan, Afd Pharmaceutics, Afd Chemical Biology and Drug Discovery, Pharmaceutics, Chemical Biology and Drug Discovery, Shi, Haili, Leonhard, Wouter N, Sijbrandi, Niels J, van Steenbergen, Mies J, Fens, Marcel H A M, van de Dikkenberg, Joep B, Toraño, Javier Sastre, Peters, Dorien J M, Hennink, Wim E, and Kok, Robbert Jan

Published
2019

23. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Author

Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, Masereeuw, Rosalinde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, and Masereeuw, Rosalinde

Abstract

Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.

Published
2019

24. Insights into maleimide - thiol conjugation chemistry: conditions for efficient surface functionalization of nanoparticles for receptor targeting

Author

Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, Hennink, Wim E, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, and Hennink, Wim E

Abstract

Maleimide-thiol chemistry is widely used for the design and preparation of ligand-decorated drug delivery systems such as poly(lactide-co-glycolide) (PLGA) based nanoparticles (NPs). While many publications on nanocarriers functionalized exploiting this strategy are available in the literature, the conditions at which this reaction takes place vary among publications. This paper presents a comprehensive study on the conjugation of the peptide cRGDfK and the nanobody 11A4 (both containing a free thiol group) to maleimide functionalized PLGA NPs by means of the maleimide-thiol click reaction. The influence of different parameters, such as the nanoparticles preparation method and storage conditions as well as the molar ratio of maleimide to ligand used for conjugation, on the reaction efficiency has been evaluated. The NPs were prepared by a single or double emulsion method using different types and concentrations of surfactants and stored at 4 or 20 °C before reaction with the targeting moieties. Several maleimide to ligand molar ratios and different reaction times were studied and the conjugation efficiency was determined by quantification of the not-bound ligand by liquid chromatography. The kind of emulsion used to prepare the NPs as well as the type and concentration of surfactant used had no effect on the conjugation efficiency. Reaction between the maleimide groups present in the NPs and cRGDfK was optimal at a maleimide to thiol molar ratio of 2:1, reaching a conjugation efficiency of 84 ± 4% after 30 min at room temperature in 10 mM HEPES pH 7.0. For 11A4 nanobody the optimal reaction efficiency, 58 ± 12%, was achieved after 2 h of incubation at room temperature in PBS pH 7.4 using a 5:1 maleimide to protein molar ratio. Storage of the NPs at 4 °C for 7 days prior to their exposure to the ligands resulted in approximately 10% decrease in the reactivity of maleimide in contrast to storage at 20 °C which led to almost 40% of the maleimide being unreactive aft

Published
2018

25. Insights into maleimide - thiol conjugation chemistry: conditions for efficient surface functionalization of nanoparticles for receptor targeting

Author

Pharmaceutics, Chemical Biology and Drug Discovery, Afd Pharmaceutics, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Celbiologie, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, Hennink, Wim E, Pharmaceutics, Chemical Biology and Drug Discovery, Afd Pharmaceutics, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Celbiologie, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, and Hennink, Wim E

Published
2018

26. Insights into maleimide - thiol conjugation chemistry: conditions for efficient surface functionalization of nanoparticles for receptor targeting

Author

Pharmaceutics, Chemical Biology and Drug Discovery, Afd Pharmaceutics, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Celbiologie, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, Hennink, Wim E, Pharmaceutics, Chemical Biology and Drug Discovery, Afd Pharmaceutics, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Celbiologie, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, and Hennink, Wim E

Published
2018

27. Insights into maleimide - thiol conjugation chemistry: conditions for efficient surface functionalization of nanoparticles for receptor targeting

Author

Pharmaceutics, Chemical Biology and Drug Discovery, Afd Pharmaceutics, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Cell Biology, Neurobiology and Biophysics, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, Hennink, Wim E, Pharmaceutics, Chemical Biology and Drug Discovery, Afd Pharmaceutics, Sub Cell Biology, Afd Chemical Biology and Drug Discovery, Cell Biology, Neurobiology and Biophysics, Martínez-Jothar, Lucía, Doulkeridou, Sofia, Schiffelers, Raymond M, Torano, Javier Sastre, Oliveira, Sabrina, van Nostrum, Cornelus F, and Hennink, Wim E

Published
2018

28. Investigation of the metabolic consequences of impregnating spinach leaves with trehalose and applying a pulsed electric field

Author

Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, Galindo, Federico Gomez, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, and Galindo, Federico Gomez

Abstract

The impregnation of leafy vegetables with cryoprotectants using a combination of vacuum impregnation (VI) and pulsed electric fields (PEF) has been proposed by our research group as a method of improving their freezing tolerance and consequently their general quality after thawing. In this study, we have investigated the metabolic consequences of the combination of these unit operations on spinach. The vacuum impregnated spinach leaves showed a drastic decrease in the porosity of the extracellular space. However, at maximum weight gain, randomly located air pockets remained, which may account for oxygen-consuming pathways in the cells being active after VI. The metabolic activity of the impregnated leaves showed a drastic increase that was further enhanced by the application of PEF to the impregnated tissue. Impregnating the leaves with trehalose by VI led to a significant accumulation of trehalose-6-phosphate (T6P), however, this was not further enhanced by PEF. It is suggested that the accumulation of T6P in the leaves may increase metabolic activity, and increase tissue resistance to abiotic stress.

Published
2016

29. Investigation of the metabolic consequences of impregnating spinach leaves with trehalose and applying a pulsed electric field

Author

Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, Sub Molecular Plant Physiology, Molecular Plant Physiology, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, Galindo, Federico Gomez, Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, Sub Molecular Plant Physiology, Molecular Plant Physiology, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, and Galindo, Federico Gomez

Published
2016

30. Investigation of the metabolic consequences of impregnating spinach leaves with trehalose and applying a pulsed electric field

Author

Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, Sub Molecular Plant Physiology, Molecular Plant Physiology, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, Galindo, Federico Gomez, Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, Sub Molecular Plant Physiology, Molecular Plant Physiology, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, and Galindo, Federico Gomez

Published
2016

31. Investigation of the metabolic consequences of impregnating spinach leaves with trehalose and applying a pulsed electric field

Author

Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, Sub Molecular Plant Physiology, Molecular Plant Physiology, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, Galindo, Federico Gomez, Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery, Sub Molecular Plant Physiology, Molecular Plant Physiology, Dymek, Katarzyna, Panarese, Valentina, Herremans, Els, Cantre, Dennis, Schoo, Rick, Torano, Javier Sastre, Schlupmann, Henriette, Wadso, Lars, Verboven, Pieter, Nicolai, Bart M., Dejmek, Petr, and Galindo, Federico Gomez

Published
2016

32. Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer

Author

Elez, Elena, Hendlisz, Alain, Delaunoit, Thierry, Valera, Javier Sastre, Cervantes, Andrés, Varea, Rocio, Chao, Graceyi, Wallin, J., Tabernero, Josep, Elez, Elena, Hendlisz, Alain, Delaunoit, Thierry, Valera, Javier Sastre, Cervantes, Andrés, Varea, Rocio, Chao, Graceyi, Wallin, J., and Tabernero, Josep

Abstract

Background:This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC).Methods:Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m -2, folinic acid 400 mg m -2, and 5-fluorouracil (400 mg m -2 bolus then 2400 mg m -2 over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate.Results:Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8-77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0-16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0-30.0) and 10.0 months (7.0-12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0-NA); median PFS 12.0 (8.0-20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0-37.0); median PFS 7.0 (4.0-18.0)). The most common grade ≥3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%).Conclusion:First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

33. Analysis of caffeine and paraxanthine in human saliva with ultra-high-performance liquid chromatography for CYP1A2 phenotyping

Author

Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., Torano, Javier Sastre, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., and Torano, Javier Sastre

Abstract

Cytochrome P450 1A2 (CYP1A2) plays an important role in drug metabolism. Caffeine (CAF) is converted into paraxanthine (PX) by this enzyme and is used as a xenobiotic substrate to determine the CYP1A2 phenotype in humans. A method for the quantification of CAF and PX in saliva was developed using liquid-liquid extraction with ethyl acetate and analysis with ultra-high-performance liquid chromatography. Peaks from CAF, PX and internal standard were resolved within 6 min. The method was validated from 0.05 to 5 mu g mL(-1) CAF and 0.025-2.5 mu g mL(-1) PX. Inter- and intra-day accuracies ranged from 91.2 to 107.2% with precisions

Published
2015

34. Analysis of caffeine and paraxanthine in human saliva with ultra-high-performance liquid chromatography for CYP1A2 phenotyping

Author

Sub Biomolecular analysis, Sub Onderwijsinstituut Farmacie, Medicinal Chemistry and Chemical Biology, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., Torano, Javier Sastre, Sub Biomolecular analysis, Sub Onderwijsinstituut Farmacie, Medicinal Chemistry and Chemical Biology, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., and Torano, Javier Sastre

Published
2015

35. Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: Long-term survival from a phase III trial

Author

Goldstein, David, Teixeira, Luis, Tortora, Giampaolo, Van Laethem, Jean-Luc, Young, Rosemary, Penenberg, Darryl Neil, Lu, Brian, Romano, Alfredo, Von Hoff, Daniel D.D., El-Maraghi, Robert Hassan, Hammel, Pascal, Heinemann, Volker, Kunzmann, Volker, Valera, Javier Sastre, Scheithauer, Werner, Siena, Salvatore, Tabernero, Josep, Goldstein, David, Teixeira, Luis, Tortora, Giampaolo, Van Laethem, Jean-Luc, Young, Rosemary, Penenberg, Darryl Neil, Lu, Brian, Romano, Alfredo, Von Hoff, Daniel D.D., El-Maraghi, Robert Hassan, Hammel, Pascal, Heinemann, Volker, Kunzmann, Volker, Valera, Javier Sastre, Scheithauer, Werner, Siena, Salvatore, and Tabernero, Josep

Abstract

Background: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. Methods: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. Results: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P <. 001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P <. 001 for CA19-9 level ≥ median and HR = 0.81, P =. 079 for NLR > 5). Conclusions: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2015

36. Analysis of caffeine and paraxanthine in human saliva with ultra-high-performance liquid chromatography for CYP1A2 phenotyping

Author

Sub Biomolecular analysis, Sub Onderwijsinstituut Farmacie, Medicinal Chemistry and Chemical Biology, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., Torano, Javier Sastre, Sub Biomolecular analysis, Sub Onderwijsinstituut Farmacie, Medicinal Chemistry and Chemical Biology, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., and Torano, Javier Sastre

Published
2015

37. Analysis of caffeine and paraxanthine in human saliva with ultra-high-performance liquid chromatography for CYP1A2 phenotyping

Author

Sub Biomolecular analysis, Sub Onderwijsinstituut Farmacie, Medicinal Chemistry and Chemical Biology, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., Torano, Javier Sastre, Sub Biomolecular analysis, Sub Onderwijsinstituut Farmacie, Medicinal Chemistry and Chemical Biology, Jordan, Nan Yeun, Mimpen, Jolet Y., van den Bogaard, Willie J. M., Flesch, Frits M., van de Meent, Michiel H. M., and Torano, Javier Sastre

Published
2015

38. Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: Long-term survival from a phase III trial

Author

Goldstein, David, Teixeira, Luis, Tortora, Giampaolo, Van Laethem, Jean-Luc, Young, Rosemary, Penenberg, Darryl Neil, Lu, Brian, Romano, Alfredo, Von Hoff, Daniel D.D., El-Maraghi, Robert Hassan, Hammel, Pascal, Heinemann, Volker, Kunzmann, Volker, Valera, Javier Sastre, Scheithauer, Werner, Siena, Salvatore, Tabernero, Josep, Goldstein, David, Teixeira, Luis, Tortora, Giampaolo, Van Laethem, Jean-Luc, Young, Rosemary, Penenberg, Darryl Neil, Lu, Brian, Romano, Alfredo, Von Hoff, Daniel D.D., El-Maraghi, Robert Hassan, Hammel, Pascal, Heinemann, Volker, Kunzmann, Volker, Valera, Javier Sastre, Scheithauer, Werner, Siena, Salvatore, and Tabernero, Josep

Abstract

Background: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. Methods: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. Results: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P <. 001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P <. 001 for CA19-9 level ≥ median and HR = 0.81, P =. 079 for NLR > 5). Conclusions: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2015

39. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer

Author

UCL - Cliniques universitaires Saint-Luc, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Unité d'oncologie médicale, Tabernero, Josep, Van Cutsem, Eric, Díaz-Rubio, Eduardo, Cervantes, Andrés, Humblet, Yves, Andre, Thierry, Van Laethem, Jean-Luc, Soulie, Patrick, Casado, Esther, Verslype, Chris, Valera, Javier Sastre, Tortora, Giampaolo, Ciardiello, Fortunato, Kisker, Oliver, de Gramont, Aimery, The American Society of Clinical Oncology Gastrointestinal Symposium, UCL - Cliniques universitaires Saint-Luc, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Unité d'oncologie médicale, Tabernero, Josep, Van Cutsem, Eric, Díaz-Rubio, Eduardo, Cervantes, Andrés, Humblet, Yves, Andre, Thierry, Van Laethem, Jean-Luc, Soulie, Patrick, Casado, Esther, Verslype, Chris, Valera, Javier Sastre, Tortora, Giampaolo, Ciardiello, Fortunato, Kisker, Oliver, de Gramont, Aimery, and The American Society of Clinical Oncology Gastrointestinal Symposium

Abstract

Purpose This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor - expressing metastatic colorectal cancer (mCRC). Patients and Methods The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2). Results The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years ( range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated. Conclusion Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

Published
2007

40. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer.

Author

Tabernero, Josep, Van Cutsem, Eric, Díaz-Rubio, Eduardo, Cervantes, Andrés, Humblet, Yves, André, Thierry, Van Laethem, Jean-Luc, Soulié, Patrick, Casado, Esther, Verslype, Chris, Valera, Javier Sastre, Tortora, Giampaolo, Ciardiello, Fortunato, Kisker, Oliver, de Gramont, Aimery, Tabernero, Josep, Van Cutsem, Eric, Díaz-Rubio, Eduardo, Cervantes, Andrés, Humblet, Yves, André, Thierry, Van Laethem, Jean-Luc, Soulié, Patrick, Casado, Esther, Verslype, Chris, Valera, Javier Sastre, Tortora, Giampaolo, Ciardiello, Fortunato, Kisker, Oliver, and de Gramont, Aimery

Abstract

This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC)., Clinical Trial, Phase II, Journal Article, Multicenter Study, info:eu-repo/semantics/published

Published
2007

41. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer.

Author

Tabernero, Josep, Van Cutsem, Eric, Díaz-Rubio, Eduardo, Cervantes, Andrés, Humblet, Yves, André, Thierry, Van Laethem, Jean-Luc, Soulié, Patrick, Casado, Esther, Verslype, Chris, Valera, Javier Sastre, Tortora, Giampaolo, Ciardiello, Fortunato, Kisker, Oliver, de Gramont, Aimery, Tabernero, Josep, Van Cutsem, Eric, Díaz-Rubio, Eduardo, Cervantes, Andrés, Humblet, Yves, André, Thierry, Van Laethem, Jean-Luc, Soulié, Patrick, Casado, Esther, Verslype, Chris, Valera, Javier Sastre, Tortora, Giampaolo, Ciardiello, Fortunato, Kisker, Oliver, and de Gramont, Aimery

Abstract

This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC)., Clinical Trial, Phase II, Journal Article, Multicenter Study, info:eu-repo/semantics/published

Published
2007

42. Caso Mercedes-Benz: lanzamiento de vehículos industriales ecológicos y la toma de decisiones

Author

Francisco Javier Sastre Segovia, Francisco Javier Sastre Segovia, Francisco Javier Sastre Segovia, and Francisco Javier Sastre Segovia

Abstract

Carlos Nieto, director de Marketing de Vehículos Industriales de Mercedes-Benz España, se encuentra ante una situación compleja, bajo un contexto económico y social incierto que caracterizó al 2010 y ante un incipiente escenario sobre la descarbonización del transporte. Tiene la oportunidad de dar un paso clave, pero sabe que las políticas de procedimientos y la cultura organizativa de la empresa son muy estrictas, y debe tomar una serie de decisiones.

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