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Vladimir Uladzimir Ladziata, Peter W Glunz, Yan Zou, Xiaojun Zhang, Wen Jiang, Swanee Jacutin-Porte, Daniel L Cheney, Anzhi Wei, Joseph M Luettgen, Timothy M Harper, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity...
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
Arjen Hg Cleven, Ghadah A Al Sannaa, Inge Briaire-de Bruijn, Davis R Ingram, Matt van de Rijn, Brian P Rubin, Maurits W de Vries, Kelsey L Watson, Kelia E Torres, Wei-Lien Wang, Sjoerd G van Duinen, Pancras Cw Hogendoorn, Alexander J Lazar, Judith Vmg Bovée
No abstract text is available yet for this article.
September 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Neyssa M Marina, Sigbjørn Smeland, Stefan S Bielack, Mark Bernstein, Gordana Jovic, Mark D Krailo, Jane M Hook, Carola Arndt, Henk van den Berg, Bernadette Brennan, Bénédicte Brichard, Ken L B Brown, Trude Butterfass-Bahloul, Gabriele Calaminus, Heike E Daldrup-Link, Mikael Eriksson, Mark C Gebhardt, Hans Gelderblom, Joachim Gerss, Robert Goldsby, Allen Goorin, Richard Gorlick, Holcombe E Grier, Juliet P Hale, Kirsten Sundby Hall, Jendrik Hardes, Douglas S Hawkins, Knut Helmke, Pancras C W Hogendoorn, Michael S Isakoff, Katherine A Janeway, Heribert Jürgens, Leo Kager, Thomas Kühne, Ching C Lau, Patrick J Leavey, Stephen L Lessnick, Leo Mascarenhas, Paul A Meyers, Hubert Mottl, Michaela Nathrath, Zsuzsanna Papai, R Lor Randall, Peter Reichardt, Marleen Renard, Akmal Ahmed Safwat, Cindy L Schwartz, Michael C G Stevens, Sandra J Strauss, Lisa Teot, Mathias Werner, Matthew R Sydes, Jeremy S Whelan
BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation...
October 2016: Lancet Oncology
Xiaojun Zhang, Peter W Glunz, James A Johnson, Wen Jiang, Swanee Jacutin-Porte, Vladimir Ladziata, Yan Zou, Monique S Phillips, Nicholas R Wurtz, Brandon Parkhurst, Alan R Rendina, Timothy M Harper, Daniel L Cheney, Joseph M Luettgen, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing...
August 11, 2016: Journal of Medicinal Chemistry
Laurens G L Sand, Dagmar Berghuis, Karoly Szuhai, Pancras C W Hogendoorn
Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy. The CCL21 RNA expression was determined in 21 Ewing sarcoma cell lines and 18 primary therapy-naive Ewing sarcoma samples...
August 2016: Cancer Immunology, Immunotherapy: CII
Pancras Ndokoye, Qidong Zhao, Xinyong Li, Tingting Li, Moses O Tade, Shaobin Wang
In this study, we demonstrate for the first time that highly branched gold nanostars (AuNSs) and silica-coated AuNSs (AuNSs@mSiO2) could potentially serve as efficient hydrogenation catalysts. The catalytic activity could be promoted by raising the number of tipped-branches of AuNSs, which reveals that the tips play an important role as active sites. The fabricated sharply-pointed AuNSs benefit the electron transfer from BH4 anions to 4-nitrophenol. Coating AuNSs with mesoporous silica (AuNSs@mSiO2) further enhanced the reduction rate and recyclability, and also contributed to reducing the induction period...
September 1, 2016: Journal of Colloid and Interface Science
Wietske van der Ent, Wouter J Veneman, Arwin Groenewoud, Lanpeng Chen, Claudia Tulotta, Pancras C W Hogendoorn, Herman P Spaink, B Ewa Snaar-Jagalska
Zebrafish embryos can be obtained for research purposes in large numbers at low cost and embryos develop externally in limited space, making them highly suitable for high-throughput cancer studies and drug screens. Non-invasive live imaging of various processes within the larvae is possible due to their transparency during development, and a multitude of available fluorescent transgenic reporter lines.To perform high-throughput studies, handling large amounts of embryos and larvae is required. With such high number of individuals, even minute tasks may become time-consuming and arduous...
2016: Advances in Experimental Medicine and Biology
Gerald Obai, Pancras Odongo, Ronald Wanyama
BACKGROUND: Anaemia is a public health problem affecting over 1.62 billion people globally. It affects all age groups of people and is particularly more prevalent in pregnant women. Africa carries a high burden of anaemia; in Uganda 24 % of women of child bearing age have anaemia. Pregnant women living in poverty are at greater risk of developing iron deficiency anaemia. The objective of this study was to determine the prevalence of anaemia and the associated risk factors in pregnant women attending antenatal care at Gulu and Hoima Regional Hospitals in Northern and Western Uganda respectively...
2016: BMC Pregnancy and Childbirth
Peter W Glunz, Luciano Mueller, Daniel L Cheney, Vladimir Ladziata, Yan Zou, Nicholas R Wurtz, Anzhi Wei, Pancras C Wong, Ruth R Wexler, E Scott Priestley
Incorporation of a methyl group onto a macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the macrocyclic structure, as demonstrated by NMR studies. We designed a conformational constraint favoring the desired atropisomer in which this methyl group interacts with the S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint was prepared and demonstrated by NMR to reside predominantly in the desired conformation. This modification improved potency 180-fold relative to the unsubstituted, racemic macrocycle and improved selectivity...
April 28, 2016: Journal of Medicinal Chemistry
Arjen H G Cleven, Ghadah A Al Sannaa, Inge Briaire-de Bruijn, Davis R Ingram, Matt van de Rijn, Brian P Rubin, Maurits W de Vries, Kelsey L Watson, Kelia E Torres, Wei-Lien Wang, Sjoerd G van Duinen, Pancras C W Hogendoorn, Alexander J Lazar, Judith V M G Bovée
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that can show overlapping features with benign neurofibromas as well as high-grade sarcomas. Additional diagnostic markers are needed to aid in this often challenging differential diagnosis. Recently mutations in two critical components of the polycomb repressor 2 (PRC2) complex, SUZ12 and EED, were reported to occur specifically in MPNSTs while such mutations are absent in neurofibromas, both in the setting of neurofibromatosis (NF) and sporadic cases...
June 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Inge F Hendriks, James G Bovill, Peter A van Luijt, Pancras Cw Hogendoorn
Nikolay Pirogov qualified as a physician from Moscow University in 1828 and then studied surgery and anatomy at University of Dorpat. He developed new surgical techniques, including the eponymous osteoplastic foot amputation. His application of scientifically based techniques extended surgery from a craft to a science. During the Crimean War he initiated the deployment of women as nurses and used triage for dealing with mass casualties. His textbook on field surgery became the standard reference on the subject and his principles remained virtually unchanged until the Second World War...
March 8, 2016: Journal of Medical Biography
Zuzanna Baranski, Tijmen H Booij, Marieke L Kuijjer, Yvonne de Jong, Anne-Marie Cleton-Jansen, Leo S Price, Bob van de Water, Judith V M G Bovée, Pancras C W Hogendoorn, Erik H J Danen
Conventional high-grade osteosarcoma is the most common primary bone cancer with relatively high incidence in young people. Recurrent and metastatic tumors are difficult to treat. We performed a kinase inhibitor screen in two osteosarcoma cell lines, which identified MEK1/2 inhibitors. These inhibitors were further validated in a panel of six osteosarcoma cell lines. Western blot analysis was performed to assess ERK activity and efficacy of MEK inhibition. A 3D culture system was used to validate results from 2D monolayer cultures...
November 2015: Genes & Cancer
Annemiek M van Maldegem, Judith V M G Bovée, Elleke F P Peterse, Pancras C W Hogendoorn, Hans Gelderblom
BACKGROUND: In the last three decades the outcome for patients with localised Ewing sarcoma (ES) has improved significantly since the introduction of multimodality primary treatment. However, for patients with (extra-) pulmonary metastatic and/or non-resectable relapsed disease the outcome remains poor and new treatment options are urgently needed. Currently the insulin-like growth factor 1 receptor (IGF-1R) pathway and the poly-ADP(adenosinediphosphate)-ribose-polymerase (PARP) pathway are being investigated for potential targeted therapies...
January 2016: European Journal of Cancer
Elena Beletkaia, Susanne F Fenz, Wim Pomp, B Ewa Snaar-Jagalska, Pancras W C Hogendoorn, Thomas Schmidt
Understanding of the regulation mechanisms of CXCR4 signaling is essential for revealing its role in physiological and pathological processes. Though biochemical pathways following CXCR4 activation by its ligand CXCL12 are well established, knowledge about the receptor dynamics on the plasma membrane remains limited. Here we used Ewing sarcoma-derived cells to unravel the processes that are involved in regulating CXCR4 dynamics on the plasma membrane during receptor signaling. Single-molecule epi-fluorescence microscopy showed that CXCR4 was present in monomeric state on the plasma membrane independent of receptor stimulation...
April 2016: Biochimica et Biophysica Acta
Pancras C Wong, Carol Watson, Earl J Crain
Adenosine diphosphate directly induces platelet aggregation via the G-protein coupled P2Y1 and P2Y12 receptors. P2Y12, but not P2Y1, receptor antagonists are available in the clinic. The relevance of the P2Y1 receptor as an antiplatelet target has been studied in rodents, but not in higher species. We therefore examined effects of the pharmacological blockade of the P2Y1 receptor with its selective antagonist MRS2500 in monkey models of electrolytic-mediated arterial thrombosis (ECAT) and kidney bleeding time (KBT)...
April 2016: Journal of Thrombosis and Thrombolysis
Pancras Ndokoye, Xinyong Li, Qidong Zhao, Tingting Li, Moses O Tade, Shaomin Liu
Fabrication of Au nanostars (AuNSs) can expand the application range of Au nanoparticles because of their high electron density and localized surface plasmon resonance (LSPR) on branches. Exploiting this potential requires further refinement of length of the branches and radius of their tips. To this end, we successfully synthesized AuNSs with uniform and sharply-pointed branches by combining benzyldimethylammonium chloride (BDAC) and cetyltrimethylammonium bromide (CTAB) at low BDAC/CTAB ratios. Once mixed with CTAB, BDAC lowers the critical micelle concentration (CMC) for quick formation of the micelles, which provides favorable growth templates for AuNSs formation...
January 15, 2016: Journal of Colloid and Interface Science
Attje S Hoekstra, Marieke A de Graaff, Inge H Briaire-de Bruijn, Cor Ras, Reza Maleki Seifar, Ivonne van Minderhout, Cees J Cornelisse, Pancras C W Hogendoorn, Martijn H Breuning, Johnny Suijker, Esther Korpershoek, Henricus P M Kunst, Norma Frizzell, Peter Devilee, Jean-Pierre Bayley, Judith V M G Bovée
Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes and tumor suppressors. Loss-of-function mutations give rise to hereditary paragangliomas/pheochromocytomas and hereditary leiomyomatosis and renal cell carcinoma. Inactivation of SDH and FH results in an abnormal accumulation of their substrates succinate and fumarate, leading to inhibition of numerous α-ketoglutarate dependent dioxygenases, including histone demethylases and the ten-eleven-translocation (TET) family of 5-methylcytosine (5 mC) hydroxylases...
November 17, 2015: Oncotarget
Zuzanna Baranski, Yvonne de Jong, Trayana Ilkova, Elisabeth F P Peterse, Anne-Marie Cleton-Jansen, Bob van de Water, Pancras C W Hogendoorn, Judith V M G Bovée, Erik H J Danen
High-grade conventional osteosarcoma is the most common primary bone tumor. Prognosis for osteosarcoma patients is poor and resistance to chemotherapy is common. We performed an siRNA screen targeting members of the Bcl-2 family in human osteosarcoma cell lines to identify critical regulators of osteosarcoma cell survival. Silencing the anti-apoptotic family member Bcl-xL but also the pro-apoptotic member Bak using a SMARTpool of siRNAs as well as 4/4 individual siRNAs caused loss of viability. Loss of Bak impaired cell cycle progression and triggered autophagy...
November 3, 2015: Oncotarget
Marieke A de Graaff, Daniëlle de Jong, Inge H Briaire-de Bruijn, Pancras C W Hogendoorn, Judith V M G Bovée, Károly Szuhai
Leiomyosarcomas are malignant mesenchymal tumors that recapitulate smooth muscle cell differentiation. Tumors are characterized by a genetic heterogeneity with complex karyotypes without a tumor-specific genetic aberration. Their pathobiology is still poorly understood and no specific targeted treatment is currently available for these aggressive tumors. For six leiomyosarcomas, cells were cultured and analyzed by combined binary ratio labeling fluorescence in situ hybridization (COBRA-FISH) karyotyping. A t(6;14) was identified in two cases...
November 2015: Cancer Genetics
Pancras C Wong, Mimi L Quan, Carol A Watson, Earl J Crain, Mark R Harpel, Alan R Rendina, Joseph M Luettgen, Ruth R Wexler, William A Schumacher, Dietmar A Seiffert
BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa...
November 2015: Journal of Thrombosis and Thrombolysis
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