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103. Identification of effective compounds in ATRX aberrant neuroblastoma cell lines

Author

Oosterhout, Romy van, Molenaar, Jan (Thesis Advisor), Oosterhout, Romy van, and Molenaar, Jan (Thesis Advisor)

Abstract

Neuroblastoom is een tumor die waarschijnlijk ontstaat vanuit voorloper cellen van het sympathische zenuwstelsel. Jaarlijks krijgen ongeveer 30 kinderen in Nederland de diagnose neuroblastoom, waarbij de meeste kinderen jonger zijn dan zes jaar. De tumor komt voornamelijk voor in de bijnieren, maar kan ook ontstaan in de buik, borstholte, hals of het bekken. Bij de diagnose wordt aan de hand van het genetische profiel, de plaats en eventuele uitzaaiingen de risico groep bepaald. Patiënten die in de lage- en gemiddelde risicogroep vallen hebben een overlevingskans van ongeveer 90 tot 100%, terwijl patiënten in de hoge risicogroep een overlevingskans van minder dan 50% laten zien, ondanks intensieve therapie. Een afwijking in het ATRX-gen is een indicatie voor het plaatsen van de patiënt in de hoge risicogroep. De meeste van deze afwijkingen betreffen deleties van hele exonen. Het ATRX eiwit is onder andere betrokken bij het reguleren van genexpressie en stabiliteit van DNA doordat het de structuur van chromatine kan veranderen. Tevens wordt er in studies voorgesteld dat het ATRX eiwit ook een rol speelt in het oplossen van secundaire DNA structuren genaamd G-quadruplexen (G4) om replicatie stress te voorkomen. Deze structuren zijn rijk aan guanine en hebben de neiging om het DNA replicatie proces te onderbreken waarbij DNA schade ontstaat. Wanneer er in kankercellen ATRX mutaties optreden worden er meer G4 complexen teruggevonden, wat leidt tot meer DNA schade in deze cellen. Op dit moment zijn er beperkte therapieën beschikbaar voor neuroblastoom patiënten met een ATRX-afwijking. In de afgelopen jaren zijn er een aantal nieuwe therapie opties gevonden voor deze specifieke groep, maar deze therapieën bleken niet erg effectief te zijn in ons lab. Hierdoor is het doel van dit project om specifieke en efficiënte compounds te identificeren voor de behandeling van ATRX neuroblastoom patiënten. In het verleden zijn modellen van de meest voorkomende ATRX deleties in patiënt

Published
2022

104. Patient-derived tumour models as predictor of treatment response in cancer patients: How precise is precision medicine?

Author

Plas, Tim van der, Molenaar, Jan (Thesis Advisor), Plas, Tim van der, and Molenaar, Jan (Thesis Advisor)

Abstract

Standard cut, poison and burn approaches to cancer treatment fail to save around 10 million patients every year across the globe. Precision medicine cancer treatment attempts to improve treatment by molecularly profiling a patient through (epi)genomics and transcriptomics to identify biomarkers in the patient's tumour. Personalized treatment is hence targeted towards these biomarkers for optimal patient care. While targeted treatment is more effective than non-targeted treatment, due to interand intratumour heterogeneity and clonal dynamics in a tumour, biomarker-targeted treatment often cannot treat a tumour completely. Combining drug candidates with patient-derived tumour models allow for sensitivity screening to assess drug efficacy before deciding on a treatment plan for an individual patient. In this literature review, five patient-derived tumour models applicable to precision medicine are discussed and compared. These include cell culture, tumour explants, mice or zebrafish xenograft transplantation and tumour organoids. The models are scored on several features regarding patient tumour representation, practicality of the model and drug screen effectiveness. Within these criteria, patient-derived organoids make a good case for suitability in a precision medicine context. Future improvements in co-culturing protocols and drug screen automation will further strengthen its position. Additionally, important considerations for drug screen study design, such as clear design and reporting guidelines and protocol standardization, will further improve the precision medicine approach to cancer treatment and allow for optimal individualized therapy.

Published
2022

105. Mutational spectrum of ATRX aberrations in neuroblastoma and associated patient and tumor characteristics

Author

Sub Bioinformatics, Afd Pharmaceutics, Theoretical Biology and Bioinformatics, Pharmaceutics, van Gerven, Michael R., Bozsaky, Eva, Matser, Yvette A.H., Vosseberg, Julian, Taschner-Mandl, Sabine, Koster, Jan, Tytgat, Godelieve A.M., Molenaar, Jan J., van den Boogaard, Marlinde, Sub Bioinformatics, Afd Pharmaceutics, Theoretical Biology and Bioinformatics, Pharmaceutics, van Gerven, Michael R., Bozsaky, Eva, Matser, Yvette A.H., Vosseberg, Julian, Taschner-Mandl, Sabine, Koster, Jan, Tytgat, Godelieve A.M., Molenaar, Jan J., and van den Boogaard, Marlinde

Published
2022

106. Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Author

Sub Cell Biology, Afd Pharmaceutics, Pharmaceutics, Schubert, Nil A, Chen, Celine Y, Rodríguez, Ana, Koster, Jan, Dowless, Michele, Pfister, Stefan M, Shields, David J, Stancato, Louis F, Vassal, Gilles, Caron, Hubert N, van den Boogaard, Marlinde L, Henssen, Anton G, Molenaar, Jan J, Sub Cell Biology, Afd Pharmaceutics, Pharmaceutics, Schubert, Nil A, Chen, Celine Y, Rodríguez, Ana, Koster, Jan, Dowless, Michele, Pfister, Stefan M, Shields, David J, Stancato, Louis F, Vassal, Gilles, Caron, Hubert N, van den Boogaard, Marlinde L, Henssen, Anton G, and Molenaar, Jan J

Published
2022

107. Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

Author

Afd Pharmaceutics, Pharmaceutics, Berlak, Mareike, Tucker, Elizabeth, Dorel, Mathurin, Winkler, Annika, McGearey, Aleixandria, Rodriguez-Fos, Elias, da Costa, Barbara Martins, Barker, Karen, Fyle, Elicia, Calton, Elizabeth, Eising, Selma, Ober, Kim, Hughes, Deborah, Koutroumanidou, Eleni, Carter, Paul, Stankunaite, Reda, Proszek, Paula, Jain, Neha, Rosswog, Carolina, Dorado-Garcia, Heathcliff, Molenaar, Jan Jasper, Hubank, Mike, Barone, Giuseppe, Anderson, John, Lang, Peter, Deubzer, Hedwig Elisabeth, Künkele, Annette, Fischer, Matthias, Eggert, Angelika, Kloft, Charlotte, Henssen, Anton George, Boettcher, Michael, Hertwig, Falk, Blüthgen, Nils, Chesler, Louis, Schulte, Johannes Hubertus, Afd Pharmaceutics, Pharmaceutics, Berlak, Mareike, Tucker, Elizabeth, Dorel, Mathurin, Winkler, Annika, McGearey, Aleixandria, Rodriguez-Fos, Elias, da Costa, Barbara Martins, Barker, Karen, Fyle, Elicia, Calton, Elizabeth, Eising, Selma, Ober, Kim, Hughes, Deborah, Koutroumanidou, Eleni, Carter, Paul, Stankunaite, Reda, Proszek, Paula, Jain, Neha, Rosswog, Carolina, Dorado-Garcia, Heathcliff, Molenaar, Jan Jasper, Hubank, Mike, Barone, Giuseppe, Anderson, John, Lang, Peter, Deubzer, Hedwig Elisabeth, Künkele, Annette, Fischer, Matthias, Eggert, Angelika, Kloft, Charlotte, Henssen, Anton George, Boettcher, Michael, Hertwig, Falk, Blüthgen, Nils, Chesler, Louis, and Schulte, Johannes Hubertus

Published
2022

108. Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies

Author

Afd Pharmaceutics, Pharmaceutics, Keller, Kaylee M., Krausert, Sonja, Gopisetty, Apurva, Luedtke, Dan, Koster, Jan, Schubert, Nil A., Rodríguez, Ana, van Hooff, Sander R., Stichel, Damian, Dolman, M. Emmy M., Vassal, Gilles, Pfister, Stefan M., Caron, Hubert N., Stancato, Louis F., Molenaar, Jan J., Jäger, Natalie, Kool, Marcel, Afd Pharmaceutics, Pharmaceutics, Keller, Kaylee M., Krausert, Sonja, Gopisetty, Apurva, Luedtke, Dan, Koster, Jan, Schubert, Nil A., Rodríguez, Ana, van Hooff, Sander R., Stichel, Damian, Dolman, M. Emmy M., Vassal, Gilles, Pfister, Stefan M., Caron, Hubert N., Stancato, Louis F., Molenaar, Jan J., Jäger, Natalie, and Kool, Marcel

Published
2022

109. Chromosome 11q loss and MYCN amplification demonstrate synthetic lethality with checkpoint kinase 1 inhibition in neuroblastoma

Author

Afd Pharmaceutics, Pharmaceutics, Keller, Kaylee M., Eleveld, Thomas F., Schild, Linda, van den Handel, Kim, van den Boogaard, Marlinde, Amo-Addae, Vicky, Eising, Selma, Ober, Kimberley, Koopmans, Bianca, Looijenga, Leendert, Tytgat, Godelieve A.M., Ylstra, Bauke, Molenaar, Jan J., Dolman, M. Emmy M., van Hooff, Sander R., Afd Pharmaceutics, Pharmaceutics, Keller, Kaylee M., Eleveld, Thomas F., Schild, Linda, van den Handel, Kim, van den Boogaard, Marlinde, Amo-Addae, Vicky, Eising, Selma, Ober, Kimberley, Koopmans, Bianca, Looijenga, Leendert, Tytgat, Godelieve A.M., Ylstra, Bauke, Molenaar, Jan J., Dolman, M. Emmy M., and van Hooff, Sander R.

Published
2022

110. RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

Author

Afd Pharmaceutics, Pharmaceutics, Nunes, Carolina, Depestel, Lisa, Mus, Liselot, Keller, Kaylee M., Delhaye, Louis, Louwagie, Amber, Rishfi, Muhammad, Whale, Alex, Kara, Neesha, Andrews, Simon R., Cruz, Filemon Dela, You, Daoqi, Siddiquee, Armaan, Cologna, Camila Takeno, De Craemer, Sam, Dolman, Emmy, Bartenhagen, Christoph, De Vloed, Fanny, Sanders, Ellen, Eggermont, Aline, Bekaert, Sarah Lee, Van Loocke, Wouter, Bek, Jan Willem, Dewyn, Givani, Loontiens, Siebe, Van Isterdael, Gert, Decaesteker, Bieke, Tilleman, Laurentijn, Van Nieuwerburgh, Filip, Vermeirssen, Vanessa, Van Neste, Christophe, Ghesquiere, Bart, Goossens, Steven, Eyckerman, Sven, De Preter, Katleen, Fischer, Matthias, Houseley, Jon, Molenaar, Jan, De Wilde, Bram, Roberts, Stephen S., Durinck, Kaat, Speleman, Frank, Afd Pharmaceutics, Pharmaceutics, Nunes, Carolina, Depestel, Lisa, Mus, Liselot, Keller, Kaylee M., Delhaye, Louis, Louwagie, Amber, Rishfi, Muhammad, Whale, Alex, Kara, Neesha, Andrews, Simon R., Cruz, Filemon Dela, You, Daoqi, Siddiquee, Armaan, Cologna, Camila Takeno, De Craemer, Sam, Dolman, Emmy, Bartenhagen, Christoph, De Vloed, Fanny, Sanders, Ellen, Eggermont, Aline, Bekaert, Sarah Lee, Van Loocke, Wouter, Bek, Jan Willem, Dewyn, Givani, Loontiens, Siebe, Van Isterdael, Gert, Decaesteker, Bieke, Tilleman, Laurentijn, Van Nieuwerburgh, Filip, Vermeirssen, Vanessa, Van Neste, Christophe, Ghesquiere, Bart, Goossens, Steven, Eyckerman, Sven, De Preter, Katleen, Fischer, Matthias, Houseley, Jon, Molenaar, Jan, De Wilde, Bram, Roberts, Stephen S., Durinck, Kaat, and Speleman, Frank

Published
2022

111. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Sub General Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Meister, Michael T., Groot Koerkamp, Marian J.A., de Souza, Terezinha, Breunis, Willemijn B., Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H.D., Janse, Alex, Dolman, M. Emmy M., Eising, Selma, Langenberg, Karin P.S., van Tuil, Marc, Knops, Rutger R.G., van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S., Flucke, Uta, Merks, Johannes H.M., van Noesel, Max M., Tops, Bastiaan B.J., Hehir-Kwa, Jayne Y., Kemmeren, Patrick, Molenaar, Jan J., van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, Holstege, Frank C.P., Sub General Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Meister, Michael T., Groot Koerkamp, Marian J.A., de Souza, Terezinha, Breunis, Willemijn B., Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H.D., Janse, Alex, Dolman, M. Emmy M., Eising, Selma, Langenberg, Karin P.S., van Tuil, Marc, Knops, Rutger R.G., van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S., Flucke, Uta, Merks, Johannes H.M., van Noesel, Max M., Tops, Bastiaan B.J., Hehir-Kwa, Jayne Y., Kemmeren, Patrick, Molenaar, Jan J., van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, and Holstege, Frank C.P.

Published
2022

112. Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Author

Afd Pharmaceutics, Pharmaceutics, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, van Noesel, Max M, Afd Pharmaceutics, Pharmaceutics, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, and van Noesel, Max M

Published
2022

113. Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

Author

Dep Scheikunde, Afd Pharmaceutics, Pharmaceutics, Langenberg, Karin P.S., Meister, Michael T., Bakhuizen, Jette J., Boer, Judith M., van Eijkelenburg, Natasha K.A., Hulleman, Esther, Ilan, Uri, Looze, Eleonora J., Dierselhuis, Miranda P., van der Lugt, Jasper, Breunis, Willemijn, Schild, Linda G., Ober, Kimberley, van Hooff, Sander R., Scheijde-Vermeulen, Marijn A., Hiemcke-Jiwa, Laura S., Flucke, Uta E., Kranendonk, Mariette E.G., Wesseling, Pieter, Sonneveld, Edwin, Punt, Simone, Boltjes, Arjan, van Dijk, Freerk, Verwiel, Eugene T.P., Volckmann, Richard, Hehir-Kwa, Jayne Y., Kester, Lennart A., Koudijs, Marco M.J., Waanders, Esme, Holstege, Frank C.P., Vormoor, H. Josef, Hoving, Eelco W., van Noesel, Max M., Pieters, Rob, Kool, Marcel, Stumpf, Miriam, Blattner-Johnson, Mirjam, Balasubramanian, Gnana P., Van Tilburg, Cornelis M., Jones, Barbara C., Jones, David T.W., Witt, Olaf, Pfister, Stefan M., Jongmans, Marjolijn C.J., Kuiper, Roland P., de Krijger, Ronald R., Wijnen, Marc H.W., den Boer, Monique L., Zwaan, C. Michel, Kemmeren, Patrick, Koster, Jan, Tops, Bastiaan B.J., Goemans, Bianca F., Molenaar, Jan J., Dep Scheikunde, Afd Pharmaceutics, Pharmaceutics, Langenberg, Karin P.S., Meister, Michael T., Bakhuizen, Jette J., Boer, Judith M., van Eijkelenburg, Natasha K.A., Hulleman, Esther, Ilan, Uri, Looze, Eleonora J., Dierselhuis, Miranda P., van der Lugt, Jasper, Breunis, Willemijn, Schild, Linda G., Ober, Kimberley, van Hooff, Sander R., Scheijde-Vermeulen, Marijn A., Hiemcke-Jiwa, Laura S., Flucke, Uta E., Kranendonk, Mariette E.G., Wesseling, Pieter, Sonneveld, Edwin, Punt, Simone, Boltjes, Arjan, van Dijk, Freerk, Verwiel, Eugene T.P., Volckmann, Richard, Hehir-Kwa, Jayne Y., Kester, Lennart A., Koudijs, Marco M.J., Waanders, Esme, Holstege, Frank C.P., Vormoor, H. Josef, Hoving, Eelco W., van Noesel, Max M., Pieters, Rob, Kool, Marcel, Stumpf, Miriam, Blattner-Johnson, Mirjam, Balasubramanian, Gnana P., Van Tilburg, Cornelis M., Jones, Barbara C., Jones, David T.W., Witt, Olaf, Pfister, Stefan M., Jongmans, Marjolijn C.J., Kuiper, Roland P., de Krijger, Ronald R., Wijnen, Marc H.W., den Boer, Monique L., Zwaan, C. Michel, Kemmeren, Patrick, Koster, Jan, Tops, Bastiaan B.J., Goemans, Bianca F., and Molenaar, Jan J.

Published
2022

114. Extracellular vesicles in the TME of neuroblastoma: modulator of efficacious immunotherapies?

Author

Berkum, Ronja van, Molenaar, Jan (Thesis Advisor), Berkum, Ronja van, and Molenaar, Jan (Thesis Advisor)

Abstract

Despite giving rise to improved survival rates in neuroblastoma, 40% of high-risk patients fail to respond or develop resistance to immunotherapy. Neuroblastoma poses a big challenge for immunotherapy by secretion of immunomodulatory proteins and extracellular vesicles (EVs) into the tumour microenvironment (TME). Therefore, we aim to investigate the optimal method to isolate extracellular vesicles from the secretome of neuroblastoma tumour organoids with the purpose of preserved functional activity of the EVs. We isolated EVs from 14 neuroblastoma tumour organoids and healthy reference cells by use of size exclusion chromatography (SEC) after which the EVs were characterised and quantified. We established the EVs preserved some functional capacity in co-culture with immune cells and demonstrated the isolation method is compatible with MS analysis of the EV protein composition. Thus this study establishes a suitable method to isolate functional EVs from tumour organoids, enabling further research into their potential immunosuppressive capacity in the TME of neuroblastoma.

Published
2022

115. RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

Author

Nunes, Carolina, Depestel, Lisa, Mus, Liselot, Keller, Kaylee M., Delhaye, Louis, Louwagie, Amber, Rishfi, Muhammad, Whale, Alex, Kara, Neesha, Andrews, Simon R., Dela Cruz, Filemon, You, Daoqi, Siddiquee, Armaan, Cologna, Camila Takeno, De Craemer, Sam, Dolman, Emmy, Bartenhagen, Christoph, De Vloed, Fanny, Sanders, Ellen, Eggermont, Aline, Bekaert, Sarah-Lee, Van Loocke, Wouter, Bek, Jan Willem, Dewyn, Givani, Loontiens, Siebe, Van Isterdael, Gert, Decaesteker, Bieke, Tilleman, Laurentijn, Van Nieuwerburgh, Filip, Vermeirssen, Vanessa, Van Neste, Christophe, Ghesquiere, Bart, Goossens, Steven, Eyckerman, Sven, De Preter, Katleen, Fischer, Matthias, Houseley, Jon, Molenaar, Jan, De Wilde, Bram, Roberts, Stephen S., Durinck, Kaat, Speleman, Frank, Nunes, Carolina, Depestel, Lisa, Mus, Liselot, Keller, Kaylee M., Delhaye, Louis, Louwagie, Amber, Rishfi, Muhammad, Whale, Alex, Kara, Neesha, Andrews, Simon R., Dela Cruz, Filemon, You, Daoqi, Siddiquee, Armaan, Cologna, Camila Takeno, De Craemer, Sam, Dolman, Emmy, Bartenhagen, Christoph, De Vloed, Fanny, Sanders, Ellen, Eggermont, Aline, Bekaert, Sarah-Lee, Van Loocke, Wouter, Bek, Jan Willem, Dewyn, Givani, Loontiens, Siebe, Van Isterdael, Gert, Decaesteker, Bieke, Tilleman, Laurentijn, Van Nieuwerburgh, Filip, Vermeirssen, Vanessa, Van Neste, Christophe, Ghesquiere, Bart, Goossens, Steven, Eyckerman, Sven, De Preter, Katleen, Fischer, Matthias, Houseley, Jon, Molenaar, Jan, De Wilde, Bram, Roberts, Stephen S., Durinck, Kaat, and Speleman, Frank

Abstract

High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.

Published
2022

116. Refractory Stage M Ganglioneuroblastoma with Bone Metastases and a Favorable, Chronic Course of Disease:Description of a Patient Cohort

Author

Tas, Michelle L., Molenaar, Jan J., Peek, Annemarie M.L., Lequin, Maarten H., Verdijk, Rob M., de Krijger, Ronald R., Tytgat, Godelieve A.M., van Noesel, Max M., Tas, Michelle L., Molenaar, Jan J., Peek, Annemarie M.L., Lequin, Maarten H., Verdijk, Rob M., de Krijger, Ronald R., Tytgat, Godelieve A.M., and van Noesel, Max M.

Abstract

Refractory stage M neuroblastoma (NB) is associated with a poor prognosis and a progressive course of disease. Here, we describe a unique group of patients with a discrepant clinical course. Seven histologically confirmed ganglioneuroblastoma (GNB) (n = 6) and differentiating NB (n = 1) patients were identified who were diagnosed with stage M disease based on iodine-123-metaiodobenzylguanidine avid bone metastases. Six patients started on high-risk treatment, without tumor response (stable disease). Treatment was discontinued before the start of consolidation treatment because of refractory response in all patients. Unexpectedly, after cessation of treatment no progression of disease occurred. In 2 patients, the primary tumors expanded (> 25%) very slowly during 1.5 and 3 years, and remained stable thereafter. Metabolically, a slow decrease of urinary homovanillic acid and vanillylmandelic acid levels and iodine-123-metaiodobenzylguanidine avidity was observed. All patients are alive with presence of metastatic disease after a median follow-up of 17 years (range: 6.7 to 27 y). Interestingly, at diagnosis, 6 patients were asymptomatic, 6 patients had GNB morphology, and 5 patients had meningeal metastases. These are all features seen in only a small minority of stage M patients. This GNB entity illustrates the clinical heterogeneity of neuroblastic tumors and can be used to further study the developmental origin of different NB subtypes.

Published
2022

117. Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'

Author

Genetica Oper.Mang. Clinical Genetics, Cancer, PMC Medisch specialisten, Arts-assistenten Kinderen, Groep Holstege, Pathologie Pathologen staf, Pathologie Groep Van Diest, Brain, Hematologie ICAT, Infection & Immunity, CDL Cluster Onderzoek en Onderwijs, Pathologie Moleculair, Genetica Sectie Genoomdiagnostiek, Onderzoek Beeld, Child Health, Neurochirurgen, Zorg en O&O, Genetica Klinische Genetica, Genetica, Zorgeenheid Kinderchirurgie Medisch, Speerpunt, CMM, Langenberg, Karin P S, Meister, Michael T, Bakhuizen, Jette J, Boer, Judith M, van Eijkelenburg, Natasha K A, Hulleman, Esther, Ilan, Uri, Looze, Eleonora J, Dierselhuis, Miranda P, van der Lugt, Jasper, Breunis, Willemijn, Schild, Linda G, Ober, Kimberley, van Hooff, Sander R, Scheijde-Vermeulen, Marijn A, Hiemcke-Jiwa, Laura S, Flucke, Uta E, Kranendonk, Mariette E G, Wesseling, Pieter, Sonneveld, Edwin, Punt, Simone, Boltjes, Arjan, van Dijk, Freerk, Verwiel, Eugene T P, Volckmann, Richard, Hehir-Kwa, Jayne Y, Kester, Lennart A, Koudijs, Marco M J, Waanders, Esme, Holstege, Frank C P, Vormoor, H Josef, Hoving, Eelco W, van Noesel, Max M, Pieters, Rob, Kool, Marcel, Stumpf, Miriam, Blattner-Johnson, Mirjam, Balasubramanian, Gnana P, Van Tilburg, Cornelis M, Jones, Barbara C, Jones, David T W, Witt, Olaf, Pfister, Stefan M, Jongmans, Marjolijn C J, Kuiper, Roland P, de Krijger, Ronald R, Wijnen, Marc H W, den Boer, Monique L, Zwaan, C Michel, Kemmeren, Patrick, Koster, Jan, Tops, Bastiaan B J, Goemans, Bianca F, Molenaar, Jan J, Genetica Oper.Mang. Clinical Genetics, Cancer, PMC Medisch specialisten, Arts-assistenten Kinderen, Groep Holstege, Pathologie Pathologen staf, Pathologie Groep Van Diest, Brain, Hematologie ICAT, Infection & Immunity, CDL Cluster Onderzoek en Onderwijs, Pathologie Moleculair, Genetica Sectie Genoomdiagnostiek, Onderzoek Beeld, Child Health, Neurochirurgen, Zorg en O&O, Genetica Klinische Genetica, Genetica, Zorgeenheid Kinderchirurgie Medisch, Speerpunt, CMM, Langenberg, Karin P S, Meister, Michael T, Bakhuizen, Jette J, Boer, Judith M, van Eijkelenburg, Natasha K A, Hulleman, Esther, Ilan, Uri, Looze, Eleonora J, Dierselhuis, Miranda P, van der Lugt, Jasper, Breunis, Willemijn, Schild, Linda G, Ober, Kimberley, van Hooff, Sander R, Scheijde-Vermeulen, Marijn A, Hiemcke-Jiwa, Laura S, Flucke, Uta E, Kranendonk, Mariette E G, Wesseling, Pieter, Sonneveld, Edwin, Punt, Simone, Boltjes, Arjan, van Dijk, Freerk, Verwiel, Eugene T P, Volckmann, Richard, Hehir-Kwa, Jayne Y, Kester, Lennart A, Koudijs, Marco M J, Waanders, Esme, Holstege, Frank C P, Vormoor, H Josef, Hoving, Eelco W, van Noesel, Max M, Pieters, Rob, Kool, Marcel, Stumpf, Miriam, Blattner-Johnson, Mirjam, Balasubramanian, Gnana P, Van Tilburg, Cornelis M, Jones, Barbara C, Jones, David T W, Witt, Olaf, Pfister, Stefan M, Jongmans, Marjolijn C J, Kuiper, Roland P, de Krijger, Ronald R, Wijnen, Marc H W, den Boer, Monique L, Zwaan, C Michel, Kemmeren, Patrick, Koster, Jan, Tops, Bastiaan B J, Goemans, Bianca F, and Molenaar, Jan J

Published
2022

118. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Groep Holstege, CMM Groep Klumperman, PMC Medisch specialisten, Cancer, CMM, CMM Groep Burgering, Meister, Michael T, Groot Koerkamp, Marian J A, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M, van Noesel, Max M, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, Holstege, Frank C P, Groep Holstege, CMM Groep Klumperman, PMC Medisch specialisten, Cancer, CMM, CMM Groep Burgering, Meister, Michael T, Groot Koerkamp, Marian J A, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M, van Noesel, Max M, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, and Holstege, Frank C P

Published
2022

119. Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Author

MS Radiologie, Circulatory Health, Pathologie Pathologen staf, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, van Noesel, Max M, MS Radiologie, Circulatory Health, Pathologie Pathologen staf, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, and van Noesel, Max M

Published
2022

120. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Meister, Michael T; https://orcid.org/0000-0001-8311-721X, Groot Koerkamp, Marian J A; https://orcid.org/0000-0002-0867-0821, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa; https://orcid.org/0000-0003-0903-869X, Brok, Mariël; https://orcid.org/0000-0001-6018-900X, DeMartino, Jeff; https://orcid.org/0000-0001-7366-4789, Manders, Freek; https://orcid.org/0000-0001-6197-347X, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S; https://orcid.org/0000-0002-6780-0585, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M; https://orcid.org/0000-0001-7659-1028, van Noesel, Max M; https://orcid.org/0000-0003-0503-5838, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick; https://orcid.org/0000-0003-2237-7354, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno; https://orcid.org/0000-0002-2941-6179, Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146, Meister, Michael T; https://orcid.org/0000-0001-8311-721X, Groot Koerkamp, Marian J A; https://orcid.org/0000-0002-0867-0821, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa; https://orcid.org/0000-0003-0903-869X, Brok, Mariël; https://orcid.org/0000-0001-6018-900X, DeMartino, Jeff; https://orcid.org/0000-0001-7366-4789, Manders, Freek; https://orcid.org/0000-0001-6197-347X, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S; https://orcid.org/0000-0002-6780-0585, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M; https://orcid.org/0000-0001-7659-1028, van Noesel, Max M; https://orcid.org/0000-0003-0503-5838, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick; https://orcid.org/0000-0003-2237-7354, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno; https://orcid.org/0000-0002-2941-6179, and Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146

Abstract

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

Published
2022

123. Author Reply to Peer Reviews of Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Holstege, Frank C. P., primary, Drost, Jarno, additional, van Boxtel, Ruben, additional, van de Wetering, Marc, additional, Molenaar, Jan J., additional, Kemmeren, Patrick, additional, Hehir-Kwa, Jayne Y., additional, Tops, Bastiaan B. J., additional, van Noesel, Max M., additional, Merks, Johannes H. M., additional, Flucke, Uta, additional, Hiemcke-Jiwa, Laura S., additional, van Scheltinga, Sheila Terwisscha, additional, Knops, Rutger R. G., additional, van Tuil, Marc, additional, Langenberg, Karin P. S., additional, Eising, Selma, additional, Dolman, M. Emmy M., additional, Janse, Alex, additional, Kerstens, Hinri H. D., additional, Calandrini, Camilla, additional, Manders, Freek, additional, DeMartino, Jeff, additional, Brok, Mariël, additional, Frazer-Mendelewska, Ewa, additional, Breunis, Willemijn B., additional, de Souza, Terezinha, additional, Groot Koerkamp, Marian J. A., additional, and Meister, Michael T., additional

Published
2022
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124. Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies

Author

Keller, Kaylee M., primary, Krausert, Sonja, additional, Gopisetty, Apurva, additional, Luedtke, Dan, additional, Koster, Jan, additional, Schubert, Nil A., additional, Rodríguez, Ana, additional, van Hooff, Sander R., additional, Stichel, Damian, additional, Dolman, M. Emmy M., additional, Vassal, Gilles, additional, Pfister, Stefan M., additional, Caron, Hubert N., additional, Stancato, Louis F., additional, Molenaar, Jan J., additional, Jäger, Natalie, additional, and Kool, Marcel, additional

Published
2022
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125. Additional file 6 of Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

Author

Berlak, Mareike, Tucker, Elizabeth, Dorel, Mathurin, Winkler, Annika, McGearey, Aleixandria, Rodriguez-Fos, Elias, da Costa, Barbara Martins, Barker, Karen, Fyle, Elicia, Calton, Elizabeth, Eising, Selma, Ober, Kim, Hughes, Deborah, Koutroumanidou, Eleni, Carter, Paul, Stankunaite, Reda, Proszek, Paula, Jain, Neha, Rosswog, Carolina, Dorado-Garcia, Heathcliff, Molenaar, Jan Jasper, Hubank, Mike, Barone, Giuseppe, Anderson, John, Lang, Peter, Deubzer, Hedwig Elisabeth, Künkele, Annette, Fischer, Matthias, Eggert, Angelika, Kloft, Charlotte, Henssen, Anton George, Boettcher, Michael, Hertwig, Falk, Blüthgen, Nils, Chesler, Louis, and Schulte, Johannes Hubertus

Abstract

Additional file 6. Supplementary Materials and Methods.

Published
2022
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126. Additional file 1 of Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

Author

Berlak, Mareike, Tucker, Elizabeth, Dorel, Mathurin, Winkler, Annika, McGearey, Aleixandria, Rodriguez-Fos, Elias, da Costa, Barbara Martins, Barker, Karen, Fyle, Elicia, Calton, Elizabeth, Eising, Selma, Ober, Kim, Hughes, Deborah, Koutroumanidou, Eleni, Carter, Paul, Stankunaite, Reda, Proszek, Paula, Jain, Neha, Rosswog, Carolina, Dorado-Garcia, Heathcliff, Molenaar, Jan Jasper, Hubank, Mike, Barone, Giuseppe, Anderson, John, Lang, Peter, Deubzer, Hedwig Elisabeth, Künkele, Annette, Fischer, Matthias, Eggert, Angelika, Kloft, Charlotte, Henssen, Anton George, Boettcher, Michael, Hertwig, Falk, Blüthgen, Nils, Chesler, Louis, and Schulte, Johannes Hubertus

Abstract

Additional file 1: Figure S1: ALK inhibitor treatment of ALK-mutated neuroblastoma cell lines for optimized screeningconditions (related to Figure 1). Figure S2: Quality control of CRISPR/Cas9 knockout screen (related to Figure 1). Figure S3: Lorlatinib- and Ceritinib- resistant NBLW-R neuroblastoma cells grow as aggressive tumors in the kidney capsule of nude mice (related to Figure 3). Figure S4: Tetracycline induced NRASQ61K expression (related to Figure 4). Figure S5: Computational modeling of ALK downstream signaling using STASNet (related to Figure 6). Figure S6: MEK inhibitor treatment of ectopic NRASQ61K expression models (related to Figure 7). Figure S7: High-throughput drug screening of LAN-5 and LAN-5 NF1 KO#2 clone (related to Figure 7). Table S1. Full clinical data on neuroblastoma patients.

Published
2022
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127. Refractory Stage M Ganglioneuroblastoma with Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Author

Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, van Noesel, Max M, Afd Pharmaceutics, Pharmaceutics, Pathology, Faculteit Medische Wetenschappen/UMCG, Paediatric Oncology, CCA - Cancer Treatment and Quality of Life, Afd Pharmaceutics, and Pharmaceutics

Subjects
Male, ganglioneuroblastoma, medicine.medical_specialty, Urinary system, Bone Neoplasms, CHILDREN, Asymptomatic, Gastroenterology, CLASSIFICATION, MATURATION, neuroblastoma, Stable Disease, Refractory, PEDIATRIC-ONCOLOGY-GROUP, Neuroblastoma, Internal medicine, medicine, Humans, metastasis, Neoplasm Metastasis, Stage (cooking), meningeal, Neoplasm Staging, Retrospective Studies, Ganglioneuroblastoma, business.industry, CENTRAL-NERVOUS-SYSTEM, Infant, Hematology, INDUCTION THERAPY, medicine.disease, Neuroblastic Tumor, CYCLOPHOSPHAMIDE DOXORUBICIN, Consolidation Chemotherapy, refractory, MANIFESTATIONS, Oncology, Child, Preschool, Chronic Disease, Pediatrics, Perinatology and Child Health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, SURVIVAL, Female, prognosis, medicine.symptom, business, Online Articles: Original Articles
Abstract

Supplemental Digital Content is available in the text., Refractory stage M neuroblastoma (NB) is associated with a poor prognosis and a progressive course of disease. Here, we describe a unique group of patients with a discrepant clinical course. Seven histologically confirmed ganglioneuroblastoma (GNB) (n=6) and differentiating NB (n=1) patients were identified who were diagnosed with stage M disease based on iodine-123-metaiodobenzylguanidine avid bone metastases. Six patients started on high-risk treatment, without tumor response (stable disease). Treatment was discontinued before the start of consolidation treatment because of refractory response in all patients. Unexpectedly, after cessation of treatment no progression of disease occurred. In 2 patients, the primary tumors expanded (>25%) very slowly during 1.5 and 3 years, and remained stable thereafter. Metabolically, a slow decrease of urinary homovanillic acid and vanillylmandelic acid levels and iodine-123-metaiodobenzylguanidine avidity was observed. All patients are alive with presence of metastatic disease after a median follow-up of 17 years (range: 6.7 to 27 y). Interestingly, at diagnosis, 6 patients were asymptomatic, 6 patients had GNB morphology, and 5 patients had meningeal metastases. These are all features seen in only a small minority of stage M patients. This GNB entity illustrates the clinical heterogeneity of neuroblastic tumors and can be used to further study the developmental origin of different NB subtypes.

Published
2022

129. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Meister, Michael T., primary, Groot Koerkamp, Marian J. A., additional, de Souza, Terezinha, additional, Breunis, Willemijn B., additional, Frazer-Mendelewska, Ewa, additional, Brok, Mariël, additional, DeMartino, Jeff, additional, Manders, Freek, additional, Calandrini, Camilla, additional, Kerstens, Hinri H. D., additional, Janse, Alex, additional, Dolman, M. Emmy M., additional, Eising, Selma, additional, Langenberg, Karin P. S., additional, van Tuil, Marc, additional, Knops, Rutger R. G., additional, van Scheltinga, Sheila Terwisscha, additional, Hiemcke-Jiwa, Laura S., additional, Flucke, Uta, additional, Merks, Johannes H. M., additional, van Noesel, Max M., additional, Tops, Bastiaan B. J., additional, Hehir-Kwa, Jayne Y., additional, Kemmeren, Patrick, additional, Molenaar, Jan J., additional, van de Wetering, Marc, additional, van Boxtel, Ruben, additional, Drost, Jarno, additional, and Holstege, Frank C. P., additional

Published
2022
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130. Mek Inhibition Causes BIM Stabilization and Increased Sensitivity to BCL-2 Family Member Inhibitors in RAS-MAPK-Mutated Neuroblastoma

Author

Eleveld, Thomas F., primary, Vernooij, Lindy, additional, Schild, Linda, additional, Koopmans, Bianca, additional, Alles, Lindy K., additional, Ebus, Marli E., additional, Dandis, Rana, additional, van Tinteren, Harm, additional, Caron, Huib N., additional, Koster, Jan, additional, van Noesel, M. M., additional, Tytgat, Lieve G.A.M., additional, Eising, Selma, additional, Versteeg, Rogier, additional, Dolman, M. Emmy M., additional, and Molenaar, Jan J., additional

Published
2022
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131. Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies

Author

Keller, Kaylee M., Krausert, Sonja, Gopisetty, Apurva, Luedtke, Dan, Koster, Jan, Schubert, Nil A., Rodríguez, Ana, van Hooff, Sander R., Stichel, Damian, Dolman, M. Emmy M., Vassal, Gilles, Pfister, Stefan M., Caron, Hubert N., Stancato, Louis F., Molenaar, Jan J., Jäger, Natalie, Kool, Marcel, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
Paediatric oncology, Cancer Research, DNA Repair, DNA repair, Replication stress, Bone Neoplasms, Cell Cycle Checkpoints, Oncology, Preclinical research, Cell cycle checkpoints, Systematic review, Humans, Targeted drugs, Cerebellar Neoplasms, Child, Medulloblastoma
Abstract

Background: Owing to the high numbers of paediatric cancer-related deaths, advances in therapeutic options for childhood cancer is a heavily studied field, especially over the past decade. Classical chemotherapy offers some therapeutic benefit but has proven long-term complications in survivors, and there is an urgent need to identify novel target-driven therapies. Replication stress is a major cause of genomic instability in cancer, triggering the stalling of the replication fork. Failure of molecular response by DNA damage checkpoints, DNA repair mechanisms and restarting the replication forks can exacerbate replication stress and initiate cell death pathways, thus presenting as a novel therapeutic target. To bridge the gap between preclinical evidence and clinical utility thereof, we apply the literature-driven systematic target actionability review methodology to published proof-of-concept (PoC) data related to the process of replication stress. Methods: A meticulous PubMed literature search was performed to gather replication stress-related articles (published between 2014 and 2021) across 16 different paediatric solid tumour types. Articles that fulfilled inclusion criteria were uploaded into the R2 informatics platform [r2.amc.nl] and assessed by critical appraisal. Key evidence based on nine pre-established PoC modules was summarised, and scores based on the quality and outcome of each study were assigned by two separate reviewers. Articles with discordant modules/scores were re-scored by a third independent reviewer, and a final consensus score was agreed upon by adjudication between all three reviewers. To visualise the final scores, an interactive heatmap summarising the evidence and scores associated with each PoC module across all, including paediatric tumour types, were generated. Results and conclusions:: 145 publications related to targeting replication stress in paediatric tumours were systematically reviewed with an emphasis on DNA repair pathways and cell cycle checkpoint control. Although various targets in these pathways have been studied in these diseases to different extents, the results of this extensive literature search show that ATR, CHK1, PARP or WEE1 are the most promising targets using either single agents or in combination with chemotherapy or radiotherapy in neuroblastoma, osteosarcoma, high-grade glioma or medulloblastoma. Targeting these pathways in other paediatric malignancies may work as well, but here, the evidence was more limited. The evidence for other targets (such as ATM and DNA-PK) was also limited but showed promising results in some malignancies and requires more studies in other tumour types. Overall, we have created an extensive overview of targeting replication stress across 16 paediatric tumour types, which can be explored using the interactive heatmap on the R2 target actionability review platform [https://hgserver1.amc.nl/cgi-bin/r2/main.cgi?option=imi2_targetmap_v1].

Published
2021

132. The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Author

Langenberg, Karin P S, Looze, Eleonora J, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, precision medicine, Childhood cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Review, Immune monitoring, Precision medicine, targeted therapy, Targeted therapy, Clinical trial, Oncology, Precision oncology, medicine, next-generation sequencing, Program Design Language, Intensive care medicine, business, RC254-282
Abstract

Simple Summary Precision medicine is a revolutionary new way to deliver cancer treatment by targeting specific genetic changes of the cancer of the individual child with the goal of improving cure rates and reducing toxicity. In this review, we illustrate the evolution of cancer treatment in this groundbreaking new era. We compare characteristics and early results of precision medicine programs in pediatric oncology as well as novel clinical trial initiatives translating these findings into potential clinical benefit for all children and adolescents with cancer. Abstract Over the last years, various precision medicine programs have been developed for pediatric patients with high-risk, relapsed, or refractory malignancies, selecting patients for targeted treatment through comprehensive molecular profiling. In this review, we describe characteristics of these initiatives, demonstrating the feasibility and potential of molecular-driven precision medicine. Actionable events are identified in a significant subset of patients, although comparing results is complicated due to the lack of a standardized definition of actionable alterations and the different molecular profiling strategies used. The first biomarker-driven trials for childhood cancer have been initiated, but until now the effect of precision medicine on clinical outcome has only been reported for a small number of patients, demonstrating clinical benefit in some. Future perspectives include the incorporation of novel approaches such as liquid biopsies and immune monitoring as well as innovative collaborative trial design including combination strategies, and the development of agents specifically targeting aberrations in childhood malignancies.

Published
2021

133. Neuroblastoma and DIPG Organoid Coculture System for Personalized Assessment of Novel Anticancer Immunotherapies

Author

M Kholosy, Waleed, Derieppe, Marc, van den Ham, Femke, Ober, Kim, Su, Yan, Custers, Lars, Schild, Linda, M J van Zogchel, Lieke, M Wellens, Lianne, R Ariese, Hendrikus, Szanto, Celina L, Wienke, Judith, Dierselhuis, Miranda P, van Vuurden, Dannis, Dolman, Emmy M, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
cancer immunotherapy, medicine.drug_class, business.industry, medicine.medical_treatment, Medicine (miscellaneous), Dinutuximab, Immunotherapy, Monoclonal antibody, medicine.disease, Article, neuroblastoma, Immune system, paediatric cancer organoids, Cancer immunotherapy, diffuse intrinsic pontine glioma (DIPG), Neuroblastoma, coculture system, Cancer research, medicine, Organoid, Medicine, business, Ex vivo
Abstract

Cancer immunotherapy has transformed the landscape of adult cancer treatment and holds a great promise to treat paediatric malignancies. However, in vitro test coculture systems to evaluate the efficacy of immunotherapies on representative paediatric tumour models are lacking. Here, we describe a detailed procedure for the establishment of an ex vivo test coculture system of paediatric tumour organoids and immune cells that enables assessment of different immunotherapy approaches in paediatric tumour organoids. We provide a step-by-step protocol for an efficient generation of patient-derived diffuse intrinsic pontine glioma (DIPG) and neuroblastoma organoids stably expressing eGFP-ffLuc transgenes using defined serum-free medium. In contrast to the chromium-release assay, the new platform allows for visualization, monitoring and robust quantification of tumour organoid cell cytotoxicity using a non-radioactive assay in real-time. To evaluate the utility of this system for drug testing in the paediatric immuno-oncology field, we tested our in vitro assay using a clinically used immunotherapy strategy for children with high-risk neuroblastoma, dinutuximab (anti-GD2 monoclonal antibody), on GD2 proficient and deficient patient-derived neuroblastoma organoids. We demonstrated the feasibility and sensitivity of our ex vivo coculture system using human immune cells and paediatric tumour organoids as ex vivo tumour models. Our study provides a novel platform for personalized testing of potential anticancer immunotherapies for aggressive paediatric cancers such as neuroblastoma and DIPG.

Published
2021

134. αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression

Author

Strijker, Josephine G M, Pscheid, Ronja, Drent, Esther, van der Hoek, Jessica J F, Koopmans, Bianca, Ober, Kimberley, van Hooff, Sander R, Kholosy, Waleed M, Cornel, Annelisa M, Coomans, Chris, Bisso, Andrea, van Loenen, Marleen M, Molenaar, Jan J, Wienke, Judith, Afd Pharmaceutics, Pharmaceutics, Center of Experimental and Molecular Medicine, AII - Cancer immunology, CCA - Cancer biology and immunology, Afd Pharmaceutics, and Pharmaceutics

Subjects
T cell, medicine.medical_treatment, Medicine (miscellaneous), Major histocompatibility complex, Article, γδ-T cells, neuroblastoma, Neuroblastoma, Interferon, MHC class I, medicine, Organoid, MHC-I, TEG002, biology, Immunotherapy, medicine.disease, medicine.anatomical_structure, Cancer research, biology.protein, Medicine, immunotherapy, medicine.drug, Extracellular matrix organization
Abstract

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.

Published
2021

135. Resection margins in oral cancer surgery: Room for improvement

Author

Smits, Roeland W.H., Koljenović, Senada, Hardillo, Jose A., ten Hove, Ivo, Meeuwis, Cees A., Sewnaik, Aniel, Dronkers, Emilie A.C., Bakker Schut, Tom C., Langeveld, Ton P.M., Molenaar, Jan, Hegt, Noordhoek V., Puppels, Gerwin J., Baatenburg de Jong, Robert J., and Eisele, David W.

Published
2016
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136. G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment

Author

Martinez Sanz, Paula, van Rees, Dieke J, van Zogchel, Lieke M J, Klein, Bart, Bouti, Panagiota, Olsman, Hugo, Schornagel, Karin, Kok, Ivana, Sunak, Ali, Leeuwenburg, Kira, Timmerman, Ilse, Dierselhuis, Miranda P, Kholosy, Waleed M, Molenaar, Jan J, van Bruggen, Robin, van den Berg, Timo K, Kuijpers, Taco W, Matlung, Hanke L, Tytgat, Godelieve A M, Franke, Katka, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, AII - Cancer immunology, CCA - Cancer biology and immunology, Paediatric Infectious Diseases / Rheumatology / Immunology, AR&D - Amsterdam Reproduction & Development, and Paediatric Oncology

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Cell Proliferation/drug effects, 0302 clinical medicine, Adjuvants, Immunologic/pharmacology, Receptors, Tumor Microenvironment, Immunology and Allergy, Cytotoxicity, Immunologic/drug effects, Trogocytosis/drug effects, immunologic, RC254-282, Antibody-dependent cell-mediated cytotoxicity, Tumor, biology, Dinutuximab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Antineoplastic Agents, Immunological/pharmacology, Immunologic/pharmacology, Cytokine, Oncology, Integrin alpha M, Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology, 030220 oncology & carcinogenesis, Neutrophils/drug effects, Molecular Medicine, cytotoxicity, CD11b Antigen/metabolism, immunotherapy, Granulocyte Colony-Stimulating Factor/pharmacology, Immunologic/drug effects, Trogocytosis, Immunology, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Antibodies, Cell Line, 03 medical and health sciences, neuroblastoma, In vivo, Neuroblastoma, Cell Line, Tumor, medicine, CD18 Antigens/metabolism, innate, Humans, Neuroblastoma/drug therapy, Adjuvants, Pharmacology, business.industry, IgG/metabolism, Basic Tumor Immunology, Immunotherapy, Receptors, IgG/metabolism, medicine.disease, immunity, Antibodies, Monoclonal/pharmacology, Coculture Techniques, cytokines, Monoclonal/pharmacology, 030104 developmental biology, Cancer research, biology.protein, Immunological/pharmacology, business
Abstract

BackgroundCurrent immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma.MethodsWe compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions.ResultsWe found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions.ConclusionsOur preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting.

Published
2021

137. High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia

Author

Wander, Priscilla, Arentsen-Peters, Susan T C J M, Pinhanҫos, Sandra S, Koopmans, Bianca, Dolman, M Emmy M, Ariese, Rijndert, Bos, Frank L, Castro, Patricia Garrido, Jones, Luke, Schneider, Pauline, Navarro, Miriam Guillen, Molenaar, Jan J, Rios, Anne C, Zwaan, C Michel, Stam, Ronald W, Afd Pharmaceutics, Pharmaceutics, Pediatrics, Afd Pharmaceutics, and Pharmaceutics

Subjects
0301 basic medicine, Drug, Cancer Research, MLL-rearranged AML, media_common.quotation_subject, Drug resistance, lcsh:RC254-282, Pediatric acute myeloid leukemia, Pyrvinium, 03 medical and health sciences, chemistry.chemical_compound, Pyrvinium pamoate, 0302 clinical medicine, SDG 3 - Good Health and Well-being, hemic and lymphatic diseases, Medicine, Viability assay, neoplasms, Original Research, media_common, business.industry, Wnt signaling pathway, Myeloid leukemia, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, medicine.anatomical_structure, chemistry, Oncology, Cell culture, High-throughput drug library screen, 030220 oncology & carcinogenesis, Cancer research, Bone marrow, business
Abstract

Highlights • Drug library screening identified pyrvinium to be effective against MLL-rearranged AML. • Pyrvinium targets the mitochondria of MLL-rearranged AML cells. • Pyrvinium does not antagonize with standard chemotherapy in MLL-rearranged AML., Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at

Published
2021

138. Loss of p16INK4a in neuroblastoma cells induces shift to an immature state with mesenchymal characteristics and increases sensitivity to EGFR inhibitors

Author

Schubert, Nil A., primary, van Hooff, Sander R., additional, Schild, Linda, additional, Ober, Kimberley, additional, Hortensius, Marjolein, additional, van den Handel, Kim, additional, Essing, Anke H.W., additional, Koopmans, Bianca, additional, Boeije, Manon, additional, Proost, Natalie, additional, van de Ven, Marieke, additional, Jansky, Selina, additional, Stainczyk, Sabine A., additional, Toprak, Umut H., additional, Westermann, Frank, additional, Eising, Selma, additional, Molenaar, Jan J., additional, and van den Boogaard, Marlinde L., additional

Published
2021
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139. Systematic discovery of gene fusions in pediatric cancer by integrating RNA-seq and WGS

Author

van Belzen, Ianthe A.E.M., primary, Cai, Casey, additional, van Tuil, Marc, additional, Badloe, Shashi, additional, Strengman, Eric, additional, Janse, Alex, additional, Verwiel, Eugène T., additional, van der Leest, Douwe F.M., additional, Kester, Lennart, additional, Molenaar, Jan J., additional, Meijerink, Jules, additional, Drost, Jarno, additional, Peng, Weng Chuan, additional, Kerstens, Hinri H.D., additional, Tops, Bastiaan B.J., additional, Holstege, Frank C.P., additional, Kemmeren, Patrick, additional, and Hehir-Kwa, Jayne Y., additional

Published
2021
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140. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., primary, Pfaff, Elke, additional, Pajtler, Kristian W., additional, Langenberg, Karin P.S., additional, Fiesel, Petra, additional, Jones, Barbara C., additional, Balasubramanian, Gnana Prakash, additional, Stark, Sebastian, additional, Johann, Pascal D., additional, Blattner-Johnson, Mirjam, additional, Schramm, Kathrin, additional, Dikow, Nicola, additional, Hirsch, Steffen, additional, Sutter, Christian, additional, Grund, Kerstin, additional, von Stackelberg, Arend, additional, Kulozik, Andreas E., additional, Lissat, Andrej, additional, Borkhardt, Arndt, additional, Meisel, Roland, additional, Reinhardt, Dirk, additional, Klusmann, Jan-Henning, additional, Fleischhack, Gudrun, additional, Tippelt, Stephan, additional, von Schweinitz, Dietrich, additional, Schmid, Irene, additional, Kramm, Christof M., additional, von Bueren, André O., additional, Calaminus, Gabriele, additional, Vorwerk, Peter, additional, Graf, Norbert, additional, Westermann, Frank, additional, Fischer, Matthias, additional, Eggert, Angelika, additional, Burkhardt, Birgit, additional, Wößmann, Wilhelm, additional, Nathrath, Michaela, additional, Hecker-Nolting, Stefanie, additional, Frühwald, Michael C., additional, Schneider, Dominik T., additional, Brecht, Ines B., additional, Ketteler, Petra, additional, Fulda, Simone, additional, Koscielniak, Ewa, additional, Meister, Michael T., additional, Scheer, Monika, additional, Hettmer, Simone, additional, Schwab, Matthias, additional, Tremmel, Roman, additional, Øra, Ingrid, additional, Hutter, Caroline, additional, Gerber, Nicolas U., additional, Lohi, Olli, additional, Kazanowska, Bernarda, additional, Kattamis, Antonis, additional, Filippidou, Maria, additional, Goemans, Bianca, additional, Zwaan, C. Michel, additional, Milde, Till, additional, Jäger, Natalie, additional, Wolf, Stephan, additional, Reuss, David, additional, Sahm, Felix, additional, von Deimling, Andreas, additional, Dirksen, Uta, additional, Freitag, Angelika, additional, Witt, Ruth, additional, Lichter, Peter, additional, Kopp-Schneider, Annette, additional, Jones, David T.W., additional, Molenaar, Jan J., additional, Capper, David, additional, Pfister, Stefan M., additional, and Witt, Olaf, additional

Published
2021
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141. Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

Author

Calandrini, Camilla, primary, van Hooff, Sander R., additional, Paassen, Irene, additional, Ayyildiz, Dilara, additional, Derakhshan, Sepide, additional, Dolman, M. Emmy M., additional, Langenberg, Karin P.S., additional, van de Ven, Marieke, additional, de Heus, Cecilia, additional, Liv, Nalan, additional, Kool, Marcel, additional, de Krijger, Ronald R., additional, Tytgat, Godelieve A.M., additional, van den Heuvel-Eibrink, Marry M., additional, Molenaar, Jan J., additional, and Drost, Jarno, additional

Published
2021
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142. The landscape of genomic alterations across childhood cancers

Author

Grbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hbschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jrgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Gnther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Lichter, Peter, Weber, Ursula, Eils, Roland, Korshunov, Andrey, Witt, Olaf, Pfister, Stefan, Reifenberger, Guido, Felsberg, Jrg, von Kalle, Christof, Schmidt, Manfred, Bartholom, Cynthia, Taylor, Michael, Jones, David, Jger, Natalie, Korbel, Jan, Sttz, Adrian, Rausch, Tobias, Radlwimmer, Bernhard, Yaspo, Marie-Laure, Lehrach, Hans, Warnatz, Hans-Jrg, Landgraf, Pablo, Brors, Benedikt, Zapatka, Marc, Wagner, Susanne, Haake, Andrea, Richter, Julia, Richter, Gesine, Lawerenz, Chris, Kerssemakers, Jules, Jaeger-Schmidt, Christina, Scholz, Ingrid, Bergmann, Anke K., Borst, Christoph, Burkhardt, Birgit, Claviez, Alexander, Dreyling, Martin, Eberth, Sonja, Einsele, Hermann, Frickhofen, Norbert, Haas, Siegfried, Hansmann, Martin-Leo, Karsch, Dennis, Kneba, Michael, Lisfeld, Jasmin, Mantovani-Lffler, Luisa, Rohde, Marius, Ott, German, Stadler, Christina, Staib, Peter, Stilgenbauer, Stephan, Trmper, Lorenz, Zenz, Thorsten, Kube, Dieter, Kppers, Ralf, Weniger, Marc, Hummel, Michael, Klapper, Wolfram, Kostezka, Ulrike, Lenze, Dido, Mller, Peter, Rosenwald, Andreas, Szczepanowski, Monika, Ammerpohl, Ole, Aukema, Sietse M., Binder, Vera, Hoell, Jessica I., Leich, Ellen, Lpez, Cristina, Nagel, Inga, Pischimariov, Jordan, Rosenstiel, Philip, Schilhabel, Markus, Schreiber, Stefan, Vater, Inga, Wagener, Rabea, Bernhart, Stephan H., Binder, Hans, Doose, Gero, Hoffmann, Steve, Hopp, Lydia, Kretzmer, Helene, Kreuz, Markus, Langenberger, David, Loeffler, Markus, Rosolowski, Maciej, Schlesner, Matthias, Stadler, Peter F., Sungalee, Stephanie, Kratz, Christian P., van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frhwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Jones, David T. W., Chavez, Lukas, and Pfister, Stefan M.

Subjects
Childhood cancer -- Genetic aspects, Cancer research, Gene mutation -- Health aspects, Genomics -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 78% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials., Author(s): Susanne N. Grbner [1, 2, 3]; Barbara C. Worst [1, 2, 3, 4]; Joachim Weischenfeldt [5, 6]; Ivo Buchhalter [7]; Kortine Kleinheinz [7]; Vasilisa A. Rudneva [5, 8]; Pascal [...]

Published
2018
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143. Author Correction: The landscape of genomic alterations across childhood cancers

Author

Gröbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Burkhardt, Birgit, Kratz, Christian P., Witt, Olaf, van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Landgraf, Pablo, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Brors, Benedikt, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Schlesner, Matthias, Eils, Roland, Jones, David T. W., Lichter, Peter, Chavez, Lukas, Zapatka, Marc, Pfister, Stefan M., ICGC PedBrain-Seq Project, and ICGC MMML-Seq Project

Published
2018
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145. International Consensus on Minimum Preclinical Testing Requirements for the Development of Innovative Therapies For Children and Adolescents with Cancer

Author

Vassal, Gilles, primary, Houghton, Peter J., additional, Pfister, Stefan M., additional, Smith, Malcolm A., additional, Caron, Huib N., additional, Li, Xiao-Nan, additional, Shields, David J., additional, Witt, Olaf, additional, Molenaar, Jan J., additional, Colombetti, Sara, additional, Schüler, Julia, additional, and Stancato, Lou F., additional

Published
2021
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146. Inclusive Agricultural Trade Scan

Author

Guijt, Joost, Molenaar, Jan Willem, and Sopov, Monika

Subjects
Advisory, Life Science
Abstract

Refugees and host community living in Arua district in Northern Uganda face health issues related to malnutrition and food insecurity. The Nutrition Income Generation Intervention (NIGI) aimed to achieve healthier lives and more resilient livelihoods for refugees and host communities through home gardens and increasing commercial vegetable production. This report evaluates the effect of two years of NIGI on the refugee community using a refugee comparison group. Results showed that households who participated in the project produce more, both in terms of quantity (KGs) as well as varieties of fruit and vegetables, and earn more income as a result. Those who participate in the project were twice (OR=2.19) as likely to consume vegetables. Furthermore, household dietary diversity increased with an average increase of 0.40 points for crop farmers participating in NIGI. NIGI was not able to reduce the practice of harmful coping strategies against food security. So, NIGI should be seen as a supplement to food access and as a useful strategy to diversify diets but food assistance is still of main importance for refugee households to achieve food security.

Published
2021

147. Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Author

Afd Pharmaceutics, Pharmaceutics, Schubert, Nil A, Schild, Linda, van Oirschot, Stijn, Keller, Kaylee M, Alles, Lindy K, Vernooij, Lindy, Nulle, Marloes E, Dolman, M Emmy M, van den Boogaard, Marlinde L, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, Schubert, Nil A, Schild, Linda, van Oirschot, Stijn, Keller, Kaylee M, Alles, Lindy K, Vernooij, Lindy, Nulle, Marloes E, Dolman, M Emmy M, van den Boogaard, Marlinde L, and Molenaar, Jan J

Published
2021

148. High-Throughput Screening Identifies Idasanutlin as a Resensitizing Drug for Venetoclax-Resistant Neuroblastoma Cells

Author

Afd Pharmaceutics, Pharmaceutics, Vernooij, Lindy, Bate-Eya, Laurel T, Alles, Lindy K, Lee, Jasmine Y, Koopmans, Bianca, Jonus, Hunter C, Schubert, Nil A, Schild, Linda, Lelieveld, Daphne, Egan, David A, Kerstjens, Mark, Stam, Ronald W, Koster, Jan, Goldsmith, Kelly C, Molenaar, Jan J, Dolman, M Emmy M, Afd Pharmaceutics, Pharmaceutics, Vernooij, Lindy, Bate-Eya, Laurel T, Alles, Lindy K, Lee, Jasmine Y, Koopmans, Bianca, Jonus, Hunter C, Schubert, Nil A, Schild, Linda, Lelieveld, Daphne, Egan, David A, Kerstjens, Mark, Stam, Ronald W, Koster, Jan, Goldsmith, Kelly C, Molenaar, Jan J, and Dolman, M Emmy M

Published
2021

149. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Author

Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, Behjati, Sam, Afd Pharmaceutics, Pharmaceutics, Kildisiute, Gerda, Kholosy, Waleed M, Young, Matthew D, Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R, Pacyna, Clarissa N, Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M, Langenberg-Ververgaert, Karin P S, Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C P, Tas, Michelle L, Wijnen, Marc H W A, van Noesel, Max M, Del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C, Haniffa, Muzlifah, Teichmann, Sarah A, Rampling, Dyanne, Sebire, Neil J, He, Xiaoling, de Krijger, Ronald R, Barker, Roger A, Meyer, Kerstin B, Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J, and Behjati, Sam

Published
2021

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