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1. Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD

Author

Knikman, Jonathan E., Zhai, Qinglian, Lunenburg, Carin A. T. C., Henricks, Linda M., Böhringer, Stefan, van der Lee, Maaike, de Man, Femke M., Offer, Steven M., Shrestha, Shikshya, Creemers, Geert-Jan, Baars, Arnold, Dezentjé, Vincent O., Imholz, Alexander L. T., Jeurissen, Frank J. F., Portielje, Johanna E. A., Jansen, Rob L. H., Hamberg, Paul, Droogendijk, Helga J., Koopman, Miriam, Nieboer, Peter, van de Poel, Marlène H. W., Mandigers, Caroline M. P. W., van Schaik, Ron H. N., Gelderblom, Hans, Mathijssen, Ron H. J., Schellens, Jan H. M., Cats, Annemieke, Guchelaar, Henk-Jan, and Swen, Jesse J.

Published
2024
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24. Dimensionality of the system usability scale among professionals using internet-based interventions for depression: a confirmatory factor analysis

Author

Mol, Mayke, van Schaik, Anneke, Dozeman, Els, Ruwaard, Jeroen, Vis, Christiaan, Ebert, David D., Etzelmueller, Anne, Mathiasen, Kim, Moles, Bárbara, Mora, Teresa, Pedersen, Claus D., Skjøth, Mette Maria, Pensado, Luisa Peleteiro, Piera-Jimenez, Jordi, Gokcay, Didem, Ince, Burçin Ünlü, Russi, Alessio, Sacco, Ylenia, Zanalda, Enrico, Zabala, Ane Fullaondo, Riper, Heleen, and Smit, Jan H.

Published
2020
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27. The impact of depression and anxiety treatment on biological aging and metabolic stress: study protocol of the Mood treatment with antidepressants or running (MOTAR) study

Author

Lever-van Milligen, Bianca A., Verhoeven, Josine E., Schmaal, Lianne, van Velzen, Laura S., Révész, Dóra, Black, Catherine N., Han, Laura K. M., Horsfall, Melany, Batelaan, Neeltje M., van Balkom, Anton J. L. M., van Schaik, Digna J. F., van Oppen, Patricia, and Penninx, Brenda W. J. H.

Published
2019
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34. EPMA-World Congress 2015: Bonn, Germany. 3-5 September 2015

Author

Abraham, Jella-Andrea, Golubnitschaja, Olga, Akhmetov, Ildar, Andrews, Russell J., Quintana, Leonidas, Andrews, Russell J., Baban, Babak, Liu, Jun Yao, Qin, Xu, Wang, Tailing, Mozaffari, Mahmood S., Bati, Viktoriia V., Meleshko, Tamara V., Levchuk, Olga B., Boyko, Nadiya V., Bauer, Joanna, Boerner, Ewa, Podbielska, Halina, Bomba, Alojz, Petrov, Viktor O., Drobnych, Volodymyr G., Bubnov, Rostyslav V., Bykova, Oksana M., Boyko, Nadiya V., Brunner-La Rocca, Hans-Peter, Fleischhacker, Lutz, Golubnitschaja, Olga, Heemskerk, Frank, Helms, Thomas, Jaarsma, Tiny, Kinkorová, Judita, Ramaekers, Jan, Ruff, Peter, Schnur, Ivana, Vanoli, Emilio, Verdu, Jose, Brunner-La Rocca, Hans-Peter, Bubnov, Rostyslav V., Grabovetskyi, Sergiy A., Mykhalchenko, Olena M., Tymoshok, Natalia O., Shcherbakov, Oleksandr B., Semeniv, Igor P., Spivak, Mykola Y., Bubnov, Rostyslav V., Ostapenko, Tetyana V., Bubnov, Rostyslav V., Kobyliak, Nazarii M., Zholobak, Nadiya M., Spivak, Mykola Ya., Cauchi, John Paul, Cherepakhin, Dmitrii, Bakay, Marina, Borovikov, Artem, Suchkov, Sergey, Cieślik, Barbara, Migasiewicz, Agnieszka, Podbielska, Maria-Luiza, Pelleter, Markus, Giemza, Agnieszka, Podbielska, Halina, Cirak, Sebahattin, Del Re, Marzia, Bordi, Paola, Citi, Valentina, Palombi, Marta, Pinto, Carmine, Tiseo, Marcello, Danesi, Romano, Einhorn, Lukas, Fazekas, Judit, Muhr, Martina, Schoos, Alexandra, Panakova, Lucia, Herrmann, Ina, Manzano-Szalai, Krisztina, Oida, Kumiko, Fiebiger, Edda, Singer, Josef, Jensen-Jarolim, Erika, Elnar, Arpiné A., Ouamara, Nadia, Boyko, Nadiya, Coumoul, Xavier, Antignac, Jean-Philippe, Le Bizec, Bruno, Eppe, Gauthier, Renaut, Jenny, Bonn, Torsten, Guignard, Cédric, Ferrante, Margherita, Chiusano, Maria Liusa, Cuzzocrea, Salvatore, O’Keeffe, Gerard, Cryan, John, Bisson, Michelle, Barakat, Amina, Hmamouchi, Ihsane, Zawia, Nasser, Kanthasamy, Anumantha, Kisby, Glen E., Alves, Rui, Pérez, Oscar Villacañas, Burgard, Kim, Spencer, Peter, Bomba, Norbert, Haranta, Martin, Zaitseva, Nina, May, Irina, Grojean, Stéphanie, Body-Malapel, Mathilde, Harari, Florencia, Harari, Raul, Yeghiazaryan, Kristina, Golubnitschaja, Olga, Calabrese, Vittorio, Nemos, Christophe, Soulimani, Rachid, Evsevyeva, Maria E., Mishenko, Elena A., Kumukova, Zurida V., Chudnovsky, Evgeniy V., Smirnova, Tatyana A., Evsevyeva, Maria E., Ivanova, Ludmila V., Eremin, Michail V., Rostovtseva, Maria V., Evsevyeva, Maria E., Eremin, Michail V., Koshel, Vladimir I., Sergeeva, Oksana V., Konovalova, Nadesgda M., Girotra, Shantanu, Golubnitschaja, Olga, Golubnitschaja, Olga, Debald, Manuel, Kuhn, Walther, Yeghiazaryan, Kristina, Bubnov, Rostyslav V., Goncharenko, Vadym M., Lushchyk, Ulyana, Grech, Godfrey, Konieczka, Katarzyna, Golubnitschaja, Olga, Erwich, Jan Jaap, Costigliola, Vincenzo, Yeghiazaryan, Kristina, Gembruch, Ulrich, Goncharenko, Vadym M., Beniuk, Vasyl O., Kalenska, Olga V., Bubnov, Rostyslav V., Goncharenko, Vadym M., Beniuk, Vasyl O., Bubnov, Rostyslav V., Melnychuk, Olga, Gorbacheva, Irina A., Orekhova, Lyudmila Y., Tachalov, Vadim V., Grechanyk, Olena I., Abdullaiev, Rizvan Ya., Bubnov, Rostyslav V., Hagan, Suzanne, Martin, Eilidh, Pearce, Ian, Oliver, Katherine, Haytac, Cenk, Salimov, Fariz, Yoksul, Servin, Kunin, Anatoly A., Moiseeva, Natalia S., Herrera-Imbroda, Bernardo, del Río-González, Sergio, Lara, Maria Fernanda, Angulo, Antonia, Machuca Santa-Cruz, Francisco Javier, Herrera-Imbroda, Bernardo, del Río-González, Sergio, Lara, Maria Fernanda, Ionescu, John, Isamulaeva, Alfiya Z., Kunin, Anatoly A., Magomedov, Shamil Sh., Isamulaeva, Aida I., Josifova, Tatjana, Kapalla, Marko, Kubáň, Juraj, Golubnitschaja, Olga, Costigliola, Vincenzo, Costigliola, Vincenzo, Kapalla, Marko, Kubáň, Juraj, Golubnitschaja, Olga, Kent, Anthony, Fisher, Tom, Dias, Tilak, Kinkorová, Judita, Topolčan, Ondřej, Kohl, Matthias, Kunin, Anatoly A., Moiseeva, Natalia S., Kurchenko, Andrii I., Beniuk, Vasyl A., Goncharenko, Vadym M., Bubnov, Rostyslav V., Boyko, Nadiya V., Strokan, Andriy M., Kzhyshkowska, Julia, Gudima, Alexandru, Stankevich, Ksenia S., Filimonov, Victor D., Klüter, Harald, Mamontova, Evgeniya M., Tverdokhlebov, Sergei I., Lushchyk, Ulyana B., Novytskyy, Viktor V., Babii, Igor P., Lushchyk, Nadiya G., Riabets, Lyudmyla S., Legka, Ivanna I., Marcus-Kalish, Mira, Mitelpunkt, Alexis, Galili, Tal, Shachar, Neta, Benjamini, Yoav, Migasiewicz, Agnieszka, Pelleter, Markus, Bauer, Joanna, Dereń, Ewelina, Podbielska, Halina, Moiseeva, Natalia S., Kunin, Anatoly A., Kunin, Dmitry A., Moiseeva, Natalia S., Ippolitov, Yury A., Kunin, Dmitry A., Morozov, Alexei N., Chirkova, Natalia V., Aliev, Nakhid T., Mozaffari, Mahmood S., Liu, Jun Yao, Baban, Babak, Mozaffari, Mahmood S., Liu, Jun Yao, Abdelsayed, Rafik, Shi, Xing-Ming, Baban, Babak, Novák, Jaroslav, Štork, Milan, Zeman, Václav, Oosterhuis, Wytze P., Theodorsson, Elvar, Orekhova, Lyudmila Y., Kudryavtseva, Tatyana V., Isaeva, Elena R., Tachalov, Vadim V., Loboda, Ekaterina S., Pazzagli, Mario, Malentacchi, Francesca, Mancini, Irene, Brandslund, Ivan, Vermeersch, Pieter, Schwab, Matthias, Marc, Janja, van Schaik, Ron H. N., Siest, Gerard, Theodorsson, Elvar, Di Resta, Chiara, Pleva, Matus, Juhar, Jozef, Pleva, Matus, Juhar, Jozef, Polívka jr., Jiří, Janků, Filip, Pešta, Martin, Doležal, Jan, Králíčková, Milena, Polívka, Jiří, Polívka, Jiří, Lukešová, Alena, Müllerová, Nina, Ševčík, Petr, Rohan, Vladimír, Richter, Kneginja, Miloseva, Lence, Niklewski, Günter, Richter, Kneginja, Acker, Jens, Niklewski, Guenter, Safonicheva, Olga, Costigliola, Vincenzo, Safonicheva, Olga, Sautin, Maxim, Sinelnikova, Janna, Suchkov, Sergey, Secer, Songül, von Bandemer, Stephan, Shapira, Niva, Shcherbakov, Aleksandr, Kunin, Anatoly A., Moiseeva, Natalia S., Shumilovich, Bogdan R., Lipkind, Zhanna, Vorobieva, Yulia, Kunin, Dmitry A., Sudareva, Anastasiia V., Smokovski, Ivica, Milenkovic, Tatjana, Solís-Herrera, Arturo, Arias-Esparza, María del Carmen, Suchkov, Sergey, Sridhar, Krishna Chander, Golubnitschaja, Olga, Studneva, Maria, Song, Sihong, Creeden, James, Мandrik, Мark, Suchkov, Sergey, Theodorsson, Elvar, Tofail, Syed A. M., Topolčan, Ondřej, Kinkorová, Judita, Fiala, Ondřej, Karlíková, Marie, Svobodová, Šárka, Kučera, Radek, Fuchsová, Radka, Třeška, Vladislav, Šimánek, Václav, Pecen, Ladislav, Šoupal, Jan, Svačina, Štěpán, Tretyak, Evgeniya, Studneva, Maria, Suchkov, Sergey, Trovato, Francesca M., Martines, Giuseppe Fabio, Brischetto, Daniela, Catalano, Daniela, Musumeci, Giuseppe, Trovato, Guglielmo M., Tsangaris, George Th., Anagnostopoulos, Athanasios K., Tsangaris, George Th., Anagnostopoulos, Athanasios K., Verdú, José, Gutiérrez, German, Rovira, Jordi, Martinez, Marta, Fleischhacker, Lutz, Green, Donna, Garson, Arthur, Tamburini, Elena, Cuomo, Stefano, Martinez-Leon, Juan, Abrisqueta, Teresa, Brunner-La Rocca, Hans-Peter, Jaarsma, Tiny, Arredondo, Teresa, Vera, Cecilia, Fico, Giuseppe, Golubnitschaja, Olga, Arribas, Fernando, Onderco, Martina, Vara, Isabel, Verdú, José, Sambo, Francesco, Di Camillo, Barbara, Cobelli, Claudio, Facchinetti, Andrea, Fico, Giuseppe, Bellazzi, Riccardo, Sacchi, Lucia, Dagliati, Arianna, Segnani, Daniele, Tibollo, Valentina, Ottaviano, Manuel, Gabriel, Rafael, Groop, Leif, Postma, Jacqueline, Martinez, Antonio, Hakaste, Liisa, Tuomi, Tiinamaija, Zarkogianni, Konstantia, Volchek, Igor, Pototskaya, Nina, Petrov, Andrey, Volchek, Igor, Pototskaya, Nadezhda, Petrov, Andrey, Voog-Oras, Ülle, Jagur, Oksana, Leibur, Edvitar, Niibo, Priit, Jagomägi, Triin, Nguyen, Minh Son, Pruunsild, Chris, Piikov, Dagmar, Saag, Mare, Wang, Wei, Wang, Wei, Weinhäusel, Andreas, Pulverer, Walter, Wielscher, Matthias, Hofner, Manuela, Noehammer, Christa, Soldo, Regina, Hettegger, Peter, Gyurjan, Istvan, Kulovics, Ronald, Schönthaler, Silvia, Beikircher, Gabriel, Kriegner, Albert, Pabinger, Stephan, Vierlinger, Klemens, Yüzbaşıoğlu, Ayşe, Özgüç, Meral, EFLM, on behalf of ZENITH consortium, and on behalf of MOSAIC consortium

Published
2016
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38. The impact of depression and anxiety treatment on biological aging and metabolic stress: study protocol of the MOod treatment with antidepressants or running (MOTAR) study

Author

Digna J. F. van Schaik, Patricia van Oppen, Laura K.M. Han, Catherine N Black, Laura S van Velzen, Neeltje M. Batelaan, Brenda W.J.H. Penninx, Lianne Schmaal, Josine E Verhoeven, Melany Horsfall, Anton J.L.M. van Balkom, Bianca A Lever-van Milligen, Dóra Révész, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, and APH - Digital Health

Subjects
Adult, Male, medicine.medical_specialty, Aging, lcsh:RC435-571, Psychological intervention, Antidepressant, Anxiety, Cortisol, Running, Study Protocol, Stress, Physiological, lcsh:Psychiatry, Surveys and Questionnaires, medicine, SSRI, Humans, Psychiatry, Telomerase activity, Depression (differential diagnoses), Inflammation, Depressive Disorder, Major, Telomere length, business.industry, Depression, fMRI, medicine.disease, Mental health, Metabolic syndrome, Anxiety Disorders, Antidepressive Agents, Running therapy, Treatment, Psychiatry and Mental health, Affect, Mood, Treatment Outcome, Female, medicine.symptom, business, Anxiety disorder, Psychopathology, Follow-Up Studies
Abstract

Background Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes). Methods The MOod Treatment with Antidepressants or Running (MOTAR) study will recruit a total of 160 patients with a current major depressive and/or anxiety disorder in a mental health care setting. Patients will receive a 16-week treatment with either antidepressant medication or running therapy (3 times/week). Patients will undergo the treatment of their preference and a subsample will be randomized (1:1) to overcome preference bias. An additional no-disease-no-treatment group of 60 healthy controls without lifetime psychopathology, will be included as comparison group for primary and secondary outcomes at baseline. Assessments are done at week 0 for patients and controls, and at week 16 and week 52 for patients only, including written questionnaires, a psychiatric and medical examination, blood, urine and saliva collection and a cycle ergometer test, to gather information about biological aging (telomere length and telomerase activity), mental health (depression and anxiety disorder characteristics), general fitness, metabolic stress-related biomarkers (inflammation, metabolic syndrome, cortisol) and genetic determinants. In addition, neurobiological alterations in brain processes will be assessed using structural and functional Magnetic Resonance Imaging (MRI) in a subsample of at least 25 patients per treatment arm and in all controls. Discussion This intervention study aims to provide a better understanding of the impact of antidepressant medication and running therapy on biological aging, metabolic stress and neurobiological indicators in patients with depressive and anxiety disorders in order to guide a more personalized medicine treatment. Trial registration Trialregister.nl Number of identification: NTR3460, May 2012.

Published
2019

41. RNA-seq and Tn-seq reveal fitness determinants of vancomycin-resistant Enterococcus faecium during growth in human serum

Author

Zhang, X., de Maat, V., Guzmán Prieto, A.M., Prajsnar, T.K., Bayjanov, J.R., de Been, M., Rogers, M.R.C., Bonten, M.J.M., Mesnage, S., Willems, R.J.L., and van Schaik, W.

Subjects
bacteria, biochemical phenomena, metabolism, and nutrition
Abstract

BACKGROUND: The Gram-positive bacterium Enterococcus faecium is a commensal of the human gastrointestinal tract and a frequent cause of bloodstream infections in hospitalized patients. The mechanisms by which E. faecium can survive and grow in blood during an infection have not yet been characterized. Here, we identify genes that contribute to growth of E. faecium in human serum through transcriptome profiling (RNA-seq) and a high-throughput transposon mutant library sequencing approach (Tn-seq). RESULTS: We first sequenced the genome of E. faecium E745, a vancomycin-resistant clinical isolate, using a combination of short- and long read sequencing, revealing a 2,765,010 nt chromosome and 6 plasmids, with sizes ranging between 9.3 kbp and 223.7 kbp. We then compared the transcriptome of E. faecium E745 during exponential growth in rich medium and in human serum by RNA-seq. This analysis revealed that 27.8% of genes on the E. faecium E745 genome were differentially expressed in these two conditions. A gene cluster with a role in purine biosynthesis was among the most upregulated genes in E. faecium E745 upon growth in serum. The E. faecium E745 transposon mutant library was then used to identify genes that were specifically required for growth of E. faecium in serum. Genes involved in de novo nucleotide biosynthesis (including pyrK_2, pyrF, purD, purH) and a gene encoding a phosphotransferase system subunit (manY_2) were thus identified to be contributing to E. faecium growth in human serum. Transposon mutants in pyrK_2, pyrF, purD, purH and manY_2 were isolated from the library and their impaired growth in human serum was confirmed. In addition, the pyrK_2 and manY_2 mutants were tested for their virulence in an intravenous zebrafish infection model and exhibited significantly attenuated virulence compared to E. faecium E745. CONCLUSIONS: Genes involved in carbohydrate metabolism and nucleotide biosynthesis of E. faecium are essential for growth in human serum and contribute to the pathogenesis of this organism. These genes may serve as targets for the development of novel anti-infectives for the treatment of E. faecium bloodstream infections.

Published
2017

43. Intravenous immunoglobulin and intravenous methylprednisolone as optimal induction treatment in chronic inflammatory demyelinating polyradiculoneuropathy: protocol of an international, randomised, double-blind, placebo-controlled trial (OPTIC).

Author

Bus, S. R. M., Zambreanu, L., Abbas, A., Rajabally, Y. A., Hadden, R. D. M., de Haan, R. J., de Borgie, C. A. J. M., Lunn, M. P., van Schaik, I. N., Eftimov, F., on behalf of the OPTIC study group, Vrancken, A. F. J. E., van Doorn, P. A., Hoeijmakers, J. G. J., Voermans, N., Wirtz, P. W., Padberg, M., de Rijk, M., Chavada, G., and Miller, J.

Subjects
CHRONIC inflammatory demyelinating polyradiculoneuropathy, OPTIC neuritis, METHYLPREDNISOLONE, MEDICAL care costs, QUALITY of life, DISEASE relapse, SALT
Abstract

Background: International guidelines recommend either intravenous immunoglobulin (IVIg) or corticosteroids as first-line treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). IVIg treatment usually leads to rapid improvement and is generally safe, but does not seem to lead to long-term remissions. Corticosteroids act more slowly and are associated with more side effects, but may induce long-term remissions. The hypothesis of this study is that combined IVIg and corticosteroid induction treatment will lead to more frequent long-term remissions than IVIg treatment alone.Methods: An international, randomised, double-blind, placebo-controlled trial, in adults with 'probable' or 'definite' CIDP according to the EFNS/PNS 2010 criteria. Three groups of patients are included: (1) treatment naïve, (2) known CIDP patients with a relapse after > 1 year without treatment, and (3) patients with CIDP who improved within 3 months after a single course of IVIg, who subsequently deteriorate at any interval without having received additional treatment. Patients are randomised to receive 7 courses of IVIg and 1000 mg intravenous methylprednisolone (IVMP) (in sodium chloride 0.9%) or IVIg and placebo (sodium chloride 0.9%), every 3 weeks for 18 weeks. IVIg treatment consists of a loading dose of 2 g/kg (over 3-5 days) followed by 6 courses of IVIg 1/g/kg (over 1-2 days). The primary outcome is remission at 1 year, defined as improvement in disability from baseline, sustained between week 18 and week 52 without further treatment. Secondary outcomes include changes in disability, impairment, pain, fatigue, quality of life, care use and costs and (long-term) safety.Discussion: In case of superiority of the combined treatment, patients will experience the advantages of two proven efficacious treatments, namely rapid improvement due to IVIg and long-term remission due to corticosteroids. Long-term remission would reduce the need for maintenance IVIg treatment and may decrease health care costs. Additionally, we expect that the combined treatment leads to a higher proportion of patients with improvement as some patients who do not respond to IVIg will respond to corticosteroids. Risks of short and long-term additional adverse events of the combined treatment need to be assessed.Trial Registration: ISRCTN registry ISRCTN15893334 . Prospectively registered on 12 February 2018. [ABSTRACT FROM AUTHOR]

Published
2021
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45. Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients

Author

Jan Terje Kvaløy, Steinar Hustad, Vessela N. Kristensen, Ersilia Bifulco, Timothy L. Lash, Thomas Helland, Bjørn Naume, Gunnar Mellgren, Håvard Søiland, Emiel A. M. Janssen, Nina Henne, Ron H.N. van Schaik, Grethe I. Grenaker Alnæs, Elin Borgen, Ernst A. Lien, and Clinical Chemistry

Subjects
0301 basic medicine, Oncology, Pharmacogenomic Variants, Survival, Endoxifen, Breast cancer, 0302 clinical medicine, Surgical oncology, Medicine, skin and connective tissue diseases, Adjuvant, Aged, 80 and over, tamoxifen, CYP2D6, Hazard ratio, Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762 [VDP], Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, overlevelse, prognose, 4OHtam, Cytochrome P-450 CYP2D6, Chemotherapy, Adjuvant, Midical sciences: 700 [VDP], 030220 oncology & carcinogenesis, Cohort, Female, Medisinske fag: 700 [VDP], medicine.drug, Adult, Evaluering av behandlinger og terapeutiske intervensjoner [Kreft], medicine.medical_specialty, Antineoplastic Agents, Hormonal, helsefag, Breast Neoplasms, lcsh:RC254-282, 03 medical and health sciences, SDG 3 - Good Health and Well-being, brystkreft, Internal medicine, Humans, Aged, Retrospective Studies, Gynecology, business.industry, Research, metabolisme, Antiestrogen, medicine.disease, Confidence interval, Tamoxifen, Metabolism, 030104 developmental biology, endoxifen, Evaluation of Treatments and Therapeutic Interventions [Cancer], Neoplasm Grading, business
Abstract

Background Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. Methods From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome. Results Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14–11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05–13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35–13.58, and HR = 3.70, 95% CI = 1.03–13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information. Conclusions Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.

Published
2017

46. COVID-19 patients exhibit less pronounced immune suppression compared with bacterial septic shock patients.

Author

Kox, Matthijs, Frenzel, Tim, Schouten, Jeroen, van de Veerdonk, Frank L., Koenen, Hans J. P. M., Pickkers, Peter, on behalf of the RCI-COVID-19 study group, Hemelaar, Pleun, Beunders, Remi, van der Hoeven, Johannes, van der Velde, Sjef, van der Eng, Hetty, Rovers, Noortje, Klop-Riehl, Margreet, Gerretsen, Jelle, Kooistra, Emma, Waalders, Nicole, Claassen, Wout, Heesakkers, Hidde, and van Schaik, Tirsa

Published
2020
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47. In-depth resistome analysis by targeted metagenomics.

Author

Lanza, Val F., Baquero, Fernando, Luís Martínez, José, Ramos-Ruíz, Ricardo, González-Zorn, Bruno, Andremont, Antoine, Sánchez-Valenzuela, Antonio, Ehrlich, Stanislav Dusko, Kennedy, Sean, Ruppé, Etienne, van Schaik, Willem, Willems, Rob J., de la Cruz, Fernando, and Coque, Teresa M.

Published
2018
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48. Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients.

Author

Helland, Thomas, Henne, Nina, Bifulco, Ersilia, Naume, Bjørn, Borgen, Elin, Kristensen, Vessela N., Kvaløy, Jan T., Lash, Timothy L., Alnæs, Grethe I. G., van Schaik, Ron H., Janssen, Emiel A. M., Hustad, Steinar, Lien, Ernst A., Mellgren, Gunnar, and Søiland, Håvard

Subjects
TAMOXIFEN, ANTINEOPLASTIC agents, BLOOD serum analysis, BREAST cancer patients, HYDROXY acids
Abstract

Background: Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients.Methods: From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome.Results: Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14-11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05-13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35-13.58, and HR = 3.70, 95% CI = 1.03-13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information.Conclusions: Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted. [ABSTRACT FROM AUTHOR]

Published
2017
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49. RNA-seq and Tn-seq reveal fitness determinants of vancomycin-resistant Enterococcus faecium during growth in human serum.

Author

Xinglin Zhang, de Maat, Vincent, Guzmán Prieto, Ana M., Prajsnar, Tomasz K., Bayjanov, Jumamurat R., de Been, Mark, Rogers, Malbert R. C., Bonten, Marc J. M., Mesnage, Stéphane, Willems, Rob J. L., and van Schaik, Willem

Subjects
RNA sequencing, NUCLEOTIDE sequence, ENTEROCOCCUS faecium, VANCOMYCIN resistance, SERUM, PHYSIOLOGY
Abstract

Background: The Gram-positive bacterium Enterococcus faecium is a commensal of the human gastrointestinal tract and a frequent cause of bloodstream infections in hospitalized patients. The mechanisms by which E. faecium can survive and grow in blood during an infection have not yet been characterized. Here, we identify genes that contribute to growth of E. faecium in human serum through transcriptome profiling (RNA-seq) and a highthroughput transposon mutant library sequencing approach (Tn-seq). Results: We first sequenced the genome of E. faecium E745, a vancomycin-resistant clinical isolate, using a combination of short- and long read sequencing, revealing a 2,765,010 nt chromosome and 6 plasmids, with sizes ranging between 9.3 kbp and 223.7 kbp. We then compared the transcriptome of E. faecium E745 during exponential growth in rich medium and in human serum by RNA-seq. This analysis revealed that 27.8% of genes on the E. faecium E745 genome were differentially expressed in these two conditions. A gene cluster with a role in purine biosynthesis was among the most upregulated genes in E. faecium E745 upon growth in serum. The E. faecium E745 transposon mutant library was then used to identify genes that were specifically required for growth of E. faecium in serum. Genes involved in de novo nucleotide biosynthesis (including pyrK_2, pyrF, purD, purH) and a gene encoding a phosphotransferase system subunit (manY_2) were thus identified to be contributing to E. faecium growth in human serum. Transposon mutants in pyrK_2, pyrF, purD, purH and manY_2 were isolated from the library and their impaired growth in human serum was confirmed. In addition, the pyrK_2 and manY_2 mutants were tested for their virulence in an intravenous zebrafish infection model and exhibited significantly attenuated virulence compared to E. faecium E745. Conclusions: Genes involved in carbohydrate metabolism and nucleotide biosynthesis of E. faecium are essential for growth in human serum and contribute to the pathogenesis of this organism. These genes may serve as targets for the development of novel anti-infectives for the treatment of E. faecium bloodstream infections. [ABSTRACT FROM AUTHOR]

Published
2017
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50. The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial.

Author

Kingslake, Jonathan, Dias, Rebecca, Dawson, Gerard R., Simon, Judit, Goodwin, Guy M., Harmer, Catherine J., Morriss, Richard, Brown, Susan, Guo, Boliang, Dourish, Colin T., Ruhé, Henricus G., Lever, Anne G., Veltman, Dick J., van Schaik, Anneke, Deckert, Jürgen, Reif, Andreas, Stäblein, Michael, Menke, Andreas, Gorwood, Philip, and Voegeli, Géraldine

Subjects
ANTIDEPRESSANTS, DEPRESSED persons, RANDOMIZED controlled trials, COGNITION, DATA analysis
Abstract

Background: Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual.Methods/design: The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depression measured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed.Discussion: This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients.Trial Registration: ClinicalTrials.gov, ID: NCT02790970 . Registered on 30 March 2016. [ABSTRACT FROM AUTHOR]

Published
2017
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