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8. Association of Timing of Plasma Transfusion With Adverse Maternal Outcomes in Women With Persistent Postpartum Hemorrhage

Author

Henriquez, D.D.C.A., Caram-Deelder, C., Cessie, S. le, Zwart, J.J., Roosmalen, J.J.M. van, Eikenboom, J.C.J., So-Osman, C., Watering, L.G. van de, Zwaginga, J.J., Koopman-van Gemert, A.W.M.M., Bloemenkamp, K.W.M., Bom, J.G. van der, Bank, C.M.C., Snuif-de Lange, Y.S., Gammeren, A.J. van, Papatsonis, D.N.M., Klinkspoor, H., Kok, M., Boer, B.A. de, Langenveld, J., Leers, M.P.G., Diris, J.H.C., Kok, R.D., Engbers, P., Hanssen, M.J.C.P., Wijngaarden, W.J. van, Schippers, D.H., Stappen, J.J. van der, Hasaart, T.H.M., Kerkhof, D.H. van de, Kok, J.B. de, Unnik, G.A. van, Kortlandt, W., Schuitemaker, N.E., Delemarre, F.M.C., Duijnhoven, H.L.P. van, Duvekot, H.J., Hogenboom, S., Kleiverda, G., Etten-van Hulst, M.J.W. van, Mirani-Oostdijk, K.P., Kampen, C. van, Weinans, M.J.N., Adriaanse, H.J., Huisjes, A.J.M., Frasa, M.A.M., Keuren, J.F.W., Meir, C.A. van, Feitsma, H., Hudig, F., Sikkema, J.M., Baas, M.I., Fouraux, M.A., Hmetz, G.C., Bijvank, B.H.N., Rondeel, H.J.M., Roelofsen, J.M.T., Doesburg-van Kleffens, M., Wit, S.C. de, Versendaal, H., Weerkamp, F., Henskens, Y.M.C., Scheepers, L.H.C.J., Ham, D.P. van der, Smit, J.W., Graaf, F. van der, Porath, M.M., Salm, P.C.M. van der, Wijnen, M. van, Pontesilli, M., Dunne, F.M. van, Ponjee, G.A.E., Post, M.S., Veen, B.S. van der, Brons, J.T.J., Slomp, J., Mare, A. de, Leyte, A., Akker, E.S.A. van den, Wet, H. de, Borden, D.M.R. van der, Bremer, H.A., Tax, G.H.M., Vries, M.J. de, Boer, K. de, Waard, H. de, Keijzer, R.H. de, Burggraaff, J.M., Pouwels, J.G.J., Gemund, N. van, Prinzen, L., Hendriks, H.A., Hermsen, B.B.J., Koehorst, S.G.A., Verhagen, T.E.M., Beek, E. van, Hackeng, C.M., Kabel, P.J., Steures, P., Dooren, I.A. van, Michielse, E.C.H.J., Chon, H., Treskes, M., Visser, H., Oostenveld, E., Peters, D.H.M., Franssen, M.T.M., Meekers, J.H., Woiski, M.D., Pampus, L.C.M. van, Oudijk, M.A., Vooght, K.M.K. de, Cikot, R.L.M., Mostert, L.J., Ceelie, H., Huijssoon, A.M.G., Groot, C.J.M. de, Visser, O., Jonker, N., Koops, A., Hooker, A., Osmanovic, N., Ulenkate, H.J.L.M., Visschers, B., Martens, G.D.M., TeMpOH-Res Grp, Athena Institute, APH - Global Health, APH - Quality of Care, Reproductive Origins of Adult Health and Disease (ROAHD), Faculteit FHML Centraal, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Obstetrie & Gynaecologie, MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, RS: Carim - B04 Clinical thrombosis and Haemostasis, and Obstetrics & Gynecology

Subjects
Adult, medicine.medical_specialty, medicine.medical_treatment, TRACHEAL INTUBATION, Blood Component Transfusion, Time-to-Treatment, Cohort Studies, MULTIPLE IMPUTATION, DOUBLE-BLIND, Plasma, PROPENSITY SCORE ANALYSIS, SDG 3 - Good Health and Well-being, medicine, Coagulopathy, MANAGEMENT, Humans, Original Investigation, FIBRINOGEN CONCENTRATE, COAGULOPATHY, Hysterectomy, business.industry, Obstetrics, Incidence (epidemiology), Research, Incidence, Postpartum Hemorrhage, HOSPITAL CARDIAC-ARREST, Obstetrics and Gynecology, TRANEXAMIC ACID, General Medicine, Odds ratio, Puerperal Disorders, medicine.disease, Uterine atony, Online Only, BALANCE, Propensity score matching, Female, business, Cohort study
Abstract

This cohort study examines the association of timing of receipt of plasma transfusions among women experiencing persistent postpartum hemorrhage with adverse maternal outcomes., Key Points Question Is plasma transfusion within the first 60 minutes of persistent postpartum hemorrhage (PPH) associated with incidence of maternal adverse outcomes? Findings In this cohort study of 114 propensity score–matched women with persistent PPH, plasma transfusion within the first 60 minutes of persistent PPH was not associated with incidence of maternal adverse outcomes compared with no or later plasma transfusion, independent of severity of PPH at the time of plasma transfusion. Meaning These findings do not support the theory that early plasma transfusion in women with persistent PPH is better than no or later plasma transfusion., Importance Early plasma transfusion for women with severe postpartum hemorrhage (PPH) is recommended to prevent coagulopathy. However, there is no comparative, quantitative evidence on the association of early plasma transfusion with maternal outcomes. Objective To compare the incidence of adverse maternal outcomes among women who received plasma during the first 60 minutes of persistent PPH vs women who did not receive plasma for similarly severe persistent PPH. Design, Setting, and Participants This multicenter cohort study used a consecutive sample of women with persistent PPH, defined as PPH refractory to first-line measures to control bleeding, between January 1, 2011, and January 1, 2013. Time-dependent propensity score matching was used to select women who received plasma during the first 60 minutes of persistent PPH and match each of them with a woman who had shown the same severity and received the same treatment of PPH but who had not received plasma at the moment of matching. Transfusions were not guided by coagulation tests. Statistical analysis was performed from June 2018 to June 2019. Exposures Transfusion of plasma during the first 60 minutes of persistent PPH vs no or later plasma transfusion. Main Outcomes and Measures Incidence of adverse maternal outcomes, defined as a composite of death, hysterectomy, or arterial embolization. Results This study included 1216 women (mean [SD] age, 31.6 [5.0] years) with persistent PPH, of whom 932 (76.6%) delivered vaginally and 780 (64.1%) had PPH caused by uterine atony. Seven women (0.6%) died because of PPH, 62 women (5.1%) had a hysterectomy, and 159 women (13.1%) had arterial embolizations. Among women who received plasma during the first 60 minutes of persistent PPH, 114 women could be matched with a comparable woman who had not received plasma at the moment of matching. The incidence of adverse maternal outcomes was similar between the women, with adverse outcomes recorded in 24 women (21.2%) who received early plasma transfusion and 23 women (19.9%) who did not receive early plasma transfusion (odds ratio, 1.09; 95% CI, 0.57-2.09). Results of sensitivity analyses were comparable to the primary results. Conclusions and Relevance In this cohort study, initiation of plasma transfusion during the first 60 minutes of persistent PPH was not associated with adverse maternal outcomes compared with no or later plasma transfusion, independent of severity of PPH.

Published
2019
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9. Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with ‘refractoriness to treatment’: a cohort study

Author

Henriquez, D.D.C.A., Gillissen, A., Smith, S.M., Cramer, R.A., Akker, T. van den, Zwart, J.J., Roosmalen, J.J.M. van, Bloemenkamp, K.W.M., Bom, J.G. van der, Adriaanse, H.J., Akker, E.S.A. van den, Baas, M.I., Bank, C.M.C., Beek, E. van, Boer, B.A. de, Boer, K. de, Borden, D.M.R. van der, Bremer, H.A., Brons, J.T.J., Burggraaff, J.M., Ceelie, H., Chon, H., Cikot, J.L.M., Delemarre, F.M.C., Diris, J.H.C., Doesburg-van Kleffens, M., Dooren, I.M.A. van, Duijnhoven, J.L.P. van, Dunn, F.M. van, Duvekot, J.J., Engbers, P., Etten-van Hulst, M.J.W. van, Feitsma, H., Fouraux, M.A., Franssen, M.T.M., Frasa, M.A.M., Gammeren, A.J. van, Gemund, N. van, Graaf, F. van der, Groot, C.J.M. de, Hackeng, C.M., Ham, D.P. van der, Hanssen, M.J.C.P., Hasaart, T.H.M., Hendriks, H.A., Henskens, Y.M.C., Hermsen, B.B.J., Hogenboom, S., Hooker, A., Hudig, F., Huijssoon, A.M.G., Huisjes, A.J.M., Jonker, N., Kabel, P.J., Kampen, C. van, Keijzer, M.H. de, Kerkhof, D.H. van de, Keuren, J.F.W., Kleiverda, G., Klinkspoor, J.H., Koehorst, S.G.A., Kok, M., Kok, R.D., Kok, J.B. de, Koops, A., Kortlandt, W., Langenveld, J., Leers, M.P.G., Leyte, A., Mare, A. de, Martens, G.D.M., Meekers, J.H., Meir, C.A. van, Metz, G.C.H., Michielse, E.C.H.J., Mostert, L.J., Bijvank, S.W.H.N., Oostenveld, E., Osmanovic, N., Oudijk, M.A., Mirani-Oostdijk, C.P., Pampus, E.C.M. van, Papatsonis, D.N.M., Peters, R.H.M., Ponjee, G.A.E., Pontesilli, M., Porath, M.M., Post, M.S., Pouwels, J.G.J., Prinzen, L., Roelofsen, J.M.T., Rondeel, J.J.M., Salm, P.C.M. van der, Scheepers, H.C.J., Schippers, D.H., Schuitemaker, N.W.E., Sikkema, J.M., Slomp, J., Smit, J.W., Snuif-de Lange, Y.S., Stappen, J.W.J. van der, Steures, P., Tax, G.H.M., Treskes, M., Ulenkate, H.J.L.M., Unnik, G.A. van, Veen, B.S. van der, Verhagen, T.E.M., Versendaal, J., Visschers, B., Visser, O., Visser, H., Vooght, K.M.K. de, Vries, M.J. de, Waard, H. de, Weerkamp, F., Weinans, M.J.N., Wet, H. de, Wijnen, M. van, Wijngaarden, W.J. van, Wit, A.C. de, Woiski, M.D., TeMpOH-1 Study Grp, Obstetrics & Gynecology, Science Communication, APH - Global Health, Athena Institute, APH - Quality of Care, Reproductive Origins of Adult Health and Disease (ROAHD), Ethics, Law & Medical humanities, Cardiology, ACS - Heart failure & arrhythmias, Obstetrics and gynaecology, Amsterdam Reproduction & Development (AR&D), Pediatric surgery, Hematology, Faculteit FHML Centraal, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), Obstetrie & Gynaecologie, and RS: Carim - B04 Clinical thrombosis and Haemostasis

Subjects
Male, Blood transfusion, Refractory period, medicine.medical_treatment, 030204 cardiovascular system & hematology, Severity of Illness Index, law.invention, Postpartum haemorrhage, 0302 clinical medicine, law, Pregnancy, Risk Factors, Netherlands, 030219 obstetrics & reproductive medicine, Obstetrics, Incidence, Obstetrics and Gynecology, Prognosis, Intensive care unit, Embolization, Therapeutic, PREVALENCE, Survival Rate, Female, Cohort study, Research Article, Maternal mortality, Adult, medicine.medical_specialty, Reproductive medicine, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Hysterectomy, lcsh:Gynecology and obstetrics, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, medicine, Humans, Blood Transfusion, lcsh:RG1-991, Retrospective Studies, SEVERE MATERNAL MORBIDITY, business.industry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Postpartum Hemorrhage, Infant, Newborn, Retrospective cohort study, Definition, Packed red blood cells, business, Maternal morbidity, Follow-Up Studies
Abstract

Background The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion The definition persistent postpartum haemorrhage identified women with severe postpartum haemorrhage at an early stage of haemorrhage, unlike definitions based on blood transfusion. It also captured a large majority of adverse maternal outcomes, almost as large as the definition of ≥1 L blood loss, which is commonly applied as a definition of postpartum haemorrhage rather than severe haemorrhage.

Published
2019
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10. Fluid resuscitation during persistent postpartum haemorrhage and maternal outcome: A nationwide cohort study

Author

Henriquez, D.D.C.A., Bloemenkamp, K.W.M., Loeff, R.M., Zwart, J.J., Roosmalen, J.J.M. van, Zwaginga, J.J., Bom, J.G. van der, Adriaanse, H.J., Akker, E.S.A. van den, Baas, M.I., Bank, C.M.C., Beek, E. van, Boer, B.A. de, Boer, K. de, Borden, D.M.R. van der, Bremer, H.A., Brons, J.T.J., Burggraaff, J.M., Ceelie, H., Chon, H., Cikot, J.L.M., Delemarre, F.M.C., Diris, J.H.C., Doesburg-van Kleffens, M., Dooren, I.M.A. van, Duijnhoven, J.L.P. van, Dunne, F.M. van, Duvekot, J.J., Engbers, P., Hulst, M.J.W.V., Feitsma, H., Fouraux, M.A., Franssen, M.T.M., Frasa, M.A.M., Gammeren, A.J. van, Gemund, N. van, Graaf, F. van der, Groot, C.J.M. de, Hackeng, C.M., Ham, D.P. van der, Hanssen, M.J.C.P., Hasaart, T.H.M., Hendriks, H.A., Henskens, Y.M.C., Hermsen, B.B.J., Hogenboom, S., Hooker, A., Hudig, F., Huijssoon, A.M.G., Huisjes, A.J.M., Jonker, N., Kabel, P.J., Kampen, C. van, Keijzer, M.H. de, Kerkhof, D.H. van de, Keuren, J.F.W., Kleiverda, G., Klinkspoor, J.H., Koehorst, S.G.A., Kok, M., Kok, R.D., Kok, J.B. de, Koops, A., Kortlandt, W., Langenveld, J., Leers, M.P.G., Leyte, A., Mare, A. de, Martens, G.D.M., Meekers, J.H., Meir, C.A. van, Metz, G.C.H., Michielse, E.C.H.J., Mostert, L.J., Bijvank, S.W.H.N., Oostenveld, E., Osmanovic, N., Oudijk, M.A., Mirani-Oostdijk, C.P., Pampus, E.C.M. van, Papatsonis, D.N.M., Peters, R.H.M., Ponjee, G.A.E., Pontesilli, M., Porath, M.M., Post, M.S., Pouwels, J.G.J., Prinzen, L., Roelofsen, J.M.T., Rondeel, J.J.M., Salm, P.C.M. van der, Scheepers, H.C.J., Schippers, D.H., Schuitemaker, N.W.E., Sikkema, J.M., Slomp, J., Smit, J.W., Snuif-de Lange, Y.S., Stappen, J.W.J. van der, Steures, P., Tax, G.H.M., Treskes, M., Ulenkate, H.J.L.M., Unnik, G.A. van, Veen, B.S. van der, Verhagen, T.E.M., Versendaal, J., Visschers, B., Visser, O., Visser, H., Vooght, K.M.K. de, Vries, M.J. de, Waard, H. de, Weerkamp, F., Weinans, M.J.N., Wet, H. de, Wijnen, M. van, Wijngaarden, W.J. van, Wit, A.C. de, Woiski, M.D., TeMpOH-Study Grp, APH - Quality of Care, APH - Global Health, Obstetrics & Gynecology, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Faculteit FHML Centraal, RS: Carim - B04 Clinical thrombosis and Haemostasis, Reproductive Origins of Adult Health and Disease (ROAHD), and Athena Institute

Subjects
Adult, medicine.medical_specialty, Resuscitation, Blood transfusion, medicine.medical_treatment, CRYSTALLOIDS, Postpartum haemorrhage, 03 medical and health sciences, RED-BLOOD-CELLS, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Interquartile range, Pregnancy, ERYTHROCYTES, medicine, Humans, Crystalloid solutions, 030212 general & internal medicine, Colloids, THROMBIN GENERATION, Netherlands, Retrospective Studies, COAGULOPATHY, 030219 obstetrics & reproductive medicine, Obstetrics, business.industry, Postpartum Hemorrhage, Obstetrics and Gynecology, Retrospective cohort study, Odds ratio, Confidence interval, Treatment Outcome, Reproductive Medicine, Fluid Therapy, TRAUMA PATIENTS, Female, Packed red blood cells, business, Cohort study
Abstract

Objective: To determine the association between increasing volumes of crystalloids and colloids administered before transfusion of packed red blood cells in women with persistent postpartum haemorrhage and adverse maternal outcomes. Study design: Retrospective cohort study in the Netherlands. Women with persistent postpartum haemorrhage and known clear fluids volume for resuscitation were included. Women who received ≤2 L of clear fluids were the reference group. We determined the effect of every additional litre of clear fluids on total blood loss, severe maternal morbidity and mortality. Results were adjusted for patient and bleeding characteristics. Results: Of the 883 included women, 199 received ≤2 L of clear fluids. Median blood loss for the reference group was 2.9 L (interquartile range 2.2–3.4). Adjusted mean difference in blood loss compared with the reference group was 0.2 L (95% confidence interval −0.1 to 0.5) for women in the >2 to ≤3 L, 0.4 L (0.1–0.7) for the >3 to ≤4 L category, 0.6 L (0.5–0.7) for the >4 to ≤5 L category, and 1.9 L (1.5–2.3) for the >5 to ≤7 L category. Adjusted odds ratios for adverse maternal outcomes were 1.0 (0.7–1.6), 1.2 (0.8–1.9), 1.8 (1.1–3.1) and 4.4 (2.6–7.5) for women in the 2 to ≤3 L category, >3 to ≤4 L, >4 to ≤5 L, and >5 to ≤7 L volume categories respectively. Results were similar in strata of different severities of bleeding. Conclusion: Clear fluids volume >4 L was independently associated with adverse maternal outcome in women with persistent postpartum haemorrhage.

Published
2019
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13. Application of computer-assisted semen analysis to explain variations in pig fertility

Author

Broekhuijse, M.L.W.J., Sostaric, E., Feitsma, H., Gadella, B.M., Biology of Reproductive Cells, Dep Gezondheidszorg Landbouwhuisdieren, and Dep Biochemie en Celbiologie

Subjects
International (English)
Abstract

Sperm quality is often evaluated through computer-assisted semen analysis (CASA) and is an indicator of boar fertility. The aim of this research was to study the relationship between CASA motility parameters and fertility results in pigs. Insemination records and semen parameters from a total of 45,532 ejaculates collected over a 3-yr period were used. The statistical model for analysis of fertility data from these inseminations included factors related to sow productivity. The boar- and semen-related variance (direct boar effect) were corrected for the effects of individual boar, genetic line of the boar, age of the boar, days between ejaculations, number of sperm cells in an ejaculate, number of sperm cells in an insemination dose, and AI station. The remaining variance was analyzed if semen motility parameters had a significant effect. This analysis revealed significant (P 0.05) were observed between effects of AI stations on fertility outcome, underscoring the objectivity of the CASA system used. Motility parameters can be measured with CASA to assess sperm motility in an objective manner. On the basis of the motility pattern, CASA enables one to discriminate between the fertilizing capacity of ejaculates, although this depends on the genetic line of the boar used in AI stations.

Published
2012

14. Lactation Weight Loss in Primiparous Sows: Consequences for Embryo Survival and Progesterone and Relations with Metabolic Profiles

Author

Hoving, L.L., Soede, N.M., Feitsma, H., and Kemp, B.

Subjects
insulin, dietary energy-source, restriction, pattern, growth-factor-i, state, hormone profiles, reproductive-performance, WIAS, Adaptation Physiology, Adaptatiefysiologie, feed-intake, mobilization
Abstract

Our objective was to study reproductive consequences of lactation bodyweight loss occurring in primiparous sows with mild feed restriction and to relate these lactation weight losses and its consequences to metabolic profiles during lactation and subsequent early gestation. After weaning, 47 first-litter sows were retrospectively assigned to a high– (HWL, >13.8%, n = 24) or low (LWL, =13.8%, n = 23)–weight loss group. Thirty-six animals received an indwelling jugular vein catheter to determine lactational and gestational profiles of insulin-like growth factor-1 (IGF-1), non-esterified fatty acids (NEFA) and urea and gestational profiles of progesterone. At day 35 after insemination, sows were euthanized and their reproductive tract collected. Pregnancy rate was 75% (18/24) for HWL and 96% (22/23) for LWL sows. High–weight loss sows had a lower number of implantation sites (17.2 ± 0.8 vs 19.5 ± 0.7, respectively, p = 0.03) and a lower embryonic survival (65.6 ± 3.4 vs 77.4 ± 2.9%, p = 0.02), resulting in fewer vital embryos (14.9 ± 0.9 vs 16.8 ± 0.7, p = 0.07) than LWL sows. Progesterone peak values were reached later in HWL than in LWL sows (day 13.4 ± 0.5 vs 12.0 ± 0.5, respectively, p = 0.05). Gestational concentrations of IGF-1, NEFA and urea were almost identical for HWL and LWL sows, whilst numerical differences were seen during lactation. The current study shows negative consequences of lactational weight loss in mildly feed-restricted primiparous sows for embryonic survival and shows that these consequences seem only mildly related with metabolic alterations during lactation and not with metabolic alterations during subsequent gestation.

Published
2012

15. An increased feed intake during early pregnancy improves sow body weight recovery and increases litter size in young sows

Author

Hoving, L.L., Soede, N.M., van der Peet-Schwering, C.M.C., Graat, E.A.M., Feitsma, H., and Kemp, B.

Subjects
animal diseases, Research, protein loss, Kwantitatieve Veterinaire Epidemiologie, gonadotropin-releasing-hormone, Quantitative Veterinary Epidemiology, live weight, gilts, multiparous sows, conceptus growth, ovarian-function, reproductive-performance, WIAS, Adaptation Physiology, primiparous sows, Adaptatiefysiologie, Wageningen Livestock Research, fetal-development, Onderzoek
Abstract

This study evaluated the effect of feeding level and protein content in feed in first- and second-parity sows during the first month of gestation on sow BW recovery, farrowing rate, and litter size during the first month of gestation. From d 3 to d 32 after first insemination, sows were fed either 2.5 kg/d of a standard gestation diet (Control, n = 49), or 3.25 kg/d (+ 30%) of a standard gestation diet (Plus Feed, n = 47), or 2.5 kg/d of a gestation diet with 30% greater level of ileal digestible AA (Plus Protein, n = 49). Feed intake during the experimental period was 29% greater for Plus Feed sows compared with Control and Plus Protein sows (93 vs. 72 kg, P

Published
2011

16. Highly Efficient ENU Mutagenesis in Zebrafish

Author

de Bruijn, E., Cuppen, E., Feitsma, H., and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
otorhinolaryngologic diseases
Abstract

ENU (N-ethyl-N-nitrosourea) mutagenesis is a widely accepted and proven method to introduce random point mutations in the genome. Because there are no targeted knockout strategies available for zebrafish so far, random mutagenesis is currently the preferred method in both forward and reverse genetic approaches. To obtain high-density mutagenized zebrafish, six consecutive ENU treatments are applied at weekly intervals to adult male zebrafish by bathing them in ENU solution. With this procedure an average germ line mutation load of one mutation every 1.0 x 10(5)-1.5 x 10(5) basepairs is reached routinely in our lab.

Published
2009

17. DNA mismatch repair, genome instability and cancer in zebrafish

Author

Feitsma, H., Cuppen, E., and University Utrecht

Subjects
tumour, animal model, sterility, cancer, DNA repair, DNA damage, meiosis, zebrafish, Biologie, genome instability, mutagenesis
Abstract

The objective of this study was to find out whether the zebrafish can be an appropriate model for studying DNA repair and cancer. For this purpose three fish lines were used that lack components of an important mechanism for the repair of small DNA damage: DNA mismatch repair. These fish are therefore hereditary predisposed to develop cancer. Several mismatch repair enzymes also have a function in meiosis, the reduction cell division that is necessary for the formation of germ cells. Male zebrafish with mutations in the mismatch repair gene mlh1 were found to be sterile and to display an arrest in spermatogenesis at metaphase I. In contrast, female mutants are fully fertile, but their progeny shows high rates of dysmorphology and mortality within the first days of development, which was found to be caused by aneuploidy resulting from meiosis I chromosomal missegregation. Surprisingly, the small percentage of progeny that develops normally has a complete triploid genome, consisting of both sets of maternal and one set of paternal chromosomes. The three different fish families with defects in the mismatch repair genes mlh1, msh2 and msh6 were indeed found to be more sensitive to the development of cancer. They develop a range of tumour types at low frequencies. Predominantly neurofibromas were observed, indicating that zebrafish mimic distinct features of the human disease resulting from lack of mismatch repair, and are complementary to mouse models. The advantage of experimental accessibility of zebrafish was used in combination with an in vivo assay for mutation detection to study the in vivo effect of alkylation damage on lethality and mutation frequency in developing embryos. Consistent with the damage-sensing role of the MMR system, mutant embryos lacking the MMR enzyme MSH6 displayed lower lethality than wild types after exposure to ENU and MNU. In line with this, alkylation-induced somatic mutation frequencies were found to be much higher in wild type embryos than in the msh6 loss-of-function mutants. These mutations were found to be chromosomal aberrations, likely caused by chromosomal breaks that in turn result from stalled replication forks. Additionally, we found that mismatch repair deficiency does not improve ENU mutagenesis in the zebrafish germ line. Altogether, this indicates that the action of the mismatch repair system in zebrafish with regard to the formation of germ cells, the growth of tumours and the response to chemotherapeutic agents is similar to that in human and mouse. This means that the zebrafish can be considered a useful model. However, within all these areas there are clear differences, which are equally important as they enable us to study new aspects of cancer - research that is not possible in mouse and human.

Published
2008

18. Relationship of flow cytometric sperm integrity assessments with boar fertility performance under optimized field conditions.

Author

Broekhuijse, M. L. W. J., Šoštarić, E., Feitsma, H., and Gadella, B. M.

Subjects
FLOW cytometry, SPERMATOZOA, BOARS, FERTILITY, DNA damage, DNA, EJACULATION
Abstract

The number of intact and functional spermatozoa in semen can be assessed with flow cytometry and is believed to relate to male fertility. The aim of this study was to examine whether currently used sperm integrity assessments with flow cytometry correlate with field fertility data obtained for boar semen. For this purpose, 20 boars were followed for a 20-wk period (with a total average production of 33 ejaculates per boar) and the obtained fertility results (farrowing rate and number of piglets born) of commercial artificial insemination doses made from these ejaculates were recorded. Fertility results were corrected for farm, sow, boar, and semen-related parameters. From the same semen samples, sperm cell integrity was assessed with respect to DNA and to membrane integrity, acrosome intactness and responsiveness, and mitochondrial potential using established flow cytometric assays. This was done on freshly produced semen and on semen stored for up to 15 d. Remarkably, none of the individual membrane integrity variables was significantly related to fertility results. In contrast, the amount of DNA damage as assessed at 7 to 10 d and at 14 to 15 d of semen storage related to farrowing rate (P = 0.0400) and total number of piglets born (P = 0.0310), respectively. Therefore, the degree of DNA damage in stored boar semen samples may be a useful factor to evaluate semen as an indicator for litter size and farrowing rate. [ABSTRACT FROM AUTHOR]

Published
2012
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19. Application of computer-assisted semen analysis to explain variations in pig fertility.

Author

Broekhuijse, M. L. W. J., Šoštarić, E., Feitsma, H., and Gadella, B. M.

Subjects
SEMEN analysis, MAMMAL reproduction, SWINE, ARTIFICIAL insemination of swine, EJACULATION, SPERMATOZOA, SEMEN
Abstract

Sperm quality is often evaluated through computer-assisted semen analysis (CASA) and is an indicator of boar fertility. The aim of this research was to study the relationship between CASA motility parameters and fertility results in pigs. Insemination records and semen parameters from a total of 45,532 ejaculates collected over a 3-yr period were used. The statistical model for analysis of fertility data from these inseminations included factors related to sow productivity. The boar- and semen-related variance (direct boar effect) were corrected for the effects of individual boar, genetic line of the boar, age of the boar, days between ejaculations, number of sperm cells in an ejaculate, number of sperm cells in an insemination dose, and AI station. The remaining variance was analyzed if semen motility parameters had a significant effect. This analysis revealed significant (P < 0.05) effects of progressive motility, velocity curvilinear, and beat cross frequency on farrowing rate (FR). Total motility, velocity average path, velocity straight line, and amplitude of lateral head displacement affected (P < 0.05) total number of piglets born (TNB). Boar- and semen-related parameters explained 5.3% of the variation in FR and 5.9% of the variation in TNB. Motility parameters, measured by CASA, explained 9% of the boar- and semen-related variation in FR and 10% of the boar- and semen-related variation in TNB. Individual boar and genetic line of the boar affected (P < 0.0001) the variation in FR and TNB. No differences (P > 0.05) were observed between effects of AI stations on fertility outcome, underscoring the objectivity of the CASA system used. Motility parameters can be measured with CASA to assess sperm motility in an objective manner. On the basis of the motility pattern, CASA enables one to discriminate between the fertilizing capacity of ejaculates, although this depends on the genetic line of the boar used in AI stations. [ABSTRACT FROM AUTHOR]

Published
2012
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20. Field Data Analysis of Boar Semen Quality.

Author

Broekhuijse, MLWJ, Feitsma, H, and Gadella, BM

Subjects
*BOARS, *SEMEN analysis, *DATA analysis, *FERTILITY, *ARTIFICIAL insemination of swine, *PARAMETER estimation, *SOWS
Abstract

Contents This contribution provides an overview of approaches to correlate sow fertility data with boar semen quality characteristics. Large data sets of fertility data and ejaculate data are more suitable to analyse effects of semen quality characteristics on field fertility. Variation in fertility in sows is large. The effect of semen factors is relatively small and therefore impossible to find in smaller data sets. Large data sets allow for statistical corrections on both sow- and boar-related parameters. Remaining sow fertility variation can then be assigned to semen quality parameters, which is of huge interest to AI (artificial insemination) companies. Previous studies of Varkens KI Nederland to find the contribution to field fertility of (i) the number of sperm cells in an insemination dose, (ii) the sperm motility and morphological defects and (iii) the age of semen at the moment of insemination are discussed in context of the possibility to apply such knowledge to select boars on the basis of their sperm parameters for AI purposes. [ABSTRACT FROM AUTHOR]

Published
2011
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22. Management and Genetic Factors Affecting Fertility in Sows.

Author

Merks, Jwm, Ducro-Steverink, Dwb, and Feitsma, H

Subjects
SOWS, FERTILITY, SWINE, GENETIC engineering, REPRODUCTION
Abstract

Contents The purpose of this article is to summarize the current knowledge on genetic and management methods for improving fertility in sows. Fertilization rate, litter size and the interval between weaning and oestrus are traits that can be monitored on farms. These traits are heritable but can also be influenced by management. Age at puberty and the interval between weaning and oestrus are genetically linked (rg = 0.3) and a shorter weaning-to-oestrus interval is related to a longer duration of oestrus. Consequently, selection may be used to simplify detection of oestrus but because of variation in duration of oestrus between lines/breeds, farm-specific insemination strategies are needed. The direct boar effect on fertilization is small, probably due to the superabundance of sperm cells that is available in each dose of semen. Consequently, the use of a large number of sperm cells per dose is the best management tool for avoiding fertilization problems in sows. Health status of the boars, both for artificial insemination and natural mating, is of importance in order to produce a large number of sperm cells/doses of good quality per ejaculate. It is concluded that factors that influence fertility in sows, particularly prior to and during fertilization, are mainly related to oestrus and the optimal timing of insemination. Selection for adequate symptoms of oestrus, together with farm-specific insemination strategies are needed. [ABSTRACT FROM AUTHOR]

Published
2000
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25. Pulmonary deposition and disappearance of aerosolised secretory leucocyte protease inhibitor.

Author

Stolk, J, Camps, J, Feitsma, H I, Hermans, J, Dijkman, J H, and Pauwels, E K

Abstract

Background: The neutrophil elastase inhibitor, secretory leucocyte protease inhibitor (SLPI), is a potential therapeutic tool in inflammatory lung diseases such as cystic fibrosis and pulmonary emphysema. The distribution and disappearance in the lung of aerosolised recombinant SLPI (rSLPI) was investigated in healthy humans and in patients with cystic fibrosis or alpha 1-antitrypsin-associated emphysema.Methods: To distinguish aerosolised rSLPI from endogenous SLPI the recombinant inhibitor was radiolabelled with 99m-technetium (99mTc) pertechnetate. Distribution and disappearance of aerosolised 99mTc-rSLPI in the lungs were studied by gamma radiation imaging.Results: The deposition of 99mTc-rSLPI in normal volunteers was homogeneous in all lung lobes, while in patients with cystic fibrosis or emphysema only well ventilated areas showed deposition of the aerosol. The disappearance rate of 99mTc-rSLPI was biexponential. The half life of the rapid phase was 0.2-2.8 hours, while that of the slow phase was more than 24 hours.Conclusions: Future aerosol therapy with rSLPI will be most beneficial for well ventilated lung tissue that needs protection against neutrophil derived elastase. It may be more difficult to neutralise the burden of elastase in poorly ventilated, highly inflamed areas as are seen in cystic fibrosis. [ABSTRACT FROM AUTHOR]

Published
1995

26. Do CASA Systems Satisfy Consumers Demands? A Critical Analysis.

Author

Feitsma, H, Broekhuijse, MLWJ, and Gadella, BM

Subjects
*SEMEN analysis, *COMPUTER assisted research, *REPRODUCTIVE technology, *COST effectiveness, *ARTIFICIAL insemination of domestic animals, *BOARS, *BIOLOGICAL variation, *TESTING
Abstract

Contents Boar studs are often offered new technologies including several CASA (computer-assisted semen analysis) systems. However, independent information to assist their purchase decisions is not available. The systems accuracy and repeatability variation because of different factors can be evaluated through duplicate testing of semen samples and comparison of the results according to WHO standards for humans. This primary analysis and a thorough economic cost benefit evaluation will help to decide whether the purchase of a CASA system will be profitable for a boar stud. Our experience of implementing several CASA systems in the cooperative Dutch Artificial Insemination (AI) centres is used as a base for this discussion. [ABSTRACT FROM AUTHOR]

Published
2011
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27. Effect of live weight development and reproduction in first parity on reproductive performance of second parity sows

Author

Hoving, L.L., Soede, N.M., Graat, E.A.M., Feitsma, H., and Kemp, B.

Subjects
*SOWS, *PARITY (Obstetrics), *DEVELOPMENTAL biology, *LIVESTOCK development, *PREGNANCY in animals, *ANIMAL litters, *LOGISTIC regression analysis, *REPRODUCTION
Abstract

Abstract: An impaired reproductive performance in second parity compared to first parity sows, decreases reproductive efficiency and, perhaps, longevity of sows. This study aims to quantify the effect of live weight development and reproduction in first parity on reproductive performance of second parity sows, i.e. pregnancy rate as well as litter size. Measures of sow development (live weight at first insemination, farrowing and weaning) and reproduction (total number of piglets born, weaning to insemination interval, lactation period, number piglets weaned) were recorded on two experimental farms. Logistic regression analysis was done for the binary outcome ‘non-pregnancy from first insemination after first weaning’ (yes/no). General linear regression analysis was used for litter size from 1st insemination in second parity. Repeat breeders were omitted from the analysis on litter size in second parity, since a prolonged period between weaning and conception can positively influence litter size. Farms differed significantly in measures of sow live weight development and therefore data were analyzed per farm. Compared with gilts from farm A, gilts from farm B were older and heavier at: first insemination (275±0.9 days and 145±0.8kg for farm B vs. 230±0.6 days and 124±0.5kg for farm A), first farrowing (resp. 189±1.1 vs. 181±0.9kg) and first weaning (resp. 165±1.1 vs. 156±0.9kg). Weight loss during pregnancy was similar for both farms (resp. 24.9±0.7 and 23.7±1.0kg). Gilts from farm A, however, gained more weight in the period between first insemination and first weaning compared with gilts from farm B (resp. 36.1±0.8 and 20.9±1.3kg). Non-pregnancy in second parity was 11% for farm A and 15% for farm B. Litter sizes in first and second parity were, respectively, 10.7±0.1 and 11.6±0.2 for farm A and 11.8±0.1 and 11.6±0.1 for farm B. Variables associated with non-pregnancy and litter size in second parity differed between farms. On farm A, mainly sow live weight development was associated with non-pregnancy and litter size in second parity, whilst on farm B variables like total number born in 1st parity and sow line, were associated with non-pregnancy and litter size in second parity. On both farms, higher weight gain from first insemination to first weaning was associated with a decrease in non-pregnancy (odds ratio 0.7 per 10kg for farm A and 0.8 per 10kg for farm B) and on farm A with higher litter size in second parity (β =0.42 per 10kg weight gain). Results show that sow live weight development affects reproductive performance in second parity, especially on farm A where gilts are relatively light or young at first insemination. Management of these animals should aim to optimize development at first insemination and to increase growth between first insemination and first weaning in order to optimize production in second parity. [Copyright &y& Elsevier]

Published
2010
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28. High Prevalence of Chromosomal Rearrangements and LINE Retrotranspositions Detected in Formalin-Fixed, Paraffin-Embedded Colorectal Cancer Tissue.

Author

Rubio-Alarcón C, Stelloo E, Vessies DCL, van 't Erve I, Mekkes NJ, Swennenhuis J, Lakbir S, van Bree EJ, Tijssen M, Delis-van Diemen P, Lanfermeijer M, Linders T, van den Broek D, Punt CJA, Heringa J, Meijer GA, Abeln S, Feitsma H, and Fijneman RJA

Subjects
Humans, Male, Female, Middle Aged, Aged, Chromosome Aberrations, Biomarkers, Tumor genetics, High-Throughput Nucleotide Sequencing methods, Colorectal Neoplasms genetics, Colorectal Neoplasms diagnosis, Paraffin Embedding, Formaldehyde, Long Interspersed Nucleotide Elements genetics, Tissue Fixation
Abstract

Structural variants (SVs) caused by chromosomal rearrangements in common fragile sites or long interspersed nuclear element (LINE) retrotranspositions are highly prevalent in colorectal cancer. However, methodology for the targeted detection of these SVs is lacking. This article reports the use of formalin-fixed, paraffin-embedded targeted-locus capture (FFPE-TLC) sequencing as a novel technology for the targeted detection of tumor-specific SVs. Analysis of 29 FFPE colorectal tumor samples and 8 matched normal samples revealed tumor-specific SVs in 24 patients (83%), with a median of 2 SVs per patient (range, 1 to 21). A total of 104 SVs were found in the common fragile site-associated genes MACROD2, PRKN, FHIT, and WWOX in 18 patients (62%), and 39 SVs caused by three LINE transposable elements were found in 15 patients (52%). Tumor specificity of SVs was independently verified by droplet digital PCR of tumor tissue DNA, and their applicability as plasma circulating tumor DNA biomarkers was demonstrated. FFPE-TLC sequencing enabled the detection of tumor-specific SVs caused by chromosomal rearrangements and LINE retrotranspositions in FFPE tissue. Therefore, FFPE-TLC sequencing facilitates the investigation of the biological and clinical effects of SVs using FFPE material from (retrospective) cohorts of cancer patients and has potential clinical applicability in the detection of SV biomarkers in the routine molecular diagnostics setting., Competing Interests: Disclosure Statement C.R.-A. declares nonfinancial support from Personal Genome Diagnostics and Cergentis BV. E.S., J.S., and H.F. are employees of Cergentis BV (a Solvias company), the inventor and owner of the patents on FFPE-TLC technology. S.L. reports nonfinancial support from Cergentis BV and a patent pending. E.J.v.B. reports nonfinancial support from Cergentis BV. D.v.d.B. has provided lectures, expert testimony, and advisory board presence to Roche Diagnostics, all outside the submitted work and all financial supports transferred to institute. G.A.M. is co-founder and board member (CSO) of CRCbioscreen BV; has had research collaboration with CZ Health Insurances (cash matching to ZonMW grant); has had research collaborations with Exact Sciences, Sysmex, Sentinel Ch SpA, Personal Genome Diagnostics, DELFi, and HMF (these companies provide materials, equipment and/or sample/genomic analyses); and has several patents pending/issued. S.A. reports public–private partnership consortia grants in collaboration with Cergentis BV, Olink Proteomics AB, and Quanterix Corporation and has a patent pending. R.J.A.F. reports public–private partnership consortia grants in collaboration with Cergentis BV; reports public–private partnership consortia grants and nonfinancial support in collaboration with Personal Genome Diagnostics, Delfi, Natera, and Merck BV outside the submitted work; and has several patents pending., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Published
2024
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29. Proximity ligation-based sequencing for the identification of human papillomavirus genomic integration sites in formalin-fixed paraffin embedded oropharyngeal squamous cell carcinomas.

Author

Demers I, Balaji H, Feitsma H, Stelloo E, Swennenhuis J, Sergeeva I, Wuerdemann N, van den Hout MFCM, Wagner S, Kremer B, Klussmann JP, Huebbers CU, and Speel EM

Subjects
Female, Humans, Male, Cell Line, Tumor, DNA, Viral genetics, Formaldehyde, Paraffin Embedding, Polymerase Chain Reaction methods, Sequence Analysis, DNA, Tissue Fixation, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell virology, Human Papillomavirus Viruses classification, Human Papillomavirus Viruses genetics, Human Papillomavirus Viruses isolation & purification, Oropharyngeal Neoplasms virology, Oropharyngeal Neoplasms genetics, Papillomavirus Infections virology, Papillomavirus Infections diagnosis, Virus Integration genetics
Abstract

Human papillomavirus (HPV) infections are an increasing cause of oropharyngeal squamous cell carcinomas (OPSCC). Integration of the viral genome into the host genome is suggested to affect carcinogenesis, however, the correlation with OPSCC patient prognosis is still unclear. Research on HPV integration is hampered by current integration detection technologies and their unsuitability for formalin-fixed paraffin-embedded (FFPE) tissues. This study aims to develop and validate a novel targeted proximity-ligation based sequencing method (targeted locus amplification/capture [TLA/TLC]) for HPV integration detection in cell lines and FFPE OPSCCs. For the identification of HPV integrations, TLA/TLC was applied to 7 cell lines and 27 FFPE OPSCCs. Following preprocessing steps, a polymerase chain reaction (PCR)-based HPV enrichment was performed on the cell lines and a capture-based HPV enrichment was performed on the FFPE tissues before paired-end sequencing. TLA was able to sequence up to hundreds of kb around the target, detecting exact HPV integration loci, structural variants, and chromosomal rearrangements. In all cell lines, one or more integration sites were identified, in accordance with detection of integrated papillomavirus sequences PCR data and the literature. TLC detected integrated HPV in 15/27 FFPE OPSCCs and identified simple and complex integration patterns. In general, TLA/TLC confirmed PCR data and detected additional integration sites. In conclusion TLA/TLC reliably and robustly detects HPV integration in cell lines and FFPE OPSCCs, enabling large, population-based studies on the clinical relevance of HPV integration. Furthermore, this approach might be valuable for clonality assessment of HPV-related tumors in clinical diagnostics., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Published
2024
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30. Summary of the Dutch Multidisciplinary Practice Guideline on Asthma and Pregnancy.

Author

Bendien SA, de Kruif MD, Feitsma H, van Hoolwerff-Blikkendaal C, Huurne KK, Kuiterman A, Baranova EV, Wittkamp A, Brons A, Poulissen M, and van der Meer AN

Subjects
Humans, Pregnancy, Female, Netherlands, Practice Guidelines as Topic, Anti-Asthmatic Agents therapeutic use, Breast Feeding, Asthma drug therapy, Asthma diagnosis, Pregnancy Complications therapy, Pregnancy Complications drug therapy
Abstract

Asthma is the most common chronic respiratory disease in women of childbearing age and during pregnancy. This paper presents a summary of the Dutch multidisciplinary guideline on asthma and pregnancy. The aim of this guideline is to provide structured, where possible, evidence-based recommendations to optimize the management of asthma during pregnancy. The main topics covered in this guideline are preconception counseling, the safety of asthma medications during pregnancy and breastfeeding and risk assessment and monitoring of asthma during pregnancy. Because many caregivers are involved and a uniform approach is desirable, this guideline has been developed in collaboration with all relevant health care providers and patient representatives., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2024
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31. Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential.

Author

Zhang C, Stelloo E, Barrans S, Cucco F, Jiang D, Tzioni MM, Chen Z, Li Y, Swennenhuis JF, Makker J, Rásó-Barnett L, Liu H, El-Daly H, Soilleux E, Shah N, Nagumantry SK, Kyaw M, Prahladan MP, Tooze R, Westhead DR, Feitsma H, Davies AJ, Burton C, Johnson PWM, and Du MQ

Subjects
Humans, Transcriptional Activation, Proto-Oncogene Proteins c-bcl-6 genetics, Translocation, Genetic, Genomics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Lymphoma, Large B-Cell, Diffuse pathology
Abstract

MYC translocation occurs in 8-14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL-MYC/BCL2-DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG::MYC fusion significantly associated with inferior survival. While DLBCL-MYC/BCL6-DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6-TH, 75 MYC/BCL2-DH and 26 MYC/BCL6-DH. FISH revealed a MYC/BCL6 fusion in 59% of DLBCL-MYC/BCL2/BCL6-TH and 27% of DLBCL-MYC/BCL6-DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL-MYC/BCL2/BCL6-TH and DLBCL-MYC/BCL2-DH, but variable LymphGen subtypes among DLBCL-MYC/BCL6-DH. MYC protein expression is uniformly high in DLBCL with IG::MYC, but variable in those with non-IG::MYC including MYC/BCL6-fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment., (© 2024. The Author(s).)

Published
2024
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32. Formalin-Fixed, Paraffin-Embedded-Targeted Locus Capture: A Next-Generation Sequencing Technology for Accurate DNA-Based Gene Fusion Detection in Bone and Soft Tissue Tumors.

Author

Stelloo E, Meijers RWJ, Swennenhuis JF, Allahyar A, Hajo K, Cangiano M, de Leng WWJ, van Helvert S, Van der Meulen J, Creytens D, van Kempen LC, Cleton-Jansen AM, Bovee JVMG, de Laat W, Splinter E, and Feitsma H

Subjects
Humans, Paraffin Embedding methods, DNA genetics, Formaldehyde, Gene Fusion, Technology, Tissue Fixation, High-Throughput Nucleotide Sequencing methods, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms genetics
Abstract

Chromosomal rearrangements are important drivers in cancer, and their robust detection is essential for diagnosis, prognosis, and treatment selection, particularly for bone and soft tissue tumors. Current diagnostic methods are hindered by limitations, including difficulties with multiplexing targets and poor quality of RNA. A novel targeted DNA-based next-generation sequencing method, formalin-fixed, paraffin-embedded-targeted locus capture (FFPE-TLC), has shown advantages over current diagnostic methods when applied on FFPE lymphomas, including the ability to detect novel rearrangements. We evaluated the utility of FFPE-TLC in bone and soft tissue tumor diagnostics. FFPE-TLC sequencing was successfully applied on noncalcified and decalcified FFPE samples (n = 44) and control samples (n = 19). In total, 58 rearrangements were identified in 40 FFPE tumor samples, including three previously negative samples, and none was identified in the FFPE control samples. In all five discordant cases, FFPE-TLC could identify gene fusions where other methods had failed due to either detection limits or poor sample quality. FFPE-TLC achieved a high specificity and sensitivity (no false positives and negatives). These results indicate that FFPE-TLC is applicable in cancer diagnostics to simultaneously analyze many genes for their involvement in gene fusions. Similar to the observation in lymphomas, FFPE-TLC is a good DNA-based alternative to the conventional methods for detection of rearrangements in bone and soft tissue tumors., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Published
2023
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33. Comparison of NTRK fusion detection methods in microsatellite-instability-high metastatic colorectal cancer.

Author

Schraa SJ, Stelloo E, Laclé MM, Swennenhuis JF, Brosens LAA, Fijneman RJA, Feitsma H, Koopman M, de Leng WW, Vink GR, and Bol GM

Subjects
Humans, Receptor, trkA genetics, In Situ Hybridization, Fluorescence, Microsatellite Repeats, Oncogene Proteins, Fusion genetics, Gene Fusion, Neoplasms genetics, Colonic Neoplasms genetics
Abstract

Tropomyosin receptor kinase (TRK) inhibitors have been approved for metastatic solid tumors harboring NTRK fusions, but the detection of NTRK fusions is challenging. International guidelines recommend pan-TRK immunohistochemistry (IHC) screening followed by next generation sequencing (NGS) in tumor types with low prevalence of NTRK fusions, including metastatic colorectal cancer (mCRC). RNA-based NGS is preferred, but is expensive, time-consuming, and extracting good-quality RNA from FFPE tissue is challenging. Alternatives in daily clinical practice are warranted. We assessed the diagnostic performance of RNA-NGS, FFPE-targeted locus capture (FFPE-TLC), fluorescence in situ hybridization (FISH), and the 5'/3' imbalance quantitative RT-PCR (qRT-PCR) after IHC screening in 268 patients with microsatellite-instability-high mCRC, the subgroup in which NTRK fusions are most prevalent (1-5%). A consensus result was determined after review of all assay results. In 16 IHC positive tumors, 10 NTRK fusions were detected. In 33 IHC negative samples, no additional transcribed NTRK fusions were found, underscoring the high sensitivity of IHC. Sensitivity of RNA-NGS, FFPE-TLC, FISH, and qRT-PCR was 90%, 90%, 78%, and 100%, respectively. Specificity was 100% for all assays. Robustness, defined as the percentage of samples that provided an interpretable result in the first run, was 100% for FFPE-TLC, yet more limited for RNA-NGS (85%), FISH (70%), and qRT-PCR (70%). Overall, we do not recommend FISH for the detection of NTRK fusions in mCRC due to its low sensitivity and limited robustness. We conclude that RNA-NGS, FFPE-TLC, and qRT-PCR are appropriate assays for NTRK fusion detection, after enrichment with pan-TRK IHC, in routine clinical practice., (© 2023. The Author(s).)

Published
2023
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34. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors.

Author

van Zogchel LMJ, Lak NSM, Gelineau NU, Sergeeva I, Stelloo E, Swennenhuis J, Feitsma H, van Min M, Splinter E, Bleijs M, Groot Koerkamp M, Breunis W, Meister MT, Kholossy WH, Holstege FCP, Molenaar JJ, de Leng WWJ, Stutterheim J, van der Schoot CE, and Tytgat GAM

Abstract

Background: Liquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors., Materials and Methods: Regions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed., Results: TLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse., Conclusion: We demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols., Competing Interests: IS, ESt, JSw, HF, MM, ESp are employees of Cergentis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 van Zogchel, Lak, Gelineau, Sergeeva, Stelloo, Swennenhuis, Feitsma, van Min, Splinter, Bleijs, Groot Koerkamp, Breunis, Meister, Kholossy, Holstege, Molenaar, de Leng, Stutterheim, van der Schoot and Tytgat.)

Published
2023
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35. Minimal residual disease (MRD) detection in acute lymphoblastic leukaemia based on fusion genes and genomic deletions: towards MRD for all.

Author

Kuiper RP, Hoogeveen PG, Bladergroen R, van Dijk F, Sonneveld E, van Leeuwen FN, Boer J, Sergeeva I, Feitsma H, den Boer ML, and van der Velden VHJ

Subjects
Child, Gene Deletion, Humans, Neoplasm, Residual genetics, Oncogene Fusion, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Neoplasm, Residual diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis
Abstract

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5-10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Published
2021
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36. Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing.

Author

Allahyar A, Pieterse M, Swennenhuis J, Los-de Vries GT, Yilmaz M, Leguit R, Meijers RWJ, van der Geize R, Vermaat J, Cleven A, van Wezel T, Diepstra A, van Kempen LC, Hijmering NJ, Stathi P, Sharma M, Melquiond ASJ, de Vree PJP, Verstegen MJAM, Krijger PHL, Hajo K, Simonis M, Rakszewska A, van Min M, de Jong D, Ylstra B, Feitsma H, Splinter E, and de Laat W

Subjects
Computational Biology methods, Gene Rearrangement, Genes, bcl-2 genetics, Genes, myc genetics, Humans, In Situ Hybridization, Fluorescence methods, Lymphoma, B-Cell diagnosis, Lymphoma, Non-Hodgkin diagnosis, Proto-Oncogene Proteins c-bcl-6 genetics, Reproducibility of Results, Retrospective Studies, Sensitivity and Specificity, High-Throughput Nucleotide Sequencing methods, Lymphoma, B-Cell genetics, Lymphoma, Non-Hodgkin genetics, Paraffin Embedding methods, Tissue Fixation methods, Translocation, Genetic
Abstract

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

Published
2021
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37. Foley catheter versus vaginal misoprostol: randomized controlled trial (PROBAAT-M study) and systematic review and meta-analysis of literature.

Author

Jozwiak M, ten Eikelder M, Oude Rengerink K, de Groot C, Feitsma H, Spaanderman M, van Pampus M, de Leeuw JW, Mol BW, and Bloemenkamp K

Subjects
Adult, Female, Humans, Pregnancy, Administration, Intravaginal, Cesarean Section statistics & numerical data, Delivery, Obstetric, Labor, Induced methods, Misoprostol administration & dosage, Oxytocics administration & dosage, Urinary Catheterization
Abstract

Objectives: To assess effectiveness and safety of Foley catheter versus vaginal misoprostol for term induction of labor., Study Design: This trial randomly allocated women with singleton term pregnancy to 30-mL Foley catheter or 25-μg vaginal misoprostol tablets. Primary outcome was cesarean delivery rate. Secondary outcomes were maternal and neonatal morbidity and time to birth. Additionally, a systematic review was conducted., Results: Fifty-six women were allocated to Foley catheter, 64 to vaginal misoprostol tablets. Cesarean delivery rates did not differ significantly (25% Foley versus 17% misoprostol; relative risk [RR] 1.46, 95% confidence interval [CI] 0.72 to 2.94), with more cesarean deliveries due to failure to progress in the Foley group (14% versus 3%; RR 4.57, 95% CI 1.01 to 20.64). Maternal and neonatal outcomes were comparable. Time from induction to birth was longer in the Foley catheter group (36 hours versus 25 hours; p < 0.001). Meta-analysis showed no difference in cesarean delivery rate and reduced vaginal instrumental deliveries and hyperstimulation in the Foley catheter group. Other outcomes were not different., Conclusion: Our trial and meta-analysis showed no difference in cesarean delivery rates and less hyperstimulation with fetal heart rate changes and vaginal instrumental deliveries when using Foley catheter, thereby supporting potential advantages of the Foley catheter over misoprostol as ripening agent., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Published
2014
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38. Improving DNA capture on microarrays by integrated repeated denaturing.

Author

Servoli E, Feitsma H, Kaptheijns B, van der Zaag PJ, and Wimberger-Friedl R

Subjects
Nucleic Acid Denaturation, Solutions, Temperature, Time Factors, DNA chemistry, DNA isolation & purification, Microfluidic Analytical Techniques instrumentation, Nucleic Acid Hybridization methods
Abstract

Hybridization of nucleic acids to microarrays is a crucial step for several biological and biomedical applications. However, the poor efficiency and resulting long incubation times are major drawbacks. In addition to diffusion limitation, back hybridization to complementary strands in solution is shown to be an important cause of the low efficiency. In this paper, repeated denaturing in an integrated device has been investigated in order to increase the efficiency of microarray hybridization. The sample solution is circulated from the microarray chamber over a denaturing zone and back in a closed loop. In addition to the improved binding rate due to flow, repeated denaturing significantly increases the total amount of molecules bound. Our results demonstrate that cyclic repeated denaturing improves the efficiency of hybridization by up to an order of magnitude over a broad range of concentrations studied (1 pM to 100 nM).

Published
2012
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39. Lactation weight loss in primiparous sows: consequences for embryo survival and progesterone and relations with metabolic profiles.

Author

Hoving LL, Soede NM, Feitsma H, and Kemp B

Subjects
Animals, Energy Metabolism physiology, Female, Food Deprivation, Pregnancy, Lactation physiology, Parity, Pregnancy, Animal physiology, Swine physiology, Weight Loss
Abstract

Our objective was to study reproductive consequences of lactation bodyweight loss occurring in primiparous sows with mild feed restriction and to relate these lactation weight losses and its consequences to metabolic profiles during lactation and subsequent early gestation. After weaning, 47 first-litter sows were retrospectively assigned to a high- (HWL, >13.8%, n= 24) or low (LWL, ≤13.8%, n = 23)-weight loss group. Thirty-six animals received an indwelling jugular vein catheter to determine lactational and gestational profiles of insulin-like growth factor-1 (IGF-1), non-esterified fatty acids (NEFA) and urea and gestational profiles of progesterone. At day 35 after insemination, sows were euthanized and their reproductive tract collected. Pregnancy rate was 75% (18/24) for HWL and 96% (22/23) for LWL sows. High-weight loss sows had a lower number of implantation sites (17.2 ± 0.8 vs 19.5 ± 0.7, respectively, p = 0.03) and a lower embryonic survival (65.6 ± 3.4 vs 77.4 ± 2.9%, p = 0.02), resulting in fewer vital embryos (14.9 ± 0.9 vs 16.8 ± 0.7, p = 0.07) than LWL sows. Progesterone peak values were reached later in HWL than in LWL sows (day 13.4 ± 0.5 vs 12.0 ± 0.5, respectively, p = 0.05). Gestational concentrations of IGF-1, NEFA and urea were almost identical for HWL and LWL sows, whilst numerical differences were seen during lactation. The current study shows negative consequences of lactational weight loss in mildly feed-restricted primiparous sows for embryonic survival and shows that these consequences seem only mildly related with metabolic alterations during lactation and not with metabolic alterations during subsequent gestation., (© 2012 Blackwell Verlag GmbH.)

Published
2012
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40. Artificial insemination in pigs: predicting male fertility.

Author

Broekhuijse ML, Feitsma H, and Gadella BM

Subjects
Animals, Flow Cytometry methods, Flow Cytometry veterinary, Image Processing, Computer-Assisted methods, Insemination, Artificial veterinary, Male, Microscopy, Phase-Contrast methods, Microscopy, Phase-Contrast veterinary, Netherlands, Semen Analysis veterinary, Sperm Motility, Fertility, Insemination, Artificial methods, Semen physiology, Semen Analysis methods, Sus scrofa physiology
Abstract

Efficient artificial insemination (AI) is essential for future challenges in the pig industry. Knowledge on the exact relation between semen quality characteristics and fertility can have a major impact on both the genetic merit of future animals and the efficiency of AI. Variation in fertility is caused not only by farm- or sow-related parameters but also by boar- and semen-related parameters. In pig AI there is no gold standard concerning semen quality assessment. Assessing semen quality characteristics objectively and relating them to large field fertility datasets leads to an efficient production of insemination doses, which results in an efficient dissemination/descent of the breeding program required genes. Overall, this contributes to the development of semen quality assessments, which improves the prediction of porcine male fertility. Knowing which semen characteristics, and to what extent, contribute to male fertility and makes the field fertility more predictable.

Published
2012
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41. Protein biomarker enrichment by biomarker antibody complex elution for immunoassay biosensing.

Author

Sabatte G, Feitsma H, Evers TH, and Prins MW

Subjects
Antigen-Antibody Complex isolation & purification, Biomarkers analysis, Biomarkers, Tumor blood, Epitopes isolation & purification, Humans, Magnetics, Male, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Proteins immunology, Biosensing Techniques methods, Immunoassay methods, Proteins isolation & purification
Abstract

It is very challenging to perform sample enrichment for protein biomarkers because proteins can easily change conformation and denature. In this paper we demonstrate protein enrichment suited for high-sensitivity integrated immuno-biosensing. The method enhances the concentration of the biomarkers and simultaneously removes matrix components that could interfere with the immunoassay. Biomarkers are captured using antibody coated magnetic particles and the biomarker antibody complexes are released by enzymatic elution. The eluted complexes are subsequently detected in a sandwich immunoassay biosensor. A scaling study of the enrichment process demonstrates an enrichment factor of 15 in buffer and plasma. We analyze the enrichment factor in terms of the three basic steps of the assay (capture, concentration, elution) and we quantify their respective efficiencies. The process is suited for integration into bio-analytical tools., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Published
2011
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42. An increased feed intake during early pregnancy improves sow body weight recovery and increases litter size in young sows.

Author

Hoving LL, Soede NM, van der Peet-Schwering CM, Graat EA, Feitsma H, and Kemp B

Subjects
Animals, Animals, Newborn, Birth Weight physiology, Body Weight physiology, Female, Litter Size physiology, Logistic Models, Pregnancy, Animal Nutritional Physiological Phenomena physiology, Diet veterinary, Eating physiology, Pregnancy, Animal metabolism, Swine physiology
Abstract

This study evaluated the effect of feeding level and protein content in feed in first- and second-parity sows during the first month of gestation on sow BW recovery, farrowing rate, and litter size during the first month of gestation. From d 3 to 32 after the first insemination, sows were fed either 2.5 kg/d of a standard gestation diet (control, n = 49), 3.25 kg/d (+30%) of a standard gestation diet (plus feed, n = 47), or 2.5 kg/d of a gestation diet with 30% greater ileal digestible AA (plus protein, n = 49). Feed intake during the experimental period was 29% greater for sows in the plus feed group compared with those in the control and plus protein groups (93 vs. 72 kg, P < 0.05). Sows in the plus feed group gained 10 kg more BW during the experimental period compared with those in the control and plus protein groups (24.2 ± 1.2 vs. 15.5 ± 1.2 and 16.9 ± 1.2 kg, respectively, P < 0.001). Backfat gain and loin muscle depth gain were not affected by treatment (P = 0.56 and P = 0.37, respectively). Farrowing rate was smaller, although not significantly, for sows in the plus feed group compared with those in the control and plus protein groups (76.6% vs. 89.8 and 89.8%, respectively, P = 0.16). Litter size, however, was larger for sows in the plus feed group (15.2 ± 0.5 total born) compared with those in the control and plus protein groups (13.2 ± 0.4 and 13.6 ± 0.4 total born, respectively, P = 0.006). Piglet birth weight was not different among treatments (P = 0.65). For both first- and second-parity sows, the plus feed treatment showed similar effects on BW gain, farrowing rate, and litter size. In conclusion, an increased feed intake (+30%) during the first month of gestation improved sow BW recovery and increased litter size, but did not significantly affect farrowing rate in the subsequent parity. Feeding a 30% greater level of ileal digestible AA during the same period did not improve sow recovery or reproductive performance in the subsequent parity.

Published
2011
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43. An ENU-mutagenesis screen in the mouse: identification of novel developmental gene functions.

Author

Wansleeben C, van Gurp L, Feitsma H, Kroon C, Rieter E, Verberne M, Guryev V, Cuppen E, and Meijlink F

Subjects
Alleles, Animals, Embryonic Development genetics, Genes, Developmental, Genetic Techniques, Lung drug effects, Mice, Models, Genetic, Mutation, Phenotype, Time Factors, Ethylnitrosourea toxicity, Mutagenicity Tests methods, Mutagens
Abstract

Background: Mutagenesis screens in the mouse have been proven useful for the identification of novel gene functions and generation of interesting mutant alleles. Here we describe a phenotype-based screen for recessive mutations affecting embryonic development., Methodology/principal Findings: Mice were mutagenized with N-ethyl-N-nitrosourea (ENU) and following incrossing the offspring, embryos were analyzed at embryonic day 10.5. Mutant phenotypes that arose in our screen include cardiac and nuchal edema, neural tube defects, situs inversus of the heart, posterior truncation and the absence of limbs and lungs. We isolated amongst others novel mutant alleles for Dll1, Ptprb, Plexin-B2, Fgf10, Wnt3a, Ncx1, Scrib(Scrib, Scribbled homolog [Drosophila]) and Sec24b. We found both nonsense alleles leading to severe protein truncations and mutants with single-amino acid substitutions that are informative at a molecular level. Novel findings include an ectopic neural tube in our Dll1 mutant and lung defects in the planar cell polarity mutants for Sec24b and Scrib., Conclusions/significance: Using a forward genetics approach, we have generated a number of novel mutant alleles that are linked to disturbed morphogenesis during development.

Published
2011
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44. Accurate SNP and mutation detection by targeted custom microarray-based genomic enrichment of short-fragment sequencing libraries.

Author

Mokry M, Feitsma H, Nijman IJ, de Bruijn E, van der Zaag PJ, Guryev V, and Cuppen E

Subjects
Gene Library, Genome, Human, Humans, Mutation, DNA Mutational Analysis methods, Oligonucleotide Array Sequence Analysis methods, Polymorphism, Single Nucleotide, Sequence Analysis, DNA methods
Abstract

Microarray-based enrichment of selected genomic loci is a powerful method for genome complexity reduction for next-generation sequencing. Since the vast majority of exons in vertebrate genomes are smaller than 150 nt, we explored the use of short fragment libraries (85-110 bp) to achieve higher enrichment specificity by reducing carryover and adverse effects of flanking intronic sequences. High enrichment specificity (60-75%) was obtained with a relative even base coverage. Up to 98% of the target-sequence was covered more than 20x at an average coverage depth of about 200x. To verify the accuracy of SNP/mutation detection, we evaluated 384 known non-reference SNPs in the targeted regions. At approximately 200x average sequence coverage, we were able to survey 96.4% of 1.69 Mb of genomic sequence with only 4.2% false negative calls, mostly due to low coverage. Using the same settings, a total of 1197 novel candidate variants were detected. Verification experiments revealed only eight false positive calls, indicating an overall false positive rate of less than 1 per approximately 200,000 bp. Taken together, short fragment libraries provide highly efficient and flexible enrichment of exonic targets and yield relatively even base coverage, which facilitates accurate SNP and mutation detection. Raw sequencing data, alignment files and called SNPs have been submitted into GEO database http://www.ncbi.nlm.nih.gov/geo/ with accession number GSE18542.

Published
2010
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45. Planar cell polarity defects and defective Vangl2 trafficking in mutants for the COPII gene Sec24b.

Author

Wansleeben C, Feitsma H, Montcouquiol M, Kroon C, Cuppen E, and Meijlink F

Subjects
Animals, Aorta, Thoracic abnormalities, Cells, Cultured, Cochlea abnormalities, Cochlea anatomy & histology, Cochlea embryology, Embryo, Mammalian abnormalities, Embryo, Mammalian anatomy & histology, Embryo, Mammalian physiology, Epithelial Cells cytology, Epithelial Cells physiology, Female, Fibroblasts cytology, Fibroblasts physiology, Heart Defects, Congenital, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Neural Tube Defects genetics, Neural Tube Defects pathology, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Vesicular Transport Proteins genetics, Cell Polarity, Mutation, Nerve Tissue Proteins metabolism, Neural Tube Defects metabolism, Signal Transduction physiology, Vesicular Transport Proteins metabolism
Abstract

Among the cellular properties that are essential for the organization of tissues during animal development, the importance of cell polarity in the plane of epithelial sheets has become increasingly clear in the past decades. Planar cell polarity (PCP) signaling in vertebrates has indispensable roles in many aspects of their development, in particular, controlling alignment of various types of epithelial cells. Disrupted PCP has been linked to developmental defects in animals and to human pathology. Neural tube closure defects (NTD) and disorganization of the mechanosensory cells of the organ of Corti are commonly known consequences of disturbed PCP signaling in mammals. We report here a typical PCP phenotype in a mouse mutant for the Sec24b gene, including the severe NTD craniorachischisis, abnormal arrangement of outflow tract vessels and disturbed development of the cochlea. In addition, we observed genetic interaction between Sec24b and the known PCP gene, scribble. Sec24b is a component of the COPII coat protein complex that is part of the endoplasmic reticulum (ER)-derived transport vesicles. Sec24 isoforms are thought to be directly involved in cargo selection, and we present evidence that Sec24b deficiency specifically affects transport of the PCP core protein Vangl2, based on experiments in embryos and in cultured primary cells.

Published
2010
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46. A novel mutant allele of Ncx1: a single amino acid substitution leads to cardiac dysfunction.

Author

Wansleeben C, Feitsma H, Tertoolen L, Kroon C, Guryev V, Cuppen E, and Meijlink F

Subjects
Action Potentials, Animals, Calcium blood, Embryo, Mammalian metabolism, Female, Ion Transport, Mice, Mice, Transgenic, Myocardial Contraction, Myocytes, Cardiac pathology, Phenotype, Placentation, Pregnancy, Sodium-Calcium Exchanger chemistry, Structure-Activity Relationship, Amino Acid Substitution, Heart Defects, Congenital genetics, Myocytes, Cardiac physiology, Sodium-Calcium Exchanger genetics
Abstract

The biological role and structure-function relationship of the Na(+)Ca(2+) exchanger NCX1 have been the subject of much investigation. Subtle mutagenesis to study the function of a protein seems only feasible in in vitro systems, but genetic forward screens have the potential to provide in vivo models to study single amino acid substitutions. In a genetic screen in mouse, we have isolated a mutant line carrying a novel mutant allele of the mouse Ncx1 gene. In this allele, a point mutation causes the substitution of a highly conserved asparagine residue (N874) with lysine. Accepted models for NCX1 structure propose that the affected amino acid is located in one of the reentrant membrane loops and experiments in vitro have identified N874 as critical for the ion transport function of NCX1. We found severe circulation defects and defective placentation in homozygous Ncx1(N87K4) mutant embryos, making the phenotype essentially indistinguishable from those of previously described null mutants. By ex vivo analysis, we demonstrated intrinsic functional abnormalities of cardiomyocytes. Western blot analysis and immunohistochemistry demonstrated normal levels and subcellular localization of the altered protein, ruling out the possibility that the abnormalities are a mere consequence of a major disturbance of protein structure. This study confirms and extends studies in vitro indicating the significance of amino acid N874 for the function of the NCX1 protein. It provides an in vivo model for this mutation and demonstrates the potential of forward genetic screens in a mammalian system.

Published
2010
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47. Highly Efficient ENU Mutagenesis in Zebrafish.

Author

de Bruijn E, Cuppen E, and Feitsma H

Subjects
Alkylating Agents administration & dosage, Animals, Animals, Genetically Modified, DNA drug effects, Drug Administration Schedule, Female, Genetic Engineering methods, Genome drug effects, Germ-Line Mutation, Male, Ethylnitrosourea administration & dosage, Mutagenesis drug effects, Zebrafish genetics
Abstract

ENU (N-ethyl-N-nitrosourea) mutagenesis is a widely accepted and proven method to introduce random point mutations in the genome. Because there are no targeted knockout strategies available for zebrafish so far, random mutagenesis is currently the preferred method in both forward and reverse genetic approaches. To obtain high-density mutagenized zebrafish, six consecutive ENU treatments are applied at weekly intervals to adult male zebrafish by bathing them in ENU solution. With this procedure an average germ line mutation load of one mutation every 1.0 x 10(5)-1.5 x 10(5) basepairs is reached routinely in our lab.

Published
2009
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48. Alkylation damage causes MMR-dependent chromosomal instability in vertebrate embryos.

Author

Feitsma H, Akay A, and Cuppen E

Subjects
Alkylation, Animals, Cell Death, Chromosome Aberrations, DNA Replication, DNA-Binding Proteins genetics, Embryo, Nonmammalian drug effects, Gene Deletion, Mutation, Zebrafish embryology, Zebrafish genetics, Alkylating Agents toxicity, Chromosomal Instability, DNA Damage, DNA Mismatch Repair, Ethylnitrosourea toxicity, Methylnitrosourea toxicity, Mutagens toxicity
Abstract

S(N)1-type alkylating agents, like N-methyl-N-nitrosourea (MNU) and N-ethyl-N-nitrosourea (ENU), are potent mutagens. Exposure to alkylating agents gives rise to O(6)-alkylguanine, a modified base that is recognized by DNA mismatch repair (MMR) proteins but is not repairable, resulting in replication fork stalling and cell death. We used a somatic mutation detection assay to study the in vivo effects of alkylation damage on lethality and mutation frequency in developing zebrafish embryos. Consistent with the damage-sensing role of the MMR system, mutant embryos lacking the MMR enzyme MSH6 displayed lower lethality than wild-type embryos after exposure to ENU and MNU. In line with this, alkylation-induced somatic mutation frequencies were found to be higher in wild-type embryos than in the msh6 loss-of-function mutants. These mutations were found to be chromosomal aberrations that may be caused by chromosomal breaks that arise from stalled replication forks. As these chromosomal breaks arise at replication, they are not expected to be repaired by non-homologous end joining. Indeed, Ku70 loss-of-function mutants were found to be equally sensitive to ENU as wild-type embryos. Taken together, our results suggest that in vivo alkylation damage results in chromosomal instability and cell death due to aberrantly processed MMR-induced stalled replication forks.

Published
2008
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49. Mismatch repair deficiency does not enhance ENU mutagenesis in the zebrafish germ line.

Author

Feitsma H, de Bruijn E, van de Belt J, Nijman IJ, and Cuppen E

Subjects
Animals, Animals, Genetically Modified, DNA Mismatch Repair drug effects, DNA-Binding Proteins genetics, Embryo, Nonmammalian, Fertilization genetics, Gene Frequency, Germ-Line Mutation, Male, Mutagenesis genetics, Mutagens toxicity, Zebrafish embryology, DNA Repair-Deficiency Disorders genetics, Ethylnitrosourea toxicity, Germ Cells drug effects, Mutagenesis drug effects, Zebrafish genetics
Abstract

S(N)1-type alkylating agents such as N-ethyl-N-nitrosourea (ENU) are very potent mutagens. They act by transferring their alkyl group to DNA bases, which, upon mispairing during replication, can cause single base pair mutations in the next replication cycle. As DNA mismatch repair (MMR) proteins are involved in the recognition of alkylation damage, we hypothesized that ENU-induced mutation rates could be increased in a MMR-deficient background, which would be beneficial for mutagenesis approaches. We applied a standard ENU mutagenesis protocol to adult zebrafish deficient in the MMR gene msh6 and heterozygous controls to study the effect of MMR on ENU-induced DNA damage. Dose-dependent lethality was found to be similar for homozygous and heterozygous mutants, indicating that there is no difference in ENU resistance. Mutation discovery by high-throughput dideoxy resequencing of genomic targets in outcrossed progeny of the mutagenized fish did also not reveal any differences in germ line mutation frequency. These results may indicate that the maximum mutation load for zebrafish has been reached with the currently used, highly optimized ENU mutagenesis protocol. Alternatively, the MMR system in the zebrafish germ line may be saturated very rapidly, thereby having a limited effect on high-dose ENU mutagenesis.

Published
2008
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50. Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors.

Author

Feitsma H, Kuiper RV, Korving J, Nijman IJ, and Cuppen E

Subjects
Abdominal Neoplasms genetics, Amino Acid Sequence, Animals, Animals, Genetically Modified, Base Sequence, Brain Neoplasms genetics, DNA Mutational Analysis, DNA-Binding Proteins genetics, Eye Neoplasms genetics, Female, Hemangiosarcoma genetics, Male, Microsatellite Instability, MutS Homolog 2 Protein genetics, Mutation physiology, Nerve Sheath Neoplasms genetics, DNA Mismatch Repair, DNA Repair Enzymes genetics, Neoplasms genetics, Neurofibromatoses genetics, Zebrafish genetics
Abstract

Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. In contrast, the rare cases with biallelic MMR mutations are juvenile patients with brain tumors, skin neurofibromas, and café-au-lait spots, resembling the neurofibromatosis syndrome. Many of them also display lymphomas and leukemias, which phenotypically resembles the frequent lymphoma development in mouse MMR knockouts. Here, we describe the identification and characterization of novel knockout mutants of the three major MMR genes, mlh1, msh2, and msh6, in zebrafish and show that they develop tumors at low frequencies. Predominantly, neurofibromas/malignant peripheral nerve sheath tumors were observed; however, a range of other tumor types was also observed. Our findings indicate that zebrafish mimic distinct features of the human disease and are complementary to mouse models.

Published
2008
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