Peter Van Der Spek | ErasmusMC Rotterdam (original) (raw)

Papers by Peter Van Der Spek

Molecular and Cellular Biology, 2006

Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced pho... more Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion-and cell-type-specific manner.

Nature Genetics, 2004

DNA repair-deficient trichothiodystrophy (TTD) results from mutations in the XPD and XPB subunits... more DNA repair-deficient trichothiodystrophy (TTD) results from mutations in the XPD and XPB subunits of the DNA repair and transcription factor TFIIH. In a third form of DNA repair-deficient TTD, called group A, none of the nine subunits encoding TFIIH carried mutations; instead, the steady-state level of the entire complex was severely reduced 1 . A new, tenth TFIIH subunit (TFB5) was recently identified in yeast 2 . Here, we describe the identification of the human TFB5 ortholog and its association with human TFIIH. Microinjection of cDNA encoding TFB5 (GTF2H5, also called TTDA) corrected the

PLoS ONE, 2014

Background: In this study we set out to investigate the clinically observed relationship between ... more Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.

Journal of Neuropathology & Experimental Neurology, 2013

The identification of differences in vascular architecture and utilization of angiogenic pathways... more The identification of differences in vascular architecture and utilization of angiogenic pathways is a first step for identifying specific targets for tailored antiangiogenic therapies of brain tumor patients. Here, we compared the proliferating vasculature of 2 glioma subtypes with entirely different biologic behaviors and molecular background at the immunophenotype and gene expression levels. Proliferating vessels in 13 pilocytic astrocytomas and 8 glioblastomas were compared for differences in the composition of the vascular walls using confocal microscopy for markers of endothelial cells and pericytes/mural cells. Endothelial, pericytic, and mural cells had normal-appearing arrangements in the vessels in pilocytic astrocytomas, whereas those in glioblastomas appeared to be more disorganized. In addition, differences in expression of angiogenesis-related genes were sought in the tumor specimens using RNA expression arrays. There were 114 out of 2,894 differentially expressed angiogenesis-related genes between these 2 glioma subtypes indicating differences in the utilization of various pathways. These results point to the need for detailed information on mechanisms of neoangiogenesis in tumor subtypes to facilitate the development of specific antiangiogenic strategies.

Blood, 2008

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnor... more T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression-based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.

Ultrasound in Medicine & Biology, 2014

In this study, a new 3-D Virtual Reality (3D VR) technique for examining placental and uterine va... more In this study, a new 3-D Virtual Reality (3D VR) technique for examining placental and uterine vasculature was investigated. The validity of placental bed vascular volume (PBVV) and fetal vascular volume (FVV) measurements was assessed and associations of PBVV and FVV with embryonic volume, crown-rump length, fetal birth weight and maternal parity were investigated. One hundred thirty-two patients were included in this study, and measurements were performed in 100 patients. Using V-Scope software, 100 3-D Power Doppler data sets of 100 pregnancies at 12 wk of gestation were analyzed with 3D VR in the I-Space Virtual Reality system. Volume measurements were performed with semi-automatic, pre-defined parameters. The inter-observer and intra-observer agreement was excellent with all intra-class correlation coefficients >0.93. PBVVs of multiparous women were significantly larger than the PBVVs of primiparous women (p = 0.008). In this study, no other associations were found. In conclusion, V-Scope offers a reproducible method for measuring PBVV and FVV at 12 wk of gestation, although we are unsure whether the volume measured represents the true volume of the vasculature. Maternal parity influences PBVV.

Meta Gene, 2014

Complete human genome sequencing was used to identify the causative mutation in a family with Pol... more Complete human genome sequencing was used to identify the causative mutation in a family with Pollitt syndrome (MIM #275550), comprising two non-consanguineous parents and their two affected children. The patient's symptoms were reminiscent of the non-photosensitive form of recessively inherited trichothiodystrophy (TTD). A mutation in the TTDN1/C7orf11 gene, a gene that is known to be involved in nonphotosensitive TTD, had been excluded by others by Sanger sequencing. Unexpectedly, we did find a homozygous single-base pair deletion in the coding region of this gene, a mutation that is known to cause nonphotosensitive TTD. The deleterious variant causing a frame shift at amino acid 93 (C326delA) followed the right mode of inheritance in the family and was independently validated using conventional DNA sequencing. We expect this novel DNA sequencing technology to help redefine phenotypic and genomic variation in patients with (mono) genetic disorders in an unprecedented manner.

Faseb Journal, 2007

Bone quality is an important determi- nant of osteoporosis, and proper osteoblast differenti- ati... more Bone quality is an important determi- nant of osteoporosis, and proper osteoblast differenti- ation plays an important role in the control and main- tenance of bone quality. We investigated the impact of activin signaling on human osteoblast differentiation, extracellular matrix formation, and mineralization. Ac- tivins belong to the transforming growth factor- su- perfamily and activin A treatment strongly inhibited mineralization

Genomics, proteomics & bioinformatics, 2003

Microarray analyses of gene expression are widely used, but reports of the same analyses by diffe... more Microarray analyses of gene expression are widely used, but reports of the same analyses by different groups give widely divergent results, and raise questions regarding reproducibility and reliability. We take as an example recent published reports on microarray experiments that were designed to identify retinoic acid responsive genes. These reports show substantial differences in their results. In this article, we review the methodology, results, and potential causes of differences in these applications of microarrays. Finally, we suggest practices to improve the reliability and reproducibility of microarray experiments.

Genes & cancer, 2014

Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers i... more Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-like cell (GSC) cultures. GSC cultures in general have a deletion in phosphatase and tensin homolog (PTEN). Synergy was determined by the Chou Talalay method. The effects on apoptosis and autophagy were studied by measuring caspase-3/7, Bcl-XL, Mcl-1 and LC3BI/II proteins. The relation between treatment response and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, recurrence and gene expression levels of the tumors were studied. Obatoclax synergized with SAHA and LBH589 and sensitized cells to HDACi/RTx. Over 50% of GSC cultures were responsive to Obatoclax with either single agent. Combined with HDACi/RTx treatment, Obatoclax increased caspase-3/7 and inhibited B...

Eurographics Workshop on Parallel Graphics and Visualization, 2002

The analysis of genomic data and integration of diverse biological data sources has become increa... more The analysis of genomic data and integration of diverse biological data sources has become increasingly difficult for researches in the life sciences. This problem is exacerbated by the speed with which new data is gathered through automated technology like DNA microarrays. We developed a virtual reality application for visualizing hierarchical relationships within a gene family and for visualizing networks of

Molecular Endocrinology, 2000

Scientific Development Group (P.J. v.d.S., M.v.D.) N.V. Organon Oss, The Netherlands 5340

Sigplan Notices - SIGPLAN, 2005

This article presents an implementation of an error repair algoritm for the JavaCC parser generat... more This article presents an implementation of an error repair algoritm for the JavaCC parser generator. Three different approaches, the Burke-Fisher error repair, follow-set error repair and panic mode, have been implemented. These algorithms have been altered and combined in order to get improved results. Using this adapted implementation of JavaCC an improved syntax error recovery mechanism is available.

Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (AL... more Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (ALL). To get more insight in signal transduction pathways involved in glucocorticoid-induced apoptosis, Affymetrix U133A GeneChips were used to identify transcriptionally regulated genes upon 3 and 8 hours of prednisolone exposure in leukemic cells of 13 children as compared to non-exposed cells. Following 3 hours of exposure no significant changes in gene expression could be identified. Following 8 hours of exposure, 51 genes were differentially expressed (p < 0.0005 and false discovery rate < 10%) with 39 genes being upregulated (median 2.4-fold) and 12 genes downregulated (median 1.7-fold). Twentyone of those genes have not been identified before to be transcriptionally regulated by prednisolone. Two of the three most highly upregulated genes were tumor suppressor genes, i.e. thioredoxin interacting protein (TXNIP, 3.7-fold) and zinc finger and BTB domain containing 16 (ZBTB16,. About 50% of the differentially expressed genes were functionally categorized in three major routes, namely MAPK pathways (9 genes), NF-κB signaling (11 genes) and carbohydrate metabolism (5 genes).

Ultrasound in Obstetrics and Gynecology, 2006

Objective: This study examines the role of virtual reality in the visualization of 3D data volume... more Objective: This study examines the role of virtual reality in the visualization of 3D data volume sets of ambiguous genitalia as acquired by 3D ultrasound. Methods: In 2005 in three patients referred to our department for prenatal ultrasound assessment ambiguous genitalia were diagnosed. Postpartum diagnosis was one case of Russell-Silver syndrome, one case of an XY-female with normal labia majora and an enlarged clitoris and a case with an unusual type of cloacal malformation with an enlarged clitoris, prominent preputium and single urogenital sinus. Prenatally, patients were examined by 2D and 3D ultrasound and subsequently the images obtained at 3D ultrasound were visualized in the Barco I-Space virtual reality system. Results: In these cases, prenatal diagnosis was impossible with 2D ultrasound. 3D ultrasound provided an impression of ambiguity, however this was incorrect in two cases. In the I-Space, a better impression of genital ambiguity was established. Particularly the bi-ocular depth perception provided by the I-space was useful when faced with the task of differentiating a micropenis from an enlarged clitoris.

Ultrasound in Obstetrics and Gynecology, 2006

Objective: Three-dimensional (3D) ultrasound imaging has greatly improved evaluation of organ cir... more Objective: Three-dimensional (3D) ultrasound imaging has greatly improved evaluation of organ circulation and might contribute new information on maternal and fetal blood supply. The aim of this study was to evaluate the relationship between 3D flow index (FI) and flow velocity in a human vessel and in a flow phantom. Study Design: A 1 cm long strip of the uterine artery was recorded in 3D power Doppler (3D-PD) mode in a cross-sectional study of 170 normal singleton pregnancies between 26 and 42 weeks of gestation. A fixed ultrasound system installation was used during the examination. Vessel volume and FI were calculated by the VOCALTM software integrated in the ultrasound unit.

Ultrasound in Obstetrics and Gynecology, 2009

for a single observer, repeated measurements of placental 3D power Doppler data produce similar a... more for a single observer, repeated measurements of placental 3D power Doppler data produce similar and reliable results.

Ultrasound in Obstetrics and Gynecology, 2009

Retrospective case note analysis of ultrasound and MRI diagnosed morbidly adherent placenta praev... more Retrospective case note analysis of ultrasound and MRI diagnosed morbidly adherent placenta praevias were obtained. In the first case, an elective Cesarean section was done for major degree placenta praevia, antenatal diagnosis of morbidly adherent placenta praevia was not made. Patient had a Cesarean hysterectomy, ureteric stenting and repair of the urinary bladder. All other cases had antenatal diagnoses of morbidly adherent placenta praevias made. Colour Doppler ultrasound scan had a 100% sensitivity. In five out of six cases MRI confirmed morbidly adherent placenta praevia giving a sensitivity of 83%. Three out of seven cases (3/7) have had Cesarean hysterectomies. In four out of seven cases, uterus was preserved. Surgical haemostatic procedures undertaken include; interventional radiological procedures, bilateral internal iliac artery occlusion and B-lynch suture. Complications of internal iliac artery occlusion includes one patient suffering from popliteal arterial occlusion and subsequent vascular surgery. Conclusion: Six out of seven cases reported were antenatally diagnosed as having morbidly adherent placenta praevias by colour Doppler ultrasound and MRI. Detailed management and care plans were outlined in each case and patients and their families were briefed about the care pathways. These six cases will highlight the necessity of multidisciplinary involvement with high quality diagnostic modalities by colour Doppler ultrasound and MRI. This will have an impact on reduced maternal mortality and morbidity in this very complex and challenging clinical situation in Obstetric surgery.

Ultrasound in Obstetrics and Gynecology, 2009

for a single observer, repeated measurements of placental 3D power Doppler data produce similar a... more for a single observer, repeated measurements of placental 3D power Doppler data produce similar and reliable results.

Ultrasound in Obstetrics and Gynecology, 2008

Methods In 2005, fetal ambiguous genitalia were diagnosed in four patients referred to our depart... more Methods In 2005, fetal ambiguous genitalia were diagnosed in four patients referred to our department for prenatal ultrasound assessment. The patients were examined by two-dimensional (2D) and 3D ultrasound and, subsequently, the volumes obtained on 3D ultrasound were visualized in the BARCO I-Space virtual reality system. This system projects stereoscopic images on three walls and the floor of a small 'room', allowing several viewers to see a 3D 'hologram' of the data being visualized. The results of 2D and 3D ultrasound examination and the virtual reality images of the I-Space were compared with diagnoses made postpartum.

Molecular and Cellular Biology, 2006

Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced pho... more Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion-and cell-type-specific manner.

Nature Genetics, 2004

DNA repair-deficient trichothiodystrophy (TTD) results from mutations in the XPD and XPB subunits... more DNA repair-deficient trichothiodystrophy (TTD) results from mutations in the XPD and XPB subunits of the DNA repair and transcription factor TFIIH. In a third form of DNA repair-deficient TTD, called group A, none of the nine subunits encoding TFIIH carried mutations; instead, the steady-state level of the entire complex was severely reduced 1 . A new, tenth TFIIH subunit (TFB5) was recently identified in yeast 2 . Here, we describe the identification of the human TFB5 ortholog and its association with human TFIIH. Microinjection of cDNA encoding TFB5 (GTF2H5, also called TTDA) corrected the

PLoS ONE, 2014

Background: In this study we set out to investigate the clinically observed relationship between ... more Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.

Journal of Neuropathology & Experimental Neurology, 2013

The identification of differences in vascular architecture and utilization of angiogenic pathways... more The identification of differences in vascular architecture and utilization of angiogenic pathways is a first step for identifying specific targets for tailored antiangiogenic therapies of brain tumor patients. Here, we compared the proliferating vasculature of 2 glioma subtypes with entirely different biologic behaviors and molecular background at the immunophenotype and gene expression levels. Proliferating vessels in 13 pilocytic astrocytomas and 8 glioblastomas were compared for differences in the composition of the vascular walls using confocal microscopy for markers of endothelial cells and pericytes/mural cells. Endothelial, pericytic, and mural cells had normal-appearing arrangements in the vessels in pilocytic astrocytomas, whereas those in glioblastomas appeared to be more disorganized. In addition, differences in expression of angiogenesis-related genes were sought in the tumor specimens using RNA expression arrays. There were 114 out of 2,894 differentially expressed angiogenesis-related genes between these 2 glioma subtypes indicating differences in the utilization of various pathways. These results point to the need for detailed information on mechanisms of neoangiogenesis in tumor subtypes to facilitate the development of specific antiangiogenic strategies.

Blood, 2008

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnor... more T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression-based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.

Ultrasound in Medicine & Biology, 2014

In this study, a new 3-D Virtual Reality (3D VR) technique for examining placental and uterine va... more In this study, a new 3-D Virtual Reality (3D VR) technique for examining placental and uterine vasculature was investigated. The validity of placental bed vascular volume (PBVV) and fetal vascular volume (FVV) measurements was assessed and associations of PBVV and FVV with embryonic volume, crown-rump length, fetal birth weight and maternal parity were investigated. One hundred thirty-two patients were included in this study, and measurements were performed in 100 patients. Using V-Scope software, 100 3-D Power Doppler data sets of 100 pregnancies at 12 wk of gestation were analyzed with 3D VR in the I-Space Virtual Reality system. Volume measurements were performed with semi-automatic, pre-defined parameters. The inter-observer and intra-observer agreement was excellent with all intra-class correlation coefficients &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.93. PBVVs of multiparous women were significantly larger than the PBVVs of primiparous women (p = 0.008). In this study, no other associations were found. In conclusion, V-Scope offers a reproducible method for measuring PBVV and FVV at 12 wk of gestation, although we are unsure whether the volume measured represents the true volume of the vasculature. Maternal parity influences PBVV.

Meta Gene, 2014

Complete human genome sequencing was used to identify the causative mutation in a family with Pol... more Complete human genome sequencing was used to identify the causative mutation in a family with Pollitt syndrome (MIM #275550), comprising two non-consanguineous parents and their two affected children. The patient's symptoms were reminiscent of the non-photosensitive form of recessively inherited trichothiodystrophy (TTD). A mutation in the TTDN1/C7orf11 gene, a gene that is known to be involved in nonphotosensitive TTD, had been excluded by others by Sanger sequencing. Unexpectedly, we did find a homozygous single-base pair deletion in the coding region of this gene, a mutation that is known to cause nonphotosensitive TTD. The deleterious variant causing a frame shift at amino acid 93 (C326delA) followed the right mode of inheritance in the family and was independently validated using conventional DNA sequencing. We expect this novel DNA sequencing technology to help redefine phenotypic and genomic variation in patients with (mono) genetic disorders in an unprecedented manner.

Faseb Journal, 2007

Bone quality is an important determi- nant of osteoporosis, and proper osteoblast differenti- ati... more Bone quality is an important determi- nant of osteoporosis, and proper osteoblast differenti- ation plays an important role in the control and main- tenance of bone quality. We investigated the impact of activin signaling on human osteoblast differentiation, extracellular matrix formation, and mineralization. Ac- tivins belong to the transforming growth factor- su- perfamily and activin A treatment strongly inhibited mineralization

Genomics, proteomics & bioinformatics, 2003

Microarray analyses of gene expression are widely used, but reports of the same analyses by diffe... more Microarray analyses of gene expression are widely used, but reports of the same analyses by different groups give widely divergent results, and raise questions regarding reproducibility and reliability. We take as an example recent published reports on microarray experiments that were designed to identify retinoic acid responsive genes. These reports show substantial differences in their results. In this article, we review the methodology, results, and potential causes of differences in these applications of microarrays. Finally, we suggest practices to improve the reliability and reproducibility of microarray experiments.

Genes & cancer, 2014

Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers i... more Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-like cell (GSC) cultures. GSC cultures in general have a deletion in phosphatase and tensin homolog (PTEN). Synergy was determined by the Chou Talalay method. The effects on apoptosis and autophagy were studied by measuring caspase-3/7, Bcl-XL, Mcl-1 and LC3BI/II proteins. The relation between treatment response and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, recurrence and gene expression levels of the tumors were studied. Obatoclax synergized with SAHA and LBH589 and sensitized cells to HDACi/RTx. Over 50% of GSC cultures were responsive to Obatoclax with either single agent. Combined with HDACi/RTx treatment, Obatoclax increased caspase-3/7 and inhibited B...

Eurographics Workshop on Parallel Graphics and Visualization, 2002

The analysis of genomic data and integration of diverse biological data sources has become increa... more The analysis of genomic data and integration of diverse biological data sources has become increasingly difficult for researches in the life sciences. This problem is exacerbated by the speed with which new data is gathered through automated technology like DNA microarrays. We developed a virtual reality application for visualizing hierarchical relationships within a gene family and for visualizing networks of

Molecular Endocrinology, 2000

Scientific Development Group (P.J. v.d.S., M.v.D.) N.V. Organon Oss, The Netherlands 5340

Sigplan Notices - SIGPLAN, 2005

This article presents an implementation of an error repair algoritm for the JavaCC parser generat... more This article presents an implementation of an error repair algoritm for the JavaCC parser generator. Three different approaches, the Burke-Fisher error repair, follow-set error repair and panic mode, have been implemented. These algorithms have been altered and combined in order to get improved results. Using this adapted implementation of JavaCC an improved syntax error recovery mechanism is available.

Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (AL... more Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (ALL). To get more insight in signal transduction pathways involved in glucocorticoid-induced apoptosis, Affymetrix U133A GeneChips were used to identify transcriptionally regulated genes upon 3 and 8 hours of prednisolone exposure in leukemic cells of 13 children as compared to non-exposed cells. Following 3 hours of exposure no significant changes in gene expression could be identified. Following 8 hours of exposure, 51 genes were differentially expressed (p < 0.0005 and false discovery rate < 10%) with 39 genes being upregulated (median 2.4-fold) and 12 genes downregulated (median 1.7-fold). Twentyone of those genes have not been identified before to be transcriptionally regulated by prednisolone. Two of the three most highly upregulated genes were tumor suppressor genes, i.e. thioredoxin interacting protein (TXNIP, 3.7-fold) and zinc finger and BTB domain containing 16 (ZBTB16,. About 50% of the differentially expressed genes were functionally categorized in three major routes, namely MAPK pathways (9 genes), NF-κB signaling (11 genes) and carbohydrate metabolism (5 genes).

Ultrasound in Obstetrics and Gynecology, 2006

Objective: This study examines the role of virtual reality in the visualization of 3D data volume... more Objective: This study examines the role of virtual reality in the visualization of 3D data volume sets of ambiguous genitalia as acquired by 3D ultrasound. Methods: In 2005 in three patients referred to our department for prenatal ultrasound assessment ambiguous genitalia were diagnosed. Postpartum diagnosis was one case of Russell-Silver syndrome, one case of an XY-female with normal labia majora and an enlarged clitoris and a case with an unusual type of cloacal malformation with an enlarged clitoris, prominent preputium and single urogenital sinus. Prenatally, patients were examined by 2D and 3D ultrasound and subsequently the images obtained at 3D ultrasound were visualized in the Barco I-Space virtual reality system. Results: In these cases, prenatal diagnosis was impossible with 2D ultrasound. 3D ultrasound provided an impression of ambiguity, however this was incorrect in two cases. In the I-Space, a better impression of genital ambiguity was established. Particularly the bi-ocular depth perception provided by the I-space was useful when faced with the task of differentiating a micropenis from an enlarged clitoris.

Ultrasound in Obstetrics and Gynecology, 2006

Objective: Three-dimensional (3D) ultrasound imaging has greatly improved evaluation of organ cir... more Objective: Three-dimensional (3D) ultrasound imaging has greatly improved evaluation of organ circulation and might contribute new information on maternal and fetal blood supply. The aim of this study was to evaluate the relationship between 3D flow index (FI) and flow velocity in a human vessel and in a flow phantom. Study Design: A 1 cm long strip of the uterine artery was recorded in 3D power Doppler (3D-PD) mode in a cross-sectional study of 170 normal singleton pregnancies between 26 and 42 weeks of gestation. A fixed ultrasound system installation was used during the examination. Vessel volume and FI were calculated by the VOCALTM software integrated in the ultrasound unit.

Ultrasound in Obstetrics and Gynecology, 2009

for a single observer, repeated measurements of placental 3D power Doppler data produce similar a... more for a single observer, repeated measurements of placental 3D power Doppler data produce similar and reliable results.

Ultrasound in Obstetrics and Gynecology, 2009

Retrospective case note analysis of ultrasound and MRI diagnosed morbidly adherent placenta praev... more Retrospective case note analysis of ultrasound and MRI diagnosed morbidly adherent placenta praevias were obtained. In the first case, an elective Cesarean section was done for major degree placenta praevia, antenatal diagnosis of morbidly adherent placenta praevia was not made. Patient had a Cesarean hysterectomy, ureteric stenting and repair of the urinary bladder. All other cases had antenatal diagnoses of morbidly adherent placenta praevias made. Colour Doppler ultrasound scan had a 100% sensitivity. In five out of six cases MRI confirmed morbidly adherent placenta praevia giving a sensitivity of 83%. Three out of seven cases (3/7) have had Cesarean hysterectomies. In four out of seven cases, uterus was preserved. Surgical haemostatic procedures undertaken include; interventional radiological procedures, bilateral internal iliac artery occlusion and B-lynch suture. Complications of internal iliac artery occlusion includes one patient suffering from popliteal arterial occlusion and subsequent vascular surgery. Conclusion: Six out of seven cases reported were antenatally diagnosed as having morbidly adherent placenta praevias by colour Doppler ultrasound and MRI. Detailed management and care plans were outlined in each case and patients and their families were briefed about the care pathways. These six cases will highlight the necessity of multidisciplinary involvement with high quality diagnostic modalities by colour Doppler ultrasound and MRI. This will have an impact on reduced maternal mortality and morbidity in this very complex and challenging clinical situation in Obstetric surgery.

Ultrasound in Obstetrics and Gynecology, 2009

for a single observer, repeated measurements of placental 3D power Doppler data produce similar a... more for a single observer, repeated measurements of placental 3D power Doppler data produce similar and reliable results.

Ultrasound in Obstetrics and Gynecology, 2008

Methods In 2005, fetal ambiguous genitalia were diagnosed in four patients referred to our depart... more Methods In 2005, fetal ambiguous genitalia were diagnosed in four patients referred to our department for prenatal ultrasound assessment. The patients were examined by two-dimensional (2D) and 3D ultrasound and, subsequently, the volumes obtained on 3D ultrasound were visualized in the BARCO I-Space virtual reality system. This system projects stereoscopic images on three walls and the floor of a small 'room', allowing several viewers to see a 3D 'hologram' of the data being visualized. The results of 2D and 3D ultrasound examination and the virtual reality images of the I-Space were compared with diagnoses made postpartum.