Oliver Steinbach - Academia.edu (original) (raw)
Papers by Oliver Steinbach
Nuclear Medicine and Biology, 2015
The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ... more The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood-brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we developed a PET-CT imaging method for non-invasive, quantitative analysis of the effect of ABCB1 and ABCG2 on brain penetration of the anti-cancer drug gefitinib, and demonstrated the applicability of this method for identification and quantification of potential modulators of ABCB1 and ABCB2 using the dual inhibitor elacridar. In vitro cellular accumulation studies with [(14)C]-gefitinib were conducted in LLC-PK1, MDCKII, and the corresponding ABCB1/Abcb1a and ABCG2/Abcg2 overexpressing cell lines. Subsequently, in vivo brain penetration of [(18)F]-gefitinib was quantified by PET-CT imaging studies in wild-type, Abcg2(-/-), Abcb1a/1b(-/-), and Abcb1a/1b;Abcg2(-/-) mice. In vitro studies showed that [(14)C]-gefitinib is a substrate of the human ABCB1 and ABCG2 transporters. After i.v. administration of [(18)F]-gefitinib (1mg/kg), PET-CT imaging showed 2.3-fold increased brain levels of [(18)F]-gefitinib in Abcb1a/1b;Abcg2(-/-) mice, compared to wild-type. Levels in single knockout animals were not different from wild-type, showing that Abcb1a/1b and Abcg2 together limit access of [(18)F]-gefitinib to the brain. Furthermore, enhanced brain accumulation of [(18)F]-gefitinib after administration of the ABCB1 and ABCG2 inhibitor elacridar (10 mg/kg) could be quantified with PET-CT imaging. PET-CT imaging with [(18)F]-gefitinib is a powerful tool to non-invasively assess potential ABCB1- and ABCG2-mediated drug-drug interactions (DDIs) in vivo. This minimally-invasive, [(18)F]-based PET-CT imaging method shows the interplay of ABCB1 and ABCG2 at the BBB in vivo. The method may be applied in the future to assess ABCB1 and ABCG2 activity at the BBB in humans, and for personalized treatment with drugs that are substrates of ABCB1 and/or ABCG2.
Atherosclerosis Supplements, 2011
The aim of this study was to investigate whether non-alcoholic fatty liver disease (NAFLD) could ... more The aim of this study was to investigate whether non-alcoholic fatty liver disease (NAFLD) could be quantified in a translational mouse model for the metabolic syndrome by repeated Magnetic Resonance Spectroscopy (MRS) measurements using a clinical 3T MR-scanner and to evaluate the effect of anti-diabetic and hypolipidemic drugs. Male APOE*3Leiden.CETP mice were fed a High Fat Diet (HFD) for 3−4 months to induce obesity, insulin resistance, hyperlipidemia and hepatosteatosis before they were treated with either vehicle (control), rosiglitazone (10 mg/kg/d) or ezetimibe (3 mg/kg/d). Mice on chow were included as healthy controls. Effects on hepatosteatosis were assessed by MRS before and after 4 weeks of treatment. The in vivo MRS data was compared to ex vivo liver analyses by histology, HPTLC, Magic Angle Spinning-NMR and near infra red (NIR) based diffuse optical spectroscopy. Dietary treatment resulted in hepatosteatosis with a hepatic fat content of 14.3±4.9% in the control group (vs 2.7±0.7% in chow), which increased to 25.8±10.6% (P < 0.05) during the study. Rosiglitazone reduced the hepatic fat content by 76% (P < 0.01) as compared to control, and even reduced hepatic fat in time by 56% (P < 0.05). Ezetimibe only prevented disease progression. Data obtained in vivo by MRS highly correlated with the ex vivo analyses histology, MAS-NMR, HPTLC and NIR spectroscopy (P < 0.001). We showed that hepatic fat can accurately be measured in vivo using a clinical 3T MR scanner in a highly translational setting to investigate the effects of new drugs on risk factors of the metabolic syndrome and its complication NAFLD.
Nature, Jan 25, 1997
In Xenopus, cells from the animal hemisphere are competent to form mesodermal tissues from the mo... more In Xenopus, cells from the animal hemisphere are competent to form mesodermal tissues from the morula through to the blastula stage. Loss of mesodermal competence at early gastrula is programmed cell-autonomously, and occurs even in single cells at the appropriate stage. To determine the mechanism by which this occurs, we have been investigating a concomitant, global change in expression of H1 linker histone subtypes. H1 histones are usually considered to be general repressors of transcription, but in Xenopus they are increasingly thought to have selective functions in transcriptional regulation. Xenopus eggs and embryos at stages before the midblastula transition are deficient in histone H1 protein, but contain an oocyte-specific variant called histone B4 or H1M. After the midblastula transition, histone B4 is progressively substituted by three somatic histone H1 variants, and replacement is complete by early neurula. Here we report that accumulation of somatic H1 protein is rate l...
Application to Drug Discovery and Challenges to Pharmaceutical Development, 2010
PURPOSE Early and definite diagnosis of Alzheimer’s disease (AD) is critical, as current treatmen... more PURPOSE Early and definite diagnosis of Alzheimer’s disease (AD) is critical, as current treatment options under consideration are not free of safety concerns. Currently, a combination of clinical, neurological and neuro-psychological testing and imaging is used in diagnosis. Visual evaluation of FDG PET brain images is challenging. Hence, the Society of Nuclear Medicine (SNM) recommends augmentation by (semi-)automatic quantification approaches. This study evaluated the impact on diagnosis of AD in FDG-PET/CT when applying voxel-based statistical testing to 3D volumes, which have been stereotactially normalized using b-splines. METHOD AND MATERIALS N = 94 subjects (50% AD and 50% normal) were selected from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database. Two readers with 1 and 6 years of clinical experience classified FDG PET images, first by visual assessment of original images, then by rating stereotactically normalized 3D volumes, on which statistically significa...
Therapeutic Delivery, 2011
The present industry update covers the period 2-28 February 2013, with information sourced from c... more The present industry update covers the period 2-28 February 2013, with information sourced from company press releases, regulatory and patent agencies, as well as from scientific literature. With the US presidential inauguration in January, the inevitable &amp;#39;fiscal cliff&amp;#39; and with the healthcare reform taking shape, there are many challenges ahead for the world&amp;#39;s largest healthcare market. Healthcare providers are preparing for the &amp;#39;accountable care organizations&amp;#39; paradigm shift and it has been reported that the pharmaceutical industry is low in public perception; only &amp;#39;for-profit&amp;#39; health insurers rank lower according to a survey recently published. Although in 2012 one could still observe a decline in the overall number of drug delivery partnering deals announced, there has been a slight recovery, thus, meaning a repeat of the lows of 2011 have not been witnessed. The experts expect a reversed trend in 2013 as larger companies seek to refill pipelines with new candidates and drug-delivery solutions. There is a lot of emphasis on altered oral delivery profiles to provide patient compliance. This is indicated by the recent licensing deals, such as that between Radius Health Inc. and 3M, TissueGen and Biomedical Structures, and new financing rounds of companies, such as SKL, Catalent and BioActiva. Injectable technology, including needle-free delivery, continues to be prevalent in deals, such as those between Clearside and Kala until compelling alternatives to the delivery of biologicals are available. Alternative routes of administration, such as nasal, buccal (Kala), sublingual (Stallergenes) see growing interest; however, bioavailability and reproducible dosing will continue to be a challenge in the foreseeable future.
The EMBO Journal, 1999
The Notch signaling cascade is involved in many developmental decisions, a paradigm of which has ... more The Notch signaling cascade is involved in many developmental decisions, a paradigm of which has been the selection between epidermal and neural cell fates in both invertebrates and vertebrates. Notch has also been implicated as a regulator of myogenesis, although its precise function there has remained controversial. Here we show that the muscle-determining factor MyoD is a direct, positive regulator of the Notch ligand Delta-1 in prospective myoblasts of the pre-involuted mesoderm in Xenopus gastrulae. Injection of a dominant MyoD repressor variant ablates mesodermal Delta-1 expression in vivo. Furthermore, MyoD-dependent Delta-1 induction is sufficient to activate transcription from promoters of E(spl)-related genes in a Notch-dependent manner. These results indicate that a hallmark of neural cell fate determination, i.e. the feedback loop between differentiation promoting basic helix-loop-helix proteins and the Notch regulatory circuitry, is conserved in myogenesis, supporting a direct involvement of Notch in muscle determination.
Magnetic Resonance in Medicine, 2011
Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in ... more Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH-dependent. Thus, a ratiometric method for pH assessment has been set-up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5-7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH-changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition.
Journal of Magnetic Resonance Imaging, 2014
Magentic Resonance/positron emission tomography (PET) has been introduced recently for imaging of... more Magentic Resonance/positron emission tomography (PET) has been introduced recently for imaging of clinical patients. This hybrid imaging technology combines the inherent strengths of MRI with its high soft-tissue contrast and biological sequences with the inherent strengths of PET, enabling imaging of metabolism with a high sensitivity. In this article, we describe the initial experience of MR/PET in a clinical cancer center along with a review of the literature. For establishing MR/PET in a clinical setting, technical challenges, such as attenuation correction and organizational challenges, such as workflow and reimbursement, have to be overcome. The most promising initial results of MR/PET have been achieved in anatomical areas where high soft-tissue and contrast resolution is of benefit. Head and neck cancer and pelvic imaging are potential applications of this hybrid imaging technology. In the pediatric population, MR/PET can decrease the lifetime radiation dose. MR/PET protocols tailored to different types of malignancies need to be developed. After the initial exploration phase, large multicenter trials are warranted to determine clinical indications for this exciting hybrid imaging technology and thereby opening new horizons in molecular imaging.
Developmental Biology, 1998
In Xenopus, the activation of the myogenic determination factors MyoD and Myf-5 in the muscle-for... more In Xenopus, the activation of the myogenic determination factors MyoD and Myf-5 in the muscle-forming region of the embryo occurs in response to mesoderm-inducing factors (MIFs). Different members of the FGF, TGF-beta, and Wnt protein families have been implicated in this process, but how MIFs induce the myogenic regulators is not known. For MyoD, the induction process may serve to locally stabilize a transient burst of ubiquitous transcription at the midblastula transition, possibly by triggering MyoD's autocatalytic loop. Here we have sought to distinguish separate activating functions during MyoD induction by analyzing when MyoD responds to different MIF signaling or to MyoD autoactivation. We show that MyoD induction depends on the developmental age of the induced cells, rather than on the type or time point of inducer application. At the permissive time, de novo MyoD induction by Activin requires less than 90 min, arguing for an immediate response, rather than a series of inductive events. MyoD autoactivation is direct, but subject to the same temporal restriction as MyoD induction by MIF signaling. Further evidence implicating MyoD autocatalysis as an essential component of the induction process comes from the observation that both autocatalysis and induction of MyoD are selectively repressed by a dominant-negative MyoD mutant. In summary, our observations let us conclude that MyoD's expression domain in the embryo results from an interplay of timed changes in cellular competence, pleiotropic signaling pathways, and autocatalysis.
Current Biology, 1998
One molecule of a linker histone such as histone H1 is incorporated into every metazoan nucleosom... more One molecule of a linker histone such as histone H1 is incorporated into every metazoan nucleosome . Histone H1 has three distinct structural domains: the positively charged amino-terminal and carboxy-terminal tails are separated by a globular domain that is similar to the winged-helix motif found in sequence-specific DNA-binding proteins [2]. The globular domain interacts with DNA immediately contiguous to that wrapped around the core histones [3,4], whereas the tail domains are important for the compaction of nucleosomal arrays . Experiments in vivo indicate that histone H1 does not function as a global transcriptional repressor, but instead has more specific regulatory roles [6-9]. In Xenopus, maternal stores of the B4 linker histone that are assembled into chromatin during the early cleavage divisions are replaced by somatic histone H1 during gastrulation [10]. This transition in chromatin composition causes the repression of genes encoding oocyte-type 5S rRNAs, and restricts the competence of ectodermal cells to differentiate into mesoderm . Here, we demonstrate that the globular domain of histone H1 is sufficient for directing gene-specific transcriptional repression and for restricting the mesodermal competence of embryonic ectoderm. We discuss our results in the context of specific structural roles for this domain in the nucleosome.
Biological Chemistry, 2000
Acetylation of nucleosome core histones, which is positively correlated with transcriptional acti... more Acetylation of nucleosome core histones, which is positively correlated with transcriptional activity, is developmentally regulated in Xenopus. Here we have used the specific histone deacetylase (HDAC)-inhibitor trichostatin A (TSA) to induce precocious histone hyperacetylation in the early frog embryo in order to investigate the potential role of the endogenous changes in chromatin acetylation for the temporally programmed induction of skeletal myogenesis. We show that TSA-treatment (i) selectively blocked the transcriptional induction of the myoD gene, and (ii) severely reduced subsequent muscle differentiation. Both phenotypes required TSA application before gastrulation. This indicates that HDAC activity is required early for the formation of the frog embryonic musculature, apparently for the induction of the MyoD-dependent muscle cell lineage.
European Journal of Radiology, 2009
The integration of therapeutic interventions with diagnostic imaging has been recognized as one o... more The integration of therapeutic interventions with diagnostic imaging has been recognized as one of the next technological developments that will have a major impact on medical treatments. Important advances in this field are based on a combination of progress in guiding and monitoring ultrasound energy, novel drug classes becoming available, the development of smart delivery vehicles, and more in depth understanding of the mechanisms of the cellular and molecular basis of diseases. Recent research demonstrates that both pressure sensitive and temperature sensitive delivery systems hold promise for local treatment. The use of ultrasound for the delivery of drugs has been demonstrated in particular the field of cardiology and oncology for a variety of therapeutics ranging from small drug molecules to biologics and nucleic acids.
Nuclear Medicine and Biology, 2015
The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ... more The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood-brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we developed a PET-CT imaging method for non-invasive, quantitative analysis of the effect of ABCB1 and ABCG2 on brain penetration of the anti-cancer drug gefitinib, and demonstrated the applicability of this method for identification and quantification of potential modulators of ABCB1 and ABCB2 using the dual inhibitor elacridar. In vitro cellular accumulation studies with [(14)C]-gefitinib were conducted in LLC-PK1, MDCKII, and the corresponding ABCB1/Abcb1a and ABCG2/Abcg2 overexpressing cell lines. Subsequently, in vivo brain penetration of [(18)F]-gefitinib was quantified by PET-CT imaging studies in wild-type, Abcg2(-/-), Abcb1a/1b(-/-), and Abcb1a/1b;Abcg2(-/-) mice. In vitro studies showed that [(14)C]-gefitinib is a substrate of the human ABCB1 and ABCG2 transporters. After i.v. administration of [(18)F]-gefitinib (1mg/kg), PET-CT imaging showed 2.3-fold increased brain levels of [(18)F]-gefitinib in Abcb1a/1b;Abcg2(-/-) mice, compared to wild-type. Levels in single knockout animals were not different from wild-type, showing that Abcb1a/1b and Abcg2 together limit access of [(18)F]-gefitinib to the brain. Furthermore, enhanced brain accumulation of [(18)F]-gefitinib after administration of the ABCB1 and ABCG2 inhibitor elacridar (10 mg/kg) could be quantified with PET-CT imaging. PET-CT imaging with [(18)F]-gefitinib is a powerful tool to non-invasively assess potential ABCB1- and ABCG2-mediated drug-drug interactions (DDIs) in vivo. This minimally-invasive, [(18)F]-based PET-CT imaging method shows the interplay of ABCB1 and ABCG2 at the BBB in vivo. The method may be applied in the future to assess ABCB1 and ABCG2 activity at the BBB in humans, and for personalized treatment with drugs that are substrates of ABCB1 and/or ABCG2.
Atherosclerosis Supplements, 2011
The aim of this study was to investigate whether non-alcoholic fatty liver disease (NAFLD) could ... more The aim of this study was to investigate whether non-alcoholic fatty liver disease (NAFLD) could be quantified in a translational mouse model for the metabolic syndrome by repeated Magnetic Resonance Spectroscopy (MRS) measurements using a clinical 3T MR-scanner and to evaluate the effect of anti-diabetic and hypolipidemic drugs. Male APOE*3Leiden.CETP mice were fed a High Fat Diet (HFD) for 3−4 months to induce obesity, insulin resistance, hyperlipidemia and hepatosteatosis before they were treated with either vehicle (control), rosiglitazone (10 mg/kg/d) or ezetimibe (3 mg/kg/d). Mice on chow were included as healthy controls. Effects on hepatosteatosis were assessed by MRS before and after 4 weeks of treatment. The in vivo MRS data was compared to ex vivo liver analyses by histology, HPTLC, Magic Angle Spinning-NMR and near infra red (NIR) based diffuse optical spectroscopy. Dietary treatment resulted in hepatosteatosis with a hepatic fat content of 14.3±4.9% in the control group (vs 2.7±0.7% in chow), which increased to 25.8±10.6% (P < 0.05) during the study. Rosiglitazone reduced the hepatic fat content by 76% (P < 0.01) as compared to control, and even reduced hepatic fat in time by 56% (P < 0.05). Ezetimibe only prevented disease progression. Data obtained in vivo by MRS highly correlated with the ex vivo analyses histology, MAS-NMR, HPTLC and NIR spectroscopy (P < 0.001). We showed that hepatic fat can accurately be measured in vivo using a clinical 3T MR scanner in a highly translational setting to investigate the effects of new drugs on risk factors of the metabolic syndrome and its complication NAFLD.
Nature, Jan 25, 1997
In Xenopus, cells from the animal hemisphere are competent to form mesodermal tissues from the mo... more In Xenopus, cells from the animal hemisphere are competent to form mesodermal tissues from the morula through to the blastula stage. Loss of mesodermal competence at early gastrula is programmed cell-autonomously, and occurs even in single cells at the appropriate stage. To determine the mechanism by which this occurs, we have been investigating a concomitant, global change in expression of H1 linker histone subtypes. H1 histones are usually considered to be general repressors of transcription, but in Xenopus they are increasingly thought to have selective functions in transcriptional regulation. Xenopus eggs and embryos at stages before the midblastula transition are deficient in histone H1 protein, but contain an oocyte-specific variant called histone B4 or H1M. After the midblastula transition, histone B4 is progressively substituted by three somatic histone H1 variants, and replacement is complete by early neurula. Here we report that accumulation of somatic H1 protein is rate l...
Application to Drug Discovery and Challenges to Pharmaceutical Development, 2010
PURPOSE Early and definite diagnosis of Alzheimer’s disease (AD) is critical, as current treatmen... more PURPOSE Early and definite diagnosis of Alzheimer’s disease (AD) is critical, as current treatment options under consideration are not free of safety concerns. Currently, a combination of clinical, neurological and neuro-psychological testing and imaging is used in diagnosis. Visual evaluation of FDG PET brain images is challenging. Hence, the Society of Nuclear Medicine (SNM) recommends augmentation by (semi-)automatic quantification approaches. This study evaluated the impact on diagnosis of AD in FDG-PET/CT when applying voxel-based statistical testing to 3D volumes, which have been stereotactially normalized using b-splines. METHOD AND MATERIALS N = 94 subjects (50% AD and 50% normal) were selected from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database. Two readers with 1 and 6 years of clinical experience classified FDG PET images, first by visual assessment of original images, then by rating stereotactically normalized 3D volumes, on which statistically significa...
Therapeutic Delivery, 2011
The present industry update covers the period 2-28 February 2013, with information sourced from c... more The present industry update covers the period 2-28 February 2013, with information sourced from company press releases, regulatory and patent agencies, as well as from scientific literature. With the US presidential inauguration in January, the inevitable &amp;#39;fiscal cliff&amp;#39; and with the healthcare reform taking shape, there are many challenges ahead for the world&amp;#39;s largest healthcare market. Healthcare providers are preparing for the &amp;#39;accountable care organizations&amp;#39; paradigm shift and it has been reported that the pharmaceutical industry is low in public perception; only &amp;#39;for-profit&amp;#39; health insurers rank lower according to a survey recently published. Although in 2012 one could still observe a decline in the overall number of drug delivery partnering deals announced, there has been a slight recovery, thus, meaning a repeat of the lows of 2011 have not been witnessed. The experts expect a reversed trend in 2013 as larger companies seek to refill pipelines with new candidates and drug-delivery solutions. There is a lot of emphasis on altered oral delivery profiles to provide patient compliance. This is indicated by the recent licensing deals, such as that between Radius Health Inc. and 3M, TissueGen and Biomedical Structures, and new financing rounds of companies, such as SKL, Catalent and BioActiva. Injectable technology, including needle-free delivery, continues to be prevalent in deals, such as those between Clearside and Kala until compelling alternatives to the delivery of biologicals are available. Alternative routes of administration, such as nasal, buccal (Kala), sublingual (Stallergenes) see growing interest; however, bioavailability and reproducible dosing will continue to be a challenge in the foreseeable future.
The EMBO Journal, 1999
The Notch signaling cascade is involved in many developmental decisions, a paradigm of which has ... more The Notch signaling cascade is involved in many developmental decisions, a paradigm of which has been the selection between epidermal and neural cell fates in both invertebrates and vertebrates. Notch has also been implicated as a regulator of myogenesis, although its precise function there has remained controversial. Here we show that the muscle-determining factor MyoD is a direct, positive regulator of the Notch ligand Delta-1 in prospective myoblasts of the pre-involuted mesoderm in Xenopus gastrulae. Injection of a dominant MyoD repressor variant ablates mesodermal Delta-1 expression in vivo. Furthermore, MyoD-dependent Delta-1 induction is sufficient to activate transcription from promoters of E(spl)-related genes in a Notch-dependent manner. These results indicate that a hallmark of neural cell fate determination, i.e. the feedback loop between differentiation promoting basic helix-loop-helix proteins and the Notch regulatory circuitry, is conserved in myogenesis, supporting a direct involvement of Notch in muscle determination.
Magnetic Resonance in Medicine, 2011
Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in ... more Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH-dependent. Thus, a ratiometric method for pH assessment has been set-up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5-7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH-changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition.
Journal of Magnetic Resonance Imaging, 2014
Magentic Resonance/positron emission tomography (PET) has been introduced recently for imaging of... more Magentic Resonance/positron emission tomography (PET) has been introduced recently for imaging of clinical patients. This hybrid imaging technology combines the inherent strengths of MRI with its high soft-tissue contrast and biological sequences with the inherent strengths of PET, enabling imaging of metabolism with a high sensitivity. In this article, we describe the initial experience of MR/PET in a clinical cancer center along with a review of the literature. For establishing MR/PET in a clinical setting, technical challenges, such as attenuation correction and organizational challenges, such as workflow and reimbursement, have to be overcome. The most promising initial results of MR/PET have been achieved in anatomical areas where high soft-tissue and contrast resolution is of benefit. Head and neck cancer and pelvic imaging are potential applications of this hybrid imaging technology. In the pediatric population, MR/PET can decrease the lifetime radiation dose. MR/PET protocols tailored to different types of malignancies need to be developed. After the initial exploration phase, large multicenter trials are warranted to determine clinical indications for this exciting hybrid imaging technology and thereby opening new horizons in molecular imaging.
Developmental Biology, 1998
In Xenopus, the activation of the myogenic determination factors MyoD and Myf-5 in the muscle-for... more In Xenopus, the activation of the myogenic determination factors MyoD and Myf-5 in the muscle-forming region of the embryo occurs in response to mesoderm-inducing factors (MIFs). Different members of the FGF, TGF-beta, and Wnt protein families have been implicated in this process, but how MIFs induce the myogenic regulators is not known. For MyoD, the induction process may serve to locally stabilize a transient burst of ubiquitous transcription at the midblastula transition, possibly by triggering MyoD's autocatalytic loop. Here we have sought to distinguish separate activating functions during MyoD induction by analyzing when MyoD responds to different MIF signaling or to MyoD autoactivation. We show that MyoD induction depends on the developmental age of the induced cells, rather than on the type or time point of inducer application. At the permissive time, de novo MyoD induction by Activin requires less than 90 min, arguing for an immediate response, rather than a series of inductive events. MyoD autoactivation is direct, but subject to the same temporal restriction as MyoD induction by MIF signaling. Further evidence implicating MyoD autocatalysis as an essential component of the induction process comes from the observation that both autocatalysis and induction of MyoD are selectively repressed by a dominant-negative MyoD mutant. In summary, our observations let us conclude that MyoD's expression domain in the embryo results from an interplay of timed changes in cellular competence, pleiotropic signaling pathways, and autocatalysis.
Current Biology, 1998
One molecule of a linker histone such as histone H1 is incorporated into every metazoan nucleosom... more One molecule of a linker histone such as histone H1 is incorporated into every metazoan nucleosome . Histone H1 has three distinct structural domains: the positively charged amino-terminal and carboxy-terminal tails are separated by a globular domain that is similar to the winged-helix motif found in sequence-specific DNA-binding proteins [2]. The globular domain interacts with DNA immediately contiguous to that wrapped around the core histones [3,4], whereas the tail domains are important for the compaction of nucleosomal arrays . Experiments in vivo indicate that histone H1 does not function as a global transcriptional repressor, but instead has more specific regulatory roles [6-9]. In Xenopus, maternal stores of the B4 linker histone that are assembled into chromatin during the early cleavage divisions are replaced by somatic histone H1 during gastrulation [10]. This transition in chromatin composition causes the repression of genes encoding oocyte-type 5S rRNAs, and restricts the competence of ectodermal cells to differentiate into mesoderm . Here, we demonstrate that the globular domain of histone H1 is sufficient for directing gene-specific transcriptional repression and for restricting the mesodermal competence of embryonic ectoderm. We discuss our results in the context of specific structural roles for this domain in the nucleosome.
Biological Chemistry, 2000
Acetylation of nucleosome core histones, which is positively correlated with transcriptional acti... more Acetylation of nucleosome core histones, which is positively correlated with transcriptional activity, is developmentally regulated in Xenopus. Here we have used the specific histone deacetylase (HDAC)-inhibitor trichostatin A (TSA) to induce precocious histone hyperacetylation in the early frog embryo in order to investigate the potential role of the endogenous changes in chromatin acetylation for the temporally programmed induction of skeletal myogenesis. We show that TSA-treatment (i) selectively blocked the transcriptional induction of the myoD gene, and (ii) severely reduced subsequent muscle differentiation. Both phenotypes required TSA application before gastrulation. This indicates that HDAC activity is required early for the formation of the frog embryonic musculature, apparently for the induction of the MyoD-dependent muscle cell lineage.
European Journal of Radiology, 2009
The integration of therapeutic interventions with diagnostic imaging has been recognized as one o... more The integration of therapeutic interventions with diagnostic imaging has been recognized as one of the next technological developments that will have a major impact on medical treatments. Important advances in this field are based on a combination of progress in guiding and monitoring ultrasound energy, novel drug classes becoming available, the development of smart delivery vehicles, and more in depth understanding of the mechanisms of the cellular and molecular basis of diseases. Recent research demonstrates that both pressure sensitive and temperature sensitive delivery systems hold promise for local treatment. The use of ultrasound for the delivery of drugs has been demonstrated in particular the field of cardiology and oncology for a variety of therapeutics ranging from small drug molecules to biologics and nucleic acids.