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Dr. Sven Gottschalk

Adresse: Spemannstr. 41
72076 Tübingen
Raum Nummer: 4.B.08
Fax: 07071 601 702

 

Bild von Gottschalk, Sven, Dr.

Sven Gottschalk

Position: Postdoc  Abteilung: Alumni Scheffler

 

MRI probes targeting glutamate receptors in the brain: Antagonist-based approach.

 

Introduction

Receptor targeting is widely used for competitive binding in brain imaging using techniques such as positron emission tomography and optical imaging. It is also an ongoing debate whether antagonist- or agonist-based approaches are more beneficial. However, an application of competitive binding for brain functional magnetic resonance imaging (fMRI) has not yet been shown. Our intention is to develop antagonist-based glutamate “responsive” MRI contrast agents (CAs) to image glutamate fluctuations in specific brain regions associated with neural activity. We have chosen CAs that bind to the metabotropic glutamate-receptor subtype 5 (mGluR5) [1]. Such molecules can bind both to neuronal postsynaptic receptors as well as to those expressed on astrocytes. They can therefore act both as “markers” of receptor density and as indicator of neuronal activation. For the latter, ideally, upon glutamate binding to the receptor (i.e. after glutamate release at the synapse) the CA will be released, hence leading to a reduction in image contrast, followed by a restoration of equilibrium and re-binding of the CA to the receptor. These events are believed to occur over a period of few seconds allowing data acquisition using modern fast MR-techniques[2].

 

Goal

The study aims on developing functional MRI methods that are not based on the BOLD signal. Such methods would allow opening up a complete new way of functional assessment of how the brain works.

 

Methods

We have designed and synthesized different prospective CAs derived from various potent mGluR5-receptor antagonists (Figure 1, alkynes like MPEP, MTEP shown in green and dipyridyl/heterobiaryl amides shown in brown) coupled to DOTA-derived macrocyclic gadolinium chelates. The CAs were evaluated in cultured primary cortical rat astrocytes, expressing mGluR5 (verified by immunofluorescence). MRI-measurements to examine the ability of the CAs for cellular labeling were done with a 3T human whole body scanner. Antagonistic potency of the CAs was assessed with a calcium fluorescence assay, by which glutamate induced intracellular calcium transients mediated by mGluR5 were measured. Antagonistic activity of the CAs was calculated as changes in EC50 of glutamate. Receptor binding was monitored for the dipyridyl derivatives, as these compounds have an inherent fluorescence that changes upon binding. Commercially available receptor membrane preparations containing recombinant human mGluR5A were used for these experiments.

 

Initial Results

Two of the gadolinium complexes retained significant antagonistic activity, one in each structural class. For the alkyne-derivative Gd.L3, an about fourfold increase of the EC50(glutamate) (100µM CA, 15min, P<0.001) was found while under similar conditions the cellular relaxation rate R1,cell increased to 126% of control (100µM, 45 minutes incubation time, P<0.001, Figure 2). The CA Gd.L8 derived from dipyridyl amides increased the EC50(glutamate) about threefold (p<0.001) and the R1,cell to 115% (p<0.05, Figure 2). Fluorescence measurements of the latter CA showed enhanced emission upon binding to mGluR5-membrane preparations. This effect was reversed when increasing concentrations of glutamate were added, consistent with the reversibility of CA-receptor binding.

 

Conclusions

Using primary rat astrocytes as cellular model system to investigate newly developed glutamate-responsive MRI contrast agents, we were able to identify two promising candidates. These CAs are based on the structures of antagonists to mGluR5 and our studies establish the validity of the concept, by which it might be possible to use MRI for brain functional measurements employing competitive binding approaches.

 

Structures of mGluR5 targeted MRI probes. 

Figure 1: Structures of mGluR5 targeted MRI probes.

  

 

Cellular Relaxation Rates.

Figure 2: Cellular 1H-MR relaxation rates R1,cell in cell suspensions after treatment of primary astrocytes with 100µM of [Gd.DOTA] or [Gd.L1-8] for 45 min.

  

 

 

Representative T1-weighted MR-images. 

 Figure 3: Representative T1-weighted MR-images of 1x107 cells treated for 45 min with 100µM [Gd.DOTA] or [Gd.L2].

 

 

References:

[1] Mishra, A., Gottschalk, S., Engelmann, J., Parker, D., Chemical Science 3(1)(2012)131-135

[2] Logothetis, N.K., Nature 453(2008)869-878

 

 

 

 

 

  

Application of CyLoP-1 for the induction of apoptosis in cancer cells.

 

Introduction

Cell penetrating peptides (CPPs) are known as transduction vectors for several years and their feasibility has been demonstrated in a wide range of in vitro studies [1]. Due to their ability to deliver a variety of compounds through cellular membranes they have also gained attention in the biomedical field. Unfortunately, uptake via endocytotic pathways and hence vesicular encapsulation limits the application of CPPs, particularly when it comes to a cargo that needs to be delivered to the cytosol of a cell. We have recently developed the new cysteine-rich CPP CyLoP-1 (Figure 1) [2]. It could be shown that the cysteines were essential for efficient uptake as well as cytosolic distribution and it was also proved that CyLoP-1 is taken up most efficiently in its natural L-form. To verify the capability of CyLoP-1 to transport a biological active cargo across cellular membranes, we attached the pro-apoptotic peptide-sequence AVPIAQK (SmacN7) to CyLoP-1. SmacN7 is derived from the N-terminus of the second mitochondria-derived activator of caspase (Smac) protein which is released from mitochondria in response to apoptotic stimuli and promotes caspase-3 activation in the cytosol [3]. The short sequence SmacN7 has been shown to be sufficient enough to maintain the original function of Smac [4]. However, SmacN7 alone is not capable of passing through cellular membranes and it needs to bind to its cytosolic target protein to exert its pro-apoptotic action [3, 4]. By measuring the apoptotic level in treated cells, SmacN7 can thus be used to prove the cytosolic delivery of CPP-SmacN7 conjugates [5].

 

Goal

The project aims on demonstrating the potential capability of CyLoP-1 for targeted cytosolic delivery of drugs or other compounds that are unable of crossing cellular membranes on their own.

 

Methods

CyLoP-1 (CRWRWKCCKK, Figure 1) was synthesized by Fmoc solid-phase synthesis. An additional lysine was attached as linker. Fluorescein isothiocyanate (FITC) as fluorophore was coupled to the ε-amino group of this additional lysine. At the α-amino group of the same lysine SmacN7 (AVPIAQK) was covalently conjugated, yielding the construct SmacN7-K(FITC)-CyLoP-1. Internalization was evaluated on NIH3T3 mouse fibroblasts [2]. Briefly, confluent cells were incubated for 18 h with 2.5 µM of CPP-conjugate. Then, nuclei were counter-stained with Hoechst 33342 and extracellular fluorescence was quenched with trypan blue. Intracellular FITC- and Hoechst-fluorescence were measured in a plate reader and microscopic images of the same cells were taken afterwards.

Apoptosis was induced in confluently grown human cancer cell line (HeLa) with the combination of an agonistic anti-Fas antibody and cycloheximide (CHX) [5]. Incubations were done for 18 hours with or without SmacN7-K(FITC)-CyLoP-1 (2.5 or 5 µM). The extent of apoptosis was also assessed after 18 hours of treatment with the SmacN7-CyLoP-1 construct alone. Caspase-3 activity as marker for the extent of apoptosis was measured in the supernatant of lysed cells with a standard enzymatic assay. The caspase-3 activity measurements were normalized on the protein content of the samples which was quantified with a standard Bradford protein assay.

 

Initial Results

Treatment of HeLa cells with only SmacN7-K(FITC)-CyLoP-1 induced already a significant and concentration dependent increase of caspase-3 activity (Figure 2). However, this increase was on a lower absolute level as compared to apoptosis induced by CHX+anti-Fas-treatment (the caspase-3 activities were 0.4±0.1 and 4.7±0.8 [DFU sec-1] for untreated control and CHX+anti-Fas, respectively). Furthermore, co-treatment of HeLa cells with CHX, anti-Fas antibody and the SmacN7-CyLoP-1 construct enhanced the level of apoptosis in addition to that already induced by CHX+anti-Fas-treatment alone (Figure 3).

 

Conclusions

We have shown that our newly developed cysteine-rich peptide CyLoP-1 is superior in reaching the cytosol of cells in comparison to other established CPPs. We have also demonstrated that the cargo construct SmacN7-CyLoP-1 was capable of inducing and enhancing apoptosis in cancer cells, thus proving the ability of CyLoP-1 to successfully deliver a fully functional attached bioactive cargo to its cytosolic site of action.

 

 

Schematic structure ofa CyLoP-1 cargo conjugate.

Figure 1: Schematic structure of a CyLoP-1 cargo conjugate.

 

 

 

Induction of Apoptosis.

Figure 2: Induction of apoptosis; Caspase-3 activity 18 h after incubation with SmacN7-K(FITC)-CyLoP-1.

 

 

 

Apoptosis Enhancement.

Figure 3: Enhancement of apoptosis; Caspase-3 activity 18 h after incubation with CHX, anti-Fas and SmacN7-K(FITC)-CyLoP-1.

 

 

 

References:

[1] Lundberg et al., J. Mol. Recognit. 16(2003)227.

[2] Jha D, Mishra R, Gottschalk S, Wiesmüller KH, Ugurbil K, Maier ME, Engelmann J. Bioconjug Chem, 22(2011)319.

[3] Fandy et al., Mol. Cancer 7(2008)60.

[4] Heckl et al., Med. Chem. 4(2008)348.

[5] Duchardt et al., Traffic 8(2007)848. 

 

 

 

seit März 2009 - Wissenschaftlicher Mitarbeiter (Postdoc) am Hochfeld-Magnetresonanz Zentrum des Max Planck Instituts für Biologische Kybernetik in Tübingen, Deutschland in der Gruppe "Neue Kontrastmittel für die MR-Bildgebung" von Joern Engelmann, Dr. rer. nat.

August 2005 - Februar 2009 - Postdoc am CRC CHUM, Hôpital Saint-Luc, Montréal, Kanada in den Arbeitsgruppen von Marc Bilodeau, Dr. Med. und Claudia Zwingmann, Dr. rer. nat.

November 2006 - September 2008 - Forschungsstipendium der Deutschen Forschungsgemeinschaft (DFG)
"
Metabolische, biochemische und molekulare Untersuchungen zur Bedeutung spezifischer früher Stoffwechselveränderungen im hepatozellulären apoptotischen Prozess"

Dezember 1999 - Januar 2004 - Doktorarbeit an der Universität Bremen (Deutschland)
"
Die molekularen Mechanismen der Neurotoxizität der Immunsuppressiva Ciclosporin, Sirolimus und Everolimus"

Juli 1999 - Diplom in Chemie

1993-1999 -Studium der Chemie an der Universität Bremen (Deutschland)

Gottschalk S (July-19-2012) Invited Lecture: Targeted Magnetic Resonance Imaging Probes, Université de Sherbrooke: Séminaire Génie chimique et génie biotechnologique , Sherbrooke, Canada.
Molecular imaging is a rather new biomedical research field investigating non-invasive visualization and characterization of biological processes at the molecular and cellular level in living systems. During the last decade since the dawn of molecular imaging a multitude of targeting strategies has been developed and different classes of targeting modalities exist, although with certain overlap among them: 1) Specific molecules on the surface of cells can be imaged (e.g. receptors). 2) Molecules specific for a certain cell type or tissue can be visualized (e.g. enzymes, mRNA). 3) The expression of certain genes can be imaged. Whereas several targeting approaches are already in clinical use with highly sensitive methods such as positron emission tomography (PET), the application for magnetic resonance imaging (MRI) is still restricted because of its low sensitivity and hence the much higher probe concentrations required for imaging. But, in combination with an ever increasing number of agents capable of generating contrast in MRI, an almost limitless number of targeted MRI probes can be envisioned. Yet, MRI contrast agents (CAs) can be basically classified into positive (appearing bright in images, e.g. paramagnetic Gadolinium chelates) and negative CAs (appearing mostly dark in images, e.g. superparamagnetic ion oxide nanoparticles). Some examples of targeted MRI CAs developed by our group will be described in detail.
html CiteID: Gottschalk2012_2

Gottschalk S (September-9-2011) Invited Lecture: Targeted Magnetic Resonance Imaging Probes, COST D38 Final Meeting: Metal-Based Systems for Molecular Imaging Applications, Oxford, UK.
html CiteID: Gottschalk2011

Gottschalk S , Engelmann J , Mishra A and Parker D (June-19-2011) Abstract Talk: Responsive MR Imaging Probes to Monitor Synaptic Glutamate Fluctuations in the Brain, 6th European Molecular Imaging Meeting (EMIM 2011), Leiden, Netherlands6 24.
mediator of excitatory signals in the nervous system and is involved in nearly all aspects of normal brain functioning (cognition, memory, learning). Our idea was to develop glutamate ‘responsive’ magnetic resonance imaging (MRI) contrast agents (CAs) to image changes in specific brain regions upon neural activation. As CAs directly responsive to glutamate would not be feasible due to the very short half-life of glutamate in the extracellular space, we chose CAs that bind to glutamate receptors instead (to be specific metabotropic glutamate-receptor subtype 5 (mGluR5)), by this increasing image contrast. Ideally, upon glutamate-binding to the receptor (e.g. after glutamaterelease at the synapse) the CA will be released, hence leading to a reduction in image-contrast, followed by a restoration of equilibrium and re-binding of the CA to the receptor. These events are believed to occur over a period of seconds allowing data acquisition using modern FLASH pulse techniques[1]. Here, we present a proof-of-concept study for such ‘indirect’ glutamate-responsive MRI CAs. Methods: We have designed and synthesized different prospective CAs derived from various potent mGluR5-receptor antagonists (alkynes like MPEP, MTEP and dipyridyl/heterobiaryl amides) coupled to DOTA-derived macrocyclic lanthanidechelates. The CAs were evaluated in cultured primary cortical rat astrocytes, expressing mGluR5 (verified by immunofluorescence). MRI-measurements to examine the ability of the CAs for cellular labeling were done with a 3T human whole body scanner. Antagonistic potency of the CAs was assessed with a calcium fluorescence assay, by which glutamate induced intracellular calcium-transients mediated by mGluR5 were measured. Antagonistic activity of the CAs was calculated as changes in EC50 of glutamate. Receptor binding was measured for the dipyridyl derivaties, as these compounds have an inherent fluorescence that changes upon binding. Commercially available receptor membrane preparations containing human mGluR5A were used for these experiments. Results: Two of the gadolinium complexes retained significant antagonistic activity, one in each structural class. For the alkyne-derivative, about a threefold increase of the EC50(glutamate) (100μM CA, 15min, P<0.001) was found while under similar conditions the cellular relaxation rate R1,cell increased to 126% of control (100μM, 45 minutes incubation time, P<0.001). The CA derived from dipyridyl amides increased the EC50(glutamate) about fourfold (p<0.001) and the R1,cell to 115% (p<0.05). Fluorescence measurements of the latter CA showed enhanced emission upon binding to mGluR5-membrane preparations. This was reversed when increasing concentrations of glutamate were added, consistent with the a reversibility of CA-receptor binding Conclusions: Using primary rat astrocytes as cellular model system to investigate newly developed glutamate-responsive MRI contrast agents, we were able to identify two promising candidates. These CAs are based on the structures of antagonists to mGluR5 and our studies establish the validity of the concept, by which it might be possible to use MRI to image transient changes in the neurotransmitter glutamate.
pdf html CiteID: GottschalkMEP2011

Pohmann R , Shajan G , Gottschalk S , Engelmann J , Balla D , Ueberberg S and Schneider S (May-12-2011) Abstract Talk: In vivo visualization of pancreatic islets in the mouse, 19th Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2011), Montréal, Canada19 648.
Detection of single pancreatic islets has many applications in diabetes research, but can be achieved in vivo with proton MRI only after transplantation of ex vivo labeled islets. Recently, successful visualization of islets in the excised mouse pancreas at 16.4T following i.v. injection of a novel beta-cell specific paramagnetic contrast agent was reported. Here we present the methodical optimization for in vivo experiments. Signal efficient 2D acquisition methods were considered. Best results were obtained with a two slice navigator based sequence. Single islets are visualized for the first time in vivo in mice after i.v. administration of a labeling agent.
pdf html CiteID: BallaGGPE2011

Ugurbil K, Jha D , Mishra R , Engelmann J and Gottschalk S (July-2010) Abstract Talk: Induction of Apoptosis by SmacN7 coupled to the Novel Cysteine-Rich Cell-Penetrating Peptide CyLoP-1, 37th Annual Meeting and Exposition of the Controlled Release Society (CRS 2010), Portland, OR, USA.
html CiteID: GottschalkJMUE2010

Gottschalk S (September-2009): Molecular in vivo MRI: Development of contrast agents that target pancreatic beta-cells, COST D38 Action & COST BM0607 Joint Working Group Meeting, Firenze, Italy.
CiteID: Gottschalk2009

Leibfritz D, Zwingmann C, Gottschalk S and Bilodeau M (April-22-2009) Abstract Talk: Liver tissue repair in a mouse model of toxicant-induced liver inury is associated with increased hepatic energy metabolism, 17th Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM 2009), Honolulu, HI, USA17 (531) .
Due to its ability regenerate, the liver is an ideal model for studying tissue repair mechanisms. Only little is known about the repair-associated changes in cellular metabolic pathways. Energy-intensive repair processes should be reflected in alterations in energy metabolism. An in vivo liver-injury model was used to generate an onset of liver tissue-repair. We assessed the extent of liver-injury and NMR-spectroscopy was used to characterize changes in energy metabolism and metabolites. Our results showed that induction of liver-regeneration was consistent with an up-regulation of the cells overall energy metabolism and a higher demand for TCA-cycle intermediates (eg. for amino-acids synthesis).
pdf html CiteID: GottschalkLZB2009

Zwingmann C, Gottschalk S , Bilodeau M, Hohnholt M and Raymond VA (March-2008): Dissecting the effect of cyclosporine on the sequence of events leading to hepatocellular apoptosis, Canadian Digestive Diseases Week & CASL Winter Meeting (CDDW 2008), Montreal, Canada.
INTRODUCTION: The immunosuppressant cyclosporine (Cyclosporin A, CsA) is known to have the capacity to prevent cellular apoptosis by inhibition of the mitochondrial permeability transition (MPT). We have recently shown that Fas receptor-mediated apoptosis in mouse liver involves early upregulations of specific glucose metabolic pathways and that pre-treatment with CsA prevented these early metabolic events. AIMS: A) In order to further characterize the protective effect of CsA on apoptotic liver injury, we analyzed the sequence of cellular events leading to hepatocyte cell death following anti-Fas injection. B) We then investigated the effects of pre-treatment with CsA on these characteristics that lead to hepatocellular cell death. METHODS: BALB/C mice were injected with anti-Fas antibody (0.5 µg/g, ip). CsA (50 mg/kg; Sandimmune®, ip) was injected 45 min prior to anti-Fas. Animals were sacrificed at five time points from 45min up to 7.5hrs after anti-Fas injection. Standard enzymatic assays were used for serum-ALT/AST and caspase-3 determinations. BID/tBID was analyzed by Western blot and GSH/GSSG by HPLC. RESULTS: A) Anti-Fas-induced liver injury followed a characteristic sequence of cellular events leading to death of the mice at around 8 hrs after anti-Fas injection. First the cleavage of BID was identified 2 hrs after injection, followed by elevation in caspase-3 activity at 3 hrs (26.8±5.3 U, P<0.001 vs. saline-treated controls). Liver cell damage was evident at 5 hrs. At this time serum ALT/AST were increased (7584±2240/5835±1158 U/L) and hepatocyte apoptosis and tissue hemorrhage were identified on histology. Intracellular GSH and GSSG started to decrease at 5 hrs but the ratio of GSH/GSSG remained constant at all time points. B) Pre-treatment with CsA significantly delayed the increase in caspase-3 activity (3 hrs: 7.6±2.1 U, P<0.01 vs. anti-Fas-only; 5 hrs: 43±6.4 U). Serum ALT were also significantly lower at 5 hrs (3100±1104 U/L, P<0.01 vs. anti-Fas-only). Histological evidence of apoptosis was markedly reduced at 7.5hrs. Interestingly, pre-treatment with the vehicle of the CsA formulation, Cremophor® EL (CrEL), offered a very similar protective effect on liver injury. CONCLUSIONS: Our results demonstrate that the protective effect of the CsA formulation occurs at all levels of the injury process. However, they also suggest that the inhibition of hepatocellular apoptosis observed with CsA has to be attributed mainly to the vehicle CrEL.
html CiteID: GottschalkHRZB2008

Zwingmann C, Gottschalk S , Bilodeau M, Hohnholt M and Boulanger Y (February-2007): Metabolic Characterization of Patients with NASH and ASH by High-Resolution Multinuclear NMR Spectroscopy on Bodyfluids, Canadian Digestive Diseases Week: 45th Annual Meeting of the Canadian Association of Gastroenterology (CDDW 2007), Banff, Canada.
INTRODUCTION: Liver steatosis is a common cause of liver disease. Non-alcoholic fatty liver disease (NASH or NAFLD) ranges from steatosis without inflammation to steatohepatitis, ballooning degeneration with or without liver fibrosis. Similar pathological findings are observed in patients with ASH (alcoholic steatohepatitis), and it is difficult to differentiate both pathologies by clinical and biochemical evaluations. High-resolution 1H-NMR has emerged as a powerful technique to simultaneously identify and quantify multiple metabolites of medical significance without a requirement for pre-selection or separation of metabolites. AIM: Since it is becoming urgent to develop new diagnostic methods for NAFLD, we applied novel multinuclear NMR methods to detect the metabolic profile in body fluids in patients with NASH and ASH. METHODS: Thirty non-alcoholic patients, 7 alcoholic steatotic patients and 30 age-matched control subjects were recruited. Urine samples were lyophilized. We used dual-extraction methods to investigate both water-soluble metabolites and lipophilic compounds involved in fatty acid- and lipid metabolism, in blood plasma and serum. Furthermore, to study metabolites not accessible by conventional 1H NMR analysis, natural abundance 13C NMR measurements were performed. To identify unknown metabolites in body fluids, two-dimensional {1H-1H} and {1H-13C} experiments were used. RESULTS: 1H- and 13C-NMR spectra of urine and blood extracts clearly showed considerable differences in specific metabolites involved in liver intermediary metabolism in patients with NASH and ASH compared to healthy controls. Selective changes in patients with ASH compared to controls were detected urine (decreases of hippurate (to 46±13%), and urea (to 37±21%), increases of TMAO (to 157±28%) and tyrosine (to 322±124%) as well as accumulation of bile acids) and in blood plasma (increases of TMAO (to 314±58%) and methionine (to 620±81%) and decreases in branched-chain amino acids (to 32±5%)). In patients with NASH, 13C-NMR spectra showed several and significant changes in metabolites involved in mitochondrial and lipid metabolism. CONCLUSIONS: New applications of NMR methods on human body fluids are of great potential to characterize NAFLD, a disease displaying multiple interrelated metabolic factors. This approach could provide new data to characterize steatosis, help to distinguish between NASH and ASH, and also give insights in the pathophysiology of both diseases.
html CiteID: HohnholtZGBB2007

Zwingmann C, Gottschalk S , Bilodeau M and Raymond VA (April-2006): The prevention of hepatocellular apoptosis by Cyclosporine A is associated with early metabolic changes, 2nd Annual Canadian Association for the Study of the Liver Winter Meeting: Updates in Hepatology ( (CASL 2006), Toronto, Canada.
CiteID: GottschalkRBZ2006

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Vorträge (10):

Balla D, Gottschalk S, Shajan G, Ueberberg S, Schneider S, Pohmann R und Engelmann J (Mai-12-2011) Abstract Talk: In vivo visualization of pancreatic islets in the mouse, 19th Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2011), Montréal, Canada 648.
pdf
Gottschalk S, Jha D, Mishra R, Ugurbil K und Engelmann J (Juli-2010) Abstract Talk: Induction of Apoptosis by SmacN7 coupled to the Novel Cysteine-Rich Cell-Penetrating Peptide CyLoP-1, 37th Annual Meeting and Exposition of the Controlled Release Society (CRS 2010), Portland, OR, USA.
Gottschalk S (September-2009): Molecular in vivo MRI: Development of contrast agents that target pancreatic beta-cells, COST D38 Action & COST BM0607 Joint Working Group Meeting, Firenze, Italy.
Gottschalk S, Leibfritz D, Zwingmann C und Bilodeau M (April-22-2009) Abstract Talk: Liver tissue repair in a mouse model of toxicant-induced liver inury is associated with increased hepatic energy metabolism, 17th Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM 2009), Honolulu, HI, USA(531).
pdf
Gottschalk S, Hohnholt M, Raymond VA, Zwingmann C und Bilodeau M (März-2008): Dissecting the effect of cyclosporine on the sequence of events leading to hepatocellular apoptosis, Canadian Digestive Diseases Week & CASL Winter Meeting (CDDW 2008), Montreal, Canada.
Hohnholt M, Zwingmann C, Gottschalk S, Boulanger Y und Bilodeau M (Februar-2007): Metabolic Characterization of Patients with NASH and ASH by High-Resolution Multinuclear NMR Spectroscopy on Bodyfluids, Canadian Digestive Diseases Week: 45th Annual Meeting of the Canadian Association of Gastroenterology (CDDW 2007), Banff, Canada.
Gottschalk S, Raymond VA, Bilodeau M und Zwingmann C (April-2006): The prevention of hepatocellular apoptosis by Cyclosporine A is associated with early metabolic changes, 2nd Annual Canadian Association for the Study of the Liver Winter Meeting: Updates in Hepatology ( (CASL 2006), Toronto, Canada.
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