Objectives: Previous reports suggest a role of platelet derived growth factor (PDGF) in the development of cardiac allograft vasculopathy (CAV). The pharmaceutical blockade of tyrosine kinases may alter the expression of different growth factor receptors: platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and hereby play a role in the context of cardiac allograft vasculopathy. Therefore the aim of this study was to determine the impact of tyrosine kinase inhibition on the development of cardiac allograft vasculopathy in a mouse model.

BACKGROUND:Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. METHODS:CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. RESULTS:Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. CONCLUSION:Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.

Objectives: Cytomegalovirus (CMV) infection after heart transplantation is considered as risk factor for the development of cardiac allograft vasculopathy (CAV), a serious long-term complication after heart transplantation. In previous work we could show that murine CMV infection (MCMV) leads to increased levels of CAV. MCMV genome encodes the G protein-coupled receptor (GPCR) M33 which is associated with virus latency and replication in the host. Therefore we analyzed if M33 knockout could prevent CMV induced CAV development.

Nintedanib is an intracellular inhibitor of receptor tyrosine kinases and blocks signal transduction of growth factors like platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). All of these growth factors are of significance in the context of transplant vasculopathy. Therefore the aim of this study was to determine the impact of tyrosine kinase inhibition by nintedanib on the development of transplant vasculopathy in a mouse model.

Background: Serotonin (5-HT), a neurotransmitter with numerous functions in the central nervous system (CNS), is emerging as an important signaling molecule in biological processes outside of the CNS. Recent advances have implicated serotonin as a regulator of inflammation, proliferation, regeneration, and repair. It may also have a role in transplant vasculopathy (TV) because after release from its main storage in platelets, a cell population we postulated of significance in the context of TV, 5-HT can exert effects via its subtype 2A receptor (5-HT2AR) on further cells involved in the development of TV. The specific aim of this study was to evaluate the role of 5-HT2A blockade on the development of TV.

Objectives: Maintenance of a functional microvasculature is of utmost importance in solid organ transplantation. Tissue hypoxia due to microvascular injury-associated ischemia can occur after thrombus formation in microvessels mediated by activated platelets. Therefore the current study sought to investigate if treatment with the platelet inhibitor clopidogrel has an impact on the microvasculature of transplanted tracheal grafts.

Maintenance of a functional microvasculature is of utmost importance in solid organ transplantation. Tissue hypoxia due to microvascular injury-associated ischemia can occur after thrombus formation in microvessels mediated by activated platelets. Therefore the current study sought to investigate if treatment with the platelet inhibitor clopidogrel has an impact on the microvasculature of transplanted tracheal grafts.

Hintergrund: Somatostatin-Analoga inhibieren Proliferation durch selektive Stimulation von Somatostatinrezeptoren (SSTR), von denen fünf Subtypen, SSTR1 bis SSTR5, bekannt sind. Die derzeit eingesetzten Somatostatin-Analoga weisen eine hohe Affinität für SSTR2, sowie mittelgradige Affinitäten für SSTR5 und SSTR3 auf. In den letzten Jahren wurden Somatostatin-Analoga zunehmend in der Therapie des fortgeschrittenen hepatozellulären Karzinoms (HCC) eingesetzt. Die Effektivität dieser Therapie ist angesichts uneinheitlicher Ergebnisse klinischer Studien umstritten. Wir konnten kürzlich mittels RT-PCR erstmals zeigen, dass HCCs differentielle Expressionsmuster für SSTR ausweisen. Ziel dieser Studie war die systematische Analyse der Inzidenz der einzelnen SSTR-Subtypen in HCCs.

Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.

Background: The mitochondrion is an essential organelles for producing most of the energy in the cell and also involved in a number of cellular activities in the cell. It plays an important role in the aging process. Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases as Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in neurodegenerative diseases. Secondary effects as proapoptotic factors and Reactive Oxygen Species (ROS) can be an early stage of several mitochondrial disorders. Objective: To evaluate the mitochondrial membrane potential, ROS generation, GSK-3β and CK-1δ activities of seven natural products (isoquercetin, rutin, avicularin, hesperetin, astragalin, luteolin and diosmin …

Weichteilsarkome der Brust sind mit etwa 0,04 bis 1% aller Brusttumoren selten. Während sekundäre Angiosarkome häufiger bei prämenopausalen Patientinnen nach BET eines Karzinoms und Radiatio beobachtet werden, beschränkt sich die Beschreibung primärer Angiosarkome in der Literatur auf Einzelfälle. Unspezifische klinische Untersuchungsergebnisse, immunhistochemischer Nachweis endothel-assoziierter Antigene, eine mittlere Überlebenszeit von etwa 13–22 Monaten nach primär operativer Behandlung und die hämatogene Metastasierung in Lunge, Pleura und Peritoneum kennzeichnen das Krankheitsbild.

Einleitung: Die Frühdiagnose des Pankreaskarzinoms ist extrem schwierig. Die Erstdiagnose erfolgt oft im späten Stadium mit entsprechend fataler Prognose. Ein Screening für das Pankreaskarzinom wird nicht routinemäßig durchgeführt, auch wenn bereits unterschiedliche Methoden hierzu beschrieben wurden.

Phosphorylation of serine, threonine and tyrosine residues by cellular protein kinases plays an important role in the regulation of various cellular processes. The serine/threonine specific casein kinase 1 and 2 protein kinase families — (CK1 and CK2) — were among the first protein kinases that had been described. In recent years our knowledge of the regulation and function of mammalian CK1 kinase family members has rapidly increased. Extracellular stimuli, the subcellular localization of CK1 isoforms, their interaction with various cellular structures and proteins, as well as autophosphorylation and proteolytic cleavage of their C-terminal regulatory domains influence CK1 kinase activity. Mammalian CK1 isoforms phosphorylate many different substrates among them key regulatory proteins involved in the control of cell differentiation, proliferation, chromosome segregation and circadian rhythms. Deregulation and/or the incidence of mutations in the coding sequence of CK1 isoforms have been linked to neurodegenerative diseases and cancer. This review will summarize our current knowledge about the function and regulation of mammalian CK1 isoforms.

BACKGROUND The more frequent use of endoscopic ultrasonography (EUS) leads to an increased number of diagnosed gastric submucosal tumors (G-SMT). Since until now rather little therapeutical success in respect of these tumors has been achieved, we evaluated our concept of watchful waiting and selective treatment of patients with G-SMT in an analysis of prospectively collected data. PATIENTS AND METHODS Forty-seven consecutive patients with G-SMT treated at our institution between 1994 and 2000, were included. All patients underwent abdominal ultrasound and EUS, and in case of suspicious findings or a tumor size > 2 cm EUS fine needle aspiration (EUS-FNA) was performed. Patients were operated on if a malignant tumor was suspected (tumor size > 2 cm; detection of metastases) or if complications occurred (e.g. bleeding, ulceration). RESULTS All 47 patients were included in this study. Typical symptoms were nausea (64%), bleeding (11%) and pain (9%). EUS showed a G-SMT averaging 6.4 (0.8 - 30) cm in size. EUS-FNA was performed in 24 patients revealing PAP III (n = 1), PAP II (n = 21) and PAP I (n = 2) scores. Surgery was performed in 33 patients, revealing gastrointestinal stromal tumors (GISTs) in 18 patients as well as several other malignant and non-malignant lesions. During follow-up (median 37 months), none of the conservatively treated patients (n = 14) developed a malignant tumor. CONCLUSIONS In one third of our patients surgery could be avoided with this strategy. No delayed diagnosis of a malignant tumor during follow-up was established. Small G-GMT's should be monitored conservatively if diagnostic procedures and follow-up was performed by EUS and eventually EUS-FNA.

Background/Aims: Transplantation of primary human hepatocytes and establishment of hepatitis B virus (HBV) infection in immunodeficient urokinase plasminogen activator (uPA) transgenic mice was shown. However, the availability of usable primary human hepatocytes is very limited. Therefore, alternative and more accessible sources of hepatocytes permissive for HBV infection are highly desirable. Here we investigated the potential of primary hepatocytes from the tree shrew Tupaia belangeri that were shown to be susceptible to HBV infection.Methods: Freshly isolated or cryopreserved primary tupaia hepatocytes were transplantated via intrasplenic injection into immunodeficient uPA/RAG-2 mice. Engrafted mice were then infected with HBV and woolly monkey (WM)-HBV positive sera.Results: Extensive proliferation of xenografted cells was demonstrated by the stable production of tupaia alpha1-antitrypsin in serum and liver of transplanted mice. Quantitative PCR assays demonstrated the presence of circulating viral particles as well as intracellular viral DNA, including covalently closed circular (ccc) DNA, in transplanted mice. Viral infection could be serially passaged in mice. Furthermore, viral replication was strongly inhibited by treating mice with adefovir dipivoxil.Conclusions: uPA mice repopulated with tupaia hepatocytes represent a useful and more accessible model for HBV infection studies, including the evaluation of antiviral therapy and cccDNA. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background/Aims: Heterotopic pancreas is usually a silent gastrointestinal malformation, but it may become clinically evident when complicated by chronic inflammation or by growth.Methodology: We report on eleven cases of heterotopic pancreatic tissue. The cases were selected from the records of our Surgical Department and Institute of Pathology. The literature about heterotopic pancreas is reviewed. Results: Nausea and vomiting (27%), epigastric pain (27%), ulceration (27%) and weight loss (18%) were the three most frequent symptoms and signs. The lesions were diagnosed as gastrointestinal tumor or ulcer by gastroduodenoscopy (36%). The other patients were diagnosed during surgery (64%). Definitive diagnosis was only achievable by pathology. Heterotopic pancreas was the reason for surgery in 36% of the cases, in another 45% diagnosis was incidental during surgery and in 18% the diagnosis was established endoscopically and surgery was not necessary.Conclusions: The diagnosis of heterotopic pancreas is rarely established, most cases remain clinically silent. In symptomatic patients diagnosis should to be secured histologically to exclude malignant disease.

To avoid the progression from mild edematous acute pancreatitis to the severe necrotising form, one therapeutic option is to improve pancreatic microcirculation. The aim of the study was to evaluate the influence of isovolemic hemodilution and additional oxygen supply (bovine hemoglobin) on pancreatic microcirculation, tissue oxygénation and survival in severe acute experimental (porcine) pancreatitis. Methods: 39 pigs (25 - 30 kg BW) were anesthetised and catheters were placed. After midline laparotomy severe acute pancreatitis was induced (intraducatal injection of glycodeoxycholic acid (0,4 ml/kg BW; 10 mmol/1) and cerulein i.v. (5 microg/kg BW/h)). After 75 minutes animals were randomised into three groups (each n = 13): 1: isovolemic hemodilution (IHD) with hydroxyethyl starch (HES) and additional bovine hemoglobin (Oxyglobin, Biopure, MD); 2: IHD with HES and 3: IHD with Ringer’s solution. Then IHD was started until a hematocrit of 15% (50% of initial hematocrit) was reached. Pancreatic microcirculation was monitored using a laser-doppler scanner (Laser Perfusion Imager, Moor, Millway, UK) and tissue oxygénation of the pancreas (tpO2) was measured using a Licox catheter (GMS, Kiel, FRG). After 6 hours, catheters were removed, the abdomen was closed and animals were extubated. After 6 days, surviving animals were sacrificed. Results: In animals of group 1 pancreatic microcirculation improved over the observational period when compared to group 3 (mean difference of area under the curve: 510,8 (SE 111,5) (p < 0,001). Also, tpO2 improved in HBOC-200 treated animals (102,6 (SE 16,4) vs. group 3 and 76,7 (SE 15,9) vs. group 2; both p < 0,001). Ten animals survived in group 1, while 8 animals in group 2 and only 2 animals in group 3 were alive at the end of the observational period (p = 0,001 Kruskal-Wallis Test). Conclusion: Improved rheology and additional supply of oxygen lead to improved pancreatic microcirculation and better tissue oxygénation in severe acute porcine pancreatitis. This novel therapeutic strategy decreased animal mortality.

A case of vascular malformations of the small intestine associated with malrotation Type 1 of the right colon is reported. Representing rare conditions, vascular malformations in the small bowel are not accessible endoscopically. Therefore, gastrointestinal haemorrhage originating from this "terra incognita" is difficult to diagnose. Our patient had a medical history of anaemia of 17 years before admitted to our hospital. After a preoperative blood pool scan had evidenced the bleeding source in the proximal jejunum, the patient underwent explorative laparotomy. The bleeding source was identified and resection of a jejunal segment was performed. Intraoperatively, malrotation type 1 was found. Histological examination revealed angiodysplasia extending full thickness of the intestinal wall with predominance in the submucosa and serosa. Secondary arterialisation was seen in the vessels of the serosa resembling varicosis-like lesions at gross inspection. The patient did not suffer from portal hypertension. Postoperative course was uneventful and no further bleeding occurred.