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Wolfram Jochum

Publications and source records attributed to Wolfram Jochum.

At least 19 recordsLinked to original sources
PubMed2006

Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus.

Four of 9 PAX transcription factor genes have been associated with chromosomal translocations in human tumors, although their oncogenic potential has not yet been demonstrated in transgenic mouse models. The B-lymphoidPAX5 gene participates in the generation of the t(9;14)(p13;q32) translocation in germinal center B cells, which leads to deregulated PAX5 expression under the control of the immunoglobulin heavy-chain (IgH) locus in a subset of B-cell non-Hodgkin lymphomas. Here we reconstructed a human t(9;14) translocation in a knock-in mouse by inserting a PAX5 minigene into the IgH locus. The IgH(P5ki) allele, which corresponds to a germline rather than somatic mutation, is activated in multipotent hematopoietic progenitors and is subsequently expressed in dendritic cells (DCs) and in natural killer (NK), T, and B cells. Ectopic Pax5 expression interferes with normal T-cell development and causes immature T-lymphoblastic lymphomas in IgH(P5ki/+) and IgH(P5ki/P5ki) mice. Aggressive T-cell lymphomas develop even faster in Ik(Pax5/+) mice expressing Pax5 from the Ikaros locus. Pax5 expression in thymocytes activates B-cell-specific genes and represses T-lymphoid genes, suggesting that Pax5 contributes to lymphomagenesis by deregulating the T-cell gene-expression program. These data identify Pax5 as a potent oncogene and demonstrate that the T-lymphoid lineage is particularly sensitive to the oncogenic action of Pax5.

Alleles↗
PubMed2006

Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment.

PURPOSE: The combined treatment modality of ionizing radiation with inhibitors of angiogenesis is effective despite the supposition that inhibition of angiogenesis might increase tumor hypoxia and thereby negatively affect radiation sensitivity. To directly assess this still controversial issue, we analyzed treatment-dependent alterations of tumor oxygenation in response to inhibition of angiogenesis alone, ionizing radiation, and combined treatment. EXPERIMENTAL DESIGN: Serial measurements with high-resolution [18F]fluoromisonidazole positron emission tomography and immunohistochemical detection of the endogenous hypoxia marker glucose transporter-1 were done to determine tumor hypoxia in a murine mammary carcinoma allograft model. RESULTS: Inhibition of angiogenesis with the clinically relevant vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 reduced microvessel density but had only minimal effects on tumor growth, tumor cell apoptosis, and proliferation. However, PTK787/ZK222584 treatment increased overall and local tumor hypoxia as revealed by extended expression of the hypoxia marker glucose transporter-1 and increased uptake of [18F]fluoromisonidazole. Fractionated irradiation induced a strong growth delay, which was associated with enhanced apoptosis and reduced proliferation of tumor cells but only minor effects on microvessel density and allograft oxygenation. Combined treatment with fractionated irradiation resulted in extended tumor growth delay and tumor cell apoptosis but no increase in tumor hypoxia. CONCLUSIONS: These results show that irradiation antagonizes the increase of hypoxia by vascular endothelial growth factor receptor tyrosine kinase inhibition and abrogates the potential negative effect on tumor hypoxia. Thus, the risk of treatment-induced hypoxia by inhibitors of angiogenesis exists but is kept minimal when combined with a cytotoxic treatment modality.

Animals↗
PubMed2006

Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma.

BACKGROUND/AIMS: (1) To evaluate the diagnostic value of integrated positron emission and computed tomography (PET/CT) in comparison with contrast-enhanced CT (ceCT) to detect biliary tract tumors and associated distant and regional lymph node metastases and (2) to evaluate the impact of PET/CT on therapy management. METHODS: From January 2001 to March 2005, each patient who was treated for a malignancy of the biliary tract underwent PET/CT examination in addition to the standard work-up imaging. Data were prospectively collected and analyzed in comparison with ceCT. RESULTS: Sixty-one patients with malignancies of the biliary tract were included into the study. Diagnosis was proven in all patients either by histology or cytology. PET/CT detected all gallbladder cancers (n=14). PET/CT and ceCT provided a comparable accuracy for the primary intra- (n=14) and extra-hepatic cholangiocarcinomas (n=33). All distant metastases (12/12) were detected by PET/CT, but only 3/12 by ceCT (p<0.001). Regional lymph node metastases were detected by PET/CT and ceCT in only 12% vs. 24%. PET/CT findings resulted in a change of management in 17% of patients deemed resectable after standard work-up. CONCLUSIONS: PET/CT is particularly valuable in detecting unsuspected distant metastases which are not diagnosed by standard imaging. Thus, PET/CT staging has an important impact on selection of adequate therapy.

Adult↗
PubMed2006

Portal vein ligation and partial hepatectomy differentially influence growth of intrahepatic metastasis and liver regeneration in mice.

BACKGROUND/AIMS: Since modern treatment of liver metastases includes serial hepatectomies and portal vein obstruction, we investigated the effects of portal vein ligation (PVL) and partial hepatectomy (PH) on tumor growth. METHODS: The effects of 70% PH and PVL on liver and lung metastases were evaluated in mice. Tumor growth and liver regeneration were assessed by morphometry and immunohistochemistry for PCNA and BrdU. The effect of growth factors of liver regeneration on CT-26 cells was tested in vitro, and TGF-beta secretion of CT-26 cells was measured by ELISA. RNA synthesis of TGF-beta and activin A was measured by RT-PCR. RESULTS: Liver regeneration after PH and PVL was similar in tumor-free mice. Intrahepatic tumor growth was lower after PH than after PVL (p=0.016). Extrahepatic tumor growth was not different. In contrast to PVL, liver regeneration was delayed after PH in metastatic livers (p=0.001). Tested growth factors of liver regeneration stimulated CT-26 cells in vitro, and CT-26 secreted significant amounts of TGF-beta in vitro and in vivo. CONCLUSIONS: Although similar in tumor-free mice, liver regeneration significantly differed between PVL and PH in metastatic livers. In addition, PH and PVL differently affected intrahepatic tumor growth.

Animals↗
PubMed2006

Platelet-derived serotonin mediates liver regeneration.

The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.

5-Hydroxytryptophan↗
PubMed2006

Kupffer cell-dependent TNF-alpha signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse.

Implantation of small liver grafts causes liver injury and defective regeneration leading to graft failure. We investigated whether Kupffer cell-dependent TNF-alpha signaling contributes to this poor outcome. Partial 30% liver transplantation was performed in C57BL/6 wild-type mice (control group), and in three groups with down-regulation of the TNF-alpha pathway: (i) TNF receptor 1 knockout [TNFR-1(-/-)] mice, and mice pretreated with (ii) gadolinium chloride or (iii) pentoxifylline (PTX). Fifty-percent partial liver transplantation, a model associated with full recovery, and transplantation in IL-6 knockout [IL-6(-/-)] mice were performed in some experiments. Graft injury, regeneration, portal flow, liver microcirculation, leukocyte adhesion, and animal survival were assessed. Animal survival rates were 14% in the control group vs. 43% in the gadolinium chloride group, 57% for the TNFR-1(-/-) group, and 86% in the PTX group (P < 0.001). Markers of liver injury were reduced in all treated groups when compared with controls. Each treated group disclosed better portal flow and sinusoid perfusion, decreased leukocyte adherence, particularly in the PTX group. Liver regeneration occurred only in the treated groups. IL-6 and IL-10 levels were dramatically up-regulated (50x) in the PTX group, and at lower levels in other experimental groups. The protective effect of PTX was lost in IL-6(-/-) mice and protection was restored by a single dose of r-IL-6. In conclusion, interruption of TNF-alpha signaling or depletion of Kupffer cells improves survival after 30% liver transplantation, reduces liver injury, and enhances regeneration. The superior effects of PTX are mediated by IL-6.

Animals↗
PubMed2006

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice.

Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2+/-) were transplanted into wild-type recipient mice. Mdr2+/- mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2-/- mice, the Mdr2+/- mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2+/- donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2+/- livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2+/- grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

USPIO-enhanced MR imaging for visualization of synovial hyperperfusion and detection of synovial macrophages: preliminary results in an experimental model of antigen-induced arthritis.

PURPOSE: To evaluate whether ultrasmall superparamagnetic iron particles (USPIO)-enhanced MRI is capable of assessing both synovial perfusion characteristics and the presence of synovial macrophages in a model of antigen-induced arthritis. MATERIALS AND METHODS: Unilateral arthritis was induced in six knees of six rabbits. The contralateral knees of the rabbits served as control knees. After onset of arthritis, all 12 knees were scanned prior to and immediately following intravenous administration of USPIO using a multiphase T1-weighted (T1w) fast gradient-echo (FGRE) sequence, and T1w spin-echo (SE), T2-weighted (T2w) FSE, T2*w GRE, and short-tau inversion recovery (STIR) sequences prior to and 24 hours following USPIO administration. SI-vs.-time curves (STCs) and the early enhancement rate during the first 56 seconds (REE(56)) were calculated from SI measurements within the synovial tissue of all knees on dynamic T1w images. MR findings were correlated to histopathology. RESULTS: REE(56) was significantly higher in the synovial tissue of arthritic knees than in the control knees (P < 0.01). Significant T1-, T2-, and T2* effects (P = 0.03-0.04) and multiple synovial vessels were visually detectable within the arthritic synovial tissue 24 hours after administration of USPIO, whereas no signal changes or synovial vessels were seen in the control knees. Histopathology revealed widened synovial blood vessels in the arthritic knees, and confirmed iron uptake by macrophages in the arthritic knees. CONCLUSION: USPIO-enhanced MRI is capable of both assessing synovial hyperperfusion and detecting macrophages in antigen-induced arthritis in rabbits.

Animals↗
PubMed2006

Pancreatic cancer in cystic fibrosis after bilateral lung transplantation.

Cystic fibrosis (CF) is the most common lethal genetic disease affecting 1 in 2500 white patients. Chronic obstructive lung disease and pancreatic insufficiency are the main clinical manifestations of CF. Lung transplantation has become a treatment option for advanced pulmonary disease during the last decade. On the other hand, there is evidence from large cohort studies that CF and immunosuppression are risk factors for pancreatic cancer. Here, we report the case of an 18-year-old female patient with CF and bilateral lung transplantation who underwent Whipple procedure for pancreatic adenocarcinoma at the age of 12 years. Because of growth retardation, the patient underwent a 2-year period of growth hormone treatment before the diagnosis of pancreatic cancer. This case should sensitize physicians to be aware of the increased risk for pancreatic cancer in CF patients especially in those after lung transplantation with immunosuppression and prolonged survival.

Adenocarcinoma↗
PubMed2006

A prospective, randomized, controlled trial comparing intermittent portal triad clamping versus ischemic preconditioning with continuous clamping for major liver resection.

OBJECTIVE: To evaluate whether ischemic preconditioning (IP) with continuous clamping or intermittent clamping (IC) of the portal triad confers better protection during liver surgery. SUMMARY BACKGROUND DATA: IP and IC are distinct protective approaches against ischemic injury. Since both strategies proved to be superior in randomized controlled trials (RCTs) to continuous inflow occlusion alone, we designed a RCT to compare IP and IC in patients undergoing major liver resection. METHODS: Noncirrhotic patients undergoing major liver resection were randomized to receive IP with inflow occlusion (n = 36) or IC (n = 37). Primary endpoints were postoperative liver injury and intraoperative blood loss. Postoperative liver injury was assessed by peak values of AST (alanine aminotransferase) and ALT (aspartate aminotransferase), as well as the area under the curve (AUC) of the postoperative transaminase course. Secondary endpoints included resection time, the need of blood transfusion, ICU, and hospital stay as well as postoperative complications and mortality. RESULTS: Both groups were comparable regarding demographics, ASA score, type of hepatectomy, duration of inflow occlusion (range, 30-75 minutes), and resection surface. The transection-related blood loss was 146 versus 250 mL (P = 0.008), and when standardized to the resection surface 1.2 versus 1.8 mL/cm (P = 0.01) for IP and IC, respectively. Although peak AST, AUCAST, and AUCALT were lower for IC, the differences did not reach statistical significance. Overall (42% vs. 38%) and major (33 vs. 27%) postoperative complications as well as median ICU (1 vs. 1 day) and hospital stay (10 vs. 11 days) were similar between both groups. CONCLUSIONS: Both IP and IC appear to be equally effective in protecting against postoperative liver injury in noncirrhotic patients undergoing major liver resection. However, IP is associated with lower blood loss and shorter transection time. Therefore, both strategies can be recommended for noncirrhotic patients undergoing liver resection.

Age Factors↗
PubMed2006

HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin.

In patients with hepatitis C virus (HCV)-related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon alpha-2a (PEG-IFN) alone, but the efficacy and tolerability of the PEG-IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment-naïve patients with biopsy proved HCV-related advanced fibrosis/cirrhosis (Ishak score F4-F6, Child-Pugh score < or =7) were randomized to 48 weeks of PEG-IFN (180 microg sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG-IFN (180 microg sc weekly) and low-dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG-IFN/STD RBV (52%) were higher--albeit not significantly--than that with PEG-IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count > or =150 x 10(9)/L were independently associated with SVR. The likelihood of SVR was < 7% if viraemia had not declined by > or =2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV-cirrhotics with STD PEG-IFN/RBV is favourable.

Adult↗
PubMed2005

Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis.

BACKGROUND/AIMS: Fatty livers are increasingly used for transplantation due to the dramatic organ shortage. While steatosis is an established risk factor for post-operative complications, the impact of macro- vs. microvesicular steatosis on ischemic injury is unclear. METHODS: The effects of ischemia and reperfusion were tested in two different models of steatotic mice: ob/ob as a model disclosing predominantly macrovesicular steatosis and choline deficient diet having mainly microvesicular steatosis. Steatotic and lean livers were subjected to 45 min of ischemia. Serial markers of hepatocellular injury, animal survival were measured. Hepatic tissue blood flow and portal vein perfusion were assessed. RESULTS: Ob/ob mice had a significantly lower tolerance to hepatic ischemia. with increased AST release and decreased survival in comparison to the choline deficient mice. No difference in ATP content was found between both steatosis models, but hepatic perfusion and portal vein flow were significantly lower after reperfusion in the ob/ob mice when compared to the choline deficient animals. Ischemic pre-conditioning significantly improved liver reperfusion and injury in both models of steatosis. CONCLUSIONS: Livers with macrovesicular steatosis have a lower tolerance to ischemic injury than those with microvesicular steatosis. Low intrahepatic and portal vein perfusion in macrovesicular fatty livers is, at least partially, responsible for the poorer outcome.

Adenosine Triphosphate↗
PubMed2005

Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis.

BACKGROUND/AIMS: Inherited dysfunction of the bile salt export pump BSEP (ABCB11) causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively. We functionally characterized novel ABCB11 mutations encountered in two patients with a PFIC2 and a BRIC2 phenotype, respectively. METHODS: BSEP expression was determined in liver biopsies by immunohistochemistry. ABCB11 mutations were functionally characterized by taurocholate transport in SF9 cells transfected with human ABCB11. RESULTS: The PFIC2 patient was compound heterozygous for a splicing mutation in intron 4 ((+3)A > C) combined with an early stop codon at position 930 (R930X), while the BRIC2 patient was compound heterozygous for two nonsynonymous mutations in exon 9 (E297G) and exon 12 (R432T), respectively. Hepatic BSEP expression was absent in PFIC2 and preserved in BRIC2. In BRIC2, taurocholate transport was decreased to 13% and 20% of reference levels for R432T and E297G, respectively. CONCLUSIONS: The intron 4 (+3)A > C, R930X and R432T represent previously undescribed mutations of the ABCB11 gene that confer a PFIC2 and a BRIC2 phenotype, respectively. By combining functional in-vitro characterization with immunohistochemical detection of variant BSEP we provide direct evidence for the role of ABCB11 mutations in the pathogenesis of different forms of intrahepatic cholestasis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation.

The anaphase-promoting complex or cyclosome (APC/C) is an ubiquitin protein ligase that together with Cdc20 and Cdh1 targets mitotic proteins for degradation by the proteosome. APC-Cdc20 activity during mitosis triggers anaphase by destroying securin and cyclins. APC-Cdh1 promotes degradation of cyclins and other proteins during G(1). We show that loss of APC/C during embryogenesis is early lethal before embryonic day E6.5 (E6.5). To investigate the role of APC/C in quiescent cells, we conditionally inactivated the subunit Apc2 in mice. Deletion of Apc2 in quiescent hepatocytes caused re-entry into the cell cycle and arrest in metaphase, resulting in liver failure. Re-entry into the cell cycle either occurred without any proliferative stimulus or could be easily induced. We demonstrate that the APC has an additional function to prevent hepatocytes from unscheduled re-entry into the cell cycle.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2004

Retroperitoneal perforation of the colon caused by colonic tuberculosis: report of a case.

We present a 25-year-old, HIV-negative patient from Kosovo, with no significant past medical history, who was admitted to a local hospital for nonspecific upper abdominal discomfort. He was transferred to us after a retroperitoneal mass with contact to the right colonic flexure had been found during workup. Colonoscopy demonstrated an edemateous area with a central fistula in the right flexure, and histology showed caseous necrosis. Although neither bacteriology nor histology could detect any germs, gastrointestinal tuberculosis seemed to be very probable. Laparotomy with a segmental resection of the colon was performed to remove the fistula-bearing segment, and histologic examination of the resected specimen confirmed the intraoperative suspect of a retroperitoneal colonic perforation. Again, all cultures from the specimen were negative for tuberculosis, but polymerase chain reaction of a regional lymph node revealed acid-fast bacilli of the Mycobacterium tuberculosis/bovis species. Although the patient had no other sites of tuberculosis infection like pulmonary or urinary, he received adjuvant standard tuberculosis treatment for six months. At control examination one year after the operation, the patient was free of recurrence and in very good general condition. We report this extremely rare presentation of gastrointestinal tuberculosis to sensitize physicians to tuberculosis again, because incidence rates are increasing and this disease will certainly play a more important role in the future.

Abdominal Pain↗
PubMed2003

Epidermal growth factor receptor is a marker for syncytiotrophoblastic cells in testicular germ cell tumors.

The epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis, therapy and prognosis of various tumor types. The aim of this study was to investigate EGFR expression in a large series of testicular germ cell tumors (TGCTs). A total of 88 TGCTs (37 of pure type and 51 of mixed type) comprising a total of 44 seminoma, 49 embryonal carcinoma, 32 yolk sac tumor, 28 teratoma and 7 choriocarcinoma components were immunostained for EGFR. EGFR reactivity was observed in the stromal cells of embryonal carcinoma (29%) and in epithelial compartments of teratoma (71%). In addition, EGFR staining was consistently detected in syncytiotrophoblastic cells of choriocarcinoma, seminoma, embryonal carcinoma and yolk sac tumor components. EGFR staining, similar to beta-human chorionic gonadotropin (HCG) immunohistochemistry, was efficiently able to identify syncytiotrophoblastic cells in TGCTs. This study shows that EGFR is expressed in a subset of testicular germ cell tumors and suggests that EGFR may be a useful marker for syncytiotrophoblastic cells.

Biomarkers, Tumor↗