[Show abstract][Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH.
Full-text · Article · Feb 2016 · Molecular Metabolism
[Show abstract][Hide abstract] ABSTRACT: Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5-10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.
Full-text · Article · Jan 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: We have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-β1-mediated cellular responses by blocking the kinase function of the TGF-β type I receptor ALK5 rather than SRC. Here, we investigated the ability of the clinically utilised SRC/ABL inhibitor dasatinib to mimic the PP2/PP1 effect.
The effect of dasatinib on TGF-β1-dependent Smad2/3 phosphorylation, general transcriptional activity, gene expression, cell motility, and the generation of tumour stem cells was measured in Panc-1 and Colo-357 cells using immunoblotting, reporter gene assays, RT-PCR, impedance-based real-time measurement of cell migration, and colony formation assays, respectively.
In both PDAC cell lines, dasatinib effectively blocked TGF-β1-induced Smad phosphorylation, activity of 3TPlux and pCAGA (12) -luc reporter genes, cell migration, and expression of individual TGF-β1 target genes associated with epithelial-mesenchymal transition and invasion. Moreover, dasatinib strongly interfered with the TGF-β1-induced generation of tumour stem cells as demonstrated by gene expression analysis and single cell colony formation. Dasatinib also inhibited the high constitutive migratory activity conferred on Panc-1 cells by ectopic expression of kinase-active ALK5.
Our data suggest that the clinical efficiency of dasatinib may in part be due to cross-inhibition of tumour-promoting TGF-β signalling. Dasatinib may be useful as a dual TGF-β/SRC inhibitor in experimental and clinical therapeutics to prevent metastatic spread in late-stage PDAC and other tumours.
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is the most common clinical disorder of bone metabolism. With regard to the growing spectrum of therapy options, treatment decisions should be made on an individual basis, taking into account the relative benefits and risks in different patient populations. Prioritization of drugs should be based on the form (primary / secondary) and severity of osteoporosis, sex, age, the specific contraindications and precautions of use of the various available medications and in particular, existing comorbidities.
No preview · Article · Nov 2015 · DMW - Deutsche Medizinische Wochenschrift
[Show abstract][Hide abstract] ABSTRACT: Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels.
No preview · Article · Nov 2015 · Cell Biology International
[Show abstract][Hide abstract] ABSTRACT: Radiotherapy, a major treatment modality against cancer, can lead to secondary malignancies but it is uncertain as to whether tumor cells that survive ionizing radiation (IR) treatment undergo epithelial-mesenchymal transition (EMT) and eventually become invasive or metastatic. Here, we have tested the hypothesis that the application of IR (10 MeV photon beams, 2-20 Gy) to lung and pancreatic carcinoma cells induces a migratory/invasive phenotype in these cells by hyperactivation of TGF-β and/or activin signaling. In accordance with this assumption, IR induced gene expression patterns and migratory responses consistent with an EMT phenotype. Moreover, in A549 cells, IR triggered the synthesis and secretion of both TGF-β1 and activin A as well as activation of intracellular TGF-β/activin signaling as evidenced by Smad phosphorylation and transcriptional activation of a TGF-β-responsive reporter gene. These responses were sensitive to SB431542, an inhibitor of type I receptors for TGF-β and activin. Likewise, specific antibody-mediated neutralization of soluble TGF-β, or dominant-negative inhibition of the TGF-β receptors, but not the activin type I receptor, alleviated IR-induced cell migration. Moreover, the TGF-β-specific approaches also blocked IR-dependent TGF-β1 secretion, Smad phosphorylation, and reporter gene activity, collectively indicating that autocrine production of TGF-β(s) and subsequent activation of TGF-β rather than activin signaling drives these changes. IR strongly sensitized cells to further increase their migration in response to recombinant TGF-β1 and this was accompanied by upregulation of TGF-β receptor expression. Our data raise the possibility that hyperactivation of TGF-β signaling during radiotherapy contributes to EMT-associated changes like metastasis, cancer stem cell formation and chemoresistance of tumor cells.
No preview · Article · Aug 2015 · Cellular and Molecular Life Sciences CMLS
[Show abstract][Hide abstract] ABSTRACT: Background
Shiga toxin-producing, enteroaggregative Escherichia coli was responsible for the 2011 outbreak of haemolytic uraemic syndrome (HUS). The present single-centre, observational study describes the 1-year course of the disease with an emphasis on kidney function. Outcome data after 1 year are associated with treatment and patient characteristics at onset of HUS.
Patients were treated according to a standardized approach of supportive care, including a limited number of plasmapheresis. On top of this treatment, patients with severe HUS (n = 35) received eculizumab, a humanized anti-C5 monoclonal antibody inhibiting terminal complement activation. The per-protocol decision—to start or omit an extended therapy with eculizumab accompanied by azithromycin—separated the patients into two groups and marked Day 0 of the prospective study. Standardized visits assessed the patients' well-being, kidney function, neurological symptoms, haematological changes and blood pressure.
Fifty-six patients were regularly seen during the follow-up. All patients had survived without end-stage renal disease. Young(er) age alleviated restoring kidney function after acute kidney injury even in severe HUS. After 1 year, kidney function was affected with proteinuria [26.7%; 95% confidence interval (CI) 13.8–39.6], increased serum creatinine (4.4%, CI 0.0–10.4), increased cystatin C (46.7%, CI 32.1–61.3) and reduced (
[Show abstract][Hide abstract] ABSTRACT: Irregular sleep patterns can adversely affect physiological functions and have been associated with increased physiological and psychological stress. Nocturnal work of physicians during 24-hour on-call shifts (OCS) disrupts the sleep/wake cycle. Chronic exposure to distress has been shown to affect cardiovascular homeostasis and to impair performance in neurocognitive and simulated clinical tasks.
In a prospective cohort study, biochemical and physiological stress parameters were assessed in 11 female and 9 male physicians (median age: 32 years, range 26-42 years) before a normal working day and after a 24-hour OCS in internal medicine. In addition, various tests of attentional performance (TAP) were conducted.
The levels of thyroid stimulating hormone (TSH) were significantly higher after a 24- hour OCS, while there were no significant changes in cortisol, epinephrine, and norepinephrine levels. Heart rate variability and skin resistance increased following an OCS, although the differences were not statistically significant. Intrinsic alertness was comparable, while phasic alertness was significantly improved following a 24-hour OCS. Focused attention tended to be better following a night shift. There was no correlation with age or medical working experience; however, men experienced more stress than women.
Following a 24-hour OCS, (i) TSH may be an early and sensitive biochemical predictor of stress; (ii) other classical biochemical stress parameters do not depict the psychological stress perceived by physicians; (iii) there may be a mismatch between experienced and objective stress levels; (iv) neurocognitive functions are not impaired, while performance may even be improved; and (v) men might be more sensitive to distress.
No preview · Article · Jun 2015 · Journal of Occupational Health
[Show abstract][Hide abstract] ABSTRACT: F1FoATP synthase (ATP synthase) is a ubiquitous enzyme complex in eukaryotes. In general it is localized to the mitochondrial inner membrane and serves as the last step in the mitochondrial oxidative phosphorylation of ADP to ATP, utilizing a proton gradient across the inner mitochondrial membrane built by the complexes of the electron transfer chain. However some cell types, including tumors, carry ATP synthase on the cell surface. It was suggested that cell surface ATP synthase helps tumor cells thriving on glycolysis to survive their high acid generation. Angiostatin, aurovertin, resveratrol, and antibodies against the α and β subunits of ATP synthase were shown to bind and selectively inhibit cell surface ATP synthase, promoting tumor cell death. Here we show that ATP synthase β (ATP5B) is present on the cell surface of mouse pheochromocytoma cells as well as tumor cells of human SDHB-derived paragangliomas (PGLs), while being virtually absent on chromaffin primary cells from bovine adrenal medulla by confocal microscopy. The cell surface location of ATP5B was verified in the tissue of an SDHB-derived PGL by immunoelectron microscopy. Treatment of mouse pheochromocytoma cells with resveratrol as well as ATP5B antibody led to statistically significant proliferation inhibition. Our data suggest that PGLs carry ATP synthase on their surface that promotes cell survival or proliferation. Thus, cell surface ATP synthase may present a novel therapeutic target in treating metastatic or inoperable PGLs.
Full-text · Article · Jun 2015 · American Journal of Cancer Research
[Show abstract][Hide abstract] ABSTRACT: In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug-related hepatotoxicity in IBD is unknown.
The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities.
Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31).
This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies.
Full-text · Article · Jun 2015 · European Journal of Gastroenterology & Hepatology
[Show abstract][Hide abstract] ABSTRACT: Due to the increasing success and survival rates in the primary treatment of malignancies derived from the central nervous (CNS) as well as the hematopoietic system endocrine late effects of cancer and its therapy are of growing importance. Despite evaluation of these late effects in patients treated for cancer in childhood, the impact on adults remains largely unclear.
1035 adult patients primarily diagnosed with a CNS malignancy, a Hodgkin (HL) or non-Hodgkin lymphoma (NHL) between 1998 and 2008 were recruited via the regional epidemiological cancer registry covering approximately 2.8 million inhabitants in the federal state of Schleswig-Holstein, Northern Germany. The prevalence of endocrine disorders and current psychosocial impairment was assessed employing several questionnaires (SF-36v1, WHO-5).
Fully completed questionnaires of 558 patients were available for subsequent analysis showing markedly reduced overall performance and psychological status when compared to German reference data. Thyroid disorders were reported in 16.3% of patients with 10.4% suffering from hypo- and 5.9% from hyperthyroidism. 17.6% stated to be affected by diabetes mellitus with an increased rate of 21.1% among NHL patients and 11.5% of participants were affected by osteoporosis.
Compared to German population based studies on the prevalence of diabetes mellitus, osteoporosis and thyroid disorders the frequency of all these endocrine problems was significantly increased in CNS, HL, and NHL cancer survivors. These data confirm that not only children and adolescents but also adult cancer patients are at risk for therapy associated endocrine late effects.
No preview · Article · May 2015 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: The risk, prevention, and treatment of colorectal neoplasia in inflammatory bowel disease (IBD) are still a matter of debate. The aim of this study was to analyze the occurrence of colorectal neoplasia in IBD patients who underwent proctocolectomy.
The study population comprised of 123 IBD patients who underwent proctocolectomy because of neoplasia, therapy refractivity, or complications between January 2000 and July 2011.
One hundred fourteen (92.7 %) patients were pre-operatively diagnosed with ulcerative colitis, 5 (4.1 %) with colitis indeterminata, and 4 (3.3 %) with colonic Crohn's disease. Colectomy was indicated in 39 (31.7 %) patients because of a neoplasia, in 68 (55.3 %) because of a refractory course of the disease, and in 16 (13.0 %) because of complications. Neoplasia was found in 36 patients on a histopathologic evaluation of the colectomy specimens. Ten (8.1 %) patients post-operatively showed a pre-operatively not described advanced neoplasia. In three (2.4 %) of these patients, the detection of advanced neoplasia (two high-grade intraepithelial neoplasias (IENs), one carcinoma) was a complete de novo finding. Carcinoma had not been diagnosed pre-operatively in six (4.9 %) patients. A multifocal distribution of neoplasia was seen in 66.7 % of patients with neoplasia. The median duration of disease was 15.5 years in case of neoplasia opposed to 6.0 years in those without neoplasia detection.
Our data demonstrate a high rate of pre-operatively undetected high-grade IENs and carcinoma and a frequent multifocal occurrence in IBD patients with long-standing inflammation of the colon. This should be kept in mind for treatment decisions particularly in patients with a chronic refractory course of the disease.
No preview · Article · Apr 2015 · International Journal of Colorectal Disease
[Show abstract][Hide abstract] ABSTRACT: Purpose: Patients with succinate dehydrogenase subunit B (SDHB) mutation-related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) PET/CT as well as CT/MRI. Experimental Design: [68Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. Results: [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%-99.5%], [18F]-FDG, [18F]-FDOPA, [18F]-FDAPET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%-89.4%; P< 0.01), 61.4% (CI, 55.6%-66.9%; P< 0.01), 51.9% (CI, 46.1%-57.7%; P < 0.01), and 84.8% (CI, 80.0%-88.5%; P < 0.01), respectively. Conclusions: [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL.
No preview · Article · Apr 2015 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 is expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 genes as well as ERK1/2, p38 and JNK1/2 signalling cascades. This has implications for understanding the role of NUCB2/nesfatin in adrenal zonal development. NUCB2/nesfatin may also be a therapeutic target for adrenal cancer. However, further studies using in vivo models are needed to clarify these concepts.
No preview · Article · Apr 2015 · Journal of Endocrinology