H Lehnert

Universität zu Lübeck, Lübeck Hansestadt, Schleswig-Holstein, Germany

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Publications (485)1255.54 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aldosterone-producing adenomas (APAs) are found in 1.5-3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca(2) (+) regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca(2) (+) levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration. © 2015 Society for Endocrinology.
    Endocrine Related Cancer 10/2015; 22(5):735-44. DOI:10.1530/ERC-15-0321 · 4.81 Impact Factor
  • Leukemia and Lymphoma 09/2015; DOI:10.3109/10428194.2015.1099648 · 2.89 Impact Factor
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    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.
    Cellular and Molecular Life Sciences CMLS 08/2015; DOI:10.1007/s00018-015-2003-2 · 5.81 Impact Factor
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    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.
    Nephrology Dialysis Transplantation 07/2015; DOI:10.1093/ndt/gfv255 · 3.58 Impact Factor
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    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.
    Journal of Occupational Health 06/2015; DOI:10.1539/joh.14-0276-OA · 1.11 Impact Factor
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    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.
    American Journal of Cancer Research 06/2015; 5(4):1558-70. · 4.17 Impact Factor
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    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.
    European Journal of Gastroenterology & Hepatology 06/2015; 27(6). DOI:10.1097/MEG.0000000000000350 · 2.25 Impact Factor
  • Leukemia & lymphoma 05/2015; DOI:10.3109/10428194.2015.1046863 · 2.89 Impact Factor
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    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.
    European Journal of Endocrinology 05/2015; 173(2). DOI:10.1530/EJE-15-0174 · 4.07 Impact Factor
  • 05/2015; DOI:10.1530/endoabs.37.EP610
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    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.
    International Journal of Colorectal Disease 04/2015; 30(6). DOI:10.1007/s00384-015-2217-7 · 2.45 Impact Factor
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    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 [(68)Ga]-DOTA(0)-Tyr(3)-octreotate ([(68)Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [(18)F]-fluorodopamine ([(18)F]-FDA), [(18)F]-fluorodihydroxyphenylalanine ([(18)F]-FDOPA), [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]- FDG) PET/CT as well as CT/MRI. Experimental design: [(68)Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [(18)F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [(18)F]-FDOPA and [(18)F]-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: [(68)Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%-99.5%], [(18)F]-FDG, [(18)F]-FDOPA, [(18)F]-FDA PET/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: [(68)Ga]-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. Clin Cancer Res; 21(17); 3888-95. ©2015 AACR.See related commentary by Hofman and Hicks, p. 3815.
    Clinical Cancer Research 04/2015; 21(17). DOI:10.1158/1078-0432.CCR-14-2751 · 8.72 Impact Factor
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    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.
    Journal of Endocrinology 04/2015; 226(1). DOI:10.1530/JOE-14-0496 · 3.72 Impact Factor
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  • 81. Jahrestagung der Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung, Mannheim; 04/2015
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    58. Jahrestagung der Deutschen Gesellschaft für Endokrinologie in Lübeck 2015; 03/2015
  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1549071 · 1.56 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547657 · 1.56 Impact Factor
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    ABSTRACT: Preparing high quality discharge summaries is difficult for first year residents. For 5 years we have been training fourth year students how to write discharge summaries. Our goal is to facilitate the students' start into clinical work. Moreover, we intend to provide the students with a scheme to better memorize patients' histories. Two years after the tutorial the graduates were asked to evaluate the tutorial and to comment on its learning effects. A total of 1228 fourth year students wrote a discharge summary on a patient in whose care the specific student was involved during his or her training in internal medicine. All summaries were read, commented on and graded by a consultant. Two years after the tutorial 310 graduates were invited to complete an online survey on this tutorial. 106 (34 %) of all invited graduates completed the survey. The opinions on the tutorial greatly differed. In principal the students agreed that the tutorial was an important part of medical training and helped to better structure patients' medical data. The majority of the surveyed graduates, however, were not convinced of its practical usefulness for daily work. The students with the poorer grading found their grade less appropriate than the students with the better grading. Though our main goal could not be achieved in the view of the graduates, the overall opinion was rather positive. Problems with this kind of tutorial lay in the enormous effort of correction and in the discouraging effect of grading on the students with difficulties in the task.
    Wiener Medizinische Wochenschrift 03/2015; 165(5-6). DOI:10.1007/s10354-015-0345-x
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    ABSTRACT: Adrenal insufficiency (AI) is a rare disease caused by destruction of the adrenal glands or dysfunction of the pituitary gland or the hypothalamus. Treatment usually requires lifelong replacement therapy with glucocorticoids. Correct use of glucocorticoids and early dose adjustments are essential to cover the increased glucocorticoid demand in stress. Repeated education of patients and their partners is the best strategy to avoid life-threatening emergencies. However, there is a debate whether physicians' knowledge regarding AI is sufficient, in part due to the rareness of this endocrine disorder. To determine the present specific knowledge of physicians in a large University Department of Internal Medicine with a clinically and scientifically active Division of Endocrinology, all interns, residents / fellows, specialists or senior physicians / consultants were asked to complete a questionnaire with various possible answers on the subject of AI (n=69, median age 30 years, range 23-49 years). The present data suggest that in the investigated University Hospital setting current physicians' knowledge of medical replacement strategies in AI may be insufficient depending on the level of education and experience. Even physicians with training in endocrinology in part demonstrated extensive knowledge gaps. There might be a need for additional structured information and training on AI, even in specialized hospitals.
    Endocrine Journal 02/2015; 62(5). DOI:10.1507/endocrj.EJ14-0612 · 2.00 Impact Factor

Publication Stats

6k Citations
1,255.54 Total Impact Points


  • 2008–2015
    • Universität zu Lübeck
      • Department of Internal Medicine I
      Lübeck Hansestadt, Schleswig-Holstein, Germany
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 2006–2015
    • The University of Warwick
      • • Warwick Medical School (WMS)
      • • Division of Metabolic and Vascular Health
      Coventry, England, United Kingdom
  • 2007–2014
    • Universitätsklinikum Schleswig - Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2013
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Роквилл, Maryland, United States
  • 2006–2011
    • Technische Universität Dresden
      • Institut für Klinische Pharmakologie
      Dresden, Saxony, Germany
  • 2010
    • Leiden University Medical Centre
      • Department of Nephrology
      Leyden, South Holland, Netherlands
  • 2005–2010
    • Coventry University
      Coventry, England, United Kingdom
  • 2009
    • Warwick Business School
      Warwick, England, United Kingdom
    • Klinikum Stuttgart
      Stuttgart, Baden-Württemberg, Germany
  • 2007–2008
    • University Hospitals Coventry and Warwickshire NHS Trust
      Coventry, England, United Kingdom
  • 1996–2008
    • Otto-von-Guericke-Universität Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 1994–2006
    • University Hospital Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 2003
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 1988–2000
    • Johannes Gutenberg-Universität Mainz
      • • III. Department of Medicine
      • • Abteilung für Retinologie
      Mayence, Rheinland-Pfalz, Germany
  • 1989–1993
    • Universität Trier
      • Department of Clinical Psychophysiology
      Trier, Rheinland-Pfalz, Germany
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 1984–1986
    • Massachusetts Institute of Technology
      • Department of Brain and Cognitive Sciences
      Cambridge, Massachusetts, United States