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Search Results: 1 - 10 of 9976 matches for " Frank Lammert "
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Identification of Combined Genetic Determinants of Liver Stiffness within the SREBP1c-PNPLA3 Pathway
Marcin Krawczyk,Frank Grünhage,Frank Lammert
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms141021153
Abstract: The common PNPLA3 (adiponutrin) variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c), we investigate two common SREBP1c variants (rs2297508 and rs11868035) for their association with liver stiffness. In 899 individuals (aged 17–83 years, 547 males) with chronic liver diseases, hepatic fibrosis was non-invasively phenotyped by transient elastography (TE). The SREBP1c single nucleotide polymorphisms (SNPs) were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection. The SREBP1c rs11868035 variant affected liver fibrosis significantly ( p = 0.029): median TE levels were 7.2, 6.6 and 6.0 kPa in carriers of (TT) ( n = 421), (CT) ( n = 384) and (CC) ( n = 87) genotypes, respectively. Overall, the SREBP1c SNP was associated with low TE levels (5.0–8.0 kPa). Carriers of both PNPLA3 and SREBP1c risk genotypes displayed significantly ( p = 0.005) higher median liver stiffness, as compared to patients carrying none of these variants. The common SREBP1c variant may affect early stages of liver fibrosis. Our study supports a role of the SREBP1c-PNPLA3 pathway as a “disease module” that promotes hepatic fibrogenesis.
Nuclear Receptor Variants in Liver Disease
Roman Müllenbach,Susanne N. Weber,Frank Lammert
Journal of Lipids , 2012, DOI: 10.1155/2012/934707
Abstract: This review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic (“Mendelian”) liver disease and their use in clinical diagnosis. Genetic analysis of multifactorial liver diseases such as viral hepatitis or fatty liver disease identifies key players in disease predisposition and progression. Evidence from these analyses points towards a role of NR polymorphisms in common diseases, linking regulatory networks to complex and variable phenotypes. The new insights into NR variants also offer perspectives and cautionary advice for their use as handles towards diagnosis and treatment. 1. Introduction Systematically, genetic analysis with regard to disease onset and progression can be separated into pre- and post-hoc examination of monogenic or polygenic diseases. Monogenic (“Mendelian”) diseases are caused by a single gene defect and follow relatively straightforward inheritance patterns. The most prominent of these disorders are rather rare, often severe, and characterized by early onset. Genetic testing for monogenic liver disease in symptomatic patients is based on known disease-associated gene variants, thereby confirming the genetic etiology and sometimes allowing prediction of disease progression [1]. In contrast, polygenic diseases such as fatty liver disease and gallstones result from combinations of multiple gene variants and environmental factors, all of which play a role in disease initiation and progression [2]. The assessment of predisposition towards polygenic disease is based on sequence analysis of known contributory genes and construction of “polygenic risk scores” from variants of these genes [1]. Still in its infancy, personal genome information might eventually be able to predict a variety of risks associated with an individual’s lifestyle such as fatty food and alcohol consumption, as well as susceptibility to infectious diseases such as infection with hepatitis B or C virus. 2. Nuclear Receptors Nuclear receptors (NRs) are a subclass of regulatory molecules that orchestrate gene transcription in response to the presence or absence of specific ligands. Due to these functional requirements, they are characterized by the presence of a ligand-binding and a DNA-binding domain. NRs represent a central point of interaction between environment and gene regulation. They are the “hinge” connecting endogenous and environmental stimuli, that is,
Innovative immunohistochemistry identifies MMP-9 expressing macrophages at the invasive front of murine HCC
Martin Roderfeld, Timo Rath, Frank Lammert, Christian Dierkes, Jürgen Graf, Elke Roeb
World Journal of Hepatology , 2010,
Abstract: AIM: To investigate the proteolytic contribution of tumor-associated macrophages (TAM) in tumor invasion, we analyzed whether TAM at the invasive front of small HCC in Abcb4-/--mice show an enhanced expression of MMP-9.METHODS: Liver cryosections of the hepatocellular carcinoma (HCC) invasive front from 12 mo old Abcb4-/--mice were stained for collagen type I and MMP-9 using Alexa488 and Alexa568 labeled secondary antibodies. Afterwards, the Alexa568 dye was bleached and the macrophage marker F4/80 was visualized using Alexa568 labeled secondary antibodies. Finally, photographs of the invasive tumor front were digitally overlaid and analyzed.RESULTS: After complete bleaching of the primary dye, specific fluorescence staining of a third antigen, here F4/80, was successfully performed on the same histological section. With this method, we were able to identify conglomerates of matrix metalloproteinase (MMP-9) expressing macrophages within the tumor capsule of HCC.CONCLUSION: MMP-9 expressing macrophages are involved in matrix remodelling at the invasive tumor front of HCC. The described staining protocol provides a simple yet powerful extension of conventional immuno-histochemistry, facilitating visualization of at least three different antigens plus nuclei in one single histological section.
A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population
Roman Müllenbach, Susanne N Weber, Marcin Krawczyk, Vincent Zimmer, Christoph Sarrazin, Frank Lammert, Frank Günhage
BMC Gastroenterology , 2012, DOI: 10.1186/1471-230x-12-63
Abstract: ABCB11 c.1331?T?>?C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness.Homo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR?=?1.41, CI?=?1.02 - 1.95, p?=?0.037). No association was detectable between the ABCB11 c.1331?T?>?C genotype and increased liver stiffness.Our data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331?T?>?C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.
Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts
Anke T?njes, Henning Wittenburg, Jan Halbritter, Olga Renner, Simone Harsch, Eduard F Stange, Frank Lammert, Michael Stumvoll, Peter Kovacs
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-149
Abstract: Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs).There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis.We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.The pathogenesis of gallstone disease is complex and a variety of environmental predisposing factors such as obesity and rapid weight loss, nutrition, certain medications and number of pregnancies have been identified [1-6]. However, human and murine data suggest a strong genetic component for the risk of gallstone formation [7-18]. Very recently, Renner et al. have identified SLC10A2 (apical sodium-dependent bile acid transporter; protein name ASBT) as a novel susceptibility gene for cholelithiasis in humans [19]. SLC10A2 encodes the cholangiocyte bile salt transporter protein whose expression is reduced by a lithogenic diet in mice [20] and mediates intestinal bile acid absorption [21,22]. ASBT is regulated by changes in gene expression in response to biliary bile salt concentration and inflammatory cytokines and is thought to enable cholangiocytes to sense biliary bile salts in order to activate intracellular signaling pathways [23] and to promote cholehepatic shunting of bile salts.
The presence of non-organ-specific autoantibodies is associated with a negative response to combination therapy with interferon and ribavirin for chronic hepatitis C
Hermann E Wasmuth, Christian Stolte, Andreas Geier, Christoph G Dietrich, Carsten Gartung, Johann Lorenzen, Siegfried Matern, Frank Lammert
BMC Infectious Diseases , 2004, DOI: 10.1186/1471-2334-4-4
Abstract: Anti-nuclear, anti-smooth muscle, anti-mitochondrial, anti-neutrophil-cytoplasmatic and anti-liver/kidney microsomal antibodies were determined in 78 consecutive anti-HCV positive patients by indirect immunofluorescence. The presence of these antibodies was related to demographic variables and to the outcome of antiviral combination therapy with interferon-α and ribavirin in 65 patients.In our study, positivity for autoantibodies was associated with higher alanine aminotransferase levels and higher mean values for HCV-RNA (p < 0.01). Furthermore, negativity for non-organ-specific autoantibodies was associated with a favourable treatment outcome of combination therapy with at least one negative RT-PCR for HCV-RNA during treatment (OR 4.65, 95% CI 1.31 to 16.48, p = 0.02). ANA and SMA staining patterns and titers were not correlated to treatment response. With multiple logistic regression analysis, positivity for autoantibodies and HCV genotype were independently associated with outcome of antiviral combination therapy (p = 0.02).The absence of non-organ-specific autoantibodies might indicate a significantly higher chance for viral clearance in response to combination therapy for chronic hepatitis C infection. Therefore, despite of an overall higher treatment response, the addition of the immunomodulatory drug ribavirin could accentuate immunological differences that affect treatment outcome and might have been less obvious in earlier studies analysing interferon monotherapy.Various immunological phenomena have been described in patients being exposed to the hepatitis C virus (HCV) [1]. Organ-specific and non-organ-specific autoantibodies are found in a considerable number of patients with acute and chronic hepatitis C [2]. Especially the high percentage of non-organ-specific autoantibodies (NOSA) in chronic infection has led to further investigation of the potential biological relevance of these findings. In recent studies the prevalence of different NOSA, including
Effects of common haplotypes of the ileal sodium dependent bile acid transporter gene on the development of sporadic and familial colorectal cancer: A case control study
Frank Grünhage, Matthias Jungck, Christoph Lamberti, Hildegard Keppeler, Ursula Becker, Hildegard Schulte-Witte, Dominik Plassmann, Nicolaus Friedrichs, Reinhard Buettner, Stefan Aretz, Tilman Sauerbruch, Frank Lammert
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-70
Abstract: We included 150 patients with sporadic CRC, 93 patients with familial CRC but exclusion of familial adenomatous polyposis and Lynch's syndrome, and 204 'hyper-normal' controls. Haplotype-tagging SLC10A2 gene variants were identified in the Hapmap database and genotyped using PCR-based 5' exonuclease assays with fluorescent dye-labelled probes. Haplotypes were reconstructed using the PHASE algorithm. Association testing was performed with both SNPs and reconstructed haplotypes.Minor allele frequencies of all SLC10A2 polymorphisms are within previously reported ranges, and no deviations from Hardy-Weinberg equilibrium are observed. However, we found no association with any of the SLC10A2 haplotypes with sporadic or familial CRC in our samples (all P values > 0.05).Common variants of the SLC10A2 gene are not associated with sporadic or familial CRC. Hence, albeit this gene might be associated with early stages of colorectal neoplasia, it appears not to represent a major risk factor for progression to CRC.Colorectal cancer (CRC) is a growing burden on health services throughout Western countries. In contrast to familial CRC syndromes, little is known about the underlying molecular mechanisms in the majority of cases. However, the current paradigm is that CRC is due to the interaction of genetic and environmental factors [1]. The effect of each variable may vary considerably, ranging from monogenic familial cancer syndromes that are predominantly caused by genetic defects to sporadic CRCs, which are probably due to life-long exposure to environmental factors with only minor effects of genetic predisposition.The genes underlying non-syndromic familial CRC are still unknown, or findings have not been reproducible among different studies. A common strategy in experimental genetics is to increase the power by identification of phenotypic extremes and employing association studies in these cohorts, since genetic effects can accumulate in these settings. We have recently succe
A Variant of the SLC10A2 Gene Encoding the Apical Sodium-Dependent Bile Acid Transporter Is a Risk Factor for Gallstone Disease
Olga Renner,Simone Harsch,Elke Schaeffeler,Stefan Winter,Matthias Schwab,Marcin Krawczyk,Jonas Rosendahl,Henning Wittenburg,Frank Lammert,Eduard F. Stange
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007321
Abstract: Cholelithiasis is a multifactorial process and several mechanisms of gallstone formation have been postulated. As one of these mechanisms, a decreased expression of the ileal apical sodium-dependent bile acid transporter gene SLC10A2 in gallstone carriers was described previously. In this study the SLC10A2 gene was investigated to identify novel genetic variants and their association with gallstone formation.
Sensing a Changing World
Arend Ligtenberg,Lammert Kooistra
Sensors , 2009, DOI: 10.3390/s90906819
Abstract: The workshop “Sensing a Changing World” was held in Wageningen, The Netherlands, from November 19–21, 2008. The main goal of the workshop was to explore and discuss recent developments in sensors and (wireless) sensor networks for monitoring environmental processes and human spatial behavior in a changing world. The challenge is then to develop concepts and applications that can provide timely and on-demand knowledge to end-users in different domains over a range of different spatial and temporal scales. During this workshop over 50 participants, representing 15 countries, presented and discussed their recent research. The workshop provided a broad overview of state-of-the-art research in a broad range of application fields: oceanography, air quality, biodiversity and vegetation, health, tourism, water management, and agriculture. In addition the workshop identified the future research challenges. One of the outcomes of the workshop was a special issue in the journal Sensors with contributions presented at the workshop. This editorial of the special issue aims to provide an overview of the discussions held during the workshop. It highlights the ideas of the authors and participants of the workshop about directions of future research for further development of sensor-webs for “sensing” spatial phenomena. The “big” question was are we already able to sense a changing world? And if the answer is positive, then what are we going to sense and for what?
Taming Density Functional Theory by Coarse-Graining
Paul E. Lammert
Physics , 2009, DOI: 10.1103/PhysRevA.82.012109
Abstract: The standard (``fine-grained'') interpretation of quantum density functional theory, in which densities are specified with infinitely-fine spatial resolution, is mathematically unruly. Here, a coarse-grained version of DFT, featuring limited spatial resolution, and its relation to the fine-grained theory in the $L^1\cap L^3$ formulation of Lieb, is studied, with the object of showing it to be not only mathematically well-behaved, but consonant with the spirit of DFT, practically (computationally) adequate and sufficiently close to the standard interpretation as to accurately reflect its non-pathological properties. The coarse-grained interpretation is shown to be a good model of formal DFT in the sense that: all densities are (ensemble)-V-representable; the intrinsic energy functional $F$ is a continuous function of the density and the representing external potential is the (directional) functional derivative of the intrinsic energy. Also, the representing potential $v[\rho]$ is quasi-continuous, in that $v[\rho]\rho$ is continuous as a function of $\rho$. The limit of coarse-graining scale going to zero is studied to see if convergence to the non-pathological aspects of the fine-grained theory is adequate to justify regarding coarse-graining as a good approximation. Suitable limiting behaviors or intrinsic energy, densities and representing potentials are found. Intrinsic energy converges monotonically, coarse-grained densities converge uniformly strongly to their low-intrinsic-energy fine-grainings, and $L^{3/2}+L^\infty$ representability of a density is equivalent to the existence of a convergent sequence of coarse-grained potential/ground-state density pairs.
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