TY  - JOUR
AB  - Regulatory T cells (Treg cells) act as a major rheostat regulating the strength of immune responses, enabling tolerance of harmless foreign antigens, and preventing the development of pathogenic immune responses in various disease settings such as cancer and autoimmunity. Treg cells are present in all lymphoid and non-lymphoid tissues, and the latter often fulfill important tasks required for the physiology of their host organ. The activation of NF-κB transcription factors is a central pathway for the reprogramming of gene expression in response to inflammatory but also homeostatic cues. Genetic mouse models have revealed essential functions for NF-κB transcription factors in modulating Treg development and function, with some of these mechanistic insights confirmed by recent studies analyzing Treg cells from patients harboring point mutations in the genes encoding NF-κB proteins. Molecular insights into the NF-κB pathway in Treg cells hold substantial promise for novel therapeutic strategies to manipulate dysfunctional or inadequate cell numbers of immunosuppressive Treg cells in autoimmunity or cancer. Here, we provide an overview of the manifold roles that NF-κB factors exert in Treg cells.
AU  - Hoevelmeyer, N.*
AU  - Schmidt-Supprian, M.*
AU  - Ohnmacht, C.
C1  - 65391
C2  - 52289
SP  - 985-995
TI  - NF-kappa B in control of regulatory T cell development, identity, and function.
JO  - J. Mol. Med.
VL  - 100
IS  - 7
PY  - 2022
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - SARS-CoV-2 has evolved to enter the host via the ACE2 receptor which is part of the kinin-kallikrein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV-2-infection and epithelial mechanisms of the kinin-kallikrein-system at the kinin B2 receptor level in SARS-CoV-2-infection that is of direct translational relevance. From acute SARS-CoV-2-positive study participants and -negative controls, transcriptomes of nasal curettages were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B2R-antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays, and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo. Here, we report a broad and strong upregulation of kallikreins and the kinin B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive study participants. A B2R-antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero-E6 cells. B2R-antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2, G protein-coupled receptor signaling, and ion transport in vitro and in a murine airway inflammation in vivo model. In summary, this study provides evidence that treatment with B2R-antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B2R-antagonists, like icatibant, in the treatment of early-stage COVID-19. KEY MESSAGES: Induction of kinin B2 receptor in the nose of SARS-CoV-2-positive patients. Treatment with B2R-antagonist protects airway epithelial cells from SARS-CoV-2. B2R-antagonist reduces ACE2 levels in vivo and ex vivo. Protection by B2R-antagonist is mediated by inhibiting viral replication and spread.
AU  - Jakwerth, C.A.
AU  - Feuerherd, M.
AU  - Guerth, F.
AU  - Oelsner, M.
AU  - Schellhammer, L.*
AU  - Giglberger, J.
AU  - Pechtold, L.*
AU  - Jerin, C.
AU  - Kugler, L.*
AU  - Mogler, C.*
AU  - Haller, B.*
AU  - Erb, A.
AU  - Wollenberg, B.*
AU  - Spinner, C.D.*
AU  - Buch, T.*
AU  - Protzer, U.
AU  - Schmidt-Weber, C.B.
AU  - Zissler, U.M.
AU  - Chaker, A.
C1  - 64513
C2  - 52189
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
SP  - 613-627
TI  - Early reduction of SARS-CoV-2-replication in bronchial epithelium by kinin B2 receptor antagonism.
JO  - J. Mol. Med.
VL  - 100
IS  - 4
PB  - Springer Heidelberg
PY  - 2022
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - In chronic kidney disease, hyperphosphatemia is a key pathological factor promoting medial vascular calcification, a common complication associated with cardiovascular events and mortality. This active pathophysiological process involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs) via complex intracellular mechanisms that are still incompletely understood. Little is known about the effects of phosphate on the bioenergetic profile of VSMCs during the onset of this process. Therefore, the present study explored the effects of the phosphate donor beta-glycerophosphate on cellular bioenergetics of VSMCs. Mitochondrial and glycolytic functions were determined utilizing extracellular flux analysis in primary human aortic VSMCs following exposure to beta-glycerophosphate. In VSMCs, beta-glycerophosphate increased basal respiration, mitochondrial ATP production as well as proton leak and decreased spare respiratory capacity and coupling efficiency, but did not modify non-mitochondrial or maximal respiration. beta-Glycerophosphate-treated VSMCs had higher ability to increase mitochondrial glutamine and long-chain fatty acid usage as oxidation substrates to meet their energy demand. beta-Glycerophosphate did not modify glycolytic function or basal and glycolytic proton efflux rate. In contrast, beta-glycerophosphate increased non-glycolytic acidification. beta-Glycerophosphate-treated VSMCs had a more oxidative and less glycolytic phenotype, but a reduced ability to respond to stressed conditions via mitochondrial respiration. Moreover, compounds targeting components of mitochondrial respiration modulated beta-glycerophosphate-induced oxidative stress, osteo-/chondrogenic signalling and mineralization of VSMCs. In conclusion, beta-glycerophosphate modifies key parameters of mitochondrial function and cellular bioenergetics in VSMCs that may contribute to the onset of phenotypical transdifferentiation and calcification. These observations advance the understanding of the role of energy metabolism in VSMC physiology and pathophysiology of vascular calcification during hyperphosphatemia.
AU  - Alesutan, I.*
AU  - Moritz, F.
AU  - Haider, T.*
AU  - Shouxuan, S.*
AU  - Gollmann-Tepeköylü, C.*
AU  - Holfeld, J.*
AU  - Pieske, B.*
AU  - Lang, F.*
AU  - Eckardt, K.U.*
AU  - Heinzmann, S.S.
AU  - Voelkl, J.*
C1  - 59307
C2  - 48779
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
SP  - 985–997
TI  - Impact of beta-glycerophosphate on the bioenergetic profile of vascular smooth muscle cells.
JO  - J. Mol. Med.
VL  - 98
PB  - Springer Heidelberg
PY  - 2020
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Patients with early-stage lung adenocarcinoma (LUAD) exhibit different overall survival (OS) rates and immunotherapy responses. Understanding the immune landscape facilitates the personalized treatment of LUAD. The immune cell populations in tumour tissues were quantified to depict the immune landscape in early-stage LUAD patients in The Cancer Genome Atlas (TCGA). Early-stage LUAD patients in three immune clusters identified by the immune landscape exhibited different survival potentials. A prognostic immune-related gene signature was built to predict the survival of early-stage LUAD patients. Several machine learning methods (support vector machine, naive Bayes, random forest, and neural network-based deep learning) were applied to train the classifiers to identify the immune clusters in early-stage LUAD based on the gene signature. The four classifiers exhibited a robust effect in identifying the immune clusters. A random forest regression model identified that TP53 was the most important gene mutation associated with the immune-related signature. Furthermore, a decision tree and a nomogram were constructed based on the immune-related gene signature and clinicopathological traits to improve risk stratification and quantify risk assessment for individual patients. Five external test cohorts were applied to validate the accuracy of the immune-related signature. Our study might contribute to the development of immunotherapy and the personalized treatment of early-stage LUAD. Key messagesImmune landscape correlates with the clinical outcome of early-stage adenocarcinoma (LUAD). Machine learning methods identifies a prognostic gene signature to predict the survival and prognosis of early-stage LUAD. TP53 gene mutation status correlates with the immune landscape in early-stage LUAD.
AU  - Bao, X.
AU  - Shi, R.*
AU  - Zhao, T.
AU  - Wang, Y.*
C1  - 58947
C2  - 48507
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
SP  - 805-818
TI  - Immune landscape and a novel immunotherapy-related gene signature associated with clinical outcome in early-stage lung adenocarcinoma.
JO  - J. Mol. Med.
VL  - 98
IS  - 6
PB  - Springer Heidelberg
PY  - 2020
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggestedPSRC1(proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation ofPSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function ofS(all) > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 x 10(-7)) in one promoter region, which was in line with a significantly lowerPSRC1mRNA expression levels in blood (P = 1 x 10(-3)). Consistently, rs629301-A allele was associated with lowerPSRC1mRNA expression (P < 1 x 10(-7)). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription ofPSRC1through alteration of YY1 binding capacity. DNA methylation studies further support the role ofPSRC1in regulation of progranulin serum levels. Key messages(proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates expression by affecting Yin Yang 1 transcription factor (YY1) binding. is also epigenetically regulated in subjects with high progranulin levels.
AU  - Keller, M.
AU  - Gebhardt, C.
AU  - Huth, S.*
AU  - Schleinitz, D.*
AU  - Heyne, H.*
AU  - Scholz, M.*
AU  - Stumvoll, M.
AU  - Böttcher, Y.*
AU  - Tönjes, A.*
AU  - Kovacs, P.*
C1  - 59603
C2  - 48869
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
SP  - 1139–1148
TI  - Genetically programmed changes in transcription of the novel progranulin regulator.
JO  - J. Mol. Med.
VL  - 98
IS  - 8
PB  - Springer Heidelberg
PY  - 2020
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Early onset infection (EOI) in preterm infants <32 weeks gestational age (GA) is associated with a high mortality rate and the development of severe acute and long-term complications. The pathophysiology of EOI is not fully understood and clinical and laboratory signs of early onset infections in this patient cohort are often not conclusive. Thus, the aim of this study was to identify signatures characterizing preterm infants with EOI by using genome-wide gene expression (GWGE) analyses from umbilical arterial blood of preterm infants. This prospective cohort study was conducted in preterm infants <32 weeks GA. GWGE analyses using CodeLink human microarrays were performed from umbilical arterial blood of preterm infants with and without EOI. GWGE analyses revealed differential expression of 292 genes in preterm infants with EOI as compared to infants without EOI. Infants with EOI could be further differentiated into two subclasses and were distinguished by the magnitude of the expression of genes involved in both neutrophil and T cell activation. A hallmark activity for both subclasses of EOI was a common suppression of genes involved in natural killer (NK) cell function, which was independent from NK cell numbers. Significant results were recapitulated in an independent validation cohort. Gene expression profiling may enable early and more precise diagnosis of EOI in preterm infants. KEY MESSAGE: Gene expression (GE) profiling at birth characterizes preterm infants with EOI. GE analysis indicates dysregulation of NK cell activity. NK cell activity at birth may be a useful marker to improve early diagnosis of EOI.
AU  - Hilgendorff, A.
AU  - Windhorst, A.*
AU  - Klein, M.*
AU  - Tchatalbachev, S.*
AU  - Windemuth-Kieselbach, C.*
AU  - Kreuder, J.*
AU  - Heckmann, M.*
AU  - Gkatzoflia, A.*
AU  - Ehrhardt, H.*
AU  - Mysliwietz, J.
AU  - Maier, M.*
AU  - Izar, B.*
AU  - Billion, A.*
AU  - Gortner, L.*
AU  - Chakraborty, T.*
AU  - Hossain, H.*
C1  - 49350
C2  - 41764
CY  - New York
SP  - 169-180
TI  - Gene expression profiling at birth characterizing the preterm infant with early onset infection.
JO  - J. Mol. Med.
VL  - 95
IS  - 2
PB  - Springer
PY  - 2017
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - We studied HLA class II molecules on blood monocyte subsets, blood dendritic cells, sputum macrophages, and monocyte-derived macrophages at the protein (flow cytometry) and mRNA level (RT-PCR) in adult patients with cystic fibrosis (CF) and healthy control subjects as putative contributors to the CF phenotype. In healthy donors, we found a high average HLA-DQ expression of 4.35 mean specific fluorescence intensity units (ΔMnI) on classical blood monocytes. In F508del homozygous CF patients, the average ΔMnI was low (1.80). Patients were divided into two groups, in which 14 of these patients had HLA-DQ expression above 2 ΔMnI (average 3.25 ΔMnI, CF-DQgroup1) and 36 below (average 1.24 ΔMnI, CF-DQgroup2). Also, the CD16-positive monocyte subset and blood dendritic cells showed much lower levels of HLA-DQ for the CF-DQgroup2 patients compared with healthy controls. In macrophages from sputum and derived from monocytes, in vitro HLA-DQ expression was dramatically decreased to background levels in CF-DQgroup2. MHC class II transcripts were reduced in CF with a sevenfold decrease in HLA-DQβ1 for CF-DQgroup2 patients. Higher levels of the inflammation marker CRP were associated with low HLA-DQ protein expression, and in vitro treatment with the inflammatory molecule lipopolysaccharide reduced HLA-DQ expression. Interferon γ (IFNγ) could overcome this effect in healthy donor cells while, in CF, the IFNγ-induced activation was impaired. Our data demonstrate a pronounced reduction of HLA-DQ expression in CF, which is associated with inflammation and a reduced response to IFNγ. Key message • CF patients show a reduced expression of MHCII molecules in monocytes and macrophages.• HLA-DQ and HLA-DR transcript levels are also reduced in CF patients.• CF patient C-reactive protein levels correlate with low HLA-DQ expression.• Reduced expression of MHC class II molecules appears to be linked to inflammation.• CF patients exhibit an impaired response to IFNgamma.
AU  - Hofer, T.P.
AU  - Frankenberger, M.
AU  - Heimbeck, I.
AU  - Burggraf, D.
AU  - Wjst, M.
AU  - Wright, A.K.A.*
AU  - Kerscher, M.*
AU  - Nährig, S.*
AU  - Huber, R.*
AU  - Fischer, R.*
AU  - Ziegler-Heitbrock, L.
C1  - 31993
C2  - 34935
SP  - 1293-1304
TI  - Decreased expression of HLA-DQ and HLA-DR on cells of the monocytic lineage in cystic fibrosis.
JO  - J. Mol. Med.
VL  - 92
IS  - 12
PY  - 2014
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Clear cell renal cell carcinoma (ccRCC) is an aggressive and difficult to manage cancer. Immunotherapy has the potential to induce long-lasting regression in a small group of patients. However, severe side effects limit broad application which highlights the need for a marker to distinguish responder from nonresponder. TNMG staging, referring to tumor size, lymph node involvement, presence of metastasis, and grade of tumor differentiation, represents an important prognostic system but is not useful for predicting responders to immunotherapy. NK cells are potent antitumor effector cells, and a role as prognostic marker in some solid tumors has been suggested. As NK cells are responsive to various immune modifiers, they may be important mediators of patient response to immunotherapies, in particular those including IL-2. We report that the NK cell percentage within RCC-infiltrating lymphocytes, as determined by flow cytometry, allows ccRCC subgrouping in NK(high)/NK(low) tissues independent of TNMG classification. Quantitative reverse transcriptase polymerase chain reaction using whole-tissue RNA identified four markers (NKp46, perforin, CX(3)CL1, and CX(3)CR1) whose transcript levels reproduced the NK(high)/NK(low) tissue distinction identified by flow cytometry with high selectivity and specificity. Combined in a multiplex profile and analyzed using neural network, the accuracy of predicting the NK(high)/NK(low) groups was 87.8%, surpassing that of each single marker. The tissue transcript signature, based on a robust high-throughput methodology, is easily amenable to archive material and clinical translation. This now allows the analysis of large patient cohorts to substantiate a role of NK cells in cancer progression or response to immunotherapy.
AU  - Eckl, J.
AU  - Buchner, A.*
AU  - Prinz, P.U.
AU  - Riesenberg, R.*
AU  - Siegert, S.I.*
AU  - Kammerer, R.*
AU  - Nelson, P.J.*
AU  - Nößner, E.
C1  - 7134
C2  - 29462
CY  - Berlin
SP  - 55-66
TI  - Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging.
JO  - J. Mol. Med.
VL  - 90
IS  - 1
PB  - Springer
PY  - 2012
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - In papillary thyroid carcinoma (PTC), metastasis is a feature of an aggressive tumor phenotype. To identify protein biomarkers that distinguish patients with an aggressive tumor behavior, proteomic signatures in metastatic and non-metastatic tumors were investigated comparatively. In particular, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to analyze primary tumor samples. We investigated a tumor cohort of PTC (n = 118) that were matched for age, tumor stage, and gender. Proteomic screening by MALDI-IMS was performed for a discovery set (n = 29). Proteins related to the discriminating mass peaks were identified by 1D-gel electrophoresis followed by mass spectrometry. The candidate proteins were subsequently validated by immunohistochemistry (IHC) using a tissue microarray for an independent PTC validation set (n = 89). In this study, we found 36 mass-to-charge-ratio (m/z) species that specifically distinguished metastatic from non-metastatic tumors, among which m/z 11,608 was identified as thioredoxin, m/z 11,184 as S100-A10, and m/z 10,094 as S100-A6. Furthermore, using IHC on the validation set, we showed that the overexpression of these three proteins was highly associated with lymph node metastasis in PTC (p < 0.005). For functional analysis of the metastasis-specific proteins, we performed an Ingenuity Pathway Analysis and discovered a strong relationship of all candidates with the TGF-β-dependent EMT pathway. Our results demonstrated the potential application of the MALDI-IMS proteomic approach in identifying protein markers of metastasis in PTC. The novel protein markers identified in this study may be used for risk stratification regarding metastatic potential in PTC.
AU  - Nipp, M.
AU  - Elsner, M.
AU  - Balluff, B.
AU  - Meding, S.
AU  - Sarioglu, H.
AU  - Ueffing, M.
AU  - Rauser, S.
AU  - Unger, K.*
AU  - Höfler, H.
AU  - Walch, A.K.
AU  - Zitzelsberger, H.
C1  - 6613
C2  - 28976
SP  - 163-174
TI  - S100-A10, thioredoxin, and S100-A6 as biomarkers of papillary thyroid carcinoma with lymph node metastasis identified by MALDI Imaging.
JO  - J. Mol. Med.
VL  - 90
IS  - 2
PB  - Spinger
PY  - 2012
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Human epidermal growth factor receptor 2 (HER2) has been successfully targeted as a breast cancer-associated antigen by various strategies. HER2 is also overexpressed in other solid tumors such as stomach cancer, as well as in hematological malignancies such as acute lymphoblastic leukemia. HER2-targeted therapies are currently under clinical investigation for a panel of malignancies. In this study, we isolated the T cell receptor (TCR) genes of a HER2-reactive allo-human leukocyte antigen-A2-restricted CTL clone and introduced the TCRalpha- and beta-chain genes into the retrovirus vector MP71. Murinization and codon optimization of the HER2-reactive TCR was required for efficient TCR expression in primary human T cells. The tumor recognition efficiency of HER2-TCR gene-modified T cells was similar to the parental CTL clone from which the TCR genes were isolated. The known cross-reactivity of the HER2-reactive TCR with HER3 and HER4 was retained when the TCR was transduced into primary T cells. Our results could contribute to the development of a TCR-based approach for the treatment of HER2-positive breast cancer, as well as of other malignancies expressing HER2, HER3, and/or HER4.
AU  - Meyerhuber, P.*
AU  - Conrad, H.
AU  - Stärck, L.*
AU  - Leisegang, M.*
AU  - Busch, D.H.
AU  - Uckert, W.*
AU  - Bernhard, H.
C1  - 4872
C2  - 27473
SP  - 1113-1121
TI  - Targeting the epidermal growth factor receptor (HER) family by T cell receptor gene-modified T lymphocytes.
JO  - J. Mol. Med.
VL  - 88
IS  - 11
PB  - Springer
PY  - 2010
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Host protection against fungi depends on intact innate and adaptive immune responses. Consistently, fungal infections can cause systemic life-threatening diseases in immunocomprimised individuals, suffering e.g. from cancer or AIDS. Recent work has uncovered essential roles for the spleen tyrosine kinase (SYK) and the cytosolic NLRP3 inflammasome for Interleukin-1beta (IL-1beta) production in innate antifungal immunity. Upon fungal infection, SYK is activated by several C-type lectin pattern recognition receptors on myeloid cells. Subsequently, SYK signals for the production of reactive oxygen species and for gene transcription to induce pro-inflammatory factors, including pro-IL-1beta to initiate antifungal responses. Mature IL-1beta production additionally requires cleavage of the pro-IL-1beta precursor protein by the inflammatory caspase-1 which is controlled within the NLRP3 inflammasome. Here, we discuss how SYK signaling cooperates with the NLRP3 inflammasome for IL-1beta production in antifungal immunity.
AU  - Poeck, H.*
AU  - Ruland, J.
C1  - 3421
C2  - 27786
SP  - 745-752
TI  - SYK kinase signaling and the NLRP3 inflammasome in antifungal immunity.
JO  - J. Mol. Med.
VL  - 88
IS  - 8
PB  - Springer
PY  - 2010
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - The development of immunotherapies for renal cell carcinoma (RCC) has been the subject of research for several decades. In addition to cytokine therapy, the benefit of various adoptive cell therapies has again come into focus in the past several years. Nevertheless, success in fighting this immunogenic tumor is still disappointing. RCC can attract a multitude of different effector cells of both the innate and adaptive immune system, including natural killer (NK) cells, gamma delta T cells, NK-like T cells, peptide-specific T cells, dendritic cells (DC), and regulatory T cells (Tregs). Based on intensive research on the biology and function of different immune cells, we now understand that individual cell types do not act in isolation but function within a complex network of intercellular interactions. These interactions play a pivotal role in the efficient activation and function of effector cells, which is a prerequisite for successful tumor elimination. This review provides a current overview of the diversity of effector cells having the capacity to recognize RCC. Aspects of the functions and anti-tumor properties that make them attractive candidates for adoptive cell therapies, as well as experience in clinical application are discussed. Improved knowledge of the biology of this immune network may help us to effectively harness various effector cells, placing us in a better position to develop new therapeutic strategies to successfully fight RCC.
AU  - Geiger, C.
AU  - Nößner, E.
AU  - Frankenberger, B.
AU  - Falk, C.S.*
AU  - Pohla, H.*
AU  - Schendel, D.J.
C1  - 914
C2  - 26160
CY  - Heidelberg
SP  - 595-612
TI  - Harnessing innate and adaptive immunity for adoptive cell therapy of renal cell carcinoma.
JO  - J. Mol. Med.
VL  - 87
IS  - 6
PB  - Springer
PY  - 2009
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - It is well established that genetic alterations may be associated to prognosis in tumor patients. This study investigates chromosomal changes that predict the clinical outcome of head and neck squamous cell carcinoma (HNSCC) and correlate to characteristic clinicopathological parameters. We applied comparative genomic hybridization (CGH) to tissue samples from 117 HNSCC patients scheduled for radiotherapy. Genomic aberrations occurring in more than five patients were studied for impact on locoregional progression (LRP)-free survival. p values were adjusted by the Hochberg-Benjamini procedure and significant aberrations and clinical variables subjected to a stepwise backwards Cox proportional model. Significant alterations were further analyzed by array-CGH and fluorescence in situ hybridization (FISH). In multivariate survival analysis gains on 1q and 16q predict reduced LRP-free survival independently from known prognostic factors. Cluster analysis separated the HNSCC cases into two groups (cluster 1 and 2) that are characterized by significant differences for imbalances in 13 chromosomal regions. Moreover, it became apparent that cluster 1 correlates to nonanemic patients, while cluster 2 represents predominantly anemic cases. Array-CGH pinpoints 16q24.3 to be the region of interest on chromosome 16 which was further verified by FISH analysis where an increased copy number of FANCA, a member of the Fanconi anemia/breast cancer pathway, could be identified. This study demonstrates that chromosomal gains on 1q and 16q as well as chromosomal loss on 18q represent prognostic markers in HNSCC and that these alterations may explain to some extent the dismal course of a subgroup of patients.
AU  - Bauer, V.L.
AU  - Braselmann, H.
AU  - Henke, M.*
AU  - Mattern, D.*
AU  - Walch, A.K.
AU  - Unger, K.
AU  - Baudis, M.*
AU  - Lassmann, S.*
AU  - Huber, R.
AU  - Wienberg, J.*
AU  - Werner, M.*
AU  - Zitzelsberger, H.
C1  - 4538
C2  - 25614
SP  - 1353-1365
TI  - Chromosomal changes characterize head and neck cancer with poor prognosis.
JO  - J. Mol. Med.
VL  - 86
IS  - 12
PB  - Springer
PY  - 2008
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - The regulated expression of ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs), a secreted metalloproteinase involved in the processing of procollagen to collagen, was studied in peripheral blood mononuclear cells (PBMC). Stimulation with glucocorticoids (GC) resulted in a pronounced dose- and time-dependent increase of ADAMTS2 mRNA levels in PBMC. The increase of ADAMTS2 expression was specific for CD14++ monocytes (440-fold) and alveolar macrophages (200-fold), whereas CD3+ (T lymphocytes), phytohemagglutinin-activated CD3+ (T lymphocytes), and CD19+ (B lymphocytes) showed no significant changes in ADAMTS2 mRNA after GC treatment. Treatment of monocyte-derived macrophages (MDM) with GC also resulted in an increase of ADAMTS2 protein in the culture tissue media. Using the GC analog RU486, GC-mediated induction of ADAMTS2 mRNA was blocked, implicating that GC acts specifically via the GC-receptor. In agreement with findings in blood monocytes, cell lines of the monocytic lineage (MM6, THP-1) showed significant GC-induced significant increases in ADAMTS2 mRNA, while in epithelial cells (A549, Calu-3, Colo320, BT-20) and fibroblast (MRC-5, WI-38, and two NHDF-c cell types from adult cheek and upper arm), they showed no or little responsiveness to GC. As macrophages have important functions in immune defense and tissue homeostasis, these findings suggest that GC-mediated specific induction of ADAMTS2 in these cells may play a crucial role in the resolution of inflammation and wound repair.
AU  - Hofer, T.P.
AU  - Frankenberger, M.
AU  - Mages, J.*
AU  - Lang, R.*
AU  - Meyer, P.*
AU  - Hoffmann, R.*
AU  - Colige, A.*
AU  - Ziegler-Heitbrock, L.
C1  - 1534
C2  - 25443
SP  - 323-332
TI  - Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids.
JO  - J. Mol. Med.
VL  - 86
IS  - 3
PB  - Springer
PY  - 2008
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Recent data provided strong evidence for the association of single nucleotide polymorphisms (SNPs) in the lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) genes with myocardial infarction (MI) in a Japanese population. For populations of other genetic background, the relevance of these polymorphisms in the pathogenesis of MI remains controversial. We aimed to define the role of LTA and LGALS2 SNPs in two German MI populations with markedly different ascertainment strategies. Two different MI populations were studied. In the first population, MI patients were ascertained by a strong family history of MI (n=1214). Controls were unrelated disease-free participants of the study (n=1080). The second population included patients suffering from sporadic (nonfamilial) MI from the German KORA register (n=607). The control group consisted of participants of the WHO MONICA survey in Germany (n=1492). TaqMan assays were used to determine the genotypes of 4 SNPs in the LTA genomic region and 1 SNP in the LGALS2 gene. Single SNPs in both genomic regions as well as haplotypes in the LTA genomic region were tested for association in various models of inheritance. No association with MI could be found for any of the examined SNPs in the LTA genomic region and LGALS2 gene, or for haplotypes spanning the LTA genomic region. In two MI populations of European descent with markedly different ascertainment strategies, we were not able to identify a significant association of SNPs in the LTA genomic region or the LGALS2 gene with MI. These variants are unlikely to play a significant role in populations of European origin.
AU  - Sedlacek, K.*
AU  - Neureuther, K.*
AU  - Mueller, J.C.*
AU  - Stark, K.*
AU  - Fischer, M.*
AU  - Baessler, A.*
AU  - Reinhard, W.*
AU  - Broeckel, U.*
AU  - Lieb, W.*
AU  - Erdmann, J.*
AU  - Schunkert, H.*
AU  - Riegger, G.*
AU  - Illig, T.
AU  - Meitinger, T.
AU  - Hengstenberg, C.*
C1  - 5888
C2  - 24584
SP  - 997-1004
TI  - Lymphotoxin-alpha and galectin-2 SNPs are not associated with myocardial infarction in two different German populations.
JO  - J. Mol. Med.
VL  - 85
IS  - 9
PB  - Springer
PY  - 2007
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Angiotensin-converting enzyme (ACE) activity is considered to be of major importance for the conversion of angiotensin (Ang) I to Ang II. Recently, a second ACE, named ACE2, has been identified. Experimental data provide evidence that ACE2 might be involved in modulating cardiac structure and function. In the present explorative study, we assessed whether polymorphisms in the ACE2 gene are related to echocardiographically determined parameters of left ventricular mass, structure or function in the general population. Five intronic single nucleotide polymorphisms (SNPs) were genotyped using the 5′-exonuclease activity (TaqMan) assay in the echocardiographic substudy of the third MONICA Augsburg survey. As ACE2 is located on the X chromosome, women and men were analysed separately. Four SNPs showed high pairwise linkage disequilibrium (rs4646156, rs879922, rs4240157 and rs233575). The minor alleles of these four SNPs were associated with higher left ventricular mass index (LVMI) and higher septal wall thickness (SWT) in men. Likewise, male carriers of a common haplotype (frequency 29.9%) consisting of the minor alleles of these four SNPs displayed higher values for LVMI and SWT than non-carriers (LVMI: TGGC 98.8±1.52 vs non-TGGC 94.8±0.99 g/m 2, p=0.027; SWT: TGGC 11.5±0.14 vs non-TGGC 11.1±0.09 mm, p=0.019). Furthermore, this haplotype was associated with an increased odds ratio (OR) for left ventricular hypertrophy (OR 3.10, p=0.006). In women, similar but less pronounced and consistent trends were observed. No association was observed between any of these SNPs and parameters of left ventricular systolic or diastolic function nor with blood pressure levels. This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, SWT and left ventricular hypertrophy in hemizygous men. © Springer-Verlag 2005.
AU  - Lieb, W.*
AU  - Graf, J.*
AU  - Götz, A.*
AU  - König, I.R.*
AU  - Mayer, B.*
AU  - Fischer, M.*
AU  - Stritzke, J.*
AU  - Hengstenberg, C.*
AU  - Holmer, S.R.*
AU  - Döring, A.
AU  - Löwel, H.
AU  - Schunkert, H.*
AU  - Erdmann, J.*
C1  - 5412
C2  - 23479
SP  - 88-96
TI  - Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men: Results of the MONICA Augsburg echocardiographic substudy.
JO  - J. Mol. Med.
VL  - 84
IS  - 1
PY  - 2006
SN  - 0946-2716
ER  - 

TY  - JOUR
AU  - Kääb, S.*
AU  - Pfeufer, A.
C1  - 4398
C2  - 22506
SP  - 308-316
TI  - Global gene expression in human myocardium-oligonuclide microarray analysis of regional diversity and transcriptional regulation in heart failure.
JO  - J. Mol. Med.
VL  - 82
PY  - 2004
SN  - 0946-2716
ER  - 

TY  - JOUR
AB  - Partial monosomy 10p is a rare chromosomal aberration. Patients often show symptoms of the DiGeorge/velocardiofacial syndrome spectrum. The phenotype is the result of haploinsufficiency of at least two regions on 10p, the HDR1 region associated with hypoparathyroidism, sensorineural deafness, and renal defects (HDR syndrome) and the more proximal region DGCR2 responsible for heart defects and thymus hypoplasia/aplasia. While GATA3 was identified as the disease causing gene for HDR syndrome, no genes have been identified thus far for the symptoms associated with DGCR2 haploinsufficiency. We constructed a. deletion map of partial monosomy 10p patients and narrowed the critical region DGCR2 to about 300 kb. The genomic draft sequence of this region contains only one known gene, BRUNOL3 (NAPOR, CUGBP2, ETR3). In situ hybridization of human embryos and fetuses revealed as well as in other tissues a strong expression of BRUNOL3 in thymus during different developmental stages. BRUNOL3 appears to be an important factor for thymus development and is therefore a candidate gene for the thymus hypoplasia/aplasia seen in partial monosomy 10p patients. We did not find BRUNOL3 mutations in 92 DiGeorge syndrome-like patients without chromosomal deletions and in 8 parents with congenital heart defect children.
AU  - Lichtner, P.
AU  - Attie-Bitach, T.*
AU  - Schuffenhauer, S.
AU  - Henwood, J.*
AU  - Bouvagnet, P.*
AU  - Scambler, P.J.*
AU  - Meitinger, T.
AU  - Vekemans, M.*
C1  - 10055
C2  - 20320
SP  - 431-442
TI  - Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p.
JO  - J. Mol. Med.
VL  - 80
PY  - 2002
SN  - 0946-2716
ER  -