@article{ModicaAltieriD’Anielloetal.2023, author = {Modica, Roberta and Altieri, Barbara and D'Aniello, Francesco and Benevento, Elio and Cannavale, Giuseppe and Minotta, Roberto and Liccardi, Alessia and Colao, Annamaria and Faggiano, Antongiulio}, title = {Vitamin D and bone metabolism in adult patients with neurofibromatosis type 1}, series = {Metabolites}, volume = {13}, journal = {Metabolites}, number = {2}, issn = {2218-1989}, doi = {10.3390/metabo13020255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303957}, year = {2023}, abstract = {Neurofibromatosis type 1 (NF1) is a genetic multisystemic autosomal dominant disorder determining reduced life expectancy due to higher risk of developing benign and malignant tumors. Low levels of vitamin D and reduced bone mineral density (BMD) have been reported in young patients with NF1. However, correlation between vitamin D and NF1 phenotype needs to be elucidated. Aim of this study was to assess vitamin D levels and bone metabolism in NF1 patients, analyzing potential correlations with clinical phenotype. A cross-sectional study was carried out in a monocentric series of NF1 patients, evaluating genotype, clinical phenotype, BMD, biochemical evaluation with focus on serum 25OH-vitamin D, parathyroid hormone (PTH), calcium and phosphate levels. Correlations between clinical manifestations, neurofibromas, and vitamin D status have been studied in comparison with healthy controls. 31 NF1 adult patients were matched for sex, age and body mass index with 31 healthy controls. A significantly difference in vitamin D level emerged in NF1 patients compared to controls. Interestingly low vitamin D levels correlated with a more aggressive phenotype and with a bigger size of neurofibromas. These data underline that vitamin D deficiency/insufficiency may play a role in clinical severity of neurofibromas in patients with NF1, suggesting the need to check bone status and replace vitamin D in these patients.}, language = {en} } @article{SieglPrustyKarunakaranetal.2014, author = {Siegl, Christine and Prusty, Bhupesh K. and Karunakaran, Karthika and Wischhusen, J{\"o}rg and Rudel, Thomas}, title = {Tumor Suppressor p53 Alters Host Cell Metabolism to Limit Chlamydia trachomatis Infection}, series = {Cell Reports}, volume = {9}, journal = {Cell Reports}, number = {3}, issn = {2211-1247}, doi = {10.1016/j.celrep.2014.10.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118200}, pages = {918-929}, year = {2014}, abstract = {Obligate intracellular bacteria depend entirely on nutrients from the host cell for their reproduction. Here, we show that obligate intracellular Chlamydia downregulate the central tumor suppressor p53 in human cells. This reduction of p53 levels is mediated by the PI3K-Akt signaling pathway, activation of HDM2, and subsequent proteasomal degradation of p53. The stabilization of p53 in human cells severely impaired chlamydial development and caused the loss of infectious particle formation. DNA-damage-induced p53 interfered with chlamydial development through downregulation of the pentose phosphate pathway (PPP). Increased expression of the PPP key enzyme glucose-6-phosphate dehydrogenase rescued the inhibition of chlamydial growth induced by DNA damage or stabilized p53. Thus, downregulation of p53 is a key event in the chlamydial life cycle that reprograms the host cell to create a metabolic environment supportive of chlamydial growth.}, language = {en} } @article{PaudelFusiSchmidt2021, author = {Paudel, Rupesh and Fusi, Lorenza and Schmidt, Marc}, title = {The MEK5/ERK5 pathway in health and disease}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms22147594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261638}, year = {2021}, abstract = {The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.}, language = {en} } @article{GrafLiHerrmannetal.2014, author = {Graf, Nicolas and Li, Zhoulei and Herrmann, Ken and Weh, Daniel and Aichler, Michaela and Slawska, Jolanta and Walch, Axel and Peschel, Christian and Schwaiger, Markus and Buck, Andreas K. and Dechow, Tobias and Keller, Ulrich}, title = {Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma}, series = {Oncotargets and Therapy}, volume = {7}, journal = {Oncotargets and Therapy}, doi = {10.2147/OTT.S59314}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117915}, pages = {789-798}, year = {2014}, abstract = {Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT). Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue. Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.}, language = {en} } @article{SagivMichaeliAssietal.2015, author = {Sagiv, Jitka Y. and Michaeli, Janna and Assi, Simaan and Mishalian, Inbal and Kisos, Hen and Levy, Liran and Damti, Pazzit and Lumbroso, Delphine and Polyansky, Lola and Sionov, Ronit V. and Ariel, Amiram and Hovav, Avi-Hai and Henke, Erik and Fridlender, Zvi G. and Granot, Zvi}, title = {Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer}, series = {Cell Reports}, volume = {10}, journal = {Cell Reports}, number = {4}, doi = {10.1016/j.celrep.2014.12.039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144102}, pages = {562-573}, year = {2015}, abstract = {Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro-and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that are derived from HDNs in a TGF-beta-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.}, language = {en} } @article{WiegeringSchlegelWinkleretal.2015, author = {Wiegering, V. and Schlegel, P. G. and Winkler, B. and Lazarus, M. and Wirth, C. and Ernestus, K. and Walles, T. and Liese, J.}, title = {Persisting Cough as the Single Presenting Symptom of an Intrathoracic Tumor in a Nine-Month-Old Child with Adenovirus Airway Infection}, series = {Journal of Case Reports and Studies}, volume = {3}, journal = {Journal of Case Reports and Studies}, number = {2}, doi = {10.15744/2348-9820.2.504}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125536}, pages = {204}, year = {2015}, abstract = {We report on a nine-month-old girl who presented with persisting cough, and diminished ventilation of the left hemithorax. Viral pneumonia was suspected after Adenovirus detection by PCR, but chest X-rays showed a persistent shadowing of the left hemithorax and persistent coughing despite clinical improvement. Because of the discrepancy between clinical and radiological signs further investigations by ultrasound and CT scan were performed, which visualized an intrathroracic tumor. Histopathology confirmed diagnosis of a teratoma. This case highlights the need for careful evaluation by the treating physicians. If the chest X-ray provides a discrepancy to the clinical findings or persistent pathologies exist, differential diagnosis should be discussed and further diagnostics be performed.}, language = {en} } @article{BiedererMirsadraeeBeeretal.2012, author = {Biederer, J{\"u}rgen and Mirsadraee, S. and Beer, M. and Molinari, F. and Hintze, C. and Bauman, G. and Both, M. and Van Beek, E. J. R. and Wild, J. and Puderbach, M.}, title = {MRI of the lung (3/3)—current applications and future perspectives}, series = {Insights into Imaging}, volume = {3}, journal = {Insights into Imaging}, number = {4}, doi = {10.1007/s13244-011-0142-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124348}, pages = {373-386}, year = {2012}, abstract = {Background MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Methods Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. Results In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. Conclusion New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations.}, language = {en} } @article{OttoRubenwolfBurgeretal.2012, author = {Otto, Wolfgang and Rubenwolf, Peter C. and Burger, Maximilian and Fritsche, Hans-Martin and R{\"o}ßler, Wolfgang and May, Matthias and Hartmann, Arndt and Hofst{\"a}dter, Ferdinand and Wieland, Wolf F. and Denzinger, Stefan}, title = {Loss of aquaporin 3 protein expression constitutes an independent prognostic factor for progression-free survival: an immunohistochemical study on stage pT1 urothelial bladder cancer}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {459}, doi = {10.1186/1471-2407-12-459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135679}, year = {2012}, abstract = {Background: Treatment of patients with stage pT1 urothelial bladder cancer (UBC) continues to be a challenge due to its unpredictable clinical course. Reliable molecular markers that help to determine appropriate individual treatment are still lacking. Loss of aquaporin (AQP) 3 protein expression has previously been shown in muscle-invasive UBC. The aim of the present study was to investigate the prognostic value of AQP3 protein expression with regard to the prognosis of stage pT1 UBC. Method: AQP 3 protein expression was investigated by immunohistochemistry in specimens of 87 stage T1 UBC patients, who were diagnosed by transurethral resection of the bladder (TURB) and subsequent second resection at a high-volume urological centre between 2002 and 2009. Patients underwent adjuvant instillation therapy with Bacillus Calmette-Guerin (BCG). Loss of AQP3 protein expression was defined as complete absence of the protein within the whole tumour. Expression status was correlated retrospectively with clinicopathological and follow-up data (median: 31 months). Multivariate Cox regression analysis was used to assess the value of AQP3 tumour expression with regard to recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS). RFS, PFS and CSS were calculated by Kaplan-Meier analysis and Log rank test. Results: 59\% of patients were shown to exhibit AQP3-positive tumours, whereas 41\% of tumours did not express the marker. Loss of AQP3 protein expression was associated with a statistically significantly worse PFS (20\% vs. 72\%, p=0.020). This finding was confirmed by multivariate Cox regression analysis (HR 7.58, CI 1.29 - 44.68; p=0.025). Conclusions: Loss of AQP3 protein expression in pT1 UBC appears to play a key role in disease progression and is associated with worse PFS. Considering its potential prognostic value, assessment of AQP3 protein expression could be used to help stratify the behavior of patients with pT1 UBC.}, language = {en} } @article{WiegeringAndresSchlegeletal.2013, author = {Wiegering, Verena and Andres, Oliver and Schlegel, Paul G. and Deinlein, Frank and Eyrich, Matthias and Sturm, Alexander}, title = {Hyperfibrinolysis and acquired factor XIII deficiency in newly diagnosed pediatric malignancies}, series = {Haematologica}, volume = {98}, journal = {Haematologica}, number = {8}, doi = {10.3324/haematol.2013.089045}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130569}, pages = {E90-E91}, year = {2013}, abstract = {No abstract available}, language = {en} } @article{GrassingerFlorenMuelleretal.2021, author = {Grassinger, Julia Maria and Floren, Andreas and M{\"u}ller, Tobias and Cerezo-Echevarria, Argi{\~n}e and Beitzinger, Christoph and Conrad, David and T{\"o}rner, Katrin and Staudacher, Marlies and Aupperle-Lellbach, Heike}, title = {Digital lesions in dogs: a statistical breed analysis of 2912 cases}, series = {Veterinary Sciences}, volume = {8}, journal = {Veterinary Sciences}, number = {7}, issn = {2306-7381}, doi = {10.3390/vetsci8070136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242690}, year = {2021}, abstract = {Breed predispositions to canine digital neoplasms are well known. However, there is currently no statistical analysis identifying the least affected breeds. To this end, 2912 canine amputated digits submitted from 2014-2019 to the Laboklin GmbH \& Co. KG for routine diagnostics were statistically analyzed. The study population consisted of 155 different breeds (most common: 634 Mongrels, 411 Schnauzers, 197 Labrador Retrievers, 93 Golden Retrievers). Non-neoplastic processes were present in 1246 (43\%), tumor-like lesions in 138 (5\%), and neoplasms in 1528 cases (52\%). Benign tumors (n = 335) were characterized by 217 subungual keratoacanthomas, 36 histiocytomas, 35 plasmacytomas, 16 papillomas, 12 melanocytomas, 9 sebaceous gland tumors, 6 lipomas, and 4 bone tumors. Malignant neoplasms (n = 1193) included 758 squamous cell carcinomas (SCC), 196 malignant melanomas (MM), 76 soft tissue sarcomas, 52 mast cell tumors, 37 non-specified sarcomas, 29 anaplastic neoplasms, 24 carcinomas, 20 bone tumors, and 1 histiocytic sarcoma. Predisposed breeds for SCC included the Schnauzer (log OR = 2.61), Briard (log OR = 1.78), Rottweiler (log OR = 1.54), Poodle (log OR = 1.40), and Dachshund (log OR = 1.30). Jack Russell Terriers (log OR = -2.95) were significantly less affected by SCC than Mongrels. Acral MM were significantly more frequent in Rottweilers (log OR = 1.88) and Labrador Retrievers (log OR = 1.09). In contrast, Dachshunds (log OR = -2.17), Jack Russell Terriers (log OR = -1.88), and Rhodesian Ridgebacks (log OR = -1.88) were rarely affected. This contrasted with the well-known predisposition of Dachshunds and Rhodesian Ridgebacks to oral and cutaneous melanocytic neoplasms. Further studies are needed to explain the underlying reasons for breed predisposition or "resistance" to the development of specific acral tumors and/or other sites.}, language = {en} } @article{HerrmannKarunakaran2022, author = {Herrmann, Thomas and Karunakaran, Mohindar M.}, title = {Butyrophilins: γδ T cell receptor ligands, immunomodulators and more}, series = {Frontiers in Immunology}, volume = {13}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.876493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265944}, year = {2022}, abstract = {Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention.}, language = {en} } @article{GrimmHufnagelWobseretal.2018, author = {Grimm, Johannes and Hufnagel, Anita and Wobser, Marion and Borst, Andreas and Haferkamp, Sebastian and Houben, Roland and Meierjohann, Svenja}, title = {BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1}, series = {Oncogenesis}, volume = {7}, journal = {Oncogenesis}, number = {71}, doi = {10.1038/s41389-018-0082-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177261}, year = {2018}, abstract = {Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.}, language = {en} }