scientific Administration ([HZI] GFW)http://hdl.handle.net/10033/3116242024-03-28T15:53:14Z2024-03-28T15:53:14ZLactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.Frank, Ann-ChristinRaue, RebeccaFuhrmann, Dominik CSirait-Fischer, EvelynReuse, CarstenWeigert, AndreasLütjohann, DieterHiller, KarstenSyed, Shahzad NawazBrüne, Bernhardhttp://hdl.handle.net/10033/6229522021-07-23T01:43:50Z2021-06-04T00:00:00ZLactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.
Frank, Ann-Christin; Raue, Rebecca; Fuhrmann, Dominik C; Sirait-Fischer, Evelyn; Reuse, Carsten; Weigert, Andreas; Lütjohann, Dieter; Hiller, Karsten; Syed, Shahzad Nawaz; Brüne, Bernhard
Background: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive. Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging. Results: Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation. Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.
2021-06-04T00:00:00ZCare of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.Boettler, TobiasNewsome, Philip NMondelli, Mario UMaticic, MojcaCordero, ElisaCornberg, MarkusBerg, Thomashttp://hdl.handle.net/10033/6229062021-06-22T10:39:28Z2020-04-02T00:00:00ZCare of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
Boettler, Tobias; Newsome, Philip N; Mondelli, Mario U; Maticic, Mojca; Cordero, Elisa; Cornberg, Markus; Berg, Thomas
The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.
2020-04-02T00:00:00ZCytotoxicity, Intracellular Replication, and Contact-Dependent Pore Formation of Genotyped Environmental Isolates from Hospital Water Systems in the West Bank, Palestine.Zayed, Ashraf RPecellin, MarinaJaber, LinaButmeh, SuhaBahader, Shereen ASteinert, MichaelHöfle, Manfred GBrettar, IngridBitar, Dina Mhttp://hdl.handle.net/10033/6228782021-05-19T04:38:49Z2021-04-01T00:00:00ZCytotoxicity, Intracellular Replication, and Contact-Dependent Pore Formation of Genotyped Environmental Isolates from Hospital Water Systems in the West Bank, Palestine.
Zayed, Ashraf R; Pecellin, Marina; Jaber, Lina; Butmeh, Suha; Bahader, Shereen A; Steinert, Michael; Höfle, Manfred G; Brettar, Ingrid; Bitar, Dina M
Legionella pneumophila is the causative agent of Legionnaires' disease. Due to the hot climate and intermittent water supply, the West Bank, Palestine, can be considered a high-risk area for this often fatal atypical pneumonia. L. pneumophila occurs in biofilms of natural and man-made freshwater environments, where it infects and replicates intracellularly within protozoa. To correlate the genetic diversity of the bacteria in the environment with their virulence properties for protozoan and mammalian host cells, 60 genotyped isolates from hospital water systems in the West Bank were analyzed. The L. pneumophila isolates were previously genotyped by high resolution Multi Locus Variable Number of Tandem Repeat Analysis (MLVA-8(12)) and sorted according to their relationship in clonal complexes (VACC). Strains of relevant genotypes and VACCs were compared according to their capacity to infect Acanthamoeba castellanii and THP-1 macrophages, and to mediate pore-forming cytotoxicity in sheep red blood cells (sRBCs). Based on a previous detailed analysis of the biogeographic distribution and abundance of the MLVA-8(12)-genotypes, the focus of the study was on the most abundant L. pneumophila- genotypes Gt4(17), Gt6 (18) and Gt10(93) and the four relevant clonal complexes [VACC1, VACC2, VACC5 and VACC11]. The highly abundant genotypes Gt4(17) and Gt6(18) are affiliated with VACC1 and sequence type (ST)1 (comprising L. pneumophila str. Paris), and displayed seroroup (Sg)1. Isolates of these two genotypes exhibited significantly higher virulence potentials compared to other genotypes and clonal complexes in the West Bank. Endemic for the West Bank was the clonal complex VACC11 (affiliated with ST461) represented by three relevant genotypes that all displayed Sg6. These genotypes unique for the West Bank showed a lower infectivity and cytotoxicity compared to all other clonal complexes and their affiliated genotypes. Interestingly, the L. pneumophila serotypes ST1 and ST461 were previously identified by in situ-sequence based typing (SBT) as main causative agents of Legionnaires' disease (LD) in the West Bank at a comparable level. Overall, this study demonstrates the site-specific regional diversity of L. pneumophila genotypes in the West Bank and suggests that a combination of MLVA, cellular infection assays and hierarchical agglomerative cluster analysis allows an improved genotype-based risk assessment.
2021-04-01T00:00:00ZPlasma Metabolome Signature Indicative of Germline Status Independent of Cancer Incidence.Penkert, JudithMärtens, AndreSeifert, MartinAuber, BerndDerlin, KatjaHille-Betz, UrsulaHörmann, PhilippKlopp, NormanProkein, JanaSchlicker, LisaWacker, FrankWallaschek, HannahSchlegelberger, BrigitteHiller, KarstenRipperger, TimIllig, Thomashttp://hdl.handle.net/10033/6228662021-05-12T02:38:58Z2021-04-07T00:00:00ZPlasma Metabolome Signature Indicative of Germline Status Independent of Cancer Incidence.
Penkert, Judith; Märtens, Andre; Seifert, Martin; Auber, Bernd; Derlin, Katja; Hille-Betz, Ursula; Hörmann, Philipp; Klopp, Norman; Prokein, Jana; Schlicker, Lisa; Wacker, Frank; Wallaschek, Hannah; Schlegelberger, Brigitte; Hiller, Karsten; Ripperger, Tim; Illig, Thomas
Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.
2021-04-07T00:00:00Z