TY  - JOUR
AU  - Prüfer, F.
AU  - Steer, B.
AU  - Kaufmann, E.
AU  - Wolf, P.*
AU  - Adler, B.*
AU  - Korfei, M.*
AU  - Günther, A.*
AU  - Königshoff, M.*
AU  - Adler, H.
C1  - 74788
C2  - 57594
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - Macrophage C1q contributes to pulmonary fibrosis by disturbing the metabolism of alveolar epithelial cells.
JO  - Clin. Transl. Med.
VL  - 15
IS  - 5
PB  - John Wiley & Sons Ltd
PY  - 2025
SN  - 2001-1326
ER  - 

TY  - JOUR
AB  - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains, a region that is highly affected during the disease process. METHODS: Tissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi-omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole-time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies. RESULTS: Our analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real-time polymerase chain reaction/western blotting) several PD-deregulated molecular candidates, including miR-539-3p, miR-376a-5p, miR-218-5p and miR-369-3p, the valid miRNA-mRNA interacting pairs miR-218-5p/RAB6C and miR-369-3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi-omic analyses allowed validating disease-mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function. CONCLUSIONS: This comprehensive assessment of PD-affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD.
AU  - Caldi Gomes, L.*
AU  - Galhoz, A.
AU  - Jain, G.*
AU  - Roser, A.E.*
AU  - Maass, F.*
AU  - Carboni, E.*
AU  - Barski, E.*
AU  - Lenz, C.*
AU  - Lohmann, K.*
AU  - Klein, C.*
AU  - Bähr, M.*
AU  - Fischer, A.*
AU  - Menden, M.P.
AU  - Lingor, P.*
C1  - 64261
C2  - 51830
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - Multi-omic landscaping of human midbrains identifies disease-relevant molecular targets and pathways in advanced-stage Parkinson's disease.
JO  - Clin. Transl. Med.
VL  - 12
IS  - 1
PB  - John Wiley & Sons Ltd
PY  - 2022
SN  - 2001-1326
ER  - 

TY  - JOUR
AB  - BACKGROUND: Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein myoglobin (MB) is primarily expressed in heart and skeletal muscle fibres, where it facilitates oxygen storage and flux to the mitochondria during exercise. In the last years, further contributions of MB have been assigned to the scavenging of reactive oxygen species (ROS), the regulation of cellular nitric oxide (NO) levels and also lipid binding. There is a substantial expression of MB in BAT, which is induced during brown adipocyte differentiation and BAT activation. This suggests MB as a previously unrecognized player in BAT contributing to thermogenesis. METHODS AND RESULTS: This study analyzed the consequences of MB expression in BAT on mitochondrial function and thermogenesis in vitro and in vivo. Using MB overexpressing, knockdown or knockout adipocytes, we show that expression levels of MB control brown adipocyte mitochondrial respiratory capacity and acute response to adrenergic stimulation, signalling and lipolysis. Overexpression in white adipocytes also increases their metabolic activity. Mutation of lipid interacting residues in MB abolished these beneficial effects of MB. In vivo, whole-body MB knockout resulted in impaired thermoregulation and cold- as well as drug-induced BAT activation in mice. In humans, MB is differentially expressed in subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots, differentially regulated by the state of obesity and higher expressed in AT samples that exhibit higher thermogenic potential. CONCLUSIONS: These data demonstrate for the first time a functional relevance of MBs lipid binding properties and establish MB as an important regulatory element of thermogenic capacity in brown and likely beige adipocytes.
AU  - Christen, L.
AU  - Broghammer, H.
AU  - Rapöhn, I.
AU  - Möhlis, K.
AU  - Strehlau, C.*
AU  - Ribas Latre, A.
AU  - Gebhardt, C.
AU  - Roth, L.*
AU  - Krause, K.*
AU  - Landgraf, K.*
AU  - Körner, A.*
AU  - Rohde-Zimmermann, K.
AU  - Hoffmann, A.
AU  - Klöting, N.
AU  - Ghosh, A.*
AU  - Sun, W.*
AU  - Dong, H.*
AU  - Wolfrum, C.*
AU  - Rassaf, T.*
AU  - Hendgen-Cotta, U.B.*
AU  - Stumvoll, M.
AU  - Blüher, M.
AU  - Heiker, J.T.
AU  - Weiner, J.*
C1  - 67004
C2  - 53404
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - Myoglobin-mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans.
JO  - Clin. Transl. Med.
VL  - 12
IS  - 12
PB  - John Wiley & Sons Ltd
PY  - 2022
SN  - 2001-1326
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE-Adult study, a well-characterised population-based cohort from Germany. RESEARCH DESIGN AND METHODS: Lifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE-Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome-wide DNA methylation analysis in blood samples employing Illumina Infinium® Methylation EPIC BeadChip system technology. RESULTS: Differences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2 ) were rather marginal compared to inter-lifestyle differences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine-fructose-6-phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (∼6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (∼5.4%) in healthy compared to unhealthy lifestyle individuals. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p < .01) and axon guidance (adj. p < .05). We showed that methylation age correlates with chronological age and waist-to-hip ratio with lower DNA methylation age (DNAmAge) acceleration distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood. CONCLUSIONS: DNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.
AU  - Klemp, I.*
AU  - Hoffmann, A.
AU  - Müller, L.*
AU  - Hagemann, T.
AU  - Horn, K.*
AU  - Rohde-Zimmermann, K.
AU  - Tönjes, A.*
AU  - Thiery, J.*
AU  - Löffler, M.*
AU  - Burkhardt, R.*
AU  - Böttcher, Y.*
AU  - Stumvoll, M.
AU  - Blüher, M.
AU  - Krohn, K.*
AU  - Scholz, M.*
AU  - Baber, R.*
AU  - Franks, P.W.*
AU  - Kovacs, P.*
AU  - Keller, M.
C1  - 65438
C2  - 52298
TI  - DNA methylation patterns reflect individual's lifestyle independent of obesity.
JO  - Clin. Transl. Med.
VL  - 12
IS  - 6
PY  - 2022
SN  - 2001-1326
ER  - 

TY  - JOUR
AU  - Prade, V.M.
AU  - Sun, N.
AU  - Shen, J.
AU  - Feuchtinger, A.
AU  - Kunzke, T.
AU  - Buck, A.
AU  - Schraml, P.*
AU  - Moch, H.*
AU  - Schwamborn, K.*
AU  - Autenrieth, M.*
AU  - Gschwend, J.E.*
AU  - Erlmeier, F.*
AU  - Hartmann, A.*
AU  - Walch, A.K.
C1  - 64343
C2  - 51954
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - The synergism of spatial metabolomics and morphometry improves machine learning-based renal tumour subtype classification.
JO  - Clin. Transl. Med.
VL  - 12
IS  - 2
PB  - John Wiley & Sons Ltd
PY  - 2022
SN  - 2001-1326
ER  - 

TY  - JOUR
AU  - Kappel, B.A.*
AU  - Moellmann, J.*
AU  - Thiele, K.*
AU  - Rau, M.*
AU  - Artati, A.
AU  - Adamski, J.
AU  - Ghesquiere, B.*
AU  - Schuett, K.*
AU  - Romeo, F.*
AU  - Stoehr, R.*
AU  - Marx, N.*
AU  - Federici, M.*
AU  - Lehrke, M.*
C1  - 62450
C2  - 50837
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - Human and mouse non-targeted metabolomics identify 1,5-anhydroglucitol as SGLT2-dependent glycemic marker.
JO  - Clin. Transl. Med.
VL  - 11
IS  - 6
PB  - John Wiley & Sons Ltd
PY  - 2021
SN  - 2001-1326
ER  - 

TY  - JOUR
AU  - Kunzke, T.
AU  - Hölzl, F.T.
AU  - Prade, V.M.
AU  - Buck, A.
AU  - Huber, K.
AU  - Feuchtinger, A.
AU  - Ebert, K.*
AU  - Zwingenberger, G.*
AU  - Geffers, R.*
AU  - Hauck, S.M.
AU  - Haffner, I.*
AU  - Luber, B.*
AU  - Lordick, F.*
AU  - Walch, A.K.
C1  - 63195
C2  - 51240
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - Metabolomic therapy response prediction in pretherapeutic tissue biopsies for trastuzumab in patients with HER2-positive advanced gastric cancer.
JO  - Clin. Transl. Med.
VL  - 11
IS  - 9
PB  - John Wiley & Sons Ltd
PY  - 2021
SN  - 2001-1326
ER  - 

TY  - JOUR
AB  - CD19-directed chimeric antigen receptors (CAR) T cells induce impressive rates of complete response in advanced B-cell malignancies, specially in B-cell acute lymphoblastic leukemia (B-ALL). However, CAR T-cell-treated patients eventually progress due to poor CAR T-cell persistence and/or disease relapse. The bone marrow (BM) is the primary location for acute leukemia. The rapid/efficient colonization of the BM by systemically infused CD19-CAR T cells might enhance CAR T-cell activity and persistence, thus, offering clinical benefits. Circulating cells traffic to BM upon binding of tetrasaccharide sialyl-Lewis X (sLeX)-decorated E-selectin ligands (sialofucosylated) to the E-selectin receptor expressed in the vascular endothelium. sLeX-installation in E-selectin ligands is achieved through an ex vivo fucosylation reaction. Here, we sought to characterize the basal and cell-autonomous display of sLeX in CAR T-cells activated using different cytokines, and to assess whether exofucosylation of E-selectin ligands improves CD19-CAR T-cell activity and BM homing. We report that cell-autonomous sialofucosylation (sLeX display) steadily increases in culture- and in vivo-expanded CAR T cells, and that, the cytokines used during T-cell activation influence both the degree of such endogenous sialofucosylation and the CD19-CAR T-cell efficacy and persistence in vivo. However, glycoengineered enforced sialofucosylation of E-selectin ligands was dispensable for CD19-CAR T-cell activity and BM homing in multiple xenograft models regardless the cytokines employed for T-cell expansion, thus, representing a dispensable strategy for CD19-CAR T-cell therapy.
AU  - Sánchez-Martínez, D.*
AU  - Gutiérrez-Agüera, F.*
AU  - Romecin, P.*
AU  - Vinyoles, M.*
AU  - Palomo, M.*
AU  - Tirado, N.*
AU  - Zanetti, S.R.*
AU  - Juan, M.*
AU  - Carlet, M.
AU  - Jeremias, I.
AU  - Menéndez, P.*
C1  - 61471
C2  - 50277
CY  - The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England
TI  - Enforced sialyl-Lewis-X (sLeX) display in E-selectin ligands by exofucosylation is dispensable for CD19-CAR T-cell activity and bone marrow homing.
JO  - Clin. Transl. Med.
VL  - 11
IS  - 2
PB  - John Wiley & Sons Ltd
PY  - 2021
SN  - 2001-1326
ER  -