TY  - JOUR
AB  - BACKGROUND: Changes in serum metabolites in individuals with altered cardiac function and morphology may exhibit information about cardiovascular disease (CVD) pathway dysregulations and potential CVD risk factors. We aimed to explore associations of cardiac function and morphology, evaluated using magnetic resonance imaging (MRI) with a large panel of serum metabolites. METHODS: Cross-sectional data from CVD-free individuals from the population-based KORA cohort were analyzed. Associations between 3T-MRI-derived left ventricular (LV) function and morphology parameters (e.g., volumes, filling rates, wall thickness) and markers of carotid plaque with metabolite profile clusters and single metabolites as outcomes were assessed by adjusted multinomial logistic regression and linear regression models. RESULTS: In 360 individuals (mean age 56.3 years; 41.9% female), 146 serum metabolites clustered into three distinct profiles that reflected high-, intermediate- and low-CVD risk. Higher stroke volume (relative risk ratio (RRR): 0.53, 95%-CI [0.37; 0.76], p-value < 0.001) and early diastolic filling rate (RRR: 0.51, 95%-CI [0.37; 0.71], p-value < 0.001) were most strongly protectively associated against the high-risk profile compared to the low-risk profile after adjusting for traditional CVD risk factors. Moreover, imaging markers were associated with 10 metabolites in linear regression. Notably, negative associations of stroke volume and early diastolic filling rate with acylcarnitine C5, and positive association of function parameters with lysophosphatidylcholines, diacylphosphatidylcholines, and acylalkylphosphatidylcholines were observed. Furthermore, there was a negative association of LV wall thickness with alanine, creatinine, and symmetric dimethylarginine. We found no significant associations with carotid plaque. CONCLUSIONS: Serum metabolite signatures are associated with cardiac function and morphology even in individuals without a clinical indication of CVD.
AU  - Maushagen, J.
AU  - Addin, N.S.
AU  - Schuppert, C.*
AU  - Ward-Caviness, C.K.*
AU  - Nattenmüller, J.*
AU  - Adamski, J.
AU  - Peters, A.
AU  - Bamberg, F.*
AU  - Schlett, C.L.*
AU  - Wang-Sattler, R.
AU  - Rospleszcz, S.
C1  - 70183
C2  - 55223
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Serum metabolite signatures of cardiac function and morphology in individuals from a population-based cohort.
JO  - Biomark. Res.
VL  - 12
IS  - 1
PB  - Bmc
PY  - 2024
ER  - 

TY  - JOUR
AB  - Background Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data. Methods We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap. Results With this technique at hand, we analyzed the role of the transcription factor Kruppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4. Conclusion Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
AU  - Liu, W.-H.
AU  - Mrozek-Gorska, P.
AU  - Wirth, A.-K.
AU  - Herold, T.
AU  - Schwarzkopf, L.
AU  - Pich, D.
AU  - Völse, K.
AU  - Melo-Narváez, C.
AU  - Carlet, M.
AU  - Hammerschmidt, W.
AU  - Jeremias, I.
C1  - 60162
C2  - 49282
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL.
JO  - Biomark. Res.
VL  - 8
IS  - 1
PB  - Bmc
PY  - 2020
ER  -