Michael Schaefers

Diabetic db/db mice do not develop heart failure upon pressure overload:A longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural, and functional adaptations

Aims Heart failure is associated with altered myocardial substrate metabolism and impaired cardiac energetics. Comorbidities like diabetes may influence the metabolic adaptations during heart failure development. We quantified to what extent changes in substrate preference, lipid accumulation, and energy status predict the longitudinal development of hypertrophy and failure in the non-diabetic and the diabetic heart. Methods and results Transverse aortic constriction (TAC) was performed in non-diabetic (db/+) and diabetic (db/db) mice to induce pressure overload. Magnetic resonance imaging, 31P magnetic resonance spectroscopy (MRS), 1H MRS, and 18F-fluorodeoxyglucose-positron emission tomography (PET) were applied to measure cardiac function, energy status, lipid content, and glucose uptake, respectively. In vivo measurements were complemented with ex vivo techniques of high-resolution respirometry, proteomics, and western blotting to elucidate the underlying molecular pathways. In non-diabetic mice, TAC induced progressive cardiac hypertrophy and dysfunction, which correlated with increased protein kinase D-1 (PKD1) phosphorylation and increased glucose uptake. These changes in glucose utilization preceded a reduction in cardiac energy status. At baseline, compared with non-diabetic mice, diabetic mice showed normal cardiac function, higher lipid content and mitochondrial capacity for fatty acid oxidation, and lower PKD1 phosphorylation, glucose uptake, and energetics. Interestingly, TAC affected cardiac function only mildly in diabetic mice, which was accompanied by normalization of phosphorylated PKD1, glucose uptake, and cardiac energy status. Conclusion The cardiac metabolic adaptations in diabetic mice seem to prevent the heart from failing upon pressure overload, suggesting that restoring the balance between glucose and fatty acid utilization is beneficial for cardiac function.

Differentiated Thyroid Cancer Patients More Than 60 Years Old Paradoxically Show an Increased Life Expectancy

The aim of this study was to compare the overall survival of a large, single-center cohort of patients who had differentiated thyroid cancer (DTC) with that of a matched general population. Methods: We analyzed 2,428 consecutive patients who had DTC and underwent treatment from 1965 to 2013 at the Department of Nuclear Medicine, University Hospital of Münster, Münster, Germany, according to international standards. Patients were classified on the basis of the current, seventh edition of the American Joint Committee on Cancer/Union for International Cancer Control classification system. Additionally, a subgroup analysis with regard to age at diagnosis was performed. The overall survival of the patients was compared with the expected survival of the general population on the basis of age and sex, as provided by the Federal Statistical Office of Germany. Results: Compared with the expected survival, the overall survival of patients with stage I disease paradoxically was significantly better (P < 0.001). In the subgroup analysis, a significantly lower mortality rate was observed in elderly patients (≥60 y old) with stage I disease. On the other hand, patients between 20 and 45 y of age and with distant metastases at diagnosis had a significantly increased standardized mortality rate. In contrast, other patients with stage II disease and more than 45 y old had a normal mortality rate. The mortality rate was significantly increased in all patients with stage IVC disease. Conclusion: Older patients with more limited disease paradoxically had better survival than would be expected on the basis of age and sex, whereas young adults as well as patients more than 45 y old and with distant metastases had increased mortality rates. For all other DTC patients, regardless of age or TNM stage, no significant survival difference was seen.

Imaging, myeloid precursor immortalization, and genome editing for defining mechanisms of leukocyte recruitment in vivo

Recruitment of leukocytes from the blood to sites of inflammation poses a promising target for new diagnostic and therapeutic approaches. We aimed to develop a novel method to non-invasively analyze molecular mechanisms of leukocyte migration in pre-clinical models of inflammation in vivo. Methods: We used the ER-HoxB8 system to transiently immortalize murine myeloid precursors from wildtype and CD18- as well as MRP14-deficient mice. A VLA4α-/- cell line was generated by CRISPR/Cas9-mediated gene editing. We analyzed the migration of wildtype and knockout leukocytes in vivo by optical and nuclear imaging in mice with irritant contact dermatitis, cutaneous granuloma, experimental arthritis and myocardial infarction. Results: Transient immortalization, gene editing and in vivo imaging can be combined to analyze migratory mechanisms of murine leukocytes, even for gene deletions resulting in lethal phenotypes in mice. We reliably confirmed known migratory defects of leukocytes deficient for the adhesion molecules CD18 or VLA4α. Also, using our new method we identified a new role of the most abundant calcium-binding proteins in phagocytes and major alarmins in many inflammatory diseases, MRP8 and MRP14, for transmigration in vivo. Conclusion: We provide a combinatorial approach to rapidly characterize molecular mechanisms of leukocyte recruitment in vivo, with the potential to aid in identification of diagnostic and therapeutic targets in inflammatory pathologies.

Prediction of postoperative histology in patients with prostate cancer using preoperative Ga-68-PSMA-PET/CT.

144 Background: Recently developed 68Ga labeled prostate specific membrane antigen (PSMA) ligands were introduced as diagnostic tools to detect prostate cancer (PCa), PCa relapse and metastases with high accuracy. In this study we assessed the usability of preoperative PSMA-PET/CT information on congruency of spread of PCA compared with postoperative PCa-maps derived from radical prostatectomy (RPE) specimens. Methods: We referred 6 patients with biopsy proven high risk PCa to PSMA-PET/CT prior to RPE. Whole body PET/CT (Biograph mCT with 128 slice CT, Siemens) was performed 62±8 minutes after injection of 160±31 MBq [68Ga]-PSMA-HBED-CC (DKFZ-Ga-PSMA-11) as described by routine acquisition protocol. After RPE, prostate specimens were processed in the local pathology department. Topographical analysis of extension of PCa was reconstructed from representative slides on a schematic diagram resulting in a PCa-map of the prostate. After aligning the cutting planes of the PSMA-PET/CT to the PCa-map we defined 2...