TY - JOUR A1 - Oelschlaegel, Diana A1 - Weiss Sadan, Tommy A1 - Salpeter, Seth A1 - Krug, Sebastian A1 - Blum, Galia A1 - Schmitz, Werner A1 - Schulze, Almut A1 - Michl, Patrick T1 - Cathepsin inhibition modulates metabolism and polarization of tumor-associated macrophages JF - Cancers N2 - Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH\(_2\), led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE\(_2\), which correlated with the upregulation of numerous NF\(_k\)B-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu. KW - cathepsin KW - activity-based probes KW - tumor-associated macrophage KW - autophagy KW - lysosome KW - lipid metabolism KW - inflammation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213040 SN - 2072-6694 VL - 12 IS - 9 ER - TY - JOUR A1 - Krug, Ralf A1 - Volland, Julian A1 - Reich, Sebastian A1 - Soliman, Sebastian A1 - Connert, Thomas A1 - Krastl, Gabriel T1 - Guided endodontic treatment of multiple teeth with dentin dysplasia: a case report JF - Head & Face Medicine N2 - Background To report the outcome of guided endodontic treatment (GET) of a case of dentin dysplasia with pulp canal calcification (PCC) and apical periodontitis based on the use of a 3D-printed template designed by merging cone-beam computed tomography (CBCT) and surface scan data. Case presentation A 12-year old female with radicular dentin dysplasia type I (DD-1) presented for endodontic treatment. Radiography revealed PCC in all teeth and apical radiolucency in seven teeth (12, 15, 26, 31, 32, 36 and 46). Tooth 36 had the most acute symptoms and was thus treated first by conventional access cavity preparation and root canal detection. Despite meticulous technique, the distal and mesiolingual canals were perforated. The perforations were immediately repaired with mineral trioxide aggregate, and the decision was made to switch to guided endodontic treatment for the remaining 6 teeth. CBCT and intraoral surface scans were acquired and matched using coDiagnostix planning software (Dental Wings Inc.), the respective drill positions for root canal location were determined, and templates were virtually designed and 3D-printed. The template was positioned on the respective tooth, and a customized drill was used to penetrate the calcified part of the root canal and perform minimally invasive access cavity preparation up to the apical region. All root canals were rapidly and successfully located with the templates. At 1-year follow-up, clear signs of apical healing were present in all treated teeth. Conclusions In patients with dentin dysplasia, conventional endodontic therapy is challenging. GET considerably facilitates the root canal treatment of teeth affected by dentin dysplasia. KW - guided endodontics KW - pulp canal calcification KW - dentin dysplasia KW - root canal treatment KW - template KW - access caity preparation KW - beam computed tomography KW - canal calcification KW - permanent KW - obliteration Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230271 VL - 16 ER -