Standardisierte Kontrastmittelsonographie (CEUS) in der klinischen Akut- und Notfallmedizin sowie Intensivmedizin (CEUS-Akut)

Die Anaesthesiologie -     

Comparison of visual outcomes after two types of mix-and-match implanted trifocal extended-depth-of-focus and trifocal intraocular lenses

Graefe's Archive for Clinical and Experimental Ophthalmology - To compare visual outcomes between two types of mix-and-match implanted trifocal extended-depth-of-focus (EDoF) and trifocal...     

A Legal Approach to Cancer Epidemiology in Public Health

The Public Health Act encompasses scientific research and law enforcement as causes, distributions, and preventive factors for diseases and injuries of a particular population. Today, the Public Health Law is growing into a field that expects to cultivate and utilize lawful practitioners who can apply specialized legal skills in health policy development and public health performance. The multidisciplinary approach of the Public Health Act integrates the legal and scientific elements of the field and the workforce, characterized by a more dynamic understanding of the health impact of legislation and the rapid deployment of effective policies. Thus, legal health interventions that manage and treat diverse populations need to be evaluated more rigorously and quickly. In addition, funding for policy surveillance and other legislation and policy mapping needs to be more sophisticated to maximize utility and avoid duplication. This study investigated legal interventions to manage and treat various groups of populations for health and discussed the necessity of public health laws.     

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3^ser461 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158-induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co-immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158-mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX-resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.     

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin‐Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)‐induced G1/S cell‐cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF‐induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal‐regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c‐Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP‐1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate‐bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage‐independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage‐independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR‐Akt‐p70S6K and mTOR‐Akt‐GSK3β‐AP‐1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2‐Akt‐p70S6k signaling pathway.