The aim of this article is to review current treatment standards for different phases of adult thoracic empyema from an interdisciplinary point of view.
RationaleWhile severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV) cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.ObjectivesWe elucidated the molecular mechanisms by which the cyclophilin inhibitors Cyclosporin A (CsA) and Alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily-available therapy in MERS-CoV infection.MethodsCalu-3 cells and primary human alveolar epithelial cells (hAEC) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including Calcineurin, NFAT, or MAP kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by qRT-PCR and TCID50. Data were validated in a murine MERS-CoV infection model.ResultsCsA and ALV both reduced MERS-CoV titers and viral RNA replication in Calu-3 and hAEC improving epithelial integrity. While neither Calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type-III-interferon (IFNλ) response and expression of antiviral genes. Down-regulation of IRF1 or IFNλ increased MERS-CoV propagation in presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.ConclusionsWe provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory, antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate to treat MERS-CoV infection.
A combined approach by VATS and VAMLA improves radicality of minimally invasive mediastinal lymphadenectomy without increase in operation time, morbidity, and drainage time.
In our experience, VAMLA is a feasible method of mediastinal staging. Its accuracy and radicality can equal open lymphadenectomy. However, VAMLA is minimally invasive and therefore pretherapeutically available. Its advantages might be of interest with neoadjuvant strategies, trials, involved field radiation, video-assisted thoroscopic lobectomy, and left-sided tumors.
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