Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGFb elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGFb signaling pathway. Alterations of epithelialto-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGFb pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGFb-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGFb signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785-801. Ó2016 AACR.
Bacterial infections are known to cause severe health-threatening conditions, including sepsis. All attempts to get this disease under control failed in the past, and especially in times of increasing antibiotic resistance, this leads to one of the most urgent medical challenges of our times. We designed a peptide to bind with high affinity to endotoxins, one of the most potent pathogenicity factors involved in triggering sepsis. The peptide Pep19-2.5 reveals high endotoxin neutralization efficiency in vitro, and here, we demonstrate its antiseptic/anti-inflammatory effects in vivo in the mouse models of endotoxemia, bacteremia, and cecal ligation and puncture, as well as in an ex vivo model of human tissue. Furthermore, we show that Pep19-2.5 can bind and neutralize not only endotoxins but also other bacterial pathogenicity factors, such as those from the Gram-positive bacterium Staphylococcus aureus. This broad neutralization efficiency and the additive action of the peptide with common antibiotics makes it an exceptionally appropriate drug candidate against bacterial sepsis and also offers multiple other medication opportunities.
Histopathologically, Legionnaires' disease, caused by the Gram-negative bacterium Legionella pneumophila, is an acute fibrinopurulent pneumonia. Since the first documented outbreak of Legionnaires' disease in 1976, several autopsy series have been published (1). Samples from patients who died from L. pneumophila pneumonia exhibit a massive infiltration of neutrophils and macrophages into the alveoli and destruction of alveolar septa. Moreover, the alveolar epithelium shows sloughs, and inflammatory cells exhibit intense necrosis. L. pneumophila is present mainly in alveoli and tends to cluster inside macrophages. In late infection stages, bacteria disseminate to the patient's spleen, kidneys, bone marrow, and lymph nodes (1-4).Different models have been established to analyze specific aspects of infection. Besides human monocellular systems such as macrophages and epithelial cells, protozoa such as Acanthamoeba castellanii, Hartmannella vermiformis, and Dictyostelium discoideum were used to study the cellular and molecular pathogenicity of L. pneumophila (5-9). These studies revealed that L. pneumophila primarily enters phagocytes and resides within a unique membrane-bound compartment termed the Legionellacontaining vacuole (LCV). The establishment of this replication niche requires the translocation of about 300 effector proteins into the host cell via a functional Dot/Icm type IV secretion (10-12). Studying transcriptional responses of L. pneumophila-infected macrophages and D. discoideum vegetative cells also shed light on the cellular mechanisms of Legionnaires' disease (13-16). Moreover, proteomic approaches were shown to be powerful tools to characterize both sides of the host-pathogen interaction (17)(18)(19). Mammalian models such as guinea pigs, mice, rhesus monkeys, and marmosets were used to address immunological, pathological, and pharmacological questions (20)(21)(22). Despite providing enormous progress in the knowledge about mechanisms of L. pneumophila infections, each of the current infection models has intrinsic limitations. Cell culture assays lack the complex interaction networks between the specialized cell types and extracellular components in the human lung. Guinea pig infections require intraperitoneal or intratracheal inoculation techniques, and owing to a different genetic and immunological background, the adequacy and transferability to humans can be questioned.Given the different model-immanent limitations, numerous intra-and extracellular interactions of L. pneumophila factors with human lung tissue structures remain unknown. For example, early infection events appear to be underexplored, since histopathology studies were performed postmortem. Even conspicuous subcellular structures, such as the abundant outer membrane vesicles (OMVs) shed by L. pneumophila, have not yet been investigated in human lung tissue. OMVs contain large amounts of degradative enzymes and other virulence-related proteins, which
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