MicroRNAs are highly expressed in endothelial cells, and recent data suggest that they regulate aspects of vascular development and angiogenesis. This study highlights the state of the art in this field and potential therapeutic opportunities. MicroRNAs (miRNAs) represent a family of conserved short (22 nt) noncoding single-stranded RNAs that have been identified in plants and animals. They are generated by the sequential processing of the RNA template by the enzymes Drosha and Dicer, and mature miRNAs can regulate the levels of gene expression at the posttranscriptional level. miRNAs participate in a diverse range of regulatory events via regulation of genes involved in the control of processes such as development, differentiation, homeostasis, metabolism, growth, proliferation, and apoptosis. However, rather than functioning as regulatory on-off switches, miRNAs often function to modulate or fine-tune cellular phenotypes. So far, more than 1000 mammalian miRNAs have been identified since the discovery of the first two miRNAs (lin-4 and let-7), and bioinformatics predictions indicate that mammalian miRNAs can regulate 30% of all protein-coding genes.

In the systemic circulation, 11,12-epoxyeicosatrienoic acid (11,12-EET) elicits nitric oxide (NO)- and prostacyclin-independent vascular relaxation, partially through the activation of large conductance Ca2+-activated potassium (BK) channels. However, in the lung 11,12-EET contributes to hypoxia-induced pulmonary vasoconstriction. Since pulmonary artery smooth muscle cells also express BK channels, we assessed the consequences of BKβ1 subunit deletion on pulmonary responsiveness to 11,12-EET as well as to acute hypoxia. In buffer-perfused mouse lungs, hypoxia increased pulmonary artery pressure and this was significantly enhanced in the presence of NO synthase (NOS) and cyclooxygenase (COX) inhibitors. Under these conditions the elevation of tissue EET levels using an inhibitor of the soluble epoxide hydrolase (sEH-I), further increased the hypoxic contraction. Direct administration of 11,12-EET also increased pulmonary artery pressure, and both the sEH-I and 11,12-EET effects were prevented by iberiotoxin and absent in BKβ1 −/− mice. In pulmonary artery smooth muscle cells treated with NOS and COX inhibitors and loaded with the potentiometric dye, di-8-ANEPPS, 11,12-EET induced depolarization while the BK channel opener NS1619 elicited hyperpolarization indicating there was no effect of the EET on classical plasma membrane BK channels. In pulmonary artery smooth muscle cells a subpopulation of BK channels is localized in mitochondria. In these cells, 11,12-EET elicited an iberiotoxin-sensitive loss of mitochondrial membrane potential (JC-1 fluorescence) leading to plasma membrane depolarization, an effect not observed in BKβ1 −/− cells. Mechanistically, stimulation with 11,12-EET time-dependently induced the association of the BK α and β1 subunits. Our data indicate that in the absence of NO and prostacyclin 11,12-EET contributes to pulmonary vasoconstriction by stimulating the association of the α and β1 subunits of mitochondrial BK channels. The 11,12-EET-induced activation of BK channels results in loss of the mitochondrial membrane potential and depolarization of the pulmonary artery smooth muscle cells.

Mucinous cystadenoma is a benign tumor commonly found in the pancreas, the ovaries or the appendix. Only very few cases of these tumors originating from the lungs have been reported worldwide, with even less cases describing malignant transformation. We present the case of a 58-year-old woman with a history of recurrent pulmonary infections who underwent left upper lobectomy for lung abscess and was initially diagnosed with pulmonary mucinous cystadenoma (PMCA). Upon thorough immunohistochemical workup, especially due to carcinoembryonic antigen (CEA) positivity, intramucinous singlet cells were eventually diagnostic for invasive carcinoma, in this case a mucinous cystadenocarcinoma arising from a PCMA. PMCA is a rare benign tumor whose potential for malignant transformation has not yet been fully understood. Due to the low number of cases further studies are needed to evaluate if there is a benefit of complete oncologic resection, provided the general condition of the patient allows it. A review of the currently available literature serves to better understand the clinical, radiological and histological features of this rare tumor.

Supporting Information available: This material is available free of charge via the internet. It includes further enzyme inhibition data (MS), enzyme kinetic analyses, detailed EPR spectroscopic analyses, NMR binding experiments of control compounds, docking structures, as well as further analyses of the cellular effects of deferasirox (cell proliferation, western blots, immunostaining). Additional experimental methods are presented. AUTHOR INFORMATION

Background: Pulmonary metastases develop in 10-15% of patients with colorectal cancer. Surgical metastasectomy currently provides the only hope for a cure for these patients. The aim of this study was to analyze the expanding role of pulmonary metastasectomy in the context of laser-assisted surgery (LAS) vs.non-laser-assisted surgery (NLAS). Methods: We performed a single-center retrospective analysis of 204 patients who underwent curative pulmonary metastasectomy for colorectal cancer between 01/2005 and 12/2016. The main endpoint was survival. The Kaplan-Meier method was applied for statistical analysis and survival rates were compared with the log rank test. Results: Median follow-up was 53 months. A total of 267 metastases were resected in 154 operations in the NLAS group (median: 1) vs. 438 metastases in 122 operations in the LAS group (median: 5; P<0.0001). The interval between treatment of the primary tumor and the first pulmonary metastasectomy was significantly shorter in the LAS group (19 vs. 32 months; P=0.008). Anatomical resections were significantly reduced using LAS, 8% vs. 23% respectively. Despite more negative predictors in the LAS group, there was no statistically significant difference in overall disease-specific 5-year survival (70% LAS vs. 58% NLAS; P=0.18).Conclusions: Survival after pulmonary metastasectomy has previously been shown to correlate with a low number of metastases and a longer disease-free interval. However, with the tissue-saving LAS technique complete resectability can be achieved in patients with more metastases and long-term survival is possible for selected patients.

Pulmonary metastasectomy is associated with good survival for selected patients with radioactive iodine-refractory metastases of differentiated thyroid cancer, especially if R0-resection can be achieved. Moreover, it is worth considering whether a significant reduction of tumour load, as indicated by thyroglobulin serum levels, seems possible.

Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis.

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