Integrin-mediated transcriptional activation of inhibitor of apoptosis proteins protects smooth muscle cells against apoptosis induced by degraded collagen

Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current study was to identify the pathway responsible for consecutive SMC survival. We show that exposure of SMC to collagen fragments resulted in a sustained activation of nuclear factor (NF)-\u3baB via phosphorylation and degradation of I\u3baB\u3b1. Its prevention through retroviral expression of superrepressor I\u3baB\u3b1 or proteasome inhibition potently induced apoptosis. In the presence of blocking antibodies to \u3b1v\u3b23 integrin and RGD peptides, collagen fragments no longer activated NF-\u3baB and apoptosis was enhanced. The mechanism by which NF-\u3baB was protecting SMC against collagen fragment-induced apoptosis was a transcriptional activation of several endogenous caspase inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments; (2) IAP expression was abrogated by superrepressor I\u3baB\u3b1; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA) resulted in enhanced apoptosis after collagen fragment treatment. Our data suggest that SMC exposed to degraded collagen are protected against apoptosis by a mechanism involving \u3b1v\u3b23-dependent NF-\u3baB activation with consequent activation of IAPs. This may constitute a novel antiapoptotic pathway ensuring SMC survival in settings of enhanced ECM degradation such as cell migration, vascular remodeling, and atherosclerotic plaque rupture

Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors

Trueness of CAD/CAM digitization with a desktop scanner – an in vitro study

Desktop scanners are devices for digitization of conventional impressions or gypsum casts by indirect Computer-Aided Design/Computer-Assisted Manufacturing (CAD/CAM) in dentistry. The purpose of this in vitro study was: 1, to investigate whether virtual models produced by the extraoral scanner have the same trueness as sectioned casts; and 2, to assess if digitization with an extraoral scanner influences the surface information

Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions

The cholesterol of high-density lipoproteins (HDLs) and its major proteic component, apoA-I, have been widely investigated as potential predictors of acute cardiovascular (CV) events. In particular, HDL cholesterol levels were shown to be inversely and independently associated with the risk of acute CV diseases in different patient populations, including autoimmune and chronic inflammatory disorders. Some relevant and direct anti-inflammatory activities of HDL have been also recently identified targeting both immune and vascular cell subsets. These studies recently highlighted the improvement of HDL function (instead of circulating levels) as a promising treatment strategy to reduce inflammation and associated CV risk in several diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In these diseases, anti-inflammatory treatments targeting HDL function might improve both disease activity and CV risk. In this narrative review, we will focus on the pathophysiological relevance of HDL and apoA-I levels/functions in different acute and chronic inflammatory pathophysiological conditions

Ball lightning - An electromagnetic hallucination?

A common ad-hoc-hypothesis tries to explain ball lightning (BL) as an electromagnetic (EM) brain effect caused by ordinary lightning, i.e. as a lightning-induced hallucination. A critical assessment of this alleged effect has to link the physical properties of lightning and its EM field with the neurophysiology of EM-induced hallucinations, so-called magnetophosphens. Using the clinical field of EM brain stimulation - Transcranial Magnetic Stimulation (TMS) and repetitive TMS (rTMS) - with its experimental phosphene data, the authors conclude that EM fields of nearby lightning flashes, because of their spatial configuration and magnetic induction, are unlikely to produce magnetophosphenes. Phosphenes do not appear in lightning accident reports. Phenomenologically, EM phosphenes as elementary hallucinations do not correspond to BL. © The International Journal of Meteorology