TREK-1 channels do not mediate nitrergic neurotransmission in circular smooth muscle from the lower oesophageal sphincter

Background and purpose:

The ionic mechanisms underlying nitrergic inhibitory junction potentials (IJPs) in gut smooth muscle remain a matter of debate. Recently, it has been reported that opening of TWIK-related K⁺ channel 1 (TREK-1) K⁺ channels contributes to the nitrergic IJP in colonic smooth muscle. We investigated the effects of TREK-1 channel blockers on nitrergic neurotransmission in mouse and opossum lower oesophageal sphincter (LOS) circular smooth muscle (CSM).

Experimental approach:

The effects of TREK-1 channel blockers were characterized pharmacologically in murine and opossum gut smooth muscle using conventional intracellular and tension recordings.

Key results:

In LOS, L-methionine depolarized the resting membrane potential (RMP) but did not inhibit the nitrergic IJP. Cumulative application of theophylline hyperpolarized the RMP and inhibited the nitrergic IJP concentration dependently. The induced membrane hyperpolarization was prevented by pre-application of caffeine, but not by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. 8-Br-cAMP significantly hyperpolarized membrane potential and increased the amplitude of the nitrergic IJP. In opossum LOS muscle strips, L-methionine increased resting tone but had no effect on nerve-mediated LOS relaxation. On the other hand, theophylline markedly inhibited tone. In CSM from mouse proximal colon, L-methionine caused modest inhibition of nitrergic IJPs.

Conclusions and implications:

TREK-1 channels were not involved in the nitrergic IJP in LOS CSM. Not only does L-methionine have no effect on the nitrergic IJP or LOS relaxation, but the effect of theophylline appears to be due to interruption of Ca²⁺-releasing pathways (i.e. caffeine-like effect) rather than via blockade of TREK-1 channels.     

Stem cell MicroRNAs in senescence and immortalization: novel players in cancer therapy

The molecular etiology of malignancy remains one of the most challenging disease processes under scientific investigation; therefore, improved approaches for their treatment are urgently needed. MicroRNAs are highly conserved nonprotein‐coding RNAs that regulate gene expression. They are involved in important homeostatic processes, such as cellular proliferation, cell death and development, and affect many diseases, including cancer. High‐throughput screenings based on microRNAs related to senescence/immortalization are potential tools for identifying novel proliferative microRNAs that might be involved in carcinogenesis. Recently, a subgroup of highly proliferative microRNAs, which belong to a cluster expressed exclusively in embryonic stem cells and their malignant derivatives (embryonic carcinoma cells), was revealed to play a role in senescence bypass, thereby providing immortalization to human cells. This finding supports the cancer stem cell theory and the relevance of microRNAs in human tumors. This article recapitulates the role of microRNAs that are associated with stem cell properties and their possible link in common pathways related to immortalization and cancer. Ultimately, cancer therapy that is based on the induction of a senescence response is proposed to be highly associated with the loss of stemness properties. Thus, it would be possible to “kill two birds with one stone”: along with the inhibition of stemness properties in cancer stem cells, the senescence response could be induced to destroy the cancer stem cell population within a tumor. © 2011 Wiley Periodicals, Inc. Med Res Rev     

Lipid body mobilization in the ExoU-induced release of inflammatory mediators by airway epithelial cells

This report addressed the question whether ExoU stimulation of airway epithelial cells may contribute to the inflammatory response detected in the course of Pseudomonas aeruginosa respiratory infections. Infection with PA103 P. aeruginosa elicited a potent release of IL-6 and IL-8, as well as of arachidonic acid (AA) and PGE(2) that was reduced by the bacterial treatment with MAFP, a cPLA(2) inhibitor. Airway cells from the BEAS-2B line and in primary culture were shown to be enriched in lipid bodies (LBs), that are cytoplasmic domains implicated in AA transformation into eicosanoids. However, cells infected with PA103 and with a mutant deficient in exoU but complemented with a functional gene exhibited reduced contents of LBs, and this reduction was inhibited by MAFP. FACS analysis showed that the decrease in the LB content correlated with the presence of intracellular PGE(2). Also, in PA103-infected cells, PGE(2) was immunolocalized in LBs, suggesting that the reduction in the cell content of the organelles was due to consumption of their glycerolipids, resulting in local synthesis of the prostanoid. In conclusion, we showed the ExoU ability to induce airway epithelial cells to overproduce PGE(2) and we speculate that LB may represent intracellular loci involved in ExoU-induced eicosanoid synthesis.     

Temporal bone trauma and the role of multidetector CT in the emergency department

The temporal bone anatomy is complex, with many critical structures in close association with one another. The temporal bone region comprises cranial nerves V, VI, VII, and VIII; vascular structures such as the internal carotid and middle meningeal arteries; sigmoid sinus; jugular bulb; and sensorineural and membranous structures of the inner ear. Most temporal bone fractures are a result of high-energy blunt head trauma. Multidetector computed tomography (CT) plays a fundamental role in the initial evaluation of patients with polytrauma in the emergency department. Multidetector CT may help identify important structural injuries that may have devastating complications such as sensorineural hearing loss, conductive hearing loss, dizziness and balance dysfunction, perilymphatic fistulas, cerebrospinal fluid leaks, facial nerve paralysis, and vascular injury. Although classifying temporal bone fractures helps physicians understand and predict trauma-associated complications and guide treatment, identifying injury to critical structures is more important for guiding management and determining prognosis than is simply classifying temporal bone fractures into a general category. Many temporal bone fractures and complications may be readily identified and characterized at routine cervical, maxillofacial, and head multidetector CT performed in patients with polytrauma, without the need for dedicated temporal bone multidetector CT. Dedicated temporal bone multidetector CT should be considered when there is a high degree of suspicion for temporal bone fractures and no fractures are identified at head, cervical, or maxillofacial CT.     

Do older patients with non-small cell lung cancer also benefit from first-line platinum-based doublet chemotherapy? Observations from a pooled analysis of 730 prospectively-treated patients (Alliance Study A151622)

Objective

This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC).