GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.

The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.

mTOR inhibitors: facing new challenges ahead.

The enzyme mammalian target of rapamycin (mTOR) is a master kinase that regulates several critical intracellular processes. It is now well established that this enzyme has a key role in cancer and its inhibition as therapeutic anti-cancer strategy is well recognised. Several clinical trials using mTOR inhibitors have been and are currently being performed. A huge scientific literature exists not only reporting the results of these trials but also discussing the reasons for the limited efficacy of strategies used so far and the need for new strategies to overcome the problem of resistance. The aim of this review is mainly to reflect on how the complexity of the mTOR-dependent signalling pathway and our difficulty to untangle it can ultimately affect the development of proper strategies to fully exploit the potential benefits of mTOR inhibition as anti-cancer strategy.

Pulmonary endothelium in acute lung injury: from basic science to the critically ill.

BACKGROUND: Pulmonary endothelium is an active organ possessing numerous physiological, immunological, and metabolic functions. These functions may be altered early in acute lung injury (ALI) and further contribute to the development of acute respiratory distress syndrome (ARDS). Pulmonary endothelium is strategically located to filter the entire blood before it enters the systemic circulation; consequently its integrity is essential for the maintenance of adequate homeostasis in both the pulmonary and systemic circulations. Noxious agents that affect pulmonary endothelium induce alterations in hemodynamics and hemofluidity, promote interactions with circulating blood cells, and lead to increased vascular permeability and pulmonary edema formation. OBJECTIVE: We highlight pathogenic mechanisms of pulmonary endothelial injury and their clinical implications in ALI/ARDS patients.

Echocardiographic and ambulatory electrocardiographic findings in elite water-polo athletes.

The aim of this study was to investigate the echocardiographic and electrocardiographic findings in top water-polo athletes and test the hypothesis that their hearts exhibit dilatation associated with hypertrophy secondary to the mixed type (isotonic and isometric) of exercise they are subjected to. Eighteen athletes of the Greek national water-polo team and 15 healthy sedentary men serving as controls were studied. All underwent an echocardiogram, a standard 12-lead ECG and 24-h ECG monitoring. In athletes, as compared to healthy controls, an increase was detected in the following indices: left ventricular (LV) end-diastolic diameter index (EDDI-LV) (by 10%; P = 0.02), interventricular septal thickness (IVS) (by 32%; P<0.001), thickness of the posterior wall (PW) (by 29%; P<0.001), relative wall thickness (IVS + PW/EDD-LV) (by 12%; P < 0.001) and LV mass index (by 82%; P < 0.001). Mild asymmetric thickening of the septum (IVS/PW = 1.40 and 1.37) was measured in two athletes. LV fractional shortening was normal. Standard 12-lead ECG abnormalities (LV hypertrophy or abnormal repolarization pattern) were observed in 33% of athletes. Athletes had sinus bradycardia during day and night, respiratory arrhythmia (RA) (83% vs 40% of controls; P = 0.03) and sinus pauses (SP) (39% vs 0% of controls; P = 0.02), with occassional arrhythmias and conduction abnormalities. We conclude that top water-polo athletes have dilatation combined with substantial hypertrophy and normal systolic function of the LV In addition they present bradycardia, RA and SP, with occassional arrhythmias and conduction abnormalities.