RASSF1A independence and early galectin‐1 upregulation in PIK3CA‐induced hepatocarcinogenesis: new therapeutic venues

Aberrant activation of the phosphoinositide 3‐kinase (PI3K)/AKT/mTOR and Ras/mitogen‐activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain‐containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild‐type mice by hydrodynamic tail vein injection combined with sleeping beauty‐mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl‐CoA desaturase‐1 (SCD1). Galectin‐1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co‐inhibitory treatment with PIK3CA inhibitors and the galectin‐1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues.     

Initial prevalence of anal human papilloma virus infection in liver transplant recipients

Although liver transplant recipients are at increased risk of human papilloma virus (HPV)‐related anal cancer, limited data are available regarding the initial prevalence of anal HPV infection in this population. Anal swabs collected from 50 liver transplant recipients within the first three postoperative weeks were subjected to real‐time polymerase chain reaction for detection of the four HPV genotypes: 6, 11, 16, and 18. Predictors of any, low‐risk, and high‐risk anal HPV infection were evaluated. Overall, the prevalence of any anal HPV infection was 18.0%, with the corresponding rates for high‐ and low‐risk HPV genotypes being 8.0% and 10.0%, respectively. Infection with any type of anal HPV was higher in patients with hepatitis B virus (HBV) infection (P = 0.027), ≥3 sexual partners (P = 0.031), and alcoholic liver disease (P = 0.063). HBV infection was the only factor significantly associated with high‐risk HPV infection (P = 0.038). Male sex (P = 0.050), age ≥52 years (P = 0.016), ≥30 sexual partners (P = 0.003), age at first intercourse ≤18 years (P = 0.045), and time since first intercourse ≥38 years (P = 0.012) were identified as predictors of low‐risk HPV infection. These results indicate that HPV vaccination of liver transplant candidates and screening for anal HPV infection in high‐risk groups should be considered.     

Interfacial Deposition of Titanium Dioxide at the Polarized Liquid–Liquid Interface

The interfacial polycondensation of titanium dioxide was studied at the bare and fiberglass membrane supported polarized liquid–liquid interface (LLI). Titanium dioxide synthesis was derived from the titanium (IV) tetrabutoxide (initially dissolved in the 1,2-dichloroethane) interfacial hydrolysis followed by its condensation. Experimental parameters, such as the pH of the aqueous phase and the influence of titanium alkoxide concentration in the organic phase on the electrochemical signal and material morphology, were investigated. The latter was achieved with fiberglass membranes used as the LLI support during TiO₂ interfacial deposition. Cyclic voltammetry was used for the in situ studies, whereas scanning electron microscopy, energy-dispersive X-ray spectroscopy, and infrared spectroscopy were used during ex situ examination. The interfacial polycondensation reaction could be studied using electrified LLI and resulted in the material being a TiO₂ film alone or film decorated with particles.     

Quality of out-of-hospital palliative emergency care depends on the expertise of the emergency medical team—a prospective multi-centre analysis

Background  

The number of palliative care patients who live at home and have non-curable life-threatening diseases is increasing. This is largely a result of modern palliative care techniques (e.g. specialised out-of-hospital palliative medical care services), changes in healthcare policy and the availability of home care services. Accordingly, pre-hospital emergency physicians today are more likely to be involved in out-of-hospital emergency treatment of palliative care patients with advanced disease.     

Effects of maternal separation on brain nociceptin/orphanin FQ peptide levels in male Wistar rats

Environmental manipulation early in life may induce persistent alterations in adult behaviour and physiology. In this study, we investigated the long-term effects of daily maternal separation, Days 1-21, on brain immunoreactive nociceptin/orphanin FQ (ir-N/OFQ) levels in male Wistar rats. The rat pups were separated in litters for 360 min (MS360) or 15 min (H15). Control rats were left undisturbed until weaning. Peptide levels were measured at 10 weeks of age. In the hypothalamus and periaqueductal gray, MS360 induced an increase in ir-N/OFQ levels in comparison with control rats. H15 rats had increased ir-N/OFQ levels in the hypothalamus and the medial prefrontal cortex compared with control animals. The rats were also tested at two occasions in an elevated plus-maze. An increased anxiety-like behaviour was shown in MS360 rats at weaning, whereas a decreased anxiety response was found at 9 weeks of age compared with control rats. The study shows that early life experiences induce long-term effects on behaviour, as well as brain N/OFQ levels.     

Nociceptin/orphanin FQ tissue concentration in the rat brain. Effects of repeated ethanol administration at various post-treatment intervals

The aim of this study was to study short- and long-term effects of repeated ethanol administration on nociceptin/orphanin FQ (N/OFQ) tissue concentrations in rat brain with radioimmunoassay. Animals were given either ethanol (intraperitoneal) or saline for 13 consecutive days. N/OFQ levels were examined at 30 min, 5 days and 21 days after the last dose on day 13. Ethanol-treated rats had significantly decreased N/OFQ tissue concentration in the hippocampus at 30 min after the last dose. N/OFQ levels were decreased in the cingulate cortex at 5 days after cessation of ethanol administration whereas no significant changes were found at 21 days. There were no significant changes in N/OFQ tissue concentrations at any time point studied in the mesolimbic dopamine (DA) system, a brain area associated with ethanol-induced activation. However, the results indicate that repeated ethanol administration may induce short- and long-term changes in N/OFQ tissue concentrations in other brain regions innervated with dopaminergic neurons.     

Conjugate Formation by Leukemic Blasts from Acute Myeloid Leukemia with Cytotoxic Lymphocytes

Conjugate formation by AML blasts with fresh peripheral blood lymphocytes (PBL) and lym-phokine activated killer (LAK) effectors was studied by flow cytometry. Leukemic blasts formed very low numbers of conjugates with fresh PBL and were resistant to natural killer (NK) cytotoxicity. When LAK effectors were used a significant increase in conjugate formation was observed, which in the majority of cases was followed by an increased killing. There was a positive correlation between the percentages of conjugates formed by AML blasts with LAK effectors and the susceptibility to lysis. No significant difference in binding activity between the CD3+ and CD56+ LAK subpopulations was found. There was no correlation between the expression of ICAM-1, LFA-3 and Transferrin receptor (CD71) and the conjugate formation. The blocking of CD71 on the control K562 cell line reduced the conjugate formation with LAK effectors but no such effect could be observed with CD71 + AML blasts.