Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia

Activation of the Wnt/beta-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/beta-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of beta-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2'-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).     

PPARα Ligands Reduce PCB-Induced Endothelial Activation: Possible Interactions in Inflammation and Atherosclerosis

Exposure to polychlorinated biphenyls (PCBs) can activate inflammatory responses in vascular endothelial cells. Activation of peroxisome proliferator-activated receptors (PPARs) by nutrients or synthetic agonists has been shown to block pro-inflammatory responses both in vitro and in vivo. Here we demonstrate that activation of PPARα by synthetic agonists can reduce 3,3′4,4′-tetrachlorobiphenyl (PCB77)-induced endothelial cell activation. Primary vascular endothelial cells were pretreated with the PPARα ligands fenofibrate or WY14643 followed by exposure to PCB77. PPARα activation protected endothelial cells against PCB77-induced expression of the pro-inflammatory proteins vascular cell adhesion molecule-1 (VCAM-1), cycloxygenase-2 (COX-2), and PCB77-induced expression and activity of the aryl hydrocarbon receptor (AHR) responsive cytochrome P450 1A1 (CYP1A1). Furthermore, basal AHR expression was downregulated by fenofibrate and WY14643. We also investigated the possible interactions between PCBs, and basal PPAR activity and protein expression. Treatment with PCB77 significantly reduced basal mRNA expression of PPARα and the PPAR responsive gene CYP4A1, as well as PPARα protein expression. Also, PCB77 exposure caused a significant decrease in basal PPAR-dependent reporter gene expression in MCF-7 cells. Overall, these findings suggest that PPARα agonists can reduce PCB77 induction of endothelial cell activation by inhibition of the AHR pathway, and that coplanar PCB induced pro-inflammatory effects could be mediated, in part, by inhibition of PPARα expression and function.     

A prospective clinical study on titanium implants in the zygomatic arch for prosthetic rehabilitation of the atrophic edentulous maxilla with a follow-up of 6 months to 5 years

Background Prosthetic rehabilitation with implant‐supported prostheses in the atrophic edentulous maxilla often requires a bone augmentation procedure to enable implant placement and integration. However, a rigid anchorage can also be achieved by using so‐called zygomatic implants placed in the zygomatic arch in combination with regular implants placed in residual bone. Purpose The aim of the present study was to report on the clinical outcome of using zygomatic and regular implants for prosthetic rehabilitation of the severely atrophic edentulous maxilla. Materials and Methods Sixty‐nine consecutive patients with severe maxillary atrophy were, during a 5‐year period, treated with a total of 69 fixed full‐arch prostheses anchored on 435 implants. Of these, 131 were zygomatic implants and 304 were regular implants. Fifty‐seven bridges were screw‐retained and 12 were cemented. The screw‐retained bridges were removed at the examination appointments and each implant was tested for mobility. In addition, the zygomatic implants were subjected to Periotest^® (Siemens AG, Bensheim, Germany) measurements. The patients had at the time of this report been followed for at least 6 months up to 5 years in loading. Results Two regular implants failed during the study period giving a cumulative survival rate of 99.0%. None of the zygomatic implants was removed. All patients received and maintained a fixed full‐arch bridge during the study. Periotest measurements of zygomatic implants showed a decreased Periotest values value with time, indictating an increased stability. Three patients presented with sinusitis 14–27 months postoperatively, which could be resolved with antibiotics. Loosening of the zygomatic implant gold screws was recorded in nine patients. Fracture of one gold screw as well as the prosthesis occurred twice in one patient. Fracture of anterior prosthetic teeth was experienced in four patients. Conclusions The results from the present study show that the use of zygomatic and regular implants represents a predictable alternative to bone grafting in the rehabilitation of the atrophic edentulous maxilla.     

Smoking among a cohort of Spanish university graduates. The SUN Project

OBJECTIVE: The objective of this study was to assess the association between employment, educational level, marital status, and smoking in a large cohort of Spanish university graduates (3- and 5-year degrees), with a predominance of health professionals. METHODS: A cross-sectional analysis of the baseline data of the first 7,508 participants in the follow-up study of the University of Navarre (SUN Project) was performed. The subjects were classified according to their smoking status. Independent variables were: employment, marital status, highest educational level attained, number of children, alcohol consumption (g/day), body mass index, and age. In the multivariate analysis, 3 non-conditional logistic regression models were built using the following outcomes: a) smokers vs never-smokers plus ex-smokers; b) smokers vs never-smokers; c) smokers of 15 or more cigarettes a day vs smokers of less than 15 cigarettes a day plus never-smokers and ex-smokers. RESULTS: Among men, no association was found between employment and smoking status in any of the comparisons. In contrast, among women, being a nurse was associated with a higher prevalence of smoking. The prevalence of current smokers among nurses was 48.5%. Female students were also more likely to smoke and had a higher risk of being heavy smokers (OR = 1.81; 95% CI, 1.28-2.57). A lower prevalence of smoking was found among participants of both sexes who had completed a doctorate. CONCLUSIONS: Among a large Spanish collective with higher education, the prevalence of smoking was higher in women with a shorter college degree. The prevalence of smoking among nurses was higher than the average among women graduates, which is a cause for concern.     

Expression of an altered form of tau in Sf9 insect cells results in the assembly of polymers resembling Alzheimer's paired helical filaments

Tau is the main component of the paired helical filaments (PHFs), aberrant structures that develop in the brain of Alzheimer's disease (AD) patients and other tauopathies like frontotemporal dementia and parkinsonism associated to chromosome 17 (FTDP-17). Previous work has shown that tau overexpression in Sf9 insect cells results in the formation of long cytoplasmatic extensions as a consequence of microtubule stabilization and bundling. Throughout this work, we have taken studies in this system further by overexpression of an altered form of tau characteristic of FTDP-17, which includes three mutations (G272V, P301L and R406W) and biochemically behaves as a hyperphosphorylated form of the protein, with the aim of developing an in vitro model which would favour the formation of tau aggregates. Our results indicate that filaments resembling PHFs assemble when Sf9 cells overexpress FTDP-17 tau. The amount of these polymers is reduced in lithium treated cells which suggests that phosphorylation of FTDP-17 tau by GSK3 induces a conformational change favouring the formation of fibrillar polymers.     

Convergence Properties of High-order Boltzmann Machines

The high-order Boltzmann machine (HOBM) approximates probability distributions defined on a set of binary variables, through a learning algorithm that uses Monte Carlo methods. The approximation distribution is a normalized exponential of a consensus function formed by high-degree terms and the structure of the HOBM is given by the set of weighted connections. We prove the convexity of the Kullback-Leibler divergence between the distribution to learn and the approximation distribution of the HOBM. We prove the convergence of the learning algorithm to the strict global minimum of the divergence, which corresponds to the maximum likelihood estimate of the connection weights, establishing the uniqueness of the solution. These theoretical results do not hold in the conventional Boltzmann machine, where the consensus function has first and second-degree terms and hidden units are used. Copyright © 1996 Elsevier Science Ltd.     

Expression of protein tyrosine kinases in head and neck squamous cell carcinomas

Protein tyrosine kinases (TKs) are overexpressed in many carcinomas and sarcomas. We studied the expression of the following TKs in head and neck squamous cell carcinoma (HNSCC): platelet-derived growth factor receptor (PDGFR), c-kit, epidermal growth factor receptor (EGFR), and a serine-threonine kinase, Akt. Formalin-fixed, paraffin-embedded tumor blocks from 44 consecutive patients with primary HNSCC and 5 specimens of benign pharyngeal and laryngeal mucosa were retrieved for immunohistochemical analysis. Of the specimens, 38 had enough material to stain for all 4 antibodies. The study included 21 pharyngeal (base of tongue, 14; tonsil, 6; soft palate, 1), 16 laryngeal, and 1 floor of the mouth carcinoma. All 4 kinases in the tumor samples were expressed highly (PDGFR, 95%-100%; EGFR, 38%-43%; c-kit, 50%-86%; p-Akt, 57%-81%), with EGFR, c-kit, and p-Akt significantly higher than in benign samples. None of the kinase expressions correlated with disease-free survival. The expression of the kinases raises the possibility of treatment of HNSCC by tyrosine and serine-threonine kinase inhibitors.