Hyperplasia of alveolar neuroendocrine cells in rat lung carcinogenesis by silica with selective expression of proadrenomedullin-derived peptides and amidating enzymes

Pulmonary neuroendocrine (NE) cells are found as clusters called neuroepithelial bodies (NEBs) or as single cells scattered in the respiratory epithelium. They express a variety of bioactive peptides, and they are thought to be the origin of NE lung tumors. Proadrenomedullin N-terminal 20 peptide (PAMP) is a peptide derived from the same precursor as adrenomedullin (AM). AM and PAMP are C-terminally amidated during their processing by a well-characterized amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). We explored AM, PAMP, and PAM expression as markers for NE hyperplasia in three rodent species (Fischer 344 rats, Syrian golden hamsters, and A/J mice) after a single intratracheal instillation of crystalline silica (quartz), which was previously found to induce different reactions in the three species. Rats developed a marked silicosis, with alveolar and bronchiolar hyperplasia and formation of peripheral lung epithelial tumors. Mice developed a moderate degree of silicosis, but not epithelial hyperplasia or tumors. Hamsters showed dust-storage lesions, but not silicosis or tumors. NE cells were immunolabeled for calcitonin gene-related peptide (CGRP), AM, PAMP, and PAM in serial sections of each lung. The numbers of positive NEBs per lung area and positive cells per NEB were quantified. A marked hyperplastic reaction in the NEBs of silica treated rats occurred only in alveolar NEBs, but not in bronchiolar NEBs. From Month 11 onwards, there were marked differences in the number of alveolar NEBs per section and in the number of cells per alveolar NEB immunoreactive for CGRP. No hyperplastic NE cell reaction was observed in silica-treated mice and hamsters. Significant PAMP and PAM expression was seen only in rat hyperplastic alveolar and in bronchiolar NEBs from Month 11 onwards. In E18, rat fetal lung NEBs were found to be strongly positive for PAMP and PAM

Towards Norm Realization in Institutions Mediating Human-Robot Societies

Social norms are the understandings that govern the behavior of members of a society. As such, they regulate communication, cooperation and other social interactions. Robots capable of reasoning about social norms are more likely to be recognized as an extension of our human society. However, norms stated in a form of the human language are inherently vague and abstract. This allows for applying norms in a variety of situations, but if the robots are to adhere to social norms, they must be capable of translating abstract norms to the robotic language. In this paper we use a notion of institution to realize social norms in real robotic systems. We illustrate our approach in a case study, where we translate abstract norms into concrete constraints on cooperative behaviors of humans and robots. We investigate the feasibility of our approach and quantitatively evaluate the performance of our framework in 30 real experiments with user-based evaluation with 40 participants

Towards Institutions for Mixed Human-Robot Societies

We report an exploration into normative reasoning for robots in human societies using the concept of institutions

Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis

Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage

Faktori rizika od karcinoma larinksa u Crnoj Gori

Laryngeal cancer is the most common head and neck cancer. There might be many risk factors for laryngeal cancer. Smoking, especially cigarette smoking and alcohol are indisputable risk factors. The authors of this paper assessed the presumed risk factors in order to identify possible aetiological agents of the disease. A hospital-based case-control study was conducted. The study group consisted of 108 histologically verified laryngeal cancer patients and 108 hospital controls matched by sex, age (±3 years) and place of residence. Laryngeal cancer patients and controls were interviewed during their hospital stay using a structured questionnaire. According to multiple logistic regression analysis six variables were independently related to laryngeal cancer: hard liquor consumption (Odd Ratio /OR/=2.93, Confidence Interval /CI/ 95 % = 1.17 to 7.31), consumption more than 2 alcoholic drinks per day (OR=4.96, CI 95 % = 2.04 to12.04), cigarette smoking for more than 40 years (OR=4.32, CI 95 % = 1.69 to 11.06), smoking more than 30 cigarettes per day (OR=4.24, CI 95 % = 1.75 to 10.27), coffee consumption more than 5 cups per day (OR=4.52, CI 95 % = 1.01 to 20.12) and carbonated beverage consumption (OR=0.38, CI 95 %= 0.16 to 0.92). The great majority of laryngeal cancers could be prevented by eliminating tobacco smoking and alcohol consumption.Maligni tumori larinksa najčešći su tumori glave i vrata. Glavni faktori rizika od razvoja malignih tumora grkljana su pušenje i konzumiranje alkoholnih pića. Cilj rada bio je ispitivanje potencijalnih faktora rizika od nastanka malignih tumora larinksa. Sprovedena je studija slučaj-kontrola. Studijsku grupu činilo je 108 pacijenata s histološki verificiranim rakom larinksa i 108 kontrola individualno izjednačenih po spolu, dobi (± 3 godine) i mjestu stanovanja. Svi ispitanici su anketirani ciljanim epidemiološkim upitnikom a u analizi podataka korištena je multivarijantna logistička regresijska analiza. Koristeći se multivarijantnom logističkom regresijskom analizom, statistički značajnu povezanost s rakom larinksa dobili smo za sljedeće varijable: konzumiranje žestokih pića (omjer izgleda /OR/=2.93, interval pouzdanosti /CI/ 95 % = 1.17 do 7.31), konzumiranje više od 2 alkoholna pića na dan (OR = 4.96, CI 95 % = 2.04 do 12.04), konzumiranje cigareta duže od 40 godina (OR = 4.32, CI 95 % = 1.69 do 11.06), konzumiranje više od 30 cigareta na dan (OR = 4.24, CI 95 % = 1.75 do 10.27), konzumiranje više od 5 šalica kave na dan (OR = 4.52, CI 95 % = 1.01 do 20.12) i konzumiranje gaziranih pića (OR = 0.38, CI 95 % = 0.16 do 0.92). Obolijevanje zbog malignih tumora larinksa moglo bi se značajno smanjiti prestankom konzumiranja duhana i alkohola

Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-γ is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-γ selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-γ is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-β/γ selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma