High frequency of immature dendritic cells and altered in situ production of interleukin-4 and tumor necrosis factor-alpha in lung cancer

Introduction Antigen-presenting cells, like dendritic cells (DCs) and macrophages, play a significant role in the induction of an immune response and an imbalance in the proportion of macrophages, immature and mature DCs within the tumor could affect significantly the immune response to cancer. DCs and macrophages can differentiate from monocytes, depending on the milieu, where cytokines, like interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) induce DC differentiation and tumor necrosis factor (TNF)-alpha induce DC maturation. Thus, the aim of this work was to analyze by immunohistochemistry the presence of DCs (S100+ or CD1a+), macrophages (CD68+), IL-4 and TNF-alpha within the microenvironment of primary lung carcinomas. Results Higher frequencies of both immature DCs and macrophages were detected in the tumor-affected lung, when compared to the non-affected lung. Also, TNF-alpha-positive cells were more frequent, while IL-4-positive cells were less frequent in neoplastic tissues. This decreased frequency of mature DCs within the tumor was further confirmed by the lower frequency of CD14-CD80+ cells in cell suspensions obtained from the same lung tissues analyzed by flow cytometry. Conclusion These data are discussed and interpreted as the result of an environment that does not oppose monocyte differentiation into DCs, but that could impair DC maturation, thus affecting the induction of effective immune responses against the tumor.

Low level laser therapy (LLLT) decreases pulmonary microvascular leakage, neutrophil influx and IL-1 beta levels in airway and lung from rat subjected to LPS-induced inflammation

Background and Objective. Low level laser therapy (LLLT) is a known anti-inflammatory therapy. Herein we studied the effect of LLLT on lung permeability and the IL-1 beta level in LPS-induced pulmonary inflammation. Study Design/Methodology. Rats were divided into 12 groups (n = 7 for each group). Lung permeability was measured by quantifying extravasated albumin concentration in lung homogenate, inflammatory cells influx was determined by myeloperoxidase activity, IL-1P in BAL was determined by ELISA and IL-1P mRNA expression in trachea was evaluated by RT-PCR. The rats were irradiated on the skin over the upper bronchus at the site of tracheotomy after LPS. Results. LLLT attenuated lung permeability. In addition, there was reduced neutrophil influx, myeloperoxidase activity and both IL-1 beta in BAL and IL-1 beta mRNA expression in trachea obtained from animals subjected to LPS-induced inflammation. Conclusion. LLLT reduced the lung permeability by a mechanism in which the IL-1 beta seems to have an important role.

Enhancement of Th1 Lung Immunity Induced by Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Attenuates Airway Allergic Disease

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) has been shown to down-regulate experimental allergic asthma, a finding that reinforced the hygiene hypothesis. We have previously found that recombinant BCG (rBCG) strain that express the genetically detoxified Si subunit of pertussis toxin (rBCG-S1PT) exerts an adjuvant effect that enhances Th1 responses against BCG proteins. Here we investigated the effect of this rBCG-S1PT on the classical ovalbumin-induced mouse model of allergic lung disease. We found that rBCG-S1PT was more effective than wild-type BCG in preventing Th2-mediated allergic immune responses. The inhibition of allergic lung disease was not associated with increased concentration of suppressive cytokines or with an increased number of pulmonary regulatory T cells but was positively correlated with the increase in IFN-gamma-producing T cells and T-bet expression in the lung. In addition, an IL-12-dependent mechanism appeared to be important to the inhibition of lung allergic disease. The inhibition of allergic inflammation was found to be restricted to the lung because when allergen challenge was given by the intraperitoneal route, rBCG-S1PT administration failed to inhibit peritoneal allergic inflammation and type 2 cytokine production. Our work offers a nonclassical interpretation for the hygiene hypothesis indicating that attenuation of lung allergy by rBCG could be due to the enhancement of local lung Th1 immunity induced by rBCG-S1PT. Moreover, it highlights the possible use of rBCG strains as multipurpose immunomodulators by inducing specific immunity against microbial products while protecting against allergic asthma.

Bradykinin inducible receptor is essential to lipopolysaccharide-induced acute lung injury in mice

Lipopolysaccharides from gram-negative bacteria are amongst the most common causative agents of acute lung injury, which is characterized by an inflammatory response, with cellular infiltration and the release of mediators/cytokines. There is evidence that bradykinin plays a role in lung inflammation in asthma but in other types of lung inflammation its role is less clear. In the present study we evaluated the role of the bradykinin B(1) receptor in acute lung injury caused by lipopolysaccharide inhalation and the mechanisms behind bradykinin actions participating in the inflammatory response. We found that in C57BI/6 mice, the bradykinin B(1) receptor expression was up-regulated 24 h after lipopolysaccharide inhalation. At this time, the number of cells and protein concentration were significantly increased in the bronchoalveolar lavage fluid and the mice developed airway hyperreactivity to methacholine. In addition, there was an increased expression of tumor necrosis factor-alpha, interleukin-1 beta and interferon-gamma and chemokines (monocytes chemotactic protein-1 and KC) in the bronchoalveolar lavage fluid and in the lung tissue. We then treated the mice with a bradykinin B, receptor antagonist, R-954 (Ac-Orn-[Oic(2), alpha-MePhe(5), D-beta Nal(7), Ile(8)]desArg(9)-bradykinin), 30 min after lipopolysaccharide administration. We observed that this treatment prevented the airway hyperreactivity as well as the increased cellular infiltration and protein content in the bronchoalveolar lavage fluid. Moreover, R-954 inhibited the expression of cytokines/chemokines. These results implicate bradykinin, acting through B(1) receptor, in the development of acute lung injury caused by lipopolysaccharide inhalation. (C) 2010 Elsevier B.V. All rights reserved.

SIGNALING PATHWAYS AND MEDIATORS IN LPS-INDUCED LUNG INFLAMMATION IN DIABETIC RATS: ROLE OF INSULIN

Diabetic patients are more susceptible to infections, and their inflammatory response is impaired. This is restored by insulin treatment. In the present study, we investigated the effect of insulin on LPS-induced signaling pathways and mediators in the lung of diabetic rats. Diabetic male Wistar rats (alloxan, 42 mg/kg i.v., 10 days) and control rats received intratracheal instillation of LPS (750 mu g/0.4 mL) or saline. Some diabetic rats were given neutral protamine Hagedorn insulin (4 IU s.c.) 2 h before LPS. After 6 h, bronchoalveolar lavage was performed for the release of mediators, and lung tissue was homogenized for analysis of LPS-induced signaling pathways. Relative to control rats, diabetic rats exhibited a significant reduction in the LPS-induced phosphorylation of extracellular signal-regulated kinase (64%), p38 (70%), protein kinase B (67%), and protein kinase C alpha (57%) and delta (65%) and in the expression of iNOS (32%) and cyclooxygenase 2 (67%) in the lung homogenates. The bronchoalveolar lavage fluid concentrations of NO (47%) and IL-6 (49%) were also reduced in diabetic rats, whereas the cytokine-induced neutrophil chemoattractant 2 (CINC-2) levels were increased 23%, and CINC-1 was not different from control animals. Treatment of diabetic rats with insulin completely or partially restored all these parameters. In conclusion, data presented show that insulin regulates mitogen-activated protein kinase, phosphatidylinositol 3`-kinase, protein kinase C pathways, expression of the inducible enzymes, cyclooxygenase 2 and iNOS, and levels of IL-6 and CINC-2 in LPS-induced lung inflammation in diabetic rats. These results suggest that the protective effect of insulin in sepsis could be due to modulation of cellular signal transduction factors.

Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue

Lung cancer is the leading cause of cancer deaths in the United States, surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/d, 5 d/wk for 3, 8, and 20 weeks). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15K cDNA microarray. Cytochrome P450 1b1, a phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17 beta-estradiol (E(2)), was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed in control and smoke-exposed lung tissues at 3, 8, and 20 weeks (P < 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure, including estrogen metabolism. In addition, E(2) was detected within murine lung tissue by gas chromatography-coupled mass spectrometry and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of E2 within lung tissue when combined with the modulation of cytochrome P450 1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer. Cancer Prev Res; 3(6); 707-17. (C) 2010 AACR.

Base Excision Repair Activities Differ in Human Lung Cancer Cells and Corresponding Normal Controls

Oxidative damage to DNA is thought to play a role in carcinogenesis by causing Mutations, and indeed accumulation of oxidized DNA bases has been observed in samples obtained from tumors but not from surrounding tissue within the same patient. Base excision repair (BER) is the main pathway for the repair of oxidized modifications both in nuclear and mitochondrial, DNA. In order to ascertain whether diminished BER capacity might account for increased levels of oxidative DNA damage in cancer cells, the activities of BER enzymes in three different lung cancer cell lines and their non-cancerous counterparts were measured using oligonucleotide substrates with single DNA lesions to assess specific BER enzymes. The activities of four BER enzymes, OGG1, NTH1, UDG and APE1, were compared in mitochondrial and nuclear extracts. For each specific lesion, the repair activities were similar among the three cell lines used. However, the specific activities and cancer versus control comparison differed significantly between the nuclear and mitochondrial compartments. OGG1 activity, as measured by 8-oxodA incision, was upregulated in cancer cell mitochondria but down-regulated in the nucleus when compared to control cells. Similarly, NTH1 activity was also up-regulated in mitochondrial extracts from cancer cells but did not change significantly in the nucleus. Together, these results support the idea that alterations in BER capacity are associated with carcinogenesis.

Cytotoxic and genotoxic effects of tambjamine D, an alkaloid isolated from the nudibranch Tambja eliora, on Chinese hamster lung fibroblasts

Marine organisms have been shown to be potential sources of bioactive compounds with pharmaceutical applications. Previous chemical investigation of the nudibranch Tambja eliora led to the isolation of the alkaloid tambjamine D. Tambjamines have been isolated from marine sources and belong to the family of 4-methoxypyrrolic-derived natural products, which display promising immunosuppressive and cytotoxic properties. Their ability to intercalate DNA and their pro-oxidant activity may be related to some of the biological effects of the 4-methoxypyrrolic alkaloids. The aim of the present investigation was to determine the cytotoxic, pro-oxidant and genotoxic properties of tambjamine D in V79 Chinese hamster lung fibroblast cells. Tambjamine D displayed a potent cytotoxic effect in V79 cells (IC50 1.2 mu g/mL) evaluated by the MTT assay. Based on the MTT result, V79 cells were treated with different concentrations of tambjamine D (0.6. 1.2. 2.4 and 4.8 mu g/mL). After 24 h, tambjamine D reduced the number of viable cells in a concentration-dependent way at all concentrations tested. assessed by the trypan blue dye exclusion test. The hemolytic assay showed that the cytotoxic activity of tambjamine D was not related to membrane disruption (EC50 > 100 mu g/mL). Tambjamine D increased the number of apoptotic cells in a concentration-dependent manner at all concentrations tested according to acridine orange/ethidium bromide staining, showing that the alkaloid cytotoxic effect was related to the induction of apoptosis. MTT reduction was stimulated by tambjamine D, which may indicate the generation of reactive oxygen species. Accordingly, treatment of cells with tambjamine D increased nitrite/nitrate at all concentrations and TBARS production starting at the concentration corresponding to the IC50. Tambjamine D, also, induced DNA strand breaks and increased the micronucleus cell frequency as evaluated by comet and micronucleus tests, respectively, at all concentrations evaluated. showing a genotoxic risk induced by tambjamine D. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Push or pull? : The relationship between quality of care and use of complementary and alternative medicine among patients with lung cancer in Sweden

Little is known about relationships between quality of care (QoC) and use of complementary and alternative medicine (CAM) among patients with lung cancer (LC). Purpose: This study examines CAM-use among patients with LC in Sweden, associations between QoC and CAM-use among these patients, and reported aspects of LC-care perceived as particularly positive and negative by patients, as well as suggestions for improving QoC. Methods: Survey data from 94 patient members of the Swedish LC patient organization about CAM-use and QoC as measured by the instrument “Quality from the patient’s perspective” were analyzed. Results: Fifty (53%) LC-patients used CAM, with 40 of the CAM-users reporting that CAM helped them. The most common CAMs used were dietary supplements and natural remedies, followed by prayer. Significantly more patients reported using prayer and meditation for cure than was the case for other types of CAM used. Less than half the CAM-users reported having spoken with staff from the biomedical health care system about their CAM-use. Patients provided numerous suggestions for improving LC-care in a variety of areas, aiming at a more effective and cohesive care trajectory. No differences in QoC were found between CAM-users and non-CAM-users, but differences in CAM-use i.e. type of CAM, reasons for using CAM, and CAM-provider consulted could be associated with different experiences of care. Conclusions: It is important to recognize that CAM-users are not a homogeneous group but might seek different types of CAMs and CAM-providers in different situations depending on experiences of care.

Compliance to law and effectiveness of the rule of law in Brazil

The goal of this paper is to debate the degree of effectiveness of the rule of law in Brazil, through a survey measuring perceptions, attitudes and habits of Brazilians in regard to compliance to law. The survey conducted in Brazil is based on the study conducted by Tom R. Tyler in the United States, entitled Why People Obey the Law? (New Haven, CT: Yale University Press, 1990). The main argument of Tyler´s study is that people obey the law when they believe it’s legitimate, and not because they fear punishment. We test the same argument in Brazil, relying on five indicators: (i) behavior, which depicts the frequency with which respondents declared to have engaged in conducts in disobedience to the law; (ii) instrumentality, measuring perception of losses associated with the violation of the law, specially fear of punishment; (iii) morality, measuring perception of how much is right or wrong to engage in certain conducts in violation of the law; (iv) social control, which measures perception of social disapproval of certain types of behavior in violation of the law, and (v) legitimacy, which measures the perception of respect to the law and to some authorities. Results indicate that fear of sanctions is not the strongest drive in compliance to law, but more than legitimacy, indicators of morality and social control are the strongest in explaining why people obey the law in Brazil.

Programas de compliance anticorrupção no contexto da Lei 12.846/13: elementos e estudo de caso

Com o fenômeno da globalização, verificou-se o aumento do volume de transações comerciais entre os países, bem como da concentração de poder econômico das organizações empresariais. Esse aumento das operações comerciais e, consequentemente, do montante de dinheiro nelas envolvido, criou ambiente mais favorável à corrupção. Pelo fato de a corrupção trazer prejuízos à ordem econômica mundial e ao sistema democrático, a comunidade mundial passou a demandar um regime de intervenção estatal maior no seu combate, principalmente a partir dos anos 90. O combate à corrupção se deu por meio dos compromissos assumidos pelos países, que assinaram Convenções nesse sentindo. O presente estudo abordou os reflexos negativos da corrupção na economia e sociedade brasileiras, e os instrumentos internacionais que foram adotados pelo país numa tentativa de diminuí-la. Tratou-se, ainda, do sistema legislativo brasileiro de combate à corrupção e dos aspectos da Lei nº 12.846/13, chamada de lei anticorrupção. Ponto importante do estudo foi a análise da possibilidade de redução das sanções trazida pela referida Lei nº 12.846/13, pela existência dos "mecanismos e procedimentos internos de integridade, auditoria e incentivo à denuncia de irregularidades e a aplicação efetiva de códigos de ética e de conduta", ou seja, os "programas de Compliance". Procurou-se analisar as implicações jurídicas da adoção de programas de Compliance anticorrupção, quais os elementos daquilo que pode ser considerado um programa efetivo com base nos parâmetros internacionais, se esses elementos podem ser eficientes e em que medida no combate à corrupção. Por fim, foi realizada uma pesquisa na companhia Localiza Rent a Car S/A, empresa locadora de veículos, a fim de verificar quais elementos constam do seu programa e se possuem os elementos tidos como mínimos e essenciais extraídos das referências internacionais e nacionais.

Compliance com os requisitos de divulgação do IFRS - International Financial Reporting Standards e sua relação com o erro de previsão dos analistas de mercado

O objetivo deste estudo é fazer uma análise da relação entre o erro de previsão dos analistas de mercado quanto à rentabilidade das empresas listadas na BM&FBOVESPA S.A. (Bovespa) e os requerimentos de divulgação do International Financial Reporting Standards (IFRS). Isto foi feito através da regressão do erro de previsão dos analistas, utilizando a metodologia de dados em painel no ano de implantação do IFRS no Brasil, 2010, e, complementarmente em 2012, para referenciamento desses dados. Partindo desse pressuposto, foi determinado o erro de previsão das empresas listadas na Bovespa através de dados de rentabilidade (índice de lucro por ação/earnings per share) previstos e realizados, disponíveis nas bases de dados I/B/E/S Earnings Consensus Information, providos pela plataforma Thomson ONE Investment Banking e Economática Pro®, respectivamente. Os resultados obtidos indicam uma relação negativa entre o erro de previsão e o cumprimento dos requisitos de divulgação do IFRS, ou seja, quanto maior a qualidade nas informações divulgadas, menor o erro de previsão dos analistas. Portanto, esses resultados sustentam a perspectiva de que o grau de cumprimento das normas contábeis é tão ou mais importante do que as próprias normas. Adicionalmente, foi verificado que quando a empresa listada na BM&FBOVESPA é vinculada a Agência Reguladora, seu erro de previsão não é alterado. Por fim, esses resultados sugerem que é importante que haja o aprimoramento dos mecanismos de auditoria das firmas quanto ao cumprimento dos requerimentos normativos de divulgação, tais como: penalidades pela não observância da norma (enforcement), estruturas de governança corporativa e auditorias interna e externa.

Turnaround de empresas com problemas de compliance - o caso Siemens

It is very relevant, for academic or for society purposes as a whole the subject "corruption", a recurring problem that plagues companies and Governments in various parts of the world. Many recent cases draw attention to this topic, but one in particular, the case of corruption of the company Siemens AG, that resulted in the payment of the largest fines in the history on your model, based on the terms of the FCPA since it became law in 1977. This event caters specifically to the objective of this work which is to make an analysis based on agency theory and the codes of good practices of corporate governance on how large companies revising their corporate management systems and practices aiming at the recovery of its institutional image after significant impact on the company, such as the corruption scandal in which Siemens was involved. For this study, we opted for qualitative research as a methodological path contemplating the single case study. In the process of data collection were used data obtained through documentary research about the corruption scandal on public collection available in the internet. Open conversations were made with 3 compliance Department officials of Siemens for the purposes of understanding the case with. At the end of this work, it was observed in the Siemens turnaround process a correlation between what was proposed by the Agency Theory about internal control Systems based on what was accomplished by the company when promoted an extensive restructuring of the Department of compliance and corporate governance system, the improvement of internal controls, as well as the creation of detection tools , control, analysis and prevention of fraud, which were used to minimize the effects generated by the conflict of interest covered by the theory of Agency. KEY WORDS: Corporate Governance; Compliance; Corruption; Turnaround, Agency Theory