300 resultados para LUNG DAMAGE

em Queensland University of Technology - ePrints Archive


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Introduction: Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. Methods: An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. Results: Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. Conclusion: Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer. © 2013 Barr et al.

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Cisplatin is one of the most potent anticancer agents, displaying significant clinical activity against a variety of solid tumours. To date, cisplatin-based combination treatment remains the most effective systemic chemotherapy for non-small cell lung cancer (NSCLC) patients. Unfortunately, the outcome of cisplatin therapy in NSCLC has reached a plateau due to the development of both intrinsic and acquired resistance that have become a major obstacle in the use of cisplatin in the clinical setting. The molecular mechanisms that underlie chemoresistance are largely unknown. Mechanisms of acquired resistance to cisplatin include reduced intracellular accumulation of the drug, enhanced drug inactivation by metallothionine and glutathione, increased repair activity of DNA damage, and altered expression of oncogenes and regulatory proteins. Cisplatin-induced cytotoxicity is mediated through the induction of apoptosis and cell cycle arrest as a result of cisplatin-DNA adduct formation, which in turn, activates multiple signaling pathways and mediators. These include p53, Bcl-2 family, caspases, cyclins, CDKs, MAPK and PI3K/Akt. Increased expression of anti-apoptotic genes and mutations in the intrinsic apoptotic pathway may also contribute to the inability of cells to detect DNA damage or to induce apoptosis. This chapter will provide an insight into the mechanisms involved in cisplatin resistance and a better understanding of the molecular basis of the cellular response to cisplatin-based chemotherapy in lung cancer.

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Orthotopic or intracardiac injection of human breast cancer cell lines into immunocompromised mice allows study of the molecular basis of breast cancer metastasis. We have established a quantitative real-time PCR approach to analyze metastatic spread of human breast cancer cells inoculated into nude mice via these routes. We employed MDA-MB-231 human breast cancer cells genetically tagged with a bacterial β-galactosidase (Lac-Z) retroviral vector, enabling their detection by TaqMan® real-time PCR. PCR detection was linear, specific, more sensitive than conventional PCR, and could be used to directly quantitate metastatic burden in bone and soft organs. Attesting to the sensitivity and specificity of the PCR detection strategy, as few as several hundred metastatic MDA-MB-231 cells were detectable in 100 μm segments of paraffin-embedded lung tissue, and only in samples adjacent to sections that scored positive by histological detection. Moreover, the measured real-time PCR metastatic burden in the bone environment (mouse hind-limbs, n = 48) displayed a high correlation to the degree of osteolytic damage observed by high resolution X-ray analysis (r2 = 0.972). Such a direct linear relationship to tumor burden and bone damage substantiates the so-called 'vicious cycle' hypothesis in which metastatic tumor cells promote the release of factors from the bone which continue to stimulate the tumor cells. The technique provides a useful tool for molecular and cellular analysis of human breast cancer metastasis to bone and soft organs, can easily be extended to other cell/marker/organ systems, and should also find application in preclinical assessment of anti-metastatic modalities.

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Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.

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Lung cancer is the leading cause of cancer-related mortality. According to WHO, 1.37 million deaths occur globally each year as a result of this disease. More than 70% of these cases are associated with prior tobacco consumption and/or cigarette smoking, suggesting a direct causal relationship. The development and progression of lung cancer and other malignancies involves the loss of genetic stability, resulting in acquisition of cumulative genetic changes; this affords the cell increased malignant potential. As such, an understanding of the mechanisms through which these events may occur will potentially allow for development of new anticancer therapies. This review will address the association between lung cancer and genetic instability, with a central focus on genetic mutations in the DNA damage repair pathways. In addition, we will discuss the potential clinical exploitation of these pathways, both in terms of biomarker staging, as well as through direct therapeutic targeting.

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Bomb attacks carried out by terrorists, targeting high occupancy buildings, have become increasingly common in recent times. Large numbers of casualties and property damage result from overpressure of the blast followed by failing of structural elements. Understanding the blast response of multi-storey buildings and evaluating their remaining life have therefore become important. Response and damage analysis of single structural components, such as columns or slabs, to explosive loads have been examined in the literature, but the studies on blast response and damage analysis of structural frames in multi-storey buildings is limited and this is necessary for assessing the vulnerability of them. This paper investigates the blast response and damage evaluation of reinforced concrete (RC) frames, designed for normal gravity loads, in order to evaluate their remaining life. Numerical modelling and analysis were carried out using the explicit finite element software, LS DYNA. The modelling and analysis takes into consideration reinforcement details together and material performance under higher strain rates. Damage indices for columns are calculated based on their residual and original capacities. Numerical results generated in the can be used to identify relationships between the blast load parameters and the column damage. Damage index curve will provide a simple means for assessing the damage to a typical multi-storey building RC frame under an external bomb circumstance.

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Vibration based damage identification methods examine the changes in primary modal parameters or quantities derived from modal parameters. As one method may have advantages over the other under some circumstances, a multi-criteria approach is proposed. Case studies are conducted separately on beam, plate and plate-on-beam structures. Using the numerically simulated modal data obtained through finite element analysis software, algorithms based on flexibility and strain energy changes before and after damage are obtained and used as the indices for the assessment of the state of structural health. Results show that the proposed multi-criteria method is effective in damage identification in these structures.

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As a part of vital infrastructure and transportation networks, bridge structures must function safely at all times. However, due to heavier and faster moving vehicular loads and function adjustment, such as Busway accommodation, many bridges are now operating at an overload beyond their design capacity. Additionally, the huge renovation and replacement costs always make the infrastructure owners difficult to undertake. Structural health monitoring (SHM) is set to assess condition and foresee probable failures of designated bridge(s), so as to monitor the structural health of the bridges. The SHM systems proposed recently are incorporated with Vibration-Based Damage Detection (VBDD) techniques, Statistical Methods and Signal processing techniques and have been regarded as efficient and economical ways to solve the problem. The recent development in damage detection and condition assessment techniques based on VBDD and statistical methods are reviewed. The VBDD methods based on changes in natural frequencies, curvature/strain modes, modal strain energy (MSE) dynamic flexibility, artificial neural networks (ANN) before and after damage and other signal processing methods like Wavelet techniques and empirical mode decomposition (EMD) / Hilbert spectrum methods are discussed here.

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This paper uses dynamic computer simulation techniques to apply a procedure using vibration-based methods for damage assessment in multiple-girder composite bridge. In addition to changes in natural frequencies, this multi-criteria procedure incorporates two methods, namely the modal flexibility and the modal strain energy method. Using the numerically simulated modal data obtained through finite element analysis software, algorithms based on modal flexibility and modal strain energy change before and after damage are obtained and used as the indices for the assessment of structural health state. The feasibility and capability of the approach is demonstrated through numerical studies of proposed structure with six damage scenarios. It is concluded that the modal strain energy method is competent for application on multiple-girder composite bridge, as evidenced through the example treated in this paper.

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Iconic and significant buildings are the common target of bombings by terrorists causing large numbers of casualties and extensive property damage. Recent incidents were external bomb attacks on multi-storey buildings with reinforced concrete frames. Under a blast load circumstance, crucial damage initiates at low level storeys in a building and may then lead to a progressive collapse of whole or part of the structure. It is therefore important to identify the critical initial influence regions along the height, width and depth of the building exposed to blast effects and the structure response in order to assess the vulnerability of the structure to disproportionate and progressive collapse. This paper discusses the blast response and the propagation of its effects on a two dimensional reinforced concrete (RC) frame, designed to withstand normal gravity loads. The explicit finite element code, LS DYNA is used for the analysis. A complete RC portal frame seven storeys by six bays is modelled with reinforcement details and appropriate materials to simulate strain rate effects. Explosion loads derived from standard manuals are applied as idealized triangular pressures on the column faces of the numerical models. The analysis reports the influence of blast propagation as displacements and material yielding of the structural elements in the RC frame. The effected regions are identified and classified according to the load cases. This information can be used to determine the vulnerability of multi-storey RC buildings to various external explosion scenarios and designing buildings to resist blast loads.

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Multi-storey buildings are highly vulnerable to terrorist bombing attacks in various parts of the world. Large numbers of casualties and extensive property damage result not only from blast overpressure, but also from the failing of structural components. Understanding the blast response and damage consequences of reinforced concrete (RC) building frames is therefore important when assessing multi-storey buildings designed to resist normal gravity loads. However, limited research has been conducted to identify the blast response and damage of RC frames in order to assess the vulnerability of entire buildings. This paper discusses the blast response and evaluation of damage of three-dimension (3D) RC rigid frame under potential blast loads scenarios. The explicit finite element modelling and analysis under time history blast pressure loads were carried out by LS DYNA code. Complete 3D RC frame was developed with relevant reinforcement details and material models with strain rate effect. Idealised triangular blast pressures calculated from standard manuals are applied on the front face of the model in the present investigation. The analysis results show the blast response, as displacements and material yielding of the structural elements in the RC frame. The level of damage is evaluated and classified according to the selected load case scenarios. Residual load carrying capacities are evaluated and level of damage was presented by the defined damage indices. This information is necessary to determine the vulnerability of existing multi-storey buildings with RC frames and to identify the level of damage under typical external explosion environments. It also provides basic guidance to the design of new buildings to resist blast loads.

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Changes in load characteristics, deterioration with age, environmental influences and random actions may cause local or global damage in structures, especially in bridges, which are designed for long life spans. Continuous health monitoring of structures will enable the early identification of distress and allow appropriate retrofitting in order to avoid failure or collapse of the structures. In recent times, structural health monitoring (SHM) has attracted much attention in both research and development. Local and global methods of damage assessment using the monitored information are an integral part of SHM techniques. In the local case, the assessment of the state of a structure is done either by direct visual inspection or using experimental techniques such as acoustic emission, ultrasonic, magnetic particle inspection, radiography and eddy current. A characteristic of all these techniques is that their application requires a prior localization of the damaged zones. The limitations of the local methodologies can be overcome by using vibration-based methods, which give a global damage assessment. The vibration-based damage detection methods use measured changes in dynamic characteristics to evaluate changes in physical properties that may indicate structural damage or degradation. The basic idea is that modal parameters (notably frequencies, mode shapes, and modal damping) are functions of the physical properties of the structure (mass, damping, and stiffness). Changes in the physical properties will therefore cause changes in the modal properties. Any reduction in structural stiffness and increase in damping in the structure may indicate structural damage. This research uses the variations in vibration parameters to develop a multi-criteria method for damage assessment. It incorporates the changes in natural frequencies, modal flexibility and modal strain energy to locate damage in the main load bearing elements in bridge structures such as beams, slabs and trusses and simple bridges involving these elements. Dynamic computer simulation techniques are used to develop and apply the multi-criteria procedure under different damage scenarios. The effectiveness of the procedure is demonstrated through numerical examples. Results show that the proposed method incorporating modal flexibility and modal strain energy changes is competent in damage assessment in the structures treated herein.