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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Adaptive Radiation Therapy for Lung Cancer

Dial, Christian W 01 January 2014 (has links)
Prognosis for lung cancer patients remains poor. For those receiving radiation therapy, local control and survival have been shown to improve with increased doses; however, deliverable dose is often limited by associated toxicity. Therefore, methods that reduce dose to normal tissues and allow isotoxic escalation are desirable. Adaptive radiation therapy seeks to improve treatment by modifying the initial plan throughout delivery, and has been shown to decrease normal tissue dose. Studies to date suggest a trend of increasing benefit with increases in replanning frequency; however, replanning is costly in terms of workload and past studies implement at most weekly adaptation. The purpose of this thesis is to quantify the benefit associated with daily replanning and characterize the tradeoff between replanning frequency and adaptive benefit. A software tool is developed to facilitate planning studies and to introduce complimentary methods for evaluating adaptive treatments. Synthetic images and contours are xii generated for each fraction of a typical fractionation schedule using principal component analysis and a novel method of sampling coefficients that preserves temporal trends in the data (e.g. tumor regression). Using the synthetic datasets, a series of adaptive schedules ranging from no adaption to daily replanning are simulated and compared to quantify adaptive benefits and characterize tradeoffs with frequency. Daily replanning resulted in significant reductions in all normal tissue planning metrics when compared to no adaptation, and incremental reductions were observed with each increase in replanning frequency while the magnitude of average reductions decreased with each step. Modest correlation between absolute change in planning target volume over the course of treatment and reductions in both mean lung dose and mean esophageal dose were observed.

Analyse de la contribution des kallicréines tissulaires 6 et 12 à la physiopathologie pulmonaire / Analysis of the contribution of tissue kallikreins 6 and 12 to lung pathophysiology

Michel, Noémie 26 March 2013 (has links)
Les kallicréines tissulaires humaines (KLK) ont récemment émergé comme une famille de protéases à serine pouvant jouer un rôle important dans la tumorigenèse. Le but de cette étude a été de mieux comprendre comment KLK6 et KLK12 pourraient intervenir dans la physiopathologie pulmonaire. Nous avons démontré qu’une expression ectopique de KLK6 induisait la prolifération des cellules A549 d’une manière dépendante de son activité enzymatique, une résistance à l’apoptose, ainsi qu’une translocation nucléaire de la β-caténine. Nous avons également montré une voie de signalisation impliquée dans la prolifération induite par KLK6 impliquant PAR2, EGFR et ERK. Nous avons identifié de nouveaux subtrats pour KLK12 : les CCN. Nous avons démontré que le clivage de CCN1 et CCN5 par KLK12 limitait leurs fixations avec le VEGF, BMP2 et le TGF-β1. / Recently, human tissue kallikreins (KLK) emerged as a new family of serine proteases which might play a major role in the tumorigenesis. The project aims at determining the contribution of KLK6 and 12 in lung pathophysiology. We showed that ectopic KLK6 promoted A549 cell proliferation in a protease activity-dependant manner, inhibited cell apoptosis and induced β-catenin nuclear translocation. Furthermore, this study uncovered a signaling pathway mediated by KLK6 in promoting A549 cell proliferation trough activation of the PAR2-EGFR-ERK pathway.We have also identified novel substrates of KLK12, the CCN family. We reported that KLK12-mediated proteolysis of CCN1 and CCN5 can reduce or abolish the binding of VEGF, BMP2, and TGF-β1.

Molecular mechanisms of apoptosis in lung cancer: a role for retinoblastoma binding protein 6 (RBBP6) and its protein products

Motadi, Lesetja Raymond 24 August 2010 (has links)
RBBP6 (retinoblastoma binding protein 6) is a 250-kDa multifunctional protein that interacts with both p53 and pRb and has been implicated in mRNA processing. It has also been identified as an E3 ubiquitin ligase due to the presence of a RING finger domain and also assumed to have a regulatory role of p53 due to the presence p53BD through MdM2, although no substrate has been identified up to now. RBBP6 gene mutants are reported to be resistant to apoptosis inducers, which led to a belief that mutation of this gene might result in the development of lung cancer. Earlier localization and expression studies have shown that RBBP6 expression and apoptosis levels are indirectly proportional. The purpose of this study is to establish the expressional pattern of the RBBP6 gene in lung cancer at both mRNA and protein levels. The objective is also to characterize the role of this gene and apoptosis in diverse lung diseases. An understanding of the role of RBBP6 in the development of lung diseases may lead to insights into developing new therapeutic measures for those lung diseases in which apoptosis plays a prominent part. This thesis elucidate the possible role of RBBP6 in lung cancer and apoptosis, to establish tissue distribution and expression levels of RBBP6 at protein and mRNA levels in lung cancer by immunocytochemistry (ICC), in situ hybridization (ISH) and confirm findings by quantitative RT-PCR. RBBP6 mRNA transcripts were expressed in the cytoplasm of normal and tumour lung epithelium. In general, expression was highest in the cytoplasm of welldifferentiated carcinoma and invasive carcinoma that showed signs of cells undergoing mitosis. Immunolabelling results further showed high level of expression in all lung cancer types except in Small and large cell carcinomas. The immunolabeling were confirmed by ISH experiments and RT-PCR. In relation to p53, RBBP6 mRNA expression was higher in lung cancer cell lines that had p53 silenced and apoptosis induced by TRAIL and camptothecin. There was no notable change in the levels of p53 expression following RBBP6 silencing and apoptosis induction. However, there was a little correlation between RBBP6 expression and apoptosis levels in both lung cancer tissues by TUNEL and lung cancer cell line following apoptosis induction by TRAIL. The ratio of Bax/Bcl-2 was seen to be upregulated following p53 and RBBP6 silencing after apoptosis induction. The most common mutation notable after RBBP6 DNA sequencing was point mutations where only single nucleotide was mutated and mostly they were observed in lung cancer tissues. This was the first demonstration that RBBP6 is expressed in lung cancers. Because of the ubiquitin-like nature of the protein and its localized up-regulation and corresponding proapoptotic activity in lung cancer cells, it is possible that further characterization of this gene could lead to its manipulation as a diagnostic marker and a potential therapeutic target for cancer treatment.

The clinical care of patients with lung cancer : identifying and supporting those with unmet care needs

Buchanan, Deans January 2010 (has links)
Lung cancer has developed from a rare condition into the leading cause of cancerrelated death in the United Kingdom. Lung cancer patients face a disease with a high symptom burden, increased psychosocial needs and a high mortality. Supportive care needs are often relevant from diagnosis. Despite this there are no clear follow-up structures for lung cancer patients that address both cancer management and supportive care. The aims of this study were to evaluate supportive care needs, assess predictors of such needs and identify factors which could aid service provision within Stobhill lung cancer services. Methods Supportive care needs were measured using an adapted Palliative Outcome Scale (POS), incorporated within a larger questionnaire. All lung cancer patients attending the clinic could complete this questionnaire. Respiratory symptoms, performance status, service usage, preferences and satisfaction were also assessed. Data were stratified to allow evaluation of three clinical groupings: all patients, newly diagnosed patients and patients in the last three months of life. Analyses were phased: descriptive analyses, univariate tests of association and multivariate regression. Results Three hundred and fifty three lung cancer patients completed questionnaires. The high symptom burden in lung cancer was confirmed. Anxiety, pain and dyspnoea were identified as the key issues. Poor performance status was identified to be an independent predictor of increased POS score, increased anxiety, increased pain and increased dyspnoea. There was no independent relationship between POS and survival. Although the majority of patients were satisfied with the care received, there was uncertainty regarding who was in charge of care and some disparity in preferred structure for follow-up. Conclusions Despite recent advances in lung cancer management, improvements are still required to address unmet supportive care needs of patients. Particular attention should be given to those with poorer performance status to effectively identify and meet such needs.

Characterizing the impact of smoking and lung cancer on the airway transcriptome using RNA sequencing

Vick, Jessica Lynn January 2012 (has links)
Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Cigarette smoke creates a molecular field of injury in epithelial cells that line the respiratory tract. We hypothesized that transcriptome sequencing (RNA-seq) will enhance our understanding of the field of molecular injury in response to tobacco smoke exposure and lung cancer pathogenesis by identifying gene expression differences not interrogated or accurately measured by microarrays. We sequenced the high- molecular weight fraction of total RNA (>200 nt) from pooled bronchial airway epithelial cell brushings (n = 3 patients per pool) obtained during bronchoscopy from healthy never smoker (NS) and current smoker (S) volunteers and smokers with (C) and without ( C) lung cancer undergoing lung nodule resection surgery. RNA-seq libraries were prepared using two distinct approaches, one capable of capturing non-polyadenylated RNA (the prototype NuGEN Ovation RNA-seq protocol) and the other designed to measure only polyadenylated RNA (the standard Illumina mRNA-seq protocol) followed by sequencing generating approximately 29 million 36 nt reads per pool and approximately 22 million 75 nt paired-end reads per pool, respectively. The NuGEN protocol captured additional transcripts not detected by the Illumina protocol at the expense of reduced coverage of polyadenylated transcripts, while longer read lengths and a paired-end sequencing strategy significantly improved the number of reads that could be aligned to the genome. The aligned reads derived from the two complementary protocols were used to define the compendium of genes expressed in the airway epithelium (n = 20,573 genes). Pathways related to the metabolism of xenobiotics by cytochrome P450, retinol metabolism, and oxidoreductase activity were enriched among genes differentially expressed in smokers, whereas chemokine signaling pathways, cytokine-cytokine receptor interactions, and cell adhesion molecules were enriched among genes differentially expressed in smokers with lung cancer. There was a significant correlation between the RNA-seq gene expression data and Affymetrix microarray data generated from the same samples (P < 0.001); however, the RNA-seq data detected additional smoking- and cancer-related transcripts whose expression was were either not interrogated by or was not found to be significantly altered when using microarrays, including smoking- related changes in the inflammatory genes SIOOA8 and SIOOA9 and cancer-related changes in MUC5AC and secretoglobin (SCGB3Al). Quantitative realtime PCR confirmed differential expression of select genes and non-coding RNAs within individual samples. These results demonstrate that transcriptome sequencing has the potential to provide new insights into the biology of the airway field of injury associated with smoking and lung cancer. The measurement of both coding and non-coding transcripts by RNA-seq has the potential to help elucidate mechanisms of response to tobacco smoke and to identify additional biomarkers of lung cancer risk and novel targets for chemoprevention. / 2031-01-01

Promotion Of Lung Cancer By Interleukin-17

Unknown Date (has links)
No description available.

Promotion Of Lung Cancer By Interleukin-17

Unknown Date (has links)
No description available.

Promotion Of Lung Cancer By Interleukin-17

Unknown Date (has links)
No description available.

The Effect of Polydimethylsiloxane Substrate Modification on A549 Human Epithelial Lung Cancer Cell Morphology and Biomechanics

Ward, Sherissa A. 01 May 2015 (has links)
In this thesis the effect of mechanical stimuli on A549 lung cancer cells is studied. Modifications of polydimethylsiloxane (PDMS) surfaces are employed to alter the mechanical stimuli applied to the cells. Flat substrates are first studied and then micropillared substrates are designed, fabricated, and tested as a method to alter the mechanical properties of the PDMS surfaces. Molds with micro-pillars are designed then fabricated from silicon using deep reactive ion etching. From these molds, a negative then a positive replicate is made using PDMS. The pillared PDMS substrates are fabricated in 10 geometries and used for experiments. A549 cells are cultured on these surfaces then analyzed using fluorescence microscopy and atomic force microscopy (AFM). Fluorescence microscopy images processed by ImageJ software measure the cell spreading area (m2) while AFM quantifies the cell stiffness (kPa). For flat substrates, the cell stiffness and spreading area increase with increasing substrate stiffness. Further, results on pillared substrates show a similar trend based on pillar geometry changes. For pillared substrates, the A549 cell stiffness and spreading area increase as the height decreases, yet there is decreased cell stiffness and spreading area as the diameter and spacing decreases. The experiments show that changes in surface properties and only mechanical stimuli alter cellular morphology and biomechanics

Rôles des ADAM(TS) au cours de la progression des cancers primitifs pulmonaires non à petites cellules

Rocks, Natacha 10 April 2008 (has links)
Le cancer du poumon est un problème majeur de santé publique et dont le coût humain et social est sans cesse en augmentation au cours des dernières années. Parmi les nombreux médiateurs susceptibles de jouer un rôle dans la croissance tumorale, nous avons étudié en détails le système des ADAM et ADAMTS protéases. Les ADAMs sont des enzymes aux fonctionnalités multiples qui interviennent dans de nombreux processus physiologiques et pathologiques. Parmi ces différents processus, certains concernent des modulations de la structure ou de létat de la matrice extracellulaire et dautres des boucles dinteractions entre différents types cellulaires reliés par des médiateurs protéiques. Les modulations apportées à ce système par les ADAM protéases résident donc dans lactivation ou linhibition de certains processus biologiques par clivage de molécules ou activation des récepteurs. Au cours de la première partie de notre travail, nous avons étudié lexpression de différentes ADAM(TS) protéases sélectionnées sur base de la littérature comme potentiellement impliquées dans la régulation de la croissance tumorale. L'analyse d'échantillons de cancers pulmonaires humains a été réalisée en collaboration avec le Professeur P BIREMBAUT (Unité INSERM U 514, Reims). Nous avons mis en évidence que lADAM-12 (forme complète membranaire) est surexprimée et que lADAMTS-1 est moins exprimée dans les tissus tumoraux pulmonaires obtenus par résection chirurgicale par rapport à des échantillons correspondants prélevés en zone saine. Ces variations ont été vérifiées par Real-Time PCR et par western blots. Les niveaux dexpression de lADAM-12 sont corrélés à lexpression des mRNAs codant pour les isoformes 121 et 165 (qui sont pro-angiogènes) du VEGF-A. Une immunohistochimie marquant l'ADAM-12 a montré une expression de cette protéase principalement dans les cellules tumorales ; l'ADAMTS-1 par contre, est surtout exprimée dans le tissu bronchique sain. Les lignées de cellules pulmonaires issues de cellules épithéliales bronchiques et alvéolaires ont été caractérisées pour leur expression en ADAM-12 et ADAMTS-1. LADAM-12 et lADAMTS-1 sont surexprimées par les cellules de type BZR et BZR T33 qui forment des tumeurs chez les souris et qui ont un caractère agressif. Au cours de ces travaux, nous avons donc clairement pu identifier deux protéases dont l'expression est modulée dans nos échantillons de tissu pulmonaire sain ou tumoral. L'ADAM-12, surexprimée dans les tumeurs, serait un modulateur "positif" de la progression tumorale et l'ADAMTS-1, dont lexpression est moindre dans les tumeurs semble être un modulateur négatif du développement tumoral (Rocks et al, Br J Cancer, 2006). Nous avons focalisé la suite de nos travaux sur létude des effets de lADAM-12 et de lADAMTS-1 sur différents phénomènes biologiques impliqués dans la progression tumorale. Sur base de l'analyse des échantillons de cancers pulmonaires, l'ADAM-12 est donc apparue comme un candidat potentiel impliqué dans la progression tumorale. Nous avons ainsi généré des clones surexprimant lADAM-12 à partir de cellules épithéliales bronchiques immortalisées (BEAS-2B). Ces clones ont été caractérisés et leur production dADAM-12 a été démontrée par RT-PCR et cytométrie de flux. Le comportement des cellules surexprimant lADAM-12 a ainsi pu être comparé à celui des cellules parentales transfectées avec le vecteur vide (contenant uniquement le gène de la résistance à la néomycine). Différentes expériences in vitro ont été réalisées sur ces cellules. Il ressort de lensemble de cette caractérisation que les cellules surexprimant lADAM-12 présentent une prolifération et une capacité à former des colonies en agar mou accrues par rapport aux cellules parentales. De plus, les cellules surexprimant lADAM-12 ont une sensibilité vis-à-vis de lapoptose diminuée par rapport aux clones contrôles. Ces processus sont dépendants dune augmentation de la production dHB-EGF mature par les clones surexprimant lADAM-12. Les clones surexprimant lADAM-12 ainsi que les clones contrôle ont été implantés au sein du tissu pulmonaire de souris et injectés dans le tissu sous-cutané. Il ressort de ces expériences que les cellules de type BEAS-2B transfectées ou non par lADAM-12 sont peu tumorigènes qu'elles soient implantées dans un site orthotopique (intra-pulmonaire) ou hétérotopique (sous-cutané) dans les souris SCID. En dépit du fait que l'ADAM-12 stimule la prolifération cellulaire et protège les cellules de lapoptose in vitro, sa surexpression nest pas suffisante en soi pour développer un phénotype tumorigène in vivo (Rocks et al, Cell Prolif, in press). Dans la troisième partie de notre travail, nous avons généré à partir de la lignée dérivée de cellules épithéliales bronchiques tumorales BZR des clones transfectés de façon stable qui surexpriment lADAMTS-1 humaine complète. Ceci est confirmé par la présence de bandes de 87 kDa en Western Blot, représentant la forme complète et active de cette protéase. In vitro, nous navons pas pu mettre en évidence de différence de prolifération, de migration, dinvasion et dapoptose entre les différents clones étudiés. Nous avons ensuite procédé à limplantation au niveau sous cutané dans des souris immunodéficientes de populations cellulaires transfectées de façon stable avec le gène de lADAMTS-1. Nous avons ainsi évalué si la surexpression de cette protéase modifiait le comportement de ces cellules en termes de prolifération in vivo. Les tumeurs formées à partir de cellules transfectées avec la forme complète de lADAMTS-1 présentent une taille plus importante que les tumeurs formées à partir de cellules BZR contrôle. Un immunomarquage pour le Proliferating Cell Nuclear Antigen (PCNA) a révélé des scores de prolifération cellulaire plus élevé dans les tumeurs dérivées de populations cellulaires surexprimant lADAMTS-1. De plus, lanalyse histochimique des tumeurs a montré, dans les tumeurs surexprimant lADAMTS-1, la présence de structures stromales composées de fibronectine (WB), collagène (marquées positivement par coloration au safran, WB) et de myofibroblastes (positifs pour lα-actine des muscles lisses). Afin détudier le potentiel chimiotactique de lADAMTS-1 sur les fibroblastes, nous avons utilisé le modèle des chambres de Boyden. Les chambres du dessous ont été remplies avec des milieux conditionnés dérivés de populations de cellules transfectées ou non avec la forme complète de lADAMTS-1. Les milieux conditionnés de cellules surexprimant lADAMTS-1 ont des capacités dattraction plus importantes sur les fibroblastes que les milieux conditionnés dérivés de cellules contrôles. Cependant, lajout dADAMTS-1 recombinante au milieu conditionné par des cellules contrôles nest pas suffisant pour augmenter la migration des fibroblastes. Nous avons donc mesuré lexpression de facteurs potentiellement impliqués dans le remodelage de la matrice extracellulaire et dans la migration de fibroblastes. Les tumeurs surexprimant lADAMTS-1 ont des taux plus élevés de MMP-13, TGF-β1 et dIL-1β. De plus, un anticorps bloquant les effets du TGF-β1 et/ou de lIL-1β diminue la migration des fibroblastes en chambre de Boyden. En résumé, nous montrons par ce travail, que les cellules BZR transfectées au moyen de la forme complète de lADAMTS-1, forment des tumeurs plus larges, infiltrées par des myofibroblastes, suggérant que les interactions tumeur-stroma influencent la prolifération de cellules tumorales En conclusion, nos travaux ont identifié que lexpression de lADAM-12 et lADAMTS-1 est modulée dans des tumeurs bronchiques humaines. LADAM-12 joue un rôle dans la prolifération cellulaire en activant le clivage de facteurs de croissance membranaires qui sont des ligands de lEGFR. Le rôle de lADAMTS-1 apparaît comme beaucoup plus complexe et nos travaux montrent que lADAMTS-1 peut influencer la croissance tumorale in vivo en modulant la composition cellulaire et matricielle du stroma. Collectivement, ces travaux confirment le rôle clé joué par les protéases de la famille des ADAMs et ADAMTS dans le développement du cancer et identifient ces enzymes comme des cibles thérapeutiques potentielles.

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