To see the other types of publications on this topic, follow the link: Lung development.
Dissertations / Theses on the topic 'Lung development'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Lung development.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Grier, D. G. "Homeobox genes in lung development." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426729.
Full text
2
Cherukupalli, Kamala. "Studies on the normal and abnormal lung growth in the human and in the rat with emphasis on the connective tissue fibers of the lung." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/30607.
Full textAbstract:
Infants with bronchopulmonary dysplasia (BPD), showed impaired body growth when compared to control infants. In terms of changes in the biochemical composition of the lung, BPD infants had higher DNA, soluble protein, collagen and desmosine contents as well as increased concentrations of DNA, collagen and desmosine in their lungs when compared to the growth patterns obtained for the lungs of control infants. Pathologically BPD was classified into 4 grades. Grade I BPD, was a phase of acute lung injury, grades II and III were proliferative phases. In grade IV BPD, lung structure returned towards normal. Evidence of fibrosis was seen by a significant increase in collagen concentration in grades II and III while desmosine concentration was seen to increase in grades III and IV suggesting that the increase in collagen and desmosine contents in the lungs of BPD infants may be controlled by two different mechanisms. Collagen type I/III ratio was seen to decrease progressively from grade II to grade IV BPD in comparison to age matched controls, indicating a higher proportion of type III collagen in the lungs of infants with BPD.
From the clinical analysis and the results obtained from discriminant analysis procedure, it was seen that there was a high degree of correlation between the continuation of the disease and collagen accumulation in the lungs suggesting that pulmonary fibrosis with excessive collagen accumulation is an integral part of BPD. This fibrotic process seemed to correlate significantly with assisted ventilation and high oxygen supplementation received by the infants, but it was difficult to assess the individual contribution of the two treatments in the pathogenesis of BPD. Other variables such as severity of the initial disease and the length of survival of the infants, made the assessment of individual contribution much more difficult.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
3
Gao, Weichen. "Development of human lung query atlas." Thesis, University of Iowa, 2010. https://ir.uiowa.edu/etd/806.
Full textAbstract:
This thesis reports on our initial work constructing a human lung query atlas which provides clinically relevant population statistics for normal and abnormal individuals. The atlas incorporates front-end interfaces with back-end database. The interfaces were developed using Microsoft Access 2007 and the database was implemented using MySQL. ODBC was used to import database into Access and provide connection for database and interfaces. VBA is used to write SQL queries and realized the interaction with interfaces. SQL queries is written to extract the data which researchers may interest in. The atlas provides measurements of the human airway tree and lung volumes from a population of individuals and also provides a population statistics based on age, race, ethnicity, gender and other information. It also provides functionality for comparing airway measurements between populations, individuals to a population, and individuals to individuals. Statistical significance, such as p-value, is provided to analyze two individuals or populations.
4
Tiozzo, Caterina. "Role of Pten in lung development." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426411.
Full textAbstract:
Rationale: Pten is a tumor-suppressor gene, involved in stem cell homeostasis and tumorigenesis. In mouse, Pten expression is ubiquitous and begins as early as 7 days of gestation. Pten-/- mouse embryos die early during gestation indicating a critical role for Pten in embryonic development.
Objective: To test the role of Pten in lung development and injury, we conditionally deleted Pten throughout the lung epithelium by crossing Ptenflox/flox with Nkx2.1-cre driver mice and throughout the lung mesenchyme by crossing Ptenflox/flox with Nkx2.1-cre driver or Dermo1-cre driver. The resulting PtenNkx2.1-cre mutants were analyzed for lung defects and response to injury.
Results: PtenNkx2.1-cre embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In vitro culture of mutant lungs also showed an altered responsed to TGF-? when in vivo In adult mice, PtenNkx2.1-cre lungs exhibit increased progenitor cell pools comprised of basal cells in the trachea, CGRP/CC10 double-positive neuroendocrine cells in the bronchi and CC10/SpC double positive cells in the bronchioalveolar duct junction (BADJ). Pten deletion impacted differentiation of various lung epithelial cell lineages, with decreased number of terminally differentiated cells. Over time, PtenNxk2.1-cre epithelial cells residing in the BADJ underwent proliferation, and formed uniform masses, supporting the concept that the cells residing in this distal niche may also be the source of pro-carcinogenic “stem” cells. Finally, increased progenitor cells in all the lung compartments conferred an overall selective advantage to naphthalene injury compared to wild type control mice.
PtenDermo1cre embryonic lungs, moreover, showed normal lung development but increased collagen1 and extracellular matrix production.
Conclusions: Pten has a pivotal role in lung stem cell homeostasis, cell differentiation and consequently resistance to lung injury in the epithelium, Further studies are necessary to clarify the real role of Pten in lung mesenchyme.Rationale: Pten e’ un gene coinvolto nell’omeostasi delle cellule staminali e nella formazione di tumori. Nei topi, Pten inizia ad essere presente 7 giorni dopo il concepimento. Pten ha un ruolo critico nello sviluppo embrionale: gli embrioni di topo Pten-/-, infatti, muoiono molto presto durante la gestazione. Scopo dello studio: Studiare il ruolo di Pten nello sviluppo polmonare, eliminando Pten nell’epitelio polmonare, incrociando Ptenflox/flox con topi portatori di Nkx2.1-cre; Pten e’ stato anche eliminato dal mesenchima polmonare incrociando Ptenflox/flox con topi Dermo1-cre. I risultanti PtenNkx2.1cre sono stati analizzati alla ricerca di difetti nello sviluppo polmonare. Risultati: I polmoni PtenNkx2.1-cre hanno evidenziato in vitro una alterata risposta al TGF-?. In vivo non presentavano nessuna alterazione nel branching bensi una iperplasia polmonare nelle vie aerre. Nei topi adulti, I polmoni PtenNkx2.1-cre presentavano un aumentato pool di cellule progenitori in tutti i distretti: nella trachea, le cellule basali, nei bronchi le cellule neuroepiteliali, positive per CGRP/CC10 ed infine, nella giunzione tra gli alveoli e I bronchi terminali (BADJ), le cellule positive per Spc/CC10. L’assenza di Pten ha un impatto nella differenziazione cellulare, con un diminuito aumento delle cellule all’ultimo stadio di differenziazione. Nel tempo, le cellule epiteliali PtenNxk2.1-cre residenti a livello del BADJ proliferano e formano delle masse di tipo tumorale; questi dati supportano l’idea che le cellule presenti in questa niche possano essere l’origine delle cosidette “pro-carcinogenic stem cells”. L’aumento delle cellule progenitrici, inoltre, conferisce un selettivo vantaggio dopo danno polmonare. I topi con Pten eliminato nell’epitelio, invece, non evidenziavano ne uno sviluppo polmonare alterato ne una alterata differenziazione delle cellule mesenchimali; tuttavia, dimostravano un aumentata deposizione di collagene1 e di matrice extracellulare. Conclusioni: Pten ha un ruolo importante nell’omeostasi delle cellule progenitori del polmone, nella differenziazione epiteliale polmonare e nella resistenza dopo danno. Ulteriori studi sono necessary per chiarire l’esatto ruolo di Pten nel mesenchima polmonare.
5
Mattes, Charlott, and Ulrich H. Thome. "Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells." Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142643.
Full textAbstract:
Alveolar fluid clearance is driven by vectorial Na+ transport and promotes
postnatal lung adaptation. The effect of insulin on alveolar epithelial Na+
transport was studied in isolated alveolar cells from 18–19-day gestational age
rat fetuses. Equivalent short-circuit currents (ISC) were measured in Ussing
chambers and different kinase inhibitors were used to determine the pathway
of insulin stimulation. In Western Blot measurements the activation of mediators
stimulated by insulin was analyzed. The ISC showed a fast dose-dependent
increase by insulin, which could be attributed to an increased ENaC (epithelial
Na+ channel) activity in experiments with permeabilized apical or basolateral
membrane. 5-(N-Ethyl-N-isopropyl)amiloride inhibition of ISC was not
affected, however, benzamil-sensitive ISC was increased in insulin-stimulated
monolayers. The application of LY-294002 and Akti1/2 both completely
blocked the stimulating effect of insulin on ISC. PP242 partly blocked the
effect of insulin, whereas Rapamycin evoked no inhibition. Western Blot measurements
revealed an increased phosphorylation of AKT after insulin stimulation.
SGK1 activity was also increased by insulin as shown by Western Blot of
pNDRG1. However, in Ussing chamber measurements, GSK650394, an inhibitor
of SGK1 did not prevent the increase in ISC induced by insulin. The application
of IGF-1 mimicked the effect of insulin and increased the ENaC
activity. In addition, an increased autophosphorylation of the IGF-1R/IR was
observed after insulin stimulation. We conclude that insulin rapidly increases
epithelial Na+ transport by enhancing the activity of endogenous ENaC
through activation of PI3K/AKT in alveolar cells.
6
Salvati, Valentina. "Development of effective lung cancer therapies based on lung cancer stem cella targeting." Doctoral thesis, Università di Catania, 2015. http://hdl.handle.net/10761/4035.
Full textAbstract:
Il carcinoma polmonare non a piccole cellule (NSCLC) rappresenta circa l 80% di tutti i tumori al polmone ed è il cancro più comune e più mortale al mondo.
Il trattamento convenzionale per il NSCLC in stadio avanzato è stato basato per molto tempo sull uso della chemioterapia, ma con basso impatto sulla sopravvivenza .
Una migliore comprensione dei meccanismi molecolari coinvolti nel processo di tumorigenesi e una maggiore capacità nell identificazione di specifiche alterazioni genetiche come bersagli terapeutici, hanno portato ad un significativo avanzamento verso lo sviluppo di terapie più efficaci.
Il recettore del fattore di crescita dell epidermide (EGFR) è spesso over-espresso nel NSCLC ed è considerato un promettente bersaglio terapeutico per il trattamento di questo tumore.
La presenza di mutazioni nel gene EGFR sono un importante predittore di risposta agli inibitori dell EGFR. Sebbene gli inibitori dell EGFR di prima generazione hanno mostrato incoraggianti risposte cliniche nei tumori al polmone, quasi tutti i pazienti sviluppano resistenza al trattamento nel corso del tempo.
La resistenza ai trattamenti potrebbe dipendere anche dalla presenza delle cellule staminali tumorali (CSCs), una sottopopolazione di cellule intrinsecamente resistenti. Così, lo studio delle cellule staminali tumorali del polmone, potrebbe essere uno strumento efficace per l identificazione e validazione di bersagli terapeutici innovativi contribuendo all'introduzione di importanti miglioramenti nell ambito dell oncologia clinica.
Pertanto, la terapia mirata verso l EGFR continua ad evolvere in seguito alla scoperta della sensibilità agli inibitori tirosin-chinasici da parte di pazienti caratterizzati da mutazioni attivanti del gene EGFR. Tuttavia, circa il 10-20% dei pazienti privi della mutazione dell EGFR, beneficiano anch essi del trattamento con gli inibitori TKIs, suggerendo che potrebbero esistere altri determinanti di risposta al trattamento, indipendenti dalla mutazione del recettore.
Questo progetto, quindi, è stato focalizzato sull analisi della via di segnale dell EGFR e sullo studio della sensibilità delle cellule staminali tumorali di polmone e di modelli murini da esse derivati, agli inibitori dell EGFR, al fine di identificare possibili biomarcatori predittivi di risposta agli TKIs, in cellule prive della mutazione dell EGFR.
Questo studio ha portato all identificazione della fosforilazione dell EGFR al residuo tirosina 1068, ma non 1173, come potenziale marcatore di risposta all Erlotinib nelle cellule staminali tumorali di polmone e negli xenografts da esse derivati.
Inoltre, anche linee cellulari commerciali di polmone sensibili all Erlotinib, esprimevano pEGFR-tyr-1068 indipendentemente dalla mutazione dell EGFR, così, l espressione di pEGFR-tyr1068 nelle cellule staminali tumorali di polmone è risultata essere associata ad una risposta positiva al trattamento con l Erlotinib.
La valutazione, mediante immunoistochimica, dello stato di fosforilazione dell EGFR in pazienti con mutazione e senza mutazione del recettore, ha portato a correlare solo pEGFR-tyr1068 e non pEGFR-tyr1173, con la mutazione dell EGFR.
In base a questi dati, quindi, è possibile ipotizzare che l identificazione del livello di fosforilazione dell EGFR al residuo tirosina 1068 nei tumori dei pazienti, permetterebbe di individuare tumori con e senza mutazione dell EGFR ma caratterizzati da attivazione del recettore, in grado probabilmente di rispondere in modo positivo al trattamento con l Erlotinib.
Questi studi potrebbero avere importanti implicazioni terapeutiche per il trattamento dei tumori al polmone e potrebbero permettere ai pazienti con NSCLC di essere selezionati per terapie più efficaci e meno tossiche.
7
Wu, Mau-Ching. "Mouse models of human lung cancer development." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624711.
Full text
8
Nickel, Jacob. "Development of an electronic lung airway atlas." Thesis, University of Iowa, 2008. http://ir.uiowa.edu/etd/14.
Full text
9
Bonner, Allison E. "Organ development and tumorigenesis: a molecular link." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1073936508.
Full text
10
Bloor, Claire Alexandra. "Insulin-like Growth Factor-1 (IGF-1) axis : role in development of lung fibrosis." Thesis, Keele University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323715.
Full text
11
Harding-Smith, Rebekka. "Gene transfer vector development to treat lung disease." Thesis, University of Oxford, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711729.
Full text
12
Dixit, Radhika Nagaraj. "The contribution of mesothelial cells to lung development." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12825.
Full textAbstract:
Thesis (Ph.D.)--Boston UniversityMesothelium-derived progenitors have been demonstrated to contribute to differentiated mesenchymal components of the heart, liver, and gut during organogenesis. The precise contribution of the mesothelium to lung development, however, has not been fully clarified and the key signals regulating mesothelial cell entry have not been identified. To rigorously address this issue, we employed mice with an inducible Cre expressed from the Wilm's tumor-1 (WT1) locus for high fidelity lineage tracing after confirming that Cre-recombinase was mesothelial-specific and faithfully recapitulated endogenous WT1 gene expression. We visualized WT1+ mesothelial cell entry into the fetal lung by live imaging and identified their progenies in subpopulations of bronchial smooth muscle cells, vascular smooth muscle cells, and desmin+ fibroblasts by lineage tagging. In view of the role of Sonic Hedgehog (Hh) signaling in regulating mesenchymal cell differentiation and epithelial-mesenchymal transition, we hypothesized that this pathway regulates events associated with migration of mesothelial cells into the developing lung. To examine for this, we first used two independent reporter mice to show that Hh signaling is active within the lung mesothelium at time points coinciding with the appearance of mesothelium-derived cells in the lung parenchyma. Using loss-of-function assays in organ cultures, and targeted mesothelial-restricted loss-of hedgehog function mice, we demonstrated that mesothelial cell movement into the lung requires the direct action of Hh signaling. In order to examine whether WT1 interacts with Hh pathway, we conducted ChIP assays on fetal lung mesothelial cells, and found that WT1 directly binds and regulates promoter elements of downstream targets of Hh pathway. Consistent with this observation, Hh pathway gene expression was down-regulated in isolated WT1 deficient fetal lung mesothelial cells. Taken together, these findings lend further support to a paradigm in which mesothelial cells are an important source of progenitors for mesenchymal structures. Our findings also reveal a role for Hh pathway in the early events associated with mesothelial cell entry and indicate that WT1 likely acts upstream of Hh signaling.
13
Gardner, Margaret A. B. S. "Cell and developmental stage specific role of Dicer1 in the lung epithelium." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427797752.
Full text
14
Blachford, Karen Grace. "Effects of loss of amniotic fluid on lung growth and maturation in rat fetuses." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/24482.
Full textAbstract:
This study was designed to examine the hypothesis that the amount of amniotic fluid present during gestation is critical to normal lung growth and maturation. On day 16 of gestation the amniotic sacs of the right or left uterine horns of timed pregnant Sprague-Dawley rats were punctured with a 20 gauge needle. The fetuses of the opposite horn served as controls. On day 21 of gestation (one day prior to natural delivery) the fetuses were delivered by Cesarean section. An unbalanced, mixed model analysis of variance was performed on the data collected from each fetus. Probability values of less than 0.05 between control and experimental animals were considered significant. Amniotic sac puncture resulted in a significant loss of amniotic fluid as indicated by reduced amniotic fluid volume on day 21. Experimental body weight was significantly reduced indicating fetal growth retardation. Lung growth was also retarded as indicated by significantly reduced lung weight to body weight ratios and lung volume to body weight ratios following amniotic sac puncture. There was a reduction in the amount of fluid present within the experimental lungs. There appeared to be no significant effect on the structural units of the lung as indicated by no significant difference between control and experimental fetal lungs in terms of cell number, cell size, total protein to body weight ratio, maturation of type II cells, volume fraction of saccular air, saccular wall, conducting air and nonparenchyma, airspace size, saccular surface area to body weight ratio and surface to volume ratio. Thus, loss of amniotic fluid significantly affected lung growth, more than it affected overall body growth, without having an effect on lung maturation.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
15
McElroy, Mary Catherine. "The role of antioxidant enzymes in human lung development." Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293725.
Full text
16
Chawsheen, Hedy. "ROLE OF SULFIREDOXIN INTERACTING PROTEINS IN LUNG CANCER DEVELOPMENT." UKnowledge, 2016. http://uknowledge.uky.edu/toxicology_etds/13.
Full textAbstract:
Sulfiredoxin (Srx) is an antioxidant enzyme that can be induced by oxidative stress. It promotes oncogenic phenotypes of cell proliferation, colony formation, migration, and metastasis in lung, skin and colon cancers. Srx reduces the overoxidation of 2-cysteine peroxiredoxins in cells, in addition to its role of removing glutathione modification from several proteins. In this study, I explored additional physiological functions of Srx in lung cancer through studying its interacting proteins. Protein disulfide isomerase (PDI) family members, thioredoxin domain containing protein 5 (TXNDC5) and protein disulfide isomerase family A member 6 (PDIA6), were detected to interact with Srx. Therefore, I proposed that TXNDC5 and PDIA6 are important for the oncogenic phenotypes of Srx in lung cancer.
In chapter one, I presented background information about the role of Srx as an antioxidant enzyme in cancer. I also explained the functional significance of PDIs as oxidoreductase and chaperones in cells. In chapter two, I verified the Srx-TXNDC5/PDIA6 interaction in HEK293T and A549 cells by co-immunoprecipitation and other assays. In TXNDC5 and PDIA6, the N-terminal thioredoxin-like domain (D1) is determined to be the main platform for interaction with Srx. The Srx-TXNDC5 interaction was enhanced by H2O2 treatment in A549 cells. Srx was determined to localize in the endoplasmic reticulum (ER) of A549 cells along with TXNDC5 and PDIA6. This localization was confirmed by both subcellular fractionation and immunofluorescence imaging experiments. In chapter three I focused on studying the physiological function of Srx interacting proteins in the ER. A549 subcellular fractionation results showed that TXNDC5 facilitates Srx retention in the ER. Moreover, TXNDC5 and Srx were found to participate in chaperone activities in lung cancer. Both proteins contributed in the refolding of heat-shock induced protein aggregates. In addition, TXNDC5 and PDIA6 were found to enhance the protein refolding in response to H2O2 treatment. Conversely, Srx appeared to have an inhibitory effect on protein folding under same treatment conditions. Downregulation of Srx, TXNDC5, or PDIA6 significantly reduced cell viability in response to tunicamycin treatment. TXNDC5 knockdown decreased the time required for the splicing of X-box binding protein-1 (XBP-1). In either knockdown Srx or TXNDC5 cells, there was an observable decrease in the expression of GRP78 and the splicing of spliced XBP-1. These results suggest a possible role of Srx in unfolded protein response signaling. TXNDC5 and PDIA6, similar to Srx, contribute to the proliferation, anchorage independent colony formation and migration of lung cancer cells.
In this dissertation I concluded that Srx TXNDC5, and PDIA6 proteins participate in oxidative protein folding in lung cancer. Srx and TXNDC5 can modulate unfolded protein response (UPR) sensor activation and growth inhibition. Furthermore, TXNDC5 and PDIA6 can promote tumorigenesis of lung cancer cells. Therefore, the molecular interaction of Srx with TXNDC5/PDIA6 has the potential to be used as novel therapeutic targets for lung cancer treatment.
17
WAN, HUAJING. "CRITICAL ROLES OF FORKHEAD BOX A2 DURING LUNG DEVELOPMENT." University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1091650603.
Full text
18
Kulkarni, Rishikesh Manohar. "Regulation of Lymphatic Endothelial Development and Function in Lung." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1242673402.
Full text
19
Pouliot, Robert A. "DEVELOPMENT AND CHARACTERIZATION OF LUNG DERIVED EXTRACELLULAR MATRIX HYDROGELS." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4465.
Full textAbstract:
Chronic obstructive pulmonary disease (COPD) including emphysema is a devastating condition, increasing in prevalence in the US and worldwide. There remains no cure for COPD, rather only symptomatic treatments. Due to unique challenges of the lung, translation of therapies for acute lung injury to target chronic lung diseases like COPD has not been successful. We have been investigating lung derived extracellular matrix (ECM) hydrogels as a novel approach for delivery of cellular therapies to the pulmonary system.
During the course of this work we have developed and characterized a lug derived ECM hydrogel that exhibits “injectability,” allowing cells or dugs to be delivered in a liquid and encapsulated at body temperature. The hydrogel self assembles in <5 minutes and achieves mechanical stiffness similar to other soft tissue ECM hydrogels. The hydrogel can support 3D cell growth and encapsulated cell viability. Encapsulated hMSCs can also still be activated by simulated inflammatory environments. Naïve mouse macrophages exposed to the fully formed gel were not significantly induced to express markers for pro or anti-inflammatory polarized phenotypes, but increased expression for several secreted inflammatory mediators was observed.
We also investigated a novel approach for preparing and solubilizing the isolated ECM proteins, using digestion time as a variable for controlling hydrogel density (interconnectivity), mechanical stiffness, component protein size distribution, and cell behavior on fully formed gels. The potential future impact for the presented research includes optimization for future animal studies, expansion to additional applications, and the development of new derivative materials.
20
Wang, Hui. "Development of nicotine loaded chitosan nanoparticles for lung delivery." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/108006/1/Hui_Wang_Thesis.pdf.
Full textAbstract:
This research offers a specific strategy for the management of a global health problem associated with smoking addiction. Novel controlled release nicotine-loaded chitosan nanoparticles have been developed as a potential therapy. In vitro and in vivo evaluation of these nanoparticles indicate that they are suitable as dry powder inhaler formulations for pulmonary delivery. Results from a mouse model should translate to humans to provide a safe and effective approach to treat smoking dependence.
21
Maas, Janet Catherine. "Development of corticosteroid liposomes for delivery to airway macrophages." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243075.
Full text
22
Laube, Mandy, Miriam Bossmann, and Ulrich H. Thome. "Glucocorticoids distinctively modulate the CFTR channel with possible implications in lung development and transition into extrauterine life." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-169679.
Full textAbstract:
During fetal development, the lung is filled with fluid that is secreted by an active Cltransport promoting lung growth. The basolateral Na+,K+,2Cl- cotransporter (NKCC1) participates in Cl- secretion. The apical Cl- channels responsible for secretion are unknown but studies suggest an involvement of the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is developmentally regulated with a high expression in early fetal development and a decline in late gestation. Perinatal lung transition is triggered by hormones that
stimulate alveolar Na+ channels resulting in fluid absorption. Little is known on how hormones affect pulmonary Cl- channels. Since the rise of fetal cortisol levels correlates with the decrease in fetal CFTR expression, a causal relation may be assumed. The aim of this
study was to analyze the influence of glucocorticoids on pulmonary Cl- channels. Alveolar cells from fetal and adult rats, A549 cells, bronchial Calu-3 and 16HBE14o- cells, and primary rat airway cells were studied with real-time quantitative PCR and Ussing chambers. In fetal and adult alveolar cells, glucocorticoids strongly reduced Cftr expression and channel activity, which was prevented by mifepristone. In bronchial and primary airway cells CFTR mRNA expression was also reduced, whereas channel activity was increased which was prevented by LY-294002 in Calu-3 cells. Therefore, glucocorticoids strongly reduce CFTR expression while their effect on CFTR activity depends on the physiological function of the cells. Another apical Cl- channel, anoctamin 1 showed a glucocorticoid-induced reduction of mRNA expression in alveolar cells and an increase in bronchial cells. Furthermore, voltage-gated chloride channel 5 and anoctamine 6 mRNA expression were increased in alveolar cells. NKCC1 expression was reduced by glucocorticoids in alveolar and bronchial cells alike. The results demonstrate that glucocorticoids differentially modulate pulmonary Clchannels and are likely causing the decline of CFTR during late gestation in preparation for
perinatal lung transition.
23
Berg, Tove. "C/EBP transcription factors in lung cellular differentiation and development /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-586-0/.
Full text
24
Boland, Rochelle Elizabeth 1974. "Factors affecting structural development of the lung in fetal sheep." Monash University, Dept. of Physiology, 2002. http://arrow.monash.edu.au/hdl/1959.1/8135.
Full text
25
Xu, Li Jing. "Oxygen and lung development in newborn rats and chick embryos." Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61955.
Full text
26
Bustani, Porus C. "The role of hyperoxia in abnormal development of fetal lung." Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/4567.
Full textAbstract:
Hyperoxia is closely linked with the development of chronic lung disease of prematurity (CLD) but the fixant mechanisms whereby hyperoxia alters lung architecture in the developing lung remain largely unknown.
27
Sitaraman, Sneha. "Alveolar type 2 epithelial cells in lung development and disease." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571062200291287.
Full text
28
Pozarska, Agnieszka [Verfasser]. "Tgfbr3 regulates alveolarisation in late lung development / Agnieszka Ewa Pozarska." Gießen : Universitätsbibliothek, 2020. http://d-nb.info/1216142548/34.
Full text
29
Fryer, Anthony Alan. "Studies on the biochemical development of human lung and brain." Thesis, Keele University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306225.
Full text
30
Nakamura, Tomonori. "Essential roles of ECAT15-2/Dppa2 in functional lung development." Kyoto University, 2011. http://hdl.handle.net/2433/151943.
Full text
31
Pozarska, Agnieszka Ewa [Verfasser]. "Tgfbr3 regulates alveolarisation in late lung development / Agnieszka Ewa Pozarska." Gießen : Universitätsbibliothek, 2020. http://d-nb.info/1216142548/34.
Full text
32
Muranishi, Yusuke. "Development of a novel lung-stabilizing device for VATS procedures." Kyoto University, 2019. http://hdl.handle.net/2433/242353.
Full text
33
Lee, Matthew John. "Ultrastructural localisation of drug-metabolising enzymes within lung and their role in the development of cell-specific lung injury." Thesis, Open University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282748.
Full text
34
McColm, Janet R. "Inflammatory mediators in the lungs of preterm infants and their role in the development of chronic lung disease." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/21402.
Full textAbstract:
The clinical pilot study enrolled 26 infants and measured IL-8, TNF-α and inflammatory cells in bronchoalveolar lavage samples. The results demonstrated that it may be possible to predict a group of babies at extremely high risk for developing chronic lung disease by early measurement of IL-8 in tracheal secretions. To further investigate the role of the genital mycoplasmas, Ureaplasma urealyticum and Mycoplasma hominis, a randomised study using an effective antibiotic, erythromycin, was carried out. A low grade untreated infection could persistently stimulate an in vivo inflammatory response, but we also wished to investigate the reported anti-inflammatory properties of erythromycin. The infection rate in the study was lower than expected (12% compared to 30% in a pilot study) and did not correlate with outcome. There was also no correlation between outcome and treatment and the inflammatory response, as measured by IL-8, did not correlate with outcome as it had in our pilot study. As part of a randomised trial of a natural and synthetic surfactant taking place on our unit, bronchoalveolar lavage samples both pre and post surfactant were analysed for cytokines and cells. Our results showed that Curosurf produced a significantly lower inflammatory response compared to Exosurf 24 hours after administration but there was no correlation between surfactant type and development of chronic lung disease. The cell population present in the lung effluent has been an area of controversy. Standard cytospin smears of bronchoalveolar lavage samples were compared using a differential stain and an immunocytochemical stain which relies on monoclonal antibodies to identify specific cell surface markers. Our results confirm that the differential stain identifies neutrophils but it significantly under-estimates cells of the monocyte/macrophage lineage. Laboratory investigations were carried out to further elucidate and quantify the response of A549 human lung epithelial cells to Ureaplasma urealyticum, and other genital isolates, a Gram-positive (Staphylococcus albus) and a Gram-negative (Eschericia coli). The cells were stimulated in the presence of TNF-α and high oxygen concentrations, and with used in the clinical management of these infants, including surfactants, antibodies and steroids.
35
Bovard, Joshua Maschio. "Does competitive swimming during puberty affect lung development in pubertal females?" Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62896.
Full textAbstract:
Whether the large lungs of competitive swimmers result from intensive swim training or genetic endowment has been widely debated. Given that peak growth velocities for the lungs occur during puberty, this longitudinal study aimed to determine if competitive swimming during puberty affected lung development. Female swimmers (n=11) and healthy controls (n=10) aged 11-14 years old were assessed before and after one competitive swimming season. Pulmonary function testing included lung volumes, spirometry, diffusion capacity (DL,CO), and maximal inspiratory (PIMAX) and expiratory (PEMAX) pressures. Ventilatory constraints, including end-expiratory lung volume (EELV), expiratory flow limitation (EFL), and utilization of ventilatory capacity (V̇E/V̇ECAP), were assessed during an incremental cycling test. Despite being of similar age (p=0.10), maturational development (p=0.27), and height (p=0.38) as controls, swimmers had a larger total lung capacity (p<0.01), forced vital capacity (p<0.01), and peak expiratory flow (p=0.03). Although DL,CO was greater in swimmers (p=0.01), there was no difference when expressed relative to alveolar volume (p=0.20). Both PIMAX (p=0.06) and PEMAX (p<0.001) were greater in swimmers. Swimmers and controls achieved a similar relative maximal oxygen consumption (p=0.32) and experienced similar ventilatory constraints as characterized by EELV (p=0.18), severity (p=0.95) and prevalence (p=0.71) of EFL, and V̇E/V̇ECAP (p=0.95). Changes over time were similar between groups (p>0.05). Pubertal female swimmers already had larger lung capacities, higher flows, and greater indices of respiratory muscle strength, but similar ventilatory constraints while cycling. One competitive swimming season did not further accentuate this enhanced function or alter exercise ventilatory mechanics, suggesting that competitive swimming during puberty did not affect lung development.Education, Faculty of
Kinesiology, School of
Graduate
36
Deimling, Julie F. "Epithelial-mesenchymal interactions and the Notch pathway in mammalian lung development." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0002/MQ46042.pdf.
Full text
37
Groenman, Frederick Anton. "Hypoxia inducible factor a breath of fresh air in lung development /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10347.
Full text
38
Chari, Rajagopal. "Development and application of an integrative genomics approach to lung cancer." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/26001.
Full textAbstract:
Lung cancer has the highest mortality rate amongst all diagnosed malignancies with adenocarcinoma (AC) being the most commonly diagnosed subtype of this disease in North America. The dismal survival statistics of lung cancer patients are largely due to the detection of the disease at an advanced stage and to a lesser extent, the limited efficacy of current front line treatments.
Genomic approaches, namely gene expression analysis, have provided tremendous insight into
lung cancer. While many gene expression changes have been identified, most changes are likely reactive to changes which have a primary role in cancer development. Moreover, one feature which can discern primary from reactive changes is the presence of concordant DNA level alteration.
Many well known genes involved in cancer such as TP53 and CDKN2A have been shown to be
affected by multiple mechanisms of alteration such as somatic mutation in or loss of DNA sequence. For a given gene, one tumor may be affected by one mechanism while another tumor may be affected by a different mechanism. Although this level of multi-dimensional analysis has been performed for specific genes, such analysis has not been done at the genome-wide level.
This thesis highlights the development and application of a multi-dimensional genetic and
epigenetic approach to identify frequently aberrant genes and pathways in lung AC. I present,
first, the design and implementation of the system for integrative genomic multi-dimensional analysis of cancer genomes, epigenomes and transcriptomes (SIGMA²). Next, analyzing a multi-dimensional dataset generated from ten lung AC specimens with non-malignant controls, I identified novel genes and pathways that would have been missed if a non-integrative approach were used. Finally, examining genes involved with EGFR signaling, I identified a gene, signal receptor protein alpha (SIRPA), which had not been previously shown to be associated with lung cancer.
Taken together, these findings demonstrate the power of a multi-dimensional approach to identify important genes and pathways in lung cancer. Moreover, identifying key genes using a multi-dimensional approach on a small sample set suggests the need of large datasets may be
circumvented by using a more comprehensive approach on a smaller set of samples.
39
Cornejo, Perales Salomon. "Mechanisms of glucocorticoid responsiveness in the lung during development and inflammation." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116918.
Full textAbstract:
Glucocorticoids (GCs) are vital hormones involved in lung development and the regulation of the inflammatory/immune response. High inter-individual variability in GC responsiveness exists among patients using steroids as treatment for inflammatory diseases. Evidence suggests that vitamin D (VitD), another player in lung development, improves GC function. Even though progress has been made in the study of steroid insensitivity, the molecular mechanisms are not completely elucidated and the effects of limited GC response during lung development have not been explored. The first objective of the present thesis was to study mechanisms of steroid responsiveness in asthma using mouse models of the disease. The Balb/c strain demonstrated a steroid insensitive phenotype associated with increased amounts of active p38 MAPK and subsequent inactivation of the GC receptor (GR) following allergen challenge. Additionally, lymphoblast cell lines derived from asthmatic children were used to study mechanisms for variable GC responsiveness and to explore the modulatory role of VitD on GC function. Poor responsiveness to steroids in asthmatic children was associated with limited GR nuclear bioavailability as a consequence of decreased baseline GR expression and faster hormone-induced downregulation. Suggestive evidence for a beneficial effect of VitD in steroid sensitivity is presented. Finally, steroid responsiveness and VitD modulation of GC function was studied in epithelial cells of the developing lung of normoresponsive and atopic rat models. The developmental airway epithelium of the atopic rat appeared to be more sensitive to steroids, possibly making the lung more susceptible to the deleterious effects of GCs, and VitD attenuated the GC response. Overall this thesis highlights the complexity of steroid function and its regulation by multiple mechanisms ranging from altered expression, reduced activation, abnormal nuclear translocation and increased homologous downregulation of GR.Les glucocorticoïdes (GC) sont des hormones vitales impliquées dans le développement des poumons et de la régulation de la réponse inflammatoire/immunitaire. Une grande variation interindividuelle de la réactivité des GC existe chez les patients utilisant des stéroïdes comme traitement pour les maladies inflammatoires. Les preuves suggèrent que la vitamine D (VitD), une autre molécule impliquée dans le développement des poumons, améliore la fonction des GC. Même si des progrès ont été réalisés dans l'étude de l'insensibilité aux stéroïdes, les mécanismes moléculaires ne sont pas complètement élucidés et les effets de la réponse compromise aux GC au cours du développement pulmonaire n'ont pas été explorés. Le premier objectif de cette thèse est d'étudier les mécanismes de réactivité des stéroïdes dans l'asthme en utilisant des modèles murins de la maladie. La souche Balb/c a démontré un phénotype d'insensibilité aux stéroïdes associé à des quantités accrues de p38 MAPK sous forme active et l'inactivation subséquente du récepteur des GC (GR) après provocation par un allergène. De plus, des lignées cellulaires lymphoblastiques provenant d'enfants asthmatiques ont été utilisées pour étudier les mécanismes de réactivité variable des GC et ont permis d'explorer le rôle modulateur de la VitD sur la fonction des GC. Chez les enfants asthmatiques, une faible réactivité aux stéroïdes a été associée à une biodisponibilité nucléaire limitée du GR à la suite de l'expression basale diminuée du GR et de la rapide régulation négative induite par l'hormone. Des évidences suggérant un effet bénéfique de la VitD sur la sensibilité aux stéroïdes sont présentées. Enfin, la réactivité des stéroïdes et la modulation de la fonction des GC par la VitD ont été étudiées dans les cellules épithéliales du poumon en développement des modèles de rats normaux et atopiques. L'épithélium des voies respiratoires du rat atopique semble être plus sensible aux stéroïdes, en rendant possiblement les poumons plus susceptibles aux effets néfastes des GC, et la réponse des GC est atténuée par la VitD. Cette thèse met en évidence la complexité de la fonction de stéroïdes et de sa régulation par des mécanismes multiples allant de l'expression altérée, l'activation réduite, la translocation nucléaire anormale et l'augmentation de la régulation négative homologue des GC.
40
Sokolova, Natalia Valerievna. "The role of vitamin A in embryonic lung development in mice." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320687.
Full text
41
Wang, Jau-Yi. "Development of multiple-breath-helium-washout system for lung function studies." Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/14451/.
Full textAbstract:
This thesis discusses the development of the multiple-breat h-helium washout (MBHW) measurement for lung-function study. Multiple-breath washout (MBW) has been regarded as a sensitive technique to study the ventilation inhomogeneity in conducting or acinar airways. The tracer gas washed out from the lungs breath by breath is monitored. By analysing the concentration of the tracer gas versus the expired tidal volumes, the washout results provide two indices Scond and Sacin which reflect the degree of ventilation inhomogeneity. Scond is the increasing rate of the noramlised phase III slopes breath by breath while the Sacin is the normalised phase III slope from the first breath with the subtraction of Scond. The higher Scond value the greater ventilation inhomogeneity in the conductive airways while the higher Sacin value the greater ventilation inhomogeneity in the acinar airways. Traditionally, nitrogen is used as the tracer gas, washed out by the pure oxygen in a multiple-breath-nitrogen washout (MBNW) measurement. It is usually chosen because it is the gas we normally breathe and has no direct influence on physiology unlike oxygen. In this study,4He gas is used as the tracer gas instead. Since helium is less dense and has higher diffusivity than nitrogen, it is believed that it will be able to reach deeper into our lungs in a given time. Therefore, helium washout may provide more ventilation information especially in the small airways. In our MBHW system, a quartz tuning fork with a resonant frequency 32768Hz is used as the gas density sensor. The resonant frequency of the tuning fork is linearly related to the surrounding gas density. The helium concentr ation is given by eliminating all other gas components and calculating it from the tuning fork signal. Considering other components of our expiration, the carbon dioxide is detected by the infrared sensor, and the water is filtered out by a trap. We have performed the washout measurements on 11 volunteers, three of them have been diagnosed having mild lung diseases (asthma), two are smokers, and the other five are normal healthy people. The peak expiratory flow is also measured for each subject. The single breath MBHW curves from asthmatic people have higher normalised phase III slopes and higher Scond or Sacin values. This shows a greater conductive or acinar ventilation inhomogeneity in asthmatics’ lungs. The lung clearance washout curves are fitted with a summation of two exponential curves which represent two compartments with different ventilation rates. The compartment with higher decay rate represents the better-ventilated compartment and the other one is the poorly-ventilated compartment. Subjects with larger proportion of poorly-ventilated compartments have a lower peak expiratory flow rate compared to the predicted values. A 2.2-litre lung model has been built. A loud speaker has been used to simulate the movement of the diaphragm. MBHW measurements have been performed on the lung model which has a 0- to 4-generation dichromatic structure. The washout results from the lung models is compared to the results from the real lungs.
42
Chudasama, Dimple. "Discovery and development of liquid biomarkers for ovarian and lung cancer." Thesis, Brunel University, 2018. http://bura.brunel.ac.uk/handle/2438/16174.
Full textAbstract:
Survival rates in cancers have improved vastly over the years. However, some survival rates remain extremely low, as is the case for ovarian and lung cancer. The lack of robust and reliable biomarkers is strongly reflected in the absence of pre-screening programs, and as such, most patients in these cancer types are diagnosed only in advanced stages, leaving few treatment options. Moreover, relapse and resistance to therapies adds to the complexities of treating these diseases, even in the era of targeted drug development. Research has shown the presence of cancer material, in the form of circulating cancer cells (CTCs) and genomic material in the blood of patients, opening the possibility of 'liquid biopsies'. Liquid biopsies allow sampling of the disease to provide phenotypic and genomic data on the cancer in real-time and on a routine basis. Moreover, they overcome obstacles currently faced by conventional tissue biopsies. In this work we evaluate the use of a novel CTC imaging flow-cytometry platform, and report the ability to characterise and quantify these cells in blood samples. Moreover, we report significantly higher levels of CTCs in cancer patients compared to controls, and found them to be associated with a poorer prognosis. In particular, in lung cancer we observe these findings even in the early stages, suggesting a potential diagnostic use for this assay. We detect a similar trend in when analysing the ctDNA and suggest the possibility of using this technique with a prognostic value in the advanced setting. We also report on the analysis of existing microarray data by use of unique gene regulatory networks to identify biomarkers of interest. RAD51AP1 was identified by this process. Clinical validation revealed an over-expression of this gene in both tissue and blood of ovarian and lung cancers. Moreover, the gene over-expression was associated with a poor overall survival. Functional analysis in vitro revealed silencing RAD51AP1 suppressed tumour growth, in addition, various tumorigenic proteins were down-regulated, whilst apoptotic and immune genes were up-regulated. These results suggest a role for RAD51AP1 as a potential therapeutic target. In this study, we also demonstrate the ability to further exploit tumour genomic material in the blood by means of RNAseq, cancer panels, and CNI scoring to identify novel markers, that play an important role in disease genesis and evolution. RNAseq analysis identified XIST as a gene up-regulated in the blood and tissue of lung cancers. The ovarian cancer panels revealed 2 unique gene signatures in the ovarian cancer patients. With the CNI analyses also highlighting chromosomal aberrations from plasma analysis of cancer patients. Collectively, the use of all these techniques and exploitation of available blood based biomarkers could see significant improvements to survival rates in these, currently devastating diseases.
43
Almurshedi, A. "Development of Afatinib lipid nanoparticles targeting non small cell lung cancer." Thesis, Liverpool John Moores University, 2018. http://researchonline.ljmu.ac.uk/9111/.
Full textAbstract:
Lung cancer is the most common cause of cancer-associated mortality in males and females globally. Widespread research is currently focused on the development of novel approaches for targeting non small cell lung cancer with different therapeutic nanotechnologies. In this study, a sensitive and selective HPLC method was developed for the quantification of afatinib (AFT) in formulations. Novel drug delivery systems based on cationic (CL) and pH-sensitive liposomes (PSL) for AFT were developed, with different ratios of lipid to AFT, using a film hydration method. The obtained liposomes had a small particle size of less than 50 nm with a low polydispersibilty index and acceptable zeta potential. The highest Encapsulation Efficiency (EE%) of AFT reached 43.20%, 50.20%, and 52.01% for NL (Non targeting liposomes), PSL, CL, respectively at the 1:0.5 ratio of AFT: lipids. The in vitro release study confirmed that all formulations had sustained release profiles in pH 7.4. However, in acidic pH values, PSL exhibited fast release. The stability study, conducted at 4°C and 25°C for 1 month, showed that the characteristics of liposomes in liquid form did not change significantly over this period. In vitro cytotoxicity studies revealed high antitumor activity of PSL on all cell lines at 0.75 μM concentration after 24 h exposure, based on using the Annexin V assay. A proteomics study identified 12 proteins which can be used as biomarkers capable of prediction of treatment response and choice of therapy for two different types of human NSCLC cells (H-1975 and H-1650). Spray drying was used to produce nanocomposite microparticles (NCMPs) using L-leucine and coated using different ratios of chitosan for the optimized PSL NPs. The particles had a corrugated surface except at high CH ratios, where more homogenous and smooth particles with some small indentations were obtained. The powder properties showed good flow properties and reproducible size. Coated NCMPs showed a delayed drug release profile compared to PSL NPs and the best correlation with the Higuchi model. A stability study at 40°C/ 75% ± 5% relative humidity (RH) showed large changes in the drug content for all coated NCMPs powders. Analysis of the in vitro aerosolization performance demonstrated a mass median aerodynamic diameter (MMAD) of 3.24 – 5.85 μm and fine particle fraction (FPF%) of 54.20-33.66%. The particle size of the reconstituted powders was ˂ 100 nm, which is within the size range to be effectively taken up by tumor cells. Assessment of the stability of spray dried liposomes after 3 months of storage at 40 °C/75% RH, showed that fusion and aggregation of the liposomes occurred in all samples tested. The C1NCMPs (lipid: LEU: CH ratio of 1:1.5:0.5) exhibited the highest FPF (51.2%) and fine particle dose (FPD) (40.0 μg of AFT) indicating deep lung deposition. Further cell viability studies of C1 NCMP, at a concentration of 0.75 μM on H-1975 NSCLC cell line showed a good toxicity profile comparable to PSL nanoparticles (NPs). The obtained data indicates that pulmonary delivery of PSL NCMPs is a potential new clinical strategy for better targetability and delivery of AFT for the treatment of lung cancer.
44
Xu, Zizhao. "Development of Lipid-based Nano Formulations of Miriplatin Against Lung Cancer." Scholarly Commons, 2020. https://scholarlycommons.pacific.edu/uop_etds/3699.
Full textAbstract:
Cancer is the second leading cause of death and is responsible for approximately 9.6 million deaths worldwide in 2018. Among all oncological diseases, lung cancer claims the highest mortality (male: 23.5%; female: 22%) and the second most new cases (male: 13%; female: 12%) in the US. Approximately 40% of newly diagnosed lung cancer patients are in the advanced stage IV, for which platinum-based chemotherapy is the first-line treatment, either by itself or in combination with surgery or radiotherapy.
Cisplatin, the first-generation platinum-based anticancer chemotherapeutic agent, has the highest potency against lung cancer but carries many severe adverse effects. Cisplatin also induces drug resistance during long-term chemotherapy. Many more platinum complexes have been investigated as better alternatives, which led to the approval of carboplatin and oxaliplatin by Food and Drug Administration (FDA). In addition, miriplatin suspended in iodolipds (lipiodolization) was approved in Japan for the treatment of hepatocellular carcinoma (HCC) in 2009. Miriplatin has the same non-leaving group as oxaliplatin but different leaving groups of two myristate chains, which make it highly lipophilic.
Several characteristics of solid tumors in lung cancer constitute a physiochemical barrier to the homogenous distribution and deep penetration of chemotherapy agents. Nanocarriers provide a promising platform to overcome the physiochemical barrier and to reduce the systemic toxicity of anticancer chemotherapy. In this study, miriplatin is formulated with various lipid-based nanocarriers including micelles and solid lipid nanoparticles (SLNs) thanks to its highly lipophilic structure. The goal of this thesis is to develop and evaluate miriplatin-loaded nano formulations against lung cancer.
Miriplatin-loaded formulations were prepared by different methods, including thin film hydration and several scale-up methods including chloroform dripping, chloroform injection, chloroform evaporation, co-solvent evaporation, chloroform slow evaporation and co-solvent slow evaporation. Between the two types of nano formulations under this study, micelles were much smaller (~10 nm in diameter) and more homogeneous (PDI < 0.3), while SLNs were bigger (~ 100 nm in diameter) and more heterogeneous (PDI ~0.8). A quantification method of miriplatin was established using inductively coupled plasma-optical emission spectrometry (ICP-OES). The quantification of platinum recovery from different miriplatin-loaded nano formulations was facilitated by digestion with 70% nitric acid and heating. The co-solvent slow evaporation method to prepare miriplatin-loaded nano formulations improved the platinum recovery prominently from 10% to 70%. Thus, co-solvent slow evaporation has been established as a pharmaceutically viable scale-up method to prepare nano formulations of miriplatin.
Miriplatin-loaded nano formulations of different compositions were negatively stained with uranyl acetate and then imaged by transmission electron microscopy (TEM), which showed the formulations’ size and morphology that were consistent with the size and PDI data from dynamic light scattering studies by the Malvern Zetasizer. In the TEM studies, micelles showed a morphology of spherical dots at around 10 nm in diameter while SLNs showed both spherical and rod structures with a size distribution from 50 to 150 nm.
A three-dimensional multicellular spheroid (3D MCS) model of A549-iRFP cells was used for in vitro evaluation of the nano formulations’ activity against lung cancer. A549-iRFP cells were engineered from the common lung cancer cell line A549 to stably express the near-infrared fluorescent protein (iRFP). The viability of A549-iRFP 3D MCS after exposure to cisplatin or nano formulations was similar to A549 3D MCS. The anticancer activity of miriplatin-loaded nano formulations against 3D MCS was positively associated with the platinum recovery as quantified by ICP-OES. The miriplatin-loaded nano formulations that had been prepared by the co-solvent slow evaporation method showed substantial anticancer activities against A549 3D MCS and A549-iRFP 3D MCS, which were comparable to cisplatin.
Taken together, miriplatin-loaded nano formulations were successfully prepared by co-solvent slow evaporation. The formulations were developed to carry favorable physiochemical properties to enhance the activities of platinum drugs against lung cancer.
45
METZGER, DAVID EDWARD. "THE ROLE OF THE ETS TRANSCRIPTION FACTOR Elf5 IN LUNG DEVELOPMENT." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1197664589.
Full text
46
Moncada, Benavides Camilo Andres. "EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/206623.
Full textAbstract:
BiochemistryPh.D.
Infection with "Pneumocystis" causes a ≥ 99% depletion of plasma S-adenosylmethionine (AdoMet) levels in both "Pneumocystis" pneumonia (PcP) animal models and patients. AdoMet is a critical cellular metabolic intermediate, with a pivotal role as methyl donor in a myriad of biochemical processes and necessary for the synthesis of the essential polyamines spermidine and spermine. In the target tissue of "Pneumocystis", the lung, levels of AdoMet were previously shown to be depleted experimentally using nicotine. Here we show that chronic administration of nicotine in an animal model of PcP resulted in decreased lung AdoMet content. Since "Pneumocystis" is dependent on this metabolite, PcP burden was also relived. We hypothesized that the underlying mechanism behind nicotine-induced AdoMet depletion was an increased consumption of AdoMet through the polyamine pathway where the increased activity of N-1-spermidine/spermine acetyl transferase raises the catabolic / anabolic cycling of polyamines, a process that utilizes AdoMet. In a critical test of our hypothesis, we found that blockage of polyamine metabolism via inhibition of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) hinders the effect of nicotine on lung AdoMet levels. Further support is provided by metabolite analyses showing nicotine to cause a strong diversion of AdoMet toward polyamine synthesis and away from methylation reactions; these shifts are also reversed by inhibition of ODC. Because the nicotine effect on "Pneumocystis" is so striking, we considered the possibility of tissue specificity. Using laser capture microdissection (LCM), we collected samples of lung alveolar regions (site of infection) and respiratory epithelium for controls. We found nicotine to cause increased ODC activity in alveolar regions but not airway epithelium; we conclude that tissue specificity likely contributes to the effect of nicotine on "Pneumocystis" pneumonia. Our studies demonstrate the feasibility of pharmacological manipulation of the polyamine pathway in order to reduce AdoMet levels in the lung and prompted the assessment of compounds alternative to nicotine with the potential to achieve a comparable effect. In vitro evaluation of the polyamine analog DENSPM along with putrescine in type II alveolar cell lines, indicates that although such a combination has the potential to induce polyamine flux, an apparent competition for the same polyamine transport system impairs simultaneous uptake of both compounds at effective concentrations. In conclusion, we showed that chronic nicotine administration causes reduction of AdoMet levels in rat lung following 21 days of treatment, by a mechanism involving the induction of polyamine flux, which is responsible of increased AdoMet utilization for polyamine biosynthesis. According to LCM-based analysis, this effect seems to be confined to the alveolar regions of the lung.
Temple University--Theses
47
Ntokou, Aglaia [Verfasser]. "The role of pulmonary fibroblast subtypes in lung development / Aglaia Ntokou." Gießen : Universitätsbibliothek, 2018. http://d-nb.info/1152943898/34.
Full text
48
Kolck, Johannes [Verfasser]. "The role of miR-154 in early lung development / Johannes Kolck." Gießen : Universitätsbibliothek, 2020. http://d-nb.info/1216145245/34.
Full text
49
Amelon, Ryan. "Development and characterization of a finite element model of lung motion." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3422.
Full textAbstract:
BACKGROUND: Finite element models of lung motion can aid in understanding mechanically driven lung deformation. Current finite element models consider each lung half as a continuum, lacking the ability to capture the displacement discontinuity at fissures caused by lobe sliding.
OBJECTIVE: The objective of this work was to develop and evaluate finite element models for simulating lung motion that incorporate the role of sliding at the lobe boundaries.
METHODS: Finite element models were developed from 4DCT of tidal breathing from five cancer subjects. To allow sliding, the lobes were modeled as independent bodies within a pleural cavity shell. Pleural cavity deformation was obtained from deformable image registration of the lung segmentations. Contact between the pleural cavity and lobes prevented penetration and allowed sliding at all interfaces. Lung parenchyma was modeled as a homogeneous, 2-parameter, Neo-Hookean finite elastic model. The parameters of the Neo-Hookean model, C1 and D1, were optimized by perturbation within realistic reported ranges; defined by the equivalent infinitesimal elasticity parameters: Young's modulus (from 0.7 kPa to 70 kPa) and ν (from 0.2 to 0.49). The frictional coefficient at fissures was perturbed between 0 (free sliding) and 1.5 (no sliding). 1,960 finite element analyses were performed across the five subjects. The optimal parameter ranges were evaluated by average landmark error and percentage of converged solutions.
The developed finite element method, using optimized material and friction parameters, was further evaluated in a data set of six healthy subjects with image pairs spanning functional residual capacity (FRC) to total lung capacity (TLC). The finite element predicted displacement field for lobe sliding finite element models and continuum-based finite element models were compared using average landmark error and correlation with the lobe-by-lobe deformable image registration results.
RESULTS AND DISCUSSION: The optimal parameters for Young's modulus were 49 kPa to 70 kPa and Poisson's ratio were 0.2 to 0.4. Variation of inter-lobar frictional coefficients did change displacement field accuracy assessed by landmark error or correlation to lobe-by-lobe deformable image registration. Characteristics of sliding predicted by the lobe sliding finite element models were consistent with characteristics in sliding observed in deformable image registration results. Also, variations in regional ventilation, quantified at the lobe level, were predicted by the finite element models and were shown to be influenced by the amount of lobe sliding allowed by the models.
50
Latzin, Philipp. "Lung development in health and disease : early-life risk factors and their impact on lung function, inflammation and respiratory symptoms /." [S.l.] : [s.n.], 2009. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Full text