To see the other types of publications on this topic, follow the link: Bleomycin.
Dissertations / Theses on the topic 'Bleomycin'
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 'Bleomycin.'
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
Absalon, Michael Joseph. "DNA double-strand cleavage mediated by bleomycin." Thesis, Massachusetts Institute of Technology, 1994. http://hdl.handle.net/1721.1/11927.
Full text
2
Nightingale, Karl. "DNA sequence recognition by the antitumour antibiotic bleomycin." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241056.
Full text
3
Currier, Sophie (Sophie Christine) 1974. "Genetic requirements for protection against bleomycin toxicity in Escherichia coli." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/73345.
Full textAbstract:
Thesis (S.M.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 1999.<br>Includes bibliographical references (leaves 46-51).<br>Bleomycin is known to cause double strand breaks in vitro. Little is known, however, about its mechanism of genotoxicity in vivo. One way to probe the mechanism of genotoxicity of a DNA damaging agent in vivo is to compare the relative sensitivities of a wild type Escherichia coli strain to a panel of isogenic repair deficient mutants. If the pathway defective in the mutant is known (e.g., base excision repair, alkyl transferase repair, nucleotide excision repair, and so on), the sensitivity of the mutant can reveal mechanistic insight into the mode of killing by the DNA damaging agent. In this study, mutants deficient in recombinational repair, specifically recF, recBCD, ruvABC, recG and recGruvC, were examined for sensitivity to bleomycin. This sensitivity was tested in both dividing and non-dividing cells in order to analyze the effect of cell division on the cytotoxicity of bleomycin. When non-dividing cells were treated, the recBCD and recGruvC mutants, demonstrated high sensitivity to bleomycin. The recF mutant, on the other hand, demonstrated no sensitivity. These results were consistent with the conclusion that bleomycin induces double strand breaks in vivo that are repaired by the recombinational repair double strand break pathway. It also suggests that no damage was induced by bleomycin that required repair by the daughter strand gap pathway. Examining the sensitivity of recombinational repair deficient mutants to bleomycin also gave new insights about the mechanism of recombinational repair. Both ruvABC and recG gene products resolve Holliday junctions; however, they are thought to work on separate recombinational pathways. In this study, although the recGruvC strain was highly sensitive to bleomycin, the ruvABC and the individual recG and ruvC strains were not. This result suggested redundancy in the functions of the RecG and RuvABC proteins. Dividing cells showed a marked increase in sensitivity to bleomycin as compared to non-dividing cells. In addition, the functional redundancy of recG and ruvABC mutants was no longer seen. The ruvABC strain demonstrated high sensitivity equal to that of the recGruvC and recBCD strains whereas the recG and ruvC strains were only slightly sensitive. Under these conditions of increased cytotoxicity, additional functions of the RuvAB enzymes became important for suppression of toxicity. This result suggested a change in the mechanism of bleomycin's genotoxicity.<br>by Sophie Currier.<br>S.M.
4
Highfield, Jacqueline Ann. "The synthesis and testing of novel anticancer agents related to bleomycin." Thesis, Brunel University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263514.
Full text
5
Li, Huawen. "Quantitative Analysis of Bleomycin in Rat Plasma by LC-MS/MS." Cleveland State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1528851820162444.
Full text
6
Kadokawa, Yoshio. "All-trans retinoic acid prevents radiation-or bleomycin-induced pulmonary fibrosis." Kyoto University, 2009. http://hdl.handle.net/2433/124297.
Full text
7
Gäng, Dominique Patricia. "Paradoxical effects of bleomycin and heavy water (D₂O) in Mice /." [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Full text
8
Lemay, Anne-Marie. "Identification of bleomycin and radiation-induced pulmonary fibrosis susceptibility genes in mice." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:8881/R/?func=dbin-jump-full&object_id=92173.
Full text
9
Lübke, Friedemann Norbert Gregor Ulrich. "Prävention der Bleomycin-induzierten Lungenfibrose durch inhalative Applikation von Heparin oder Urokinase." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=974923818.
Full text
10
Murrell, Jeffrey Michael. "Investigation of sugar biosynthesis pathways of antitumor antibiotics C-1027 and bleomycin /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2003. http://uclibs.org/PID/11984.
Full text
11
Cory, Sean M. "Integrative bioinformatics for the discovery of genetic modifiers of bleomycin-induced pulmonary fibrosis." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112392.
Full textAbstract:
Bleomycin-induced pulmonary fibrosis (BIPF) is a disease caused by the chemotherapeutic bleomycin in which normal lung tissue is replaced with fibrous tissue that is unable to fulfill the normal functions of oxygen exchange in the lung. The development of this disease is dictated, in part, by a set of genes governing susceptibility. Knowledge of such genetic modifiers offers novel therapeutic targets and improved understanding of the pathways involved in the disease process. Our method integrates different data types to identify genes that have a single nucleotide polymorphism (SNP) disrupting a transcription factor binding site that modifies the outcome of BIPF. Our current approach examines over 7 million SNPs, phenotypes from 11 inbred mice strains, mRNA expression data, linkage data, and over 600 transcription factor binding sites from the TRANSFAC database. Each gene is scored with respect to each data type and then integrated using a weighted multiplicative model. Our integrative method produces a list of potential genetic modifiers that will be validated using allelic imbalance tests, existing knockout mice if available, siRNA or antibodies. By investigating these genes, we have identified several that are related to known genetic modifiers or others that make biological sense such as H2-Q2, an antigen presentation gene, and Runx1, a transcription factor known to interact with the known BIPF genetic modifiers Smad3 and Cdkn1a.
12
O'Donoghue, Robert Joseph James. "The role of directed gp130-mediated signalling in bleomycin-induced murine pulmonary fibrosis." University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2009.0111.
Full textAbstract:
[Truncated abstract] Fibrosis is a feature of many pulmonary conditions, including idiopathic pulmonary fibrosis (IPF), which is characterised by the accumulation of fibroblasts/myofibroblasts and excessive deposition of collagen. IPF is a disease of unknown aetiology that is unresponsive to current therapy and is typically fatal. The inflammatory cytokine interleukin (IL)-6 is elevated in patients with IPF and recent studies have shown that IL-6-induced signalling is altered in lung fibroblasts from patients with IPF. IL-6 belongs to the gp130 cytokine family, which is a group of ten structurally related cytokines, that all require the membrane bound glycoprotein gp130 to activate intracellular signalling pathways. Gp130 activates intracellular signalling through the Shp2-ERK1/2 and STAT1/3 pathways to mediate cellular activities. This thesis tests the hypothesis that gp130-mediated signalling is dysregulated in the development and progression of pulmonary fibrosis. To address this hypothesis, I assessed the role of gp130-mediated signalling in a mouse model of bleomycin-induced lung fibrosis. This thesis utilised two novel gp130 mutant mice strains with directed and enhanced gp130-mediated Shp2-ERK1/2 (gp130¿STAT/¿STAT) or STAT1/3 (gp130757F/757F) signalling. I observed complete protection from fibrosis in gp130¿STAT/¿STAT mice up to 60 days after bleomycin treatment and profound fibrosis in gp130757F/757F mice compared to wt controls. The enhanced fibrosis observed in gp130757F/757F mice was diminished by monoallelic deletion of STAT3 (gp130757F/757F;STAT3+/-), identifying gp130-STAT3 signalling as a novel promoter of lung fibrosis. ... In addition, IL-6/11 activation of gp130-mediated signalling modulated transforming growth factor (TGF)-ß-induced effects on adult fibroblast proliferation and myofibroblast differentiation. Interaction between IL-6/11 and TGF-ß1 on fibroblast proliferation was dependent on both the gp130-ERK1/2 and gp130-STAT1/3 pathways. Loss of either pathway abrogated the effects of IL-6 and IL-11 on TGF-ß1- 4 induced fibroblast proliferation. However, it was clear that gp130-STAT3 signalling inhibited TGF-ß1-induced myofibroblast differentiation of primary lung fibroblasts. The inhibition of myofibroblast differentiation was associated with gp130-STAT3 dependent inhibition of TGF-ß1-induced Smad3 phosphorylation. These results indicate that IL-6 and IL-11 promote myofibroblastic differentiation of lung fibroblasts, while gp130-STAT3 signalling inhibits TGF-ß1-induced Smad3 phosphorylation and myofibroblastic differentiation of lung fibroblasts While the pathogenesis of IPF is unknown, it is believed that excessive collagen deposition, aberrant fibroblast behaviour and an inflammatory response are critical to the progression of this disease. It has been shown here that IL-6 family cytokines mediate the development and progression of bleomycin-induced lung fibrosis by increasing collagen synthesis, fibroblast proliferation, myofibroblast differentiation and inflammation through gp130-STAT3 signalling. This thesis has demonstrated that differential activation of cytoplasmic signalling pathways by a membrane bound receptor can have a profound effect on pulmonary responses to injury. Furthermore, this thesis is the first study to identify the gp130-STAT3 pathway as a therapeutic target in the treatment of IPF.
13
Park, Sung-Hae 1971. "Role of endothelin-1 and endothelin converting enzyme-1 in bleomycin-induced pulmonary fibrosis in rats." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=24032.
Full textAbstract:
Idiopathic pulmonary fibrosis (IPF) belongs to the group of the interstitial lung diseases and is characterized by inflammation, proliferation of fibroblasts and type II pneumocytes, and increased collagen deposition. Inflammatory cells, by releasing mediators and cytokines, participate in the pathogenesis of IPF. Endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide, is one of the mediators that has been shown to be involved in the fibrotic process of IPF in humans. There are, however, no studies examining the role of ET-1 in animal models of IPF. We used the rat model of pulmonary fibrosis, induced by bleomycin, to study the role of ET-1 and endothelin converting enzyme-1 (ECE-1) in IPF using immunohistochemistry (IHC). We also studied by morphometry the effect of bosentan, the mixed ET-A/B receptor antagonist, on the severity of the fibrosis. We found increased ET-1 and ECE-1 immunoreactivities in the lungs of the fibrosis group compared with the control group (P $<$ 0.05), principally in epithelial cells. By morphometry, we found a decrease in the volume fraction (Vv) of air and an increase in the Vv of connective tissue in the fibrosis group compared with control. The fibrosis was significantly reduced by bosentan (P $<$ 0.05). These results are consistent with the notion that ET-1 is an important mediator of bleomycin-induced pulmonary fibrosis.
14
Ryynänen, Päivi. "Kinetic mathematical modesl for the 111In-labelled bleomycin complex and 10B in boron neutron capture therapy." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/fysik/vk/ryynanen/.
Full text
15
Iemmolo, Maria. "Effetti protettivi della Timosina-beta4 in un modello murino di danno polmonare da Bleomicina." Doctoral thesis, Università di Catania, 2013. http://hdl.handle.net/10761/1435.
Full textAbstract:
EFFETTI PROTETTIVI DELLA TIMOSINA-beta4 IN UN MODELLO MURINO DI DANNO POLMONARE DA BLEOMICINA
Background. La Timosina-beta4, isolata dal timo per la prima volta da Goldstain e collaboratori. nel 1966, è il membro più abbondante della famiglia delle beta-Timosine e risulta la principale proteina sequestrante l actina nella cellula. Ha attività biologica pleiotropica e le varie funzioni sono attribuite a particolari siti attivi contenuti nei peptidi prodotti da attività endoproteinasiche, come ad esempio nel frammento Ac-SDKP. Molti studi attribuiscono ad Ac-SDKP potere antinfiammatorio e alla forma ossidata della Timosina-beta4 (Timosina-beta4-sulfoxide) potere antiossidante. Inoltre, il trattamento di cellule cardiache con la Timosina-beta4 impedisce l espressione di geni profibrotici sia in vitro che in vivo.
In un recente studio sono state descritte elevate concentrazioni di beta-Timosine (Timosina-beta4, Timosina-beta4-sulfoxide, Timosina-beta10) nel BAL di una coorte di soggetti con sclerodermia a coinvolgimento polmonare. L ipotesi che la Timosina-beta4 possa esercitare un effetto cito-protettivo nel danno polmonare nasce dall osservazione che quando la concentrazione della proteina si abbassa si verifica una più veloce progressione dell interstiziopatia polmonare. Scopo di questa tesi è stato verificare i possibili effetti protettivi della Timosina-beta4 in un modello in vivo di fibrosi polmonare. Tali effetti risulterebbero particolarmente utili nella FPI, in particolare per rallentare la fase precoce del processo fibrotico, dove danni tissutali da ROS e da cellule infiammatorie concorrono attivamente all espressione del fenotipo fibrotico.
Materiali e Metodi. In questo studio è stato utilizzato il modello murino, molto noto ed utilizzato, di danno polmonare indotto da Bleomicina,, anche se per un periodo limitato a 7 giorni. I topi appartenenti al ceppo C57BL/6 sono stati trattati con Bleomicina (BLEO 1 mg/Kg) in assenza e/o in presenza di Timosina-beta4 (6 mg/kg per via intraperitoneale dal giorno di trattamento con BLEO e per ulteriori due dosi).
Dopo il sacrificio avvenuto una settimana più tardi, sono stati eseguiti: a) la misurazione del fluido e il contenuto di collagene del polmone; b) la conta cellulare e l analisi citobiologica differenziale nel lavaggio broncoalveolare (BAL); c) saggio per la misurazione dell attività mieloperossidasica; d) istologia polmonare; e) immunoistochimica (IHC); f) analisi al citofluorimetro (FACS) di cellule T estratte dal sangue periferico e dalla milza per la valutazione della percentuale di cellule positive per IL-17A, CD4, CD25 e Fox-p3.
Risultati. Nei topi co-trattati con Timosina-beta4 è stato osservato un calo del peso corporeo meno evidente e un tasso di mortalità più basso rispetto ai topi trattati con BLEO. Inoltre, l infiammazione e il danno polmonare indotti da BLEO sono stati ridotti grazie al co-trattamento con Timosina-beta4, cosi come dimostrato dalla riduzione significativa di: a) edema; b) contenuto di collagene totale, c) infiltrazione leucocitaria polmonare; d) attività mieloperossidasica; e) danno al polmone evidenziato dall' analisi istologica. Inoltre, i risultati dell' IHC mostrano una più forte reattività alla Timosina-beta4, con evidente localizzazione alveolare, in topi trattati con la proteina esogena rispetto ai topi trattati solo con BLEO. L analisi al FACS mostra una ridotta percentuale di cellule T positive per IL-17A ed un aumento della percentuale di cellule positive per CD4,CD25 e Fox-p3 nei topi trattati con Timosina-beta4 rispetto ai topi trattati con BLEO.
Conclusioni. Questo studio mostra un ruolo protettivo della Timosina-beta4 nel modello murino di danno polmonare indotto da Bleomicina e individua alcuni meccanismi immunologici che potrebbero determinarlo. Ulteriori studi sono necessari per valutare la durata degli effetti protettivi della Timosina-beta4 e il suo eventuale ruolo terapeutico.
16
Firth, G. B. "A study of the potential application of bleomycin entrapped within liposomes in the treatment of human cerebral gliomas." Thesis, University of Surrey, 1986. http://epubs.surrey.ac.uk/847431/.
Full textAbstract:
Human cerebral gliomas are the most commonly occurring form of brain tumour, yet treatment has only a marginal effect on the outcome, with poorly differentiated gliomas having a mean survival time of between six months and one year. In view of the large kinetic difference in cell division-rates of the tumour and normal brain tissue, chemotherapy might be expected to be effective in the treatment of this condition, yet the blood-brain barrier prevents the delivery of most chemotherapeutic agents at therapeutic concentrations to the tumour following systemic administration. Local injection of drug into the tumour has been attempted, but the vascularity of the glioma tissue bed is such that sufficiently high concentrations of drug cannot be sustained for an adequate period of time. An inert depot preparation of the drug injected locally, giving sustained release of drug at therapeutic concentrations, might be more effective and therefore an investigation has been made of the use of liposomes containing high concentrations of bleomycin as a means of achieving this goal. By careful study of the factors affecting incorporation of drugs within liposomes, high entrapment efficiencies of bleomycin have been achieved and these preparations have been shown to have similar dose-response curves against a glioma cell line as free preparations of the drug. Following intracerebral injection of bleomycin entrapped within liposomes in rats , no detectable cerebral toxicity could be demonstrated, and a delayed clearance of the drug from the injection site occurred as compared with local injection of similar concentrations of free bleomycin. Liposome-bleomycin preparations, when injected through Ommaya reservoirs into the residual tumour bed of patients with grade IV cerebral gliomas following surgery, were well tolerated with only minimal side effects being observed. Only very low concentrations of bleomycin appeared in the blood, and urinary clearance of the drug was considerably reduced as compared to when free drug was injected via the reservoir. These preliminary observations suggest a role for the local delivery of drugs entrapped within liposomes in the treatment of human cerebral gliomas.
17
Bantsimba-Malanda, Claudie. "Cellules dendritiques et fibrose pulmonaire : étude sur un modèle animal de fibrose induite par la bléomycine chez la souris." Thesis, Paris Est, 2009. http://www.theses.fr/2009PEST0059.
Full textAbstract:
Les cellules dendritiques, puissantes cellules présentatrices d'antigène, jouent un rôle-clé dans l'initiation et la régulation des réponses immunitaires et inflammatoires (Lipscomb et al., 2002). Elles sont présentes à l'état de cellules immatures dans la plupart des muqueuses, disséminées dans le tissu interstitiel et les épithéliums. Elles sont chargées de capter les antigènes exogènes, de les apprêter et de migrer vers les organes lymphoïdes pour les présenter aux lymphocytes T spécifiques. Au cours de cette migration, elles acquièrent les caractéristiques des cellules dendritiques matures présentes dans les organes lymphoïdes (expression forte des molécules HLA de classe II et des molécules de costimulation CD40, CD80, CD83, CD86). Les cellules dendritiques sont présentes dans le poumon normal (Vermaelen et al., 2005). Elles sont impliquées dans la physiopathologie de différentes maladies pulmonaires et jouent un rôle pathogénique essentiel dans certaines d'entre elles comme l'histiocytose langerhansienne ou l'asthme (Tazi et al ., 2000; Lambrecht et Hammad, 2003). Leur rôle au cours des processus fibrosants n'a cependant jamais été évalué. En effet, contrairement à d'autres cellules présentatrices d'antigènes que sont les macrophages, dont le rôle dans la réaction fibrosante est clairement établi (Agostini et al ., 1997), le rôle des cellules dendritiques au cours des processus de réparation alvéolaire n'a pas été étudié. Notre travail visait à étudier in vivo le rôle des cellules dendritiques au cours de la fibrose pulmonaire sur un modèle animal par induction d’une fibrose à la bléomycine chez la souris. Les premières étapes du projet ont consisté à caratériser par cytométrie en flux la présence de cellules dendritiques dans le poumon des animaux 3, 7 et 14 jours après instillation intratrachéale de bléomycine. L'étude s'est poursuivie par une caractérisation du phénotype de surface des cellules dendritiques en cherchant à préciser leur état d’activation et de maturation. L'étape suivante a consisté à rechercher par RT-QPCR les principales chimiokines responsables du recrutement des cellules dendritiques. Les résultats montrent une augmentation du nombre des cellules dendritiques CD11c+ / CMH II+ infiltrant le poumon dès J7, avec une sous-population de cellules activées exprimant fortement les molécules CMH II. Ces résultats sont corroborés par une augmentation de la population cellulaire totale du broyat de poumon dès J3, ainsi que par une augmentation de la cellularité totale et du nombre de cellules inflammatoires dans les lavages bronchoalvéolaires (LBA) à J7 et J14. L'étude a été complétée par une caractérisation plus approfondie du phénotype de surface des cellules dendritiques en cherchant à préciser leur état d’activation/maturation. [...]<br>Dendritic cells (DCs), potent antigen-presenting cells, play a key role in the initiation and regulation of immune and inflammatory responses (Lipscomb et al., 2002). Immature DCs are present in the most of mucous membranes, disseminated in the interstitial tissue and the epithelia. They are able to deal with exogenous antigens, to process them and to migrate to lymphoid organs and to present them to T lymphocytes. During their migration, they have the characteristics of mature DCs in lymphoid organs (higher expression of MHC class-II molecules and costimulation-molecules (CD40, CD80, CD83, CD86). Dendritic cells are present in the normal lung (Vermarlen et al., 2005). They are implicated in the pathophysiology of different pulmonary diseases and play a crucial pathogenic role in some of them like Langerhan’s cell Histiocytosis or asthma (Tazi et al., 2000; Lambrecht et Hammad, 2003). However, their role in the fibrosing process has never been studied. In fact, the role of macrophages (other antigen presenting cells (APCs)) in fibrosing reaction has been clearly established (Agostini et al., 1997), but DCs function during the alveolar healing process has not been studied. The purpose of this thesis is to study the in vivo role of DCs in bleomycin-induced pulmonary fibrosis in mice. The first step of this project is to demonstrate by flow cytometry the presence of DCs in the lung of these animals 3, 7 and 14 days after intratracheal bleomycin instillation. We continued our research with the surface phenotypic characterization of DCs identifying their activation state and maturation. The next step consists to search the main chemokines which are responsive for dendritic cells recruitment by RT-qPCR. Our results show an increase of CD11c+ / MHC class II+ DCs number infiltrating the lung after D7, with an activated cell subpopulation which strongly express MHC class II molecules. The results are corroborated by an increase of the total cell population in the lung homogenate after D3 and by an increase of the total cellularity and inflammatory cells number in broncho-alveolar lavages (BAL) at D7 and at D14. This study was completed by the surface phenotypic characterization of DCs identifying their activation state and maturation. [...]
18
Schumacher, Julian Verfasser], Andreas [Akademischer Betreuer] Ludwig, and Gabriele [Akademischer Betreuer] [Pradel. "Role of the proteases ADAM8, ADAM10 and ADAM17 in bleomycin induced lung inflammation / Julian Schumacher ; Andreas Ludwig, Gabriele Pradel." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1169915183/34.
Full text
19
Schumacher, Julian [Verfasser], Andreas Akademischer Betreuer] Ludwig, and Gabriele [Akademischer Betreuer] [Pradel. "Role of the proteases ADAM8, ADAM10 and ADAM17 in bleomycin induced lung inflammation / Julian Schumacher ; Andreas Ludwig, Gabriele Pradel." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1169915183/34.
Full text
20
Mabeta, Peaceful Lucy. "The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo." Thesis, University of Pretoria, 2008. http://hdl.handle.net/2263/24472.
Full textAbstract:
Angiogenesis, the process of new vessel formation, appears to be a central mechanism that underlies the development of haemangiomas. Recently, intralesional bleomycin injection was used to treat paediatric haemangiomas with very good results. The purpose of this study was to determine whether there was significant systemic circulatory spill-over of bleomycin in haemangioma patients treated with intralesional bleomycin to determine safety of use. Furthermore, in order to elucidate bleomycin’s mechanism of action in inducing haemangioma regression, this study aimed at determining the effects of bleomycin on aspects of angiogenesis, namely, endothelial cell migration, growth and apoptosis, and comparing these effects with those of drugs previously reported to inhibit various aspects of the angiogenic process (mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D). Lastly, the effects of bleomycin, mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D were studied in an animal haemangioma model. A rapid and highly sensitive high performance liquid chromatographic (HPLC) method was developed. Blood samples were collected from four haemangioma patients before and after (over a 24 hour period) intralesional bleomycin (IB) therapy. As a control, blood samples were also collected at identical time intervals from four patients undergoing intravenous (IV) bleomycin chemotherapy for various malignant tumours. The HPLC method was used to quantitate bleomycin fractions in patient samples. The mean bleomycin concentration detected in plasma samples obtained from IB treated patients was 0.00 ìg/ml for both bleomycin A<Sub>2 and B2 over the 24-hour period following therapy. Plasma bleomycin A2 and B2 levels of 360.79 and 158.85 ìg/ml respectively were detected in samples obtained from cancer patients treated with bleomycin IV. These findings indicate that the low levels detected may translate to a significantly lesser risk of pulmonary fibrosis following IBI. The effect of drugs on endothelial cell migration was analyzed by wounding a confluent monolayer of cells and determining the number of cells that had migrated from the wound edge. Endothelial cell growth was determined in cells treated with various drug concentrations while apoptosis was examined using hematoxylin and eosin staining, DNA fragmentation assay and acridine orange staining. The effect of test drugs on in vitro angiogenesis was determined on endothelial cells induced to form capillary-like tubes in collagen gel. Test drugs were then evaluated for antitumour activity in an animal haemangioma model. Data demonstrated that test drugs inhibited endothelial cell migration, with the exception of mitomycin C. All test drugs induced a reduction in the percentage of viable endothelial cell in a dose-dependant manner, and also induced endothelial cell apoptosis. The drugs inhibited angiogenesis in vitro and inhibited tumour development in vivo with varying potency. In general, results from this study indicated that there was negligible systemic spill-over of bleomycin following IB administration in patients with haemangiomas, suggesting a much lesser risk of developing bleomycin-induced pulmonary fibrosis. This study also showed that test drugs inhibited angiogenesis in vitro and haemangioma development in vivo in a mouse model. Taken together, these observations demonstrate that bleomycin may inhibit haemangioma growth by inhibiting angiogenesis. In addition, mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D may have potential in the treatment of haemangiomas of infancy, and should be investigated further in a murine haemangioma model to determine effective dose schedules.<br>Thesis (PhD)--University of Pretoria, 2009.<br>Physiology<br>unrestricted
21
Juknevičiūtė, Eglė. "Bleomicino pernaša į navikines ląsteles in vivo ir navikų gydymas taikant elektroporaciją ir sonoporaciją." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2012. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2012~D_20120620_150221-72168.
Full textAbstract:
Apie vėžį yra žinoma jau daug ir įvairios informacijos, taip pat netrūksta žinių ir kokiais būdais bei vaistais galima kovoti su šia liga. Farmacijoje yra atrasta ir sukurta nemažai aktyvių antivėžinių chemoterapinių preparatų vėžiui gydyti ar skirtų bent šios ligos slopinimui ir gyvenimo trukmės prailginimui. Todėl kita svarbi ir aktuali problema yra vaistų patekimas į reikiamą vietą – taikinį, kaip padėti vaistui patektį būtent į vėžines ląsteles ar audinį ir sumažinti riziką, kad vaistas pažeis normalius, sveikus audinius ir organus ir nepakenks jų funkcionavimui.
Šiame tiriamajame darbe ir stengiamasi atsakyti į šią problemą, pasitelkus du metodus, kurie palengvina medžiagų patekimą į ląsteles – elektroporaciją ir sonoporaciją. Šių metodų funkcija yra panaši, tiek elektroporacijos, tiek sonoporacijos metu ląstelių plazminėse membranose susiformuoja poros, pro kurias gali patekti įvairios medžiagos (vaistai, dažai, baltymai, genai), kurios natūraliu būdu į ląstelę nepatenka arba patenka labai maži jų kiekiai, jei pernašoje dalyvauja ląstelės membranoje esantys baltymai nešikliai.
Šiame darbe naudojami šie du, jau minėti metodai siekiant palengvinti chemoterapijoje naudojamo vaisto bleomicino patekimą į vėžines ląsteles in vivo. Tyrimams in vivo objektu buvo pasirinktos CBA – klono linijos pelės, kurioms į viršutinę nugaros dalį buvo įskiepyta MH22A hepatoma.
Eksperimento duomenys rodo, kad tiek elektroporacija, tiek sonoporacija ir suminis abiejų metodų poveikis yra... [toliau žr. visą tekstą]<br>There is a lot of various information about cancer as well as plenty of knowledge and types of drugs to treat this disease. Pharmacy has discovered and developed a number of active anti-cancer chemotherapeutic agents for cancer treatment, or at least useful for reducing the spread of cancer. Therefore, another important and urgent problem is development of new method that would help to deliver directly into cancer cells or tissue. This in turn would allow to reduce side effects of the drug and preserve healthy tissues and organs.
In this experimental work we attempted to answer this problem, using two methods that facilitate the transfer of materials into the cells - electroporation and sonoporation. These methods are based on similar principle: both electroporation and sonoporation affects the cell membranes to form pores that allow for various products (medicines, dyes, proteins, genes) to get access into the cell. The cell naturally is not accessible for those materials or the permeability is very small, in case special or nonspecific transport systems exist for this specific molecule.
In this study we used the following two methods in order to facilitate the anticancer drug bleomycin delivery into cancer cells in vivo. The subject of these experiments in vivo is CBA – line clone mice bearing MH22A hepatoma tumors, transplanted on upper part of the flank.
Experimental data showed that both electroporation and sonoporation and combination of both methods are effective in... [to full text]
22
FRAGNI, DEBORA. "Identification of novel readouts to assess anti-fibrotic efficacy of new compounds in a bleomycin-induced pulmonary fibrosis mouse model." Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1190103.
Full textAbstract:
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and very limited therapeutic options. To date, Pirfenidone and Nintedanib are the only two therapies approved for IPF worldwide. However, these drugs can slow-down lung function decline without really stopping or reverting the fibrotic process, and in addition their use is associated with a series of side effects. The incomplete understanding of the disease and the limitations of current treatments make IPF a disease with a high medical need requiring novel treatment approaches. For these reasons, the new drugs coming from the research and development pipelines will be crucial to get new treatments for patients.
Despite widely used, the current animal models of IPF need to be improved in order to be as much predictive as possible in identifying new promising treatments for pulmonary fibrosis. One of the most challenging aspects of drug discovery for IPF is the identification of new therapies that can be translated effectively to the clinic, implying that very few compounds that have shown efficacy in animal models have been successful in human clinical trials and concluding that most of the preclinical models are poorly predictive and scarcely resembling the human disease. Currently the majority of new drugs investigated in preclinical models of IPF are dosed using a prophylactic dosing regimen, whereas patients are almost always treated after the fibrosis is well established. Moreover, the most popular endpoints examined in preclinical models of IPF are histological scoring and lung collagen content; however, lung function tests are more commonly used as primary endpoints in IPF patients.
In this scenario, considering the high unmet medical need and some limits that the preclinical research has to face, the main goal of this PhD project was to generate a robust and reliable preclinical model of pulmonary fibrosis, introducing novel readouts, suitable to select and to identify new pharmacological treatments for IPF with an higher translational potential. The approach pursued by this study could be very impactful to identify new potential treatments for IPF. To achieve the goal of this PhD project, performed in collaboration with Chiesi Farmaceutici, we (1) reproduced the most described preclinical model for IPF, the bleomycin (BLM)-induced pulmonary fibrosis mouse model by intratracheal (IT) administration, and we analyzed its main limitations; (2) looking at the clinic, we optimized the BLM model with the introduction of clinically more relevant parameters (i.e., lung function tests, lung imaging, oximetry (Sp02), and fibrotic biomarkers) through a new BLM oropharyngeal (OA) protocol and finally, (3) we explored the added value of these more relevant readouts by investigating the efficacy of Nintedanib, which was tested under therapeutic regimen.
The characterization of the BLM IT model proved to be useful in better understanding the development of BLM-induced lung fibrosis and allowed to define the therapeutic protocol to test the anti-fibrotic efficacy of Nintedanib in the model; however, it highlighted several limitations such as a patchy distribution of fibrotic lesions and poor sensitivity to pharmacological treatment using the two traditional preclinical readouts, histology and hydoxyproline (Hyp) lung content.
Those limitations were overcome by the use of the OA administration of BLM which led to a more homogeneous fibrosis throughout the lung lobes and by the introduction of more clinically relevant endpoints such as micro-computer tomography (CT) imaging and lung function measurements that are the same tests used to diagnose and monitor patients with IPF, as well as of emerging biomarkers currently under evaluation in the clinical setting, with the final aim to create a link between the preclinical model and the clinical practice. All these new readouts showed the same profile over time observed with histology in terms of development of fibrotic disease, and Nintedanib was able to significantly modulate them, confirming their relevance for monitoring lung fibrosis as well as the efficacy of new treatments. Among them, the measurement of lung function, in particular the forced vital capacity (FVC), demonstrated to be the most sensitive readout to assess the compounds efficacy and was selected also in our preclinical studies as the primary endpoint as for clinical trials, thus creating an important link between the preclinical model and the clinical setting.
In addition, we also worked to refine the histological analysis which still remains an important complementary evaluation to be coupled to the functional readouts. Currently the common histological analysis utilized in preclinical models of lung fibrosis is represented by the Ashcroft scoring system, which revealed some disadvantages such as a time-consuming process, operator-dependent results, limited sensitivity and, most critical, inability to get a direct link to clinics. Therefore, we introduced an automated image analysis by using an artificial intelligence (AI) approach, which improved this analysis recognizing histological features with more accuracy and consistency, reducing significantly the time of the analysis and making the evaluation independent from the operator.
In summary, this project demonstrated that in the mouse BLM-induced lung fibrosis model it has been possible to explore the same clinically relevant parameters used in IPF patients; in particular lung function tests such as FVC, that for its high translational value together with the high sensitivity to assess the efficacy of the compounds has been chosen as the primary endpoint to support the selection of novel treatments within our internal drug discovery IPF projects. Furthermore, the introduction of these different readouts, that all go to the same direction, has from one side increased the robustness of the model and from the other side has allowed to bring this preclinical model to a level of complexity that mirrors the one observed in human IPF.
Overall, this PhD work has enhanced the translational value of the data obtained with the mouse BLM model increasing the chance of selecting promising compounds to advance to clinical trials and has concretely led to significant benefits to drug discovery process in the IPF research, improving the quality and the reliability of the search of novel anti-fibrotic drugs.
23
Gattazzo, Cristina. "Role of inflammation in the development of lung fibrosis and in the pathogenesis of pulmunary hypertension." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426484.
Full textAbstract:
ABSTRACT
Background: The bleomycin is a glycopeptide with antitumor and antiviral activity utilized in clinical for chemotherapeutic treatment of several neoplasms. Unfortunately the 10% of treated patients develops interstitial pneumonia that progresses to fibrosis. The fibrogenesis is linked to develop of a Th2 cellular response with proinflammatory chemokines release.
Glycogen Synthase Kinase 3 (GSK-3) is a pivotal element for the control of immune response because modulates the inflammatory cytokines production. Since lung injury caused by bleomycin is characterized by an inflammatory response followed by a fibrotic degeneration, we postulated that blocking GSK-3 kinase activity with a specific inhibitor could affect the bleomycin-induced pulmonary inflammatory and pro-fibrotic cytokine network. Moreover it has been demonstrated that the develop of pathologies which elicit a Th2 inflammatory response could be mitigated by agents able to induce a Th1 immune response. Indeed administration of Neutrophil-Activating Protein of Helicobacter pylori (HP-NAP) was found to be able to down modulate the Th2 immune response in a asthma ovalbumin-induced model mouse by eliciting a Th1 immune response and resulted effective in preventing allergic asthma in the model mouse.
Purpose of the study: We investigated the effects of the specific and selective ATP-competitive GSK-3 inhibitor, SB216763, and the effects of HP-NAP administration on the onset and development of inflammation and fibrosis in a bleomycin-induced lung fibrosis mouse model.
Methods: We differently randomised cohorts of C57BL6 mice to receive intratracheal instillation of inhibitor SB216763, HP-NAP, bleomycin, bleomycin plus SB216763 or bleomycin plus HP-NAP and followed their health status for 28 days. Bronchoalveolar lavage (BAL) was performed and mice were sacrificed at different interval times (2, 7, 14 and 28 days). Histopathological analysis of the lungs, flow-cytometry studies and Cell Sorting of BAL pulmonary monocytes were then performed. Finally we examined cytokines gene expression levels in lung monocytes trough Real Time PCR analysis.
Results: SB216763 and HP-NAP administration prevented lung inflammation and the subsequent fibrosis when co-administrated with bleomycin. BALF analysis of mice revealed a significant reduction in bleomycin-induced alveolitis. SB216763 treatment was associated with a significantly lower production of inflammatory cytokines (TNF-α and CCL12) by macrophages. Moreover we observed that HP-NAP administration downmodulated the Th2 inflammatory response bleomycin-induced by eliciting a Th1 phenotype (downmodulating IL-4 chemokine and upregulating the IFN-γ).
Conclusions: These findings suggest that GSK-3 inhibition induces a protective effect on lung fibrosis triggered by bleomycin and candidate GSK-3 as a potential therapeutic target for preventing pulmonary fibrosis. Furthermore our results suggest that also HP-NAP, preventing lung fibrosis develop, might be a possible new tool for therapeutic strategies aimed to redirect Th2 into less aggressive Th1 response.<br>RIASSUNTO
Background: La bleomicina è un glicopeptite con attività antitumorale e antivirale utilizzata in clinica come chemio-terapico per il trattamento di diversi tumori. Sfortunatamente il 10% dei pazienti trattati sviluppa polmonite interstiziale che progredisce in fibrosi. La fibrogenesi è collegata allo sviluppo di una risposta immunitaria di tipo Th2 accompagnata dal rilascio di chemiochine pro-infiammatorie.
La Glicogeno Sintetasi Chinasi 3 (GSK-3, Glycogen Synthase Kinase 3)
è un fattore centrale per il controllo della risposta immunitaria poiché modula la produzione di citochine infiammatorie. Visto che il danno polmonare è caratterizzato da una risposta infiammatoria seguita da una degenerazione fibrotica, noi abbiamo ipotizzato che l’inibizione dell’attività di GSK-3, tramite uno specifico inibitore, potrebbe influenzare l’infiammazione del polmone ed il network di citochine pro-infiammatorie indotti dalla bleomicina. Recentemente è anche stato visto che lo sviluppo di patologie sostenute da un’infiammazione di tipo Th2 possono essere mitigate da agenti in grado di indurre una risposta infiammatoria di tipo Th1. In accordo con questi risultati la proteina attivante i neutrofili, prodotta dal batterio Helicobacter pylori (HP-NAP), stimolando una risposta immunitaria di tipo Th1, si è dimostrata capace di modulare la risposta immunitaria di tipo Th2 indotta dall’ ovalbumina in un modello murino di asma, risultando quindi efficace nel prevenire lo sviluppo dell’asma allergica.
Scopo dello studio: In questa ricerca abbiamo investigato gli effetti della somministrazione dell’inibitore SB216763, specifico per GSK-3, e della somministrazione della proteina HP-NAP nello sviluppo dell’infiammazione e della fibrosi nel modello murino di fibrosi polmonare indotta da bleomicina.
Metodi: Differenti coorti di topi C57BL6 sono state randomizzate per ricevere instillazione di SB216763, HP-NAP, bleomicina, bleomicina più SB216763 o bleomicina più HP-NAP, ed il loro stato di salute è stato monitorato per 28 giorni. I topi sono stati sacrificati ed i lavaggi broncho alveolari (BALs) eseguiti a diversi intervalli di tempo (a 2, 7, 14 e 28 giorni). Quindi sono stati eseguiti l’analisi istopatologia dei polmoni e valutazioni citoflurimetriche del BAL. Infine sono stati esaminati, tramite Real Time PCR, i livelli di espressione genica delle citochine nei monociti di polmone purificati dai BALs tramite sorting.
Risultati: La somministrazione dell’inibitore SB216763 e della proteina HP-NAP, quando co-somministrati con la bleomicina, sono stati in grado di prevenire l’instaurarsi dell’infiammazione e il conseguente sviluppo di fibrosi nel polmone. L’analisi dei BALs ha infatti rivelato una significativa riduzione dell’alveolite indotta dalla bleomicina. Il trattamento con l’SB216763 si è associato con una ridotta produzione, da parte di macrofagi, di citochine infiammatorie (TNF-α and CCL12), mentre la somministrazione di HP-NAP ha down-modulato la risposta infiammatoria di tipo Th2 indotta dalla bleomicina, stimolando il tipo Th1(diminuendo il livello di espressione delle chemiochina IL-4 ed aumentando invece quello di IFN-γ).
.Conclusioni: I risultati ottenuti in questo progetto di ricerca suggeriscono che l’inibizione di GSK-3 ha un effetto protettivo nella fibrosi polmonare indotta dalla bleomicina e candidano GSK-3 come potenziale target terapeutico per prevenire la fibrosi polmonare; inoltre suggeriscono che la proteina HP-NAP, prevenendo lo sviluppo della fibrosi polmonare tramite l’induzione di una risposta di tipo Th1, potrebbe essere una nuova strategia terapeutica per ridirezionare la risposta infiammatoria dal fenotipo Th2 verso quello meno aggressivo Th1.
24
Sweetman, Sandra Frances. "An investigation of bleomycin induced DNA damage and repair in wild-type and thymidine kinase deficient human and murine cell lines." Thesis, University of Ulster, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242069.
Full text
25
Chen, Jingyang Ph D. Massachusetts Institute of Technology. "Mechanistic studies of bleomycin-mediated double-stranded DNA cleavage and structural studies of DNA containing normal and 4'-oxidized abasic sites." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/34498.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006.<br>Vita.<br>Includes bibliographical references.<br>In order to examine the role of partial intercalation in double-stranded (ds) DNA cleavage mediated by a single bleomycin (BLM), a bulky group ([-cyclodextrin) was chemically attached to the polyamine tail of BLM A5 to prevent the intercalation of the bithiazole tail. The ability of this analog (CD-BLM) to effect ds-DNA cleavage was quantitatively analyzed using the internally [132P-labeled hairpin DNA technology and the supercoilded DNA relaxation assay. CD-BLM can mediate both ss and ds-DNA cleavage, although 5-fold less efficient than BLM A5. Analysis of DNA cleavage by CD-BLM with competitive BLM-Co(III)-OOH indicates that the ds-DNA cleavage is mediated by two CD-BLM molecules, suggesting that the partial intercalation is essential for one BLM molecule to mediate ds-DNA cleavage. A "hot spot" for blunt-ended ds-cleavage by BLM (5'-GTCA-3'/3'-CAGT-5') has been identified in an effort to obtain structural insights into the mechanism of the blunt-ended ds-DNA cleavage. A 3'-phosphoglycolate/5'-phosphate (3'PG/5'P) gapped lesion in this "hot spot" has been synthesized to probe the structural basis for re-organization of BLM to the second cleavage site. This lesion was titrated with BLM-Co(III)-OOH. The resulting mixture of complexes was in fast exchange on the NMR time scale, which precluded further structural characterization.<br>(cont.) In order to understand the mechanism(s) of recognition and repair of DNA lesions generated by BLM, a duplex DNA containing a 4'-oxidized abasic site (X) in d(CCAAAGXACCGGG)-d(CCCGGTACTTTGG) (1) was synthesized and characterized by 2D NMR spectroscopy and molecular modeling. The results indicate that the 4'- oxidized abasic site adopts an intrahelical conformation, in contrast to a normal abasic site in the same sequence context, which is partially extrahelical. A systematic structural characterization was performed using 2D NMR methods and molecular modeling on an oligonucleotide containing a normal abasic site (Y) with four different bases (A, G, T, or C) opposite the lesion in d(CCAAAGYACCGGG). The results suggest that the conformation in the abasic site region is more perturbed with a pyrimidine opposite the abasic site. This study provides the first structural insight into the dynamics of abasic sites that are intrinsically modulated by the opposite and neighboring bases.<br>by Jingyang Chen.<br>Ph.D.
26
Nowrotek, Agata [Verfasser], and Michael [Akademischer Betreuer] Pfeifer. "Untersuchung zur Bedeutung der prophylaktischen und therapeutischen Gabe von Simvastatin bei Bleomycin induzierter Lungenfibrose am Tiermodell / Agata Nowrotek. Betreuer: Michael Pfeifer." Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1053555490/34.
Full text
27
Resch, Johannes [Verfasser], and Michael [Akademischer Betreuer] Pfeifer. "Auswirkungen des Endothelinrezeptorantagonisten Bosentan auf die Leistungsfähigkeit bei pulmonaler Hypertonie im Tiermodell der Bleomycin-induzierten Lungenfibrose / Johannes Resch. Betreuer: Michael Pfeifer." Regensburg : Universitätsbibliothek Regensburg, 2015. http://d-nb.info/1071713299/34.
Full text
28
Van, Houtte Paul. "Etude expérimentale de l'effet des irradiations et des agents chimiothérapiques sur le poumon et le métabolisme du surfactant." Doctoral thesis, Universite Libre de Bruxelles, 1985. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/241286.
Full text
29
Brunner, Carlos Henrique Maciel. "Avaliação do comportamento vascular do tumor de Ehrlich na forma sólida em camundongos submetidos à eletroquimioterapia com bleomicina." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-26012016-160046/.
Full textAbstract:
A eletroquimioterapia (EQT) é uma modalidade de tratamento recente que se baseia na associação de quimioterápicos potencializados pela eletroporação. Possui indicação para neoplasias sólidas de origens histológicas distintas, apresentando baixa morbidade e elevada eficiência. A ação da EQT ocorre em múltiplos sítios, tanto envolvendo a quebra da molécula de DNA, quanto exercendo efeito sobre a vasculatura tumoral. No presente estudo buscou-se maior compreensão dos eventos vasculares, avaliando-se qualitativamente e quantitativamente, com auxílio de marcação imunológica, com fator VIII e VEGF-A, a vascularização do tumor de Ehrlich implantado na forma sólida em camundongos, não tratados e submetidos à EQT com bleomicina, após sete dias de tratamento. No intuito de melhor elucidar os fenômenos vasculares, também foi investigado o efeito do resveratrol associado à EQT. O resveratrol, presente em vegetais como as uvas, possui efeitos de inibição do HIF1-α, reconhecida proteina que estimula a angiogênese em condições de hipoxia tumoral. Os animais submetidos à quimioterapia com bleomicina não apresentaram redução de volume tumoral, ao contrário dos que sofreram EQT com o mesmo fármaco. Evidenciou-se maior densidade microvascular tumoral em animais tratados com quimioterapia, quando comparados aos não tratados e aos submetidos à EQT. O tratamento com resveratrol diminuiu a expressão de VEGF-A e obteve efeito mais pronunciado quando associado à EQT com bleomicina. Através dos fenômenos pesquisados pôde-se evidenciar que a EQT com bleomicina foi efetiva na redução do volume do tumor de Ehrlich e que houve redução da atividade proliferativa assim como da densidade microvascular tumoral. Também observou-se que o resveratrol, ainda mais quando associado à EQT com bleomicina, reduz a proliferação tumoral e a expressão de VEGF-A<br>The electrochemotherapy (EQT) is a new treatment modality based on the association of chemotherapy potentiated by electroporation. Has indication for solid neoplasms of histological distinct origins, presenting low morbidity and high efficiency. The action of the EQT occurs in multiple sites, both involving the breakage of the DNA molecule, as having an effect on the tumor vasculature. The present study aimed at better understanding of vascular events, evaluating qualitatively and quantitatively, using immune labeling, with factor VIII and VEGF-A, the vascularization of the Ehrlich tumor implanted in solid form in mice, untreated and submitted to EQT with bleomycin, after seven days of treatment. In order to better elucidate the vascular phenomena, was also investigated the effect of resveratrol associated with EQT. The resveratrol present in plants such as grapes, has inhibitory effects of HIF1-α, a protein that is recognized to stimulates angiogenesis in tumor hypoxia. The animals submitted to chemotherapy with bleomycin showed no reduction of tumor volume, unlike those who suffered EQT with the same drug. It was evidenced increased microvessel density tumor in animals treated with chemotherapy, when compared to untreated and those submitted to EQT. The treatment with resveratrol decreased the expression of VEGF-A and obtained effect was more pronounced when associated to the EQT with bleomycin. This research can prove that the EQT with bleomycin was effective in reducing the volume of Ehrlich tumor and that there was a reduction of proliferative activity as well as of microvascular density tumor. Also it was observed that the resveratrol, even more when associated with EQT with bleomycin, reduces the tumor proliferation and the expression of VEGF-A
30
Lehmann, Heinz [Verfasser], and Michael [Akademischer Betreuer] Pfeifer. "Therapie mit dem HMG-CoA-Reductase-Hemmer Simvastatin bei Lungenfibrose und pulmonaler Hypertonie im Bleomycin-Tiermodell der Ratte / Heinz Lehmann. Betreuer: Michael Pfeifer." Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1062770188/34.
Full text
31
Alnajar, Abdulaleem [Verfasser], and Viktor [Akademischer Betreuer] Wixler. "The role of the Four and a half LIM only protein 2 (FHL2) in bleomycin induced lung fibrosis / Abdulaleem Alnajar ; Betreuer: Viktor Wixler." Münster : Universitäts- und Landesbibliothek Münster, 2013. http://d-nb.info/1141383721/34.
Full text
32
Grabarz, Felipe. "Células NKT, macrófagos M2 e o desenvolvimento da fibrose pulmonar." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-20022015-171616/.
Full textAbstract:
A fibrose pulmonar é uma via comum de várias doenças agudas e crônicas do interstício pulmonar que pode resultar na cicatrização anormal do pulmão. Há acúmulo excessivo das proteínas da matriz extracelular levando a desestruturação das paredes alveolares, e consequente perda das trocas gasosas pelos pulmões. As células NKT são grande fonte de citocinas e podem ser cruciais na polarização de macrófagos para o fenótipo M2. O projeto tem a hipótese de que as células NKT podem influenciar o desenvolvimento da fibrose pulmonar via modulação de macrófagos. Para isso, animais selvagens e knockout para células NKT invariante (Ja18-/-) foram submetidos ao protocolo de indução de fibrose pulmonar pela bleomicina. Os resultados indicam que o grupo Ja18-/- assim como os grupos experimentais que receberam agonistas para células NKT apresentaram uma proteção contra a fibrose pulmonar uma vez que houve menor síntese de hidroxiprolina, deposição de colágeno, citocinas pró-fibróticas e a manutenção de macrófagos M1 no tecido pulmonar.<br>Pulmonary fibrosis is a common pathway of various acute and chronic interstitial lung diseases that may result in abnormal healing of the lung. There is excessive accumulation of extracellular matrix proteins, leading to disruption of the alveolar walls and the consequent loss of gas exchange through the lungs. NKT cells are a big source of cytokines and may be crucial in the polarization of macrophages to the M2 phenotype. This project has hypothesized that NKT cells can influence the development of pulmonary fibrosis through modulation of macrophages. For this, wild and knockout invariant NKT cells (Ja18-/-) mice were subjected to the protocol of bleomycin induced pulmonary fibrosis. The results indicate that the group Ja18-/- as well as the experimental groups receiving agonists for NKT cells showed protection against lung fibrosis since there was less synthesis of hydroxyproline, collagen deposition, pro-fibrotic cytokines and maintenance of macrophages M1 in lung tissue.
33
Wappler, Juliane Christin. "Untersuchung somatischer Chromosomenveränderungen bei amyotropher Lateralsklerose." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2006. http://dx.doi.org/10.18452/15491.
Full textAbstract:
Die ALS ist eine fortschreitende neurodegenerative Erkrankung, deren Symptome durch den Untergang der Motoneuronen bedingt sind. Neueste zytogenetische Untersuchungen zeigen ein vermehrtes Auftreten konstitutioneller Chromosomenveränderunge bei ALS-Patienten. Dies lässt eine Verbindung zwischen dem Ausbruch der Erkrankung und der auffälligen Zytogenetik vermuten. Das Auftreten spontaner Chromosomenveränderungen als Zeichen einer chromosomalen Instabilität wurde in der vorliegenden Arbeit an ALS-Patienten untersucht. METHODE: Neben der Karyotypisierung, der Bestimmung der SCE-Rate und der Bruchrate nach Behandlung mit Bleomycin kam die Fluoreszenz in situ Hybridisierung zum Einsatz. Die Untersuchungen wurden an Patienten mit sporadischer ALS (45), an Kontrollpersonen (38) und Verwandten (9) durchgeführt. ERGEBNISSE: Die Karyotypisierung ergab bei den Patienten eine spontane Translokationsrate von 0,02 Translokationen/Zelle (t/Z), bei den Kontrollen 0,04 t/Z. Weitere numerische oder strukturelle Auffälligkeiten waren nicht signifikant verschieden. Es wurden keine konstitutionellen Chromosomenaberrationen gefunden. Die Häufigkeit der Schwesterchromatidaustausche (SCE-Rate) bewegte sich mit 7-8 SCE/Z in der Patientengruppe innerhalb der Normwerte. Durch die Zugabe von Bleomycin in die Zellkultur stieg die Zahl der Chromatidbrüche von 0,0 auf 0,8 Brüche/Z an. Dabei zeigten die untersuchten Gruppen ähnliche Progredienzen in den Bruchraten. Mit der Fluoreszenz in situ Hybridisierung werden quantitative Aussagen über spontane Translokationsraten gemacht. Sie betrug in der Kontroll-und Patientengruppe 0,03 bis 0,04 t/Z. DISKUSSION: Die vorliegenden Ergebnisse liefern keinen Anhalt für eine chromosomale Instabilität als Risikofaktor für die Entstehung der sporadischen ALS. Indizien für eine chromosomale Instabilität wie erhöhte Bruchraten und SCEs als auch vermehrtes Auftreten somatischer Aberrationen konnten bei den ALS-Patienten nicht nachgewiesen werden. Über mögliche Auffälligkeiten in den Motoneuronen lässt sich allerdings mit den Untersuchungen an Blutlymphozyten keine hinreichend sichere Aussage machen.<br>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which is characterized by the degeneration of motor neurons. Recently, a high rate of constitutional structural chromosomal rearrangements has been reported in apparently sporadic ALS patients. It remains questionable whether or not these genomic rearrangements are caused by a chromosomal instability involved in the pathogenesis of the disease. Therefore, we performed different cytogenetic studies on chromosomal instability. METHOD: We performed chromosome analyses from patients (N=45), control subjects (N=38), and relatives (N=9) after culturing blood lymphocytes. Conventional chromosome analysis after GTG-banding, chromosomal breakage test after Bleomycin treatment, the rate of sister chromatid exchange (SCE), and whole chromosome painting were used for these analyses. RESULTS: Neither karyotyping nor whole chromosome painting revealed higher levels of structural or numerical aberrations in lymphocytes of patients with sALS. After karyotyping we found 0.02 t/cell in patients and 0.04 t/cell in controls. Whole chromosome painting revealed 0.04 t/cell in patients and 0.03 t/cell in controls. The chromosomal breaks increased likewise after Bleomycin treatment in the control group and the patient group as well. Cell cultures without Bleomycin did not show any breaks while the highest Bleomycin concentration induced up to 0.08 breaks/cell. The SCE rate in patients which corresponds to the chromatid repair activity did not rise to a higher level than in the control individuals. Both groups were in the normal range of 7 to 8 SCE/cell. DISCUSSION: The pathomechanism of neurodegeneration in ALS patients is still unknown. We tried to find a cytogenetic correlative being a risk factor for the development of ALS. However, so far there is no clue for chromosomal instability being involved in the neurodegenerative process.
34
Pinart, Gilberga Mariona. "Time course of biochemical, biomechanical, and histological changes for the assesment of inflammation and remodelling in a bleomycin-induced murine model of lung injury." Doctoral thesis, Universitat de Barcelona, 2009. http://hdl.handle.net/10803/1140.
Full textAbstract:
Las enfermedades pulmonares intersticiales difusas (EPID), constituyen un grupo variado de trastornos inflamatorios difusos de las vías aéreas inferiores causadas por inflamación, fibrosis (cicatritzación) de las paredes alveolares y grosor del espacio intersticial. Como muchas de estas EPID dan lugar a la formación de fibrosis, también se las llama fibrosis pulmonar (FP). Tanto la fisiopatología de la enfermedad como los mecanismos bioquímicos que se desencadenan son poco conocidos. La lesión pulmonar inducida por fármacos como la bleomicina, es heterogénea y rápida en su inicio, con una fase de alveolitis inicial caracterizada por la presencia de edema intersticial y de infiltración de células inflamatorias como los neutrófilos, macrófagos y limfocitos, que a su vez conducirán a una proliferación de los fibroblastos. Después hay una segunda fase, más fibrótica, que se caracteriza por la deposición de colágeno y de otros componentes de la matriz extracelular que resultarán en una distorsión de la arquitectura pulmonar. <br/><br/>Como creemos que los parámetros biomecánicos pueden ser de gran utilidad en el seguimiento de las estrategias terapéuticas así como también del conocimiento general de la historia natural de las EPID, queremos saber cuál es la influencia de la respuesta inflamatoria en las diferentes fases evolutivas de la FP sobre la biomecánica del parénquima. Por eso utilizamos un modelo murino de lesión pulmonar de dos semanas o de un mes de durada, inducida por dosis única o dosis repetidas de bleomicina respectivamente. <br/><br/>En el primer trabajo, utilizamos tiras de paánquima pulmonar para el estudio biomecánico (elastancia, resistencia (R0) e histeresividad (mi(0)) los días 3, 7 y 15 después de una instilación única sub-letal de bleomicina. Se analizaron también el impacto de la inflamación pulmonar (mieloperoxidasa (MPOL), índice de inflamación pulmonar (LI) y el contenido de agua pulmonar (WL)) y de la remodelación pulmonar (hidroxiprolina (HPL) y fibras elásticas) en los mismos días en los que se hizo el estudio mecánico. Los hallazgos más significativos sugieren que este modelo proporciona nuevas evidencias para la comprensión de la fisiopatología de la lesión pulmonar inducida por bleomicina y la relación entre los cambios inflamatorios y la mecánica del tejido pulmonar. Los parámetros disipativos del tejido pulmonar se vieron modificados después de la lesión: tanto R0 como mi(0) estuvieron correlacionadas con la MPOL, WL y LI. No encontramos correlaciones significativas entre HPL y los parámetros mecánicos, pero si de la elastina con mi(0) i el grosor de la paret alveolar. <br/><br/>En el segundo trabajo, usamos tiras de parénquima pulmonar para hacer el estudio mecánico el día 28 después de una instilación única sub-letal o después de tres dosis de bleomicina cada dos semanas. Se analizó el impacto de la inflamación pulmonar (MPOL y LI) y de la remodelación pulmonar (fibras de colágeno) en los mismos días en que se hizo el estudio mecánico. En el modelo de tres dosis repetidas por bleomicina se halló una infiltración de células inflamatorias, un incremento de la MPO y de las fibras de colágeno, la presencia de focos fibroblásticos y un aumento tanto de la elastancia (H) como de la amortiguación tisular (G), 28 dáas después de la última dosis. Sin embargo, en el modelo de dosis única, el colágeno aumentó sin que hubiesen cambios significativos en la mecánica pulmonar.
35
Ehlebracht, Catharina [Verfasser], and Oliver [Akademischer Betreuer] Eickelberg. "Monitoring der Bleomycin-induzierten Lungenfibrose durch repetitive Lungenfunktionsmessung im Maus-Modell und die Rolle der Protein-Arginin Methylierung für die Fibroseentwicklung / Catharina Ehlebracht ; Betreuer: Oliver Eickelberg." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1182228550/34.
Full text
36
Andrade, Lara Filipe Rocha. "Hereditary hemochromatosis: cellular response to oxidative stress." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12495.
Full textAbstract:
Mestrado em Bioquímica - Bioquímica Clínica<br>Iron is a key element for basic cellular functions. If iron homeostasis is not maintained it may lead to iron overload. Patients with Hereditary Hemochromatosis (HH) and with the C282Y HFE mutation have a progressive severe iron overload that, if it is not treated, may lead to tissue damage, that mostly culminate in hepatic cirrhosis and carcinoma. Having in mind that tissue damage in HH may be related with oxidative stress (OS) caused by iron toxicity, it is important to understand in what way the OS defense is acting in cells from HH patients with severe forms of iron overload. Few studies have been performed concerning the eventual prooxidant state in blood cells, which bear a major source of OS. Nevertheless, in a recent study it was shown that cultured lymphocytes (LY) from HH, when compared with cultured LY from controls and patients with secondary forms of hemochromatosis, have an increased protection against chromosome instability (CI) induced by 1,2:3,4 diepoxybutane (DEB) – an OS-related alkylating agent. This suggests an adaptive response of HH cells to the high level of OS. However, it is not known yet if the same response can be observed with other sources of iron toxicity, namely in the presence of bleomycin (BLM), that acts forming a complex with non-transferrin bound iron (NTBI).
In order to better understand the oxidant status of HH blood cells and the putative adaptive response of HH cells to iron toxicity, a study was performed to characterize two selected OS parameters: evaluation of reduced glutathione (GSH) depletion and of lipid peroxidation (LPO). The study was performed in red blood cells (RBC) and lymphocytes (LY), either basal and after 36h in culture, with and without induction of OS. Induction of OS was performed with DEB and with BLM. A second objective of the present work was to test if the previously observed adaptive response of HH cells to DEB-induced OS can also be observed after induction with BLM.
Characterization of the OS parameters was performed in RBC and LY from 5 HH patients with severe iron overload and 6 healthy donors (HD), at day 0 and after 36h of culture, non-treated and treated with DEB or BLM. Studies of CI were performed in BLM-induced LY from the same 5 HH patients and 6 HD.
The results show that RBC from HH patients, compared with those from HD, have a larger GSH depletion and more LPO, either at day 0 and after 36h in culture medium. This suggests an increased level of OS in HH RBC. On the contrary, LY from HH patients present less GSH depletion after 36h of culture than LY from HD, being this effect more pronounced in DEB and BLM-treated cultures. Additionally, LPO levels were decreased in LY from HH patients after 36h of culture when compared with LY from HD. This result suggests that HH cultured LY, either non-treated or treated with DEB and BLM, have a still not completely understood mechanism of defense against OS. BLM-induced CI in cultured LY from HH patients was not different from the observed in cultured LY from HD. Therefore, we can postulate that toxicity induced by BLM did not increased CI in cells from HH patients with severe iron overload.<br>O ferro é um dos elementos chave para as funções celulares básicas. Se a sua homeostasia não for corretamente mantida, poderá ocorrer uma sobrecarga de ferro no organismo. Os doentes com Hemocromatose Hereditária (HH), com a mutação C282Y no gene HFE, possuem uma progressiva e severa sobrecarga de ferro que, se não for tratada, pode levar a dano nos tecidos, podendo mesmo culminar em cirrose hepática e carcinoma. Tendo em conta que o dano tecidular pode estar associado ao stress oxidativo (OS) causado pela sobrecarga de ferro, é importante perceber de que modo atua o sistema de defesa contra o OS nas células dos doentes HH com forma severa de sobrecarga de ferro. Poucos estudos foram realizados sobre o potencial estado oxidante nas células do sangue, onde se encontra uma das maiores fontes de reações oxidativas. Contudo, num estudo recente foi demonstrado que linfócitos de doentes com HH, quando comparados com linfócitos de controlos e pacientes com formas secundárias de hemocromatose, apresentam uma maior proteção relativamente à instabilidade cromossómica (CI) induzida por 1,2:3,4 diepoxibutano (DEB) – um agente alquilante que provoca OS. Este estudo sugere uma resposta adaptativa das células HH a níveis elevados de OS. No entanto, ainda não se sabe se esta mesma resposta pode ser observada com outras fontes de toxicidade do ferro, nomeadamente na presença de bleomicina (BLM) cuja atividade depende da formação de complexos com o ferro não ligado à transferrina (NTBI).
Para compreender melhor o estado oxidante das células do sangue dos doentes HH e a suposta resposta adaptativa das células dos doentes de HH à toxicidade do ferro, foi feita a análise de dois parâmetros de OS selecionados: avaliação da depleção da glutationa reduzida (GSH) e da peroxidação lipídica (LPO). Esta análise foi efetuada em eritrócitos (RBC) e linfócitos (LY), tanto no tempo 0 como passadas 36h em cultura, com ou sem indução de OS. O segundo objetivo deste trabalho foi testar se a BLM promove uma resposta adaptativa à CI comparável à que foi observada com o DEB.
Tanto a caracterização dos parâmetros de OS como os estudos de CI foram efetuados em células de 5 doentes com HH, com elevada sobrecarga de ferro, e em células de 6 dadores saudáveis (HD).
Os resultados mostraram que os RBC dos doentes com HH, comparativamente com os dos HD, apresentam uma maior depleção de GSH e maior LPO, quer ao dia 0 quer após 36h em meio de cultura. Estes resultados sugerem um aumento de OS nos RBC dos doentes. Contrariamente, os LY dos doentes de HH apresentaram menor depleção de GSH após 36h de cultura, sendo esta mais notória nas culturas induzidas com DEB e BLM. Adicionalmente, os níveis de LPO são menores em LY dos doentes de HH, após 36h de cultura, comparativamente com os dos HD. Isto sugere que culturas de LY, quer não-tratadas quer tratadas com DEB ou BLM, têm um algum tipo de mecanismo de defesa contra o OS, ainda não compreendido. A frequência de CI induzida por BLM em LY de doentes com HH não é significativamente diferente da observada em LY de HD, não se observando assim uma diferença na capacidade de resposta à BLM, entre células de doentes e controlos. Pode-se então concluir que a toxicidade induzida por BLM não aumenta a CI em células de doentes com HH com forma severa de sobrecarga de ferro.
37
Choi, Seojin. "Flaxseed oil and prevention of pulmonary fibrosis." Diss., Kansas State University, 2012. http://hdl.handle.net/2097/15106.
Full textAbstract:
Doctor of Philosophy<br>Department of Human Nutrition<br>Richard C. Baybutt<br>Weiqun George Wang<br>Although omega-3 fatty acids have been a hot issue in nutrition for years, there remains a
paucity of research on the topic of omega-3 fatty acid and pulmonary fibrosis and the mechanism
is still unclear. The purpose of this research is to investigate the preventive effects of flaxseed oil
for bleomycin-induced pulmonary fibrosis in rats and to find the possible underlying
mechanisms. There are two experiments demonstrated in this dissertation, one is with various
doses of flaxseed oil in the diet (0, 2.5, 5, 7.5, 10, 12.5, and 15 % (w/w)), and the other is with
different times of sacrificing animals after oropharyngeal bleomycin treatment (days 7 and 21).
In the first study, three proteins including transforming growth factor-[beta] (TGF-[beta]),
interleukin-1 (IL-1), and [alpha]-smooth muscle actin ([alpha]-SMA), commonly associated with fibrotic
inflammation in the lung, were examined by Western blot and fatty acids composition of the
diets and tissues were analyzed by gas chromatography (GC). Fifteen percent of flaxseed oil
group significantly reduced septal and vascular thickness and fibrosis in the lung, and significant
cardiac fibrosis in the heart. The amount of IL-1 and [alpha]-SMA decreased significantly as the
amount of omega-3 fatty acids increased, whereas TGF-[beta] did not change significantly.
The next study further reported the time-course effect and potential underlying
mechanisms. Both interleukin-6 (IL-6), a protein associated with fibrotic inflammation in the
lung, and renin, an enzyme related to renin-angiotensin system, were examined by Western blot.
The time-dependent increase of IL-6 in response to bleomycin treatment was reversed by
flaxseed oil diet. Although renin was not significantly different in the kidney, it suggested that
the renin-angiotensin system may be involved locally. In addition, the profiles of fatty acids in
both liver and kidney tissues as measured by lipidomics demonstrated a significant increase of
omega-3: omega-6 ratio in the flaxseed oil-fed groups.
Overall, these results indicated for the first time that the omega-3 fatty acids rich in
flaxseed oil inhibited the formation of pulmonary fibrosis in a dose-dependent manner - however
the moderate dose of flaxseed oil was most effective - via anti-inflammatory mechanisms, which
appears associated with the modulated fatty acid composition in the tissues.
38
Campana, Luca Giovanni. "Sviluppo delle applicazioni cliniche dell'elettroporazione nel trattamento delle metastasi cutanee e dei tumori dei tessuti molli." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3423124.
Full textAbstract:
Introduction. The principle of cell electroporation (EP) (the temporary permeabilization of the cytoplasmatic membrane by means of electric fields) has been applied to the treatment of tumors with the intent of increasing the concentration of anticancer drugs (cisplatin and bleomycin) within the tumor cell and hence their cytotoxic effect. Until 2006, the year of standardization of the electrochemotherapy (ECT) procedure, clinical experience was limited to small heterogeneous series, mainly focused on local activity data in patients with superficial metastases.
Aims. The aim of this project was to investigate the efficacy of ECT in homogeneous populations of cancer patients of different histotypes (patients with skin metastases from malignant melanoma, recurrent breast cancer on the chest wall, recurrent soft tissue sarcomas and tumors of the head and neck area). Furthermore, it was investigated the feasibility and efficacy of a new device (electric pulse generator and dedicated needle electrodes), capable of applying homogeneous electric fields also to deep tumors. Finally, we investigated, both at clinical and preclinical level, the possibility of improving the effectiveness of ECT by, respectively, the evaluation of some immune effect of treatment (i.e., the induction of the Toll-like receptors, TLRs) and the evaluation of the tumor sensitizing action to ECT of buthionine sulfoximine (BSO), an inhibitor of glutathione biosynthesis.
Methods. Overall, four prospective, phase-II, clinical trials were designed, three of them have been concluded and a fourth is still ongoing and patientsâ enrollment is open. Moreover, a retrospective study was performed on head and neck cancer patients. In some patients, tissue samples were analyzed before and after ECT, to evaluate the expression of TLRs. Finally, some in vitro tests were conducted on tumor cell lines to assess the sensitizing effect of BSO pre-treatment to BLM + EP administration.
Results. All the histotypes showed high local response rates and ECT activity was more pronounced than standard chemotherapy regimens employed in current oncology practice. Local response translated in an appreciable local control of the treated tumors, while toxicity was limited and mainly local.
TLRs levels in post-ECT tumor biopsies was not significantly different, compared with pre-ECT samples. However, the immune reaction seems to play a role since a high lymphocytic infiltrate into the electroporated lesions was associated with higher response rates. In vitro tests, BSO pretreatment enhanced the cytotoxicity of BLM + EP. Of note, we also found an increased toxicity of melphalan, a drug currently used in the treatment of locoregional melanoma, in association with EPs. Thanks to the multi-disciplinary collaboration and clinical case management, we have individuated some technical aspects that deserve further improvement in order to increase the effectiveness of treatment application and the number of patients who can benefit from it.
Conclusions. ECT has proved a highly active treatment in recurrent melanoma, breast cancer, soft tissue sarcomas and cancers of the head and neck region. The preliminary clinical experience with a new device and dedicated electrodes indicates the feasibility to treat percutaneously even large, deep-seated tumors. Although ECT treatment do not seem to raise the levels of TLRs in the electroporated tumors, however the levels of lymphocytic infiltration were associated with better local response. In vitro, BSO pre-treatment is able to sensitize tumor cells to the combined treatment of BLM and EP.
Electroporation deserves further investigation also in combination with melphalan, which is currently used in locoregional chemotherapy of in transit metastases from melanoma.
In conclusion, ECT has the potential to be implemented in the oncology field through the multidisciplinary collaboration of oncologists, surgeons, radiation oncologists, biologists and engineers.<br>Introduzione. Il principio fisico dell'elettroporazione (EP) cellulare (la temporanea permeabilizzazione della membrana citoplasmatica per mezzo di campi elettrici) è stato applicato al trattamento dei tumori con l'intento di aumentare la concentrazione dei farmaci antiblastici (bleomicina e cisplatino) all'interno della cellula tumorale e, di conseguenza, la loro azione citotossica. Fino al 2006, anno di standardizzazione della procedura dell'elettrochemioterapia (ECT), l'esperienza clinica con questo tipo di trattamento era limitata ad alcuni studi di efficacia.
Scopo. Lo scopo del progetto è stato quello di indagare l'efficacia dell'ECT in popolazioni omogenee di pazienti oncologici (pazienti con metastasi cutanee da melanoma, recidiva da carcinoma mammario sulla parete toracica, recidiva di sarcoma dei tessuti molli, tumori del distretto capo-collo). Inoltre, è stata indagata la fattibilità e l'efficacia di una nuova apparecchiatura, in grado di applicare il trattamento anche a tumori profondi. Infine, è stata indagata, a livello clinico e preclinico la possibilità di migliorare l'efficacia del trattamento tramite, rispettivamente, la valutazione degli effetti immunologici del trattamento (induzione dei Toll-like receptors, TLRs) e la valutazione dell'effetto sensibilizzante della butionina sulfossimina (BSO) all'azione della bleomicina.
Metodi. Complessivamente, sono stati disegnati quattro studi clinici prospettici di fase II, di cui tre conclusi ed uno attualmente in corso di arruolamento, ed uno retrospettivo. Inoltre, sono stati analizzati i campioni tessutali di alcuni pazienti prima e dopo il trattamento per analizzare i livelli di espressione dei TLRs. In fine, sono stati condotti degli studi su linee cellulari per valutare l'effetto sensibilizzante della BSO al trattamento con BLM + EP.
Risultati. In tutti gli istotipi tumorali trattati l'ECT ha dimostrato, a livello locale, un livello di attività superiore a quello dei regimi di chemioterapia attualmente impiegati. Questo si è tradotto in un apprezzabile controllo locale dei tumori trattati, a fronte di una tossicità limitata e perlopiù locale.
Nei campioni tissutali prelevati prima e dopo il trattamento, la variazione dei livelli dei TLRs non è risultata significativa, ma un elevato infiltrato linfocitario nella lesione è risultato correlato con il grado di risposta locale. In vitro, il pretrattamento con BSO aumenta la citotossicità del trattamento con BLM + EP. Un risultato ancillare è stato anche il riscontro di un aumento della tossicità del melphalan, un farmaco attualmente impiegato nella terapia loco regionale del melanoma, in associazione all'EP. La applicazione clinica dell'ECT ha permesso di rilevare (anche grazie alla collaborazione multidisciplinare) alcuni aspetti tecnici (applicazione e gestione del campo elettrico sui tessuti) meritevoli di essere migliorati per aumentare l'efficacia del trattamento ed il numero di pazienti che possono beneficiarne.
Conclusioni. L'ECT si è dimostrata un trattamento dotato di un'elevata attività nel trattamento delle recidive di melanoma, carcinoma mammario, sarcomi dei tessuti molli e tumori del distretto capo-collo. L'esperienza clinica iniziale con una nuova apparecchiatura ed elettrodi dedicati ha rilevato la possibilità di trattare efficacemente anche i tumori profondi. Il trattamento di ECT sembra non ha innalzato significativamente i livelli di TLRs nei tumori dei pazienti trattati, ma livelli elevati di infiltrato linfocitario nel tumore sono risultati correlati con livelli maggiori di risposta locale. La BSO è in grado di sensibilizzare in vitro i tumori al trattamento combinato con BLM ed EP. L'EP merita di essere ulteriormente indagata, anche in associazione al melphalan nei pazienti con melanoma.
In conclusione, l'ECT ha la potenzialità di essere implementata in campo oncologico attraverso la collaborazione multidisciplinare di oncologo, chirurgo, radioterapista, biologo ed ingegnere.
39
Opalek, Judy Marcus. "I. Differential gene expression in human peripheral blood monocytes and alveolar macrophages II. Macrophage colony-stimulating factor is important in the development of pulmonary fibrosis." Columbus, Ohio : Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1075754091.
Full textAbstract:
Thesis (Ph. D.)--Ohio State University, 20043.<br>Title from first page of PDF file. Document formatted into pages; contains xiv, 115 p.; also includes graphics. Includes abstract and vita. Advisor: Clay B. Marsh, Dept.of Pathology. Includes bibliographical references (p. 102-115).
40
Cabral, Rosa Maria. "Modelo experimental de doença pulmonar intersticial fibrosante associado à terapia celular utilizando células mononucleares de medula óssea." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-07042008-161855/.
Full textAbstract:
Doenças pulmonares intersticiais fibrosantes são doenças que afetam homens, mulheres e crianças, tem prognóstico ruim e os pacientes possuem sobrevida estimada entre 3 e 5 anos após a confirmação diagnóstica, sobretudo os portadores de Fibrose pulmonar idiopática. Estudos recentes demonstram a capacidade das células-tronco em se diferenciar em diferentes linhagens celulares e tecidos, como já comprovado em órgãos como coração, fígado, trato gastrointestinal, sistema nervoso e pulmão. Os objetivos deste trabalho foram os de estabelecer a espécie suína como modelo experimental e utilizar a terapia celular experimentalmente como possibilidade de estudo para tratamento das doenças pulmonares intersticiais fibrosantes. Para estabelecer o modelo experimental e induzir a doença nos dois grupos de animais estudados (grupos tratado e controle) foi utilizado sulfato de bleomicina pela via intratraqueal em procedimento único. Após a instalação da doença, os animais dos grupos tratado e controle foram submetidos a tomografia computadorizada de alta resolução (TCAR); um grupo tratado com terapia celular e após noventa dias os dois grupos reavaliados com TCAR antes da eutanásia, totalizando para os dois grupos, cento e oitenta dias de doença instalada. As análises tomográficas mostraram que o tempo para que a doença intersticial seja estabelecida ocorre até três meses após a infusão de bleomicina. As provas histológicas corroboram a viabilidade do modelo testado e as análises imunohistoquímicas sugerem a migração das células mononucleares de medula óssea para os pulmões, bem como a presença de populações celulares que indicam provável reestruturação do parênquima pulmonar.<br>Fibrotic Interstitial pulmonary illnesses affect men, women and children, and presents bad prognostic, 3-5 years depending on the diagnostic confirmation, mainly in idiopathic pulmonary fibrosis. Recent studies demonstrate the capacity of the stem cells in differentiating into different cellular lineages and different tissues, as in heart, liver, gastrointestinal, nervous system and lung. The objectives of this study were to investigate the possibility to consider the swine as experimental model of fibrotic pulmonary disease and experimental stem cell therapy. Bleomycin sulphate was injected into the trachea to induce the pulmonary disease in control and treatment groups. High resolution computed scan (TCAR) was carried out in both groups after the confirmation of the disease. The tomographic analyses showed that the interstitial illness was established after three months of the bleomicine infusion. Histologic investigation revealed the viability of the tested model and the imunohistochemical analyses suggest the migration of the mononuclear cells to the lungs, as well as the presence of new cellular populations that would indicate probable reorganization of the pulmonary parenchyma.
41
Silve, Aude. "Nouveaux dispositifs pour l'application contrôlée d'impulsions électriques nanosecondes et pour la détection de leurs effets sur les cellules : Nouveaux résultats et hypothèses sur les paramètres contrôlant l'électroperméabilisation des cellules biologiques." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00684394.
Full textAbstract:
La manipulation des membranes des cellules en suspension ou dans des tissus au moyen d'impulsions électriques constitue un sujet de recherche majeur au cœur du bio-électromagnétisme. A ce jour les impulsions de quelques microsecondes voire millisecondes ont été principalement étudiées. Elles n'affectent que la membrane plasmique des cellules. Les impulsions nanosecondes de fort niveau de champ (de l'ordre de quelques MV/m) ouvrent la voie vers la manipulation des organelles intra-cellulaires. En outre, elles constituent un nouvel outil pour l'étude des mécanismes de la perméabilisation. Les travaux de cette thèse ont été principalement consacrés aux effets des impulsions de 10 ns sur la membrane plasmique. Des protocoles expérimentaux permettant d'appliquer de façon reproductible et contrôlée les impulsions sur des objets vivants ont été définis. Des moyens de mesure (D-dot et B-dot) adaptés aux hautes tensions et hautes fréquences ont été développés et mis en œuvre, permettant un contrôle en temps réel des impulsions délivrées.Différentes approches ont permis de mettre en évidence la perméabilisation des cellules par des impulsions de 10 ns. Ces techniques regroupent notamment le suivi de bio-impédance dans les tissus et l'internalisation de molécules cytotoxiques non perméantes dans des cellules en suspension et in vivo sur des tumeurs. Les expériences conduites ont permis de mettre en évidence la plus grande efficacité des basses fréquences de répétition dans la perméabilisation d'un tissu végétal (la pomme de terre). De plus l'influence de la conductivité du milieu extracellulaire sur le niveau de perméabilisation a été investiguée. Ces expériences ont permis de mettre en évidence l'importance de la dynamique d'établissement et de relaxation de la différence de potentiel transmembranaire dans l'efficacité de la perméabilisation.Enfin un microscope CARS (Coherent Anti-stokes Raman Scattering) plein-champ a été développé. Sa conception a été pensée en vue de l'étude des effets des impulsions ultra-courtes sur le vivant à l'échelle moléculaire. A ce jour il permet d'obtenir des images de cellules en CARS en 3 ns.
42
Trajano, Larissa Alexsandra da Silva Neto. "Influência do desequilíbrio redox e resposta inflamatória na fibrose pulmonar associada a estímulo inflamatório prévio." Universidade do Estado do Rio de Janeiro, 2013. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=6791.
Full textAbstract:
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro<br>A fibrose pulmonar é uma doença pulmonar crônica caracterizada pelo acúmulo excessivo de matriz extracelular (MEC) e um remodelamento na arquitetura pulmonar. Embora já se saiba da participação do estresse oxidativo e da inflamação na fibrose de forma isolada, é importante observar como se comporta o estresse oxidativo na fibrose quando esta ocorre associada a uma doença de base. O presente estudo teve como objetivo investigar o perfil inflamatório e oxidativo na fibrose pulmonar associado ao enfisema pulmonar prévio. Camundongos C57BL/6 foram divididos em três grupos: grupo controle (n=5) que receberam salina intranasal (50 l) e foram sacrificados no 21 dia; grupo bleomicina (BLEO) (n=15) que receberam bleomicina intratraqueal (0.1 U/animal) no dia 0 e foram sacrificados nos 7 (n=5), 14 (n=5) e 21 (n=5) dias e grupo PPE (elastase) + BLEO (n=21) que receberam elastase (3U/animal) e após 14 dias receberam bleomicina e foram sacrificados nos 14(n=7), 21 (n=7), 28 (n=7) e 35 (n=7) dias. Foram realizadas análises histológicas através de H&E e picro-sirius; análises bioquímicas para superóxido dismutase (SOD), catalase (CAT), glutationa peroxidase (GPx) e glutationa-S-transferase (GST) e ELISA para Interleucina (IL)-1β e IL-6. A fibrose pulmonar ocorreu a partir do 14 dia (p<0.001) e o enfisema concomitante a fibrose pulmonar a partir do 28 dia (p<0.001) e um aumento de fibras colágenas no grupo BLEO 21(p<0.001) e PPE + BLEO 21(p<0.001). As enzimas antioxidantes CAT (p<0.01), SOD (p<0.01) e GPx (p<0.01) reduziram e a GST aumentou no grupo BLEO 21 dias (p<0.05). No grupo PPE + BLEO 21 dias houve redução das enzimas antioxidantes CAT, SOD, GPx (p<0.05) e GST. Os níveis de óxido foram altos nos grupos BLEO 21 dias (p<0.01) e PPE + BLEO 21 dias (p<0.01). A IL-1β mostrou-se elevada no grupo BLEO 7 dias quando comparado ao controle (p<0.001) e ao grupo PPE + BLEO 7 dias (p<0.01). Concluímos que a resposta inflamatória inibiu a ação do sistema antioxidante contribuindo para o agravamento da lesão. Isso sugere que terapias anti-inflamatórias podem contribuir tanto para redução da resposta inflamatória quanto de forma indireta no sistema antioxidante.<br>Pulmonary fibrosis (PF) is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling in the lung architecture. Although it is already known the role of oxidative stress and inflammation in the isolated pulmonary fibrosis, it is important to observe how it behaves oxidative stress in pulmonary fibrosis when it occurs associated with an underlying disease. The present study aimed to investigate the inflammatory status and oxidative pulmonary fibrosis associated with pulmonary emphysema prior. C57BL / 6 mice were divided into three groups: control group (n = 5) who received intranasal saline (50l) and were sacrificed at 21 days, bleomycin (BLEO) group (n=15) who received intratracheal bleomycin (0.1U/animal) in the day 0 and were sacrificed at 7 (n=5), 14 (n=5) and 21 (n=5) days and the PPE + BLEO group (n=21) received elastase (PPE)(3U/animals) and 14 days after receiving bleomycin and were sacrificed at 14 (n = 7), 21 (n = 7) 28 (n = 7) and 35 (n = 7) days. Histological analysis was achieved using H&E and Sirius red staining; biochemical analysis for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) and ELISA for IL-1β and IL-6 were conducted. Pulmonary fibrosis occurred from day 14 (p<0.001) emphysema and pulmonary fibrosis from day 28 (p <0.001) and occurred an increase of collagen fibers in the BLEO group 21days (p<0.001) and PPE + BLEO 21days (p <0.001). Antioxidant enzymes CAT (p <0.01), SOD (p <0.01), and GPx (p <0.01) were reduced and GST increased in the BLEO group 21 days (p<0,05). In the PPE + BLEO group 21 days occurred an decreased antioxidant enzymes CAT, SOD, GPx (p <0.05), and GST. Oxide levels were higher in the BLEO groups 21 days (p <0.01), and PPE + BLEO group 21 days (p <0:01). IL-1β was elevated in the group BLEO 7 days when compared to control (p <0.001) and the PPE + BLEO group 7 days (p<0.01). The inflammatory response inhibited the action of the antioxidant system contributes to the aggravation of the injury. This suggests that anti-inflammatory therapies may contribute to reducing the inflammatory response as indirectly to the antioxidant system.
43
Guisado, Barrios Gregorio. "Towards the development of selective hydrocarbon oxygenation catalysts." Thesis, University of St Andrews, 2010. http://hdl.handle.net/10023/925.
Full textAbstract:
The synthesis of pure tris(6-hydroxymethyl-2-pyridylmethyl)amine (H₃L₁₁) is reported for the first time. New complexes of H₃L₁₁ with copper(II), manganese(II) and iron(III) have been characterised by X-ray crystallography. Linear [Fe₃(L₁₁)₂](ClO₄)₃ reveals the tightest Fe-O-Fe angle (87.6°) and shortest Fe...Fe distance (2.834 Å) presently found for a weakly antiferromagnetically-coupled high spin alkoxide-bridged polyiron(III) system. H₃L₁₁ provides a route to various hydrophobic peralkylated TPA ligand derivatives for creating a hydrophobic pocket for the assembly of iron catalysts for the novel 1-hydroxylation of n-alkanes. New 6-py substituted TPA ligands containing methyl (L₁₅) and n-octyl (L₁₆) ether linkages were synthesised via alkylation. Two further novel 6-py substituted ligands were synthesized incorporating n-hexyl substituents on one (L₂₁) and two (L₂₂) of the py moieties. Here a urea spacer group was used to promote hydrogen–bond assisted heterolytic O-O cleavage (generation of the potent FeV=O oxidant) within the hydroxoperoxoiron(III) precursor. High spin [FeII(L)(CH₃CN)[subscript(x)]](CF₃SO₃)₂ complexes (x = 0–2, L = L₁₅,₁₆,₂₁,₂₂) were characterised in solution by ¹H NMR. The structure of [Fe(L₂₂)](CF₃SO₃)₂ reveals a distorted iron(II) centre bound to four N atoms and two urea carbonyls. Iron(II) complexes of H₃L₁₁, L₁₅,₁₆,₂₁,₂₂ and tris(6-Br)-TPA (L₂₄), were investigated for catalysis of the oxygenation of cyclohexane by H₂O₂. Reaction of the iron(II) complexes with H₂O₂ and [superscript(t)]BuOOH was followed by time-resolved EPR and UV-VIS spectrophotometry. A correlation between the observed catalytic activity and the nature of the FeIII(L)-OOR intermediates generated is apparent. A convenient ‘one-pot’ synthesis of benzene-1,3,5-triamido-tris(l-histidine methyl ester) is reported along with attempts at preparing N,N’-bis(pyridylmethyl)-1,3- diaminopropane-2-carboxylic acid (L₂₅), a new water soluble pyridine-amine ligand. The final demetallation step resulted in ligand hydrolysis to the novel amino acid; 1,3-diaminopropane- 2-carboxylic acid which was characterised as its HCl salt by X-ray crystallography.
44
Litvin, David Gregory Litvin. "Immune-to-brain communication driven by sterile lung injury." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1528469492924001.
Full text
45
Günther, Sven. "Remodelage vasculaire pulmonaire associé à la fibrose pulmonaire : implication de l'axe MIF-CD74 A role of MIF and D-DT in immune-inflammatory, autoimmune, and chronic respiratory diseases: from pathogenic factors to therapeutic targets MIF inhibition in a murine model of bleomycin-induced pulmonary fibrosis." Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2253&f=14280.
Full textAbstract:
Des travaux récents ont mis en évidence une surexpression du facteur MIF (facteur inhibiteur de la migration des macrophages), un des plus anciens médiateurs immunologiques connus, et de son récepteur CD74 dans l'hypertension pulmonaire idiopathique. Or, la sur-activation de cet axe MIF-CD74 est connue pour contribuer à l'acquisition et au maintien d'un phénotype pro-inflammatoire de la cellule endothéliale pulmonaire (Le Hiress et al. 2015). Les taux sériques élevés de MIF ont été mis en évidence dans de nombreuses pathologies respiratoires chroniques, notamment dans la fibrose pulmonaire idiopathique (FPI) et l'hypertension pulmonaire (HTP) associée ou non à une sclérodermie systémique (SSc) (Olivieri et al. 2016 ; Bargagli et al. 2009 ; Marshall et al. 2017 ; Le Hiress et al. 2015 ; Stefanantoni et al. 2015). De plus, il est bien établi que les maladies respiratoires chroniques ont un fort retentissement sur la circulation pulmonaire et peuvent conduire à son remodelage et donc au développement d'HTP, ce qui assombrit encore plus le pronostic de ces patients surtout lorsque celle-ci est dépistée tardivement. Nous avons donc émis l'hypothèse qu'une sur-activation de l'axe MIF/CD74 pourrait contribuer au remodelage structurelle et fonctionnelle de la circulation pulmonaire dans le contexte d'une fibrose pulmonaire. Pour tester cette hypothèse, notre projet s'est articulé autour de deux objectifs. D'abord, nous avons étudié l'état d'activation de l'axe MIF/CD74 dans les poumons de patients avec fibrose pulmonaire idiopathique présentant ou non une HTP. Ces mêmes expériences ont ensuite été menées sur des poumons de souris présentant une fibrose pulmonaire induite par injection intra-trachéale de bléomycine. Puis, nous avons testé l'efficacité de l'inhibition du facteur MIF dans un modèle murin de fibrose pulmonaire induite par la bléomycine à l'aide de deux antagonistes spécifiques de cette voie : le (S, R)-3-(4-hydroxyphényl)-4,5-dihydro-5-isoxazole acétique ester méthylique d'acide (ISO-1) et le N-(5-méthylphényl)-benzoxazol-2-one 31 (composé 31) (Le Hiress et al. 2018). Pour cela, une évaluation de l'hémodynamique pulmonaire par cathétérisme cardiaque droit a été réalisée, ainsi qu'une étude histologique afin d'évaluer le remodelage vasculaire pulmonaire, l'infiltration inflammatoire ainsi que le dépôt de collagènes chez des souris traitées ou non pendant 21 jours avec les deux antagonistes spécifiques du MIF (20mg/kg/j, par gavage). Contrairement à l'endothélium des artères pulmonaires de patients avec IPF, nous avons ainsi pu mettre en évidence une surexpression de MIF et de son récepteur CD74 dans l'endothélium dysfonctionnel des artères pulmonaires remodelées de patients IPF avec HTP. De plus, ces observations ont pu être reproduites dans les poumons de souris traitées à la bléomycine. De manière intéressante, nos données montrent que les souris bléomycine développent des HTP modérées et que des traitements chroniques avec ISO-1 ou le composé 31 atténuent partiellement la sévérité de cette HTP, ainsi que le dépôt de collagène et l'infiltration pulmonaire de cellules inflammatoires. En conclusion, nos données indiquent que MIF et son récepteur CD74 représentent des cibles thérapeutiques potentielles qui pourraient prévenir le remodelage vasculaire pulmonaire induit par le développement de la fibrose pulmonaire<br>Recently, it has been demonstrated that MIF (macrophage migration inhibitory factor) and its endothelial receptor CD74 are up-regulated in idiopathic pulmonary hypertension (iPH) and contribute to the pro-inflammatory endothelial phenotype (Le Hiress et al. 2015). However, it is well established that chronic respiratory diseases have a strong impact on the homeostasis of the pulmonary circulation which can lead to its remodeling and the development of PH, that further darkens the prognosis of these patients. In addition, it is known that high serum MIF levels are found in several chronic respiratory diseases, particularly in patients with idiopathic pulmonary fibrosis (IPF) or PH associated with or not to systemic scleroderma (SSc) (Bargagli et al. 2009; Le Hiress et al. 2015; Stefanantoni et al. 2015 ; Olivieri et al. 2016; Marshall et al. 2017). We therefore hypothesized that over-activation of the MIF/CD74 axis could contribute to the pulmonary vascular remodeling and the development of PH in the context of pulmonary fibrosis. To test this hypothesis, we first studied the activation state of the MIF/CD74 axis in idiopathic pulmonary fibrosis patients with or without PH. Similar investigations were also performed on pulmonary sections of lungs of mice with established pulmonary fibrosis induced by intra-tracheal injection of bleomycin. Second, we tested the effect of MIF inhibition in a murine model of bleomycin-induced pulmonary fibrosis using two antagonists specific for this pathway: (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(5-methylphenyl)-benzoxazol-2-one 31 (compound 31) (Le Hiress et al. 2018). Pulmonary hemodynamic parameters were measured by right heart catheterization and histological analyses were performed to evaluate the degree of pulmonary vascular remodeling, lung infiltration of inflammatory cells, and collagen deposition in mice treated or not with the two specific MIF antagonists (20mg/kg/day for 21 days, per os). In contrast to the pulmonary endothelium of IPF patients, our data indicate that an over-expression of MIF and its CD74 receptor in the dysfunctional pulmonary endothelium of remodeled vessels of pulmonary fibrosis patients with PH. In addition, these observations were replicated in lungs of bleomycin-treated mice. Interestingly, we also found that bleomycin-injected mice exhibit mild PH as reflected by increased values of right ventricular systolic pressure (RVSP), of Fulton index (right ventricular hypertrophy) and of percentage of muscularized pulmonary arteries. In addition, we found that chronic treatments of bleomycin-injected mice with ISO-1 or compound 31 partially attenuated PH, collagen deposition and pulmonary inflammatory infiltration. Taken together, our data support that MIF and its CD74 receptor could represent an attractive therapeutic target for preventing pulmonary vascular remodeling induced by the development of pulmonary fibrosis
46
Vannière, Florence Michèle Marie-Claude. "Les complications pulmonaires de la bleomycine chez l'homme : approche clinique a propos de 2 observations." Université Louis Pasteur (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR1M104.
Full text
47
BERGDOLL, MARC. "Etude structurale d'une proteine bacterienne de resistance a la bleomycine." Université Louis Pasteur (Strasbourg) (1971-2008), 1997. http://www.theses.fr/1997STR13260.
Full textAbstract:
Ce travail s'inscrit dans le cadre de l'etude de la resistance bacterienne aux antibiotiques. Le but en etait la determination par cristallographie de la structure de prb, la proteine qui confere la resistance envers la bleomycine a streptoalloteichus hindustanus. La structure, determinee a une resolution de 2. 3a, montre un dimere sur lequel deux sites actifs ont pu etre caracterises entre les deux protomeres qui sont associes par echange de bras n-terminaux. Peu de choses sont connues sur les mecanismes impliques lors de l'oligomerisation avec echange de bras mais une proline situee a la base du bras de la prb est importante pour l'echange. Son role a ete verifie par mutagenese dirigee et generalise par une analyse des banques de donnees de structures et de sequences. Chaque monomere est constitue de deux domaines identiques formes d'un feuillet antiparallele et d'une helice. L'occurrence de ce motif en 13 exemplaires dans 8 proteines differentes indique une stabilite elevee et laisse supposer qu'il s'agit d'un nouveau motif topologique. Deux proteines parmi les huit, une dioxygenase et une glyoxalase, sont tres semblables a la prb. En depit de sequences, de fonctions et de substrats differents, il a ete possible de montrer qu'elles possedent un ancetre commun. Cette parente suggere qu'au niveau bacterien, resistance aux antibiotiques et detoxification sont des notions proches. Elle etablit un lien entre resistance a la bleomycine et a la fosfomycine en montrant que prb et fosa sont homologues bien qu'elles exercent deux types de resistances differents. Enfin, cette homologie incite a penser que certaines prb pourraient etre ou avoir ete des metallo-enzymes impliquees dans la biosynthese des bleomycines. Il est etabli que dissemination et acquisition de resistances trouvent souvent leur origine chez les organismes producteurs d'antibiotiques mais une telle derive de la synthese vers la resistance n'avait pas encore ete demontree dans le cas de la bleomycine.
48
Jacquot, Eric. "Toxicologie expérimentale de la bléomycine." Paris 5, 1988. http://www.theses.fr/1988PA05P266.
Full text
49
Morii, Takashi. "Chemical Approach to the Molecular Mechanisms of DNA Strand Cleavage by Bleomycins." Kyoto University, 1988. http://hdl.handle.net/2433/74709.
Full text
50
Tossou, Viviane Marie. "Toxicologie de la bléomycine." Paris 5, 1992. http://www.theses.fr/1992PA05P092.
Full text