Rozprawy doktorskie: „Advanced therapy medicine”

1

VIGANI, BARBARA. "Development of Advanced Therapy Medicinal Products for Regenerative Medicine". Doctoral thesis, Università degli studi di Pavia, 2017. http://hdl.handle.net/11571/1203351.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

2

Coward, Jermaine. "The effects of anti-IL-6 therapy in advanced ovarian cancer". Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/457.

Pełny tekst źródła

Streszczenie:

IL-6 is a pleiotropic cytokine that has a significant role in inflammatory processes. In relation to ovarian cancer biology there is emerging evidence that it mediates processes relating to tumour growth, invasion, angiogenesis and chemo-resistance that lead to disease with poor prognosis. The aim of this thesis was to evaluate the efficacy and mechanism of action of an anti-human IL-6 antibody, CNTO328, in ovarian cancer. These aims were achieved with a clinical trial that was conducted in parallel with pre-clinical experiments. 18 patients with advanced platinum-resistant ovarian cancer were treated with CNTO328 in a phase II clinical trial. One patient had a partial response and seven patients attained stable disease at the end of the initial 6-week study period with correlations seen between clinical benefit and baseline levels of CRP, β2- microglobulin, TNF-α, IL-8 and VEGF. Four patients completed 6 months of treatment and had significantly decreased plasma CCL2 and increased sgp130 concentrations. Furthermore, immunohistochemical analysis of diagnostic biopsies suggested that clinical benefit was related to a lower macrophage infiltrate and increased stromal expression of IL-6, IL-6 receptors and SOCS3. I have found two ovarian cancer cell lines that secreted IL-6 and expressed both components of the IL-6 receptor signalling complex. When these cells were grown on plastic, CNTO328 had no effect on cell proliferation or survival. This suggested that IL-6 was not a growth factor for ovarian cancer cells in vitro. However, CNTO328 reduced constitutive secretion of IL-6, IL-1β, TNF-α, IL-8 and CCL2 by the ovarian cancer cells. The in vivo studies with human ovarian cancer xenograft models in nude mice showed that anti-IL-6 treatment had biological activity by inhibiting cell proliferation, macrophage infiltration and angiogenesis. In conclusion, the xenograft models and cell line experiments together with the clinical trial show that IL-6 may be a therapeutic target in ovarian cancer and exhibits both autocrine and paracrine actions within the ovarian cancer microenvironment.

Style APA, Harvard, Vancouver, ISO itp.

3

Fall, Per-Arne. "Aspects of Parkinson's disease. Epidemiology, risk factors and ECT in advanced disease". Doctoral thesis, Linköpings universitet, Geriatrik, 1999. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-5011.

Pełny tekst źródła

Streszczenie:

The purpose was to investigate some aspects of epidemiology, risk factors and treatment with ECT in advanced Parkinson’s disease (PD). In study I, we performed a descriptive epidemiologic population-based survey in the Central Health Care District in Östergötland in south-east Sweden, with a population of almost 150,000 inhabitants 1989. The case finding was accomplished in three ways: 1. Collection of all prescriptions for Parkinson’s disease. 2. Search in medical files. 3. Checking with all nursing homes in the area. The crude prevalence was found to be 115 per 100,000 inhabitants. When we used the European Standard Population as a tool for easy comparisons of PD prevalence between different areas and time periods 76 PD-cases per 100,000 inhabitants were found. The corresponding incidences were 11.0 (crude) and 7.9 (age standardised) per 100,000 person-years. Mean age at onset was 65.6. A low prevalence and a high age at onset suggested that e.g. environmental factors could influence the occurrence of PD, and the results implies that only few such factors were present in the investigated area. The findings led to study II, a case-control study which investigated the possible impact of nutritional and environmental risk factors for idiopathic Parkinson’s disease (IP), including 113 cases and 263 control subjects. Dietary, drinking, and smoking habits, as well as previous occupation, were requested in a structured questionnaire. No increased risk was found for any of the nutrients. A reduced risk was found for coffee, wine, and spirits but also for broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. These findings could indicate an antioxidant effect. Frequency of preceding and present smoking was reduced in IP patients. Possible mechanisms are discussed. Various occupational groups and exposures were analysed and increased risks of IP in men were found for agricultural work, pesticide exposure, male carpenters, and in female cleaners. In advanced PD there is a need for further therapeutic improvements, and electroconvulsive therapy (ECT) is one insufficiently explored and evaluated method. In study III ECT 16 non-depressed, nondemented PD patients with advanced disease were treated with ECT. In all patients an antiparkinsonian effect of ECT was seen, lasting between a few days and 18 months. Five patients, all with signs of blood brain barrier damage, developed transitory mental confusion after ECT. The results indicated that ECT could cause increased dopaminergic activity, which led us to study IV. Single photon emission computed tomography (SPECT) with the cocaine analogue [123I]-β-CIT was used in order to visualise dopaminergic neurones in the brain. Six patients with PD were examined before and after a series of ECT, and in three cases SPECT was also repeated after one year. The side-to-side difference in the radiotracer uptake was found to be significantly lower in striatum located contralaterally to the part of the body with most pronounced symptomatology. No significant change in uptake of [123I]-β-CIT was seen after ECT, although all patients improved and the most pronounced improvement was seen in patients with less advanced PD. Study V points at two new positive observations with maintenance ECT (MECT). i.e. repeated ECT treatment of PD. One patient had either severe mental side effects on higher L-dopa doses or intolerable parkinsonian symptoms on lower doses. MECT implied marked improvement in parkinsonian symptoms without mental side effects. Another PD patient, who also had a mental depression, showed slight improvement of motor symptoms on a series of ECT. When treated with MECT further antiparkinsonian effects were seen.
On the day of the public defence the status of the article IV was: Submitted; articel V was: Accepted for publication after revision.

Style APA, Harvard, Vancouver, ISO itp.

4

水野, 正明, 純. 吉田, Masaaki Masaaki Mizuno i Jun Yoshida. "悪性グリオーマに対する遺伝子治療". 日本脳神経外科コングレス, 2006. http://hdl.handle.net/2237/10865.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

5

Gonzalez, Gomez Mayte Lorena. "Methylglyoxal Effects in Cell Therapy for Myocardial Infarction". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38431.

Pełny tekst źródła

Streszczenie:

Methylglyoxal (MG), a highly reactive dicarbonyl accumulates after myocardial infarction (MI), causing adverse remodelling and cardiac dysfunction. We hypothesized that therapy using bone marrow cells (BMCs) overexpressing glyoxalase1 (Glo1), the main enzyme that metabolizes MG, injected into mouse MI model would translate into better survival of transplanted cells and improve their therapeutic effect. We found that Glo1 expression is significantly reduced at 7 days post-MI. Glo1 BMCs exposed to MG in vitro displayed greater angiogenic potential and reduced reactive oxygen species production compared to wild type (WT) BMCs. However, in the mouse MI model, Glo1 BMCs did not improve cardiac function or vascularity or reduce scar formation compared to WT BMCs and saline treatments. In conclusion, Glo1 overexpression in BMCs does not confer superior therapeutic efficacy for treating MI under the conditions tested.

Style APA, Harvard, Vancouver, ISO itp.

6

Balbadhur, Raksha. "Understanding the dignity experience and exploring the impact of dignity therapy and guided imagery on patients with advanced disease - a South African perspective". Master's thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/24874.

Pełny tekst źródła

Streszczenie:

Objectives: This study was conducted to understand the dignity experience of patients with advanced disease from diverse socio-economic and cultural backgrounds in a South African context. In addition, the psychotherapeutic interventions, Dignity Therapy and Guided Imagery (focused on intrinsic dignity), were implemented to enhance the dignity experience of these patients and its impact explored. Method: This was a qualitative study where a semi-structured interview guide was used in the exploration of the understanding of the dignity experience of patients with advanced diseases, receiving home care from two hospices in the North of Durban, KwaZulu-Natal. Interviews were audiotaped and transcribed verbatim. Data was analysed using thematic analysis. Dignity Therapy and Guided Imagery were subsequently implemented with these patients. Dignity therapy is an appreciative enquiry into the lives of patients to allow them to discuss aspects of their life that matter most, and the legacy and words of advice they would want most remembered. The sessions are audiotaped, transcribed and edited to produce a legacy document that can be given to their family or loved ones, if they so wish. Guided Imagery was implemented to affirm a practical experience of patients' intrinsic dignity and worth as beings. A post intervention patient feedback questionnaire, which involved a quantitative and qualitative component, was used to explore the impact of these interventions on different aspects of psychosocial and existential distress. The qualitative feedback was analysed using content analysis to determine the themes and sub-themes of benefit derived from the bundled interventions. Results: Four major themes defined the dignity experience: physical concerns, psychological concerns and coping mechanisms, social concerns and spiritual concerns and coping mechanisms. These themes and the numerous sub-themes provide an understanding of the total dignity experience of South African patients living with advanced disease. This study provided quantitative and qualitative data illustrating the impact of Dignity Therapy and Guided imagery, which proved to enhance the dignity experience of patients with advanced disease. The beneficial impact of Dignity Therapy and Guided Imagery on the dignity experience of dying patients was documented with confirmations on measures of helpfulness (100%), satisfaction (100%), a heightened sense of dignity (75%), purpose (100%) and meaning in life (92%). Further endorsements were expressed in terms of 83% sharing that it had lessened their sense of suffering, and feelings of anxiety and depression (92%) and improved their will to live (83%). The participants also expressed that the beneficial impact of interventions would spread beyond themselves to help their families (92%) and to benefit their relationship with their healthcare providers (92%). The interventions were shown qualitatively to have a beneficial impact on the Physical, Psychological, Social and Spiritual Domains of the participants' lives and these emerged as the four themes with various sub-themes. Conclusion: With this awareness of the biopsychosocial and existential concerns and psycho-existential coping mechanisms that affect the total dignity experience, healthcare providers can optimise dignity conserving care to improve the quality of lives of patients living with advanced disease. In this small study, Dignity Therapy and Guided Imagery are shown to be relevant, feasible and acceptable, short psychotherapeutic interventions that can be conducted at the bedside by healthcare providers to enhance the dignity experience of patients. A Guided Imagery focused on intrinsic dignity is shown to be a novel beneficial 5-minute intervention that can augment Dignity Therapy, or be used on its own, to affirm and strengthen the experience of the intrinsic worth of patients with advanced disease. Healthcare professionals have an influence in the area of the extrinsic sources of dignity in advanced disease, and can enhance dignity in providing respectful compassionate care. To add to the knowledge on dignity research, this study specifically highlights the need to affirm intrinsic dignity in dying patients, to affirm their personal worth.

Style APA, Harvard, Vancouver, ISO itp.

7

Hasfal, Sharon hasfal. "Development of a Scholarly Educational Intervention to Improve Inpatient Diabetes Care". ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/5086.

Pełny tekst źródła

Streszczenie:

Advanced practice providers (APPs), consisting of nurse practitioners and physician assistants, face many challenges in the provision of evidence-based practice in their management of hospitalized adult patients with diabetes. Some of the barriers faced by APPs at a Northeast acute care facility are poor communication between disciplines, lack of confidence in initiating insulin, limited understanding of the management of insulin and the insulin pump, and insufficient treatment of the hospitalized patient with diabetes that aligns with current clinical guidelines for the management of inpatient hyperglycemia. This quality improvement project focused on the development of an evidence-based theory supported educational intervention to improve APPs' knowledge regarding glycemic management. An interdisciplinary team created the educational intervention using the analyze, design, develop, implement, and evaluate (ADDIE) instructional model. A 10-member expert panel validated the program utilizing both a formative and summative evaluation. The results from the formative evaluation was discussed with the interdisciplinary team, corrections were made, and was returned to the expert panel. Once the changes were made to the satisfaction of the expert panel, the program was then validated and submitted to the institution as a completed project to be used by the institution for APPs. This project addresses social change by increasing awareness in the management of inpatients with diabetes therefore decreasing fragmented care delivered by the APPs which will improve quality of care and patient safety.

Style APA, Harvard, Vancouver, ISO itp.

8

Fornaguera, Puigvert Cristina. "Development of multifunctional polymeric nanoparticles by nano-emulsion templating as advanced nanocarriers targeting the blood-brain barrier". Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/285368.

Pełny tekst źródła

Streszczenie:

Multifunctional polymeric nanoparticles (NP) represent a promising alternative for the treatment of neurodegenerative diseases using the intravenous route (i.v.). In current treatments, the effects of the intravenously injected drugs are systemic, requiring high drug doses to achieve therapeutic effects, thus causing severe side effects. NP can act specifically in a tissue provided that they are properly designed. An interesting approach is the preparation of NPs by nano-emulsion templating. Nano-emulsions (NE) are fine emulsions, with droplet sizes typically between 20 – 200nm. They can be prepared by the phase inversion composition (PIC) method, a low-energy emulsification method appropriate for pharmaceutical applications, since it can be performed at mild process conditions. Nanoparticles are obtained from nano-emulsions by solvent evaporation. To target the central nervous system (CNS), a specific targeting moiety on the nanoparticle surface is required to cross the blood-brain barrier (BBB), which is a current key goal under intense investigations. The aim of this work was to obtain multifunctional polymeric NP as advanced delivery systems able to cross the BBB. O/W polymeric NE were prepared by the PIC method and polymeric NPs were obtained by solvent evaporation. Polymeric NP with appropriate sizes for the i.v. administration (<1milimicron) were obtained. With the aim to design imaging systems, a model fluorescent dye and magnetic nanoparticles were encapsulated in polymeric NPs. An analgesic and an antiapoptotic drugs were also encapsulated into PLGA NP for therapeutic purposes. High encapsulation efficiencies were found for all tested compounds, attributed to the method of nanoparticle preparation as well as to low solubility of the components in the aqueous dispersion media. In addition, a sustained and controlled release of fluorescent dyes / drugs was achieved. NP surface was functionalized using various elements. On the one hand, it was functionalized with a monoclonal antibody against the transferring receptor, overexpressed in the BBB, to achieve an active targeting to the BBB. On the other hand, NPs were functionalized with oligonucleotides, to be used as non-viral gene delivery systems. Firstly, carbosilane cationic dendrons were covalently attached to nanoparticle surface to achieve a cationic surface. In a further step, antisense oligonucleotides, siRNA and plasmids were electrostatically bound to cationized nanoparticles. In vitro tests showed that the formulated NP did produce neither cytoxicity nor hemolysis. In addition, they were weak activators of the immune system and produced only a slight adsorption of blood proteins. Therefore, they are appropriate to be used by the i.v. route. NPs functionalized with oligonucleotides enhanced gene transfection in cell cultures, up to values comparable to those of commercial values (up to 90%). These NPs are advantageous in terms of toxicity issues over the commercial formulations. Therefore, they represent promising non-viral gene delivery systems. In vivo tests, which measured the central analgesia produced by an encapsulated drug into nanoparticles (loperamide) that is not able to cross the BBB, confirmed a central analgesic effect, reaching a potency of analgesia comparable to positive controls when nanoparticles were functionalized with the antibody. Therefore, the antibody functionalized nanoparticles efficiently crossed the BBB. In conclusion, the designed polymeric nanoparticles, functionalized with the antitransferrin receptor antibody, are able to cross the BBB with high efficiency. These nanoparticles represent promising nanosystems to deliver actives to the central nervous system.
Les nanopartícules polimèriques multifuncionals (NPs) representen una alternativa prometedora pel tractament de malalties neurodegeneratives, a través de l’administració intravenosa (i.v.), ja que els tractaments actuals provoquen molts efectes secundaris. Les NPs, en canvi, si estan correctament dissenyades, poden actuar específicament en el teixit diana. Ja que l’òrgan diana és el cervell, és necessari un element de vectorització per poder creuar la barrera hemato-encefàlica (BBB). En aquest context, l’objectiu de la present tesi és l’obtenció de NPs com a sistemes avançats d’alliberament de principis actius que travessin la BBB. Es van obtenir NPs a partir de nano-emulsions (NE) plantilla, emprant l’àcid poli-(làctic-co-glicòlic) com a polímer i el mètode d’inversió de fases a temperatura constant per emulsionar, seguit d’evaporació de solvent per obtenir NPs. Les NPs obtingudes tenen mides apropiades per l’administració i.v.. Es va aconseguir encapsular un fluorescent i NPs magnètiques dins les NPs polimèriques, per fer-les servir com a sistemes d’imatge. També es van encapsular fàrmacs per usar-les com a sistemes terapèutics. En tots els casos, es van aconseguir eficiències d’encapsulació molt elevades i un alliberament del fàrmac controlat i prolongat en el temps. A més, es va aconseguir funcionalitzar la superfície de les NPs amb diferents elements. Es van unir covalentment dendrons catiònics per posteriorment unir oligonucleòtids electrostàticament. També es va afegir una coberta exterior de polietilenglicol per protegir el material genètic. Per altra banda, es va funcionalitzar la superfície de les NPs amb un anticòs específic contra el receptor de la transferrina, sobreexpressat a la BBB. A continuació, es van fer assajos in vitro, que van posar de manifest que les NPs no són citotòxiques ni hemolítiques. També es va estudiar l’eficiència de transfecció cel•lular del material genètic, arribant a eficiències de transfecció equivalents a les dels vectors comercials. Assajos in vivo van permetre confirmar el pas a través de la BBB, sobretot de les NPs funcionalitzades amb l’anticòs. Els resultats obtinguts permeten concloure que s’ha aconseguit dissenyar noves NPs polimèriques a partir de NE, apropiades per l’administració i.v. i amb capacitat de travessar la BBB.

Style APA, Harvard, Vancouver, ISO itp.

9

Daum, Ruben [Verfasser]. "Development and Non-invasive Quality Assessment of Advanced Therapy Medicinal Products / Ruben Daum". Tübingen : Universitätsbibliothek Tübingen, 2021. http://d-nb.info/1232725773/34.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

10

Abou, El-Enein Mohamed [Verfasser]. "The economics of manufacturing clinical-grade advanced therapy medicinal products (ATMPs) / Mohamed Abou El-Enein". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1046832859/34.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

11

Smart, Susanna Jennifer. "Grounded Theory of Rosen Method Bodywork". Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1524757138389208.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

12

Zscharnack, Matthias, Christoph Krause, Gabriela Aust, Christian Thümmler, Frank Peinemann, Thomas Keller, Jeske J. Smink i in. "Preclinical good laboratory practice-compliant safety study to evaluate biodistribution and tumorigenicity of a cartilage advanced therapy medicinal product (ATMP)". Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-170184.

Pełny tekst źródła

Streszczenie:

Background: The clinical development of advanced therapy medicinal products (ATMPs), a new class of drugs, requires initial safety studies that deviate from standard non-clinical safety protocols. The study provides a strategy to address the safety aspects of biodistribution and tumorigenicity of ATMPs under good laboratory practice (GLP) conditions avoiding cell product manipulation. Moreover, the strategy was applied on a human ATMP for cartilage repair.

Style APA, Harvard, Vancouver, ISO itp.

13

Serhal, Nada. "Analyse du potentiel pro-angiogénique de vésicules extracellulaires libérées par des cellules souches mésenchymateuses, en vue de leur utilisation dans le traitement de l'artériopathie oblitérante des membres inférieurs". Electronic Thesis or Diss., Reims, 2024. http://www.theses.fr/2024REIMS007.

Pełny tekst źródła

Streszczenie:

Les cellules stromales mésenchymateuses (MSCs) présentent un potentiel pro-angiogénique prometteur dans le traitement des maladies artérielles ischémiques, en particulier l’artériopathie oblitérante des membres inférieurs. Les petites vésicules extracellulaires (sEVs) issues de ces cellules pourraient avoir un potentiel comparable. En effet, ces sEVs agissent comme des véhicules de livraison (cargo), transportant des matériaux biologiques vers des cellules cibles dans les sites d’ischémie. Cette étude se consacre à la caractérisation des MSCs indifférenciées et des MSCs de phénotype "endothelial like" cultivées en condition hypoxique (MSC-ELH) et des sEVs que ces cellules produisent. Les MSC-ELH se caractérisent par la surexpression des principaux ARNm endothéliaux ; elles sécrètent de grande quantité des sEVs et des facteurs pro-angiogéniques et mitogènes et de faible quantité IL-6, ce qui leur confère un avantage dans la mesure où cette cytokine est délétère dans un contexte d’ischémie tissulaire. Les sEVs libérées par les MSC-ELH sont dotées d’un haut potentiel pro-angiogénique car elles contiennent les ARNm codant pour le VEGF-A, FGF2, EGF et les protéines correspondantes. Les sEVs s’internalisent dans les cellules endothéliales (CE) et les cellules musculaires squelettiques. Les MSC-ELH sEVs stimulent la prolifération des CE et la formation de pseudotubes in vitro. Ce travail souligne l'impact bénéfique de l'hypoxie et de la différenciation endothéliale sur les sEVs issues des MSC-ELH. Les sEVs pourraient être utilisés comme vecteurs thérapeutiques dans le traitement des maladies artérielles ischémiques, en tant que thérapie innovante “sans cellule”
Mesenchymal stromal cells (MSCs) show promising angiogenic potential for the treatment of ischemic arterial diseases, particularly in peripheral arterial disease. The small extracellular vesicles (sEVs) produced by these cells may have comparable potential. Indeed, sEVs act as cargo, transporting biological materials to transfer to host cells in the sites of ischemia. This study focuses on the characterization of undifferentiated MSCs and endothelial-like MSCs cultured under hypoxic conditions (MSC-ELH) and their sEVs. MSC-ELH are characterized by the overexpression of key endothelial mRNAs; they can produce large amount of sEVs, pro-angiogenic and mitogenic factors, and a small quantity of IL-6, a cytokine that is deleterious in the context of tissue ischemia. MSC-ELH-derived sEVs are endowed with high pro-angiogenic potential as they contain the mRNAs coding for VEGF-A, FGF2, EGF and corresponding proteins. sEVs can internalize in endothelial cells and skeletal muscle cells. MSCs-EVs can deliver their content to target cells and stimulate their proliferation and pseudo-tube formation, in an in vitro assay. This work highlights the beneficial impact of hypoxia and endothelial differentiation on MSC-ELH. Derived sEVs, may be used as therapeutic vectors for the treatment of ischemic arterial disease, as an innovative "cell-free" therapy

Style APA, Harvard, Vancouver, ISO itp.

14

ANDRENELLI, ELISA. "Advanced technologies enhance exercise effectiveness in neurodegenerative disorders: evidence from neuroplasticity studies". Doctoral thesis, Università Politecnica delle Marche, 2019. http://hdl.handle.net/11566/263447.

Pełny tekst źródła

Streszczenie:

Le malattie neurodegenerative come la Malattia di Parkinson e la Sclerosi Multipla sono caratterizzate dalla comparsa di cellule microgliali e astrogliali reattive, un processo noto come neuroinfiammazione. L'attivazione delle cellule gliali può indurre un aumento dei livelli di citochine pro- e antinfiammatorie e di ossigeno reattivo, che può portare alla modulazione della funzione neuronale e della neurotossicità osservata in diverse patologie neurologiche. Non ci sono prove conclusive che possano classificare l'infiammazione come una causa o una conseguenza dell'insorgenza della malattia. Tuttavia, approcci terapeutici specificamente mirati alla neuroinfiammazione e alla neuroplasticità possono rappresentare una strategia efficace per interferire con la progressione della malattia e di conseguenza per prevenire o trattare i sintomi correlati. È noto che l'esercizio fisico moduli efficacemente l'infiammazione e aumenti la plasticità sinaptica influenzando direttamente la struttura sinaptica e indirettamente rafforzando i sistemi sottostanti di supporto ad essa tra cui la neurogenesi, il metabolismo e la funzione vascolare. Sono necessari ulteriori studi per chiarire i parametri dell’esercizio necessari per modulare infiammazione e neuroplasticità, come l‘intensità, la durata, la frequenza e il tipo (aerobico o task oriented) di esercizio. Negli studi seguenti abbiamo dimostrato come un allenamento specifico dell'andatura potrebbe migliorare i sintomi che non rispondono o che rispondono scarsamente al trattamento farmacologico in due comuni disordini neurodegenerativi, la malattia di Parkinson e la sclerosi multipla. Tutti i pazienti arruolati, sia affetti da malattia di Parkinson che da sclerosi multipla, alla valutazione basale hanno mostrato un’alterata neuroplasticità che in entrambi gli studi si è ripristinata solo dopo training del cammino con robot. Questo dato neurofisiologico si è tradotto nel miglioramento clinico del freezing del cammino nella malattia di Parkinson e del cammino ed equilibrio nella sclerosi multipla.
Neurodegenerative diseases such as Parkinson’s disease and multiple sclerosis are characterised by the appearance of reactive microglial and astroglial cells, a process referred to as neuroinflammation. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. There is no conclusive evidence that can classify the inflammation as a cause or a consequence of the disease onset. However, therapeutic approaches specifically targeting neuroinflammation and neuroplasticity may represent an effective strategy to interfere with the disease progression and consequently for preventing or treating the related symptoms. Exercise is known to effectively modulate inflammation and has been reported to change the inflammatory state to become anti-inflammatory or neuroprotective. Moreover, exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and indirectly by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. More studies are needed to elucidate the likely range of intensity, duration, frequency, and type (aerobic or task oriented) of exercise that is required to induce such important target responses. In the following studies we showed how specific gait training could improve symptoms that are unresponsive or that poorly respond to pharmacological treatment in two common neurodegenerative disorders, Parkinson's disease and multiple sclerosis. At baseline assessment, all patients enrolled, either suffering from Parkinson's disease or multiple sclerosis, showed an impaired neuroplasticity that recovered only after robot gait training. This neurophysiological result was correlated to clinical improvement of the freezing of gait in Parkinson's disease and gait and balance in multiple sclerosis.

Style APA, Harvard, Vancouver, ISO itp.

15

Magalon, Jérémy. "Développement d'un médicament de thérapie innovante utilisant la fraction vasculaire stromale du tissu adipeux autologue dans la sclérodermie systémique : de la caractérisation biologique à l'identification de biomarqueurs potentiels d'efficacité". Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0048.

Pełny tekst źródła

Streszczenie:

L’objectif de ce travail est de caractériser les effets antifibrotiques et angiogéniques de la FVS et d’évaluer l’impact du contexte sclérodermique sur ces propriétés angiogéniques. D’autre part, d’identifier une stratégie de monitoring biologique de cette thérapie applicable au contexte sclérodermique.Le premier volet a été de déterminer si la FVS injectée localement peut limiter les processus de fibrose in vivo. L’injection de FVS réalisée précocement ou tardivement s'accompagne d'une réduction significative de la surface de fibrose au profit des surfaces musculaires dans un modèle porcin d’incontinence urinaire. Le deuxième volet a été de rechercher si le contexte autologue de la sclérodermie systémique affecte les propriétés angiogéniques de la FVS. Cette étude a montré une légère altération de la capacité angiogénique sur des tests de Matrigel Plug in vivo associé à une signature transcriptomique de la FVS de patients sclérodermiques. Le troisième volet a été d’identifier une stratégie de monitoring biologique utile pour évaluer objectivement l’impact de nouvelles thérapies sur la vasculopathie associée à la sclérodermie systémique. L’élévation des PECs et de la Fractalkine prédisent de manière indépendante le score de sévérité de la maladie et la gravité de la fibrose pulmonaire. Ce travail a ainsi permis de progresser dans le développement d’une thérapie cellulaire innovante pour limiter la vasculopathie ischemique et la fibrose à l’origine du handicap des mains chez les patients sclérodermique et de monitorer son efficacité dans le futur
The aim of this work is to characterize the antifibrotic and angiogenic effects of FVS and to evaluate the impact of the scleroderma context on these angiogenic properties. On the other hand, to identify a strategy of biological monitoring of this therapy applicable to the sclerodermic context.The first step was to determine whether locally injected FVS can limit fibrosis in vivo. The injection of SVF performed early or late is accompanied by a significant reduction in the area of fibrosis in favor of muscle surfaces in a porcine model of urinary incontinence. The second component was to investigate whether the autologous context of systemic scleroderma affects the angiogenic properties of SVF. This study showed a slight alteration of angiogenic capacity on in vivo Matrigel Plug assays associated with a transcriptomic signature of SVF of scleroderma patients. The third component was to identify a biological monitoring strategy that could be used to objectively evaluate the impact of new therapies on vasculopathy associated with systemic sclerosis. The elevation of EPCs and Fractalkine independently predict the severity score of the disease and the severity of pulmonary fibrosis.This work has made it possible to progress in the development of an innovative cell therapy to limit the ischemic vasculopathy and the fibrosis causing hand handicap in scleroderma patients and to monitor its effectiveness in the future

Style APA, Harvard, Vancouver, ISO itp.

16

Trigueros, Angelique Francesca. "Using Parent-Identified Strengths of Autistic Children to Advance Strength-Based Intervention". ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/5803.

Pełny tekst źródła

Streszczenie:

Questions remain about the range of abilities autistic children possess and what constitutes effective treatment. Strength-based intervention contrasts with traditional autistic intervention approaches that focus on children's deficits. Studies on strength-based intervention approaches have not revealed how children's strengths are identified and have not used the insights of parents for this purpose. Neurodiversity serves as the conceptual framework because the tenets of neurodiversity align with those of strength-based approaches and hold that autism is a variation of the human condition rather than a disability. The purpose of this qualitative interpretive phenomenological study was to explore how the parent-identified strengths of autistic children may act as the basis for the advancement of strength-based intervention. The research questions focused on identifying the strengths of autistic children through semistructured interviews with 15 parents of high-functioning autistic children, who were recruited using purposive sampling. Data were analyzed using a three-level method, and six themes emerged: Routine, Caring for Others, Relationship with Parent, Intervention in School, Therapy, and Outlook for the Future. Practical implications for community psychology include development of strength-based approaches based on altruism, parent-child relationships, and positive outlooks for the future. Further research is recommended on caring for others and displaying affection in relation to strength-related constructs, such as resiliency and growth. Effective strength-based interventions may help autistic children develop based on their strengths, leading to positive social change.

Style APA, Harvard, Vancouver, ISO itp.

17

Moisan, Anaïck. "Mécanismes d'action de la thérapie cellulaire par cellules souches mésenchymateuses après infarctus cérébral chez le rat. Développement d'un médicament de thérapie innovante". Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENS033/document.

Pełny tekst źródła

Streszczenie:

L'accident vasculaire cérébral (AVC) représente la première cause de handicap acquis de l'adulte. A l'heure actuelle, moins de 10% des patients peuvent bénéficier de la thrombolyse, et aucun traitement, en dehors de la rééducation, ne permet de réduire efficacement le handicap. Il existe donc un réel besoin de disposer de nouvelles thérapeutiques permettant d'améliorer la récupération et pouvant être administrées dans un délai élargi par rapport à celui de la thrombolyse. Nos travaux expérimentaux chez le rat, associant imagerie IRM de la microvascularisation, analyse de l'expression des gènes de l'angiogenèse et étude comportementale, ont permis de définir une phase de transition (J3-J7) suivie d'une phase subaigüe (J7-J25) post-AVC. Ces deux phases sont apparues comme des fenêtres thérapeutiques potentielles pour l'administration de traitement pro-angiogéniques. Depuis près de 20 ans, de nombreuses équipes se sont tournées vers la thérapie cellulaire, notamment par cellules souches/stromales mésenchymateuses humaines (CSMh), comme thérapie réparatrice dans les AVC avec un triplement du nombre d'essais cliniques au cours des 10 dernières années. Cependant, les données de la littérature ne permettent pas de bien comprendre le mécanisme d'action des CSMh, particulièrement après une administration à la phase subaigüe. Nos travaux ont permis de progresser dans la compréhension de l'effet microvasculaire des CSMh, administrées dans les conditions d'un essai clinique de phase II qui se déroule actuellement à Grenoble (ISIS : Intravenous Stem Cells After Ischemic Stroke). Nous avons montré que la récupération sensori-motrice et cognitive post-ischémique observée après administration intraveineuse de CSMh était liée à une augmentation de l'angiogenèse. Les facteurs angiogéniques Ang2, Ang1, SDF-1 et TGFβ1, dont la sécrétion endogène est augmentée par les CSMh, semblent participer à une meilleure stabilisation vasculaire et pourrait expliquer l'effet bénéfique de ces cellules. Dans le cadre du développement des CSMh en tant que médicament de thérapie innovante, nous avons montré l'absence de potentiel tumorigène des CSMh par une étude toxicologique de tumorigénicité in vivo. Par analyse rétrospective des CSMh produites dans le cadre de l'essai clinique de phase II, nous avons montré la faisabilité de la production de CSMh conformes aux spécifications et en quantité suffisante par l'Unité de Thérapie Cellulaire. Par ailleurs, ces CSMh cultivées ex vivo peuvent présenter des anomalies caryotypiques erratiques, non clônales. Ces anomalies semblent être liées au maintien en culture, plus qu'au procédé lui-même. Une composante "donneur" semble également contribuer à l'apparition de ces anomalies
Stroke is the leading cause of disability in adult. Less than 10% of patients can be treated with thrombolysis. Except rehabilitation, no effective treatment exists to improve functional recovery after the acute phase. Therefore, there is a wide need to develop an effective therapy applicable after several days or weeks following stroke. Using a multiparametric approach (microvascular MRI, analysis of angiogenic genes expression and behavioral study) in rat ischemic stroke model, we defined a transition stage (D3-D7) followed by a subacute phase (D7-D25) during post-stroke remodeling. These two phases represent an interesting target time-window for administration of pro-angiogenic therapies. Since 20 years, cell therapy, notably by human mesenchymal stem/stromal cells (hMSC), emerged as a “regenerative treatment” with threefold increase in clinical trial during the last 10 years. However, still limited data are available regarding the mechanisms by which hMSC benefit, especially at the subacute phase. We progressed in understanding the microvascular plasticity that occurs after an intravenous injection of hMSC in a rat model of transient focal cerebral ischemia. Our preclinical studies were carried out simultaneously with a phase II clinical trial that currently goes on in Grenoble (ISIS: Intravenous Stem Cells After Ischemic Stroke). We reported a sustained functional and cognitive long-term benefit of hMSC IV injected at the subacute stage correlated to an increase of angiogenesis. Ang2, Ang1, SDF-1 and TGFβ1, whose endogenous level tends to be overexpressed by hMSC, would enhance stabilization and survival of newborn vessels, accounting for benefit of these cells. As part of the hMSC development as an advanced therapy medicinal product, we realized an in vivo tumorigenicity assay and showed the absence of tumor development after hMSC injection. We also retrospectively analyzed hMSC produced for the phase II clinical trial. We confirmed the feasibility to produce hMSC, conformed to specifications and in adequate quantity, in the Cell Therapy Unit. In addition, we showed that ex vivo expanded hMSC can present, non clonal, erratic chromosomal abnormalities. Such chromosomal abnormalities appeared to be more related to the maintenance in culture than to the manufacturing process. A “donor” component may also contribute to emergence of such abnormalities

Style APA, Harvard, Vancouver, ISO itp.

18

Avercenc-Léger, Léonore. "Devenir des propriétés immunomodulatrices des cellules souches mésenchymateuses de la gelée de Wharton au cours de la différenciation chondrocytaire". Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0210/document.

Pełny tekst źródła

Streszczenie:

Ce travail a pour objet de déterminer les conditions optimales de production de substituts allogéniques capables de combler les lésions cartilagineuses dans le cadre du traitement de l’arthrose. Il s’oriente particulièrement sur la composante cellulaire de ces substituts. L’usage de cellules souches mésenchymateuses issues de cordons ombilicaux (CSM-GW) implique de déterminer quels facteurs obstétricaux, liés à l’environnement direct et indirect des CSM-GW, peuvent influencer leur prolifération ainsi que leur différenciation chondrocytaire. Dans une première partie de ce travail, trois types de facteurs ont été étudiés : les facteurs liés à l’enfant donneur, au déroulement de l’accouchement et de la délivrance, à la grossesse et à la mère. Nos données montrent que les CSM-GW ont des capacités prolifératives améliorées lorsque l’accouchement s’est déroulé à terme et sans complication, avec utilisation de Syntocinon® pendant le travail. Sur la base de ces résultats, nous avons utilisé les CSM-GW les plus efficaces dans le cadre de l’ingénierie du cartilage. Il a ensuite été essentiel d’élucider le profil d’action des CSM-GW dans un contexte allogénique. Le deuxième temps de ce travail a donc consisté à chercher le profil de stimulation le plus performant, au regard de la viabilité des cellules et de l’évolution de la sécrétion des facteurs solubles responsables des propriétés immunomodulatrices des CSM-GW au cours de la différenciation chondrocytaire. Nous avons alors mimé, in vitro et en biomatériaux d’Alginate/Acide hyaluronique (Alg/HA) une telle situation en stimulant les CSM-GW avec différentes doses d’IFN-γ et de TNF-α. Selon nos résultats, la stimulation par IFN-γ et TNF-α sur les CSM-GW en biomatériaux d’Alg/HA est plus efficace lorsque ces deux cytokines sont utilisées conjointement et n’est pas délétère pour la viabilité cellulaire aux concentrations respectives de 20 et 30 ng/mL. Cette double stimulation induit une augmentation de la sécrétion d’IL-6 et de PGE-2 par les CSM-GW, ne modifie pas leur sécrétion de TGF-β, et diminue la sécrétion de VEGF. Nous avons confirmé ces données lors d’une mise en situation fonctionnelle : des cocultures avec des cellules mononucléées de sang périphérique (PBMC) de donneurs sains nous ont permis d’évaluer la réponse des CSM-GW lors d’une situation allogénique. Ces mises en situations allogéniques ont été étudiées à différents temps afin d’évaluer les propriétés immunologiques des CSM-GW au cours du temps passé en biomatériaux. Nos résultats montrent que les CSM-GW peuvent exprimer des molécules HLA-G ainsi qu’IDO, mais ces expressions sont limitées en biomatériaux d’Alg//HA. Les CSM-GW en biomatériaux d’Alg/HA en situation allogénique ne sont pas immunogènes, quel que soit le temps de différenciation. En revanche, leurs capacités immunomodulatrices décroissent au cours du temps et sont plus fortes à J0 et J3 de la différenciation chondrocytaire, ce qui oriente vers une utilisation précoce de ces cellules. Les conclusions de ce travail permettent de (i) sélectionner les cordons idoines à l’ingénierie cellulaire et l’ingénierie du cartilage, (ii) définir les conditions permettant de mimer une situation allogénique in vitro, (iii) connaitre les propriétés immunomodulatrices des CSM-GW au cours de la culture en biomatériaux d’Alg/HA, y compris en situation allogénique
The purpose of this work is to determine the optimal conditions for allogeneic substitutes production, adapted to filling the cartilaginous lesions in osteoarthritis treatment. It focuses on the cellular component of these substitutes. The use of mesenchymal stem cells from umbilical cords (WJ-MSC) involves determining which factors, related to direct and indirect environment of the WJ-MSC, can influence their proliferation and chondrogenic differentiation. In a first part of our work, three types of factors were studied: related to the donor child, the course of labor and delivery, pregnancy and the mother. Our results show that WJ-MSC have enhanced proliferative capacities when coming from full-term birth and without complications, with the use of Syntocinon® during labor. On this basis, we used the most effective WJ-MSC for cartilage engineering. It was then essential to elucidate their action profile in allogeneic context. We stimulated WJ-MSC embedded in Alginate/Hyaluronic Acid (Alg/HA) scaffolds with different concentrations of IFN-γ and TNF-α in order to determine the most effective stimulation profile, with regard to viability of the cells and evolution of immunomodulatory soluble factors secretion. According to our results, the stimulation by IFN-γ and TNF-α on WJ-MSC in Alg/HA scaffolds is more effective when these two cytokines are used together and is not deleterious for cell viability at the concentrations of 20 and 30 ng/mL, respectively. This double stimulation induces an increase in the secretion of IL-6 and PGE-2 by the WJ-MSC, a decrease in the secretion of VEGF and does not modify the secretion of TGF-β. We confirmed these data during a functional study: cocultures with peripheral blood mononuclear cells (PBMC) from healthy donors allowed us to evaluate the response of WJ-MSC in an allogeneic situation. These allogeneic situations have been studied at different times to evaluate the immunological properties of WJ-MSC during the time of chondrogenic differentiation. Our results show that WJ-MSC can express HLA-G molecules as well as IDO, but these expressions are limited in Alg/HA biomaterials. Finally, the WJ-MSC in Alg/HA biomaterials in allogeneic conditions are not immunogenic, regardless of the time of differentiation. On the other hand, their immunomodulatory capacities decrease over time and are stronger at day 0 and day 3 of chondrogenic differentiation, which leads to an early use of these cells. Finally, this work allows us to (i) select the umbilical cords suitable for cellular and cartilage engineering, (ii) define the conditions mimicking in vitro an allogeneic situation, (iii) elucidate the immunomodulatory properties of WJ-MSC during Alg/HA biomaterials chondrogenic differentiation, including allogeneic situations

Style APA, Harvard, Vancouver, ISO itp.

19

Wagner, Quentin. "Optimisation de dispositifs médicaux thérapeutiques implantables pour l'ingénierie tissulaire osseuse et cartilagineuse". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ114/document.

Pełny tekst źródła

Streszczenie:

Notre équipe a optimisé la formulation de dispositifs médicaux implantables pour l’ingénierie tissulaire osseuse et cartilagineuse. A ces fins, nous nous sommes basés sur des implants nanostructurés d’origine naturelle ou synthétique conçus au sein du laboratoire par la méthode d’électrospinning, pour imiter la matrice extracellulaire du compartiment osseux, et un hydrogel composé d’alginate et d’acide hyaluronique imitant la composition du compartiment cartilagineux. Dans une première partie de mon travail, pour la régénération osseuse, nous avons optimisé la formulation d’un implant nanostructuré à base de chitosane pour une accélération de cette régénération. Ceci a été possible en rendant actif ce dispositif médical implantable par incorporation de nanoparticules de silice, conférant à la construction nanocomposite des propriétés mécaniques accrues, et une excellente biocompatibilité avec le tissu hôte. Une autre étude pour la même visée a permis d’élaborer une nouvelle stratégie d’ensemencement de dispositif implantable synthétique et nanostructuré par des microtissus cellulaires, remplaçant un ensemencement de cellules isolées et permettant des performances de minéralisation accrues à l’intérieur de l’implant. Dans un deuxième temps, pour la régénération de l’unité ostéoarticulaire, nous avons proposé deux implants bi-compartimentés et hybrides comportant des microtissus de cellules souches mésenchymateuses. Ces implants sont composés d’un hydrogel contenant les cellules souches permettant la régénération du cartilage, et d’une membrane collagénique naturelle (Bio-Gide®) ou synthétique (membrane de polycaprolactone), dotée de nanoréservoirs (technologie brevetée par le laboratoire) de facteur de croissance ostéogénique (BMP-7) pour une régénération du socle osseux (os sous-chondral) de l’unité os-cartilage. La troisième partie de mon travail a concerné la vascularisation des implants osseux et particulièrement l’accélération du recrutement vasculaire. Dans ce cadre plus vasculaire, nous avons proposé une stratégie qui vise à doter un implant synthétique nanostructuré de facteur de croissance angiogénique (VEGF), puis à lui appliquer un ensemencement séquentiel de cellules mésenchymateuses adultes « ostéoblastes humains» et de cellules endothéliales humaines (HUVECs). Cette stratégie a permis un recrutement et une hiérarchisation accrue des cellules endothéliales dans l’implant. En conclusion, l’optimisation des implants développés au laboratoire permettra sans nul doute de proposer dans un futur proche de nouveaux dispositifs médicaux implantables (DMI) thérapeutique combinés de type DMI-MTI (Médicaments de Thérapie Innovante) pour l’ingénierie tissulaire osseuse et cartilagineuse en particulier en médecine régénérative ostéo-articulaire
Our team optimized the formulation of implantable medical devices for bone and cartilage tissue engineering. To that end, we based our work on nanostructured implants, either natural or synthetic, made in the laboratory by electrospinning process, to mimic bone extracellular matrix, and hydrogel of alginate/hyaluronic acid to mimic cartilage extracellular matrix. First, concerning bone regeneration, we optimized the formulation of a nanostructured scaffold composed of natural chitosan to enhance bone regeneration. This was made possible by doping this implantable medical device with silica nanoparticles, offering this nanocomposite better mechanical properties, and excellent biocompatibility with host tissue. Another study with the same aim allowed elaborating a new cell seeding strategy, to seed these implantable medical devices with cell microtissues instead of single cells, offering higher mineralisation efficiencies within the implant. Consequently, for the regeneration of the osteochondral unit, we proposed two compartmented and hybrid implants comprising mesenchymal stem cells microtissues. Those implants are made of a hydrogel containing the stem cells, allowing the regeneration of cartilage, and a membrane, either natural (collagenic Bio-Gide®) or synthetic (electrospun polycaprolactone) equipped with nanoreservoirs (technology patented by the laboratory) of osteogenic growth factor (BMP-7) for the regeneration of osseous stand (the subchondral bone) of the bone-cartilage unit. Finally, to study the improvement in vascular recruitment, we proposed a new strategy combining the modification of an implantable device with angiogenic growth factor (VEGF), prior to its sequential seeding with mesenchymal cells “human osteoblasts” and human endothelial cells (HUVECs). This strategy allowed higher recruitment and structuration of endothelial cells within the implant. To conclude, the implant optimisation strategies developed in the laboratory will certainly allow proposing in the near future new combined Advanced Therapy Medicinal Products (ATMPs) and Implantable Medical Device for bone and cartilage regeneration, in particular in the field of osteoarticular regenerative nanomedicine

Style APA, Harvard, Vancouver, ISO itp.

20

Nieves, Christina Impoco. "Expressive Arts Intervention for the Adult Cancer Survivor in the Community Support Group Setting". Kent State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1573897771394791.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

21

McCune, Susana Lauraine. "Worlds of Connection: A Hermeneutic Formulation of the Interdisciplinary Relational Model of Care". Antioch University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=antioch1404395833.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

22

Patout, Maxime. "Evaluation des techniques pour la prise en charge diagnostique et thérapeutique de l'insuffisance respiratoire chronique A Randomized controlled trial on the effect of needle gauge on the pain and anxiety experienced during radial arterial puncture Long term survival following initiation of home non-invasive ventilation : a European study Neural respiratory drive predicts long-term outcome following admission for exacerbation of COPD : a post hoc analysis Neural respiratory drive and cardiac function in patients with obesity hypoventilation syndrome following initiation of non-invasive ventilation Polysomnography versus limited respiratory monitoring and nurse-led titration to optimise non-invasive ventilation set-up a pilot randomised clinical trial Chronic ventilator service Step-down from non-invasive ventilation to continuous positive airway pressure : a better phenotyping is required AVAPS-AE versus ST mode : a randomized controlled trial in patients with obesity hypoventilation syndrome Technological advances in home non-invasive ventilation monitoring : reliability of data and effect on patient outcomes Efficacy of a home discharge care bundle after acute exacerbation of COPD Prediction of severe acute exacerbation using changes in breathing pattern of COPD patients on home noninvasive ventilation Charasteristics and outcome of patients set up on high-flow oxygen therapy at home Trial of portable continuous positive airway pressure for the management of tracheobronchomalacia". Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR115.

Pełny tekst źródła

Streszczenie:

L’insuffisance respiratoire chronique est un syndrome défini par une défaillance monoviscéralerespiratoire. Sa principale origine est aujourd’hui le syndrome obésité-hypoventilation qui concerne 4 à 5% des patients obèses. L’IRC est aussi le stade évolutif terminal de la bronchopneumopathie chronique obstructive qui touche 6 à 8% de la population adulte. L’incidence de ces pathologies et donc de l’insuffisance respiratoire est en augmentation constante. Dans cette thèse, nous avons évalué les nouvelles modalités diagnostiques et thérapeutiques qui pourraient améliorer la prise en charge des patients atteints d’insuffisance respiratoire chronique.Concernant la prise en charge diagnostique, nous avons montré que les données fournies par l’électromyographie de surface des muscles intercostaux, outil qui évalue le travail respiratoire, constituent un marqueur pronostique indépendant chez les patients atteints de bronchopneumopathie chronique obstructive. Nous avons également montré leur pertinence pour prédire l’efficacité clinique et l’observance à la ventilation non-invasive à domicile.Concernant la prise en charge thérapeutique, nous avons montré que l’utilisation d’un mode semi-automatisé de ventilation non-invasive a la même efficacité que celle de modes classiques en permettant une mise en place plus rapide du traitement. Nous avons également rapporté l’intérêt de l’oxygénothérapie à haut débit au domicile alors que ce traitement était utilisé jusque-là dans le seul cadre des soins intensifs. Enfin, nous avons rapporté les bénéfices de la pression positive continue au cours de l’effort chez les patients ayant une trachéobronchomalacie. Concernant le suivi des patients, nous avons montré que les données des logiciels de ventilation non invasive permettent de prédire la survenue d’une exacerbation sévère de BPCO mais que l’utilisation de la télémédecine chez les patients insuffisants respiratoires chroniques ne peut être encore pleinement intégrée dans la pratique clinique. Au cours de cette thèse, nous avons identifié de nouveaux outils physiologiques, de nouvelles modalités d’administration des traitements et de nouveaux outils de suivi à domicile, à même d’améliorer la prise en charge des patients insuffisants respiratoires chroniques
Single-organ respiratory failure defines chronic respiratory failure. Obesity hypoventilation syndrome is the main cause of chronic respiratory failure and occurs in 4 to 5% of obese patients. Chronic respiratory failure is also the end-stage evolution of chronic obstructive pulmonary disease that has a prevalence of 6 to 8% in the adult population. The incidence of these diseases increases so does the incidence of chronic respiratory failure. In this thesis, we will evaluate novel diagnostic and therapeutic modalities that could improve the care of patients with chronic respiratory failure. Regarding diagnostic modalities, we have seen that evaluating the work of breathing with surface parasternal electromyography was an independent prognostic marker in patients with chronic obstructive pulmonary disease. We have also seen that it was a relevant tool to predict the clinicalefficacy and compliance to home non-invasive ventilation. Regarding therapeutic modalities, we have shown that the use of a semi-automatic mode of non-invasive ventilation had the same efficacy of a standard mode with a shorter length of stay for its setup. We have shown the relevance and feasibility of the use of high-flow oxygen therapy in the home setting whilst it was only used in intensive care units. Finally, we have shown the benefits of continuous positive airway pressure during exertion in patients with tracheobronchomalacia. Regarding patients’ follow-up, we have shown that the use of data from built-in software could predict the onset of a severe exacerbation of chronic obstructive pulmonary disease. However, we also show that the implementation of tele-medicine in patients with chronic respiratory failure cannot be included in daily clinical practice yet. In this thesis, we have identified novel physiological tools, novel ways to administer treatments and novel follow-up tools that can improve the management of patients with chronic respiratory failure

Style APA, Harvard, Vancouver, ISO itp.

23

Pugliano, Marion. "Conception et optimisation d'un implant thérapeutique combiné à des organoïdes de cellules souches pour la nanomédecine régénérative ostéoarticulaire". Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ111.

Pełny tekst źródła

Streszczenie:

Notre équipe a mis au point une stratégie innovante d’implants thérapeutiques biphasiques, pour une régénération plus efficace et plus durable du cartilage articulaire, dans le cadre du traitement des lésions ostéochondrales. Ces implants pourraient représenter de meilleures alternatives aux traitements actuellement utilisés en chirurgie orthopédique. Dans un premier temps, nous avons élaboré un modèle d’implant thérapeutique à base de collagène de type II dérivé de méduse, fonctionnalisé par des nanoréservoirs de facteurs de croissance TGF-β3 et équipé de cellules souches mésenchymateuses humaines (hCSMs) dérivées de la moelle osseuse. La biocompatibilité et les propriétés chondrogéniques de cet implant ont été validées par des analyses in vitro, confirmant son potentiel thérapeutique pour la régénération du cartilage articulaire. Dans un second temps, nous nous sommes plus particulièrement concentrés sur la régénération de l’unité ostéochondrale. Il est en effet essentiel de régénérer un os sous-chondral sain, pour permettre une régénération stable du cartilage articulaire en surface. Dans ce but, nous avons développé un implant thérapeutique doté de deux compartiments : (i) un premier compartiment élaboré à partir d’un biomatériau synthétique de poly-ε-caprolactone (PCL), doté de nanoréservoirs de facteur de croissance BMP-7, pour la régénération de l’os sous-chondral : (ii) un second compartiment à base d’un hydrogel d’alginate et d’acide hyaluronique, ensemencé d’organoïdes hybrides de hCSMs et de chondrocytes humains, pour la régénération du cartilage articulaire. L’efficacité de cet implant biphasique a été confirmée in vitro et in vivo chez la souris. Dans un troisième temps, nous avons évalué notre stratégie d’implant thérapeutique biphasique en site intra-articulaire, chez l’animal de grande taille (brebis). Ces travaux ont permis de valider la faisabilité et l’efficacité de notre stratégie, combinant cette fois-ci : (i) un implant collagénique commercial, doté de nanoréservoirs de facteur de croissance BMP-2, pour la régénération de l’os sous-chondral ; (ii) un hydrogel d’alginate et d’acide hyaluronique, incorporant des organoïdes de CSMs de moelle osseuse de brebis, pour la régénération du cartilage articulaire. En conclusion, ces médicaments combinés de thérapie innovante, associant des biomatériaux naturels ou synthétiques (dispositif médical implantable), des molécules thérapeutiques et des cellules souches mésenchymateuses (médicament de thérapie innovante), permettent la régénération de l’unité ostéochondrale dans son ensemble. Cette stratégie novatrice permettra sans nul doute de grandes avancées en nanomédecine régénérative ostéoarticulaire, dans l’optique d’améliorer toujours plus le traitement et le confort des patients
Our team has developed an innovative strategy based on biphasic therapeutic implants allowing a more effective and long-lasting regeneration of articular cartilage in the treatment of osteochondral lesions. These implants may represent better alternatives to the current treatments used in orthopaedic surgery. First, we developed a jellyfish type II collagen therapeutic implant model, functionalized with TGF-β3 growth factor nanoreservoirs, and equipped with human bone marrow-derived mesenchymal stem cells (hMSCs). The biocompatibility and chondrogenic properties of this implant have been validated in vitro, confirming its therapeutic potential for the regeneration of articular cartilage. In a second time, we focused more on the regeneration of the osteochondral unit. Indeed, it is crucial to regenerate a healthy subchondral bone, to allow a stable regeneration of articular cartilage on the surface. To this end, we have developed a therapeutic implant with two compartments : (i) a first compartment based on a synthetic poly-ε-caprolactone (PCL) biomaterial, equipped with BMP-7 growth factor nanoreservoirs, for the regeneration of the subchondral bone ; (ii) a second compartment based on a hydrogel of alginate and hyaluronic acid, seeded with hybrid organoids of hMSCs and human chondrocytes, for the regeneration of the articular cartilage. The effectiveness of this biphasic implant has been confirmed in vitro and in vivo in mice. Thirdly, we evaluated our biphasic therapeutic implant strategy in the large animal (sheep). This work validated the feasibility and effectiveness of our strategy, by combining : (i) a commercial collagen implant with BMP-2 growth factor nanoreservoirs, for the regeneration of the subchondral bone ; (ii) a hydrogel of alginate and hyaluronic acid, incorporating organoids of sheep bone marrow MSCs, for the regeneration of articular cartilage. In conclusion, these combined advanced medicinal products (ATMPs), combining natural or synthetic biomaterials (implantable medical device), therapeutic molecules and mesenchymal stem cells, allow the regeneration of the entire osteochondral unit. This innovative strategy will undoubtedly lead to major advances in osteoarticular regenerative nanomedicine, aiming to improve the treatment and comfort of patients

Style APA, Harvard, Vancouver, ISO itp.

24

Lee, Yuan-Wen, i 李元文. "Traditional Chinese Medicine as Adjunctive Therapy for Patients with Advanced Breast Cancer". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/37gmmr.

Pełny tekst źródła

Streszczenie:

博士
臺北醫學大學
藥學系(碩博士班)
102
Traditional Chinese medicine (TCM) is one of the most common complementary and alternative medicines employed in the treatment of breast cancer patients. However, the clinical evidences of TCM in large scale studies on survival, which is the major concern for breast cancer patients are still lacking. This study used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a retrospective population-based cohort study of advanced breast cancer patients between 2001 and 2010. The patients were separated into TCM user and nonuser groups, and Cox regression models were applied to determine the association between the use of TCM and patient survival. In addition, this study investigated the effects on systemic infection, severe complications, analgesic usage, and health care utilization when using TCM in this specific population. Total of 729 advanced breast cancer patients receiving taxanes were included in this study, 115 TCM users and 614 TCM nonusers with the mean age of 52.0 years. The mean time of follow-up was 2.8 years, with 277 deaths during the 10-year period. Multivariate analysis demonstrated that, compared with nonusers, the use of TCM was associated with a significantly decreased risk of all-cause mortality (adjusted hazard ratio [HR], 0.55 [95% CI, 0.33–0.90] for TCM use for 30-180 days; adjusted HR, 0.46 [95% CI, 0.27–0.78] for use more than 180 days). Further analysis in 115 TCM users, the most frequent TCMs used by breast cancer patients were Jia Wei Xiao Yao San, Pu Gong Ying, and Bai Hua She She Cao. In addition, the results showed that the use of TCM would reduce systemic infection, analgesic usage, and the length of hospitalization for these cancer patients. Adjunctive TCM therapy with taxanes may lower the risk of death and systemic infection in advanced breast cancer patients. It could also reduce analgesic usage and the length of hospitalization among these patients. Future randomized controlled trials are still needed to validate these findings.

Style APA, Harvard, Vancouver, ISO itp.

25

Garcia-Neuer, Marlene. "Systematic diagnostic evaluation for immune-related colitis: a single institutional review of advanced melanoma patients treated with ipilimumab". Thesis, 2016. https://hdl.handle.net/2144/17019.

Pełny tekst źródła

Streszczenie:

Colitis can be a life-threatening immune-related adverse event (irAE) for patients with metastatic melanoma treated with immune checkpoint blockade, a new anti-cancer immunotherapy. With the increasing use of PD-1/PD-L1 and CTLA-4 inhibitors, particularly in combination in melanoma and other cancers, timely and accurate diagnosis of colitis will become increasingly important for oncologists. The main goal of this study is to understand the clinical presentation of ipilimumab-induced colitis and to validate the use of CT scans as a safe and effective diagnostic tool. We analyzed a cohort of 303 patients who received ipilimumab at Dana Farber Cancer Institute on an expanded access protocol or standard of care between the years of 2008 and 2015. Age, number of doses and frequency of ipilimumab doses were found to be clinical characteristics which could help differentiate patients who develop ipilimumab induced colitis from those who only present with diarrhea and other gastrointestinal symptoms. Of the 303 patients, 100 (33%) developed diarrhea and 43 (14%) received treatment with corticosteroids for ipilimumab-induced colitis. For all patients with suspected immune-related colitis, an effort was made to firmly establish the diagnosis prior to or immediately after initiation of treatment. Forty-one of 43 patients (95%) who received steroids for presumed immune-related colitis had a colonoscopy and 27 of 43 (63%) patients had both computed tomography (CT) of the abdomen/pelvis and a colonoscopy including biopsy. In the 31 patients with a CT and biopsy, CT was highly predictive of the presence of colitis on biopsy (sensitivity 85%, specificity 75%, PPV 96%) and the absence of CT findings was predictive of a negative biopsy (negative LR 0.2). In the 44 patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (sensitivity 85%, specificity 88%, PPV 92%, positive LR 7.3). Fifteen of the 17 patients with negative CT findings did not require steroids to reach resolution of symptoms. In conclusion, CT of the abdomen/pelvis is a fast, reliable, and non-invasive mode of diagnosing ipilimumab-induced immune-related colitis, whereas colonoscopy may not be needed to firmly establish that diagnosis

Style APA, Harvard, Vancouver, ISO itp.

26

"A prospective longitudinal observational study on the effectiveness of Chinese herbal medicine in advanced cancer patients". 2010. http://library.cuhk.edu.hk/record=b5894361.

Pełny tekst źródła

Streszczenie:

Wong, Ka Yee.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2010.
Includes bibliographical references (leaves 177-189).
Abstracts in English and Chinese; includes Chinese.
Abstract --- p.i
摘要 --- p.iii
Acknowledgements --- p.v
Table of Contents --- p.vii
List of Appendices --- p.xi
List of Tables --- p.xii
List of Figures --- p.xiv
Abbreviations --- p.xvi
Chapter Chapter 1 --- Introduction --- p.1
Chapter 1.1 --- General Introduction --- p.1
Chapter 1.2 --- Background to the study --- p.2
Chapter 1.2.1 --- Epidemiology of cancer --- p.2
Chapter 1.2.1.1 --- Incidence and mortality in the World --- p.2
Chapter 1.2.1.2 --- Incidence and mortality in Hong Kong --- p.4
Chapter 1.2.2 --- Prevalence of Traditional Chinese Medicine (TCM) --- p.5
Chapter 1.2.3 --- Prevalence of Traditional Chinese Medicine (TCM) in cancer --- p.6
Chapter 1.2.4 --- Development of TCM in Hong Kong --- p.7
Chapter 1.3 --- Theoretical rationale of the study --- p.8
Chapter 1.4 --- Significance of the study --- p.11
Chapter Chapter 2 --- Literature Review --- p.13
Chapter 2.1 --- Introduction --- p.13
Chapter 2.2 --- The concept of Advanced Cancer --- p.13
Chapter 2.2.1 --- Pathology of Advanced Cancer --- p.14
Chapter 2.2.1.1 --- Metastatic Cancer --- p.14
Chapter 2.2.2 --- Sign and Symptoms of Advanced Cancer --- p.19
Chapter 2.2.3 --- Diagnosis of Advanced Cancer --- p.19
Chapter 2.2.4 --- Current Treatment for Advanced Cancer --- p.21
Chapter 2.2.5 --- Limitation of Current Treatments --- p.24
Chapter 2.3 --- Diagnosis and Treatment by TCM of Advanced Cancer --- p.26
Chapter 2.3.1 --- (Advanced) Cancer from the TCM perspectives --- p.26
Chapter 2.3.2 --- Diagnosis by TCM of Advanced Cancer --- p.27
Chapter 2.3.3 --- Treatment by TCM of Advanced Cancer --- p.28
Chapter 2.4 --- Current Evidences about the Clinical Effectiveness of TCM on Cancer Patients --- p.29
Chapter 2.5 --- The concept of Health-related Quality of Life (HRQOL) --- p.35
Chapter 2.5.1 --- The importance of HRQOL to cancer patients --- p.35
Chapter 2.5.2 --- HRQOL instruments --- p.37
Chapter 2.5.2.1 --- EORTC QLQ-C30 --- p.38
Chapter 2.5.2.2 --- SF-36 --- p.39
Chapter 2.6 --- Summary of Literature Review --- p.40
Chapter 2.7 --- The research questions --- p.41
Chapter 2.8 --- Research Hypotheses --- p.42
Chapter 2.9 --- The design of TCM protocol --- p.42
Chapter Chapter 3 --- Methodology --- p.45
Chapter 3.1 --- Introduction --- p.45
Chapter 3.2 --- Protocol --- p.45
Chapter 3.2.1 --- Study Design --- p.46
Chapter 3.2.2 --- Selection of Participants --- p.46
Chapter 3.2.2.1 --- Inclusion criteria --- p.48
Chapter 3.2.2.2 --- Exclusion criteria --- p.49
Chapter 3.2.3 --- Sample size calculation --- p.50
Chapter 3.2.4 --- Setting --- p.51
Chapter 3.2.5 --- Interventions --- p.51
Chapter 3.2.5.1 --- Treatment --- p.51
Chapter 3.2.5.2 --- Medication and dose/dosage --- p.52
Chapter 3.2.5.3 --- Treatment Assignment --- p.55
Chapter 3.2.5.4 --- Concurrent Medications --- p.56
Chapter 3.2.6 --- Procedure and Methods --- p.56
Chapter 3.2.6.1 --- Informed Consent --- p.56
Chapter 3.2.6.2 --- Documentation --- p.57
Chapter 3.2.6.3 --- Assessment Procedure --- p.57
Chapter 3.2.7 --- Outcome Measurements --- p.62
Chapter 3.2.7.1 --- Survey Questionnaire --- p.62
Chapter 3.2.7.2 --- Quality of life (QOL) instruments --- p.62
Chapter 3.2.7.3 --- Global Ratings --- p.64
Chapter 3.2.7.4 --- Physical Examination and Laboratory tests --- p.65
Chapter 3.2.8 --- Safety Considerations --- p.66
Chapter 3.2.8.1 --- Adverse Events (AE) --- p.66
Chapter 3.2.8.2 --- Serious Adverse Event (SAE) --- p.66
Chapter 3.2.8.3 --- Causality Assessment --- p.67
Chapter 3.2.9 --- Ethical consideration --- p.68
Chapter 3.2.10 --- Data Collection --- p.69
Chapter 3.3 --- Data analysis --- p.69
Chapter 3.4 --- Expected Outcomes of Study --- p.71
Chapter Chapter 4 --- Results --- p.72
Chapter 4.1 --- Study Progress --- p.72
Chapter 4.2 --- The Participants --- p.72
Chapter 4.3 --- Clinical characteristics and Socio-demographics of Participants --- p.75
Chapter 4.4 --- Main Outcome - Quality of Life --- p.78
Chapter 4.4.1 --- QLQ-C30 --- p.79
Chapter 4.4.1.1 --- Scoring and Transforming of items into scales --- p.79
Chapter 4.4.1.2 --- Changes of Individual Scale at Different Visits --- p.80
Chapter 4.4.1.3 --- Clinical significance of Scales --- p.98
Chapter 4.4.2 --- SF-36 --- p.104
Chapter 4.4.2.1 --- Scoring and Transforming of items into scales --- p.104
Chapter 4.4.2.2 --- Changes of Individual Scale at Different Visits --- p.104
Chapter 4.4.2.3 --- SF-36 Summary Scales --- p.113
Chapter 4.4.3 --- Correlation of QLQ-C30 and SF-36 --- p.115
Chapter 4.5 --- Measurement of Physical examination --- p.117
Chapter 4.5.1 --- Body Weight --- p.117
Chapter 4.6 --- Measurement of Laboratory Blood tests --- p.118
Chapter 4.6.1 --- "Comparison of CBC, RFT, LFT and LD" --- p.118
Chapter 4.6.2 --- Tumor Markers --- p.120
Chapter 4.7 --- Adverse Events and Serious Adverse Events --- p.121
Chapter 4.8 --- Global Ratings --- p.123
Chapter 4.8.1 --- Global Rating 1 - Severity of Disease --- p.123
Chapter 4.8.2 --- Global Rating 2 - Global Disease Status --- p.124
Chapter 4.8.2.1 --- Change in Global Disease Status --- p.125
Chapter 4.8.2.2 --- Agreement between RCMP and clinician --- p.125
Chapter 4.8.2.3 --- Patients' perception after treatment --- p.126
Chapter 4.9 --- Distribution of TCM patterns and Chinese herbal medicines --- p.127
Chapter 4.10 --- Survival Rate --- p.132
Chapter 4.11 --- Conclusion --- p.133
Chapter Chapter 5 --- Discussion --- p.135
Chapter 5.1 --- Conclusion on findings --- p.135
Chapter 5.2 --- Baseline profile of participants --- p.137
Chapter 5.3 --- Feasibility of TCM on advanced cancer patients --- p.139
Chapter 5.3.1 --- Recruitment of Participants --- p.139
Chapter 5.3.2 --- Compliance of participants to the study schedule --- p.140
Chapter 5.4 --- Health-related Quality of Life --- p.142
Chapter 5.5 --- Safety of TCM --- p.149
Chapter 5.6 --- Chinese medicine practitioner vs Western medicine doctor --- p.150
Chapter 5.7 --- TCM pattern differentiation and treatment --- p.151
Chapter 5.8 --- Implication of study --- p.154
Chapter 5.8.1 --- Clinical implication --- p.154
Chapter 5.8.2 --- Policy implication --- p.154
Chapter 5.9 --- Limitations of the study --- p.155
Chapter 5.10 --- Recommendations for further studies --- p.157
Chapter 5.11 --- Overall Conclusion --- p.158
Appendices --- p.160
References --- p.177

Style APA, Harvard, Vancouver, ISO itp.

27

Mendes, João Pedro Pereira. "Chromatographic purification of virus particles for advanced therapy medicinal products". Master's thesis, 2017. http://hdl.handle.net/10362/24749.

Pełny tekst źródła

Streszczenie:

The increasing number of cancer diagnoses in the last decades is associated with behavioral risks, in addition with those genetically originated. The fight against the disease usually relapses in not selective mechanisms like chemotherapy or radiotherapy, that induce the organism in deep alterations and side effects. One of the alternative strategies relies on the use of advanced therapies medicinal products suchlike viruses, to carry out the treatment in each cell taking advantage of their invading abilities. The cost of producing this oncolytic virus directly influences process engineering, and thus, numerous efforts have been made to improve each purification step. The development of the downstream process begins with the clarification of the viruses harvested from the bioreactor with two depth-filtration steps. This allows a gradual removal of larger impurities like cell debris with a complete virus recovery. Afterwards, a tangential flow filtration step enables volume reduction. After concentration, the retentate is subjected to diafiltration which allows not only the permeation of impurities but also the formulation of the concentrated product for the next processing step. The following step in the purification train is anion exchange chromatography. The chromatographic media used was selected after successive screening tests with a library of resins and membranes. The conditions used reflect the study carried out, in the sense that the load employed corresponds to the DBC10% obtained of 6.2 x 1011 (TP/ml) particles per millilitre and the elution of the viruses is preceded by a low salt concentration elution (200 mM) in order to remove impurities. The yield obtained is 85%. The purification process ends with polishing and sterile filtration to achieve the specified conditions, through a size-exclusion chromatography and membrane filters, respectively, obtaining a total yield of 53%. The study also opens perspectives on innovation and future development with the performance of multi-column chromatography assays and automated filtration tests, both in specialized equipment.

Style APA, Harvard, Vancouver, ISO itp.

28

Carvalho, Marta Alexandra Bogalho Rodrigues de. "Advanced therapy medicinal products : new strategies for clinical applications of cell and gene therapy". Doctoral thesis, 2020. http://hdl.handle.net/10451/48501.

Pełny tekst źródła

Streszczenie:

Advanced therapy medicinal products (ATMPs) have a massive potential to address existing unmet medical needs. Specifically, gene therapy medicinal products (GTMPs) may potentially provide cure for several genetic diseases. Despite much research conducted in this field, only a modest number of products are approved and available. This thesis intends to develop an end-to-end understanding of ATMPs, identifying regulatory and patient access hurdles on gene therapy use In Chapter 1, broad research conducted in this field over the last few decades is explored as well as different clinical applications investigated worldwide. These are based on diverse strategies that range from direct gene replacement or addition to more complex pathways such as specific gene editing or RNA targeting. Important safety risks, limited efficacy, manufacturing hurdles, or ethical conflicts may represent challenges in the success of a candidate GTMP. During the development process, it is fundamental to take such aspects into account and establish overcoming strategies. Then, the current European legal framework of ATMPs is reviewed and an overview of the clinical applications for approved and investigational GTMPs is provided. In Europe, the ATMP regulation was fully implemented in 2009 and, at this point, the Committee for Advanced Therapies was created as a dedicated group of specialists to evaluate medicinal products requiring specific expertise in this area. In Chapter 2, major objections, issues, or concerns raised during the Marketing Authorization Application (MAA) for GTMPs between 2009 and 2017 were identified. During the first few years following CAT establishment, quality issues were often identified as major deficiencies, whereas issues at the nonclinical level appeared to be less frequent. Clinical efficacy and safety issues appeared to have a major role in unsuccessful MAA outcome for GTMPs. Most deficiencies were addressed through clarification during the MAA review or in post-marketing settings. The MAA procedure for GTMPs is complex and it is anticipated that continuous MAA submissions will further enhance the experience of both regulators and applicants, reducing the attrition rate for approval. Despite having a positive Marketing Authorization, this does not mean that these products are being used in clinical practice. In Chapter 3, a full set of hurdles potentially preventing patient access to Gene Therapies is identified based on the most recently available literature. A review of the literature using a systematic approach in two distinct databases was performed by identifying relevant, peerreviewed publications, between 2012 and 2018. Seven major topics were identified as potential patient access hurdles, namely affordability, assessment of value, development of therapy, ethical/social factors, evidence generation, operational implementation and regulatory hurdles. From these, twenty-five additional subthemes were further identified. The most frequently mentioned obstacle in the literature is related to the affordability aspect especially focusing on high cost of therapy (84%) and therapy payment/reimbursement (51%). Importantly, the evidence generation focusing on limited trial outcomes (81%) seems to be a strong obstacle in patient access to these therapies. In Chapter 4, a global discussion on the results obtained in chapter 2 and 3 is presented and summarized in the context of the current body of evidence, as well as the current GTMP landscape. A growing number of Gene Therapies are expected to be developed and made available to patients and health care professionals. This thesis contributed to understanding all hurdles, in a complete and integrated fashion, so that strategies are timely established to ensure gene therapy’s benefits are provided to patients and to the society.

Style APA, Harvard, Vancouver, ISO itp.

29

Antunes, Brígida Isabel do Amaral Neves. "Developing an Advanced Therapy Medicinal Product (ATMP) for the treatment of GvHD". Master's thesis, 2014. http://hdl.handle.net/10362/31884.

Pełny tekst źródła

Streszczenie:

Mesenchymal stem/ stromal cells (MSCs) have been proved to be capable to modulate the immune system through direct interactions target cell-MSC and secretion of soluble molecules that are induced or upregulated following cross-talk with target cells. In this study, a full biological characterization of ImmuneSafe® (IS) features including identity, potency and safety which constitute the Critical Quality Attributes (CQAs) of the product was performed with purpose of providing tools that will assure the consistency and robustness of the manufacturing process or demonstrating product/ process comparability after a particular change in the manufacturing process. In order to achieve this goal a (bio) assay panel was developed and applied to IS in two different steps of manufacturing process. IS CQAs allowed a robust and reproducible characterization of the product, demonstrating their potential to be used throughout the production stage. Similar studies were also performed with similar cell types, such as human skin fibroblasts and MSCs differentiated in adipocytes and osteocytes, which were then benchmarked with IS. The results showed that none of these cell types demonstrated a comparable level of therapeutic potency to IS. The patient enrolling protocol for IS clinical trial to treat GvHD will include the administration of immunosuppressive drugs (methylprednisolone or prednisolone) concomitantly with IS administration. The impact of these drugs on IS identity was evaluated through immunophenotype characterization and potency was evaluated through the activation of the different immunomodulatory pathways. The results showed that immunosuppressive drugs tested, methylprednisolone and prednisolone, did not seem to have a beneficial or detrimental interaction with IS. MSCs are commonly stored in cryopreservation conditions before the deliver to the patient. However, recent studies have shown that banked fresh thawed MSCs have impaired immunomodulatory properties compared to MSCs in culture. IS response to an inflammatory microenvironment was compared in different times of release and fresh thawed cells revealed to have several responses compromised under pro-inflammatory environment. Additionally, IS secretome was also affected, since the production of several cytokines were decreased or even switched off, as well as the immunosuppressive activity of the product. For these reasons the implementation of a release culture step was found to be advantageous in order to maximize the therapeutic potency of IS. Another important issue for cell-based therapies is the product delivery to the hospital. Cells should be formulated in a suitable excipient for intravenous infusion capable of maintaining the cell viability and therapeutic potential during the purposed product shelf-life. For this purpose IS was formulated in a saline solution and identity and potency tests were performed. Hypothermosol was capable of maintaining at least 70% of initial cell number population with 80% of viability, as well as its identity and potency features within a 48h-window. These studies enable a comprehensive IS characterization and the set-up of the assays to be used in the manufacturing process under GMP conditions. Additionally, no detrimental effects on the therapeutic potency of IS were associated with the interactions with the immunosuppressive drugs that will be used in the clinical trial, thus indicating the clinical results will not probably be affected by the background therapy applied to patients. The process of product release was also optimized to guarantee a cell product with maximized immunomodulatory properties and a 48-hour shelf-life was determined, which is a critical issue for the planning of IS logistics for the clinical trial.

Style APA, Harvard, Vancouver, ISO itp.

30

Pinheiro, João Pedro Vicente. "Terapias Avançadas: Perspetiva Regulamentar". Master's thesis, 2019. http://hdl.handle.net/10316/88391.

Pełny tekst źródła

Streszczenie:

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
The big news of this new therapeutic line is mainly the customization of the products to theneeds of a particular patient, striving for uniqueness and specificity.The exponential increase of scientific knowledge in the areas of biotechnology,medicine and cell biology has led to the evolution of very promising new therapies indisease prevention, control and treatment.Advanced therapy medicinal products (ATMP) have revolutionized the field of innovative therapies by offering therapeutic solutions for diseases whose treatmentes were limited or nonexistente. As such a new, innovative, complex and heterogeneous sector, strict regulatory scrutiny is of the most importance and the European Medicines Agency (EMA) has set up the Committee for Advanced Therapies (CAT), which is responsible for regulating and promoting development of this sector. Most of the entities involved in the development of this products are smal and medium enterprises (SMEs), hospitals and academic institutions, entities with limited human and financial resources, barriers that need to be overcome in order to boost this market. Some measures are underway to assist these entitites with regard to the regulatory and economic aspects, including thereduction of fees or opinion on the classification of products. Advanced therapies may in future be seen as a therapeutic pillar of health care, filling areas not covered by so-called conventional therapies, serving to increase the quality and average life expectancy of people with rare diseases hitherto inhealed.
A aumento exponencial do conhecimento científico nas áreas da biotecnologia, medicina e biologia celular conduziu à evolução de novas terapias muito promissoras na prevenção, controlo e tratamento de doenças.Os medicamentos de terapia avançada(ATMP) vieram revolucionar a área das terapias inovadoras, oferecendo soluções terapêuticas para doenças cujos tratamentos eram limitados ou inexistentes com alto grau de personalização. Por ser um setor tão recente, inovador, complexo e heterogéneo é de fulcral importância um controlo rigoroso do ponto de vista regulamentar e, com isso em vista, a Agência Europeia do Medicamento criou o Comité das Terapias Avançadas, responsável pelo regulamento e promoção do desenvolvimento deste setor. A maioria das entidades quese dedica ao desenvolvimento e comercialização destes produtos são pequenas e médias empresas (PMEs), hospitais e instituições académicas, entidades com recursos limitados a nível humano e financeiro, barreiras que necessitam de ser ultrapassadasde formaa impulsionar este mercado. Estão em curso diversas medidas que visam auxiliar estas entidades no que concerne à parte regulamentar e económica, nomeadamente redução de taxas ou opinião sobre a classificação dos produtos. As terapias avançadas poderão no futuro ser vistas como um pilar terapêutico dos cuidados de saúde, preenchendo áreas não cobertas pelas terapias ditas convencionais, servindo para aumentar a qualidade e esperança média de vida em pessoas com doenças raras ou até aí sem cura.

Style APA, Harvard, Vancouver, ISO itp.

31

Costa, Joana Isabel da Conceição Curate Alves da. "Terapias avançadas: enquadramento legal e regulamentar". Master's thesis, 2016. http://hdl.handle.net/10284/5833.

Pełny tekst źródła

Streszczenie:

Medicamentos de terapia avançada (ATMPs) são medicamentos para uso humano que têm por base genes, células ou tecidos. Trata-se de um grupo de medicamentos inovadores, de natureza específica, tanto no seu fabrico, como no mecanismo de ação, que vêm oferecer novas oportunidades no tratamento de doenças. Estão classificados em quatro grupos: medicamentos de terapia genética; medicamentos de terapia com células somáticas; medicamentos de engenharia de tecidos e medicamentos combinados de terapia avançada. A necessidade de harmonização legislativa no espaço europeu deve-se, em grande medida, à natureza complexa e específica destes medicamentos e de obviar a heterogeneidade existente, quer ao nível das exigências (em que cada Estado-Membro estabelece um quadro regulamentar próprio), quer ao nível da qualidade dos tratamentos recebidos. A presente dissertação tem por objectivo apresentar as terapias avançadas, bem como o seu enquadramento legal, abordando os principais diplomas que vigoram no espaço europeu e apresentar os medicamentos atualmente autorizados, suspensos e retirados pela EMA.
Advanced therapy medicinal products are medicines for human use based on genes, cells or tissues. It is a group of innovative medicines, of specific nature regarding its fabric and as well its mechanism of action, that present new opportunities for treatment of diseases. These medicines are classified in four groups: gene therapy medicinal products; somatic cell therapy medicinal products; tissue engineered medicinal products and combined advanced therapy medicinal products. The need for legislative harmonisation in the european area is, to a great extent, due to the complex and specific nature of these medicines and also to remedy the existing diversity in what concerns legal requirements (each Member State has its own legal framework) and also the quality of the treatments received. The purpose of the present dissertation is to present the legal framework of the advanced therapies, addressing the main legal acts in force on the European area and also to draw its current outlook.

Style APA, Harvard, Vancouver, ISO itp.

32

Stehlík, David. "Mezenchymové stromální multipotentní buňky v ortopedii: potenciace hojení kosti". Doctoral thesis, 2015. http://www.nusl.cz/ntk/nusl-349328.

Pełny tekst źródła

Streszczenie:

The aim of the thesis was development of an innovative treatment of bone defects. Human multipotent mesenchymal stromal cells (MSC) play a crucial role in bone healing. Clinical applications of MSC require large amount of cells, which could be obtained by autologous expansion of MSC harvested from bone marrow. As a first step, the standard protocol of MSC expansion based on αMEM medium and fetal bovine serum (FBS) was used. Experiments replacing FBS by pooled human serum (HS) in the culture medium concluded in patenting of a new MSC cultivation protocol (EU 1999250, CR 301141). This one-step cultivation protocol and xenogeneic protein-free cultivation medium is based on CellGro® for Hematopoietic Cells' Medium, HS, human recombinant growth factors, dexamethasone, insulin and ascorbic acid. The preclinical in vitro and in vivo experiments with MSC from both expansion protocols were carried out. Fibrillar polylactic scaffolds were seeded with MSC, cultured, differentiated and implanted in immunodeficient mice (NOD/LtSz-Rag1-). Bone-like mineralized tissue containing vessels was observed. The MSC cultured according to patented method were classified as Advanced-therapy Medicinal Product and has to fulfil the European Medicines Agency regulations to enter the clinical trials. Nevertheless the use of MSC seems...

Style APA, Harvard, Vancouver, ISO itp.

33

Lourenço, Lúcia Machado. "Aspetos de Qualidade críticos para Farmacovigilância de Medicamentos de Terapia Génica - Células Geneticamente Modificadas". Master's thesis, 2019. http://hdl.handle.net/10316/88219.

Pełny tekst źródła

Streszczenie:

Dissertação de Mestrado em Biotecnologia Farmacêutica apresentada à Faculdade de Farmácia
Os medicamentos de terapia avançada são um tema de grande destaque da atualidade no setor da Indústria Farmacêutica. O seu caráter inovador tem sido relacionado com novas abordagens terapêuticas e patologias limitantes ou fatais, para as quais, não existia no mercado nenhum tratamento eficiente.Um exemplo são as células CAR-T (Chimeric Antigen Receptor T Cells). Estas surgem como uma abordagem disruptiva no tratamento de patologias com altas taxas de recidivas. Deste tipo foram já aprovados o Yescarta (Axicabtagene ciloleucel) e o Kymriah (Tisagenlecleucel). O Tisagenlecleucel foi o primeiro medicamento com células CAR-T a receber aprovação, em 2017, da U.S. Food & Drug Administration para o tratamento de Leucemia Linfoblástica Aguda percussora de células B refratária ou com mais do que duas recidivas em crianças e jovens adultos até aos 25 anos. Em 2018, este medicamento recebeu a segunda indicação, ao ter sido indicado para adultos com linfoma de grandes células B, refratário ou com recidiva após duas ou mais linhas de terapia sistémica. De igual forma, o Tisagenlecleucel também se encontra aprovado pela Agência Europeia do Medicamento (EMA), tendo obtido aprovação em 2018 para as mesmas duas indicações acima indicadas.Os medicamentos de terapia avançada consistem em medicamentos biológicos com base em células retiradas do doente e de seguida, estas são devidamente modificadas em laboratório, sendo posteriormente difundidas no mesmo doente, de modo a potenciar a resposta imune. Devido a sua complexidade, tanto no mecanismo de ação como no método de produção, é necessário existirem, a nível regulamentar, meios que permitam a sua correta produção e utilização assim como, metodologias que assegurem a segurança após Autorização de Introdução no Mercado (AIM).Recorrendo à informação existente, regulamentar e científica, no presente trabalho são apresentados orientações e requisitos de qualidade para a produção e controlo de medicamentos de terapia avançada com base em células T geneticamente modificadas. É dado especial relevo ao medicamento Kymriah embora quase em simultâneo tenha sido também autorizado o Yescarta. São abordados requisitos de qualidade, desde a adequada recolha de células do doente, a utilização de vetores virais recombinantes para a inserção de genes nas células T obtidas e o processo de apara a sua modificação. Inclui também a avaliação de risco ambiental no contexto específico da libertação deliberada de organismos geneticamente modificados (OGM).Inclui toda a informação relevante na caracterização dos riscos, nomeadamente na enumeração e análise de medidas de gestão e mitigação de risco que devem ser aplicadas com o objetivo de alcançar a qualidade, a segurança e eficácia de longo prazo. Os riscos identificados devem ser devidamente caracterizados e controlados devido à curta duração da sua Autorização de Introdução no Mercado e ao facto de ser um medicamento biológico, com características e propriedades específicas.
Advanced therapy medicinal products (ATMP) are an important topic today for the Pharmaceutical Industry sector. Its innovative character has been related to new therapeutic approaches and limiting or fatal pathologies, for which no efficient treatment existed on the market.One ATMP example are those composed of CAR-T cells (Chimeric Antigen Receptor T Cells). These emerge as a disruptive approach in the treatment of pathologies with high relapse rates. Two CAR-T Cell ATMP, Yescarta (Axicabtagene ciloleucel) and Kymriah (Tisagencleucel), have already been approved. Tisagencleucel was the first CAR-T cell medicinal product to receive approval in 2017 from US Food & Drug Administration for the treatment of refractory B-cell percursor Acute Lymphoblastic Leukemia (ALL) with more than two relapses in children and young adults to 25 years. In 2018, this product received the second indication as it was extended to adults with refractory or relapsed B-cell Lymphoma after two or more lines of systemic therapy. Similarly, Tisagencleucel is also approved by the European Medicines Agency (EMA) in 2018.and was approved for the same indications as above.Advanced therapy medicinal products consist of biological products where T cells are taken from the patient and then appropriately modified in the laboratory and then diffuse into the same patient to enhance the immune response against the selected epitope. Due to their complexity, both in the mechanism of action and in the production method, it is necessary, at a regulatory level, to establish methodologies for its correct production and use, as well to ensure their continuous safety after marketing authorization (AIM).Using existing regulatory and scientific information, this master’s thesis presents guidelines and quality requirements for the production and control of advanced therapy medicinal products based on genetically modified autologous T-cells. Special emphasis is given to the drug Kymriah although almost simultaneously Yescarta has also been authorized. Quality requirements are addressed, from adequate collection of patient cells, their genetic modification, use of viral vectors for the transduction of the gene of interest. It also addresses the environmental risk assessment in the specific context of deliberate release of genetically modified organisms (GMOs). It covers all the relevant information on risk characterization, namely enumeration and analysis of risk management and mitigation measures that should be applied to achieve long-term quality, safety and efficacy. The identified risks must be properly characterized and controlled because of the limited experience of their post marketing surveillance and the fact that is a biological medicinal product with specific characteristics and properties.

Style APA, Harvard, Vancouver, ISO itp.

34

Ewen, Andreas. "Onkologische Ergebnisse sowie objektive und subjektive Erfassung der Kehlkopffunktion nach organerhaltender lasermikrochirurgischer Resektion und adjuvanter Radio(chemo)therapie bei lokal fortgeschrittenen Larynxkarzinomen". Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-AFDD-1.

Pełny tekst źródła

Style APA, Harvard, Vancouver, ISO itp.

Rozprawy doktorskie na temat „Advanced therapy medicine”

Utwórz poprawne odniesienie w stylach APA, MLA, Chicago, Harvard i wielu innych