The effect of atorvastatin on prosurvival mechanisms in myocardial ischaemia reperfusion injury.

The treatment of acute myocardial infarction has long involved rapid reperfusion of the area at risk. Reperfusion of ischaemic myocardium, however, is not without hazard and can paradoxically result in myocyte death, in a process known as lethal reperfusion- induced injury. Attenuation of this reperfusion-induced injury has become a focus for the treatment of acute coronary artery disease in a clinical setting. In recent years the "Reperfusion Injury Salvage Kinase pathway" the so-called "RISK" pathway has been proposed as a key factor in ensuring myocardial survival. Several agents have been shown to attenuate lethal reperfusion induced injury via this mechanism, and the identification of clinically effective drugs that influence this pathway has taken on some urgency. Over the last two decades 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) reductase inhibitors called "statins" have revolutionised the treatment of hypercholesterolaemia. Meta-analysis of data from clinical trials investigating the effects of statins, however, have indicated that these drugs may have additional beneficial effects independent of their cholesterol-lowering properties. Amongst the pleiotropic effects which have not yet been fully investigated is their potential cardioprotective action. The aim of the present study was to investigate if atorvastatin reduces reperfusion induced injury by activation of the RISK pathway. Using an isolated perfused mouse heart model, the actions of atorvastatin given at reperfusion on infarct size and on the phosphorylation of the anti-apoptotic phosphatidylinositol-3-OH kinase (PI3K)-AKT, the P44/42 extra-cellular signal-regulated kinases (Erk 1/2), and the molecular chaperone Heat Shock Protein (HSP) 27 were studied. The data presented in this thesis indicate that atorvastatin, when administered at reperfusion, results in a significant reduction in infarct size and causes the phosphorylation of these prosurvival kinases. This reduction is sensitive to wortmannin and U0126, which are inhibitors of PBKinase and P44/42 respectively. In addition to the actions described atorvastatin also increased HSP25 phosphorylation (HSP25 is the murine equivalent of the human HSP27) an effect that was abrogated by the p38MAPK inhibitor SB203580, which prevents phosphorylation of p38 and its down stream target HSP25. In view of these findings the potential therapeutic role of human HSP27 was further investigated. Transgenic mice overexpressing HSP27, were found to be protected from lethal ischaemia compared to their HSP27 negative litter mates. In conclusion, this thesis provides evidence that atorvastatin attenuates lethal reperfusion induced injury in a process involving activation of the RISK pathway, and increase of HSP25 phosphorylation. In addition it is demonstrated that overexpression of HSP27 protects against lethal ischaemia

Posterior capsular opacification: Incidence and factors influencing and rate of Nd:YAG capsulotomy in diabetic and uveitic patients and after multifocal intraocular lens implantation.

This thesis examined the incidence and factors affecting the rate of posterior capsular opacification (PCX)), the most common complication of cataract surgery, in diabetic and uvcitic patients and in patients with multifocal intraocular lenses (IOLs). These patients arc particularly sensitive to PCO development because of the risks associated with Nd:YAG capsulotomy in the former two groups and the potential effect on visual function in the latter group. PCO rate was estimated both retrospectively, using Nd:YAG capsulotomy as a surrogate measure of clinically significant PCO, as well as prospectively using clinical and imaging methods. Diabetic patients were found to have a lower incidence and risk of Nd:YAG capsulotomy than non-diabetic patients within 4 years after surgery. Young age, postoperative inflammation, pars plana vitrectomy and, in comparison to 3-piece silicone lOL, polymethylmethacrylate (PMMA) and plate-haptie silicone IOLs were associated with increased risk of Nd:YAG capsulotomy. In subgroup analysis, male gender was found to be a risk factor in the non-diabetic group and the duration and type of diabetes and diabetic retinopathy grade were not risk factors. In a prospective randomised trial, hydrophobic acrylic IOLs, while associated with a higher flare value within the early postoperative period, had a significantly lower rate of PCX) development than plate-haptic silicone IOLs after 6 months and 1 year in diabetic patients. Optical coherence tomography revealed the development of a characteristic mid-peripheral apposition between the optic and the posterior capsule with hydrophobic acrylic IOLs both early and late after surgery, and the lack thereof with plate-haptic silicone IOLs, which is consistent with and explains the difference in PCO rate between the two IOLs. In uveitic patients, the incidence of Nd:YAG capsulotomy was higher within the first two years after surgery than in non-uveitic patients, although the presence of uveitis was not an independent risk factor for an increased rate of NdrYAG capsulotomy. The use of preoperative systemic steroids reduced the risk of Nd.YAG capsulotomy and, in comparison to PMMA IOLs, silicone IOLs reduced the risk of Nd.YACi capsulotomy while hydrophilic acrylic IOLs and young age increased it. In patients with multifocal IOLs, within 4 years of follow-up the incidence of PCX) and Nd:YAG capsulotomy were similar to those reported with monofocal implants and young age was a risk factor for the development of PCO. Patients with multifocal IOLs present for Nd:YAG capsulotomy with earlier loss of high and low- contrast acuity, which could increase the rate of Nd:YAG capsulotomy in these patients

Characterization of vascular heterogeneity of astrocytomas grade 4 for supporting patient prognosis estimation, and treatment response assessment

[ES] Los tumores cerebrales son una de las enfermedades más devastadoras en la actualidad por el importante deterioro cognitivo que sufren los pacientes, la elevada tasa de mortalidad y el mal pronóstico. Los astrocitomas de grado 4 conllevan una supervivencia de cinco años en aproximadamente el 5% de los pacientes diagnosticados, siendo los tumores más agresivos y letales del Sistema Nervioso Central (SNC). Los astrocitomas de grado 4 siguen siendo un problema médico complejo aún sin resolver. A pesar de representar más del 60% de los tumores cerebrales malignos en adultos, estos tumores tienen una baja prevalencia relativa y se consideran una enfermedad huérfana, lo que dificulta el desarrollo de nuevos fármacos o tratamientos que puedan beneficiar a los pacientes. La agresividad de estos tumores se debe a diferentes características, como la fuerte angiogénesis, la necrosis, la microproliferación vascular, la capacidad de invasión e infiltración de las células tumorales y un microambiente inmunológico particular. Además, debido a la rápida progresión de los astrocitomas de grado 4, en la zona de la lesión coexisten diferentes regiones específicas que cambian con el tiempo. Esta naturaleza compleja, junto con la marcada heterogeneidad interpaciente, intratumoral y longitudinal, complica el éxito de un único tratamiento eficaz para todos los pacientes. La imagen de resonancia magnética (MRI) supone una técnica útil para caracterizar la morfología y la vascularidad del tumor. El uso de métodos avanzados y robustos para analizar las imágenes de MR recogidas en las fases iniciales del tratamiento de los pacientes permite la delimitación de las diferentes regiones de los astrocitomas de grado 4, convirtiéndose en herramientas útiles para investigadores, radiólogos y neurocirujanos. Además, el cálculo de biomarcadores vasculares de imagen, como los propuestos en esta tesis, facilitaría la caracterización del tumor, la estimación del pronóstico y los enfoques de tratamiento más personalizados. Esta tesis propone cuatro pilares fundamentales para avanzar en el manejo de los astrocitomas de grado 4. Estos incluyen I) la caracterización multinivel del tumor para mejorar las clasificaciones de los gliomas de alto grado del SNC; II) la búsqueda y desarrollo de biomarcadores robustos para estimar el pronóstico de los pacientes desde el momento prequirúrgico; III) así como para evaluar la respuesta a los tratamientos y la selección de los pacientes que pueden beneficiarse de terapias específicas; y IV) el diseño e implementación de estudios clínicos y protocolos para la recogida de datos a largo plazo de cohortes de pacientes notables a nivel internacional. Para abordar estos cuatro pilares, se ha utilizado un enfoque interdisciplinario que combina el análisis de imágenes médicas, técnicas avanzadas de inteligencia artificial y variables moleculares, histopatológicas y clínicas. En conclusión, hemos abordado la influencia de la heterogeneidad interpaciente e intratumoral del astrocitoma de grado 4 para la caracterización y clasificación del tumor, la estimación del pronóstico del paciente y la predicción de las respuestas al tratamiento. Además, se han diseñado e implementado diferentes estudios clínicos que permiten la recogida de datos multinivel de cohortes internacionales de pacientes con astrocitoma de grado 4.[CA] Els tumors cerebrals són una de les malalties més devastadores en l'actualitat per la important deterioració cognitiva que pateixen els pacients, l'elevada taxa de mortalitat i el mal pronòstic. Els astrocitomes de grau 4 comporten una supervivència de cinc anys en aproximadament el 5% dels pacients diagnosticats, sent els tumors més agressius i letals del Sistema Nerviós Central (SNC). Els astrocitomes de grau 4 continuen sent un problema mèdic complex encara sense resoldre. Malgrat representar més del 60% dels tumors cerebrals malignes en adults, aquests tumors tenen una baixa prevalença relativa i es consideren una malaltia òrfena, la qual cosa dificulta el desenvolupament de nous fàrmacs o tractaments que puguen beneficiar als pacients. L'agressivitat d'aquests tumors es deu a diferents característiques, com la forta angiogènesis, la necrosi, la microproliferació vascular, la capacitat d'invasió i infiltració de les cèl·lules tumorals i un microambient immunològic particular. A més, a causa de la ràpida progressió dels astrocitomes de grau 4, en la zona de la lesió coexisteixen diferents regions específiques que canvien amb el temps. Aquesta naturalesa complexa, juntament amb la marcada heterogeneïtat interpacient, intratumoral i longitudinal fa que es complique l'èxit d'un únic tractament eficaç per a tots els pacients. L'imatge de ressonància magnètica (MRI) suposa una tècnica útil per a caracteritzar la morfologia i la vascularitat del tumor. L'ús de mètodes avançats i robustos per a analitzar les imatges de MR recollides en les fases inicials del tractament dels pacients permet la delimitació de les diferents regions dels astrocitomes de grau 4, convertint-se en eines útils per a investigadors, radiòlegs i neurocirugians. A més, el càlcul de biomarcadors vasculars d'imatge, com els proposats en aquesta tesi, facilitaria la caracterització del tumor, l'estimació del pronòstic i els enfocaments de tractament més personalitzats. Aquesta tesi proposa quatre pilars fonamentals per a avançar en el maneig dels astrocitomes de grau 4. Aquests inclouen I) la caracterització multinivell del tumor per a millorar les classificacions dels gliomes d'alt grau del SNC; II) la cerca i desenvolupament de biomarcadors robustos per a estimar el pronòstic dels pacients des del moment prequirúrgic; III) així com per a avaluar la resposta als tractaments i la selecció dels pacients que poden beneficiar-se de teràpies específiques; i IV) el disseny i implementació d'estudis clínics i protocols per a la recollida de dades a llarg termini de cohorts de pacients notables a nivell internacional. Per a abordar aquests quatre pilars, s'ha utilitzat un enfocament interdisciplinari que combina l'anàlisi d'imatges mèdiques, tècniques avançades d'intel·ligència artificial i variables moleculars, histopatològiques i clíniques. En conclusió, hem abordat la influència de l'heterogeneïtat interpacient i intratumoral del astrocitoma de grau 4 per a la caracterització i classificació del tumor, l'estimació del pronòstic del pacient i la predicció de les respostes al tractament. A més, s'han dissenyat i implementat diferents estudis clínics que permeten la recollida de dades multinivell de cohorts internacionals de pacients amb astrocitoma de grau 4.[EN] Brain tumors are one of the most devastating diseases today because of the significant cognitive impairment suffered by patients, high mortality rates, and poor prognosis. Astrocytomas grade 4 bring five-year survival in approximately 5% of diagnosed patients, being the most aggressive and lethal tumors of the Central Nervous System (CNS). Astrocytomas grade 4 continue to be an unresolved complex medical problem. Despite accounting for more than 60% of malignant brain tumors in adults, these tumors have a low relative prevalence and are considered an orphan disease, making difficult developing new drugs or treatments that might benefit patients. The aggressiveness of these tumors is due to different characteristics, such as strong angiogenesis, necrosis, vascular microproliferation, the capacity of the tumor cells to invade and infiltrate, and a particular immune microenvironment. In addition, due to the rapid progression of astrocytomas grade 4, different specific regions coexist in the lesion area which change over time. This complex nature, along with the marked interpatient, intratumor, and longitudinal heterogeneity, makes complicate the success of a single efficient treatment for all patients. Magnetic Resonance Imaging (MRI) represents a useful technique to characterize tumor morphology and vascularity. Using advanced and robust methods to analyze MR images collected from initial stages of patient management allows the delineation of different regions of astrocytomas grade 4, becoming useful tools for researchers, radiologists and neurosurgeons. In addition, the calculation of imaging vascular biomarkers, such as those proposed in this thesis, would facilitate tumor characterization, prognosis estimation and more personalized treatment approaches. This thesis proposes four fundamental pillars to advance the management of astrocytomas grade 4. These include I) the multilevel characterization of the tumor to improve classifications of high-grade CNS gliomas; II) the search and development of robust biomarkers for estimating patient prognosis from the presurgical moment; III) as well as for evaluating the response to treatments and the selection of patients who may benefit from specific therapies; and IV) the design and implementation of clinical studies and protocols for long-term collecting data from internationally remarkable cohorts of patients. To address these four pillars, an interdisciplinary approach has been used that combines medical imaging analysis, advanced artificial intelligence techniques, and molecular, histopathological, and clinical variables. Concluding, we have addressed the influence of both interpatient and intratumor heterogeneity of astrocytoma grade 4 for tumor characterization and classification, patient prognosis estimation and predicting treatment responses. In addition, different clinical studies have been designed and implemented allowing the collection of multilevel data from international cohorts of patients with astrocytoma grade 4.Álvarez Torres, MDM. (2022). Characterization of vascular heterogeneity of astrocytomas grade 4 for supporting patient prognosis estimation, and treatment response assessment [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/18895

Microscopy Conference 2017 (MC 2017) - Proceedings

Das Dokument enthält die Kurzfassungen der Beiträge aller Teilnehmer an der Mikroskopiekonferenz "MC 2017", die vom 21. bis 25.08.2017, in Lausanne stattfand

Microscopy Conference 2017 (MC 2017) - Proceedings

Das Dokument enthält die Kurzfassungen der Beiträge aller Teilnehmer an der Mikroskopiekonferenz "MC 2017", die vom 21. bis 25.08.2017, in Lausanne stattfand

Urological Cancer 2020

This Urological Cancer 2020 collection contains a set of multidisciplinary contributions to the extraordinary heterogeneity of tumor mechanisms, diagnostic approaches, and therapies of the renal, urinary tract, and prostate cancers, with the intention of offering to interested readers a representative snapshot of the status of urological research