2,117 research outputs found
Marcelo dascal and the literal meaning debates
No full textWhat role does literal meaning play in people’s understanding of indirect and figurative language? Scholars from many disciplines have debated this issue forseveral decades. This chapter describes these debates, especially focusing on the arguments between the author and Marcelo Dascal. I suggest that Dascal’s defense of “moderate literalism” may have some validity, contrary to some of my earlier arguments against this point of view. The chapter acknowledges the strong contribution that Marcelo Dascal has made to interdisciplinary discussions on language and thought
Novel Strategies for the Prolonged Preservation of Donor Lungs Prior to Transplantation
No full textThe gold standard of lung preservation involves cold flushing the organ with a specialized solution, which is subsequently followed by storage in an ice cooler at a resting temperature of approximately 4°C. Developed over 30 years ago, this method continues to be used without significant advances due to its logistical simplicity. Although the primary goal of this approach is to shutdown cellular activity, several deleterious processes may ensue, ultimately compromising the length of time the organ can be kept in this state. According to international large registry reports, average clinical preservation times are only 5-6h. We hypothesized that through the implementation of novel strategies aimed to optimize the current cold storage protocol, prolonged preservation periods could be obtained. We first evaluated the effects of supplementing a novel extracellular oxygen within the standard preservation solution. Although the lungs are stored inflated with oxygen, some regions of the lung may be poorly inflated, leading to a risk of cellular damage over extended periods of time. By storing the lungs with an extracellular oxygen carrier supplemented solution during a prolonged preservation period, we show that cellular oxygen levels can be better maintained, and that post-transplant graft function is enhanced.
We then go on to evaluate the role of temperature during prolonged cold storage periods. Previous literature has suggested 10°C to be the optimal lung storage temperature, however, little is known about the mechanism by which it is functionally superior. With the use of a simple thermoelectric cooler, we demonstrate prolonged storage at 10°C to be superior to current methods and identify mitochondrial protection to be a key determinant of this strategy. As a proof-of-concept, we further go on to demonstrate 10°C storage as a feasible approach to allow for clinical semi-elective transplantation.
Lastly, we aimed to evaluate the potential of normothermic ex vivo lung perfusion (EVLP) to allow for multi-day preservation. Although initially developed as a tool for organ assessment, EVLP presents itself as an opportunity to interrupt the continuous manifestation of cold damage. By subjecting lungs to an intermittent EVLP protocol, we achieved successful 3-day lung preservation with excellent post-transplant outcomes.Ph.D
Novel Ex-Vivo Strategies to Predict and Prevent Reactivation of Latent Human Cytomegalovirus in Lung Transplant Patients
No full textCytomegalovirus (HCMV) transmission from a latently infected donor lung with subsequent viral reactivation after transplantation is common and has impact on quality of life and survival in lung transplant patients. Therefore, efforts to decrease the transmission of donor virus by targeting its latent reservoir would be the ideal strategy for these patients. Recently, a highly specific immunotoxin named F49A-FTP that targets US28 expressed in the membrane of HCMV-infected cells has shown efficacy in killing HCMV-latently infected cells with subsequent reduction of HCMV reactivation. Ex-vivo lung perfusion (EVLP) is an innovative platform that creates a window of opportunity for the reconditioning and treatment of donor allografts before transplantation. Moreover, EVLP is an excellent platform for drug discovery and diagnostics. In this thesis, we first explored the feasibility and efficacy of delivering F49A-FTP to human donor lungs during EVLP. Since the virus is species-specific, the use of animal models of EVLP followed by LTx was not possible here. Therefore, the first main objective was to develop an assay capable of detecting HCMV reactivation events in lung tissue specimens to use as an efficacy read-out for the EVLP phase. After I successfully developed the reactivation assay, we moved on to deliver F49A-FTP to human lungs. HCMV-seropositive donor lungs were perfused for 6 hours with F49A-FTP and resulted in much lower reactivation events when compared to control EVLP lungs that were perfused as in the clinical practice. Importantly, we didn’t observe any acute effects on the donor lungs when delivering F49A-FTP.
In the last part of the thesis, we wanted to elucidate whether the higher-risk donors associated with EVLP assessment could have any impact on HCMV viremia rates after transplantation. By performing a retrospective clinical analysis of more than 1000 lung transplant recipients, we did not observe any negative impact of EVLP practice on HCMV outcomes. We then collected EVLP clinical perfusate samples from 203 HCMV-seropositive donors to measure a 15-plex panel of pro-inflammatory cytokines and associate their levels with HCMV outcomes. Interestingly, we identified that higher levels of IL-7 and IL-12 are both associated with the development of viremia and significantly fewer HCMV-free days after transplant.
Both prediction of higher-risk donor lungs prone to develop HCMV after transplant and a highly efficient targeted therapeutic approach to clear the latent HCMV reservoir investigated in this thesis, are promising for clinical translation and may not only improve survival but also improve patients’ quality of life and decrease costs of managing HCMV complications post-transplantation.Ph.D.2023-11-11 00:00:0
Novel Strategies to Extend In Situ Lung Preservation In An Uncontrolled DCD Large Animal Model
No full textClinical series reported successful transplantation of uDCD lungs preserved by pulmonary inflation up to 3h postmortem. We investigated the additive effects of in situ intrapleural cooling and sevoflurane perconditioning on lung grafts in a porcine uDCD model. After uDCD induction, donors were allocated to: (1) control, (2) topical cooling, or (3) sevoflurane group. Lungs were preserved for 6h, then assessed on EVLP. The group with best performance was evaluated by allotransplantation in a second phase.
Intrathoracic temperature <15°C was achieved within 1h in intervention groups. All lungs in group 1 failed on EVLP. Group 3 outperformed group 2 during 6h-EVLP and presented lower levels of pro-inflammatory cytokines. Post-transplant graft assessment in group 3 showed excellent oxygenation.
Preservation of uDCD lungs with sevoflurane, static lung inflation and intrapleural cooling maintains good function up to 6h postmortem, with excellent early post-transplant performance. These interventions could potentially expand clinical utilization of uDCD lungs.M.Sc
Marcelo Cohen’s Work : Between Fantastic Sociology and Fictional Geography
No full textCette thèse étudie les notions de géographie imaginaire et de sociologie fantastique dans l’œuvre de Marcelo Cohen (Buenos Aires, 1951). Le corpus de travail comprend l’ensemble de la production de fiction narrative de l’auteur (contes, nouvelles et romans en une vingtaine d’ouvrages) entre son premier recueil de récits, Lo que queda (1972), et son roman Balada (2011). La thèse est organisée en trois parties : la première (« Marcelo Cohen et son œuvre. Perspectives théoriques et méthodologiques ») propose une présentation de l’auteur et de son œuvre et un bilan théorique et pratique des notions de géographie imaginaire et de sociologie fantastique ; la deuxième (« Écrire l’espace ») analyse la construction de l’espace dans le corpus choisi dans une double démarche chronologique et figurative ; la troisième (« Littérature et société ») se penche sur les manifestations des dimensions idéologiques, sociales et politiques, et sur les relations entre l’individu et la société dans les ouvrages de Marcelo Cohen. Le travail s’achève par une réflexion globale sur la poétique et l’esthétique de l’auteur argentin.This thesis considers such concepts as fictional Geography and fantastic Sociology in Marcelo Cohen’s work (Buenos Aires, 1951).The body of this research includes all the narrative fiction by this author (some twenty tales, short stories and novels in total), between his first collection of stories, Lo que queda (1972), and his novel Balada (2011).Our thesis develops three domains : the first one (« Marcelo Cohen and his work, a theoretical and methodological outlook ») introduces the author and his work, along with a theoretical and practical evaluation of such concepts as fictional Geography and fantastic Sociology ; the second one (« Space in writing ») analyzes the make of space in the selected books, in a dual approach : both chronological and representational ; the last one (« Literature and society ») addresses the expressions of ideological, sociological and political dimensions, plus the relationship between a particular person and his/her society in Marcelo Cohen’s works. This research ends with a global consideration of poetry and estheticism in the work of our Argentinean author
Urgent Writings. On science, education and justice. Reflections on the neoliberal advance
No full textBook review: "Escritos Urgentes. On science, education and justice. Reflexiones ante el avance neoliberal". Author: Grupo CyTA Year 2017. Editorial: Punto de Encuentro. Origin: Argentina By Marcelo Rui
Photodynamic Therapy During In Vivo Lung Perfusion for Treatment of Lung Metastases
No full textIsolated lung metastases in sarcoma and colorectal cancer patients are inadequately treated with current standard therapies. In Vivo Lung Perfusion, a novel platform, could overcome limitations to photodynamic therapy treatment volumes by using low cellular perfusate, removing blood, and thus theoretically allowing greater light penetration. Development of personalized photodynamic therapy protocols requires in silico light propagation simulations based on optical properties and maximal permissible photodynamic threshold doses of lung tissue. This approach aims to maximize the effective treatment dose to the lung while avoiding toxicity to healthy lung tissue. Based on this rationale, the overall objective of this thesis is to create a whole-lung perfusion assisted PDT protocol for the treatment of lung metastases demonstrating adequate safety and feasibility to guide clinical translation. To achieve this goal, the first aim is to quantify key biophysical properties necessary for PDT; specifically, the optical properties for blood and low-cellular perfusion and the photodynamic threshold dose for 5-ALA and Chlorin e6. This will demonstrate the difference in light penetration for low cellular perfusate vs. blood. The second aim of this work is to develop a 72-hr porcine In Vivo Lung Perfusion survival model to allow assessment of acute and delayed lung toxicity. This model is validated using an accelerated titration dose-escalation study of delivery of oxaliplatin chemotherapy. The final aim of this work involves combining the previous aims to develop a full treatment protocol. Firstly, a light delivery system is created that can homogenously deliver light to the entire lung, and using Monte Carlo simulation software, can be used to simulate personalized treatment plans. The safety and feasibility of a full treatment protocol of whole-lung perfusion-assisted photodynamic therapy is then demonstrated, examining the maximally tolerated doses of 5-ALA and Chlorin e6 photosensitizers. Overall, the protocols and knowledge from this work will provide the basis for Phase 1 clinical trials assessing the safety of whole-lung perfusion assisted PDT.Ph.D
Development of In Vivo Lung Perfusion Strategy for the Treatment of Lung Metastases
No full textIn Vivo Lung Perfusion (IVLP) can potentially enhance the treatment of lung metastases by allowing the delivery of elevated doses of chemotherapy to the lungs without systemic exposure. Previously, experimental and clinical studies reported questionable efficacy and frequent lung toxicity, hindering the broad application of this technique. We have developed a modified IVLP strategy that avoids acute lung injury using a protective mode of ventilation/perfusion. Our IVLP strategy enabled an extended perfusion time using chemotherapy doses usually given intravenously to patients. Additionally, we successfully administered higher chemotherapy levels in a safe manner and found higher lung tissue levels of chemotherapeutic drugs compared to previous studies. Importantly, these findings were possible without acute lung injury, demonstrating a likely protective effect of our IVLP strategy. This is a significant step towards a safer and more effective IVLP technique to help patients with pulmonary metastases, minimizing the adverse effects of chemotherapy to the lungs.M.Sc
O impacto prognóstico da invasão da pleura visceral por metástases de sarcoma de tecidos moles e osteosarcomas nos pacientes submetidos a metastasectomia pulmonar
No full textObjetivo: avaliar o impacto da invasão da pleural visceral na sobrevida de pacientes com metástases pulmonares de sarcomas de tecidos moles e osteossarcomas submetidos à metastasectomia pulmonar. Métodos: revisamos retrospectivamente 133 casos de metastasectomia pulmonar, devido ao sarcoma de tecidos moles e osteosarcomas, no Toronto General Hospital, no Canadá, de janeiro de 2010 a dezembro de 2019. As informações foram coletadas usando como base a primeira metastasectomia pulmonar registrada no prontuário eletrônico do paciente no referido hospital. Resultados: ao todo, 133 pacientes foram submetidos à metastasectomia pulmonar por sarcoma de partes moles e osteossarcoma no Toronto General Hospital, em Toronto, Canadá. O acompanhamento médio foi de 65 meses. A mediana do intervalo livre de doença foi de 23,4 meses. Para toda a coorte, a sobrevida global em 5 anos foi de 48,9%. A invasão da pleura visceral foi observada em 61 pacientes (46%). A sobrevida para pacientes com invasão da pleura visceral, em 3 e 5 anos, foi de 49,2% e 41%, respectivamente. Ao todo, 32 (21%) pacientes tiveram recorrência de doença na pleura parietal, sendo que 18 (29%) apresentavam invasão da pleura visceral. A sobrevida em 5 anos para pacientes com recorrência de doença em pleura parietal foi de 22,6% (P<0,001). A invasão da pleura visceral foi associada a um pior prognóstico (OR=1,89; IC 95%, 1,07 - 3,35; P=0,027), bem como o intervalo livre de doença ≥ 24 meses foi relacionado a um melhor prognóstico (OR=0,175; IC 95%, 0,08 – 0,35; P<0,0001). Conclusão: a invasão pleural visceral foi considerada um fator preditor significativo de morte em 3 anos em pacientes com metástases pulmonares de sarcoma. A invasão da pleura visceral foi associada a uma pior sobrevida, porém, não foi relacionada à recorrência de doença na pleura parietal. Dada a heterogeneidade e complexidade desses tumores associados à doença em estágio avançado, novos estudos são necessários para melhor entender o real impacto desses achados.Objective: to evaluate the overall survival prognostic impact of the visceral pleural invasion in patients with soft tissue sarcomas and osteosarcomas submitted for a sarcoma lung metastasectomy. Methods: we retrospectively reviewed 133 cases of sarcoma lung metastasectomy at Toronto General Hospital, Canada, from January 2010 to December 2019. All the variables information was collected using the first lung metastasectomy recorded in the electronic patient records. Results: from January 2010 to December 2019, 133 patients underwent lung metastasectomy due to soft tissue sarcoma and osteosarcoma in our institution (Toronto General Hospital, Toronto, Canada). The median follow-up was 65 months. The median disease-free interval was 23.4 months. For the entire cohort, the 5- years overall survival was 48.9%. The visceral pleural invasion was seen in 61 patients (46%). The survival for patients with visceral pleural invasion in 3-year and 5-year were 49.2% and 41% respectively. Parietal pleural recurrence was observed in 32 patients (21%). Of those who developed pleural recurrence, 18 (29%) had visceral pleural invasion. The 5- year survival for those with pleural recurrence was 22.6% (P<0.001). The visceral pleural invasion was related to a worse prognosis in both univariate and multivariable analyzes (OR = 1.89; 95% CI, 1.07 - 3.35; P=0.027) as well the disease-free interval ≥ 24 months was associated with a better prognosis (OR = 0.175; 95% CI, 0.08 – 0.35; P < 0.0001). Conclusion: visceral pleural invasion was found to be a significant predictor of death in 3 years in patients with sarcoma lung metastases. Pleural recurrence was also associated with a worse prognostic factor in this population and no correlation was found between VPI and pleural recurrence. Given the heterogeneity and complexity of these tumours associated with advanced-stage disease, new studies are needed to understand better the real impact of these findings
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