In cell culture, the cellular responses on Day 6 and Day 18, and matrix mineralization (Day 35) of human periosteal cells after stimulated by ESW, LIPUS and ESW+LIPUS treatments were studied. Our results showed that LIPUS only exerted transiently beneficial effects on Day 6, but no effect was observed on Day 18. In contrast, ESW inhibited the differentiation on Day 6, and then exerted a time-delayed stimulation effect on cellular response and matrix mineralization. Data of the ESW+LIPUS showed that it was mainly under ESW effects, but LIPUS might impact the beneficial effect of ESW on Day 18, leading to reduced ALP and matrix mineralization. The potentials of the osteocytes to function as mechanosensors and signal relay were also investigated with untreated periosteal cells that separately received conditioned medium from MLO-Y4 osteocyte-like cells, which received the ESW LIPUS and ESW+LIPUS treatments. The periosteal cells showed stimulated proliferation in the ESW+LIPUS and ESW groups, indicating that the stimulus of ESW was transferred in the conditioned medium. / In conclusion, although our in vivo and in vitro findings did not support our hypothesis of the beneficial effects of combined treatment, but ESW had been shown to improve BMD and bone microarchitecture in osteoporotic bone, by stimulation of osteogenic activities in osseous cells. ESW might potentially be developed as treatment for osteoporosis. Our study also indicated that stimulation of osteogenic activities may be the direct interaction of ESW on osteoblast/periosteal cells, or indirectly through biochemical signals relayed by the osteocytes which acted as mechanosensors. / Osteoporosis is a bone disorder with decreased bone mass and deteriorated microarchitecture, leading to increased fracture risk. By using non-invasive biophysical interventions that stimulate osteogenesis, i.e. extracorporeal shockwave (ESW) and low-intensity pulsed ultrasound (LIPUS), may reduce bone loss effectively. We hypothesized that the combined treatment of ESW and LIPUS might produce synergistic effects on osteoporotic bone. The aim of this study was to investigate the efficacy of using ESW treatment alone and combined treatment of ESW and LIPUS to increase bone mineral acquisition on intact osteoporotic bone in vivo, and to investigate their underlying mechanisms in vitro. / Ten osteoporotic goats were used and divided into ESW and ESW+LIPUS groups (n=5). The ESW group received shockwave at calcaneus, distal radius, and femoral condyle on the left limbs once per month. The ESW+LIPUS group also received ESW treatment monthly and LIPUS for 6 day/week. The opposite limbs served as contralateral control. After nine months, percentage BMD changes, mineral apposition rate, trabecular thickness in treatment sites were found higher than that of controls in both groups. Cumulatively increase of serum bone-specific alkaline phosphatase indicated that the improvements were due to the increased osteogenic activities in bone. Of all parameter, no significant difference was found between the ESW+LIPUS and ESW groups. / by Tam Kam Fai. / "August 2006." / Adviser: Kwok Sui Leung. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1550. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 156-184). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Physical activity of moderate intensity and duration leads to healthy biological adaptations in humans. However, very intense and prolonged exercise may induce disruption in redox balance, potentially increasing oxidative stress. In addition, exposure to environmental heat stress and associated hyperthermia further increases oxidative stress and may induce the expression of heat shock proteins. However, antioxidant supplementation is believed to minimise the effect of oxidative stress and may therefore help reduce or limit the heat shock response to exercise heat stress. The first study (Chapter 4) examined whether exertional heat illness (EHI) casualties among military recruits may exhibit greater disturbances in redox balance following exercise compared to non-EHI controls. Nine (n=9) recruits were identified as having suspected EHI during the Loaded March (LM) on day 1, with a peak mean (SD) body core temperature of 40.1 (0.5) °C. Fifteen (n=15) recruits were identified as having suspected EHI during the Log Race (LR) on day 2, with a peak mean (SD) body core temperature of 39.7 (0.5) °C. A further twenty-one (n=21) recruits, which successfully finished both LM and LR events, were treated as controls (CON). Interestingly, the plasma antioxidant concentration was significantly elevated from pre to post-exercise (p < 0.001) for EHI and CON groups, during both LM and LR events, with no changes on lipid peroxide protein carbonyl concentrations. These data suggest there is no increase in lipid peroxide or protein carbonyl level damage in response to intense hyperthermic military exercise, regardless of acute heat illness. It is possible that military training augments the body's defence capabilities, thus reducing oxidative stress and damage induced by free radical production. To date there is a scarcity of data examining the effects of acute intake of antioxidant supplements on oxidative stress and heat shock response during continuous exercise in a hot environment. Hence, the aims of the second study (Chapter 5) were to examine the effects of acute ingestion of Quercetin (Q), Quercetin + vitamin C (QC) or placebo (P) 14 hours before, 2 hours before and every 20 minutes during trials on oxidative stress and heat shock response. In this randomised, crossover study 10 recreationally active males (age 21±2 y, V̇ O2max 54.9±8.4 ml.kg.min-1) completed three running trials at 70% V̇ O2max for 60 minutes in the heat (33.0±0.3°C; 28.5±1.8% relative humidity). Exercise heat stress significantly elevated plasma quercetin (p=0.02), antioxidant power (FRAP) (p < 0.001),plasma heat shock protein 70 (HSP70) (p=0.009) and plasma heat shock protein 90α(HSP90α) (p < 0.001) over time, but no differences were detected between trials. Also, no changes were observed in protein carbonyl concentration. Acute intake of quercetin significantly increased the level of plasma quercetin however, this did not affect the plasma antioxidant capacity or heat shock response to exercise heat stress. The increases in plasma HSP70 and HSP90α concentrations might act as supplementary antioxidants, reducing the oxidative damage reflected in the absence of changes in protein carbonyl. Exercise heat stress is effective in inducing both intracellular HSP70 (muscle and peripheral blood mononuclear cell (PBMC)) and extracellular HSP70 (plasma) concentrations. Thus, the third study (Chapter 6) tested the hypothesis that this acute quercetin supplementation would induce similar trends in plasma HSP70 and intracellular HSP70 concentrations 2 days following exercise heat stress. In this randomised, crossover study, 9 recreationally active males (age 22±2y, V̇ O2max 50.3±3.3ml.kg.min-1) completed three running trials at 70% V̇ O2max for 60 minutes in the heat (32.9±0.3°C; 28.3±1.2% relative humidity). This study demonstrated that there is no positive relationship between both intracellular of HSP70 (muscle and PBMC) and plasma HSP70 (eHSP70) 2 days following exercise heat stress. These data suggest that the release of eHSP70 could originate from others tissue or cells. Additionally, the absence of differences between trials in the expression of muscle HSP70, PBMC HSP70 and plasma HSP70 might indicate it is implausible that quercetin might inhibit the expression of HSP70 in plasma, muscle and PBMC 2 days following the exercise heat stress stimulus. Overall, the results from this thesis emphasise that the hyperthermia experienced in response to exercise and environmental heat stress could potentially influence the human redox response and heat shock response. Besides, there is reasonable evidence that acute quercetin co-ingestion with vitamin C has the potential to improve the bioavailability and bioactive effects of quercetin, however, the effects of quercetin supplementation in reducing oxidative stress in response to exercise heat stress remains to be elucidated. In addition, the anti-oxidative ability of acute ingestion of quercetin to suppress the intracellular and extracellular heat shock response remains uncertain and worthy for further investigation.

Objectives: Negative energy balance can impair regeneration of the respiratory epithelium and limit the functionality of respiratory muscles, which can prolong mechanical ventilation. The present study sought to quantify and identify deviation in energy requirements of patients with septic shock during and upon liberation from mechanical ventilation. Methods: Patients admitted into intensive care with initial diagnosis of septic shock and mechanical ventilation-dependent were recruited. Their metabolic requirements before and after liberation from mechanical ventilation were measured by indirect calorimetry. Paired t-test was used to examine the variance between the two modes of breathing and Spearman rho correlation coefficient to examine relationship of selected indicators. Results: Thirty-five patients, 20 males and 15 females mean age 69 ±10 years, body height of 1.58 ±0.08 meters, and ideal body weight 59.01 ±7.63 kg were recruited. Median APACHEII score was 22, length of stay in the intensive care was 45 ±65 days and duration on mechanical ventilation was 24 ±25 days. Measured energy expenditure during ventilation was 2090 ±489 kcal∙d-1 upon liberation from ventilation was 1910 ±579 kcal∙d-1, and actual caloric intake was 1148 ±495 kcal∙d-1. Paired-t test showed that measured energy expenditure (p=0.02), actual calories provision and energy expenditure with (p=0.00) and without (p=0.00) ventilator support were all significantly different. Mean carbohydrate oxidation was 0.17 ±0.09 g·min-1 when patients were on mechanical ventilation compared to 0.14 ±0.08 g·min-1 upon liberalization from it, however, the results were not statistically significant. Furthermore, mean lipid oxidation was 0.08 ±0.05 g·min-1 during mechanical ventilation and 0.09±0.07 g·min-1 upon liberalization from it and the mean difference was not statistically significant. Spearman correlation coefficient showed a positive relationship between actual calorie provision and duration of stay in intensive care (r=0.41 and p=0.01) and duration on mechanical ventilation (r=0.55 and p=0.00). Oxygen consumption (r=0.49 and p=0.00) and carbon dioxide production (r=0.4 and p=0.02) were moderately strong and positive during and upon liberation from mechanical ventilation. Correlation between lipid oxidation and oxygen consumption during ventilation (r=0.74, p=0.00) and after ventilation (r=0.82, p=0.00) as well as lipid oxidation and carbon dioxide production during ventilation (r=0.37, p=0.03) and liberation from ventilator (r=0.91, p=0.00) were significantly correlated with each other in grams per minute only. Conclusions: This is a pioneering study to examine energy expenditure and substrate utilization and oxidation within a single cohort of patients. The lower measured energy expenditure upon liberation from mechanical ventilation among critically ill patients could result from positive pressure support from ventilation, the repeated cycle of “rest” and “work” during weaning from ventilators and the asynchronization between self-initiated breathing effort and the ventilatory support. The positive relationship in duration on mechanical ventilation and length of stay with calorie consumption could be longer stay led to more time for progression to reach nutrition targets. . Any discrepancy in energy expenditure and substrate utilization with and without ventilatory support should be monitored. Future studies are important to examine whether matching energy expenditure with energy intake could promote positive clinical outcomes.

Orientador: Ilda de Godoy / Resumo: O tabagismo é responsável pelo maior número de mortes evitáveis ​​no mundo e está relacionado ao desenvolvimento de várias doenças, principalmente a doença pulmonar obstrutiva crônica (DPOC). Assim, a busca por biomarcadores precoces torna-se relevante para sua identificação e para o sucesso terapêutico. Os objetivos do nosso estudo foram avaliar a concentração da proteína de choque térmico 70 (HSP70), expressão do gene HSP70, anticorpos anti-HSP70 auto, marcador inflamatório sistêmico através da citocina interleucina-8 (IL-8) e proteína C reativa (PCR), alterações imunológicas e danos no DNA no sangue periférico de fumantes crônicos assintomáticos e não fumantes. Nossos resultados mostraram concentrações séricas aumentadas de HSP70, anti-HSP70, IL-8, PCR e neutrófilos, e danos no DNA de células sanguíneas de fumantes em comparação ao não-fumantes. Portanto, o tabagismo foi responsável por levar a alteração nos parâmetros fisiológicos e moleculares associados ao risco de desenvolver DPOC e outras doenças pulmonares. Com base nos dados, sugerimos que a HSP70 pode ser responsável pelo aumento dos níveis de citocinas inflamatórias e, consequentemente, o aumento do influxo de neutrófilos para os pulmões e aumento dos danos ao DNA e auto-anticorpos anti-HSP70. / Abstract: Smoking is responsible for the largest number of preventable deaths in the world, and is related to the development of several diseases, mainly chronic obstructive pulmonary disease (COPD). Thus, the search for early biomarkers of such diseases becomes relevant for their identification and for successful therapy. The objectives of our study were to evaluate the concentration of heat shock protein 70 (HSP70), expression of the HSP70 gene, anti-HSP70 auto antibodies, the systemic inflammatory marker through cytokine interleukin-8 (IL-8) and CPR, immunological changes and DNA damage in peripheral blood of chronic asymptomatic smokers and non-smokers. Our results showed increased serum concentrations of HSP70, anti-HSP70, IL-8, CPR and neutrophils, and DNA damage in blood cells of smokers than in non-smokers. Therefore, cigarette smoking was confirmed as a noxious agent on physiological and molecular parameters associated with the risk for developing COPD and other lung diseases. Based on the data we suggest that HSP70 can be responsible for the increased levels of inflammatory cytokines, and consequently, the increased influx of neutrophils into the lungs and increased DNA damages e anti-HSP70 auto antibodies. / Doutor

The Work-Based Project (WBP) set out to explore how international students in a Swiss hospitality institution manage to cope with two quite different cultures to where they came from i.e. the Swiss national culture and the British academic culture. Previous research on international students have been in locations where the host culture student is in plentiful supply which is a way to help the international student adjust socioculturally. Within this WBP, the student body is made up of mainly international students and very few Swiss students. Concepts that were used to assist the exploration of this topic include: what influenced the choice of Switzerland and the institution as a place to study, along with how the information was searched for (Mazzarol and Soutar’s, 2002 Push-Pull Model; The Model of International Students’ Preferences by Cubillo, Sánchez and Cerviño, 2006). Hyde’s (2012) adaptation of Oberg’s 1960 stages of adaptation explored culture shock as a concept followed by Berry’s (1997) acculturation and coping strategies. It investigated the use of friendship networks as a way to help students cope in this new environment (Bochner, McLeod and Lin, 1977; Schartner, 2015). These models were used to provide a framework for the questioning used in the gathering of the primary research. The study is applied in nature and using a case study allowed for the exploration of the rich detail that was needed to understand how the international student feels in this environment and how they cope with it in an effort to instigate change as a result of the findings. Focus groups were used as a scoping tool to identify the key themes which were then developed into a questionnaire for distribution among the wider student body. The key findings indicate that reputation of Swiss hospitality education is influential in the decision making of the student. Word of mouth through previous students is a key way for the students to find out the information they believe they need. The findings revealed that the student views both the Swiss and academic culture of the institution as one and the same. The issue of culture shock is difficult to plot as there was such a mix of feelings identified when the decision to come to Switzerland is made and when the student arrives. The friendships that are generated have evolved since the creation of the Bochner et al (1977) Model and Schartner (2015) identified a newer group which could be added to this model i.e. friends back home as a way to help with psychological adjustment. The key conclusions drawn from the research indicate that the students use word-of-mouth to a great extent in preparation for their study abroad however, the information received is informal in nature. Those that used more sources of information felt they arrived more prepared. Friends were referred to throughout the study for many reasons however, the addition of the 4th group of friends i.e. friends back home, were used as a form of escape to cope with the challenges experienced (whether national or academic culture) due to both cultures being viewed as one and the same. Implications of this relate to how information is provided to the potential student Dissemination of the findings to those that prepare the students for their venture e.g. agents and those that have to help the student adjust upon their arrival e.g. institution members so that the student can adapt more quickly in the 18 weeks that they have to feel comfortable in their new environment.

Tyrosine kinase inhibitors (TKIs) are currently the first therapy option for chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients. However, many patients affected by CML and AML may develop resistance to TKIs or may not recover under this treatment regime. New potential and more effective treatments are recently emerging. Heat shock protein inhibitors (HSPIs) and the proteasome inhibitor Bortezomib are drugs which have been yet to be successfully tested on leukemic patients, despite being successful on other malignancies such as multiple myeloma (MM). The combination between HSPIs and Bortezomib could potentially be successful in killing leukemic cells, by enhancing their respective molecular mechanisms. Indeed, HSPIs would bind to HSP72 avoiding the protein to exert its ligase function to the proteasome, whilst Bortezomib could stop the ubiquitinated proteins to enter the proteasome and ultimately inducing apoptosis. To test the effects of such combination, cell viability was measured via MTS assay, apoptosis levels were tested through Annexin V\PI assays. Involvement of HSP72 and pro-survival protein Bcl-2 were measured via flow-cytometry. The cells were administered with HSPIs and Bortezomib first as single agents for 24 hours, to establish working minimal concentration. Also, the drugs were tested for a shorter time, to understand when the drugs start to be effective. It emerged that one hour is sufficient for the drugs to give an initial effect in terms of cell viability and apoptosis. Following, combination experiments of HSPIs and Bortezomib were performed; the first drug was administered for one hour, the second following one hour and the cells were incubated for 24 hours. This was repeated alternatively for both type of drugs on the different cell lines. MTS and Annexin V\PI showed that there is not a synergistic effect between drugs, but instead there is antagonism. No necrosis was found at any level of the study. The cells were then probed for HSP72 and Bcl-2, to investigate their involvement in apoptosis mechanisms. Following 6 hours of combined and single agent treatment, both type of drugs inhibit HSP72 but failed to reduce the expression of Bcl-2, particularly on AML cells. It is thus proposed that CML and AML cells may die by apoptosis following a short time of treatment with HSPIs and Bortezomib by an extrinsic pathway of apoptosis, independent from Bcl-2 involvement and from mitochondrial pathway of apoptosis. This study may be the first to indicate a potential use of HSPIs and Bortezomib on CML and AML patients for a short time of treatment, although not in combination. Future studies are needed to further investigate the mechanisms of action of these drugs, aiming to potentially give CML and AML patients another successful therapy option to overcome resistance to canonic chemotherapy.

O desempenho é foco de diversos estudos atuais, a comunidade técnica está buscando melhorar os sistemas construtivos. Apesar de ser discutido há décadas, este tema foi recentemente revigorado pela elaboração e publicação da norma de desempenho NBR 15575 (ABNT, 2013a). Este documento apresenta requisitos mínimos a serem atingidos pelas edificações, bem como metodologia para a avaliação destes parâmetros. Dentre os ensaios apresentados, consta em seu anexo E um método para avaliação de vedações verticais frente a choques térmicos. Inúmeras pesquisas adotam os choques térmicos como agente de degradação, contudo não existe um consenso quanto às condições de contorno ou mesmo as dimensões dos corpos de prova. A norma brasileira recomenda que as essas possuam 120 cm de largura e altura equivalente a 1 pé direito, entretanto em determinadas situações tais dimensões inviabilizam o programa experimental, dado a falta de equipamentos deste porte. Assim, encontram-se na literatura técnica pesquisas realizadas sobre protótipos reduzidos de sistemas de vedação. Este trabalho buscou identificar a influência das dimensões e condições de contorno dos corpos de prova nos resultados obtidos em ensaios de choques térmicos Para tal, foram ensaiadas amostras em 3 tamanhos diferentes, as dimensões propostas pela NBR 15575 e duas variações reduzidas. Os corpos de prova reduzidos foram ensaiados livres e com restrições as dilatações. Todas as combinações foram sujeitas a 10 e 30 choques térmicos e as avaliações foram realizadas antes e após os ciclos. As variáveis de resposta adotadas foram a resistência à aderência, fissuração e permeabilidade, também foram mensuradas as variações lineares em momentos pré-determinados. Os choques térmicos não provocaram a perda da aderência, uma vez que as amostras apresentaram aderências estatisticamente iguais antes e após os ciclos, com exceção da amostra grande exposta a 30 choques, que teve sua aderência majorada. Apenas nas amostras grandes ocorreu alteração do índice de fissuras decorrente da exposição aos choques. Majoritariamente, a permeabilidade das amostras não foi alterada com a exposição aos choques, com exceção das amostras reduzidas livres expostas a 30 choques que apresentaram uma redução da absorção, indicando o fechamento dos poros. / Performance is the focus of many current researches, the technical community is searching to improve building systems. Despite being discussed for decades, this subject has recently been reinvigorated by the elaboration and publication of performance standard NBR 15575 (ABNT, 2013a). This document presents minimum requirements to be achieved by the buildings, as well a methodology for the evaluation of these parameters. Among the tests presented, attachment E shows a method for evaluating vertical seals against thermal shocks. Numerous researches adopt thermal shocks as a degradation agent, however, there is no consensus regarding the boundary conditions or even about the dimensions of the specimens. The Brazilian standard recommends that these specimens have at least 120 cm wide and height equivalent to room's height, however in certain situations such dimensions make the experimental program unfeasible, given the lack of equipment of this size. Thus, we find in the technical literature researches on reduced prototypes of walls. This study aimed to identify the influence of the dimensions and boundary conditions of the specimens on the results of thermal shock tests. For this, samples were tested in 3 different sizes, the dimensions proposed by NBR 15575 and two reduced variations The reduced specimens were tested without and with dilation restrictions. All combinations were subjected to 10 and 30 thermal shocks and the evaluations were performed before and after the cycles. The tests adopted to evaluate were resistance to adhesion, cracking and permeability, and linear variations were also measured at predetermined moments. The thermal shocks did not cause the loss of adhesion, since the samples had statistically equal adhesions before and after the cycles, except for the large sample exposed to 30 shocks, which had its adherence increased. Only in large samples occurred change of cracks index from exposure to shocks. The permeability of the samples was not altered with the exposure to shocks, except for the unrestricted reduced samples exposed to 30 shocks that showed a reduction of the absorption, indicating the closure of the pores.

A obra escrita de Tarkovski e o filme O Espelho são analisados à luz da teoria psicanalítica da interpretação dos sonhos articulando conceitos vindos de outros campos do conhecimento, quais sejam inconsciente ótico e choque em Walter Benjamin. O filme se passa em lugares do passado de Tarkovski, evocados a partir de lembranças encobridoras, sonhos e devaneios, em que o cineasta é espectador e ator. Há a referência, no título e ao longo das cenas, ao espelho, também usado por Lacan, como modelo de dispositivo ótico, ao teorizar sobre a formação da função do “Eu”. Através desta análise, pretendeu-se aproximar a linguagem do filme à linguagem do sonho, encontrando conteúdos oníricos latentes. São analisadas as filiações e influências, o roteiro, e aquilo que fala nas lembranças de infância, nos sonhos e devaneios associados às tradições culturais russas, ao poeta Puchkin e a Dostoievski. Identificam-se aspectos do pensamento utópico e articulações psicanalíticas na cena do devaneio do personagem Ignat. Também são comentadas articulações à estética do choque em Walter Benjamin, nas cenas de déjà vu de Ignat e no fenômeno análogo que acometeu Maria na cena da tipografia. O conceito de Outra cena, do campo freudiano, é contextualizado na discussão do filme e também cotejado com elementos da teoria platônica apontados por Lacan em seus seminários. Finalmente, a cena de levitação de Maria é comparada com a cena da pintura de Füssli The Nightmare e interpretada como sendo de um sonho de angústia. / Tarkovski's written work and the film The Mirror are analyzed in the light of psychoanalytic theory of interpretation of dreams being articulated with concepts from other fields of knowledge, such as optic unconscious and shock at Walter Benjamin’s writings. The film takes place somewhere in Tarkovski’s past, evoked from screen memories, dreams and daydreams, in which the filmmaker is a spectator and an actor at a time. There is a reference, in the title and throughout the scenes, to the mirror, which is also used by Lacan, as the model of an optical device, in theorizing about the formation of the function of the "self". Through this analysis, it was intended to approximate the language of the film to the language of the dream and find latent dreams contents. The affiliations and influences, the script, and what he talks about in the memories of childhood, the dreams and daydreams associated with Russian cultural traditions, the poet Puchkin and Dostoyevsky are analyzed. We identify aspects of utopian thinking and psychoanalytic articulations in the scene of Ignat's daydream. Similarly, articulations among the aesthetics of the shock in Walter Benjamin, in the déjà vu scenes of Ignat and in the analogous phenomenon that rushed Maria in the typography scene are also commented in this work. The concept of Other scene, from the freudian field, is contextualized in the discussion of the film and also compared with elements of the platonic theory pointed out by Lacan in his seminars. Finally, the levitation scene of Mary is compared to the painting scene of Füssli The Nightmare and interpreted as being of a dream of anguish.

Thesis. 1975. M.S.--Massachusetts Institute of Technology. Dept. of Civil Engineering. / Bibliography: leaves 97-98. / M.S.

La myélofibrose (MF) est la plus agressive des néoplasies myéloprolifératives (NMP). Elle porte à elle seule le plus mauvais pronostic pour les patients puisqu’elle s’accompagne d’une fibrose de la moelle osseuse évoluant vers une insuffisance médullaire. Les inhibiteurs de la kinase JAK2 ont apporté de nouveaux espoirs pour le traitement des NPM mais leurs effets ont été essentiellement bénéfiques sur les symptômes et non sur la fibrose elle-même ni sur le cours de la maladie. Plus récemment, la protéine de choc thermique 90 (HSP90) - connue pour stabiliser JAK2 - est apparue comme une cible thérapeutique prometteuse pour les NMP. Cependant, les inhibiteurs de la HSP90 ont montré une toxicité importante accompagnée d’une expression compensatoire des HSPs inductibles (i.e HSP70, HSP27), connues pour favoriser l’émergence de phénomène de résistance. Par ailleurs, des études ont montré que HSP27 était fortement exprimée chez les patients présentant une fibrose pulmonaire idiopathique ou rénale montrant l’importance de HSP27 dans les processus fibrotiques. Sur la base de l’ensemble de ces données, nous avons évalué d’une part l'efficacité chez l’animal d'un oligonucléotide inhibiteur spécifique de HSP27 appelé OGX-427 (en essai clinique dans plusieurs cancers). D’autre part, nous avons déterminé le niveau d’expression intra- et extracellulaire de HSP27 chez des patients atteints de MF. L'effet de l'OGX-427 a été évalué dans deux modèles murins de myélofibrose, laquelle est induite soit par la sécrétion excessive de thrombopoïétine (TPOhigh) soit par la mutation JAKV617F. Nous avons mis en évidence dans les souris traitées par l’OGX-427, une réduction de la taille de la rate, de la prolifération mégacaryocytaire et de l’hématopoïèse extramédullaire par rapport aux souris contrôles, révélant ainsi un effet bénéfique de l’inhibition de HSP27 sur la progression de la maladie. De toutes récentes observations complémentaires à ce travail ont également montré une diminution de la fibrose réticulinique dans la moelle osseuse de souris JAKV617F. Au niveau moléculaire, nous démontrons que l'effet prolifératif induit par la voie de signalisation exacerbée - JAK2/STAT5 - est régulé par HSP27 via des interactions directes. Pour finir, nous avons détecté une augmentation de l'expression de HSP27 aussi bien dans les progéniteurs circulants CD34+ que dans le sérum des patients atteints de NMP avec MF. Ce travail révèle pour la première fois le rôle intra et extracellulaire de HSP27 dans la physiopathologie de la MF et le bénéfice thérapeutique potentiel de l’utilisation des inhibiteurs de HSP27 dans cette maladie. / Myelofibrosis (MF) is the most aggressive myeloproliferative neoplasms (MPN) with the highest degree of morbidity and mortality, including progressive bone marrow fibrosis resulting into bone marrow failure. JAK2 kinase inhibitors have been successfully used for a few years in MPN and more particularly for MF treatment. Nevertheless, their beneficial effects are mainly restricted on symptoms and not on the course of the disease. Recently, heat shock protein 90 (HSP90) - known to stabilize JAK2 - has been reported as a promising therapeutic target in MPN. However HSP90 inhibitors show toxicity and induce the expression of stress-inducible proteins such as HSP70 and, most likely HSP27 as previously shown in other cancers. In addition, we and others have shown that HSP27, was strongly expressed in patients with idiopathic pulmonary or kidney tubulointerstitial fibrosis, underlying a relevant role of HSP27 in fibrotic processes. Taking into account both the beneficial effects of HSP inhibitors in leukemia and in MPN, and the possible implication of HSP27 in fibrosis, we have evaluated here the status of HSP27 in MF patient’s samples and assess the effectiveness of an HSP27 oligonucleotide inhibitor called OGX-427 in murine models. We report here the effect of OGX-427 in two murine models of thrombopoietin- and JAKV617F-induced myelofibrosis. OGX-427 limited the progression of the disease associated with a reduction of spleen weight and of megakaryocytic expansion. And more recently, our additional results show a decrease of reticulin fibrosis in JAK2V617F’s bone marrow. We show that HSP27 regulates JAK2/STAT5 proliferative effect through direct interactions, and we report an increase expression of HSP27 both in CD34+ circulating progenitors and in the serum of patients with NMP with fibrosis. Taking altogether, this work supports that extra and intracellular HSP27 plays a key role of in the pathophysiology in MF and highlight the potential therapeutic benefit of HSP27 inhibitors in this disorder.