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The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation / MEK阻害剤トラメチニブは膵島移植後の拒絶反応を抑制するTada, Seiichiro 23 March 2021 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第23079号 / 医博第4706号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 道行, 教授 稲垣 暢也, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Evaluation of Cardiotoxicity in Children and Young Adults Treated with MEK Inhibitors for a Hematologic/Oncologic DiagnosisBender, Jonathan 25 May 2023 (has links)
No description available.
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ROLE OF BCL-2 FAMILY MEMBERS TO PROMOTE GLUCOCORTICOID –INDUCED APOPTOSIS BY MEK INHIBITORS IN LEUKEMIC CELLSRAMBAL, ANILA 20 April 2009 (has links)
Glucocorticoids (GC) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic BCL-2 family-regulated pathway. It has been shown that BIM (BCL-2 interacting mediator of cell death), a BH3-only pro-apoptotic protein, is up-regulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia (ALL) cells. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation. We therefore hypothesized co-treatment with Dex and MEK/ERK inhibitors would promote apoptosis in ALL cells through BIM up-regulation and activation. We show here that a MEK inhibitor, PD184352 synergistically enhances Dex lethality in CCRF-CEM (T-ALL) cells. Co-treatment with Dex and PD184352 results in BIM accumulation. Down-regulation of BIM by short-hairpin RNA in CCRF-CEM cells suppressed apoptosis by Dex/PD184352 co-treatment. In contrast, another BH3-only protein, BAD is dispensable. Thus, BIM is a critical molecule in this regimen, and targeting BIM by drugs combination could be effective on ALL and possibly other malignancies.
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Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation / MEK阻害剤トラメチニブはラット肺移植モデルにおいて遅発性拒絶反応を抑制し胸腺機能を温存するTakahagi, Akihiro 23 March 2021 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第23099号 / 医博第4726号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 濵﨑 洋子, 教授 浅野 雅秀, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Interakce vybraných protinádorových látek ze skupiny inhibitorů MAPK/ERK signalizační kaskády s ABC lékovými transportéry / Interactions of selected anticancer drugs of the MAPK/ERK signaling pathway inhibitors group with the ABC drug transportersSlatinský, Lukáš January 2018 (has links)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lukáš Slatinský Supervisor: Assoc. prof. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Interactions of selected anticancer drugs of the MAPK/ERK signaling pathway inhibitors group with the ABC drug transporters ABCB1 (Pgp, P-glycoprotein) and ABCG2 (BCRP, breast cancer resistance protein) are members of a transmembrane efflux ATP dependent transporter family, so called ATP-binding cassettes (ABC). Physiologicaly they are expressed in the cellular membrane and protect body tissues against potentially toxic xenobiotics including drugs. They represent also one of the tumor defense mechanisms when being able to efflux a wide variety of cytotoxic drugs out of the cancer cells leading to treatment failure. BRAF protein plays an important regulatory and signal role in MAPK/ERK pathway affecting cell division, differentiation and secretion. Mutations of BRAF lead to overactivity in MAPK/ERK pathway in many cancer cells and can be therefore targeted by anticancer therapy. Cobimetinib and dabrafenib are relatively new anticancer therapeutics inhibiting the signal pathway mentioned above and they are used in treatment of melanoma carrying the BRAF mutation. The aims of this project were to...
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Cellular and molecular analysis of fracture healing in a neurofibromatosis type 1 conditional knockout mice modelEl-Khassawna, Thaqif 27 July 2013 (has links)
NF1 ist eine autosomal dominante Erbkrankheit, die durch inaktivierende Mutationen im Neurofibromin-Gen verursacht wird. NF1 manifestiert sich durch eine erhöhte Tumor-Inzidenz des neuralen Gewebes in der Haut (Neurofibroma). Neben diesen häufigeren klinischen Manifestationen haben rund 50% der NF1-Patienten Skelett-Anomalien. Häufiger sind Röhrenknochen betroffen, die klinischen Symptome reichen von Tibia-Krümmung über Spontanfrakturen bis hin zu Nonunions. Diese Studie analysiert den Heilungsverlauf von Femurfrakturen in Nf1Prx1- Mäusen. Der Frakturkallus von Mäusen wurde an den Tagen 7, 10, 14 und 21 durch µCT, Histologie und molekulare Analysen evaluiert. µCT und histologische Analysen haben eine beeinträchtigte Knochenheilung in Nf1Prx1-Mäusen gezeigt. Eine erhöhte periostale Knochenbildung in den frühen Stadien der Heilung war zu beobachten, sowie eine reduzierte, aber anhaltende Knorpelbildung und Bindegewebs-Akkumulation innerhalb der Fraktur. Wir konnten zeigen, dass der normalen Heilungsprozess durch dieses Bindegewebe behindert wird, welches durch alpha smooth muscle actin-positive Myofibroblasten gebildet wird, die ihrerseits aus einer bisher noch nicht identifizierten Muskelfaszie abgeleitet sind. Dieser Zusammenhang wird durch eine Microarray-Analyse der Kallus-Gewebe bestätigt, die ergab, dass durch den Knock-Out Gene reguliert wurden, die in Physiologie, Proliferation und Differenzierung von Muskelzellen involviert sind. Darüber hinaus waren extrazelluläre-Matrix-Gene in den Mutanten hoch regeuliert. Zusammenfassend konnten wir zeigen, dass eine Ähnlichkeit des Heilungsverlauf zwischen dem Nf1Prx1-Mausmodell und NF1-Patienten besteht. Folglich kann an diesem Mausmodell untersucht werden, durch welche Mechanismen die Mutationen im NF1 zu Knochenheilungsstörungen führen. Außerdem konnte in einer Pilotstudie der Effekt des Neurofibromin-Mangels auf die Knochenheilung durch Behandlung mit MEK-Inhibitoren in vitro und in vivo weitestgehend behoben werden / Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease resulting from inactivating mutations in the gene encoding the protein neurofibromin. NF1 patients – around 50% – have abnormalities of the skeleton. Long bones are often affected, and the clinical signs range from tibial bowing to spontaneous fractures and even non-unions. Moreover, NF1 mice models could provide the understanding of the cell types involved in the resulting non-union and their behavior. This study analyzed the healing progress of femur fractures in a model of NF1 long bone dysplasia. Fracture callus was assessed at days 7, 10, 14, and 21 by µCT, histology, biomechanics, and molecular analyses. Bone healing was impaired in Nf1Prx1 mice femoral fracture. Results revealed increased periosteal bone deposition at the early stages of healing, decreased but persistent cartilage formation concomitant with fibrous tissue accumulation within the fracture site, decreased torsional stiffness, decreased bone mineral density, and increased fibrous tissue infiltration in the callus of mutant mice. This fibrous tissue accumulation hindered bone fracture healing, and was deposited by alpha smooth muscle actin-positive myofibroblasts, which were derived from a yet unidentified muscle fascia. This is further supported by the microarray analysis of callus tissues showing that genes crucial to muscle cells physiology, proliferation and differentiation were affected. In addition, extracellular matrix related genes were up-regulated in the mutants. In summary, this study shows a resemblance in the healing progression to the Nf1Prx1 mice model and NF1 patients, thereby, confirming the suitability of this mice model to explore the mechanism by which mutations in NF1 lead to non-unions. Moreover, in vitro and in vivo pilot assessments of MEK inhibitor treatment demonstrated a potential remedy for the lack of neurofibromin in bone healing.
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Enhanced ERK1/2 activity a central feature of cystogenesis in ARPKD. Implications for ion transport phenotypeVeizis, Ilir Elias January 2005 (has links)
No description available.
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WISP1 and EMT-associated response and resistance to immune checkpoint blockadeGaudreau, Pierre-Olivier 09 1900 (has links)
Les immunothérapies de type immune checkpoint blockade (ICB) ont révolutionné les
approches thérapeutiques en oncologie médicale et ont largement contribué au fait que
l’immunothérapie est maintenant considérée comme le quatrième pilier des traitements anticancer,
aux côtés d’approches traditionnelles telles que la chirurgie, la radiothérapie et la
chimiothérapie. Malgré les résultats encourageants des études cliniques évaluant ce type
d’immunothérapie, la majorité des patients décèderont des suites de leur maladie.
Conséquemment, le domaine de recherche visant à comprendre les mécanismes de résistance aux
immunothérapies est en expansion constante. Plusieurs stratégies visant à améliorer les issues
cliniques ont été proposées, parmi lesquelles figurent: 1) la recherche de nouvelles cibles
thérapeutiques dans le microenvironnement immun tumoral et; 2) les études de combinaisons
thérapeutiques où une immunothérapie est jumelée à d’autres types de modalités thérapeutiques
potentiellement synergiques. Chacune des études présentées dans cette thèse de recherche
s’apparente à l’une ou l’autre de ces stratégies.
Dans le cadre de notre première étude, nous démontrons que la protéine WISP1
représente une cible prometteuse à l’intérieur du microenvironnement de plusieurs types de
tumeurs solides étant donné son association avec différentes variables pronostiques et proinflammatoires,
ainsi qu’avec un programme épigénétique complexe, la transition épithélialemésenchymateuse
(Epithelial-Mesenchymal Transition; EMT). De plus, nous démontrons que
les niveaux d’expression de WISP1 sont significativement plus élevés au sein des tumeurs
démontrant une résistance primaire aux immunothérapies de type ICB, particulièrement lorsque
qu’une signature reliée à l’EMT peut être retrouvée de façon concomitante. Pour notre deuxième
étude, nous avons utilisé des modèles murins in vivo de cancer pulmonaire non à petites cellules
KRAS-mutés afin de tester différentes combinaisons thérapeutiques jumelant une thérapie dite
ciblée (i.e., un inhibiteur de MEK) a différentes immunothérapies de type ICB. Nos résultats
démontrent que l’ajout d’une immunothérapie anti-CTLA-4 à l’inhibiteur de MEK AZD6244
(selumetinib) et une immunothérapie anti-PD-L1 augmente significativement la survie, et que
ces bénéfices sont associés à une diminution de marqueurs reliés à l’EMT.
Il existe donc un lien commun entre ces deux études qui repose sur l’importance de
l’EMT comme facteur favorisant la résistance thérapeutique aux immunothérapies. De plus, nous
démontrons pour la première fois que les bénéfices associés à la triple combinaison
thérapeutique susmentionnée peuvent être corrélés à une diminution d’expression de marqueurs
liés à l’EMT. Par conséquent, nos résultats sont discutés en tant que base potentielle pour de
futures études visant à réduire la résistance thérapeutique reliée à l’EMT. Nous discutons
également de la valeur translationnelle de nos résultats à travers le développement d’une étude
clinique. / Immune checkpoint blockade (ICB) has revolutionized therapeutic approaches in the
field of medical oncology and has largely contributed to the fact that immunotherapy is now
being regarded as the fourth pillar of cancer treatment alongside surgery, radiotherapy and
chemotherapy. Despite encouraging results from clinical trials using ICB, most patients
ultimately relapse or succumb to their disease. Therefore, the field of immunotherapeutic
resistance research is rapidly expanding. Many strategies to improve ICB responses have been
undertaken, including: 1) the search for novel, actionable targets in the immune tumor
microenvironment (TME) and; 2) therapeutic combination studies where an ICB backbone is
combined with different, synergistic treatment modalities. Each of the studies presented in this
research thesis embraces one of these strategies.
In our first study, we show that WISP1 represents a promising TME target in multiple
solid tumor types by demonstrating its association with prognostic and pro-inflammatory
variables, as well as to a complex epigenetic program termed Epithelial-Mesenchymal Transition
(EMT). Furthermore, we show that increased WISP1 expression is associated to primary
resistance to ICB, particularly when EMT-related signatures are found concomitantly. In our
second study, we used in vivo mouse models of KRAS-mutant Non-Small Cell Lung Cancer
(NSCLC) to test different therapeutic combinations of targeted therapies (i.e., MEK inhibitor)
and ICB. We found that the addition of anti-CTLA-4 ICB to MEK inhibitor AZD6244
(selumetinib) and anti-PD-L1 ICB increases survival, and that these benefits are associated with
the downregulation of EMT-related markers.
Therefore, there exists a common link between these studies, which relies on the
significance of EMT as a detrimental factor within the TME and its association with ICB
resistance. Moreover, we show for the first time that the benefits of ICB combination therapy can
be associated to the downregulation of EMT markers in vivo. Consequently, we discuss how our
results may constitute the basis for future work aiming at reducing EMT-mediated therapeutic
resistance, as well as the translational relevance of our pre-clinical results through the
development of a clinical trial.
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