381 research outputs found
The role of metabolic rewiring in endocrine resistance
No full textBreast cancer is the most common cancer type in women population affecting a large number of women worldwide. Due to its highly heterogenous molecular characteristics, there is not a default treatment strategy for breast cancer. Almost two third of breast cancer cases are estrogen receptor positive ER (+). Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to prevent or delay recurrence of ERα (+) tumors. The overall objective of this dissertation project is to define the interaction among endocrine resistance, nuclear export system, and cellular metabolic pathways, and to evaluate the metabolic impact of combinational ER and XPO1 targeting by using combination of endocrine therapy agents and a XPO1-specific small molecule inhibitor (Selinexor-SEL) in different endocrine resistant ER (+) breast cancer cell lines. The long term goal is to develop effective treatment strategies to overcome endocrine resistance in ER (+) breast cancer.
In the first part of this project, we focused on the characterization of XPO1 protein in tamoxifen resistance. In this part, we used endocrine-sensitive and -resistant breast cancer cell lines (in vitro) and tumor xenograft models (in vivo) to test our hypothesis. Our results showed that expression profile of XPO1 protein has a pivotal role in the progression of tamoxifen resistance in ER (+) breast cancer cell models. We found out that XPO1 protein modulates tamoxifen resistance due to its function to determine subcellular localization of important kinases.
In the second part of the project, we investigated how nuclear export system contribute to tamoxifen resistance development by testing with a novel combinational targeting strategy using 4-OHT and SEL in Luminal B type breast cancer cell lines, and to investigate the metabolic outcomes of this novel therapy. To test our hypotheses, we used actual patient tumor samples and endocrine-sensitive and -resistant breast cancer cell lines (in vitro). Our findings indicated that XPO1 expression is significantly higher in Luminal B subtype compared to other molecular subtypes. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways (e.g. Akt pathway), and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy.
Lastly, we assessed the impact of other endocrine therapy options alone or in combination with Selinexor on metabolism in different endocrine resistant breast cancer cell lines and possible metastatic organ sites. We used 3-D cell culture models and endocrine-sensitive and -resistant breast cancer cell lines (in vitro). Using a combination of transcriptomics, kinase arrays, metabolomics and metabolic flux experiments, we identified glutamine metabolism pathways to be rewired during endocrine resistance. In limited media conditions mimicking nutrient deprived tumor microenvironment, endocrine resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SEL and cells were more dependent on glutamine. The effect of glutamine was dependent on conversion of the glutamine to glutamate and mitochondrial complex 1 activity. In order to examine metabolites that might result in the observed phenotype we performed GC/MS whole metabolite profiling and identified amino acid metabolism pathways to be upregulated when cells were treated with SEL.
In conclusion, our study indicated that remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2021-08-01The student, Eylem Kulkoyluoglu Cotul, accepted the attached license on 2019-06-10 at 19:00.The student, Eylem Kulkoyluoglu Cotul, submitted this Dissertation for approval on 2019-06-10 at 19:02.This Dissertation was approved for publication on 2019-07-09 at 11:23.DSpace SAF Submission Ingestion Package generated from Vireo submission #14020 on 2019-11-26 at 13:59:38Made available in DSpace on 2019-11-26T20:58:27Z (GMT). No. of bitstreams: 8
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Previous issue date: 2019-07-09Embargo set by: Seth Robbins for item 113006
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Abstract 3615: Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce apoptosis and overcome tamoxifen resistance
No full textAbstract
There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway analysis, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tam and Selinexor (SXR), being evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies, inhibited Akt phosphorylation by changing the localization of the kinase. Since we observed dramatic changes in Akt activity we hypothesized that glucose utilization pathways and metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We showed that combined targeting of XPO1 and ERα rewires metabolic pathways, increase demand on mitochondria and causes increased production of ROS that would eventually lead to apoptosis. Re-modelling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences.
Citation Format: Eylem Kulkoyluoglu-Cotul, Zeynep Madak-Erdogan, Yosef Landesman, Kinga Wrobel. Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce apoptosis and overcome tamoxifen resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3615. doi:10.1158/1538-7445.AM2017-3615</jats:p
PERBANDINGAN HUBUNGAN SIPIL-MILITER DI INDONESIA PADA MASA ABDURRAHMAN WAHID DENGAN ERDOGAN DI TURKI
No full textAbstract: This paper aims to compare civil-military relations in Indonesia during Abdurrahman Wahid's (1999-2001) period with Turkey during Erdogan's (2003-2011) by looking at civilian control over the military. The study looks at the differences and similarities between the two countries and the causes of Erdogan's success and Abdurrahman Wahid's failure to control the military. In this research, the author used a qualitative approach. The results showed that there were similarities and differences in civil-military relations between Gus Dur and Erdogan, as seen from civil control over the military. The similarities could bee seen at the beginning of their reign. Abdurrahman and Erdogan had strong civilian control over the military so that they could reduce the military's role in politics with various policies issued. This strong control is also supported by political conditions, political elites, and society. However, there were differences in civil-military relations at the end of the Gus Dur and Erdogan governments. Civilian control over the military weakened at the end of the Gus Dur’s reign which caused him to fall from his position as the President of the Republic of Indonesia, whereas Erdogan’s civilian control over the military was getting stronger. The failure factor for Abdurrahman to strengthen civilian control over the military was a radical change. In contrast to Erdogan who made changes gradually with the support of politics and society.Keywords: Turkey; Indonesia; Abdurrahman Wahid; Erdogan; Civil-Military Relation
Authoritarianism, Erdogan and Anti-Secularisation in Turkey
No full textBakalaura darba “Autoritārisms, Erdogans un antisekulārisms Turcijā” mērķis ir izpētīt, kā Turcijas prezidents Redžeps Tajips Erdogans, izmantojot sabiedrības vēsturisko un šī brīža polarizāciju un varas konsolidēšanas metodes, veic konservatīvas politiskās reformas, kas sekmē antisekulārisma politiku Turcijā, graujot sekulāro institūciju integritāti. Darbā tiek analizēta Erdogana virzītā reforma par izstāšanos no Stambulas konvencijas. Šis ir ļoti nozīmīgs temats, jo tas tiešā mērā ietekmē Latvijas kā Eiropas Savienības dalībvalsts un Turcijas attiecības starptautiskā kontekstā. Darba izstrādes laikā autore ir secinājusi, ka Redžeps Tajips Erdogans ar veiksmīgu politisko stratēģiju un varas konsolidācijas metodēm, izmantojot polarizāciju valstī un uzrunājot konservatīvo sabiedrības daļu, ir stiprinājis un centralizējis varu AKP un savās rokās. Pieņemot konservatīvas reformas un likumprojektus, kas grauj sekulāro institūciju integritāti un darbošanās spējas, Erdogans veido antisekulārisma politiku Turcijā, kas veicina valstī pieaugošo autoritārismu.Bachelor’s thesis “Authoritarianism, Erdogan and Anti-secularism in Turkey” objective is to discover how the president of Turkey Recep Tayyip Erdoğan utilises the historical and current societal polarisation and power consolidation methods to implement conservative political reforms, furthering anti-secularism politics in Turkey, whilst undermining the integrity of secular institutions. In the bachelor’s thesis the author has analyzed Erdogans push for withdrawal of Istanbul convention. This is an important topic as it directly influences Latvia as a part of European Union and the international relations on global scale. During the development of bachelor’s thesis, the author has concluded that Recep Tayyip Erdoğan with successful political strategy, power consolidation methods and utilisation of societal polarisation has strengthened and centralised the power in the hands of Justice and Development party(AKP) and himself. Whilst adopting conservative reforms and policies Erdogan has eroded the integrity and role of secular institutions. The promotion of anti-secular politics in Turkey fosters increasing authoritarianism in Turke
Erratum to: Vinpocetine and Vasoactive Intestinal Peptide Attenuate Manganese-Induced Toxicity in NE-4C Cells (Biol Trace Elem Res (2016), 10.1007/s12011-016-0742-z)
No full textIn the above-mentioned article, the author names Mumin Alper Erdogan and Saylav Bora were written incorrectly as Alper Mümin Erdoğan and Ejder Saylav Bora, respectively. However, these errors have been already corrected in both the referenced article and in the author listing for this article. The authors regret the oversight. © 2016, Springer Science+Business Media New York
ERDOGAN STAYS: PROSPECTS FOR TURKEY’S RELATIONS WITH THE US, EU AND RUSSIA. PART 1
No full textIn the second round on May 28, 2023, Turkish presidential candidate R.T. Erdogan defeated his rival. The victory was expected, but by no means triumphant, as the supporters of the current government hoped. This insignificant advantage was achieved, according to the author, due to
the successes in Erdogan’s foreign policy. Thus, the main task was solved, in the name of which he
sought to create the image of a «Strong Turkey», aggravating relations with his partners in NATO
and the EU – the extension and strengthening of his own power. In this article, the author focuses
on the question: will Erdogan also base his third term through a «tough» (forceful) policy or will he
soften relations with partners in the alliance and the EU? An analysis of the available material
gives grounds to believe that today Ankara is working for a second option (reducing tension) in relations with partners. The contours of this line appear quite clearly. The author also puts a question
– what can Ankara’s progress in this direction mean for its relations with Moscow
Hagia Sophia and its Role in Politics of R. T. Erdogan
No full textPráce je zaměřena na Hagii Sofii a její roli v politice tureckého prezidenta Recepa Tayyipa Erdogana, za jehož vlády byla v červenci 2020 přeměněna na mešitu. Práce představuje historicko-politický kontext a symboliku, kterou Hagia Sofia za svou existenci jako kostel, mešita a muzeum zastávala, a objasňuje, proč je v mnohých ohledech tolik výjimečná a jak tuto důležitost prezident Erdogan využívá ve svůj prospěch. Skrze analýzu oficiálních prohlášení turecké vlády ohledně Hagie Sofie práce ukazuje, že se v přeměně Hagie Sofie na mešitu zrcadlí mnohé aspekty prezidentovy politiky jako proislámské a neo-osmanské postoje, potřeba dokázat suverénnost země nebo jeho role zachránce všech muslimů. Se zaměřením na silně polarizovanou společnost Turecka a jeho politickou scénu, dochází autorka k závěru, že přeměna Hagie Sofie na mešitu i přes pozornost, kterou obdržela na mezinárodní úrovni, měla politický dopad pouze na domácí půdu. Prezident Erdogan se tímto krokem snažil kompenzovat ztráty voličů z posledních let a získat tak přízeň z řad konzervativců a nacionalistů. Přeměna Hagie Sofie nicméně nepřinesla v tomto směru očekávané výsledky, vůči opozici prezident a jeho strana AKP i nadále ztrácí.The work focuses on Hagia Sophia and its role in the politics of Turkish President Recep Tayyip Erdogan, under whose rule it was transformed into a mosque in July 2020. The work presents the historical-political context and symbolism that Hagia Sophia held for its existence as a church, mosque, and museum explains why it is so special in many respects and how President Erdogan uses this importance to his advantage. Through an analysis of the official statements of the Turkish government regarding Hagia Sophia, the work shows that the transformation of Hagia Sophia into a mosque reflects many aspects of the president's policy such as pro-Islamic and neo-Ottoman attitudes, the need to prove the country's sovereignty or his role as savior of all Muslims. Focusing on Turkey's highly polarized society and its political scene, the author concludes that the transformation of Hagia Sophia into a mosque, despite the attention it received at the international level, had a political impact only on domestic soil. With this move, President Erdogan sought to compensate for the loss of voters in recent years, gaining the favor of conservatives and nationalists. However, the transformation of Hagia Sophia did not bring the expected results in this direction, the president and his AKP party continue to lose to the opposition.Fakulta filozofickáStudentka představila komisi diplomové práce. Vedoucí práce shrnul svůj posudek. Poté byl přečten posudek oponenta.Na tyto posudky studentka reagovala. Zodpověděla také doplňující otázkyDokončená práce s úspěšnou obhajobo
Cognitive AF Relay Networks over Asymmetric Shadowing/Fading Channels in the Presence of Low-Rate Feedback
No full textJoint user and relay selection for relay-aided RF/FSO systems over Exponentiated Weibull fading channels
No full textIn this paper, we investigate the performance of joint user and relay selection scheme for a multi-user relayed network over mixed radio-frequency (RF) and free space optical (FSO) system. In this set-up, the non line-of-sight (NLOS) RF link is modeled with Rayleigh fading whereas the LOS FSO path is modeled with Exponentiated Weibull (EW) distribution. We assume that the multiple users at source terminal communicate with the destination over multiple decode and forward relays which are located at the rooftops of the buildings to provide a perfect LOS path. In the proposed scheme, all users send pilot signals to the destination through relay terminals and the latter jointly selects the best user and relay based on the maximization of the end-to-end signal-to-noise ratio (SNR). To quantify the performance of the proposed scheme, closed form outage and error probability are derived. Moreover, asymptotic analysis is performed to obtain important system parameters including fading severity, number of users and relays in the system. Finally, Monte-Carlo (MC) simulations are carried out the verify the performance of the considered scheme
ERDOGAN STAYS: PROSPECTS FOR TURKEY’S RELATIONS WITH THE US, EU AND RUSSIA. PART 2
No full textThe first part of the article examines the fundamental aspects of the transformation of foreign policy concepts and strategies of the Republic of Turkey at the end of the second and beginning
of the third presidential terms of Recep Tayyip Erdogan. The author’s assumption that the newly
elected president in foreign policy is likely to follow the path of overcoming tensions with his Western allies and partners is justified by the analysis of the events taking place in Ankara’s relations
with Washington given in the article. In the second part, the author of the article focuses on the
emerging prospects for Turkey’s relations with the EU countries. The emphasis is on the analysis of
the events of «crisis periods» in bilateral relations between Ankara and Brussels (in 2016 and 2020)
and attempts to overcome their consequences. An important milestone in the trajectory of their reconciliation was Russia’s Special Military Operation on the territory of Ukraine. In its context, Erdogan continues to assert his role as an intermediary not only between Moscow and Kiev, but also
as a channel of communication between Russia and the NATO countries as a whole
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