İmparatorlukların yıkılıp ulus-devletlerin kurulduğu 20. yüzyıla varan süreçte Osmanlı, Habsburg, Romanov ve Kaçar imparatorluklarının sınırlarına büyük bir hareketlilik hâkimdi. Kalıplaşmış siyasi... Show moreİmparatorlukların yıkılıp ulus-devletlerin kurulduğu 20. yüzyıla varan süreçte Osmanlı, Habsburg, Romanov ve Kaçar imparatorluklarının sınırlarına büyük bir hareketlilik hâkimdi. Kalıplaşmış siyasi hayat baştan aşağıya değişiyordu. Asiler Devri, bu süreçte Balkanlar’dan Kafkasya ve Ortadoğu’ya uzanan geniş bir coğrafyayı şiddet yoluyla şekillendiren eşkıyaların, isyancıların, çetecilerin ve eylemcilerin izini sürüyor. Ramazan Hakkı Öztan ve Alp Yenen’in derlediği bu çalışma, Kafkas eşkıyalar ile Balkan devrimcilerin, İranlı çeteciler ile İttihatçıların kurulu düzeni ihlal etmelerine yol açan koşulları ve eylemlerinin sonuçlarını, çeşitli vakalar üzerinden tarihsel ve biyografik yaklaşımlarla ele alıyor. Show less
Entretien sur Annelies Schulte Nordholt, Georges Perec et ses lieux de mémoire. Le projet de Lieux. Propos recueillis par Maxime Decout. Interview on Annelies Schulte Nordholt, Georges Perec et...Show moreEntretien sur Annelies Schulte Nordholt, Georges Perec et ses lieux de mémoire. Le projet de Lieux. Propos recueillis par Maxime Decout. Interview on Annelies Schulte Nordholt, Georges Perec et ses lieux de mémoire. Le projet de Lieux, by Maxime Decout. Show less
Immunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these... Show moreImmunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these breakthroughs, the 5-year survival rate of patients with advanced-stage melanoma is at most 50%, emphasizing the need for additional therapeutic strategies. Adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) is a therapeutic modality that has, in the past few years, demonstrated long-term clinical benefit in phase II/III trials involving patients with advanced-stage melanoma, including those with disease progression on ICIs and/or BRAF/MEK inhibitors. In this Review, we summarize the current status of TIL therapies for patients with advanced-stage melanoma, including potential upcoming marketing authorization, the characteristics of TIL therapy products, as well as future strategies that are expected to increase the efficacy of this promising cellular immunotherapy.Despite dramatic progress over the past decade, only around 50% of patients with advanced-stage melanoma derive durable benefit from immune-checkpoint inhibitors (ICIs) and/or BRAF and MEK (BRAF/MEK) inhibitors. Over the past few years, adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) has demonstrated encouraging efficacy including in patients with disease progression on ICIs or BRAF/MEK inhibitors. In this Review, the authors summarize the role of TIL therapies in the management of these patients and describe future research strategies that might improve safety or efficacy.Tumour-infiltrating lymphocyte (TIL) therapy shows consistent clinical activity in patients with advanced-stage melanoma, including after disease progression on or after immune-checkpoint inhibitors and BRAF plus MEK inhibitors, and is manageable in most patients.Selection of tumour-reactive T cells and improvements in T cell function during the manufacturing process are expected to further improve the clinical activity of TIL therapy while limiting toxicity.Further clinical implementation of TIL therapy will require the establishment of infrastructure for centralized TIL production or point-of-care manufacturing, as well as treatment by an experienced medical team.Centralized TIL production and treatment of patients at dedicated centres might be important to enhance the clinical feasibility of TIL therapy and will drive further technological innovation. Show less
ObjectiveThere is a continued need for improvement of second-line systemic treatment for metastatic and/or recurrent endometrial cancer.MethodsIn this phase II, open-label study, eligible patients... Show moreObjectiveThere is a continued need for improvement of second-line systemic treatment for metastatic and/or recurrent endometrial cancer.MethodsIn this phase II, open-label study, eligible patients had histologically or cytologically confirmed endometrial cancer, documented progressive disease, and a WHO performance status of <= 2. All participants received treatment with pazopanib 800 mg once daily until progression, unacceptable toxicity, or patient refusal. The primary endpoint was progression-free survival at 3 months, with secondary outcomes of overall response rate, progression-free survival, overall survival, and toxicity. The study was powered to demonstrate 50% progression-free survival at 3 months with alpha=0.05 and beta=80%.ResultsBetween January 2011 and February 2016, 60 eligible patients were included (intention-to-treat population). Median age was 68 (range, 53-85) years. Previous treatment included pelvic radiotherapy (58%), chemotherapy (90%), and hormonal therapy (43%). Three-month progression-free survival was 63.3% in the intention-to-treat population, with median progression-free survival and overall survival of 3.4 and 7.5 months, respectively. Overall response rate was 8.3%, and median follow-up 7.6 months. The most common grade 3 or higher adverse events were gastrointestinal toxicity in 21% of participants, including two patients with a gut perforation, one fatal gastrointestinal hemorrhage, one enterocutaneous fistula, and one fatal enterovaginal fistula. Extensive peritoneal disease existed in 80% of the patients with severe gastrointestinal toxicity. A definite correlation with previous radiotherapy could not be established.ConclusionsPazopanib met its primary endpoint of 3 months' progression-free survival in advanced endometrial cancer (63.3%), but response rates were modest. There may be a correlation for rare but severe gastrointestinal toxicity with previous treatments and/or disease site that has yet to be elucidated. Show less
The Indo-European u-stem nouns merged almost completely with the o-stems in all Slavic languages. In every Slavic language, their combined paradigm shows traces of both original sets of endings.... Show moreThe Indo-European u-stem nouns merged almost completely with the o-stems in all Slavic languages. In every Slavic language, their combined paradigm shows traces of both original sets of endings. The merger of the two paradigms began before the earliest attestations of Slavic, but the attested evidence allows us to determine that the paradigms must have been distinct in late Common Slavic. The original distribution between u- and o-stems was blurred when they started to merge. The endings were redistributed on the basis of phonological and semantic criteria. In this paper it is argued that a similar process took place in the accentuation of masculine o- and u-stems in Slavic. The accentual phenomena discussed here have alternatively been explained as reflexes of a Proto-Slavic accentual pattern referred to as accent paradigm d. Show less
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