TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content

BackgroundTNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known.MethodsPrimary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients.ResultsTRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content.ConclusionsTRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization

According to hadiths Emr-i Bi'l-ma'rûf Nehy-i Ani'l-Munker and righteous

06.03.2018 tarih ve 30352 sayılı Resmi gazetede yayımlanan “Yükseköğretim Kanunu İle Bazı Kanun Ve Kanun Hükmünde Kararnamelerde Değişiklik Yapılması Hakkında Kanun” ile 18.06.2018 tarihli “Lisansüstü Tezlerin Elektronik Ortamda Toplanması, Düzenlenmesi ve Erişime Açılmasına İlişkin Yönerge” gereğince tam metin erişime açılmıştır.İyilik, kötülük, emr-i bi'l-ma'rûf nehy-i ani'l-münker, salih amel gibi kavramlar darb-ı mesel olmuşlardır. Herkes tarafından anlaşılabilen açıklamaya gerek kalmayan kavramlardan bazılarıdır. Bu konuyla ilgili soru işaretlerinin kalkması için tez de bu konu işlenmiştir. Öncelikli olarak tanımı, mahiyeti hakkında açıklamalarda bulunulmuştur. Kur'ân'a göre âyetler ışığında değerlendirilmelerde bulunulmuştur. Ehl-i Kitâb'ın bakış açısına yer vermek amacıyla Kitâb-ı Mukaddese başvurduk. Konuyla ilgili Hadislerden seçmelere yer verilmiştir. Hadisleri sınırlandırıp konuyla ilgili olanları değerlendirmeye alınmıştır. Sahâbe-i Kirâm'ın sünnet ve hadislerde iyiliği emretme kötülükten sakındırma prensibini nasıl ele aldığına değilmiştir. Prensibin devlet yönetiminde ve sosyal hayattaki kurum olarak karşılığı olan İhtisâb konusuna yer verdilmiştir. İslam Düşüncesinde yer alan iyiliği emretme kötülükten sakındırma prensibi ile ilgili görüşlere yer verilmiştir. Bu ele alınan konular çerçevesinde konu değerlendirip anlatılmaya çalışılmıştır. İyiliği emretme kötülükten sakındırma kavramının İslam Hukûku'nda ele alınışını, hükmünü ve diğer Hukuk sistemleriyle karşılaştırmasına kısaca değinilmiştir. Hz. Peygamber dönemini ve haleflerinin yaklaşımı ele alınıp günümüzle bağ kurulmaya çalışılmıştır.The concepts such as goodness, evil, al-Amr bi al-maruf and nahy an al-munkar and righteous deeds have been the parable. Some of the concepts that can be understood by everyone do not need explanation. In order to remove the question marks on this subject, this thesis has been studied. Firstly, the definition and nature of the description has been made. According to the Qur'an, evaluations were made in the light of verses. We applied to the Holy Bible in order to include the perspective of the People of the Book. Selected selections from the hadiths related to the subject. The hadiths were limited and the relevant ones were evaluated. Companies circumcision and hadiths in order to avoid the evil is not how to handle the principle of good. The subject of Specialization, which is the equivalent of the principle as an institution in state administration and social life, is briefly mentioned. The views on the principle of commanding goodness in Islamic thought and avoiding evil are given. Within the framework of these topics, the subject was evaluated and explained. It is briefly mentioned that the concept of ordering good and avoiding evil is discussed in Islamic Law and its comparison with other legal systems. Hz. The period of the Prophet and his successors were approached and tried to be connected with the present day

Sperchon (Scutosperchon) akdagensis sp. n. (Acari: Hydrachnidia: Sperchontidae) from Turkey

The structural characteristics, unique features, various organ measurements of males and females of the Sperchon (Scutosperchon) akdagensis sp. n. water mite from Turkey are described. In addition, morphological characteristics of the new species are compared with related species

According to hadiths emr-i bi’l-ma’rûf nehy-i ani’l-munker and righteous

06.03.2018 tarih ve 30352 sayılı Resmi gazetede yayımlanan “Yükseköğretim Kanunu İle Bazı Kanun Ve Kanun Hükmünde Kararnamelerde Değişiklik Yapılması Hakkında Kanun” ile 18.06.2018 tarihli “Lisansüstü Tezlerin Elektronik Ortamda Toplanması, Düzenlenmesi ve Erişime Açılmasına İlişkin Yönerge” gereğince tam metin erişime açılmıştır.İyilik, kötülük, emr-i bi‟l-ma‟rûf nehy-i ani‟l-münker, salih amel gibi kavramlar darb-ı mesel olmuşlardır. Herkes tarafından anlaşılabilen açıklamaya gerek kalmayan kavramlardan bazılarıdır. Bu konuyla ilgili soru işaretlerinin kalkması için tez de bu konu işlenmiştir. Öncelikli olarak tanımı, mahiyeti hakkında açıklamalarda bulunulmuştur. Kur‟ân‟a göre âyetler ışığında değerlendirilmelerde bulunulmuştur. Ehl-i Kitâb‟ın bakış açısına yer vermek amacıyla Kitâb-ı Mukaddese başvurduk. Konuyla ilgili Hadislerden seçmelere yer verilmiştir. Hadisleri sınırlandırıp konuyla ilgili olanları değerlendirmeye alınmıştır. Sahâbe-i Kirâm‟ın sünnet ve hadislerde iyiliği emretme kötülükten sakındırma prensibini nasıl ele aldığına değilmiştir. Prensibin devlet yönetiminde ve sosyal hayattaki kurum olarak karşılığı olan İhtisâb konusuna yer verdilmiştir. İslam Düşüncesinde yer alan iyiliği emretme kötülükten sakındırma prensibi ile ilgili görüşlere yer verilmiştir. Bu ele alınan konular çerçevesinde konu değerlendirip anlatılmaya çalışılmıştır. İyiliği emretme kötülükten sakındırma kavramının İslam Hukûku‟nda ele alınışını, hükmünü ve diğer Hukuk sistemleriyle karşılaştırmasına kısaca değinilmiştir. Hz. Peygamber dönemini ve haleflerinin yaklaşımı ele alınıp günümüzle bağ kurulmaya çalışılmıştır.The concepts such as goodness, evil, al-Amr bi al-maruf and nahy an al-munkar and righteous deeds have been the parable. Some of the concepts that can be understood by everyone do not need explanation. In order to remove the question marks on this subject, this thesis has been studied. Firstly, the definition and nature of the description has been made. According to the Qur'an, evaluations were made in the light of verses. We applied to the Holy Bible in order to include the perspective of the People of the Book. Selected selections from the hadiths related to the subject. The hadiths were limited and the relevant ones were evaluated. Companies circumcision and hadiths in order to avoid the evil is not how to handle the principle of good. The subject of Specialization, which is the equivalent of the principle as an institution in state administration and social life, is briefly mentioned. The views on the principle of commanding goodness in Islamic thought and avoiding evil are given. Within the framework of these topics, the subject was evaluated and explained. It is briefly mentioned that the concept of ordering good and avoiding evil is discussed in Islamic Law and its comparison with other legal systems. Hz. The period of the Prophet and his successors were approached and tried to be connected with the present day

A New Water Tick for Turkey Fauna (Acari, Hydrachnidia) Type; Axonopsis (Hexaxonopsis) rotundifrons (Viets, 1922)

Bu çalışmada; Türkiye su kenesi faunası için yeni kayıt olan Axonopsis (Hexaxonopsis) rotundifrons (Viets,1922)’un erkeklerinin yapısal özelliklerinin tanımı verilmiş, çeşitli organlarının örnekler üzerinden şekilleri çizilmiş, ölçümleri yapılmış ve ayrıca batı palearktikteki zoocoğrafik dağılımı ile yaşama ortamları üzerinde durulmuştur.In this study, the morphological features various body organs and drawings, meassurements of Axonopsis rotundifrons males which is just recorded for Turkish water mite fauna given and mentioned to distributions in the world

Cross-cultural adaptation, validity and reliability of Turkish version of Oxford Ankle Foot Questionnaire for children with congenital talipes equinovarus & nbsp

Background: The purpose of the study was to evaluate the reliability and validity of the Turkish version of the Oxford Ankle Foot Questionnaire (OxAFQ) to provide cultural adaptation. Methods: This study involved translation, back translation, and cross-cultural adaptation. Forty-nine patients with congenital talipes equinovarus were evaluated using the Turkish version of OxAFQ. Turkish version of the Childhood Health Assessment Questionnaire (CHAQ) was used as a gold standard to validate the Turkish version of the OxAFQ. The validation was assessed with Spearman correlation analysis by using CHAQ. The reliability of the questionnaire was assessed with Cronbach alpha (internal consistency) and exploratory factor analysis. Results: High validity was found between OxAFQ and CHAQ (r =-0.422-0.292) (p < 0.01). Reliability analysis showed that OxAFQ had a high level of Cronbach alpha (alpha = 0.88-0.96) and internal consistency (ICC = 0.90-0.96). Conclusion: The Turkish version of OxAFQ is a valid, reliable and useful quality of life questionnaire in patients with congenital talipes equinovarus and it is proper for use by health professionals and researchers

TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content

Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known. Methods: Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients. Results: TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content. Conclusions: TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization

Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines

Epigenetic deregulation is a critical theme which needs further investigation in bladder cancer research. One of the most highly mutated genes in bladder cancer is KDM6A, which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of KDM6A in normal versus tumor settings, we identified the genomic landscape of KDM6A in normal, immortalized, and cancerous bladder cells. Our results showed differential KDM6A occupancy in the genes involved in cell differentiation, chromatin organization, and Notch signaling depending on the cell type and the mutation status of KDM6A. Transcription factor motif analysis revealed HES1 to be enriched at KDM6A peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in KDM6A and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed TLE co-repressors and HES1 as potential truncated and wild-type KDM6A interactors. With the aid of structural modeling, we explored how truncated KDM6A could interact with TLE and HES1, as well as RUNX and HHEX transcription factors. These structures provide a solid means of studying the functions of KDM6A independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer