Search

During vascular development endothelial junctions mature and vessel integrity is established to form the endothelial barrier. The molecular mechanisms by which lymphatic vessels induce cell contact inhibition are not understood. Here, we uncover the cGMP-dependent phosphodiesterase 2A (PDE2A) as a selective regulator of lymphatic, but not blood endothelial contact inhibition. Conditional deletion ofPde2ain mouse embryos reveals severe lymphatic dysplasia, while large blood vessel architecture remains unaltered. In the absence of PDE2A, human lymphatic endothelial cells fail to induce mature junctions and cell cycle arrest, while cGMP levels, but not cAMP levels, are increased. Loss of PDE2A-mediated cGMP hydrolysis leads to downregulation of NOTCH signaling. Vice versa, DLL4-induced NOTCH activation restores junctional maturation in PDE2A-deficient lymphatic endothelial cells. Our data demonstrate that PDE2A selectively modulates a crosstalk between cGMP and NOTCH signaling to finetune lymphatic development and suggest that PDE2A may be a druggable target to control lymphatic leakage and regeneration.

Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.

Peritoneal adhesions are a poorly understood but highly prevalent condition that can lead to intestinal obstruction, pelvic pain, and infertility. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the process of their formation remained elusive to date. Herein, we show that neutrophil extracellular traps (NETs) serve as essential scaffold for adhesion formation and that DNases interfere with this process. Thus, peritoneal adhesions in murine models and in humans showed that these lesions are largely based on extracellular DNA derived from neutrophils. Furthermore, treatment with DNASE1 or a DNASE1L3 analog significantly reduced or even prevented peritoneal adhesions in experimental models. These data not only suggest that NET formation plays an essential role in peritoneal adhesions but also show that therapeutic application of DNases can prevent the formation of peritoneal adhesions.

Ependymomas encompass multiple, clinically relevant tumor types based on localization, genetic alterations, and epigenetic and transcriptomic profiles. Tumors belonging to the methylation class of spinal ependymoma (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, molecular data of SP-EPN are scarce, and clear treatment recommendations are lacking. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations. Yet, it remains unclear whether SP-EPN with germline or sporadic NF2 mutations or with NF2 wild type status differ clinically or molecularly. To provide a comprehensive molecular profile of SP-EPN, we integrated epigenetic, genomic, transcriptomic, and histological analyses of up to 237 cases. Clustering of methylation data revealed two distinct molecular SP-EPN subtypes. The distribution of NF2 mutated cases differed significantly across these subtypes (p

Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. T cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how cerebral glioma impacts systemic T cell immunobiology. We performed gene expression profiling of peripheral blood T cells in patients with IDHwt glioblastomas as well as in a murine glioma model. In addition, we analyzed the levels of soluble immune biomarkers in patient blood and performed flow-cytometric phenotyping of human peripheral blood CD3+ T cells. We discovered a significant skewing of peripheral T cell phenotypes in IDHwt glioblastoma patients compared to healthy donors (HD), showing CD4+ TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells, while TH2 and TH17 percentages remained stable. Interestingly, peripheral memory CD4+ T cells exhibited reduced Fas and PD-1 expression, while CD8 T cells were primarily affected in the non-memory CD45RA+ compartment, displaying reduced numbers of CD8+ CD127+ CD27+ cells. Compared to healthy individuals, GBM patients had significantly increased levels of soluble CD27 while levels of soluble CD25 were reduced (p < 0.05). GSEA and ORA analysis of differentially expressed genes in murine gliomas showed alterations in RNA binding and processing, as well as ribosomal activity in both cell types, indicating systemic modulation in translational- and cell cycle pathways in glioblastoma. Taken together, our results demonstrate a significant skewing of the peripheral T immunobiology in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a systemic disease that fundamentally alters the immune repertoire in affected patients.

NK cells are able to upregulate SIRPα, which transmits a strong inhibitory signal upon CD47 engagement. Modulation of this immune checkpoint can enable the generation of universal allogeneic regenerative cell products or enhance NK cell–mediated tumor cell killing., Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I–deficient target cells against SIRPα+ primary NK cells, but not against SIRPα− NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα–CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα–CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell–mediated killing of allogeneic and xenogeneic tissues., Graphical Abstract

The purpose of the present study is to examine fine arts students’ attitudes towards art education based on some variables. The data were collected through the “Attitude Scale towards Art Education” developed by AyaydA±n and Kurtuldu and “Personal Information Form” developed by the researcher. Cronbach’s alpha reliability coefficient of the 32-item-scale is .90. The research consists of 234 students in the Art Teaching and Music Education Department, Faculty of Education, Fine Arts Education, Adnan Menderes University in 2017-2018 academic year. In the study, a descriptive screening model was used. Statistical analyses were performed using SPSS Version 21. Since the data were not normally distributed, differences between the groups were analyzed with the Mann-Whitney U test for comparison of 2 groups and the Kruskal-Wallis test for comparison of more than 2 groups. It was found that participants’ attitude scores significantly varied with their gender, grade level, department, mothers’ educational level, parents’ income level and their frequency of attending art events. On the other hand, their attitude towards art education did not significantly vary based on the type of high school they graduated from, fathers’ educational level, long-time neighborhood, employment status and whether or not receiving scholarship Key words: Art education, attitude, art teaching, music education.

The aim of this study is to determine the relationship between the disposition of critical thinking and the perception about problem solving skills of the students. In descriptive studies correlational model was used. Disposition of critical thinking points data was collected in this study by using the "The California Critical Thinking Disposition Inventory" developed by Facione, Facione and Giancarlo(1988) and the perceptions about Problem Solving Skills data was collected by using the problem solving skills inventory adapted into Turkish by Sahin, Sahin and Heppner (1993). Based on the findings of the study, it was revealed that there was a moderate, positive and significant relationship between pre-service music teachers' disposition of critical thinking and perceptions about problem solving. (C) 2015 The Authors. Published by Elsevier Ltd.

Music course aims to develop children's abilities in all aspects. In order to have individuals who possess certain ethical and moral values, maintain a consciousness of national unity, and feel responsible for themselves and their countries, value education should also be given importance in the music course. The aim of this study is to examine the songs included in the music course books of primary level 2nd, 3rd and 4th grades in delivering certain values. Content analysis was used since it was aimed to examine the songs in the music course books. In the study, by examining the songs in the 2nd, 3rd and 4th grade music course books in detail, it was tried to identify the target values exposed to students. The values that were included in the texts were identified, and the sentences including these values were typed and saved on computer. The identified values were grouped using certain codes and categories were made up based on these codes. It was determined that 19 different values were used in lyrics referred in music education course books. Love of country, love of animal, and enjoy life were most frequently repeated values.

Bu arastirmanin amaci; aktif ogrenmenin muzik tarihi dersine iliskin basari, tutum ve ozyeterlik uzerindeki etkisini olcmektir. Arastirmada ontest-sontest kontrol gruplu deneysel model kullanilmistir. Arastirma, Adnan Menderes Universitesi Egitim Fakultesi Guzel Sanatlar Egitimi Bolumu Muzik Egitimi Anabilim Dali’nda ogrenim goren 29 ogrenci uzerinde gerceklestirilmistir. 14 hafta suren arastirma asamasinda 12 hafta boyunca deney grubuna aktif ogrenme yontemiyle, kontrol grubuna ise edilgin ogretme yontemi ile muzik tarihi dersi islenmistir. Arastirmacilar tarafindan gelistirilen basari testi, tutum olcegi ve ozyeterlik olcegi veri toplama araclari olarak kullanilmistir. Verilerin cozumlenmesinde FINESSE ve SPSS istatistik programindan yararlanilmistir. Arastirma sonuclarina gore; deney grubunda ogrenim goren muzik ogretmeni adaylarinin muzik tarihi dersine iliskin basarilari ve tutumlari, edilgin ogrenme yontemiyle ders islenen kontrol grubuna gore anlamli duzeyde farkli bulunmustur. Ancak katilimcilarin ozyeterlik duzeylerinde belirgin bir farklilik gorulmemistir.

The aim of this study is to reveal the relationship between individual social responsibilities and personal values of primary school and music teacher candidates on the basis of gender, school grade and department variables. Survey model among quantitative methods was used in the research. The research sample consist of 162 (69.8%) primary school teacher candidates and 70 (30.2%) music teacher candidates receiving education in Adnan Menderes University Faculty of Education. 146 (62.9%) of the participants are female, and 86 (37.1%) were male teacher candidates. Also 104 (44.8%) freshman and 128 (55.2%) senior students were joined into the research. Questionnaire on Individual Social Responsibility and Questionnaire on Personal values were used as data collection tools. SPSS 21.00 statistics software was used for data analysis. Due to the normal distribution of data, t-test and one-way analysis of variance were conducted, then Pearson correlation coefficients were calculated and regression analysis was performed. According to the obtained findings, personal values total scores of the participating teacher candidates did not significantly differ based on their gender and department, whereas they significantly differed in a school-grade based evaluation. The individual social responsibility total scores of the teacher candidates did not show a statistically significant difference on the basis of gender. Individual social responsibility levels were found to differ significantly based on school grade and department variables. Statistically significant positive and low level (between .18 and .39) correlations were found between the teacher candidates’ social responsibilities and academic average and personal values subscales.

Today, entrepreneurship has gained great importance, especially with the transition from industrial society to information society. Therefore, in order to ensure economic and social development of societies, entrepreneurship must comprehensively be supported, encouraged and entrepreneurship education has to be provided. Many similar qualities and skills among individuals having reflective thinking abilities and entrepreneurial individuals arise when reflective thinking, one of the higher-level thinking skills, is defined as the cognitive inquiry that will lead the individual to produce new knowledge and develop alternative ways. The purpose of this research is to identify whether physical education and sports teachers' reflective thinking themes predict entrepreneurial characteristics. Research is designed in accordance with the relational screening model. Semerci (2007), “Reflective Thinking Tendency Scale” and Yilmaz and Sunbul (2009), “Entrepreneurship Scale for University Students” were used as data collection tool. Multilevel regression analysis was benefitted in the analyze of the data. As a result of this research, it is determined that effective and interrogated teaching sub-dimension was the most independent variable contributing to the entrepreneurial characteristics of physical education and sports pre-service teachers and this was followed by continuous and intentional thinking, responsibility of teaching and science and looking professional sub-dimensions. It has also been determined that sub-dimensions such as open-mindedness, foresighted and sincere and researcher do not make a meaningful contribution to the prediction of entrepreneurial characteristics. Based on these results, it can be said that a pre-service teacher with high entrepreneurial characteristics will have higher reflective thinking tendencies. Besides, it is also possible to analyze how thinking skills such as critical thinking, creative thinking, problem solving and supra-cognitive thinking predict entrepreneurial characteristics.

The aim of this research is to examine the relationship between the values of primary and music teacher candidates and their cheating attitudes in terms of different variables. The study group of the research is composed of 249 students who are studying at the Departments of Primary School Teaching and Music Education at Adnan Menderes University Faculty of Education. In the research, Portrait Values Questionnaire and personal information form were used. In the analysis of data, t test, ANOVA, correlation analysis and tukey HSD test was used. It was detected that teacher candidates had high levels of value perceptions and the three most important values were universalism, security and self-direction. It was found that there was a statistically significant difference in primary school and music teacher candidates in all values except achievement, hedonism and stimulation according to their departments. This difference was on behalf of primary school teacher candidates. Another conclusion of the research was the gender variable. In all values except power, significant difference was on behalf of females. When the value scores of primary school and music teacher candidates were examined, all the values except for power were on behalf of freshmen. It was seen that there were significant differences between the teacher candidates’ academic achievement perceptions and their value scores of achievement, stimulation, self-direction, universalism, benevolence, tradition, conformity and security except power and hedonism values. Findings related to cheating, which was another variance of the research, are as follows; cheating attitudes of primary school and music teacher candidates were moderate. It was detected that the participants had negative attitudes towards cheating. A significant difference was detected in cheating attitude according to the department. In other words, it was seen that music teacher candidates were more positive towards cheating. When cheating attitudes according to gender variable were examined, it was seen that there was a significant difference on behalf of females.

Sanatin, bilimin ve gunluk hayatin isleyisini belirleyen etkenler zaman ilerledikce hizla degismektedir. Bu degisimler ve gelismeler egitim anlayisinda ki degisiklikleri de beraberinde getirmektedir. Onceki yillarda ogretmenin aktif oldugu yontemler artik yerini ogrencinin aktif oldugu anlayislara birakmistir. Ogrenci merkezli egitim yontemlerinden bir tanesi de yaratici dramadir. Bu arastirmanin amaci Pamukkale ve Adnan Menderes Universitelerinde ogrenim goren sinif ogretmeni adaylarinin yaratici drama yontemi kullanmaya iliskin ozyeterlik algilarini cesitli degiskenlere gore degerlendirmektir. Arastirmada betimsel arastirma modellerinden tarama yontemine basvurulmustur. Tarama modelinde arastirmaya konu olan birey, konu ya da nesne, kendi kosullari icinde, var oldugu sekliyle tanimlanmaya calisilir. Arastirma Pamukkale Universitesi ve Adnan Menderes Universitelilerinin Egitim Fakultelerinde ogrenim gormekte olan toplam 380 sinif ogretmeni adayi ile gerceklestirilmistir. Arastirma verilerinin elde edilmesinde Can ve Gunhan (2009) tarafindan gelistirilmis olan “Yaratici Drama Yontemini Kullanmaya Yonelik Ozyeterlik Algisi Olcegi” kullanilmistir. Bu arastirmada ogrencilerin yaratici drama yontemini kullanmaya yonelik ozyeterlilik algilari belirlenmeye calisilmistir. Her iki Universitenin sinif ogretmenligi anabilim dallarinda ogrenim goren ogretmen adaylarina uygulanan olcek verilerinden elde edilen puanlar SPSS 18.00 istatistik programinda degerlendirilmistir. Verilerin cozumlenmesinde yuzde, frekans, t-testi ve tek yonlu varyans analizinden yararlanilmistir. Yaratici drama yontemini kullanmaya yonelik ozyeterlik algilari acisindan PAU ve ADU ogrencileri arasinda anlamli bir farklilik oldugu ancak “sinif duzeyi, atolye egitimi almis olma, ogretim elemaninin yeterli bulma” degiskenlerinde anlamli bir farklilik olmadigi tespit edilmistir.