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As one of the most significant modernization projects of the early Republican era, culture parks, with their entertainment facilities and recreational activities, represented contemporary ways of living in urban green spaces. Culture parks aimed to educate and enlighten people according to new national ideals, cultural norms, social behavior, and western lifestyles. They symbolized Republican modernity starting in the 1930s. With new spatial explorations, they mediated the appropriation of leisure activities and socio-cultural practices in the public space. As a later example of culture parks, this study examines Konya Culture Park within the framework of its historical and spatial development over its conceptions and associations of political ideologies in Turkey. The study traces the creation of Konya Culture Park area and compares the differences between the original Culture Park of the late 1960s based on the preceding examples, and its replacement in 2008. Thereby, it reveals politics and space relationship. The formation of Konya Culture Park in line with politics of modernization and its spatial representation in the socio-cultural context of transformation is critically scrutinized. Thus, the foundational differentiation between the original and the new Culture Park is revealed with respect to architectural language, socio-cultural norms, spatial practices, and political discourses., Erken Cumhuriyet Dönemi’nin en önemli modernizasyon projelerinden biri olan kültürparklar, barındırdıkları eğlence tesisleri ve rekreasyonel faaliyetleri ile çağdaş yaşam modelini kentsel yeşil alanda temsil etmişlerdir. Halkı eğitmek ve aydınlatmak için ulusal idealleri ve Cumhuriyet modernitesini sembolize eden kültürparklar, serbest zaman aktivitelerinin sosyal ve kültürel pratiklerle içselleştirildiği yeni mekânsal arayışların ürünleridir. Türkiye’de 1930’larla birlikte modernitenin yansıması olarak pek çok kentte yaygınlaşan kültürpark fikri, kültürel normların ve sosyal davranışların batılı yaşam tarzını inşa ettiği kamusal alan olarak süregelmiştir. Bu çalışma Konya Kültürpark’ı, tarihsel ve mekânsal gelişimi çerçevesinde ileri dönem kültürparkların bir örneği olarak Türkiye’deki siyasi ideolojiler üzerinden algılanma biçimleri ve çağrışımları ile birlikte incelemektedir. Çalışma, kendinden önceki örneklere dayanarak 1960 ve 70’lerin modern dilinin yansıması olarak oluşturulan Konya Kültürpark’ı, aynı alanda 2008 yılında dönüştürülerek yeniden üretilen bir kültürpark ile karşılaştırmakta ve farklılıklarını ortaya koymaktadır. Konya Kültürpark’ın modernleşme politikaları doğrultusunda şekillenmesi ve mekânsal temsiliyete ilişkin pratiklerin mekân siyaseti üzerinden sosyo-kültürel bağlamda dönüşümü bu çalışmada eleştirel bir yaklaşımla irdelenmiştir. Böylece Konya Kültürpark’a ilişkin mimari dil, biçim, politik söylemler ve toplumsal pratikler kıyaslama yapılarak incelenmiştir.

This article looks through the lense of an entertainment building in Izmir, Turkey, within the larger framework of modernity and identity in order to scrutinise ways in which cross-cultural influences are mediated. The programme of the building is conceptualised as a social structure and its aesthetics as a cultural form, which work to connect localities to the processes of modernisation and westernisation in the Turkish context of the 1950s' era. The analysis exposes how the edifice operates as a spatial structure that influences cultural norms and Western behaviour through practices of entertainment and architectural design, simultaneously serving as a medium through which people could perform and express their modernity. © 2011 The Journal of Architecture.

Spencer et al. report the first description of human IL-6R deficiency in two patients presenting with recurrent infections, atopy, elevated IgE, and abnormal acute-phase responses., IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.

Structured as a think piece, this study examines the transformation of Turkish middle-class living room practices and their material settings from the 1930s to the 2010s in accommodating the changing uses of that space. First, the spatial division between the public and private aspects of domestic interiors in the culture of the early Turkish Republic is discussed, with a focus on the change from traditional uses to more Westernized and modern functions and styles; through the review of relevant literature, the development of the living room as it reflects changes in the domestic culture of the early Turkish Republic is traced. Next, the closed-salon practice, which excludes daily routines and everyday clutter and requires a high level of cleanliness and order, is discussed as the dominant prototype. Finally, the paper analyzes the transformation of this prototype to meet the evolving role of the living room in the middle-class Turkish home.

Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.

The persistence leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) despite tyrosine kinase inhibition (TKI) may explain relapse after TKI withdrawal. Here we performed genome-wide transcriptome analysis of highly refined CML and normal stem and progenitor cell populations to identify novel targets for the eradication of CML LSCs using exon microarrays. We identified 97 genes that were differentially expressed in CML versus normal stem and progenitor cells. These included cell surface genes significantly upregulated in CML LSCs: DPP4 (CD26), IL2RA (CD25), PTPRD, CACNA1D, IL1RAP, SLC4A4, and KCNK5. Further analyses of the LSCs revealed dysregulation of normal cellular processes, evidenced by alternative splicing of genes in key cancer signaling pathways such as p53 signaling (e.g. PERP, CDKN1A), kinase binding (e.g. DUSP12, MARCKS), and cell proliferation (MYCN, TIMELESS); downregulation of pro-differentiation and TGF-β/BMP signaling pathways; upregulation of oxidative metabolism and DNA repair pathways; and activation of inflammatory cytokines, including CCL2, and multiple oncogenes (e.g., CCND1). These data represent an important resource for understanding the molecular changes in CML LSCs, which may be exploited to develop novel therapies for eradication these cells and achieve cure.

A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells. These invasive properties involve altered dynamics of the cytoskeleton and one of its major structural components β-actin. Here we identify AIM1 (absent in melanoma 1) as an actin-binding protein that suppresses pro-invasive properties in benign prostate epithelium. Depletion of AIM1 in prostate epithelial cells increases cytoskeletal remodeling, intracellular traction forces, cell migration and invasion, and anchorage-independent growth. In addition, decreased AIM1 expression results in increased metastatic dissemination in vivo. AIM1 strongly associates with the actin cytoskeleton in prostate epithelial cells in normal tissues, but not in prostate cancers. In addition to a mislocalization of AIM1 from the actin cytoskeleton in invasive cancers, advanced prostate cancers often harbor AIM1 deletion and reduced expression. These findings implicate AIM1 as a key suppressor of invasive phenotypes that becomes dysregulated in primary and metastatic prostate cancer., Invasion of malignant cells involves changes in cytoskeleton dynamics. Here the authors identify absent in melanoma 1 as an actin binding protein and show that it regulates cytoskeletal remodeling and cell migration in prostate epithelial cells, acting as a metastatic suppressor in cancer cells.

Human cancers nearly ubiquitously harbor epigenetic alterations. While such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. Here, we carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation “cityscape” plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked inter-individual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer and development/differentiation related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment of cancer-related genes. Interestingly, whereas some regions showed intra-individual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.

Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of androgen receptor signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the androgen receptor ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies including CRPC therapies such as abiraterone and MDV3100. While the canonical full-length androgen receptor (AR-FL) and AR-Vs are both increased in CRPCs, their expression regulation, associated transcriptional programs, and functional relationships have not been dissected. In this study, we show that suppression of ligand-mediated AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPCs. Importantly, treatment-induced AR-Vs activated a distinct expression signature enriched for cell-cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppressed the AR-Vs signature and activated expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 or abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, paralleled increased expression of the androgen receptor–driven cell-cycle gene UBE2C. Expression of AR-V7, but not AR-FL, was positively correlated with UBE2C in clinical CRPC specimens. Together, our findings support an adaptive shift toward AR-V–mediated signaling in a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapy. Cancer Res; 72(14); 3457–62. ©2012 AACR.

Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. Transcriptional programs directed by the canonical full-length AR (AR-FL) are well characterized, but those directed the AR-Vs are not well understood. In addition, AR-FL and AR-Vs are both increased in CRPC, underscoring the critical importance of dissecting the complex interplay between AR-FL and AR-Vs. In this study, we employed a set of detection and targeting tools that differentiate the AR-FL and AR-Vs to investigate the functional distinctions between AR-FL and AR-V. We show that suppression of endogenous AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V-mediated transcriptional programs but activates genes mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting a functional dichotomy between AR-FL and AR-Vs in a therapeutic setting. The dynamic interplay between AR signaling mediated by AR-FL and AR-V should be further explored in rational development of novel CRPC therapies and multipurpose biomarkers for CRPC. Citation Format: Rong Hu, Changxue Lu, Elahe A. Mostaghel, Srinivasan Yegnasubramanian, Meltem Gurel, Clare Tannahill, Joanne Edwards, William Isaacs, Peter S. Nelson, Eric Bluemn, Stephen R. Plymate, Jun Luo. Transcriptional programs directed by the androgen receptor splice variants [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA21.

This article explores how women’s practices transformed abstract space into lived space in the context of women’s matinees in the entertainment venues of Izmir Culture Park, a historical marker of Turkish modernity. Drawing on collective memory, Lefebvrian spatial theories, and gender studies, the article sets out an analytical framework through which to explore women’s spatial preferences and performances. Engaging with oral histories and archival material, the study reads women’s agency in 1970s matinees, arguing that these events opened up an alternative public space for women to liberate themselves by applying their own rituals and tactics in this space. They thus added new layers of meaning about women’s spatiality to the historicity of the park.