1,506 research outputs found

    The interplay between Natural Killer cells and Pancreatic Stellate cells in Pancreatic Ductal Adenocarcinoma

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    Pancreatic ductal adenocarcinoma (PDAC) is a disease with dismal prognosis. With five-year survival rates of less than 11%, PDAC is set to become the second leading cause of cancer related deaths by 2040. The role of pancreatic stellate cells in pancreatic ductal adenocarcinoma has been well established. However, to date, little remains know about the interaction between these crucial stromal cells and the innate lymphocytes, natural killer (NK) cells, in PDAC. Herein we demonstrate that naïve NK cells possess the functional efficacy to target and kill both quiescent (qPSC) and activated (aPSC) pancreatic stellate cells. Furthermore, qPSC, but not aPSC education of NK cells resulted in decreased NK cell-mediated cancer cell cytotoxicity. NK-PSC direct co-culture was found to modulate both PSC and NK phenotype, as well as functional changes within NK cells, an effect not observed with TranswellTM separation. Multiplex Luminex ELISA further revealed upregulation of IFN-γ and related chemokines in NK cells co-cultured with PSC (activated/quiescent), suggesting that this pathway may be involved in phenotypic modulation. Through global proteomic analysis we demonstrate NK cell-induced differential protein changes in aPSC versus qPSC. Furthermore, we demonstrate changes in intracellular NK pathways as a result of direct contact with PSCs, indicating a dynamic, bidirectional interaction between these two key players. Using multiplex immunohistochemical analysis, we demonstrate that NK cell proximity to CAFs, and not total NK cell infiltrate is correlated with overall survival in PDAC. Consequently, we suggest that the spatial biology of NK/CAFs may play a prognostic role in PDAC and may potentially be used as a tool for patient stratification Taken together, our results demonstrate a significant bidirectional relationship between NK cells and PSC/CAFs in the context of PDAC, providing novel insight into this crucial cell-cell interaction

    The Analysis of Novice English Teacher Talk in Junior High School under SETT Framework

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    In the realm of English teaching, teacher talk stands as a pivotal instructional instrument, serving both as a vital tool for teachers and a primary conduit for knowledge input for students. Effective classroom instruction is intricately woven with the dynamic, two-way interaction between teachers and students, which is expertly guided by the teacher talk. While numerous scholars have delved into the exploration of teacher talk, there remains a dearth of research investigating the specific landscape of novice English teachers’ classroom talk, particularly within the framework of Walsh’s Self-Evaluation of Teacher Talk (SETT). This study addresses this gap by observing the classes of four novice English teachers in junior high schools based on Walsh’s SETT framework to meticulously examine the current state of novice middle school English teachers’ classroom discourse. The objective is to cultivate teachers’ reflective awareness regarding their own discourse in the classroom and enhance their capacity to critically evaluate its efficacy as well as elevating the overall effectiveness of English classroom interactions in the context of secondary education

    Principles of generalization for sensorimotor cerebellar learning

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    The cooperation-competition paradox: Managing coopetition across firm sizes

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    This publication-based dissertation investigates how firms of different sizes and structures manage simultaneous cooperation and competition (coopetition). It includes five self-contained research papers, four designed for publication in peer-reviewed academic journals, and one developed for publication as an academic teaching case study. The first paper is a systematic literature review that identifies recent accomplishments and future trends in coopetition research. It delivers a comprehensive, unique, and updated view on the field, unifying scattered research findings into a cohesive and overarching framework. The second paper is a single-case study, zooming in on the inner workings of a corporate incubator. It explores the role and management of internal coopetition to develop entrepreneurial competencies for business model innovation. The third paper shifts the research focus toward large multinational enterprises to explore the formation of new coopetition relationships. It illuminates a new organizational design and accompanying management principles to address paradoxical tensions in the first and potentially most difficult phase of coopetition. The fourth paper taps into the complexities of coopetition between small- and mid-sized firms and large corporates. It uncovers three coopetition strategies and a mix of management principles for smaller firms to navigate asymmetrical risks in coopetition with larger companies. The fifth paper expands the scope of the dissertation to include an entire industry, analyzing the drivers, strategies, and outcomes of coopetition in a highly concentrated and regulated sector. Taken together, the five research papers collectively contribute to a more nuanced understanding about the management of coopetition and provide valuable implications and recommendations for practitioners

    Targeting immune and desmoplastic tumor microenvironment to sensitize gynecological cancer cells to therapy

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    Cancer is a pervasive global threat that manifests with diverse clinical attributes and notable mortality rates, particularly attributable to its metastatic potential in solid cancers. These tumours encompass various types including epithelial cancers like high-grade serous ovarian cancer (HGSC) and mesenchymal cancers like uterine sarcomas (USs). Despite the differing origins of USs and HGSCs, the pivotal concept of the transition between epithelial and mesenchymal states remains remarkably plastic, occurring frequently in these cancers. This plasticity holds immense significance in understanding tumour invasiveness and metastasis. The TME emerges as a crucial influencer as exerting its impact on cancer progression, epithelial-mesenchymal transition (EMT), metastasis, and even chemoresistance. The TME comprises various elements, with the extracellular matrix (ECM) containing structural proteins like collagens, standing out as a key constituent. Moreover, immune cells within the TME, such as lymphocytes and macrophages, actively engage in interactions with both the ECM and cancer cells shaping local responses to kill the cancer cells or support their growth. Understanding the intricate tumour-TME interactions become imperative in formulating effective strategies aimed at modulating the immune response and halting cancer progression. Therefore, a nuanced comprehension of these complexities is crucial in developing strategies to combat cancer effectively. This thesis focuses on identifying TME factors, including ECM components and immune cell interactions in gynaecological cancers for improved precision medicine including immunotherapies and other novel treatments. In Paper I, Uterine sarcomas present distinct immune signatures with prognostic value, independent of tumour type. FOXP3+ cell density and CD8+/FOXP3+ ratio (CFR) correlated with favourable survival in endometrial stromal sarcomas (ESS) and undifferentiated uterine sarcomas (USS). The CFR also highlighted the correlation between CFR high and upregulation of ECM organization pathways. In Paper II conversely, uterine leiomyosarcomas (uLMS) showed distinct behaviours, with lower collagen density and upregulated ECM remodelling enzymes correlating with aggressiveness. MMP-14 and yes-associated protein 1 (YAP) were required for uLMS growth and invasion. In Paper Ⅲ, shifting to HGSC, matrisome, a group of proteins encoded by genes for core ECM proteins 4 (collagens, proteoglycans, and ECM glycoproteins) and ECM-associated proteins (proteins structurally resembling ECM proteins, ECM remodelling enzymes, and secreted factors) in the ECM, showed changes in expression depending on the type of tumour host tissues and after chemotherapy. Collagen VI, among scrutinized proteins, exhibited elevated expression linked to shortened survival in ovarian cancer patients. Mechanistically, collagen VI promoted platinum resistance via the stiffness-dependent β1 integrin-pMLC and YAP/TAZ pathways in HGSC cell lines In summary, this integrated exploration of uterine sarcomas and ovarian cancer provides a comprehensive understating of their TME. The study elucidates diverse immune and molecular features, offering potential prognostic markers and therapeutic targets. The findings underscore the complexity of these gynaecological malignancies, emphasizing the need for tailored approaches in understanding and combating these diseases

    Intestinal innervation and its role in mucosal damage and inflammation

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    The regulatory role of the autonomic nervous system (ANS) in intestinal inflammation and immunity is widely acknowledged. In this thesis, we investigated mediating pathways and demonstrated a pivotal role for the spleen. We studied the effect of electrical splenic nerve bundle stimulation (SpNS) in a mouse model of experimental colitis induced by dextran sulfate sodium and showed that SpNS reduced colitis. Further, we elucidated effects of sympathetic activity on intestinal mucosal homeostasis. Chemical sympathetic denervation through 6-hydroxydopamine led to enhanced intestinal inflammation, and impaired barrier integrity. In contrast, adrenergic receptor stimulation through UK 14,304, a specific receptor agonist, led to increased proliferation and stem cell function. Adrenergic receptor α2A was found to act as molecular delegate of intestinal epithelial sympathetic activity controlling cell proliferation, differentiation, and host defense. The ANS is a complex network activating numerous pathways and therefore effects can be ambiguous and are often challenging to interpret. Our studies increased the understanding of effects of autonomic neuronal activity on intestinal processes, and future studies should continue investigations with not only experimental, but also clinical research. Ultimately, a role for bioelectronic medicine in intestinal immunity and mucosal healing can be allocated and neuromodulatory techniques are to be examined as a plausible treatment modality

    Principles of generalization for sensorimotor cerebellar learning

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    The cellular triumvirate: fibroblasts entangled in the crosstalk between cancer cells and immune cells

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    This review article will focus on subpopulations of fibroblasts that get reprogrammed by tumor cells into cancer-associated fibroblasts. Throughout this article, we will discuss the intricate interactions between fibroblasts, immune cells, and tumor cells. Unravelling complex intercellular crosstalk will pave the way for new insights into cellular mechanisms underlying the reprogramming of the local tumor immune microenvironment and propose novel immunotherapy strategies that might have potential in harnessing and modulating immune system responses

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK
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