Physiological beta-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma

BACKGROUND: A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/beta-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological beta-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of beta-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells. RESULTS: Introduction of increased beta-catenin signaling, haploid expression of beta-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/beta-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous beta-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/beta-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-beta, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using beta-catenin shRNA inhibitory assays, a dominant role for beta-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres. CONCLUSIONS: Wnt/beta-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/beta-catenin signaling with stemness transition networks.published_or_final_versio

UV-Diagram: A Voronoi Diagram for Uncertain Spatial Databases

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Interventions to improve the sleep quality of adults with personality disorder: a systematic review

Poor quality sleep is common for people who have a diagnosis of personality disorder (PD). Core cognitive and behavioral features of PD may cause and perpetuate poor sleep, but to date, no review has collated the evidence on the efficacy of interventions to improve sleep quality for people with PD. Structured searches for interventional studies among adults with PD and reporting validated measures of sleep quality were conducted up to November 2022 in multiple databases. Single-case reports were excluded. Study quality was assessed with standardized risk of bias tools. Unreported data was sought systematically from authors. This review was pre-registered with an international prospective register of systematic reviews (PROSPERO) (CRD42021282105). Of the 3503 identified studies, nine met inclusion criteria, representing a range of psychological, pharmaceutical, and other interventions and outcome measures. Meta-analytic methods were not feasible because of the serious risk of bias in all studies, and results were therefore synthesized narratively. There is limited and low-quality evidence of the effects of a variety of interventions to improve the sleep quality of people living with PD. Further research might consider specifically including people diagnosed with PD in trials of sleep interventions and using sleep outcome measures in trials of established PD treatments

Wnt-C59 arrests stemness and suppresses growth of nasopharyngeal carcinoma in mice by inhibiting the Wnt pathway in the tumor microenvironment

Wnt/β-catenin signaling is responsible for the generation of cancer stem cells (CSCs) in many human tumors, including nasopharyngeal carcinoma (NPC). Recent studies demonstrate that Wnt or PORCN inhibitor, Wnt-C59, inhibits tumor growth in MMTV-WNT1 transgenic mice. The effect of Wnt-C59 in human tumors is not clear. In this study, the NPC cell lines investigated manifest heterogeneous responses to Wnt-C59 treatment. Wnt-C59 decreased tumor growth of SUNE1 cells in mice immediately following the administration of Wnt-C59. Mice injected with HNE1 cells did not develop visible tumors after the treatment of Wnt-C59, while control mice developed 100% tumors. Wnt-C59 inhibited stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. Thus, Wnt-C59 has the potential to eradicate CSCs in human tumors. Active β-catenin and Axin2 proteins were strongly expressed in stromal cells surrounding growing tumors, confirming the importance of Wnt signaling activities in the microenvironment being driving forces for cell growth. These novel findings confirm the ability of Wnt-C59 to suppress Wnt-driven undifferentiated cell growth in NPC. Both anti-Wnt signaling and anti-CSC approaches are feasible strategies in cancer therapy.published_or_final_versio

Differential expression of Toll-like receptor 4 in healthy and diseased human gingiva

BACKGROUND AND OBJECTIVE: Lipopolysaccharide (LPS)-mediated signaling in host cells involves Toll-like receptor 4 (TLR4) accessory molecules, including LPS-binding protein (LBP), cluster of differentiation 14 (CD14) and lymphocyte antigen 96 (MD-2). However, expression of these innate defense molecules in various compartments of the human periodontium is unclear. The aim of this study was to investigate the expression profile of TLR4 in human gingiva. MATERIAL AND METHODS: Human gingival biopsies were collected from healthy gingival or chronic periodontitis tissue. Primary gingival keratinocytes and fibroblasts were cultured. Immunohistochemical analysis for TLR4 was performed. Transcripts of TLR4, MD-2, CD14 and LBP, and their protein products, were examined using RT-PCR, immunoprecipitation and immunoblotting. The interactions between these molecules in keratinocytes and fibroblasts were investigated by co-immunoprecipitation. RESULTS: TLR4 immunoreactivity was found in healthy gingival epithelium and periodontitis tissue, and appeared to be lower in junctional epithelium ( p </= 0.01). Fibroblasts and inflammatory cells stained more strongly for TLR4 in diseased periodontal tissues (p < 0.001). Three TLR4 splicing variants, two MD-2 splicing variants and one CD14 mRNA were expressed by gingival keratinocytes and fibroblasts. Expression of TLR4, CD14 and MD-2 proteins was detected in keratinocytes and fibroblasts in vitro. TLR4 protein from gingival keratinocytes and fibroblasts could be co-immunoprecipitated with CD14 or MD-2, suggesting an association between the related molecules in vivo. LBP transcript was detected in gingival biopsies, but not in primary cultures of gingival keratinocytes or fibroblasts. CONCLUSION: TLR4, CD14 and MD-2, but not LBP, are expressed in human gingival keratinocytes and fibroblasts. The TLR4 expression level in the junctional epithelium appeared to be lowest within the periodontal epithelial barrier.postprin

Inhibition of both physiological and aberrant Wnt/b-catenin signaling activities associated with stemness in NPC

This journal suppl. entitled: Proceedings: AACR Annual Meeting 2014; April 5-9, 2014 ...Tumor Biology - Poster Presentations - Proffered Abstracts - Poster Presentations - Developmental Pathways in Cancer: abstract no. 1938We previously demonstrated that basic or physiological levels of β-catenin signaling and tissue context play decisional roles in the regulation of self-renewal networks in nasopharyngeal carcinoma (NPC) HONE1 cells. Introduction of physiological levels of β-catenin signaling in HONE1 hybrid cells plays a central role in the control of other pathway activities, such as TGF-β, Activin, and pluripotency maintenance (LIFR and IL6ST), during the stemness transition process. These results revealed novel regulatory ...postprin

A Method to Improve the Early Stages of the Robotic Process Automation Lifecycle

The robotic automation of processes is of much interest to organizations. A common use case is to automate the repetitive manual tasks (or processes) that are currently done by back-office staff through some information system (IS). The lifecycle of any Robotic Process Automation (RPA) project starts with the analysis of the process to automate. This is a very time-consuming phase, which in practical settings often relies on the study of process documentation. Such documentation is typically incomplete or inaccurate, e.g., some documented cases never occur, occurring cases are not documented, or documented cases differ from reality. To deploy robots in a production environment that are designed on such a shaky basis entails a high risk. This paper describes and evaluates a new proposal for the early stages of an RPA project: the analysis of a process and its subsequent design. The idea is to leverage the knowledge of back-office staff, which starts by monitoring them in a non-invasive manner. This is done through a screen-mousekey- logger, i.e., a sequence of images, mouse actions, and key actions are stored along with their timestamps. The log which is obtained in this way is transformed into a UI log through image-analysis techniques (e.g., fingerprinting or OCR) and then transformed into a process model by the use of process discovery algorithms. We evaluated this method for two real-life, industrial cases. The evaluation shows clear and substantial benefits in terms of accuracy and speed. This paper presents the method, along with a number of limitations that need to be addressed such that it can be applied in wider contexts.Ministerio de Economía y Competitividad TIN2016-76956-C3-2-

PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma

Protein Tyrosine Phosphatase, Receptor Type G (PTPRG) was identified as a candidate tumor suppressor gene in nasopharyngeal carcinoma (NPC). PTPRG induces significant in vivo tumor suppression in NPC. We identified EGFR as a PTPRG potential interacting partner and examined this interaction. Dephosphorylation of EGFR at EGFR-Y1068 and -Y1086 sites inactivated the PI3K/Akt signaling cascade and subsequent down-regulation of downstream pro-angiogenic and -invasive proteins (VEGF, IL6, and IL8) and suppressed tumor cell proliferation, angiogenesis, and invasion. The effect of Akt inhibition in NPC cells was further validated by Akt knockdown experiments in the PTPRG-down-regulated NPC cell lines. Our results suggested that inhibition of Akt in NPC cells induces tumor suppression at both the in vitro and in vivo levels, and also importantly, in vivo metastasis. In conclusion, we confirmed the vital role of PTPRG in inhibiting Akt signaling with the resultant suppression of in vivo tumorigenesis and metastasis.published_or_final_versio

Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing

We developed analytical models of DNA replication that include probabilistic initiation of origins, fork progression, passive replication, and asynchrony.We fit the model to budding yeast genome-wide microarray data probing the replication fraction and found that initiation times correlate with the precision of timing.We extracted intrinsic origin properties, such as potential origin efficiency and firing-time distribution, which cannot be done using phenomenological approaches.We propose that origin timing is controlled by stochastically activated initiators bound to origin sites rather than explicit time-measuring mechanisms

Lorentz Violation in Warped Extra Dimensions

Higher dimensional theories which address some of the problematic issues of the Standard Model(SM) naturally involve some form of $D=4+n$-dimensional Lorentz invariance violation (LIV). In such models the fundamental physics which leads to, e.g., field localization, orbifolding, the existence of brane terms and the compactification process all can introduce LIV in the higher dimensional theory while still preserving 4-d Lorentz invariance. In this paper, attempting to capture some of this physics, we extend our previous analysis of LIV in 5-d UED-type models to those with 5-d warped extra dimensions. To be specific, we employ the 5-d analog of the SM Extension of Kostelecky et. al. ~which incorporates a complete set of operators arising from spontaneous LIV. We show that while the response of the bulk scalar, fermion and gauge fields to the addition of LIV operators in warped models is qualitatively similar to what happens in the flat 5-d UED case, the gravity sector of these models reacts very differently than in flat space. Specifically, we show that LIV in this warped case leads to a non-zero bulk mass for the 5-d graviton and so the would-be zero mode, which we identify as the usual 4-d graviton, must necessarily become massive. The origin of this mass term is the simultaneous existence of the constant non-zero $AdS_5$ curvature and the loss of general co-ordinate invariance via LIV in the 5-d theory. Thus warped 5-d models with LIV in the gravity sector are not phenomenologically viable.Comment: 14 pages, 4 figs; discussion added, algebra repaire