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Alzheimer's disease (AD) is a prevalent neurodegenerative disease and the world's primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aβ) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one of the major features of AD, which involves a network of interactions between immune cells. The mast cell (MC) is an innate immune cell type known to serve as a first responder to pathological changes and crosstalk with microglia and neurons. Although an increased number of mast cells were found near the sites of Aβ deposition, how mast cells are activated in AD is not clear. We developed a 3D culture system to culture MCs and investigated the activation of MCs by Aβ peptides. Because collagen I is the major component of extracellular matrix (ECM) in the brain, we encapsulated human LADR MCs in gels formed by collagen I. We found that 3D-cultured MCs survived and proliferated at the same level as MCs in suspension. Additionally, they can be induced to secrete inflammatory cytokines as well as MC proteases tryptase and chymase by typical MC activators interleukin 33 (IL-33) and IgE/anti-IgE. Culturing with peptides Aβ1-42, Aβ1-40, and Aβ25-35 caused MCs to secrete inflammatory mediators, with Aβ1-42 inducing the maximum level of activation. These data indicate that MCs respond to amyloid deposition to elicit inflammatory responses and demonstrate the validity of collagen gel as a model system to investigate MCs in a 3D environment to understand neuroinflammation in AD. [ABSTRACT FROM AUTHOR]

Purpose: Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein‐coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1‐retinopathy. Methods: Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel‐based genetic analysis. Results: Study subjects had a median age of 8 years (range: 3–20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease‐associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini‐gene assay highlighted that this change results in mis‐splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case. Conclusion: Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein‐coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large‐scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities. [ABSTRACT FROM AUTHOR]

Background: Cancer stem cells (CSCs) are the root of human cancer development and the major cause of treatment failure. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of human cancer and promotes cancer development. However, the role of SOX4 in CSCs, especially at a proteome-wide level, has remained elusive. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study. Results: Overexpression of SOX4 promotes sphere formation and self-renewal of colorectal cancer cells in vitro and in vivo and elevates the expression levels of CSCs markers. Through iTRAQ-based quantitative proteomics analysis, 215 differentially expressed proteins (128 upregulated, 87 downregulated) in SOX4-overexpressing HCT-116 spheres were identified. The bioinformatic analysis highlighted the importance of HDAC1 as the fundamental roles of its impacted pathways in stem cell maintenance, including Wnt, Notch, cell cycle, and transcriptional misregulation in cancer. The mechanistic study showed that SOX4 directly binds to the promoter of HDAC1, promotes HDAC1 transcription, thereby supporting the stemness of colorectal cancer cells. HDAC1 hallmarks colorectal cancer stem cells and depletion of HDAC1 abolished the stimulatory effect of SOX4. Furthermore, SOX4-HDAC1 axis is conserved in multiple types of cancer. Conclusions: The results of this study reveal SOX4-induced proteome changes in HCT-116 spheres and demonstrates that transcriptional activation of HDAC1 is the primary mechanism underlying SOX4 maintaining CSCs. This finding suggests that HDAC1 is a potential drug target for eradicating SOX4-driven human CSCs. [ABSTRACT FROM AUTHOR]

We propose a visual servoing (VS) approach with deep learning to perform precise, robust, and real-time six degrees of freedom (6DOF) control of robotic manipulation to ease the extraction of image features and estimate the nonlinear relationship between the two-dimensional image space and the three-dimensional Cartesian space in traditional VS tasks. Owing to the superior learning capabilities of convolutional neural networks (CNNs), autonomous learning to select and extract image features from images and fitting the nonlinear mapping is achieved. A method for designing and generating a dataset from few or one image, by simulating the motion of an eye-in-hand robotic system is described herein. Therefore, network training requiring a large amount of data and difficult data collection occurring in actual situations can be solved. A dataset is utilized to train our VS convolutional neural network. Subsequently, a two-stream network is designed and the corresponding control approach is presented. This method converges robustly with the experimental results, in that the position error is less than 3 mm and the rotation error is less than 2.5° on average. [ABSTRACT FROM AUTHOR]

Identifying climate change risks, vulnerabilities of exposed populations, and implemented responses to climate change are crucial for developing effective strategies to mitigate climate hazards. However, existing climate change assessment indexes still have some limitations, such as insufficient consideration of policy response, limited coverage of countries, and lack of a multidimensional perspective. In this study, we developed a novel climate change impacts and responses (CCIR) index that incorporates comprehensive information on climate risks, disease burden, and mitigation actions in response to climate risks and damage. To our best knowledge, the CCIR index is the first of its kind that explores variations in climate risks, impacts, and responses across countries to identify vulnerabilities and find more targeted solutions. A positive correlation was found between the CCIR index and national Gross Domestic Product per capita, indicating that wealthier countries might allocate more resources toward mitigating climate impacts. Moreover, countries with better climate education tended to have a lower carbon footprint, highlighting the importance of climate education. Furthermore, countries with lower risks of emerging infectious diseases were more likely to consume more renewable energy. The results highlight the value of using a multidimensional CCIR framework to analyze the interactions among socioeconomic factors, environmental policies, and climate change risks in 158 countries. This comprehensive approach provides actionable insights to mitigate climate impacts and improve national climate resilience. It also streamlines monitoring efforts and promotes joint climate action across international boundaries. By identifying climate risks and opportunities, the CCIR index can help policymakers design, refine, and implement adaptation policies and measures to respond to the impacts of climate change. CCIR index evaluates countries' climate change mitigation and adaptation efforts. Wealthier countries invest more in mitigating climate change. Lower-income and coastal nations are vulnerable to climate change impacts. Countries at lower risk of emerging infectious diseases consume more renewable energy. Climate change education is associated with a lower carbon footprint. [ABSTRACT FROM AUTHOR]

Forest planners employ various techniques to mitigate the visible effects of harvesting, including by manipulating the shape of harvest blocks. Shape is a common indicator of preference in aesthetic evaluations of landscape and harvest block design. However, the majority of perception-based research in the field of landscape aesthetics has focused on the perspective view. This study investigates the perceptual effects of two shape characteristics: complexity and image mode, as viewed from the air. Order and subjects’ area of study were also tested. Forty-five aerial images of harvest blocks and 45 digitally-manipulated harvest block shapes were used as the harvest and shape image sets, respectively. Seventy-five subjects rated each image for preference. Complexity was the strongest predictor of preference. Preference increased as complexity level increased, regardless of the image mode in which the shapes were presented. Subjects with an environmental focus in their area of study demonstrated a more prominent complexity effect than those from non-environmental fields. Both image mode and area of study had small but significant effects on preference ratings. These results confirm previous findings pertaining to complexity in psychology and landscape aesthetics, in which complexity, as a characteristic of shape, plays a role in predicting preference. [ABSTRACT FROM AUTHOR]

Background: Best vitelliform macular dystrophy (BVMD) is an autosomal dominant hereditary retinal disease caused by BEST1 gene mutations. Macular hole is a rare complication of BVMD. We are the first to report a BVMD case with bilateral macular holes and a new onset vitelliform lesion after a vitrectomy surgery. Materials and methods: A woman with a history of BVMD suffered from a 1-year vision loss in both eyes. Complete ophthalmologic examinations and BEST1 gene screening were performed on the patient. Results: Ophthalmoscopic examinations revealed bilateral macular holes with atrophic photoreceptors and retinal pigment epithelium (RPE). A disease-causing BEST1 mutation N296S (c.887A>G) was detected. A vitrectomy surgery with internal limiting membrane (ILM) peeling and gas tamponade was performed on the right eye. The macular hole closed and maintained stable for 1 year. A new extramacular vitelliform lesion was observed during the follow-up. Conclusions: Macular hole is an unusual but severe complication in the end stage of BVMD as the macular thinning is accompanied with vitreous traction. A vitrectomy surgery is effective to close the hole while further study is required to elucidate the pathophysiology of macular hole formation and the new vitelliform lesion in such a case. [ABSTRACT FROM PUBLISHER]

Purpose: To describe the clinical features and to analyze BEST1 mutations in patients with Best vitelliform macular dystrophy (BVMD). Methods: Thirteen individuals affected by BVMD from 6 unrelated Chinese families were studied. Complete ophthalmological examinations were performed, and the BEST1 gene was screened in all participants and 100 controls. Follow-ups were arranged within 12 months. Results: All 6 probands showed typical fundus appearances of BVMD. One of the 6 had a history of angle closure glaucoma, and another showed a unilateral focal choroidal excavation on optical coherence tomography. One patient experienced progression of the macular lesion during the follow-up. The asymptomatic mutation carriers had normal fundus but abnormal Arden ratios on electro-oculograms. Besides 4 previously reported mutations (p.Ser16Phe, p.Ser144Asn, p.Glu292Lys, p.Glu300Lys), 2 novel disease-causing mutations (p.Thr307Asp, p.Arg47His) were identified, of which p.Arg47His has been reported in adult-onset vitelliform macular dystrophy. Conclusions: Our findings have expanded the mutational and clinical spectrum of BVMD in a Chinese population. Clinical presentations of angle closure glaucoma and/or focal choroidal excavation may be related to BVMD, underlining the necessity of multimodal studies and risk assessment of angle closure glaucoma in BEST1 mutation carriers. BVMD and adult-onset vitelliform macular dystrophy may share a common etiology in some cases. [ABSTRACT FROM AUTHOR]

As an important form of renewable energy utilization, microgrid (MG) is considered to be the main bearing form of distributed generation in the future. One of the most concerning issues in the operation of MG is how to realize its economic dispatch (ED). Nowadays, distributed algorithms have been increasingly used to solve the economic dispatch problem of MG. However, the MG based on the distributed optimization architecture must bear higher cyber‐attack risks. To address this issue, this paper investigates the distributed robust ED problem of MG. Firstly, a multi‐objective dispatch model of MG using a linear weighted sum (LWS) algorithm is developed, which considers the environmental and economic costs. On this basis, an event‐triggered fully distributed algorithm is proposed, which can effectively reduce communication times. Furthermore, an attack resilient strategy against false data injection (FDI) attacks is implemented in the proposed fully distributed algorithm, which has strong robustness against various colluding attacks and non‐colluding attacks, and can eliminate incorrect measurement of incremental cost and power generation data. Finally, the effectiveness of the proposed distributed control strategy is demonstrated through case studies in this paper. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Suanzaorenhehuan Formula (SHF) is a Chinese herbal formula for the treatment of depression-like disorders. It contains four herbs: Semen Ziziphi spinosae, Cortex Albiziae, Radix Paeoniae Alba and Semen Platycladi. The present study is to investigate the antidepressant-like effect of the ethanolic extract of SHF and its possible mechanisms. Materials and methods: Mouse models of depression including the tail suspension test (TST), forced swimming test (FST) and chronic unpredicted mild stress (CUMS) were used to evaluate the effects of SHF extract. The mechanisms were examined by measuring monoamine neurotransmitters in mice hippocampus and frontal cortex, testing monoamine oxidase enzyme (MAO) activities in brain of CUMS-exposed mice. Results: After one-week treatment, SHF extract (50, 100 and 200mg/kg) induced a significant decrease on immobility time in TST. After two-week treatment, SHF extract (50, 100 and 200mg/kg) led to a reduction in the immobility period in TST and FST. The 5-HT levels in mice hippocampus were increased only after 200mg/kg SHF extract treatment. The noradrenaline (NE) levels were increased after 200mg/kg SHF extract treatment in mice hippocampus and frontal cortex. SHF extract (50, 100 and 200mg/kg) significantly inhibited monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) after 21-day CUMS exposure. Conclusion: These findings demonstrated that ethanolic SHF extract produced an antidepressant-like effect and the mechanism of action involves the serotonergic, noradrenergic and monoamine oxidase enzyme systems although underlying mechanism still remains to be further elucidated. [Copyright &y& Elsevier]

Choroidal neovascularization (CNV) is a devastating pathology of numerous ocular diseases, such as wet age-related macular degeneration (wAMD), which causes irreversible vision loss. Although anti-vascular endothelial growth factor (VEGF) therapy has been widely used, poor response or no response still exists in some cases, suggesting that there are other components involved in the angiogenic process. Therefore, the underlying mechanism needs to be clarified and new target of anti-angiogenic therapy is urgently needed. It has been demonstrated that damaged retinal pigment epithelium (RPE) cells can activate inflammasome, driving a degenerative tissue environment and an enhanced pro-angiogenic response, which implies that RPE dysfunction may be a hallmark of the pathogenesis. Previously, we have shown that DNA damage can induce RPE dysfunction, triggering senescence-associated secretory phenotype (SASP) and local inflammation. In this study, we identify that chrysin can reduce DNA damage, especially telomere erosion in vitro , thus compromise the dysfunction of RPE and the decreased expression of SASP factor. Importantly, we find that DNA damage of RPE cells is remarkable in laser-induced CNV lesion, resulting in inflammatory response, which can be ameliorated by chrysin, mainly through IL-17 signaling pathway and its downstream signal transducer and activator of transcription 3 (STAT3) activities. In summary, our results indicate the interplay between DNA damage, perturbed RPE homeostasis, inflammatory response and angiogenesis in laser-induced CNV, and more importantly, chrysin may be an effective therapeutic supplement for CNV. • Our results indicate the interplay between DNA damage, perturbed RPE homeostasis, inflammation and angiogenesis in CNV. • Chrysin can ameliorate DNA damage and inflammatory response through IL-17 signalling pathway and STAT3 activities in CNV. • Chrysin can reduce DNA damage, thus alleviating RPE dysfunction and decreasing the expression of SASP factors. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to reveal the mechanism underlying baicalin-suppressing ovarian cancer stemness. Methods: OVCAR-3 and the primary ovarian cancer cells were used for cell model. The ovarian cancer stem cells were isolated by suspension culture. Cell viability and clonogenicity were examined by CCK-8 assay and colony formation assay. The self-renewal of the cells was evaluated by the determination of sphere-forming capacity and the frequency of in vitro sphere-forming and in vivo tumor-initiating cells. The mRNA and protein levels were relatively quantified by qRT-PCR and Western blot. The transcription regulation of target genes was tested by luciferase reporter assay and a modified nuclear rn-on qRT-PCR assay. Results: Treatment with a non-toxic dose of baicalin significantly inhibited the spherogenicity of ovarian cancer cells. Moreover, a non-toxic dose of baicalin treatment suppressed the frequency of sphere-forming and tumor-initiating ovarian cancer cells. Furthermore, the expression of ovarian cancer stem cell markers (CD133 and ALDH1A1) was inhibited by a non-toxic dose of baicalin treatment. Baicalin inhibits YAP activity and suppresses RASSF6, a positive regulator of YAP, at the transcriptional level. Overexpression of both YAP and RASSF6 abolished the inhibitory effect of baicalin on the proliferation and stemness of ovarian cancer cells. Conclusion: The results in this study demonstrated that baicalin suppresses the stemness of ovarian cancer cells by attenuating YAP activity via inhibiting RASSF6 at the transcriptional level. This finding revealed baicalin as a novel YAP inhibitor that could serve as an anti-cancer drug for eradicating ovarian cancer stem cells. [ABSTRACT FROM AUTHOR]

Objective: The reverse of chemoresistance and the improvement of sensitivity to chemotherapeutic agents of colorectal cancer cells have great clinical significance and the mechanism underlying the drug resistance is still unclear. REG Iα was reported to be upregulated in colorectal cancer tissues, but the roles of chemoresistance are still unclear. Materials and Methods: The expression of REG Iα in colorectal cancer cell lines was assessed by quantitative real-time polymerase chain reaction (Q-PCR). The expression of REG Iα in HCT116 and LOVO cells was knockdown by siRNA. The cell viability and IC50 (half maximal inhibitory concentration) values were analyzed by the CCK8 assay. The proportion of apoptosis and cell cycles were analyzed by flow cytometry. The migration potency of HCT116 and LOVO cells was analyzed by cell migration assay. The protein level of Cyclin D1, CDK4 (cyclin-dependent kinase 4), Bax and Bcl-2 were analyzed by western blot. Results: Knockdown of REG Iα enhances the sensitivity to 5-Fu of colorectal cancer cells. REG Iα knockdown promoted the cell apoptosis of HCT116 and LOVO under the 5-Fu treatment. The cell migration and cycle of colorectal cancer cells was also inhibited by REG Iα knockdown. We also found that REG Iα knockdown induced cell cycle arrest and cell apoptosis by Cyclin D1/CDK4 pathway and BAX/BCL-2 pathways. Conclusions: Knockdown of REG Iα enhances the sensitivity to 5-Fu of colorectal cancer cells via cyclin D1/CDK4 pathway and BAX/BCL-2 pathways. [ABSTRACT FROM AUTHOR]

Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent lens extraction for ectopia lentis between 2013 and 2017 were identified, and gene panel testing findings and surgical outcomes were collected. Overall, 10/11 cases received a probable molecular diagnosis. Genetic variants were identified in four genes: FBN1 (associated with Marfan syndrome and cardiovascular complications; n = 6), ADAMTSL4 (associated with non-syndromic ectopia lentis; n = 2), LTBP2 (n = 1) and ASPH (n = 1). Parents appeared unaffected in 6/11 cases; the initial presentation of all six of these children was to an ophthalmologist, and only 2/6 had FBN1 variants. Notably, 4/11 cases required surgery before the age of 4 years, and only one of these children carried an FBN1 variant. In summary, in this retrospective cohort study, panel-based genetic testing pointed to a molecular diagnosis in >90% of paediatric ectopia lentis cases requiring surgery. In a subset of study participants, genetic analysis revealed changes in genes that have not been linked to extraocular manifestations and highlighted that extensive systemic investigations were not required in these individuals. We propose the introduction of genetic testing early in the diagnostic pathway in children with ectopia lentis. [ABSTRACT FROM AUTHOR]

As environmental protection greatly influences the social development, for the multi-energy systems (MES) equipped with a cluster of energy devices, the economic dispatch (ED) problem should not only be considered but also the environmental protection problem should be considered in energy utilization. To address this issue, a multi-objective dispatch model of MES using a linear weighted sum algorithm (LWS) is developed in this paper, which considers the environmental and economic costs. On this basis, a fully distributed algorithm with the coupled control mechanism of power and heat is presented to realize coordination optimization between the environmental and economic benefits. Furthermore, an event-triggered communication strategy is implemented in the fully distributed algorithm, which can be effectively applied to the multi-objective dispatch model, to reduce the communication burden. Finally, the simulation results verify the effectiveness of the proposed distributed control strategy. • A multi-objective dispatch model of MES using a LWS algorithm is given. • The coupled control mechanism based on the consensus protocol is proposed. • An event-triggered strategy is implemented in the fully distributed algorithm. [ABSTRACT FROM AUTHOR]

Background: One Health has become a global consensus to deal with complex health problems. However, the progress of One Health implementation in many countries is still relatively slow, and there is a lack of systematic evaluation index. The purpose of this study was to establish an indicator framework for global One Health Intrinsic Drivers index (GOH-IDI) to evaluate human, animal and environmental health development process globally. Method: First, 82 studies were deeply analyzed by a grounded theory (GT) method, including open coding, axial coding, and selective coding, to establish a three-level indicator framework, which was composed of three selective codes, 19 axial codes, and 79 open codes. Then, through semi-structured interviews with 28 health-related experts, the indicators were further integrated and simplified according to the inclusion criteria of the indicators. Finally, the fuzzy analytical hierarchy process combined with the entropy weight method was used to assign weights to the indicators, thus, forming the evaluation indicator framework of human, animal and environmental health development process. Results: An indicator framework for GOH-IDI was formed consisting of three selective codes, 15 axial codes and 61 open codes. There were six axial codes for "Human Health", of which "Infectious Diseases" had the highest weight (19.76%) and "Injuries and Violence" had the lowest weight (11.72%). There were four axial codes for "Animal Health", of which "Animal Epidemic Disease" had the highest weight (39.28%) and "Animal Nutritional Status" had the lowest weight (11.59%). Five axial codes were set under "Environmental Health", among which, "Air Quality and Climate Change" had the highest weight (22.63%) and "Hazardous Chemicals" had the lowest weight (17.82%). Conclusions: An indicator framework for GOH-IDI was established in this study. The framework were universal, balanced, and scientific, which hopefully to be a tool for evaluation of the joint development of human, animal and environmental health in different regions globally. [ABSTRACT FROM AUTHOR]

The muscle of aquatic crustaceans is perishable and susceptible to environmental contamination. Vibrio harveyi is a widely occurring pathogen in aquatic animals. Here, bath treatment with a virulent V. harveyi strain (which was added directly in the rearing water to imitate environmental contamination) isolated from the muscle of the whiteleg shrimp, Litopenaeus vannamei, caused the muscle of Li. vannamei to display a whitish-opaque appearance due to microscopic changes including muscle lysis, muscle fiber damage and microbial colonization. When administered orally by incorporating this isolate in feed (which is an imitation of infection via natural route), rather than direct invasion followed by colonization in the muscle, this isolate indirectly stimulated severe muscle necrosis in Li. vannamei via steering the enrichment of two important (human) pathogens, V. cholerae and V. vulnificus, and one environmental bacterium Pseudomonas oleovorans, based on the meta-taxonomic analyses. In addition to the scientifically proven viral diseases, our research proved that bacterial agents are also capable of causing muscle spoilage in crustaceans via changing the microbial composition, and that the crustaceans might be exploited as the wide-spectrum sensitive bio-detector to indicate the extent of microbial contamination. [ABSTRACT FROM AUTHOR]

Probiotics when applied in complex evolving (micro-)ecosystems, might be selectively beneficial or detrimental to pathogens when their prophylactic efficacies are prone to ambient interactions. Here, we document a counter-intuitive phenomenon that probiotic-treated zebrafish (Danio rerio) were respectively healthy at higher but succumbed at lower level of challenge with a pathogenic Vibrio isolate. This was confirmed by prominent dissimilarities in fish survival and histology. Based upon the profiling of the zebrafish microbiome, and the probiotic and the pathogen shared gene orthogroups (genetic niche overlaps in genomes), this consequently might have modified the probiotic metabolome as well as the virulence of the pathogen. Although it did not reshuffle the architecture of the commensal microbiome of the vertebrate host, it might have altered the probiotic-pathogen inter-genus and intra-species communications. Such in-depth analyses are needed to avoid counteractive phenomena of probiotics and to optimise their efficacies to magnify human and animal well-being. Moreover, such studies will be valuable to improve the relevant guidelines published by organisations such as FAO, OIE and WHO. [ABSTRACT FROM AUTHOR]

Background: Accurately forecasting the prognosis could improve cervical cancer management, however, the currently used clinical features are difficult to provide enough information. The aim of this study is to improve forecasting capability by developing a miRNAs-based machine learning survival prediction model. Results: The expression characteristics of miRNAs were chosen as features for model development. The cervical cancer miRNA expression data was obtained from The Cancer Genome Atlas database. Preprocessing, including unquantified data removal, missing value imputation, samples normalization, log transformation, and feature scaling, was performed. In total, 42 survival-related miRNAs were identified by Cox Proportional-Hazards analysis. The patients were optimally clustered into four groups with three different 5-years survival outcome (≥ 90%, ≈ 65%, ≤ 40%) by K-means clustering algorithm base on top 10 survival-related miRNAs. According to the K-means clustering result, a prediction model with high performance was established. The pathways analysis indicated that the miRNAs used play roles involved in the regulation of cancer stem cells. Conclusion: A miRNAs-based machine learning cervical cancer survival prediction model was developed that robustly stratifies cervical cancer patients into high survival rate (5-years survival rate ≥ 90%), moderate survival rate (5-years survival rate ≈ 65%), and low survival rate (5-years survival rate ≤ 40%). [ABSTRACT FROM AUTHOR]

Stromal/cytoplasmic collagen XIαI (COL11A1) has been highlighted in the process of neoplastic transformation, including epithelial mesenchymal transition (EMT), metastasis and invasiveness. In this study, we aim to illuminate the clinical significance and biological role of COL11A1 in esophageal squamous cell carcinoma (ESCC). Herein, we investigated COL11A1 expression in 16 pairs of ESCC and adjacent normal tissues by RT-PCR and western blotting analysis. Correlations of COL11A1 expression with clinicopathologic parameters and survival status were then determined by immunohistochemistry in 116 ESCC and 50 normal specimens. Furthermore, bioinformatics was used for mechanisms exploration. And in vitro knockdown experiments were also performed. We found that COL11A1 expression was significantly higher in ESCC than in paired normal tissues at both mRNA and protein level. Immunohistochemistry showed that COL11A1 was predominantly localized to the cytoplasm rather than tumor stroma, patients with high COL11A1 expression had a poorer overall survival (OS) rate than those with low COL11A1 expression. Besides, increased COL11A1 expression was dramatically correlated with advanced clinical stage, invasion depth and lymph node metastases and served as an independent prognostic marker for ESCC. Likewise, COL11A1 dependent nomogram predicted a more precise survival outcome than traditional staging system. Moreover, COL11A1 silencing resulted in impaired cell proliferation and EMT, and subdued EMT inhibited cells aggressiveness. These biological processes (BPs) might be modulated by COL11A1 via the intracellular AKT/ERK/c-Myc cascades. [ABSTRACT FROM AUTHOR]

Long-term use of low-toxic natural products holds the promise for eradicating cancer stem cells. In this study, we report that luteolin, a natural flavonoid, attenuates the stemness of ovarian cancer stem cells (OCSCs) by directly binding to KDM4C and epigenetic suppression of PPP2CA/YAP axis. Ovarian cancer stem like cells (OCSLCs) isolated by suspension culture and CD133 + ALDH+ cell sorting was employed as OCSCs model. The maximal non-toxic dose of luteolin suppressed stemness properties, including sphere-forming capacity, the expression of OCSCs markers, sphere-initiating and tumor-initiating capacities, as well as the percentage of CD133 + ALDH+ cells of OCSLCs. Mechanistic study showed that luteolin directly binds to KDM4C, blocks KDM4C-induced histone demethylation of PPP2CA promoter, inhibits PPP2CA transcription and PPP2CA-mediated YAP dephosphorylation, thereby attenuating YAP activity and the stemness of OCSLCs. Furthermore, luteolin sensitized OCSLCs to traditional chemotherapeutic drugs in vitro and in vivo. In summary, our work revealed the direct target of luteolin and the underlying mechanism of the inhibitory effect of luteolin on the stemness of OCSCs. This finding thus suggests a novel therapeutic strategy for eradicating human OCSCs driven by KDM4C. [Display omitted] • The inhibitory effect of luteolin on the stemness of ovarian cancer stem cells was revealed for the first time. • A novel direct target of luteolin, KDM4C, in ovarian cancer cells was revealed. • A novel oncogenic axis, KDM4C/PPP2CA/YAP, was revealed. [ABSTRACT FROM AUTHOR]

The purpose of this study was to retrospectively validate the prognostic value of revised 2018 FIGO stage IIIC This is a retrospective analysis of patients with cervical cancer in stage III of the revised 2018 FIGO Staging System who received standardized treatment from 2011 to 2014 at a cancer hospital. Multi-group comparisons were performed with the Kruskal-Wallis H test and chi-square test. Survival curves were calculated using the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was used for multivariable analysis. A total of 418 women were included, 42(10.0%) stage IIIA, 120(28.7%) stage IIIB, 190(45.5%) stage IIIC1 and 66(15.8%) stage IIIC2, there was no significant difference in histological type, tumor differentiation, tumor size, type of radiotherapy, consolidation chemotherapy among the four groups (all, P > 0.05). The stage IIIC1 patients were younger compared to those with stage IIIA (P <0.001) and IIIB(P =0.01). On univariate survival analyses, the 2018 FIGO staging system was significantly associated with survival in stage III cervical cancer (P <0.001). Women with stage IIIC1 disease had significantly improved survival compared to those with stage IIIC2 (P <0.001); Survival of women with stage IIIC1 was similar compared to those IIIA (P =0.484) and IIIB (P =0.042) (5-year OS rates:54.1% for IIIC1, 43.3% for IIIA, 40.6% for IIIB, 23.1% for IIIC2). In a multivariable model, stage IIIC2 disease was independently associated with a two-fold increased mortality risk compared to stage IIIC1 (HR = 2.066, 95% CI: 1.438-2.969, P <0.001), 2.6-fold compared to stage IIIB (HR=2.606, 95% CI 1.752-3.877, P <0.001) or nearly 3-fold compared to stage IIIA (HR = 2.958, 95% CI 1.757-4.983, P <0.001). Survival of stage IIIC1 disease significantly differed based on T-stage (5-year OS rates:72.2% for T1 vs 54.1% for T2 vs 18.6% for T3, P <0.001). Patients with stage IIIC1 (T1) had better OS compared with stage IIIA (P =0.004) and IIIB (P <0.001); Patients with stage IIIC1(T3) had worse OS compared with stage IIIA and IIIB (both P =0.001). On multivariable analysis, T-stage remained an independent prognostic factor for survival in patients with 2018 FIGO stage IIIC1 (P <0.001). Stage IIIC1(T1) was independently associated with improved survival compared to stage IIIA (HR = 0.514, 95% CI 0.287-0.921, P =0.025) or stage IIIB disease (HR = 0.420, 95% CI 0.263-0.672, P <0.001). The best prognostic cut-off value of the number of metastatic pelvic lymph node (MPLNs) was 2 for stage IIIC1p(T1/T2a). Patients with >2 MPLNs had worse OS compared with those having <2 (5-year OS rates were 76% and 47.9%, respectively, P <0.001). Multivariate analyses demonstrated that the extent of MPLNs yield impact on OS(HR = 2.753, 95% CI 1.527-4.965, P =0.001). Patients with stage IIIC1 represent a heterogeneous population with a variable prognosis, using T stage and a cut-off value of 2 MPLNs could gain a better predict prognostic outcomes. [ABSTRACT FROM AUTHOR]