Baileysilverman2441

Collectively, our findings highlighted the role of the miR-135/ZNF217/METTL3/NANOG axis in the progression of BC, emphasizing potential therapeutic targets ZNF217 silencing and miR-135 upregulation in preventing or treating BC.Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening showed that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson's disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has preclinical value to be repurposed for OS.Bacteria can form dense communities called biofilms, where cells are embedded in a self-produced extracellular matrix. Exploiting competitive interactions between strains within the biofilm context can have potential applications in biological, medical, and industrial systems. By combining mathematical modelling with experimental assays, we reveal that spatial structure and competitive dynamics within biofilms are significantly affected by the location and density of the founder cells used to inoculate the biofilm. Using a species-independent theoretical framework describing colony biofilm formation, we show that the observed spatial structure and relative strain biomass in a mature biofilm comprising two isogenic strains can be mapped directly to the geographical distributions of founder cells. Moreover, we define a predictor of competitive outcome that accurately forecasts relative abundance of strains based solely on the founder cells' potential for radial expansion. Consequently, we reveal that variability of competitive outcome in biofilms inoculated at low founder density is a natural consequence of the random positioning of founding cells in the inoculum. Extension of our study to non-isogenic strains that interact through local antagonisms, shows that even for strains with different competition strengths, a race for space remains the dominant mode of competition in low founder density biofilms. Our results, verified by experimental assays using Bacillus subtilis, highlight the importance of spatial dynamics on competitive interactions within biofilms and hence to related applications.Uterine leiomyosarcoma is the most common uterine mesenchymal malignancy. The majority present at stage I, and clinical outcomes vary widely. However, no widely accepted risk stratification system for stage I uterine leiomyosarcoma is currently available. We studied 17 routinely evaluated clinicopathologic parameters in 203 stage I uterine leiomyosarcoma from three institutions to generate a novel risk stratification model for these tumors. Mitoses >25 per 2.4 mm2 (10 high-power fields), atypical mitoses, coagulative necrosis, lymphovascular invasion, and serosal abutment were significantly associated with disease-free and disease-specific survival in univariate and multivariate analyses. These prognostic parameters were each scored as binary ("yes" or "no") variables and fitted to a single optimized algebraic risk modelRisk score = (coagulative necrosis)(1) + (mitoses > 25 per 2.4 mm2)(2) + (atypical mitoses)(2) + (lymphovascular invasion)(3) + (serosal abutment)(5)By logistic regression, the risk model was significantly associated with 5-year disease-free (AUC = 0.9270) and 5-year disease-specific survival (AUC = 0.8517). Internal and external validation substantiated the model. The continuous score (range, 0-13) was optimally divided into 3 risk groups with distinct 5-year disease-free and disease-specific survival low risk (0-2 points), intermediate risk (3-5 points), and high risk (6-13 points) groups. Our novel risk model performed significantly better than alternative uterine leiomyosarcoma risk stratification systems in predicting 5-year disease-free and disease-specific survival in stage I tumors. A simplified risk model, omitting terms for serosal abutment and lymphovascular invasion, can be accurately applied to myomectomy or morcellated specimens. We advocate routine application of this novel risk model in stage I uterine leiomyosarcoma to facilitate patient counseling and proper risk stratification for clinical trials.Mycobacterium avium complex pulmonary disease (MAC-PD) requires long-term treatment. We analyzed the outcomes of 992 MAC-PD patients according to disease severity and compared the outcomes of intermittent and daily therapy for mild disease. Patients were divided into groups according to severity using the body mass index, age, cavity, erythrocyte sedimentation rate, and sex (BACES) system, and culture conversion rates were evaluated. We also evaluated the effects of intermittent treatment on the culture conversion rates in mild disease group. Using the BACES, 992 patients were divided into mild (n = 331), moderate (n = 503), and severe (n = 158) disease groups, and culture conversion at the end of treatment was achieved in 85% (282/331), 80% (403/503), and 61% (97/158), respectively. Differences in culture conversion among the severity groups were significant (p  less then  0.001). In patients with mild disease, culture conversion rates were similar between intermittent (84%, 166/198) and daily (87%, 116/133) treatment (p = 0.396), and intermittent antibiotic therapy did not negatively impact culture conversion (adjusted hazard ratio 1.08; confidence interval 0.83-1.41; p = 0.578). MAC-PD patients with mild disease had higher culture conversion rates. Daily and intermittent therapy yielded similar culture conversion rates for mild disease. Treatment strategies with lower pill burden may be applicable in mild MAC-PD.Various materials are used in bone tissue engineering (BTE). Graphene oxide (GO) is a good candidate for BTE due to its antibacterial activity and biocompatibility. In this study, an innovative biomaterial consists of GO, agarose and hydroxyapatite (HA) was synthesized using electrophoresis system. The characterization of the synthesized biomaterial showed that needle-like crystals with high purity were formed after 10 mA/10 h of electrophoresis treatment. Furthermore, the calcium-phosphate ratio was similar to thermodynamically stable HA. In the synthesized biomaterial with addition of 1.0 wt% of GO, the colony forming units test showed significantly less Staphylococcus aureus. Initial attachment of MC3T3-E1 cells on the synthesized biomaterial was observed which showed the safety of the synthesized biomaterial for cell viability. This study showed that the synthesized biomaterial is a promising material that can be used in BTE.Technical advances at the interface of biology and computation, such as single-cell RNA-sequencing (scRNA-seq), reveal new layers of complexity in cellular systems. An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells. The diverse spectra of immune cell phenotypes, sparsity of immune cell numbers in vivo, limitations in the number of metabolites identified, dynamic nature of cellular metabolism and metabolic fluxes, tissue specificity, and high dependence on the local milieu make investigations in immunometabolism challenging, especially at the single-cell level. In this review, we define the systemic nature of immunometabolism, summarize cell- and system-based approaches, and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells. We close the review by discussing the applications and shortcomings of metabolic modeling techniques. With systems-oriented studies of metabolism expected to become a mainstay of immunological research, an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels ('bullseye' parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations.The role of β-catenin and Dickkopf-1 (DKK1) is dependent on the specific immunobiology of T cell inflammation in biliary tract cancer (BTC). We aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC, and determine the clinical associations of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocytes (TIL). We used data from The Cancer Genome Atlas Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. CD8+ TIL expression was a significant predictor of favorable overall survival (OS) and relapse-free survival (RFS) (median OS, 34.9 months in high-TIL, 16.7 months in low-TIL, P  less then  0.0001 respectively; median RFS, 27.1 months in high-TIL, 10.0 months in low-TIL, P  less then  0.0001 respectively). In the high-CD8+ TIL BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS. In the low-TIL BTC group, there were no differences according to ß-catenin and DKK1 expression. Sanjoinine E Cox regression multivariate analysis demonstrated that CD8+ TIL and β-catenin retained significant association with OS. Among patients with resected BTC, the β-catenin and DKK1 protein and high CD8+ TIL levels were associated with poor and good clinical outcomes, respectively.