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Abstract Background Solute carrier family 38 member 5 (SLC38A5) is an amino acid transporter that plays a significant role in various cellular biological processes and may be involved in regulating the progression of tumors However, its function and underlying mechanism in osteosarcoma remain unexplored. Methods Utilizing various database analyses and experiments, we have explored the dysregulation of SLC38A5 in osteosarcoma and its prognostic value. A series of in vitro functional experiments, including CCK-8, colony formation, wound healing, and transwell invasion assays, were conducted to evaluate the effects of SLC38A5 on the proliferation, migration, and invasion of osteosarcoma cells. Downstream pathways of SLC38A5 were explored through methods such as western blot and metabolic assays, followed by a series of validations. Finally, we constructed a subcutaneous xenograft tumor model in nude mice to explore SLC38A5 function in vivo. Results SLC38A5 is upregulated in osteosarcoma and is associated with poor prognosis in patients. Upregulation of SLC38A5 promotes proliferation, migration, and invasion of osteosarcoma cells, while the PI3K inhibitor BKM120 can counteract these effects. Additionally, silencing of SLC38A5 inhibits tumor growth in vivo. Mechanistically, SLC38A5 mediates the activation of the PI3K/AKT/mTOR signaling pathway by transporting glutamine, which subsequently enhances the SREBP1/SCD-1 signaling pathway, thereby suppressing ferroptosis in osteosarcoma cells. Conclusion SLC38A5 promotes osteosarcoma cell proliferation, migration, and invasion via the glutamine-mediated PI3K/AKT/mTOR signaling pathway and inhibits ferroptosis. Targeting SLC38A5 and the PI3K/AKT signaling axis may provide a meaningful therapeutic strategy for the future treatment of osteosarcoma. Graphical abstracts

Abstract Background Juvenile idiopathic arthritis (JIA) is a type of chronic childhood arthritis with complex pathogenesis. Immunological studies have shown that JIA is an acquired self-inflammatory disease, involving a variety of immune cells, and it is also affected by genetic and environmental susceptibility. However, the precise causative relationship between the phenotype of immune cells and JIA remains unclear to date. The objective of our study is to approach this inquiry from a genetic perspective, employing a method of genetic association analysis to ascertain the causal relationship between immune phenotypes and the onset of JIA. Methods In this study, a two-sample Mendelian randomization (MR) analysis was used to select single nucleotide polymorphisms (SNPs) significantly associated with immune cells as instrumental variables to analyze the bidirectional causal relationship between 731 immune cells and JIA. There were four types of immune features (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)). Finally, the heterogeneity and horizontal reproducibility of the results were verified by sensitivity analysis, which ensured more robust results. Results We found that CD3 on CM CD8br was causally associated with JIA at the level of 0.05 significant difference (95% CI = 0.630 ~ 0.847, P = 3.33 × 10−5, PFDR = 0.024). At the significance level of 0.20, two immunophenotypes were causally associated with JIA, namely: HLA DR on CD14+ CD16- monocyte (95% CI = 0.633 ~ 0.884, P = 6.83 × 10–4, PFDR = 0.16) and HLA DR on CD14+ monocyte (95% CI = 0.627 ~ 0.882, P = 6.9 × 10−4, PFDR = 0.16). Conclusion Our study assessed the causal effect of immune cells on JIA from a genetic perspective. These findings emphasize the complex and important role of immune cells in the pathogenesis of JIA and lay a foundation for further study of the pathogenesis of JIA.

Abstract Sarcopenia and anemia are common complications in patients with Crohn’s Disease (CD). However, few studies have shown the association between sarcopenia and hemoglobin levels in CD patients. This retrospective study aimed to explore such association in Chinese patients with CD. Two hundred and twelve adult CD inpatients who underwent computed tomography (CT) or magnetic resonance imaging (MRI) examinations from July 2019 to December 2021 were included in the study. Sarcopenia was defined according to the cutoff value of skeletal muscle index of lumbar spine 3 (SMI-L3) (

Objective: Biological age may be more accurate than chronological age in determining chronic health outcomes. However, few studies have shown the association between biological age and acute ischemic stroke (AIS). In this study we showed the association between phenotypic age (PhenoAge) or accelerated aging and severity and disability in patients with AIS. Design: Retrospective study. Setting and subjects: 936 patients with AIS during January 2019 to July 2021 and 512 patients during June 2022 to July 2023 for a validation. Methods: Stroke severity was evaluated based on the National Institute of Health stroke scale (NIHSS) questionnaire scale. Disability was evaluated by modified Rankin Scale. PhenoAge was calculated based on chronological age and 9 clinical chemistry biomarkers. Logistic regression analyses were applied to estimate the relationship between PhenoAge and the severity and disability. Results: PhenoAge (odds ratio [OR] = 1.03, 95% confidence interval [CI]: 1.0–1.04, for NIHSS ≥ 5; OR = 1.05, 95%CI: 1.03−1.07, for NIHSS ≥ 10) was independently associated with stroke severity. The probability of NIHSS ≥ 5 or NIHSS ≥ 10 was significantly increased in individuals with accelerated ageing versus individuals with no accelerated aging (age gap: OR = 1.79, 95%CI: 1.18−2.72; OR = 3.53, 95%CI: 1.60−7.77; phenotypically older vs. phenotypically younger: OR = 2.01, 95%CI: 1.21−3.35; OR = 3.69, 95%CI: 1.36−10.0). Similar trends was observed when accelerated aging was defined by residual discrepancies between PhenoAge and chronological age (OR = 1.02, 95%CI: 1.01−1.04, for NIHSS ≥ 5; OR = 1.05, 95%CI: 1.02−1.08, for NIHSS ≥ 10). The area under the curve of PhenoAge was higher than that of chronological age in identifying patients with NIHSS ≥ 5 (0.66, 95%CI:0.62−0.70 vs. 0.61, 95%CI: 0.58−0.65, p

Abstract Background Osteosarcoma (OS) is the most common primary malignancy of bone tumors. More and more ARHGAP family genes have been confirmed are to the occurrence, development, and invasion of tumors. However, its significance in osteosarcoma remains unclear. In this study, we aimed to identify the relationship between ARHGAP family genes and prognosis in patients with OS. Methods OS samples were retrieved from the TCGA and GEO databases. We then performed LASSO regression analysis and multivariate COX regression analysis to select ARHGAP family genes to construct a risk prognosis model. We then validated this prognostic model. We utilized ESTIMATE and CIBERSORT algorithms to calculate the stroma and immune scores of samples, as well as the proportions of tumor infiltrating immune cells (TICs). Finally, we conducted in vivo and in vitro experiments to investigate the effect of ARHGAP28 on osteosarcoma. Results We selected five genes to construct a risk prognosis model. Patients were divided into high- and low-risk groups and the survival time of the high-risk group was lower than that of the low-risk group. The high-risk group in the prognosis model constructed had relatively poor immune function. GSEA and ssGSEA showed that the low-risk group had abundant immune pathway infiltration. The overexpression of ARHGAP28 can inhibit the proliferation, migration, and invasion of osteosarcoma cells and tumor growth in mice, and IHC showed that overexpression of ARHGAP28 could inhibit the proliferation of tumor cells. Conclusion We constructed a risk prognostic model based on five ARHGAP family genes, which can predict the overall survival of patients with osteosarcoma, to better assist us in clinical decision-making and individualized treatment.

Abstract Background Jaundice occurs in some pancreatic disease. However, its occurrences and role in pancreatic neuroendocrine neoplasms (PNENs) has not been well studied. In this study we showed the association between jaundice and the risk of high grade and poorly differentiated PNENs. Methods Ninety-three patients with head-neck PNENs were included. Poorly differentiated pancreatic neuroendocrine neoplasms were defined by a ki67 index > 55.0%. Logistic regression was used to show the association between demographic information, clinical signs and symptoms and the risk of poorly differentiated tumors. A nomogram model was developed to predict poorly differentiated tumor. Results Eight of 93 PNEN patients (8.6%) had jaundice. The age and ki67 index in patients with jaundice were significantly higher than those patients without jaundice. All jaundice occurred in patients with grade 3 PNENs. Mutivariable regression analysis showed that age (odds ratio(OR) = 1.10, 95% confidence interval (CI):1.02–1.19), tumor size (OR = 1.42, 95%CI:1.01-2.00) and jaundice (OR = 14.98, 95%CI: 1.22-184.09) were associated with the risk of poorly differentiated PNENs. The age and size combination showed a good performance in predicting poorly differentiated PNENs (area under the curve (AUC) = 0.81, 95% CI: 0.71–0.90). The addition of jaundice further improved the age- and size-based model (AUC = 0.86, 95% CI: 0.78–0.91). A nomogram was developed based on age, tumor size and jaundice. Conclusion Our data showed that jaundice was associated with the risk of high grade PNENs and poorly differentiated PNENs.

Ferroptosis is a novel form of non-apoptotic cell death that mainly results from the iron-dependent lethal accumulation of lipid peroxidation products. Here, we defined differentially expressed genes between control and RSL3-treated osteosarcoma cells as ferroptosis-associated genes (FAGs). These FAGs were then subjected to weighted gene correlation network analysis (WGCNA), and we found that the turquoise module, containing 71 FAGs, was markedly related to the patient’s vital status. After that, FAGs in the turquoise module were utilized to construct a prognostic multigene (COL5A2, HOXB4, and UNC5B) signature for risk stratification in osteosarcoma. Validation in internal and external cohorts indicated the accuracy and clinical applicability of this signature in predicting the prognosis of patients with osteosarcoma. Univariate and multivariate Cox regression analyses suggested that the signature-derived risk score is an independent indicator of patient prognosis. Immunological analysis indicated that significant variations in stromal and ESTIMATE scores, as well as tumor purity, were found when the high- and low-risk groups were compared. Regarding immune cell infiltration, the proportion of activated CD4 memory T cells was significantly lower in the high-risk group than that in the low-risk group. The ssGSEA results suggested that CD8+ T, Tfh, and Th1 cell scores were consistently lower in the high-risk group than those in the low-risk group. In terms of immune-related activities, the high-risk group had considerably lower scores for promoting inflammation, T-cell co-inhibition, and T-cell co-stimulation than the low-risk group, indicating the differential immunological state of the high- and low-risk groups. Of the three FAGs included in the signature, the expression of COL5A2, HOXB4, and UNC5B was higher in the high-risk groups, and the expression of COL5A2 and UNC5B was negatively associated with patient prognosis. Additionally, the mRNA levels of COL5A2 and HOXB4 were lower and those of UNC5B were higher in RSL3-treated cells than in control cells. In all, we systematically analyzed the transcriptional changes of osteosarcoma cells induced by RSL3 and constructed a novel three-gene signature with regard to ferroptosis, prognosis prediction, and immune microenvironment. We also identified COL5A2, HOXB4, and UNC5B as potential therapeutic targets and important regulators of ferroptosis in osteosarcoma.

Purpose We aimed to investigate the role of microRNA-5100 (miRNA-5100) in oral squamous cell carcinoma (OSCC) and its underlying mechanisms. Material/Methods: The expression of miR-5100 and suppressor of cancer cell invasion (SCAI) in OSCC cell lines were examined. A luciferase reporter assay was applied to confirm the combination between miR-5100 and SCAI. Then, miR-5100 inhibitor or small hairpin RNA (shRNA)-SCAI were transfected into cells. Cell Counting Kit-8 assay was executed for testing cell proliferation ability. Flow cytometry assay was exploited for measuring cell cycle. Invasion and migration of OSCC cells were assessed using Transwell assay and wound healing assay. The expression of proteins were detected using western blotting. Results The results demonstrated that the level of miR-5100 was upregulated while SCAI was downregulated in OSCC cells. SCAI was verified as a direct target of miR-5100. MiR-5100 silencing suppressed proliferation of OSCC cells, increased cells in the G1 and G2 phases, and reduced those in the S phase, which was reversed after transfection with shRNA-SCAI. Moreover, miR-5100 inhibitor downregulated the expression of cyclin-dependent kinase-2 (CDK-2) and cyclinD1, accompanied by upregulation in p27 expression, whereas SCAI silencing had the opposite results. The invasion and migration abilities of OSCC cells were reduced after treatment with miR-5100 inhibitor, whereas SCAI silencing suppressed the effects of miR-5100 inhibitor on OSCC cell behaviors. Conclusion These findings suggested that miR-5100 silencing inhibit proliferation, invasion and migration of OSCC cells via upregulating the expression of SCAI, which provides theoretical basis and treatment strategies for the treatment of OSCC.

Liquid accelerating agents have the advantages of simple operation and fast construction, and have become indispensable admixtures in shotcrete. However, most liquid accelerating agents in the market at present contain alkali or fluorine, which adversely affect concrete and seriously threaten the physical and mental health of workers. Therefore, in view of the above deficiencies, it is necessary to develop a new type of alkali-free fluorine-free liquid accelerating agent. In this paper, the polyaluminum sulfate early strength alkali-free liquid accelerator is prepared using polymeric aluminum sulfate, diethanolamine, magnesium sulfate heptahydrate and nano-silica. The influence of this agent on the setting time of fresh cement paste and compressive strength of the corresponding cement mortar is determined. Thermogravimetric analysis curves, X-ray diffraction and scanning electron microscopy images are obtained to investigate the mechanism. Findings show that the initial setting time and the final setting time of cement paste are 2 min 30 s and 7 min 25 s. The compressive strengths of cement mortar cured for 1 d, 28 d and 90 d are 2.4 MPa, 52.2 MPa and 54.3 MPa respectively. Additionally, the corresponding flexural strengths are 3.4 MPa, 9.8 MPa, 11.8 MPa. When the mass rate of accelerator is 7%, the mechanical strengths of cement mortar are the highest. The additions of fly ash and blast furnace slag can affect the mechanical of cement mortar mixed with accelerator. When the mass ratio of the fly ash and blast furnace slag is 15%, the mechanical strengths of cement mortar reach the highest. Moreover, the hydration heat release rate of cement is increased by the accelerator and the corresponding time of hydration heat peak is decreased by the accelerator. The accelerator can decrease the amount of needle-like hydration products and improve the compactness. The mechanical strengths are improved by consuming a large amount of Ca(OH)2 and forming more compact hydration products. It is recommended that the optimum dosage range of the polyaluminum sulfate early strength alkali-free liquid accelerator is 7%.

A nanocatalytic antimicrobial gel responsive to the bacterial infection microenvironment (IME) possessing highly specific antimicrobial properties provides an opportunity to address the bacterial drug resistance. However, the pH conditions and low substrate concentration in the IME limit the catalytic antimicrobial efficiency of these agents, resulting in unsatisfactory performance. The reported transition metal peroxide alleviates endogenous substrate insufficiency due to H2O2 self-supplying properties, but still suffers from difficulties of simple synthesis, long-stem storage and lower intrinsic catalytic efficiency responsive to the IME. In this paper, we report for the first time the use of cerium-manganese bimetallic peroxide nanoparticles (CeMnOx) as a nanocatalyst with high pH responsiveness, H2O2 self-supplying properties, multiple ROS-generating activity and synergistic effect-enhanced cascade catalytic reactions for efficient antimicrobial therapy. CeMnOx achieved more than 95% kill rate at 50 mg mL-1 for E. coli and 100 mg mL-1 for S. aureus, which was superior to those of previously reported works. To further improve the availability, nanoparticle-carrying hydrogels with excellent antimicrobial properties were prepared through in situ gelation, thus adapting to a wider range of antimicrobial application scenarios. Therefore, the in situ molded nanocatalytic antimicrobial gels provide a promising paradigm for efficient treatment of bacterial infections. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the mechanism of action of Celastrus orbiculatus extract (COE) on oral squamous carcinoma cells. Methods: Tca8113 cells were divided into negative control and three COE treatment groups, viz, 20, 40, and 80 μg/mL of COE. Succinate dehydrogenase activity assay (MTT assay) and flow cytometry were used to assess cell proliferation and apoptosis. Cell migration and invasion were assessed by Transwell chamber and wound healing assays while relative protein expression was determined by Western blot. Results: As the concentration of COE increased, the number of cells arrested in the G0/G1 phase increased (p < 0.05), expressions of cell-cycle-related proteins decreased (p < 0.001); the number of apoptotic cells increased (p < 0.001), and the rates of cell migration and invasion decreased (p < 0.001). Exogenous COE significantly inhibited p-IκBα accumulation in the cytoplasm and induced IκBα accumulation. Nuclear p65 recruitment was reduced in cells treated with COE compared to untreated control cells (p < 0.001), suggesting that the classical NF-κB pathway was blocked by COE. Conclusion: These results demonstrate that COE inhibits the proliferation and migration of oral squamous cell carcinoma cells while promoting apoptosis by blocking NF-κB pathway. These findings suggest that Celastrus orbiculatus extract possesses a potential therapeutic effect on oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]