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A kinase anchor protein 12 (AKAP12) as a tumor suppressor in various cancers has been extensively studied and confirmed. However, its immune implication in stomach adenocarcinoma (STAD) remains uncertain. Here, using The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), Cancer Cell Line Encyclopedia (CCLE), integrated repository portal for tumor-immune system interactions (TISIDB), and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) database, we systematically analyzed the immune correlation of AKAP12 from three aspects including immune infiltration cells, immune-related pathways, and immunomodulators and developed a AKAP12-related 4-gene signature for prognosis prediction. Our results showed that AKAP12 mRNA and protein levels were downregulated in STAD patients, and its expression was positively related to CD4+ T cells and macrophages. In addition, the immune cell infiltration levels were associated with AKAP12 gene copy number deletion in STAD. Based on CCLE database, we found that AKAP12 coexpressed genes were enriched in several immune- and cancer-related pathways, which was further validated by Gene Set Enrichment Analysis (GSEA). Moreover, we identified 46 immunomodulators that were significantly related to AKAP12 expression using TISIDB database, and these immunomodulators were involved in immune-related pathways including Th17 cell differentiation and natural killer cell-mediated cytotoxicity. Additionally, based on the 46 AKAP12-related immunomodulators, a 4-gene risk prediction signature was developed using the Cox regression model. The risk signature was identified as an independent prognostic factor, which can accurately predict the prognosis of patients with STAD, showing good predictive performance. Furthermore, we constructed a prognostic nomogram and calibration to predict and assess patient survival probabilities by integrating the risk score and other clinical factors. In conclusion, our study provides strong evidence that AKAP12 is closely related to tumor immunity in STAD from three aspects: immune infiltration cells, immune pathways, and immunomodulators. More importantly, the AKAP12-related prognostic signature may have a good application prospect for clinical practice. [ABSTRACT FROM AUTHOR]

Negative thermal expansion (NTE) materials can offset the high expansion of metal brazing alloys, and play a key role in alleviating the residual stress and improving the mechanical properties of the joint. However, in Sc 2 W 3 O 12 reinforced AgCuTi composite filler, the strong interfacial reaction between active Ti and Sc 2 W 3 O 12 has become a bottleneck restricting the NTE behavior of Sc 2 W 3 O 12. Herein, a novel strategy is proposed by designing a carbon barrier layer between active filler and Sc 2 W 3 O 12 materials. Under the guidance of experimental results and theoretical analysis, the interface evolution mechanism is proposed. The results show that the carbon barrier layer increases the diffusion path of Ti atoms and weakens the interfacial reaction. With the help of carbon barrier layer, Sc 2 W 3 O 12 gives full play to its NTE behavior during brazing, and the retention rate increases from 65.8% to 97.6%. Consequently, a highest shear strength of ∼77 MPa is achieved in the C/SiC-GH3536 joints by the designed composites filler, which is 1.3 times higher than that without carbon barrier layer and 3.2 times higher than that of AgCuTi filler. Our work opens the way for expanding the application of NTE materials in brazing process, and also provides new insights for the development of low-CTE composites. [Display omitted] [ABSTRACT FROM AUTHOR]

Background. Currently, immunotherapy is widely used for breast cancer (BC) patients, and tumor mutation burden (TMB) is regarded as a valuable independent predictor of response to immunotherapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immune cells in BC are not fully understood. Methods. Comprehensive bioinformatic analyses were performed using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Survival curves were analyzed via Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used for prognosis analysis. Gene set enrichment analysis (GSEA) was performed to explore regulatory mechanisms and functions. The CIBERSORT algorithm was used to calculate the tumor-infiltrating immune cell fractions. Results. We analyzed somatic mutation data of BC from TCGA and ICGC datasets and found that 19 frequently mutated genes were reported in both cohorts, namely, SPTA1, TTN, MUC17, MAP3K1, CDH1, FAT3, SYNE1, FLG, HMCN1, RYR2 (ryanodine receptor 2), GATA3, MUC4, PIK3CA, KMT2C, TP53, PTEN, ZFHX4, MUC16, and USH2A. Among them, we observed that RYR2 mutation was significantly associated with higher TMB and better clinical prognosis. Moreover, GSEA revealed that RYR2 mutation-enriched signaling pathways were related to immune-associated pathways. Furthermore, based on the CIBERSORT algorithm, we found that RYR2 mutation enhanced the antitumor immune response by enriching CD8+ T cells, activated memory CD4+ T cells, and M1 macrophages. Conclusion. RYR2 is frequently mutated in BC, and its mutation is related to increased TMB and promotes antitumor immunity; thus, RYR2 may serve as a valuable biomarker to predict the immune response. [ABSTRACT FROM AUTHOR]

Background. Currently, immunotherapy is widely used for breast cancer (BC) patients, and tumor mutation burden (TMB) is regarded as a valuable independent predictor of response to immunotherapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immune cells in BC are not fully understood. Methods. Comprehensive bioinformatic analyses were performed using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Survival curves were analyzed via Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used for prognosis analysis. Gene set enrichment analysis (GSEA) was performed to explore regulatory mechanisms and functions. The CIBERSORT algorithm was used to calculate the tumor-infiltrating immune cell fractions. Results. We analyzed somatic mutation data of BC from TCGA and ICGC datasets and found that 19 frequently mutated genes were reported in both cohorts, namely, SPTA1, TTN, MUC17, MAP3K1, CDH1, FAT3, SYNE1, FLG, HMCN1, RYR2 (ryanodine receptor 2), GATA3, MUC4, PIK3CA, KMT2C, TP53, PTEN, ZFHX4, MUC16, and USH2A. Among them, we observed that RYR2 mutation was significantly associated with higher TMB and better clinical prognosis. Moreover, GSEA revealed that RYR2 mutation-enriched signaling pathways were related to immune-associated pathways. Furthermore, based on the CIBERSORT algorithm, we found that RYR2 mutation enhanced the antitumor immune response by enriching CD8+ T cells, activated memory CD4+ T cells, and M1 macrophages. Conclusion. RYR2 is frequently mutated in BC, and its mutation is related to increased TMB and promotes antitumor immunity; thus, RYR2 may serve as a valuable biomarker to predict the immune response. [ABSTRACT FROM AUTHOR]

Objective: Colon cancer (CC) is one of the most common cancers whose progression is regulated by a number of factors, including circular RNAs (circRNAs). Nonetheless, circ_0038718 is a novel circRNA, and its regulatory mechanism in CC remains unclear. Methods: Real-time quantitative PCR (qRT-PCR) was performed to detect the expression of circ_0038718, miR-195-5p and Axin2. Western blot was conducted to determine the protein expression of Axin2 and the key proteins on Wnt/β-catenin signaling pathway. Oligo (dT) 18 primers and RNase R were employed to identify the circular features of circ_0038718, and the location of circ_0038718 in cells was detected via nucleocytoplasmic separation. Dual-luciferase reporter assay and RNA binding protein immunoprecipitation experiment were carried out to investigate the molecular mechanism of circ_0038718/miR-195-5p/Axin2. Additionally, MTT assay was conducted to assess cell proliferation; Transwell assay was performed to evaluate cell migration and invasion, respectively. The effect of circ_0038718 on CC tumor growth was tested through tumor formation in nude mice. Results: circ_0038718 was highly expressed in CC and could sponge miR-195-5p in cytoplasm. Silencing circ_0038718 suppressed the proliferative, migratory and invasive abilities of CC cells, while the promoting effect of high circ_0038718 expression on CC cells was reversed upon miR-195-5p over-expression. Axin2 was a downstream target of miR-195-5p and could regulate the Wnt/β-catenin signaling pathway. Axin2 expression was modulated by circ_0038718/miR-195-5p. Knockdown of Axin2 could also attenuate the promoting effect of high circ_0038718 expression on CC cell malignant progression, thus inhibiting tumor growth. Conclusion: circ_0038718 is able to facilitate CC cell malignant progression via the miR-195-5p/Axin2 axis, which will provide a new idea for finding a novel targeted treatment of CC. [ABSTRACT FROM AUTHOR]

High-entropy carbide ceramic materials exhibited excellent thermal and mechanical properties, making them highly sought after in high-temperature applications. However, the oxidation resistance of high-entropy carbide ceramic needed to be further improved. This work unraveled the oxidation behavior and mechanism of high-entropy carbide ceramic by introducing the Cr 3 C 2. The results indicated that the oxidation rate of (TiZrTaNbCr)C initially decreased with temperature up to 900 °C, followed by an increased with further temperature rise up to 1100 °C. At 800 and 900 °C, the parabolic oxidation rate constants were 0.70 and 0.17 mg2cm−4min−1, respectively. And the minimum thickness of oxidized layer was 60 µm at 900 °C for 120 min. This unusual phenomenon suggested the formation of different oxidation products. Specifically, the CrNbO 4 and Nb 2 Zr 6 O 17 oxide layer were formed at 900 °C, leading to an increased resistance to oxygen diffusion. Subsequently, loose oxidation products of Nb 2 O 5 were formed after 1000 °C, hindering the oxidation resistance. In the current study on oxidation resistance of high entropy carbides, this work showed a competitive performance. Overall, this study illustrated the oxidation mechanism and behavior of (TiZrTaNbCr)C and proposed a new avenue for the design of high-entropy ceramic components. [ABSTRACT FROM AUTHOR]

Background: There is little prospective evidence exists about whether adherence to a diabetes risk reduction diet (DRRD) is related to a significant reduction in renal cancer risk. We sought to clarify whether adherence to DRRD was associated with a reduced risk of renal cancer in a US population. Methods: A population-based cohort of 101,755 American adults was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A DRRD score was calculated to assess adherence to this dietary pattern, where increased scores indicated greater adherence. The relationship between DRRD score and risk of renal cancer was assessed based on the hazard ratios (HRs) and 95% confidence intervals (CIs), which were both calculated using Cox regression. Non-linear association was determined through restricted cubic spline regression. Potential effect modifiers were identified through subgroup analyses. Results: Over a mean follow-up of 8.8 years, 446 renal cancers were detected. In this analysis, the fully adjusted model depicted a notable 29% reduction in the risk of renal cancer among individuals in the highest quartile of DRRD score in comparison with the lowest quartile individuals (HRQ4 vs. Q1: 0.71; 95% CI = 0.54, 0.94; Ptrend = 0.008). This association remained consistent across a series of sensitivity analyses. A non-linear inverse dose–response association between renal cancer risk with DRRD score was observed (Pnonlinearity = 0.026). Subgroup analyses showed that this favorable link was more prominent in participants with low Healthy Eating Index-2015 (Pinteraction = 0.015). Regarding the individual components of DRRD, a decrease in the risk of renal cancer was linked to increased intake of cereal fiber and whole fruit, and lower sugar-sweetened beverage consumption (all Ptrend < 0.05). Conclusions: Our findings indicate that individuals adhering to DRRD are associated with a reduction in the risk of renal cancer. [ABSTRACT FROM AUTHOR]

To development large-size and complex high-entropy ceramic (HEC) components, the joining of (Ti 0.2 Zr 0.2 Nb 0.2 Ta 0.2 Cr 0.2)C and Nb metal with nickel-based filler alloy was performed. The microstructure was characterized by SEM and the phase composition was analyzed by EDS and XRD. The brazing mechanism of the joint was mainly derived from the diffusion of Nb, which formed the NbC reaction layer in the HEC part and the diffusion zone in Nb metal part. The highest shear strength of the brazed joints at 1170 °C/10min was 139 MPa at room temperature and 117 MPa at 800 °C. In addition, the effect of brazing temperature on the microstructure and shear strength was discussed. This work provided a key method to prepare high-temperature resistant complex and large-size HEC components. • This work provides a feasible method to fabricate large-size and complex HEC component. • The brazing mechanism is ascribed to the diffusion of Nb to form Nb(s,s) diffusion zone and NbC reaction layer. • A maximum shear strength of the joint is 139 MPa at room temperature and 119 MPa at 800 °C. [ABSTRACT FROM AUTHOR]

Aggravated endoplasmic reticulum stress (ERS) and apoptosis in podocytes play an important role in lupus nephritis (LN) progression, but its mechanism is still unclear. Herein, the role of SMURF1 in regulating podocytes apoptosis and ERS during LN progression were investigated. MRL/lpr mice was used as LN model in vivo. HE staining was performed to analyze histopathological changes. Mouse podocytes (MPC5 cells) were treated with serum IgG from LN patients (LN-IgG) to construct LN model in vitro. CCK8 assay was adopted to determine the viability. Cell apoptosis was measured using flow cytometry and TUNEL staining. The interactions between SMURF1, YY1 and cGAS were analyzed using ChIP and/or dual-luciferase reporter gene and/or Co-IP assays. YY1 ubiquitination was analyzed by ubiquitination analysis. Our results found that SMURF1, cGAS and STING mRNA levels were markedly increased in serum samples of LN patients, while YY1 was downregulated. YY1 upregulation reduced LN-IgG-induced ERS and apoptosis in podocytes. Moreover, SMURF1 upregulation reduced YY1 protein stability and expression by ubiquitinating YY1 in podocytes. Rescue studies revealed that YY1 knockdown abrogated the inhibition of SMURF1 downregulation on LN-IgG-induced ERS and apoptosis in podocytes. It was also turned out that YY1 alleviated podocytes injury in LN by transcriptional inhibition cGAS/STING/IFN-1 signal axis. Finally, SMURF1 knockdown inhibited LN progression in vivo. In short, SMURF1 upregulation activated the cGAS/STING/IFN-1 signal axis by regulating YY1 ubiquitination to facilitate apoptosis in podocytes during LN progression. [ABSTRACT FROM AUTHOR]

Negative thermal expansion materials show great potential in brazing field, which is used to compensate high thermal expansion of metal fillers. However, the limited content and agglomeration have always been the key problems restricting its development. Herein, a novel strategy is developed by constructing a three-dimensional (3D) Sc 2 W 3 O 12 interpenetrating network structure. With the help of 3D network interlayer, the Sc 2 W 3 O 12 materials are evenly distributed in the brazing seam and the volume fraction is increased to 20%. From the finite element analysis results, the residual stress in X directions is decreased from 475/-400 MPa to 367/-358 MPa. After introduced the Sc 2 W 3 O 12 network interlayer, the maximum shear strength is about 96 MPa, which is 1.3 times that of the joint without network structure and 4 times that of the joint directly brazed by AgCuTi. In this study, a new method to improve the application of reinforced phases is proposed, which provides a new method for the development of NTE materials reinforced metal composites. [Display omitted] [ABSTRACT FROM AUTHOR]

Accumulated evidence implicates lipid peroxidation as a key mechanism contributing to the pathogenesis of lupus nephritis (LN). Ferroptosis is a specialized form of cell death induced by loss or deficient activity of the glutathione peroxidase 4 (GPX4) and decreased clearance of polyunsaturated fatty acid hydroperoxides. STING production may lead to the occurrence of intracellular lipid peroxidation, ultimately triggering ferroptosis, but it has not been clarified whether STING can aggravate LN via ferroptosis. The adjacent normal kidney tissues from renal cell carcinoma and biopsied kidney tissue samples from LN patients were used for research, and the expression of STING protein in kidney tissue was detected by immunohistochemistry and RT-qPCR. MRL/lpr mice, a model of LN, were used to detect STING expression in kidney tissue. STING expression in the kidney tissue of MRL/lpr mice was knocked down by sh-STING-AAV, and then levels of 4-HNE, MDA, ROS, iron ion, blood urea nitrogen and serum creatinine, IL-6, IL-1β, and TNF-α, and the protein expression of STING, TBK1, NF-κB, GPX4, ACSL4, and SLC7A11 were subsequently examined. STING was elevated in the kidney tissue of LN patients and MRL/lpr mice. Compared with the MRL/lpr group, liproxstatin-1 or ferrostatin-1 treatment alleviated ferroptosis-related indicators 4-HNE, MDA, ROS, iron ion release, and GPX4 and SLC7A1 expression, whereas the treatment enhanced ACSL4 expression. STING interference observably decreased 4-HNE, ROS, MDA, iron ion, STING, and ACSL4 levels, and increased GPX4 and SLC7A11 expression in MRL/lpr mice kidney tissues. Besides, inhibition of STING reduced kidney tissue damage and inflammatory cell infiltration in MRL/lpr mice, and levels of serum creatinine, blood urea nitrogen, serum anti-double-stranded DNA antibody, inflammatory factors IL-6, IL-1β, and TNF-α, as well as phosphorylation of NF-κB were all significantly decreased in MRL/lpr mice. TBK1 overexpression reversed the impact of STING inhibition on ferroptosis and inflammatory response. STING contributed to ferroptosis and inflammatory response by activating the TBK1/NF-κB pathway, suggesting that STING may be a potent therapeutic target in LN. [ABSTRACT FROM AUTHOR]

Background: The plant-based paleolithic diet (PD) and the paleolithic-like lifestyle (PLL) may reduce the risk of chronic diseases, including colorectal adenomas. These dietary and lifestyle approaches are proposed to exert their effects through mechanisms such as reducing inflammation, oxidative stress, and insulin levels. However, whether PD and PLL is associated with the risk of colorectal cancer (CRC) has not been determined. Methods: A cohort of 74,721 individuals who participated in the PLCO study were included in this analysis. Adherence to the PD and PLL was assessed using PD and PLL scores, where higher scores indicated greater adherence. Multivariable Cox models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subsites (proximal colon cancer and distal CRC). Subgroup analyses were conducted to identify potential effect modifiers. Results: During a mean follow-up of 9.2 years, a total of 694 CRC cases were identified. Participants in the highest compared with the lowest quartiles of PD score had a lower risk of CRC (Q4 vs Q1: HR 0.76, 95% CI 0.61–0.95, Ptrend = 0.009) and proximal colon cancer (Q4 vs Q1: HR 0.73, 95% CI 0.55–0.97, Ptrend = 0.02). A stronger inverse association was observed for PLL score with the risk of CRC (Q4 vs Q1: HR 0.64, 95% CI 0.51–0.81, Ptrend < 0.001), proximal colon (Q4 vs Q1: HR 0.62, 95% CI 0.46–0.83, Ptrend = 0.001) and distal CRC (Q4 vs Q1: HR 0.69, 95% CI 0.48–0.98, Ptrend = 0.03). Subgroup analyses revealed the inverse association of PD score with the risk of CRC was more pronounced in participants with BMI < 30 (Q4 vs Q1: HR 0.68, 95% CI 0.53–0.87) than in those with BMI ≥ 30 (Q4 vs Q1: HR 1.07, 95% CI 0.68–1.67) (Pinteraction = 0.02). Conclusions: Our findings suggest that adhering to the PD and PLL could be a new option to reduce CRC risk. [ABSTRACT FROM AUTHOR]

Liver hepatocellular carcinoma (LIHC) is one of the main cancers worldwide and has high morbidity and mortality rates. Although previous studies have shown that ANXA10 is expressed at low levels in LIHC tumor tissues, the biological function of ANXA10 in LIHC is still unclear. Therefore, we utilized TCGA, TIMER, GEPIA2, TISIDB, LinkedOmics, ssGSEA algorithms and CIBERSORT methodology to preliminarily evaluate the potential mechanism of ANXA10 in LIHC. In vitro experiments were used to further verify some functions of ANXA10. Consequently, we found that ANXA10 mRNA/protein expression was downregulated in LIHC tissue compared to normal tissue. ANXA10 was significantly linked with clinicopathological features, immunocytes, multiple cancer-related pathways, m6A modification and a ceRNA network. A three-gene prognostic signature rooted in ANXA10-related immunomodulators was determined and found to be an independent prognostic predictor. A nomogram was constructed to predict survival with good accuracy. Additionally, in vitro trials revealed that ANXA10 upregulation inhibited LIHC cell proliferation and migration. This study reveals that ANXA10 may serve as a prognostic marker and promising therapeutic target in LIHC clinical practice through various biologic functions. [ABSTRACT FROM AUTHOR]

Objective: To observe the efficacy and safety of telitacicept in refractory childhood-onset systemic lupus erythematosus (cSLE). Methods: A self-controlled before–after trial. Children with active SLE, aged 5–18 years, who cannot tolerate side effects of glucocorticoid, were enrolled in our study. Patients received subcutaneous injection of telitacicept weekly based on the standard treatment. SLE responder index-4 (SRI-4) was assessed before the first administration and at least 4 weeks after the first administration. Results: Among the 15 cases of refractory cSLE, three were males (20%) and 12 were females (80%). The median age and weight were 13 years old and 52 kg, respectively. The median duration of disease was 30 months. 5–26 weeks (80 or 160 mg per week) after administration of telitacicept, 66.7% (n =10) reached SRI-4 response. 12 cases reduced their glucocorticoid intake from 40 mg/d to 17.5 mg/d. The urinary protein after treatment declined in 8 cases whose 24-h proteinuria was >0.5 g at baseline. The urinary protein in two of the eight cases turned negative and plasma albumin in five of the eight cases rose to normal. In addition, three of these eight cases demonstrated varying degrees of improvement in renal impairment, whose estimated glomerular filtration rate (eGFR, ml/min·1.73 m2) rose from 17.4 to 26.6, 40.7 to 48.2, and 63.2 to 146.0, respectively. There were mild to moderate adverse events after treatment. Conclusion: Telitacicept combined with the standard treatment may significantly increase the SRI-4 response rate and reduce the glucocorticoid dosage in refractory cSLE, and also shown efficacy on lupus nephritis. The related adverse drug events were controllable. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune-mediated diffuse connective tissue disease characterized by immune inflammation with an unclear aetiology and pathogenesis. This work profiled the intestinal flora and faecal metabolome of patients with SLE using 16S RNA sequencing and gas chromatography-mass spectrometry (GC-MS). We identified unchanged alpha diversity and partially altered beta diversity of the intestinal flora. Another important finding was the increase in Proteobacteria and Enterobacteriales and the decrease in Ruminococcaceae among SLE patients. For metabolites, amino acids and short-chain fatty acids were enriched when long-chain fatty acids were downregulated in SLE faecal samples. KEGG analysis showed the significance of the protein digestion and absorption pathway, and association analysis revealed the key role of 3-phenylpropanoic acid and Sphingomonas. Sphingomonas were reported to be less abundant in healthy periodontal sites of SLE patients than in those of HCs, indicating transmission of oral species to the gut. This study contributes to the understanding of the pathogenesis of SLE disease from the perspective of intestinal microorganisms, explains the pathogenesis of SLE, and serves as a basis for exploring potential treatments for the disease. [ABSTRACT FROM AUTHOR]