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Hyperlipidemia is a vital etiology of acute pancreatitis (AP), 12 to 20% of which have a history of hyperlipidemia. Multiple organ failure is the major cause of the high mortality rate of AP. Liver injury has been discovered in 80% of AP patients. The relationship and role of IRF9 and SIRT1 have not been presented in AP and hyperlipidemia AP (HLAP) with liver injury. This investigation was designed to explore the function and relationship of IRF9 and SIRT1. HLAP model in vivo was performed by feeding high-fat forage and induced by peritoneal injection with 20% L-arginine. The severity of pancreas and liver tissues was assessed. Cell apoptosis in the liver was determined by the TUNEL experiment. IRF9, SIRT1, p53, and acetylated p53 (Ac-p53) expression levels in liver tissues were detected by qRT-PCR and Western blot. The association of IRF9 expression with SIRT1 levels was evaluated. The relevance of triglyceride level to tissue damage was analyzed. Our observation exhibited more distinct liver damage, a large number of hepatic cell apoptosis, marked raised IRF9, Ac-p53, and sharply dropped SIRT1 in the AP and HLAP groups. Compared with other groups, HLAP showed the most significant changes in liver injury, hepatic cell apoptosis, protein, and mRNA levels. The declined expression of SIRT1 was correlated with the elevated expression of IRF9. The damage of the pancreas and liver exacerbated with the increase in triglyceride levels. Elevated IRF9 in pancreatitis with liver injury raised cell apoptosis and tissue damage by decreasing SIRT1 expression.

Members of the interferon regulatory factor (IRF) family are transcriptional regulators that play vital roles in the inflammatory response of macrophages. IRF1, IRF3, and IRF9 regulate the expression of immune-responsive gene 1 (IRG1) in macrophages. However, the role of IRF2 in the inflammatory response of macrophages remains somewhat contradictory. The regulatory relationship between IRF2 and IRG1 and their role in macrophages remain unclear. This study aimed to explore the role of IRF2 and IRG1 in macrophages. Overexpression plasmids of IRF2 (IRF2-pcDNA3.1) and silencing siRNA targeting IRF2 and IRG1 (si-IRF2, si-IRG1) were constructed and transfected into RAW264.7 cells respectively. Subsequently, cells were treated with LPS and IFN-γ for 24 h. The expression of IRF2, IRG1, iNOS, IL-6, and BCL-xl was detected using Western blotting and qRT-PCR. Cell viability, migration and apoptosis were determined by CCK-8, transwell and flow cytometry. The IRG1 promoter region was cloned into the pGL3-basic plasmid. A dual-luciferase reporter assay was performed to verify the regulatory relationship between IRF2 and IRG1. IRF2 overexpression inhibited the expression of IL-6 and iNOS, cell migration, and apoptosis and elevated the expression of BCL-xl, IRG1, and cell viability of LPS- and IFN-γ-induced macrophages. IRF2 silencing had an opposite effect. IRF2 activated the promoter activity of IRG1. The inhibitory effects on LPS- and IFN-γ-induced proinflammatory responses, cell migration, apoptosis, and enhancing effects on the cell viability of over-expressed IRF2 were reversed by IRG1 silencing. IRF2 promoted the promoter activity of IRG1 and regulated directly the expression of IRG1. IRF2 inhibited LPS and IFN-γ-induced pro-inflammatory responses, cell migration and apoptosis, enhanced cell viability in macrophages through regulating IRG1. IRF2 affected LPS- and IFN-γ-induced pro-inflammatory responses, cell viability, migration and apoptosis of macrophages by regulating IRG1.

Offshore development tends to aim for high production with fewer wells, which leads to large well spacing and wide range of low-pressure gradient. Compared with onshore, the low-velocity nonlinear flow, matrix stress sensitivity, and CO2 miscibility have significant impacts on the injection optimization design. However, existing studies rarely examine the impact of these characteristics on injection parameters, including injection fluid selection, injection rate and timing. Therefore, we first establish a 3D embedded discrete fracture model for compositional simulation. Multiple mechanisms, including low-velocity nonlinear flow, matrix and fracture stress sensitivity are considered comprehensively. After evaluating the sweep area, injection capacity, and production performance of different injection fluid (H2O, CO2, N2), a fluid selection strategy was proposed. The cumulative oil production under a certain water cut/gas-oil ratio is taken as the objective function. Then the injection rate and timing are studied. Results show that, when the injection rate of CO2 and H2O is high, the fluid breakthrough comes early. When the injection rate is low, the reservoir pressure is poorly maintained, resulting strong matrix stress sensitivity, and low CO2 miscibility efficiency. Therefore, there is an optimal CO2 and H2O injection rate. In comparison with the traditional Darcy flow, the optimal H2O injection rate is higher. The maximum difference reaches 11.1% with matrix permeability of 5 × 10−3 μm2. As the matrix permeability increases, optimal CO2 injection timing is gradually advanced. While the optimal H2O injection timing is gradually delayed. The proposed 3D-EDFM compositional simulator can serve as an effective and reliable method for injection-production optimization. [Display omitted]

Background: Members of the interferon regulatory factor (IRF) family are transcriptional regulators that play vital roles in the inflammatory response of macrophages. IRF1, IRF3, and IRF9 regulate the expression of immune-responsive gene 1 (IRG1) in macrophages. However, the role of IRF2 in the inflammatory response of macrophages remains somewhat contradictory. The regulatory relationship between IRF2 and IRG1 and their role in macrophages remain unclear. This study aimed to explore the role of IRF2 and IRG1 in macrophages. Methods: Overexpression plasmids of IRF2 (IRF2-pcDNA3.1) and silencing siRNA targeting IRF2 and IRG1 (si-IRF2, si-IRG1) were constructed and transfected into RAW264.7 cells respectively. Subsequently, cells were treated with LPS and IFN-[gamma] for 24 h. The expression of IRF2, IRG1, iNOS, IL-6, and BCL-xl was detected using Western blotting and qRT-PCR. Cell viability, migration and apoptosis were determined by CCK-8, transwell and flow cytometry. The IRG1 promoter region was cloned into the pGL3-basic plasmid. A dual-luciferase reporter assay was performed to verify the regulatory relationship between IRF2 and IRG1. Results: IRF2 overexpression inhibited the expression of IL-6 and iNOS, cell migration, and apoptosis and elevated the expression of BCL-xl, IRG1, and cell viability of LPS- and IFN-[gamma]-induced macrophages. IRF2 silencing had an opposite effect. IRF2 activated the promoter activity of IRG1. The inhibitory effects on LPS- and IFN-[gamma]-induced proinflammatory responses, cell migration, apoptosis, and enhancing effects on the cell viability of over-expressed IRF2 were reversed by IRG1 silencing. Conclusion: IRF2 promoted the promoter activity of IRG1 and regulated directly the expression of IRG1. IRF2 inhibited LPS and IFN-[gamma]-induced pro-inflammatory responses, cell migration and apoptosis, enhanced cell viability in macrophages through regulating IRG1. IRF2 affected LPS- and IFN-[gamma]-induced pro-inflammatory responses, cell viability, migration and apoptosis of macrophages by regulating IRG1. Keywords: IRF2, IRG1, macrophages, pro-inflammatory responses, apoptosis

Isoprene is a substantial contributor to global secondary organic aerosol (SOA). The formation of isoprene SOA (SOA I ) is highly influenced by anthropogenic emissions. Currently, there is rare information regarding SOA I in polluted regions. In this study, one-year concurrent observation of SOA I tracers was undertaken at 12 sites across China for the first time. The tracers formed from the HO 2 -channel exhibited higher concentrations at rural sites, while the tracer formed from the NO/NO 2 -channel showed higher levels at urban sites. 3-Methyltetrahydrofuran-3,4-diols exhibited linear correlations with their ring-opening products, C 5 -alkenetriols. And the slopes were steeper in the southern China than the northern China, indicating stronger ring-opening reactions there. The correlation analysis of SOA I tracers with the factor determining biogenic emission and the tracer of biomass burning (levoglucosan) implied that the high level of SOA I during summer was controlled by biogenic emission, while the unexpected increase of SOA I during winter was largely due to the elevated biomass burning emission. The estimated secondary organic carbon from isoprene (SOC I ) exhibited the highest levels in Southwest China. The significant correlations of SOC I between paired sites implied the regional impact of SOA I in China. Our findings implicate that isoprene origins and SOA I formation are distinctive in polluted regions.

Background There is no consensus on whether triplet regimen is better than doublet regimen in the first‐line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. Methods This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non‐inferiority in progression‐free survival (PFS) for XELOX as compared with EOX on an intention‐to‐treat basis. Results Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5‐6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0‐6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812‐1.203; Pnon‐inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health‐related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. Conclusions This non‐inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first‐line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

Background Rapid progression contributes to treatment failure in anaplastic thyroid carcinoma (ATC) patients. In a preliminary study, we demonstrated that some hematopoietic factors may be involved in the progression of ATC. The adaptor protein LNK, which is a negative regulator of hematopoietic cytokine signalling, has been studied extensively in malignant hematopoietic cells. However, there are few studies on LNK in solid tumours. Methods Real-time PCR, immunohistochemistry (IHC) and western blot analysis of LNK were performed on ATC cells, differentiated thyroid cancer (DTC) cells and normal thyroid cells. In vitro assays (including pull-down, liquid chromatography-mass spectrometry (LC–MS), co-IP, MTT and colony formation) were performed to validate the effect of LNK on ATC progression and elucidate the molecular mechanisms. Results Compared with DTC cells and normal thyroid cells, ATC cells exhibit overexpression of LNK. In addition, LNK overexpression results in increased proliferation of ATC cells. Conversely, LNK knockdown significantly suppresses ATC cell proliferation. LC–MS identified the 14-3-3 ε/γ protein as a LNK binding partner. Finally, the results indicate that LNK overexpression significantly enhances the anti-apoptotic ability of ATC cells via the Akt-NFκB-Bcl-2/Bcl-xL pathway and that the oncogenic effect of LNK largely depends on 14-3-3 ε/γ binding. Conclusions The present study elucidated the important role of LNK in the growth of ATC opposite to its behaviour in the hematopoietic system and indicates that LNK is a potential target for the treatment of ATC.

The cover image is based on the Original Article XELOX doublet regimen versus EOX triplet regimen as first‐line treatment for advanced gastric cancer: An open‐labeled, multicenter, randomized, prospective phase III trial (EXELOX) by Wei‐Jian Guo et al., https://doi.org/10.1002/cac2.12278.

EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next‐generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co‐occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins‐positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression‐free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insFQEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first‐generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first‐line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co‐occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type. EGFR exon 20 insertions (EGFR e20ins) were highly diversified in terms of insertion patterns and co‐occurring mutations, and these EGFR e20ins variants showed different clinical responses to various EGFR tyrosine kinase inhibitors (TKIs) in lung cancer, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type.