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Fatty acid synthesis facilitates tumor cell immune escape and immunotherapy resistance. Cytochrome P450 (CYP) 4A and 4F, the major ω-hydroxylases that convert arachidonic acid (AA) into 20-hydroxyeicosatetraenoic acid (20-HETE), are implicated in inflammation and cancer. However, the role of CYP4 ω-hydroxylases in immune evasion remains unclear. Here, we determined that 20-HETE derived from the CYP4F2 isoenzyme governs immune evasion in non–small cell lung cancer (NSCLC) in a CD8+ T-cell-dependent manner. Mechanistically, CYP4F2 induced expression of immune checkpoint PD-L1 and production of proangiogenic factors IL6 and TGFβ in cancer-associated fibroblasts (CAF) via the 20-HETE-GPR75-STAT3-c-Jun axis. Tumors with high CYP4F2 expression were more resistant to anti-PD-1 treatment, whereas inhibition of CYP4F2 enhanced the efficacy of anti-PD-1 therapy in human NSCLC organoids and mouse models. Collectively, these data delineate that CYP4F2-dependent AA metabolism controls CAF-mediated immune evasion. CYP4F2 inhibition combined with PD-1 antibody represents a promising therapeutic approach for immunotherapy-resistant lung cancer.Significance:The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non–small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2.See related article by Van Ginderachter, p. 3882

Supplementary Data from CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non–Small Cell Lung Cancer

In this paper, the free Phospholipase A(1) (PLA(1)) was immobilized on a magnetic carrier. The average particle diameter of the magnetic carrier was 97 ± 1.3 nm, and the average particle diameter of the magnetically immobilized PLA(1) was 105 nm ± 1.3 nm. The enzyme activity was 1940.5 U/g. The magnetic enzyme was chemically modified with formaldehyde, dextran-aldehyde, and dextran-aldehyde-glycine. The proportions of primary amino groups in the modified magnetic immobilized enzyme PLA(1) were 0, 53.5% and 47.3%, respectively. The optimum pH of the enzyme after chemical modification was 6.5. When the system temperature was 60 °C, the magnetically immobilized PLA(1) modified with dextran-aldehyde-glycine had the optimal activity and stability. This chemically modified magnetic immobilized PLA(1) was applied to soybean oil degumming at 60 °C, 6.5 h (reaction time), and 0.10 mg/kg (enzyme dosage). The phosphorus content in the degummed oil was 9.2 mg/kg. The relative enzyme activity was 77.6% after 7 reuses which would be potentially advantageous for industrial applications. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s13197-021-05017-4).

A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system xc-, a key regulator for ferroptosis, to amplify the therapeutic efficacy of cancer ferrotherapy. The prodrug nanosystem is assembled between sulfasalazine (SSZ, a ferroptosis resistance inhibitor) and disulfide-bridged levodopa (DSSD) that can chelate Fe2+ ions to form SSZ-Fe2+@DSSD, and the resulting nanoassembly can not only inhibit ferroptosis resistance, but also generate ROS in the tumor microenvironment. Whereas the prodrug nanosystem is stable in the physiological environment, it becomes unstable in the tumoral and intracellular reductive microenvironment, where the disulfide linkers are disrupted by high levels of glutathione (GSH), triggering the release of active Fe2+ and SSZ. Under the Fenton reaction, the released Fe2+ thus can induce ferroptosis, which is amplified by SSZ-mediated inhibition of ferroptosis resistance to synergistically improve the therapeutic efficacy of ferroptosis. Our study thus provides an innovative prodrug strategy to advance anticancer ferroptosis.

The effect of electrolysis on soy protein isolate (SPI) was studied by Raman spectroscopy and ultraviolet spectroscopy. The results showed that with the prolongation of electrolysis time, the α-helix content decreased first and then increased. Trp and Tyr residues tended to be exposed from their original embedded state, while electrolysis gradually shifted the SPI disulfide bond from the g–g–g configuration to g–g–t and t–g–t configuration. Therefore, the electrolysis treatment influences the SPI disulfide bond, resulting in intermolecular disulfide bond. Raman spectra showed the secondary and tertiary structure changes of SP and revealed that the structure of SPI would be affected by electrolysis. And the results of UV scanning spectrum confirm the above conclusions.

This work evaluated the anionic polysaccharides to improve the functional properties and antioxidant activities, and compared the effects on covalently-linked the soy protein isolate (SPI)- (–)-epigallocatechin-3-gallat (EGCG) binary complexes. The increasing molecular weight via covalent insertion of (–)-epigallocatechin-3-gallat (EGCG) into the soy protein isolate (SPI) was verified by SDS-PAGE. The addition of polysaccharides had no obvious effects on the molecular weight, indicating noncovalent insertion by adsorption. Fourier transform infrared spectroscopy (FT-IR) analysis suggested that SPI-EGCG complexes mixed with polysaccharides changed the secondary structures of SPI with a decrease in α-helix and an increase in β-turn. The emulsions exhibited better stability index (ESI) by adding polysaccharides than the binary complexes emulsion, with decreased particle sizes and increased absolute ζ-potential values, while the value of ESI for the pectin mixed increased more. The 1,1-diphenyl-2-picrylhydrazyl radical (DPPH•) scavenging capacity of SPI-EGCG complexes with the addition of polysaccharides were both greater than 70 %. These findings indicated that anionic polysaccharides could be potentially used as a natural and safe alternative for regulating covalently-linked SPI-EGCG emulsion stability and improving emulsion oxidation resistance.

The combination therapy with different treatment modalities has been widely applied in the clinical applications of cancer treatment. However, it stills a considerable challenge to achieve co-delivery of different drugs because of distinct drug encapsulation mechanisms, low drug loading, and high excipient-related toxicity. Cancer stem cells (CSCs) are closely related to tumor metastasis and recurrence due to high chemoresistance. Herein, we report a stimuli-responsive and tumor-targeted small-molecule self-assembled nanodrug for the combination therapy against CSCs and normal cancer cells. The hydrophobic differentiation-inducing agent (all-trans retinoic acid, ATRA) and hydrophilic anticancer drug (irinotecan, IRI) constitute this amphiphilic nanodrug, which could self-assemble into stable nanoparticles and encapsulate the photothermal agent IR825. Upon cellular uptake, this nanodrug display good release profiles in response to acid and esterase microenvironments by ester linkage. The released drugs not only increase chemotherapy sensitivity by the differentiation of CSCs into non-CSCs, but also exhibit superior cytotoxicity in cancer cells. In addition, IR825 within this nanodrug enables in vivo fluorescence/photoacoustic (PA) imaging allowing for tracking drug distribution. Moreover, the DSPE-PEG-RGD-functionalized nanodrug displayed high tumor accumulation and good biocompatibility, enabling efficient inhibition of tumor growth and tumor metastasis in tumor-bearing mice.

Fatty acid synthesis facilitates tumor cell immune escape and immunotherapy resistance. Cytochrome P450 (CYP) 4A and 4F, the major ω-hydroxylases that convert arachidonic acid (AA) into 20-hydroxyeicosatetraenoic acid (20-HETE), are implicated in inflammation and cancer. However, the role of CYP4 ω-hydroxylases in immune evasion remains unclear. Here, we determined that 20-HETE derived from the CYP4F2 isoenzyme governs immune evasion in non–small cell lung cancer (NSCLC) in a CD8+ T-cell-dependent manner. Mechanistically, CYP4F2 induced expression of immune checkpoint PD-L1 and production of proangiogenic factors IL6 and TGFβ in cancer-associated fibroblasts (CAF) via the 20-HETE-GPR75-STAT3-c-Jun axis. Tumors with high CYP4F2 expression were more resistant to anti-PD-1 treatment, whereas inhibition of CYP4F2 enhanced the efficacy of anti-PD-1 therapy in human NSCLC organoids and mouse models. Collectively, these data delineate that CYP4F2-dependent AA metabolism controls CAF-mediated immune evasion. CYP4F2 inhibition combined with PD-1 antibody represents a promising therapeutic approach for immunotherapy-resistant lung cancer. Significance: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non–small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882

A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system x

The JCSM concept (short for Jackup Combined Semisubmersible Multifunction Platform) is a new type of semisubmersible platform presented by the first author, which overcomes the shortcomings of the available semisubmersible platforms, and combines the advantages of the traditional semisubmersible platform, the Jackup platform and the new FPSO concept - IQFP. Due to the complicated interaction between stability and hydrodynamic performance, it is necessary to explore the effect of geometrical parameters of the main body on the stability and hydrodynamic performance in order to obtain the optimal design plan of a JCSM platform. Firstly, the structure components and innovations of the JCSM were briefly reviewed in order to facilitate readers to understand its full picture. Then, six independent geometric parameters were selected by carefully studying the shape characteristics of the initial design plan of a JCSM study case. Furthermore, the stability heights and motion responses of various floating bodies of the JCSM case with different geometric parameters in wave were calculated using boundary element method based on potential flow theory. Lastly, effect of the shape parameters on stability and hydrodynamic performance of the JCSM was qualitatively evaluated. The research would shed lights on the shape design of the JCSM main body.

High-fat diet (HFD) promotes lung pre-metastatic niche formation and metastasis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrate that glycyrrhizic acid (GA) prevents HFD-enhanced pre-metastatic niche formation and metastasis through gut microbiota. GA reduced HFD-enhanced myeloid-derived suppressor cell recruitment, pro-metastatic protein S100A8/A9 expression and metastasis burden of 4T1 breast cancer and B16F10 melanoma, accompanied by gut microbiota alteration and colonic macrophage polarization far away the M1-like phenotype. These parameters were greatly decreased by treatment with antibiotics, recolonization of Desulfovibrio vulgaris and Clostridium sordellii, and administration of lipopolysaccharide or deoxycholic acid. Macrophage depletion attenuated HFD-enhanced pre-metastatic niche formation and metastasis, but failed to further affect the effects of GA. Mechanistically, counteraction of HFD-enhanced gut microbiota dysbiosis by GA inhibited Gr-1+ myeloid cell migration and S100A8/A9 expression through decreasing the proportion of M1-like macrophages and their production of CCL2 and TNF-α in the colons via LPS/HMGB1/NF-κB signaling inactivation. Together, targeting the gut microbiota by GA to modulate colonic macrophages could be a novel strategy for the prevention of HFD-enhanced pre-metastatic niche formation and metastasis.

BACKGROUND This study sought to systematically evaluate the distribution characteristics and high-risk factors of pulmonary mycosis pathogens, and provide evidence for the clinical treatment and prognosis of patients with pulmonary mycosis. METHODS The Embase, Ovid, PubMed, Medline, and Springer databases were searched to find publications on the distribution characteristics and high-risk factors of pulmonary mycosis pathogens that had been published between the establishment of the databases and April 1, 2021. The Cochrane Handbook 5.0.2 was used to evaluate the risk of bias of the articles included in this study, and Review Manager 5.3 was used to conduct a meta-analysis of the included articles. RESULTS Eleven articles were included in this study, comprising 6,415 subjects. The meta-analysis results showed that pathogen infection significantly increased the mortality of patients [MD =2.67; 95% confidence interval (CI): (1.52, 4.68); Z=3.43; P=0.0006]. Patient age was significantly correlated with the incidence of pulmonary mycosis [MD =1.21; 95% CI: (0.78, 1.86); Z=0.84; P=0.40]. The use of antibiotics was significantly correlated to the incidence of pulmonary mycosis [MD =1.41; 95% CI: (1.15, 1.72); Z=3.30; P=0.001]. Glucocorticoid use was significantly correlated to the incidence of pulmonary mycosis [MD =1.81; 95% CI: (1.13, 2.91); Z=2.45; P=0.01]. However, gender had no obvious correlation with the incidence of pulmonary mycosis [MD =1.21; 95% CI: (0.78, 1.86); Z=0.84; P=0.40]. Further, no correlation was found between smoking history and the incidence of pulmonary mycosis [MD =0.86; 95% CI: (0.51, 1.45); Z=0.57; P=0.57]. DISCUSSION The main types of bacterial infections in patients with pulmonary mycosis were Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Candida albicans, and Helicobacter pylori. In addition to the lungs, pathogens were found to be distributed in the intestines, urinary tract, and digestive tract. Additionally, patient age, antibiotic use, and glucocorticoid use increased the incidence of pulmonary mycosis. Thus, these factors should be paid attention to in the clinical treatment of patients with pulmonary mycosis.

BackgroundAs an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin’s lymphoma (NHL) is rare, especially in the treatment of ICIs.Case presentationA 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment.ConclusionTislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.

Enzyme-assisted aqueous extraction of rice germ oil (RGO) was performed in this study. The physicochemical properties, fatty acid composition, bioactive substances and antioxidant activity of RGO were analyzed. An enzyme composed of alcalase and cellulase (1:1, w/w) was found to be the most effective in the extraction yield of oil. The optimal oil yield of 22.27% was achieved under the conditions of an enzyme concentration of 2% (w/w), incubation time of 5 h, incubation temperature of 50°C, water to seed ratio of 5:1, and pH 6.0. The predominant fatty acids of RGO were oleic acid (39.60%), linoleic acid (34.20%) and palmitic acid (20.10%). The total saturated fatty acid (SFA), monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) composition of RGO were 22.50%, 39.60% and 36.00%, respectively. RGO yielded a high content of γ-oryzanol (530 mg/100 g oil), tocotrienol (62.96 mg/100 g oil), tocopherol (23.24 mg/100 g oil) and a significant amount of phytosterol (372.14 mg/100 g oil). It exhibited notable antioxidant activities with IC50 values of 32.37 and 41.13 mg/mL, according to the DPPH radical scavenging assay and β-carotene/linoleic acid bleaching test, respectively.

In this paper, the esterification of phytosterol and free fatty acids (FFA) in rice bran oil (RBO) was studied using Novozym 435 in supercritical CO₂. It was found that with the increase in CO₂ filling pressure, the esterification reaction rate also increased. When the pressure exceeded the critical point, CO₂ fluid had a great effect on phytosterol conversion. Therefore, enzymatic esterification deacidification was studied when the CO₂ filling pressure was 8.0 MPa, the results showed that when the lipase dosage was 3.0%, the phytosterol concentration was 18.0%, the molecular sieve addition was 10.0%, and the esterification temperature was 78°C, after 41 hr the FFA content of RBO decreased to 1.1%, the phytosterol conversion rate reached 93.2%, and the vitamin E (VE) retention in the product was 80.0%. Therefore, the esterification by Novozymes 435 in supercritical CO₂ could have several applications in fats and oils industry. PRACTICAL APPLICATIONS: Much research has been done on the interesterification of vegetable oil in order to produce edible fats and oils. The current study provides a reliable and simple method for the esterification of phytosterol and free fatty acids (FFA) in rice bran oil (RBO). The optimal operating conditions lead to high quality oil. The FFA content of RBO decreased to 1.1%, the phytosterol conversion rate reached 93.2%, and the VE content in the product was 80.0%. The esterification by Novozymes 435 in supercritical CO₂ could be applied in fats and oils industry.

The traditional single base station GNSS deformation monitoring system is greatly influenced by the base station stability and data quality. In order to improve the accuracy and reliability of monitoring system, this paper develops a new method of real-time kinematic relative positioning based on multiple base stations and multi-GNSS. Aiming at the problem of weight allocation of multiple base station and different GNSS, the idea of Helmert variance component estimation and robust estimation are introduced. Through a real example analysis, the robust variance component weighting method is more efficient and reliable than the traditional range-based (baseline length) weighting method for different base station and empirical weighting method for different GNSS. The accuracy of the deformation monitoring of the proposed method is higher and more reliable than those of single base station with GNSS or multi-GNSS.

The nanomagnetic carrier (Fe3O4@SiO2@p(GMA)) was prepared by atom transfer radical polymerization, and then, the free phospholipase C (PLC) was immobilized on it proved by the results of FT-IR analysis. The enzyme loading was 135.64 mg/g, the enzyme activity was 8560.7 U/g, the average particle size was 99.86 ± 0.80 nm, and the specific saturation magnetization was 16.00 ± 0.20 emu/g. PLC-Fe3O4@SiO2@p(GMA) showed the highest activities at the pH of 7.5, and tolerance temperature raised to 65°C in soybean lecithin emulsion. Enzymatic degumming with PLC-Fe3O4@SiO2@p(GMA) under the conditions of the enzyme dosage of 110 mg/kg, reaction temperature of 65°C, pH of 7.5, and reaction time of 2.5 h resulted in residual phosphorus of 64.7 mg/kg, 1,2-diacylglycerol (1,2-DAG) contents of 1.07%, and oil yield of 98.1%. Moreover, PLC-Fe3O4@SiO2@p(GMA) still possessed more than 80% of its initial activity after 5 cycles.

A photothermal genome-editing strategy is described to improve immune checkpoint blockade (ICB) therapy by CRISPR/Cas9-mediated disruption of PD-L1 and mild-hyperthermia-induced activation of immunogenic cell death (ICD). This strategy relies on a supramolecular cationic gold nanorod that not only serves as a carrier to deliver CRISPR/Cas9 targeting PD-L1, but also harvests the second near-infrared-window (NIR-II) light and converts into mild hyperthermia to induce both ICD and gene expression of Cas9. The genomic disruption of PD-L1 significantly augments ICB therapy by improving the conversion of dendritic cells to T cells, followed by promoting the infiltration of cytotoxic T lymphocytes into tumors, thereby reprogramming immunosuppressive tumor microenvironment into immunoactive one. Such a therapeutic modality greatly inhibits the activity of primary and metastatic tumors and exhibits long-term immune memory effects against both rechallenged and recurrent tumors. The current therapeutic strategy for synergistic PD-L1 disruption and ICD activation represents an appealing way for cancer immunotherapy.

To apply the scour protection device with the flexible material developed by the author to engineering practice, orthogonal optimization design of the device for a fixed offshore platform in Chengdao Oilfield as a case study was presented. The influences of main design parameters, such as pile diameter, thickness of flexible material and elastic modulus of flexible material on the protective effect of the device were studied by two-way fluid-solid interaction numerical simulation based on ANSYS workbench platform. Then, the optimal design plan of the scour protection device with flexible material was determined. Furthermore, by comparing and contrasting the results of the flow field calculation for the pile legs with versus without protective devices were compared and analysed, the device’s good effective protection effect functionality was demonstrated. The research results will shed light on the practical engineering design of the flexible energy dissipation guiding antiscour device.

The aim of this work was to study the stability of oil-in-water emulsions formed by corn oil with rice bran protein and rice bran protein-catechin complexes, at a (+)-catechin concentration of 0.05%–0.25% (w/v). The experimental results showed that the addition of (+)-catechin decreased the α-helix and β-sheet content to 10.15% and 36.68%, respectively. The surface hydrophobicity increased, and the oil-water interfacial tension decreased to 11.52 mN/m. The emulsions using the rice bran protein-catechin complex (0.15%, w/v) showed the smallest droplet size and the best emulsifying properties. However, a (+)-catechin concentration above 0.20% (w/v) negatively affected the emulsion stability, with increasing droplet size and decreasing absolute ζ-potential values due to protein aggregation. Rheological behavior analyses suggested that the rice bran protein-catechin complex emulsion had higher viscosity and viscoelasticity than the emulsion formed with the control rice bran protein.

Checkpoint blockade therapy has been proven efficacious in lung cancer patients. However, primary/acquired resistance hampers its efficacy. Therefore, there is an urgent need to develop novel strategies to improve checkpoint blockade therapy. Here we tested whether dual inhibition of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) by flavonoid melafolone improves program death 1 (PD-1) checkpoint blockade therapy through normalizing tumor vasculature and PD-1 ligand (PD-L1) downregulation. Virtual screening assay, cellular thermal shift assay, and enzyme inhibition assay identified melafolone as a potential inhibitor of COX-2 and EGFR. In Lewis lung carcinoma (LLC) and CMT167 models, dual inhibition of COX-2 and EGFR by melafolone promoted survival, tumor growth inhibition, and vascular normalization, and ameliorated CD8+ T-cell suppression, accompanied by the downregulation of transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and PD-L1 in the tumor cells. Mechanistically, dual inhibition of COX-2 and EGFR in lung cancer cells by melafolone increased the migration of pericyte, decreased the proliferation and migration of endothelial cells, and enhanced the proliferation and effector function of CD8+ T cells through VEGF, TGF-β, or PD-L1 downregulation and PI3K/AKT inactivation. Notably, melafolone improved PD-1 immunotherapy against LLC and CMT167 tumors. Together, dual inhibition of COX-2 and EGFR by melafolone improves checkpoint blockade therapy through vascular normalization and PD-L1 downregulation and, by affecting vessels and immune cells, may be a promising combination strategy for the treatment of human lung cancer.

Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the synovial fluid macrophages. In addition, leonurine decreased representative M1 marker (iNOS and CD86) expression, NLRP3 inflammasome activation and M1 cytokine (TNF-α and IL-1β) production. In the in vitro cultured RAW264.7 and human monocyte-derived macrophages (MDMs), blockade of COX-2/mPGES-1 and 5-LOX by leonurine inhibited macrophage M1 polarization and NLRP3 inflammasome activation in response to MSU crystals, and thus down-regulated IL-1β and TNF-α with STAT1 and NF-κB inactivation. Conversely, these effects were partially abolished by overexpression of COX-2, mPGES-1, 5-LOX or STAT1. Furthermore, leonurine prevented a positive feedback loop between COX-2/mPGES-1/5-LOX and IL-1β/TNF-α in MSU crystal-induced inflammation. Together, simultaneous down-regulation of COX-2/mPGES-1 and 5-LOX by leonurine ameliorates MSU crystal-induced inflammation through decreasing IL-1β and TNF-α production. Our study may provide novel multi-target agents toward the arachidonic acid (AA) network for gouty arthritis therapy.