Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer
. Many efforts are therefore underway to ...identify new approaches that enhance such immune 'checkpoint' therapy
(so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism
-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.
•A novel SACe-N-C nanozyme with high POD-like activity was used to construct bioactive paper.•The bioactive paper offered a portable approach to detect pesticide residues in fruits and vegetables ...within 30 min.•An on-site portable testing device was proposed by integrating SACe-N-C bioactive paper into 3D printed platform.•The proposed assay for omethoate, methamidophos, carbofuran, and carbosulfan showed an acceptable limit of detection.
Rapid detection of pesticide residues based on enzyme mimics has recently attracted much interest. However, most nanozymes have low activity. Herein, a “single-atom Ce-N-C nanozyme” (SACe-N-C nanozyme) was rationally devised and verified to mimic peroxidase (POD-like) with superior activity. Based on its high POD-like activities and cascaded catalytic reactions with acetylcholinesterase (AChE), we constructed a bioactive paper for the detection of pesticide residues, which offered a portable approach to monitor fruits and vegetables within 30 min. More importantly, a 3D printed platform was integrated on the basis of SACe-N-C bioactive paper to achieve on-site portable testing of omethoate, methamidophos, carbofuran, and carbosulfan, showing limits of detection (LODs) of 55.83, 71.51, 81.81, and 74.98 ng/mL, respectively. The recovery rates were 84.09–104.68%. This study provided new insight into the design of novel single-atom nanozymes for cascaded catalytic detection and other rapid detection applications with high efficiency and low cost.
•A brand-new dual S-scheme Ag2CO3/Bi4O5I2/g-C3N4 composite was prepared.•The Ag2CO3/Bi4O5I2/g-C3N4 composite shows excellent photocatalytic activity for TC degradation.•The charge transfer mechanism ...of S-scheme enhances the redox ability.•The mechanism and driving force of charge transfer and separation in photocatalytic degradation of TC were discussed.
In recent years, the construction of step-scheme (S-scheme) heterojunction has proved to be a promising method to improve the degradation performance of photocatalysts. Importantly, S-scheme heterojunction system shows great potential in accelerating the separation and transformation of photogenerated carriers and obtaining strong light oxidation ability. In this paper, Ag2CO3/Bi4O5I2/g-C3N4 dual S-scheme heterojunction material was designed and constructed by heat treatment and subsequent in-situ wet chemistry. Compared with the original Bi4O5I2 and g-C3N4, Ag2CO3/Bi4O5I2/g-C3N4 hybrid catalyst showed remarkably enhanced photocatalytic performance in tetracycline degradation. The tetracycline degradation rate constant of Ag2CO3/Bi4O5I2/g-C3N4 is 0.03892 min−1, which is about 2.09, 5.80 and 13.33 times higher than that of pure Ag2CO3 (0.01865 min−1), Bi4O5I2 (0.00671 min−1) and g-C3N4 (0.00292 min−1), respectively. The apparent enhancement of photocatalytic activity is not only due to the formation of ternary complex, which can enlarge the visible light response of g-C3N4, but also due to the S-scheme heterojunction. When the interface is illuminated by visible light, the establishment of the built-in electric field and the resulting bending of the band edge promote the recombination of photogenerated carriers with weaker redox ability in the composite while retaining electrons and holes with stronger redox ability. Therefore, the residual electrons and holes with high reducing and oxidizing properties endow the composite with extremely high redox ability. In addition, the driving force and mechanism of charge transfer and separation in dual S-scheme heterojunction photocatalyst were studied and discussed. This study expands the application range of g-C3N4 material, and also discusses the reaction mechanism of Ag2CO3/Bi4O5I2/g-C3N4 composite material in dual S-scheme reaction system in detail.
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•Solid solution hardening in high entropy alloys is modelled by machine learning.•Complex local atomic environment and interactions are emphasized.•A methodology for discovering new ...high hardness high entropy alloys is provided.•The proposed methodology is validated by experiment.
High entropy alloys (HEAs) are considered as a way to unlock the unlimited potentials of materials during material design, where solid solution hardening (SSH) is one of the major contributors to their excellent mechanical properties. In this work, machine learning (ML) is applied for modelling SSH in HEAs, and a ML system is established for designing solid solution hardened HEAs. The ML-SSH model is built by considering critical factors in SSH theories and parameters associated with the atomic environment and interactions in HEAs as input features, and is demonstrated to be superior to physical SSH models in terms of hardness prediction. The effects of charge transfer and short range order (SRO) and local composition fluctuations on SSH in HEAs are confirmed using feature engineering approaches. Furthermore, two physical models are modified by introducing charge transfer to enhance their accuracy. Finally, an alloy design system is built by combining the ML-SSH model and ML models for single solid solution phase prediction, achieving good agreement with the experimental results of FeNiCuCo and CrMoNbTi families. The non-equiatomic counterparts with 28.3% and 8.8% hardness values higher than their equiatomic counterparts of FeNiCuCo and CrMoNbTi families respectively are discovered.
PEGylation (PEG) is the most commonly adopted strategy to prolong nanoparticles’ vascular circulation by mitigating the reticuloendothelial system uptake. However, there remain many concerns in ...regards to its immunogenicity, targeting efficiency, etc., which inspires pursuit of alternate, non-PEGylated systems. We introduced here a PEG-free, porphyrin-based ultrasmall nanostructure mimicking nature lipoproteins, termed PLP, that integrates multiple imaging and therapeutic functionalities, including positron emission tomography (PET) imaging, near-infrared (NIR) fluorescence imaging and photodynamic therapy (PDT). With an engineered lipoprotein-mimicking structure, PLP is highly stable in the blood circulation, resulting in favorable pharmacokinetics and biodistribution without the need of PEG. The prompt tumor intracellular trafficking of PLP allows for rapid nanostructure dissociation upon tumor accumulation to release monomeric porphyrins to efficiently generate fluorescence and photodynamic reactivity, which are highly silenced in intact PLP, thus providing an activatable mechanism for low-background NIR fluorescence imaging and tumor-selective PDT. Its intrinsic copper-64 labeling feature allows for noninvasive PET imaging of PLP delivery and quantitative assessment of drug distribution. Using a clinically relevant glioblastoma multiforme model, we demonstrated that PLP enabled accurate delineation of tumor from surrounding healthy brain at size less than 1 mm, exhibiting the potential for intraoperative fluorescence-guided surgery and tumor-selective PDT. Furthermore, we demonstrated the general applicability of PLP for sensitive and accurate detection of primary and metastatic tumors in other clinically relevant animal models. Therefore, PLP offers a biomimetic theranostic nanoplatform for pretreatment stratification using PET and NIR fluorescence imaging and for further customized cancer management via imaging-guided surgery, PDT, or/and potential chemotherapy.
Metal-organic framework (MOF) materials have highly sought after in electromagnetic materials and functional devices, due to the unique three-dimensional structure and electronic state. Herein, the ...tailoring strategy of MOF materials, including MOF precursors and carbonized derivatives, is combed for high-efficiency microwave absorbers. The design idea from microstructure to electromagnetic response is constructed. Based on these theories, the current research progress about MOF-based absorbers is presented, and the effect of microstructure tailoring to electromagnetic property and microwave absorption is revealed. In addition, the application of MOF materials in functional device is outlined. Finally, the current challenges for MOF materials and devices are overviewed, and the future development is expected.
Display omitted Tailoring the microstructure of MOF materials can effectively tune electromagnetic property and obtain great microwave absorbers and devices.
Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells ...rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.
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•Arginine methylation at R248 negatively regulates MDH1 activity•PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization•MDH1 methylation suppresses glutamine metabolism of pancreatic cancer•R248 methylation of MDH1 is downregulated in clinical PDAC samples
Wang et al. show that arginine methylation at R248 of MDH1, which is catalyzed by PRMT4/CARM1, regulates glutamine metabolism and redox homeostasis of pancreatic cancer cells. MDH1 methylation is downregulated in human PDAC samples.
Lower blood pressure (BP) within the normotensive range has been suggested to be deleterious in diabetic people using antihypertensive drugs. We hypothesized that BP <120/80 mm Hg and BP trajectories ...may predict further risk of all-cause mortality or cardiovascular events in normotensive diabetic individuals. We included 3159 diabetic adults, free of hypertension, atherosclerotic cardiovascular diseases, or cancer in 2006 (baseline), from a community-based cohort including 101 510 participants. A total of 831 participants with BP <120/80 mm Hg and 2328 participants with BP of 120 to 139/80 to 89 mm Hg were included. BP and other clinical covariates were repeatedly measured every 2 years. During 7 years of follow-up, we documented 247 deaths and 177 cardiovascular events. Diabetic people with BP <120/80 mm Hg had a 46% increased risk of all-cause mortality (95% confidence interval, 10%-93%) compared with those with BP of 120 to 139/80 to 89 mm Hg at baseline. We then estimated the association between BP trajectories from 2006 to 2008 and adverse events among 2311 diabetic people who had both BP measures at 2006 and 2008. Relative to stable BP of 120 to 139/80 to 89 mm Hg, having persistently BP <120/80 mm Hg (hazard ratio: 2.35; 95% confidence interval, 1.10-5.01) or a spontaneous decrease in BP from 120 to 139/80 to 89 to <120/80 mm Hg (hazard ratio: 3.04; 95% confidence interval, 1.56-5.92) was significantly associated with an increased risk of all-cause mortality during 2008 to 2014. A rise in BP from 120 to 139/80 to 89 to ≥140/90 mm Hg conferred a high risk of cardiovascular events (hazard ratio: 1.98; 95% confidence interval, 1.24-3.17). In normotensive diabetic people having a low BP or a decline in BP was both associated with an increased risk of all-cause mortality, whereas development of incident hypertension increased the risk of cardiovascular events.
Objective
To test the significance of serum C‐reactive protein (CRP), the erythrocyte sedimentation rate (ESR), the platelet count/mean platelet volume ratio (PC/MPV), plasma fibrinogen, and D‐Dimer ...in periprosthetic joint infection (PJI) diagnosis.
Methods
We retrospectively analyzed the clinical data of 149 patients diagnosed from July 2016 to December 2019 with primary osteoarthritis (OA group, average age 63.18 years range, 53–82 years 18 males, 46 females), PJI (PJI group, average age 63.74 years range, 52–81 years, 16 males, 31 females), and aseptic loosening (aseptic group, average age 63.18 years range, 53–80 years, 12 male, 26 female) in our department. Demographic data and the sensitivity and specificity of preoperative CRP, ESR, PC/MPV, fibrinogen, and D‐Dimer in PJI diagnosis were compared.
Results
There were no significant differences when the demographic data of the three groups were compared. The expression level of CRP (50.67 ± 58.98 mg/L), ESR (50.55 ± 25.81 mm/h), PC/MPV (35.79 ± 18.00), and fibrinogen (4.85 ± 1.33 μg/mL) in the PJI group were higher than in the OA group (CRP: 4.09 ± 9.68 mg/L; ESR:13.44 ± 9.32 mm/1 h; PC/MPV: 24.97 ± 7.58; fibrinogen: 3.09 ± 0.55 μg/mL) and the aseptic group (CRP: 7.01 ± 11.83 mg/L; ESR: 22.47 ± 17.53 mm/1 h; PC/MPV: 25.18 ± 11.48; fibrinogen: 3.39 ± 0.80 μg/mL), respectively. The expression level of plasma D‐dimer (1.60 ± 1.29 mg/L) in the PJI group was higher than in the OA group (0.49 ± 0.42 mg/L) but similar to that in the aseptic group (1.21 ± 1.35 mg/L). Receiver operating characteristic (ROC) curve analysis demonstrated that the areas under the ROC curve (AUC) for CRP, ESR, PC/MPV, fibrinogen, and D‐dimer were 0.892 (95% confidence interval, 0.829–0.954), 0.888 (0.829–0.947), 0.686 (0.589–0.784), 0.873 (0.803–0.943), and 0.835 (0.772–0.899), respectively. When PC/MPV > 31.70, fibrinogen >4.01 μg/mL, and D‐dimer >1.17 mg/L were set as the threshold values for the diagnosis of PJI, the sensitivity of PC/MPV in PJI diagnosis was lower than that of ESR and plasma fibrinogen. In contrast, there was no significant difference when comparing the specificity of CRP, ESR, PC/MPV, fibrinogen, and D‐dimer in PJI diagnosis.
Conclusion
Plasma fibrinogen is a good new auxiliary diagnostic marker for PJI.
Platelet count and mean platelet volume ratio and plasma D‐dimer should not be used as the first screen markers for PJI diagnosis, whereas plasma fibrinogen can be used as an auxiliary marker for PJI diagnosis.
Complete androgen insensitivity syndrome (CAIS) is a rare disease that can be easily misdiagnosed. Before puberty, this condition is easily misdiagnosed as an inguinal hernia. This case report ...describes a 31-year-old phenotypically female patient with CAIS who was misdiagnosed twice previously with an inguinal hernia. Her karyotype analysis showed that she was 46, XY. She underwent a bilateral gonadectomy and long-term hormone replacement therapy. A Leydig cell tumour of the right testis was diagnosed postoperatively. This report also reviews the current understanding of the diagnosis and treatment of CAIS.
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