LAG3 is the most promising immune checkpoint next to PD-1 and CTLA-4. High LAG3 and FGL1 expression boosts tumor growth by inhibiting the immune microenvironment. This review comprises four sections ...presenting the structure/expression, interaction, biological effects, and clinical application of LAG3/FGL1. D1 and D2 of LAG3 and FD of FGL1 are the LAG3-FGL1 interaction domains. LAG3 accumulates on the surface of lymphocytes in various tumors, but is also found in the cytoplasm in non-small cell lung cancer (NSCLC) cells. FGL1 is found in the cytoplasm in NSCLC cells and on the surface of breast cancer cells. The LAG3-FGL1 interaction mechanism remains unclear, and the intracellular signals require elucidation. LAG3/FGL1 activity is associated with immune cell infiltration, proliferation, and secretion. Cytokine production is enhanced when LAG3/FGL1 are co-expressed with PD-1. IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. The clinical use of anti-FGL1 antibodies has not been reported. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.
Background
The effect of corticosteroids on influenza A(H1N1)pdm09 viral pneumonia patients remains controversial, and the impact of dosage has never been studied.
Methods
Using data of hospitalized ...adolescent and adult patients with influenza A(H1N1)pdm09 viral pneumonia, prospectively collected from 407 hospitals in mainland China, the effects of low‐to‐moderate‐dose (25‐150 mg d−1) and high‐dose (>150 mg d−1) corticosteroids on 30‐day mortality, 60‐day mortality, and nosocomial infection were assessed with multivariate Cox regression and propensity score‐matched case–control analysis.
Results
In total, 2141 patients (median age: 34 years; morality rate: 15.9%) were included. Among them, 1160 (54.2%) had PaO2/FiO2<300 mm Hg on admission, and 1055 (49.3%) received corticosteroids therapy. Corticosteroids, without consideration of dose, did not influence either 30‐day or 60‐day mortality. Further analysis revealed that, as compared with the no‐corticosteroid group, low‐to‐moderate‐dose corticosteroids were related to reduced 30‐day mortality (adjusted hazard ratio aHR 0.64 95% CI 0.43‐0.96, P=.033). In the subgroup analysis among patients with PaO2/FiO2<300 mm Hg, low‐to‐moderate‐dose corticosteroid treatment significantly reduced both 30‐day mortality (aHR 0.49 95% CI 0.32‐0.77) and 60‐day mortality (aHR 0.51 95% CI 0.33‐0.78), while high‐dose corticosteroid therapy yielded no difference. For patients with PaO2/FiO2 ≥300 mm Hg, corticosteroids (irrespective of dose) showed no benefit and even increased 60‐day mortality (aHR 3.02 95% CI 1.06‐8.58). Results were similar in the propensity model analysis.
Conclusions
Low‐to‐moderate‐dose corticosteroids might reduce mortality of influenza A(H1N1)pdm09 viral pneumonia patients with PaO2/FiO2<300 mm Hg. Mild patients with PaO2/FiO2 ≥300 mm Hg could not benefit from corticosteroid therapy.
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•Using recycled brick powder (RBP) derived from C&D waste as SCM to prepare UHPC.•Using 15% RBP instead of silica fume improves the solid packing state and mechanical properties of ...the UHPC mixture.•The 15% RBP reduces the content of unhydrated and pore phase in the UHPC matrix, but increases the content of UHD C-S-H.•It is feasible to use 15% RBP to replace silica fume to produce eco-friendly UHPC mixture.
Using recycled brick powder (RBP) as an alternative material in cement-based materials is an effective way to make high-value utilization of construction and demolition (C&D) waste. In this study, RBP was used to replace part of silica fume (SF) to improve the volume stability and environmental benefits of ultra-high performance concrete (UHPC), and the influence of different RBP contents on the mechanical strength, autogenous shrinkage, and microstructure of UHPC mixture was explored. The results show that although using 30–45% of RBP to replace SF reduces the strengths, an appropriate amount of RBP (15%) can significantly improve the mechanical strength of UHPC. Meanwhile, as the replacement rate of RBP increases, the autogenous shrinkage of UHPC decreases significantly. In addition, the incorporation of 15% RBP improves the solid packing state, and the internal curing effect of RBP improves the performance of the interface transition zone. From the perspective of nano-scale characteristics, the appropriate amount of RBP (15%) reduces the content of unhydrated phase, pore phase and high-density C-S-H in the matrix, while makes the ultra high-density C-S-H content increase significantly. Furthermore, UHPC mixed with 15% RBP shows lower cost and CO2-e emission. Therefore, it is feasible to use 15% RBP to replace SF to produce eco-friendly UHPC mixture.
Desktop three-dimensional (3D) printers (D3DPs) have become a popular tool for fabricating personalized consumer products, favored for low cost, easy operation, and other advantageous qualities. This ...study focused on the potential for using D3DPs to successfully, rapidly, and economically print customized implants at medical clinics. An experiment was conducted on a D3DP-printed anterior cruciate ligament surgical implant using a rabbit model. A well-defined, orthogonal, porous PLA screw-like scaffold was printed, then coated with hydroxyapatite (HA) to improve its osteoconductivity. As an internal fixation as well as an ideal cell delivery system, the osteogenic scaffold loaded with mesenchymal stem cells (MSCs) were evaluated through both in vitro and in vivo tests to observe bone-ligament healing via cell therapy. The MSCs suspended in Pluronic F-127 hydrogel on PLA/HA screw-like scaffold showed the highest cell proliferation and osteogenesis in vitro. In vivo assessment of rabbit anterior cruciate ligament models for 4 and 12 weeks showed that the PLA/HA screw-like scaffold loaded with MSCs suspended in Pluronic F-127 hydrogel exhibited significant bone ingrowth and bone-graft interface formation within the bone tunnel. Overall, the results of this study demonstrate that fabricating surgical implants at the clinic (fab@clinic) with D3DPs can be feasible, effective, and economical.
Background and Purpose
Aseptic prosthesis loosening, caused by wear particles, is one of the most common causes of arthroplasty failure. Extensive and over‐activated osteoclast formation and ...physiological functioning are regarded as the mechanism of prosthesis loosening. Therapeutic modalities based on inhibiting osteoclast formation and bone resorption have been confirmed to be an effective way of preventing aseptic prosthesis loosening. In this study, we have investigated the effects of sophocarpine (SPC, derived from Sophora flavescens) on preventing implant loosening and further explored the underlying mechanisms.
Experimental Approach
The effects of SPC in inhibiting osteoclastogenesis and bone resorption were evaluated in osteoclast formation, induced in vitro by the receptor activator of NF‐κB ligand (RANKL). A rat femoral particle‐induced peri‐implant osteolysis model was established. Subsequently, micro‐CT, histology, mechanical testing and bone turnover were used to assess the effects of SPC in preventing implant loosening.
Key Results
In vitro, we found that SPC suppressed osteoclast formation, bone resorption, F‐actin ring formation and osteoclast‐associated gene expression by inhibiting NF‐κB signalling, specifically by targeting IκB kinases. Our in vivo study showed that SPC prevented particle‐induced prosthesis loosening by inhibiting osteoclast formation, resulting in reduced periprosthetic bone loss, diminished pseudomembrane formation, improved bone‐implant contact, reduced bone resorption‐related turnover and enhanced stability of implants. Inhibition of NF‐κB signalling by SPC was confirmed in vivo.
Conclusion and Implications
SPC can prevent implant loosening through inhibiting osteoclast formation and bone resorption. Thus, SPC might be a novel therapeutic agent to prevent prosthesis loosening and for osteolytic diseases.
Water treatment sludge (WTS) management is a growing global problem, which is often disposed as a hazardous material in landfill space. This paper aims to use modified WTS as a novel supplementary ...cementitious material, by determining the effects of calcined WTS addition on the composition and performance of Portland cement composites. The effect of WTS to replace cement partially by weight on the mechanical properties and drying shrinkage of specimens has experimentally been studied, and the internal microstructure is also determined by scanning electron microscope and nanoindentation techniques. The results showed that mortar with 10% modified WTS presented higher 90-day compressive strength although specimens with 20% and 30% modified WTS showed 10.54% and 16.20% reduction compared to the control group. Meanwhile, the modified WTS has pozzolanic activity and can react with cement hydration products to increase the compactness of the microstructure, thereby reducing the drying shrinkage of the pastes (10% modified WTS). When 10% of the cement was replaced by modified WTS, the volume fraction of unhydrated clinker and pore phase in the matrix decreased significantly, while the volume fraction of C–S–H phase increased. In addition, the interface transition zone (ITZ) width of the specimen (10% WTS) is the smallest, and as the replacement rate of modified WTS increases, the ITZ width of the specimen increases significantly. This paper proves that the modified WTS, as a supplementary cementitious material, can be considered a feasible and sustainable alternative for use in the building materials.
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•The modified WTS can be considered a feasible and sustainable alternative for use in the Portland cement.•The nano-scale characteristics of the mortar mixed with modified WTS are investigated by nanoindentation technology.•Mortar mixed with 10% modified WTS has good microstructure and mechanical properties.
Glutamine:fructose-6-phosphate aminotransferase (GFAT) and phosphofructokinase (PFK) are enzymes related to chitin metabolism. RNA interference (RNAi) technology was used to explore the role of these ...two enzyme genes in chitin metabolism. In this study, we found that GFAT and PFK were highly expressed in the wing bud of Nilaparvata lugens and were increased significantly during molting. RNAi of GFAT and PFK both caused severe malformation rates and mortality rates in N. lugens. GFAT inhibition also downregulated GFAT, GNPNA, PGM1, PGM2, UAP, CHS1, CHS1a, CHS1b, Cht1-10, and ENGase. PFK inhibition significantly downregulated GFAT; upregulated GNPNA, PGM2, UAP, Cht2-4, Cht6-7 at 48 h and then downregulated them at 72 h; upregulated Cht5, Cht8, Cht10, and ENGase; downregulated Cht9 at 48 h and then upregulated it at 72 h; and upregulated CHS1, CHS1a, and CHS1b. In conclusion, GFAT and PFK regulated chitin degradation and remodeling by regulating the expression of genes related to the chitin metabolism and exert opposite effects on these genes. These results may be beneficial to develop new chitin synthesis inhibitors for pest control.
Background
Whether T2 esophageal squamous cell carcinoma should be subclassified remains controversial. We aimed to investigate the impact of the depth of muscularis propria invasion on nodal status ...and survival outcomes.
Methods
We identified patients with pT2 esophageal squamous cell carcinoma who underwent primary surgery from January 2009 to June 2017. Clinical data were extracted from prospectively maintained databases. Tumor muscularis propria invasion was stratified into superficial or deep. Binary logistic regression was used to determine risk factors for lymph node metastases. The impact of the depth of muscularis propria invasion on survival was investigated using Kaplan‒Meier analysis and a Cox proportional hazard regression model.
Results
A total of 750 patients from three institutes were investigated. The depth of muscularis propria invasion (odds ratio OR: 3.95, 95% confidence interval CI: 2.46–6.35; p < 0.001) was correlated with lymph node metastases using logistic regression. T substage (hazard ratio HR: 1.37, 95% CI: 1.05–1.79; p < 0.001) and N status (HR: 1.51, 95% CI: 1.05–2.17; p < 0.001) were independent risk factors in multivariate Cox regression analysis. The deep muscle invasion was associated with worse overall survival (HR: 1.52, 95% CI: 1.19–1.94; p = 0.001) than superficial, specifically in T2N0 patients (HR: 1.38, 95% CI: 1.08–1.94; p = 0.035).
Conclusions
We found that deep muscle invasion was associated with significantly worse outcomes and recommended the substaging of pT2 esophageal squamous cell carcinoma in routine pathological examination.
MicroRNA168 (miR168) is a key miRNA that targets Argonaute1 (AGO1), a major component of the RNA-induced silencing complex
. Previously, we reported that miR168 expression was responsive to infection ...by Magnaporthe oryzae, the causal agent of rice blast disease
. However, how miR168 regulates immunity to rice blast and whether it affects rice development remains unclear. Here, we report our discovery that the suppression of miR168 by a target mimic (MIM168) not only improves grain yield and shortens flowering time in rice but also enhances immunity to M. oryzae. These results were validated through repeated tests in rice fields in the absence and presence of rice blast pressure. We found that the miR168-AGO1 module regulates miR535 to improve yield by increasing panicle number, miR164 to reduce flowering time, and miR1320 and miR164 to enhance immunity. Our discovery demonstrates that changes in a single miRNA enhance the expression of multiple agronomically important traits.
Abstract The analgesic efficacy and safety of periarticular multimodal drug injection (PMDI) compared with femoral nerve block (FNB) for postoperative pain management in total knee arthroplasty (TKA) ...still remains controversial. We therefore conducted a meta-analysis to quantitatively compare PMDI to FNB in TKA. 10 randomized controlled trials (RCTs) with 744 TKAs in 728 patients were included in this study. The meta-analysis showed that single shot FNB may have better pain relief in the early postoperative period compared with single shot PMDI, and continuous PMDI provided postoperative analgesia comparable to that of continuous FNB. No significant difference was seen in regard to the complications between the two groups. However, due to the variation of the included studies, no firm conclusions can be drawn.
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