Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy.

BACKGROUND: Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative. METHODS: SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model. RESULTS: SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8+ T and M1-type macrophages into tumor sites, while also priming the function of CD8+ T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy. CONCLUSION: Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy.

Toxic effects of bisphenol S on mice heart and human umbilical cord endothelial cells.

Bisphenol S (BPS) exerts toxic effects on hippocampal HT22 cells, endocrine secretion, and reproductive capacity. However, whether BPS exerts toxic effects on the heart requires further investigation. Therefore, we investigated the effects of BPS on mouse heart tissues and predicted possible underlying molecular mechanisms of action. Our study showed that BPS induced apoptosis, increased oxidative stress response. Using electron microscopy, we found that BPS disrupted sarcomere arrangement in myocardial cells and caused reduction in the number of plasmalemmal vesicles in endothelial cells in the mouse heart tissues. Also, BPS increased expression levels of P-NF-κB in mouse heart tissues. Furthermore, we found that BPS induced reactive oxygen species (ROS) generation, NF-κB activation, promoted apoptosis, elevated expression of BAX and Caspase 3, and decreased expression of Bcl-2 in H9c2 cells and HUVECs. However, after the addition of n-acetylcysteine or pyrrolidinedithiocarbamate, ROS generation, NF-κB activation, apoptosis, and expression of BAX and Caspase 3 were reduced, whereas expression of Bcl-2 was elevated. Our results demonstrated that BPS induced apoptosis of myocardial and endothelial cells through oxidative stress by activation of NF-κB signaling pathway.

NO2 Sensing Capability of Pt-Au-SnO2 Composite Nanoceramics at Room Temperature.

Composite ceramics of metal oxides and noble metals have received much attention for sensing reducing gases at room temperature. Presently, composite ceramics of SnO2 and noble metals have been prepared and investigated for sensing oxidizing NO2 at room temperature. While dramatic increases in resistance were observed for both 1 wt% Pt-SnO2 and 5 wt% Au-SnO2 composite nanoceramics after being exposed to NO2 at room temperature, the largest increase in resistance was observed for 1 wt% Pt-5 wt% -Au-SnO2 composite nanoceramics among the three composites. The response to 0.5 ppm NO2--20% O2-N2 was as high as 875 at room temperature, with a response time of 2566 s and a recovery time of 450 s in the air of 50% relative humidity (RH). Further investigation revealed that water molecules in the air are essential for recovering the resistance of Pt-Au-SnO2 composite nanoceramics. A room temperature NO2-sensing mechanism has been established, in which NO2 molecules are catalyzed by Pt-Au to be chemisorbed on SnO2 at room temperature, and desorbed from SnO2 by the attraction of water molecules in the air. These results suggest that composite ceramics of metal oxides and noble metals should be promising for room temperature sensing, not only reducing gases, but also oxidizing gases.

The effect of periapical bone defects on stress distribution in teeth with periapical periodontitis: a finite element analysis.

BACKGROUND: Apical periodontitis directly affects the stress state of the affected tooth owing to the destruction of the periapical bone. Understanding the mechanical of periapical bone defects/tooth is clinically meaningful. In this study, we evaluate the effect of periapical bone defects on the stress distribution in teeth with periapical periodontitis using finite element analysis. METHODS: Finite element models of normal mandibular second premolars and those with periapical bone defects (spherical defects with diameters of 5, 10, 15, and 20 mm) were created using a digital model design software. The edges of the mandible were fixed and the masticatory cycle was simplified as oblique loading (a 400 N force loaded obliquely at 45° to the long axis of the tooth body) to simulate the tooth stress state in occlusion and analyze the von Mises stress distribution and tooth displacement distribution in each model. RESULTS: Overall analysis of the models: Compared to that in the normal model, the maximum von Mises stresses in all the different periapical bone defect size models were slightly lower. In contrast, the maximum tooth displacement in the periapical bone defect model increased as the size of the periapical bone defect increased (2.11-120.1% of increase). Internal analysis of tooth: As the size of the periapical bone defect increased, the maximum von Mises stress in the coronal cervix of the tooth gradually increased (2.23-37.22% of increase). while the von Mises stress in the root apical region of the tooth showed a decreasing trend (41.48-99.70% of decrease). The maximum tooth displacement in all parts of the tooth showed an increasing trend as the size of the periapical bone defect increased. CONCLUSIONS: The presence of periapical bone defects was found to significantly affect the biomechanical response of the tooth, the effects of which became more pronounced as the size of the bone defect increased.

The effect of root canal treatment and post-crown restorations on stress distribution in teeth with periapical periodontitis: a finite element analysis.

AIM: To evaluate the effects of root canal treatment (RCT) and post-crown restoration on stress distribution in teeth with periapical bone defects using finite element analysis. METHODOLOGY: Finite element models of mandibular second premolars and those with periapical bone defects (spherical defects with diameters of 5, 10, 15, and 20 mm) were created using digital model design software. The corresponding RCT and post-crown restoration models were constructed based on the different sizes of periapical bone defect models. The von Mises stress and tooth displacement distributions were comprehensively analyzed in each model. RESULTS: Overall analysis of the models: RCT significantly increased the maximum von Mises stresses in teeth with periapical bone defects, while post-crown restoration greatly reduced the maximum von Mises stresses. RCT and post-crown restoration slightly reduced tooth displacement in the affected tooth. Internal analysis of tooth: RCT dramatically increased the maximum von Mises stress in all regions of the tooth, with the most pronounced increase in the coronal surface region. The post-crown restoration balances the internal stresses of the tooth and is most effective in periapical bone defect - 20-mm model. RCT and post-crown restoration slightly reduced the tooth displacement in all regions of the affected tooth. CONCLUSIONS: Root canal treatment seemed not to improve the biomechanical state of teeth with periapical bone defects. In contrast, post-crown restoration might effectively balance the stress concentrations caused by periapical bone defects, particularly extensive ones.

Proliferation in the developing intestine is regulated by the endosomal protein Endotubin.

During postnatal intestinal development, the intestinal epithelium is highly proliferative, and this proliferation is regulated by signaling in the intervillous and crypt regions. This signaling is primarily mediated by Wnt, and requires membrane trafficking. However, the mechanisms by which membrane trafficking regulates signaling during this developmental phase are largely unknown. Endotubin (EDTB, MAMDC4) is an endosomal protein that is highly expressed in the apical endocytic complex (AEC) of villus enterocytes during fetal and postnatal development, and knockout of EDTB results in defective formation of the AEC and giant lysosome. Further, knockout of EDTB in cell lines results in decreased proliferation. However, the role of EDTB in proliferation during the development of the intestine is unknown. Using Villin-CreERT2 in EDTBfl/fl mice, we deleted EDTB in the intestine in the early postnatal period, or in enteroids in vitro after isolation of intervillous cells. Loss of EDTB results in decreased proliferation in the developing intestinal epithelium and decreased ability to form enteroids. EDTB is present in cells that contain the stem cell markers LGR5 and OLFM4, indicating that it is expressed in the proliferative compartment. Further, using immunoblot analysis and TCF/LEF-GFP mice as a reporter of Wnt activity, we find that knockout of EDTB results in decreased Wnt signaling. Our results show that EDTB is essential for normal proliferation during the early stages of intestinal development and suggest that this effect is through modulation of Wnt signaling.

Comprehensive Techno-environmental Evaluation of a Pilot-Scale PHA Production from Food Waste in China.

Polyhydroxyalkanoates (PHAs), a biodegradable plastic that might replace petroleum-based plastics, can be recovered from organic waste using mixed microbial cultures (MMCs). Research in this field has been ongoing for about 25 years and is now in a critical commercialization period. However, few pilot-scale studies are available to analyze its technical feasibility and environmental impact. We ran an MMC PHA production pilot plant for 6 months using local food waste as the feedstock. The traditional three-stage process achieved PHA content of 47.91 ± 1.91% dry cell weight and volumetric productivity of 9.94 ± 0.01 g/L·d, while a novel rapid proliferation stage was built in, the PHA content and productivity could reach 41.39 ± 2.39% cell dry weight and 20.02 ± 0.01 g/L·d, respectively. Life cycle assessment using field data showed that greenhouse warming potential was much more than five times that of the known literature, and the fossil depletion potential was 10.30 (scenario #1)/7.59 (scenario #2) times higher than petroleum-based polyethylene (PE) plastic. However, establishing a resource-energy-water union instead of an isolated plant could achieve environmental benefits compared to PE plastic. This techno-environmental analysis provides emerging MMC PHA producers worldwide with a valuable reference for further development opportunities and market planning.

Interaction Structure and Affinity of Zwitterionic Amino Acids with Important Metal Cations (Cd2+, Cu2+, Fe3+, Hg2+, Mn2+, Ni2+ and Zn2+) in Aqueous Solution: A Theoretical Study.

Heavy metals are non-biodegradable and carcinogenic pollutants with great bio-accumulation potential. Their ubiquitous occurrence in water and soils has caused serious environmental concerns. Effective strategies that can eliminate the heavy metal pollution are urgently needed. Here the adsorption potential of seven heavy metal cations (Cd2+, Cu2+, Fe3+, Hg2+, Mn2+, Ni2+ and Zn2+) with 20 amino acids was systematically investigated with Density Functional Theory method. The binding energies calculated at B3LYP-D3/def2TZVP level showed that the contribution order of amino acid side chains to the binding affinity was carboxyl > benzene ring > hydroxyl > sulfhydryl > amino group. The affinity order was inversely proportional to the radius and charge transfer of heavy metal cations, approximately following the order of: Ni2+ > Fe3+ > Cu2+ > Hg2+ > Zn2+ > Cd2+ > Mn2+. Compared to the gas-phase in other researches, the water environment has a significant influence on structures and binding energies of the heavy metal and amino acid binary complexes. Collectively, the present results will provide a basis for the design of a chelating agent (e.g., adding carboxyl or a benzene ring) to effectively remove heavy metals from the environment.

Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma.

Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKß2). The TUG1/miR-455-3p/AMPKß2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. CONCLUSION: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKß2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203).

Long Non-Coding RNAs as Mediators of Tumor Microenvironment and Liver Cancer Cell Communication.

The tumor microenvironment is an important concept that defines cancer development not only through tumor cells themselves but also the surrounding cellular and non-cellular components, including stromal cells, blood vessels, infiltrating inflammatory cells, cancer stem cells (CSC), cytokines, and growth factors, which act in concert to promote tumor cell survival and metastasis. Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Poor prognosis is largely attributable to the high rate of tumor metastasis, highlighting the importance of identifying patients at risk in advance and developing novel therapeutic targets to facilitate effective intervention. Long non-coding RNAs (lncRNA) are a class of non-protein coding transcripts longer than 200 nucleotides frequently dysregulated in various cancer types, which have multiple functions in widespread biological processes, including proliferation, apoptosis, metastasis, and metabolism. lncRNAs are involved in regulation of the tumor microenvironment and reciprocal signaling between cancer cells. Targeting of components of the tumor microenvironment or cancer cells has become a considerable focus of therapeutic research and establishing the effects of different lncRNAs on this network should aid in the development of effective treatment strategies. The current review provides a summary of the essential properties and functional roles of known lncRNAs associated with the tumor microenvironment in HCC.

Comparative outcomes of femtosecond laser-assisted cataract surgery and manual phacoemusification: a six-month follow-up.

BACKGROUND: To explore efficacy and safety outcomes in patients undergoing femtosecond laser-assisted cataract surgery (FLACS) versus manual phacoemulsification cataract surgery (PCS). DESIGN: Prospective consecutive nonrandomized comparative cohort study. PARTICIPANTS: A total of 124 eyes from 106 patients (70 in FLACS and 54 in PCS). METHODS: Comparison of FLACS with PCS over 6 months. MAIN OUTCOME MEASURES: Macular central subfield thickness (CST), cube volume (CV), cube average thickness (CAT), endothelial cell density (ECD), central corneal thickness (CCT) and photon count value (PCV). RESULTS: CST, CV and CAT increased postoperatively, which did not return to preoperative levels by 6 months. The values were similar between groups throughout the follow-up, and comparison of changes from baseline also showed no significant difference. Preoperative ECD showed significant difference, which decreased postoperatively and remained stable during follow-up, being lowest at 1 month. FLACS had greater endothelial cell loss than PCS, which was not significant. CCT in both groups increased, reaching maximum on day one and tended to decrease thereafter. No significant differences were found regarding postoperative values and the mean increase. In both groups, mean PCV increased from preoperatively to day one, week one and month one. Flare values in FLACS were lower than PCS, reaching statistical significance at 6 months (P = 0.001). However, the differences in changes of PCV were not significantly different at any visit. CONCLUSIONS: Both FLACS and PCS achieved similar safety and efficacy outcomes for performing cataract surgery. Flare values in eyes with FLACS were lower than those with PCS at 6 months postoperatively.

Repression of microRNA-130b by thyroid hormone enhances cell motility.

BACKGROUND & AIMS: Thyroid hormone (T3) and its receptor (TR) are involved in cell growth and cancer progression. Although deregulation of microRNA (miRNA) expression has been detected in many tumor types, the mechanisms underlying functional impairment and specific involvement of miRNAs in tumor metastasis remain unclear. In the current study, we aimed to elucidate the involvement of deregulated miRNA-130b (miR-130b) and its target genes mediated by T3/TR in cancer progression. METHODS: Quantitative reverse transcription-PCR, luciferase and chromatin immunoprecipitation assays were performed to identify the miR-130b transcript and the mechanisms implicated in its regulation. The effects of miR-130b on hepatocellular carcinoma (HCC) invasion were further examined in vitro and in vivo. Clinical correlations among miR-130b, TRs and interferon regulatory factor 1 (IRF1) were examined in HCC samples using Spearman correlation analysis. RESULTS: Our experiments disclosed negative regulation of miR-130b expression by T3/TR. Overexpression of miR-130b led to marked inhibition of cell migration and invasion, which was mediated via suppression of IRF1. Cell migration ability was promoted by T3, but partially suppressed upon miR-130b overexpression. Furthermore, miR-130b suppressed expression of epithelial-mesenchymal transition (EMT)-related genes, matrix metalloproteinase-9, phosphorylated mammalian target of rapamycin (mTOR), p-ERK1/2, p-AKT and p-signal transducer and activator of transcription (STAT)-3. Notably, miR-130b was downregulated in hepatoma samples and its expression patterns were inversely correlated with those of TRα1 and IRF1. CONCLUSIONS: Our data collectively highlight a novel pathway interlinking T3/TR, miR-130b, IRF1, the EMT-related genes, p-mTOR, p-STAT3 and the p-AKT cascade, which regulates the motility and invasion of hepatoma cells.

A novel phenotype-genotype correlation with an Arg555Trp mutation of TGFBI gene in Thiel-Behnke corneal dystrophy in a Chinese pedigree.

BACKGROUND: To investigate the molecular defects in a four-generation Chinese pedigree affected with Thiel-Behnke corneal dystrophy (TBCD). And to further study the relationship between genetic mutation and clinical manifestations. METHODS: Individuals of the pedigree were recruited for extensive ophthalmic examinations. Histological studies of two corneal buttons obtained from lamellar keratoplasty were conducted. Peripheral blood was collected in EDTA for genomic DNA isolation from leukocytes of all affected and unaffected members. All 17 exons of the TGFBI gene were screened for mutations by polymerase chain reaction and direct DNA sequencing. RESULTS: Clinical examinations revealed a typical pattern of honeycomb-like TBCD. Histopathology study demonstrated eosinophilic deposits that were congo-red-positive and did not stain with periodic acid Schiff or Masson's trichrome. Genetic analysis disclosed a heterozygous p. Arg555Trp mutation resulted from a missense c. 1663C > T nucleotide change in exon 12 of TGFBI gene in all affected members. Morever, a second rare variant in exon 6 of the TGFBI gene (p. Arg257Trp) also cosegregated within this family and has been confirmed to be a single nucleotide polymorphism (SNP) not previously reported. CONCLUSIONS: The p. Arg555Trp mutation of the TGFBI gene was associated with TBCD, which revealed a novel phenotype-genotype correlation within the mutational spectrum of phenotypically diverse corneal dystrophies.

Re-considering and designing microbiomes for future waste biorefinery.

It is an increasingly promising research direction using microbiomes to produce various chemicals in order to support people's growing need for sustainability. Currently, bottom-up constructed defined microbiomes and top-down constructed undefined microbiomes play an essential role in the fields of synthetic biology and environmental engineering, respectively. However, if we are goal-oriented and want to align scientific principles with technology and engineering in future waste biorefinery, we need to reconsider and design microbiomes interdisciplinarily. In this editorial, we briefly review the latest applications of two approaches to microbiome design (bottom-up and top-down) and the dilemmas faced in using complex waste. Consequently, we introduce the concept of 'sustainable synthetic microbiomics' to apply combined bottom-up and top-down constructed microbiomes to provide products for human needs from low-value waste. Furthermore, we outline the relatively comprehensive research contents and expected prospects based on the pressing problems. Finally, burning questions on key research contents are proposed for specific cases, hoping to provide valuable views for future microbiome biorefinery.

The Influence of Erbium Laser Pretreatment on Dentin Shear Bond Strength and Bond Failure Modes: A Systematic Review and Network Meta-Analysis.

PURPOSE: To systematically review in-vitro studies that evaluated the influence of erbium laser pretreatment on dentin shear bond strength (SBS) and bond failure modes. MATERIALS AND METHODS: Electronic databases (PubMed, Cochrane Central, Embase, and Web of Science) were searched. Only in-vitro studies involving erbium laser irradiation of the dentin surface and SBS testing of the bonded resin block were included. The three common modes of bond failure (1. adhesive, 2. cohesive, and 3. mixed) were observed and analyzed. The network meta-analysis (NMA) was performed by Stata 15.0 software, the risk of bias was evaluated, and the certainty of the evidence was assessed by the Confidence in Network Meta-analysis (CINeMA). RESULTS: Forty studies with nine pretreatments (1. blank group: BL; 2. phosphoric acid etch-and-rinse: ER; 3. self-etch adhesive: SE; 4. Er:YAG laser: EL; 5. Er,Cr:YSGG laser: ECL; 6. ER+EL; 7. ER+ECL; 8. SE+EL; 9. SE+ECL) were included in this analysis. The NMA of SBS showed that ER+EL [SMD = 0.32, 95% CI (0.11, 0.98)] had the highest SBS next to ER, especially when using one of the 3M ESPE adhesives, followed by EL, ECL, SE and SE+EL. The Ivoclar Vivadent adhesives significantly increased the SBS of the ECL [SMD = 0.37, 95% CI (0.16,0.90)] and was higher than ER+EL [SMD = 0.25,95% CI (0.07,0.85)]. Finally, the surface under the cumulative ranking curve (SUCRA) value indicated that ER+EL (SUCRA = 71.0%) and EL (SUCRA = 62.9%) were the best treatments for enhancing dentin SBS besides ER. ER+EL (SUCRA = 85.3%), ER (SUCRA = 83.7%) and ER (SUCRA = 84.3%) had the highest probability of occurring in adhesive, cohesive and mixed failure modes, respectively. CONCLUSION: Er:YAG and Er,Cr:YSGG lasers improved dentin SBS compared to the blank group, especially when the acid etch-and-rinse pretreatment was combined with Er:YAG laser. Shear bond strength and failure mode do not appear to be directly related.

Regulation of YAP and Wnt signaling by the endosomal protein MAMDC4.

Maintenance of the intestinal epithelium requires constant self-renewal and regeneration. Tight regulation of proliferation and differentiation of intestinal stem cells within the crypt region is critical to maintaining homeostasis. The transcriptional co-factors ß-catenin and YAP are required for proliferation during normal homeostasis as well as intestinal regeneration after injury: aberrant signaling activity results in over proliferation and tumorigenesis. Although both YAP and ß-catenin activity are controlled along canonical pathways, it is becoming increasingly clear that non-canonical regulation of these transcriptional regulators plays a role in fine tuning their activity. We have shown previously that MAMDC4 (Endotubin, AEGP), an integral membrane protein present in endosomes, regulates both YAP and ß-catenin activity in kidney epithelial cells and in the developing intestinal epithelium. Here we show that MAMDC4 interacts with members of the signalosome and mediates cross-talk between YAP and ß-catenin. Interestingly, this cross-talk occurs through a non-canonical pathway involving interactions between AMOT:YAP and AMOT:ß-catenin.

The role of oxidative stress biomarkers in the development of peri-implant disease: A systematic review and meta-analysis.

OBJECTIVES: To analyze the role of oxidative stress (OS) biomarkers in peri­implant diseases using a systematic review and meta-analysis approach. DATE: The review incorporated cross-sectional studies, randomized controlled trials, and case-control trials to evaluate the differences in OS biomarkers of peri­implant disease. SOURCES: A comprehensive literature search was conducted in electronic databases such as PubMed, Scopus, Embase, Web of Science, and CNKI, and no restrictions were applied during the search process. STUDY SELECTION: A total of 452 studies were identified, of which 18 were eligible for inclusion. Risk of bias and sensitivity analysis were assessed using Egger's test and funnel plots. RESULTS: We found that the levels of glutathione peroxidase (GSH-Px) in the peri­implant sulcus fluid (PISF) of patients with peri­implant diseases were significantly reduced (SMD = -1.40; 95 % CI = 1.70, -1.11; p < 0.001), while the levels of total myeloperoxidase (MPO) and malondialdehyde (MDA) were significantly increased (SMD = 0.46; 95 % CI = 0.12, 0.80; p = 0.008; SMD = 0.28; 95 % CI = 0.01, 0.56; p = 0.043). However, there were no significant differences of MPO concentration (SMD = 0.38; 95 % CI = -0.39, 1.15; p = 0.331) and superoxide dismutase (SOD)(SMD = -0.43; 95 % CI = -1.94, 1.07; p = 0.572) in PISF between peri­implant disease group and control group. Similarly, salivary MPO did not show significant differences (SMD = 1.62; 95 % CI = -1.01, 4.24; p = 0.227). CONCLUSIONS: Our results supported that the level of local OS biomarkers was closely related to peri­implant diseases. GSH-Px, total MPO and MDA may be PISF biomarkers with good capability to monitor the development of peri­implant disease. CLINICAL SIGNIFICANCE: This study found significant differences in the levels of local OS biomarkers (GSH-Px, total MPO, and MDA) between patients with peri­implant diseases and healthy subjects, which may be ideal candidate biomarkers for predicting and diagnosing peri­implant diseases.

Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy.

The immune checkpoint TIGIT/PVR blockade exhibits significant antitumor effects through activation of NK and CD8+ T cell-mediated cytotoxicity. Immune checkpoint blockade (ICB) could induce tumor ferroptosis through IFN-γ released by immune cells, indicating the synergetic effects of ICB with ferroptosis in inhibiting tumor growth. However, the development of TIGIT/PVR inhibitors with ferroptosis-inducing effects has not been explored yet. In this study, the small molecule Hemin that could bind with TIGIT to block TIGIT/PVR interaction was screened by virtual molecular docking and cell-based blocking assay. Hemin could effectively restore the IL-2 secretion from Jurkat-hTIGIT cells. Hemin reinvigorated the function of CD8+ T cells to secrete IFN-γ and the elevated IFN-γ could synergize with Hemin to induce ferroptosis in tumor cells. Hemin inhibited tumor growth by boosting CD8+ T cell immune response and inducing ferroptosis in CT26 tumor model. More importantly, Hemin in combination with PD-1/PD-L1 blockade exhibited more effective antitumor efficacy in anti-PD-1 resistant B16 tumor model. In summary, our finding indicated that Hemin blocked TIGIT/PVR interaction and induced tumor cell ferroptosis, which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies.

Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.

NorMASS: A normative MAS-based modeling approach for simulating incentive mechanisms of Q&A communities.

Incentive mechanisms steer users in Q&A communities to achieve community goals, which need to be cautiously reviewed and revised before actual industrial application. Simulating incentive mechanisms is significant for predicting how changes in incentive mechanisms will affect community emergence, such as user answering patterns. However, due to the complexity of Q&A communities, the challenge faced by simulating incentive mechanisms lies in the difficulty of establishing micro-macro connections in the communities to simulate their emergence. To fill this gap, this paper proposes a Normative Multi-Agent System based Simulation (NorMASS) approach to simulate community emergence. The NorMASS models a Q&A community as a normative multi-agent system and adopts agents to formally express community users. Moreover, the approach provides an open-source simulator with a data generator to simulate community emergence. An evaluation of the NorMASS comparing simulation emergence with the counterpart of an actual community demonstrates that the proposed approach provides an effective solution for simulating incentive mechanisms of Q&A communities, with a similarity of 80% or above.