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Both Bactrocera minax and Bactrocera dorsalis are phytophagous insects, and their larvae are latent feeders, which cause great damage and economic losses to agriculture production and trade. This study aimed to provide a scientific reference for researching and developing the feasible countermeasures against these two pests. Based on the distribution data of B. minax and B. dorsalis in China, obtained from the Chinese herbaria, investigation and literature. Four niche models (Garp, Bioclim, Domain, and Maxent) were used to analyze the key environmental factors affecting the distribution of both pests and to build prediction models of the potential distribution in Sichuan Basin. Combined with two statistical standards, area under the receiver operating characteristic curve (AUC) and Kappa, the validity of prediction models were analyzed and compared. The results show that: the average AUC values of the four models are all above 0.90, and the average Kappa values are all above 0.75, indicating that the four models are suitable for predicting the potential distribution area of B. minax and B. dorsalis. The annual range of temperature, the mean temperature in the driest quarter, the mean temperature in the warmest quarter, the annual precipitation, and the precipitation in driest month are the key environmental factors affecting the distribution of B. minax, while the mean diurnal temperature range, the mean temperature in the driest quarter, the seasonal temperature variations and the precipitation in driest month affect the potential distribution of B. dorsalis. The suitable areas for B. minax are mainly concentrated in the eastern of Sichuan Basin, while the suitable areas for B. dorsalis are concentrated in the southeastern. Except for the Bioclim model, the highly-suitable area for both pests predicted by the other three models are all greater than 15.94 × 104 km2 and the moderately-suitable areas are greater than 13.57 × 104 km2. In conclusion, the suitable areas for both pests in Sichuan Basin are quite wide. Therefore, the relevant authorities should be given strengthened monitoring of both pests, especially in areas with high incursion rates.

Abstract In a previously published clinical trial, we demonstrated that tirofiban was effective and safe in acute ischemic stroke (AIS) patients who did not undergo early recanalization treatments. We aimed to evaluate neuroimaging characteristics and their clinical significance to guide tirofiban treatment. In this post hoc analysis, location of infarcts (anterior circulation stroke [ACS] vs. posterior circulation stroke [PCS]), degree of cerebral artery stenosis (≤69% vs. ≥70% or occlusion), total infarct volume, and ASPECTS were used to predict the treatment effects of tirofiban, defined as the proportions of excellent and favorable functional outcome (modified Rankin Scale [mRS] score of 0–1, 0–2) at 90 days. ACS patients were more likely to achieve excellent (OR 2.08; 95% CI 1.25–3.45; p = 0.004) and favorable functional outcome (OR 2.28; 95% CI 1.24–4.22; p = 0.008) when treated with tirofiban. However, there was no significant difference in PCS patients between tirofiban and the control group. For patients with severe stenosis (≥70% or occlusion), tirofiban treatment improved the proportion of good outcomes (OR 2.84; 95% CI 1.44–5.60; p = 0.002 for mRS 0–1; OR 2.42; 95% CI 1.22–4.77; p = 0.011 for mRS 0–2). Meanwhile, we found that tirofiban improved outcome in patients with ASPECTS 8–10 and was independent of total infarct volume. These findings support the hypothesis that patients with ACS and severe stenosis may be recommended for tirofiban treatment, which can be predicted independent of total infarct volume.

With the rapid development of electronic technology and information technology, personal computer has gradually become the public's office or entertainment tools, which also makes the computer mouse a widely used tool. However, most computer mouse on the market today come with batteries. In this context, it is necessary to design a batteryless mouse that without using power supply such as battery. In view of such demand, on the basic of theoretical analysis, this paper summarizes and designs a classical wireless transmission structure – magnetic resonant coupling and antenna that used to transmit and received power for communication devices. In order to understand the operation of wireless power transmission technology, the paper analysed antenna construction and wireless power transmission technology. The basic design parameters of the axial mode helical antenna structure are also explained. Finally, by using CST STUDIO software, axial mode helical antenna with gain of 6.45 dBi was obtained. The system's output voltage is successfully simulated at 1.516 V that can powered up the computer mouse.

Advanced knowledge of glacier ice volume is vital for water resource assessment. Previous studies have focused on the estimation of ice volume, but the quantitative understanding of the spatial variability of ice volume across High Mountain regions is currently lacking. Here, we used global-scale ice thickness, debris cover and equilibrium line data to analyse ice-volume differences at various scales across High Mountain Asia (HMA). The results showed that 6.3% of the HMA glaciers are covered by debris, with debris area and volume accounting for 9% and 13.8% of the total glacier area and volume, respectively. An average debris-cover volume ratio of 13% was observed. The spatial distribution of ice volume across the HMA varies considerably from region to region. The ice volume is predominately distributed on north-facing slopes and accounts for approximately 38% of the total. It is very common in Altay and Sayan, East Tian Shan, West Kunlun, East Kunlun and Qilian Shan. Meanwhile, ice volumes in the Himalayas and Hengduan Shan are mainly distributed on the southeast aspect. Relative weight functions showed that glacier area, maximum length and average thickness are closely related to ice volume, with average relative weights of 63.7%, 22.5% and 9.8%, respectively. This study is important for the evolution of glacier volume and water resource assessment.

Objective Distal clavicle fracture classification directly affects the treatment decisions. It is unclear whether the classification systems implemented differ depending on surgeons' backgrounds. This study aimed to compare the interobserver agreement of four classification systems used for lateral clavicle fractures by shoulder specialists and general trauma surgeons. Methods Radiographs of 20 lateral clavicle fractures representing a full spectrum of adult fracture patterns were analyzed by eight experienced shoulder specialists and eight general trauma surgeons from 10 different hospitals. All cases were graded according to the Orthopedic Trauma Association (OTA), Neer, Jäger/Breitner, and Gongji classification systems. To measure observer agreement, Fleiss' kappa coefficient (κ) was applied and assessed. Results When only X‐ray films were presented, both groups achieved fair agreement. However, when the 3D‐CT scan images were provided, improved interobserver agreement was found in the specialist group when the OTA, Jäger/Breitner, and Gongji classification systems were used. In the generalist groups, improved agreement was found when using the Gongji classification system. In terms of interobserver reliability, the OTA, Neer, and Jäger/Breitner classification systems showed better agreement among shoulder specialists, while a slightly lower level of agreement was found using the Gongji classification system. For the OTA classification system, interobserver agreement had a mean kappa value of 0.418, ranging from 0.446 (specialist group) to 0.402 (generalist group). For the Neer classification system, interobserver agreement had a mean kappa value of 0.368, ranging from 0.402 (specialist group) to 0.390 (generalist group). For the Jäger/Breitner classification system, the inter‐observer agreement had a mean kappa value of 0.380, ranging from 0.413 (specialist group) to 0.404 (generalist group). For the Gongji classification system, interobserver agreement had a mean kappa value of 0.455, ranging from 0.480 (specialist group) to 0.485 (generalist group). Conclusion Generally speaking, 3D‐CT scans provide a richer experience that can lead to better results in most classification systems of lateral clavicle fractures, highlighting the value of digitization and specialization in diagnosis and treatment. Competitive interobserver agreement was exhibited in the generalist group using the Gongji classification system, suggesting that the Gongji classification is suitable for general trauma surgeons who are not highly experienced in the shoulder field.

Objective Open arthrolysis (OA) combined with hinged external fixator (HEF) is a promising surgical option for patients with elbow stiffness. This study aimed to investigate elbow kinematics and function following a combined treatment with OA and HEF in elbow stiffness cases. Methods Patients treated with OA with or without HEF due to elbow stiffness were recruited between August 2017 and July 2019. Elbow flexion‐extension motion and function (Mayo elbow performance scores, MEPS) were recorded and compared between patients with and without HEF during a 1‐year follow‐up period. Additionally, those with HEF were assessed by dual fluoroscopy at week 6 postoperatively. Flexion‐extension and varus‐valgus motions, as well as ligament insertion distances of the anterior medial collateral ligament (AMCL) and lateral ulnar collateral ligament (LUCL), were compared between the surgical and intact sides. Results This study included 42 patients, of which 12 with HEF demonstrated a similar flexion‐extension angle and range of motion (ROM) and MEPS as the other patients. In patients with HEF, the surgical elbows showed limitations in flexion‐extension (maximal flexion, 120.5° ± 5.3° vs 140.4° ± 6.8°; maximal extension, 13.1° ± 6.0° vs 6.4° ± 3.0°; ROM, 107.4° ± 9.9° vs 134.0° ± 6.8°; all Ps

Abstract Macrophages play an important role in the development of life-threatening sepsis, which is characterized by multiorgan dysfunction, through their ability to produce inflammatory cytokines. Carvacrol is a phenolic compound that has been confirmed to possess strong anti‑inflammatory activity. In this study, we mainly investigated the effect of carvacrol on lipopolysaccharide (LPS)-induced macrophage proinflammatory responses and endotoxic shock. The results showed that carvacrol significantly reduced mouse body weight loss and ameliorated pathological damage to the liver, lung, and heart under LPS-induced sepsis. Carvacrol attenuated inflammatory responses by inhibiting the LPS-induced production of inflammatory cytokine interleukin-6 (IL-6) in vivo and in vitro. Mechanistically, carvacrol inhibited IL-6 production mainly through the ERK1/2 signalling pathway in macrophages. Furthermore, carvacrol improved the survival of septic mice. This study sheds light on the role of carvacrol in the pathogenesis of LPS-induced sepsis, and thus, its potential in treating sepsis patients may be considered.

With the development of posterior chamber phakic intraocular lenses implantation and the constant improvement of the implantable collamer lens(ICL), ICL V4c implantation has become one of the main methods for correcting moderate and high myopia. Vault is an important indicator to evaluate the security of posterior chamber intraocular lens implantation. In recent years, optimizing surgical procedures to obtain the ideal vault in ICL V4c implantation surgery has become a research hotspot. This paper aims to provide help for improving surgical safety by summarizing and analyzing the optimized programs of ICL V4c implantation surgery. The focus will be on preoperative examination, intraoperative surgical design, and postoperative follow-up.

Abstract The type of reactions and the availability of monomers for the synthesis of sp 2 -c linked covalent organic frameworks (COFs) are considerably limited by the irreversibility of the C=C bond. Herein, inspired by the Claisen-Schmidt condensation reaction, two propenone-linked (C=C–C=O) COFs (named Py-DAB and PyN-DAB) are developed based on the base-catalyzed nucleophilic addition reaction of ketone-activated α-H with aromatic aldehydes. The introduction of propenone structure endows COFs with high crystallinity, excellent physicochemical stability, and intriguing optoelectronic properties. Benefitting from the rational design on the COFs skeleton, Py-DAB and PyN-DAB are applied to the extraction of radionuclide uranium. In particular, PyN-DAB shows excellent removal rates (>98%) in four uranium mine wastewater samples. We highlight that such a general strategy can provide a valuable avenue toward various functional porous crystalline materials.

IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

Alport syndrome (AS) is one of the important causes of chronic kidney disease and end-stage renal disease. It is the second most common inherited kidney disease after autosomal dominant polycystic kidney disease. Autosomal dominant inheritance is a very rare mode of inheritance in AS, and patients with autosomal dominant forms of AS (ADAS) were previously reported to progress to end-stage renal disease at a later age. This article reported a patient who was diagnosed with ADAS in the Pediatric Nephrology Department of the First Affiliated Hospital of Henan University of CM on September 5, 2019 because of abnormal urine test findings for 4 years. The clinical data and genetic test results were reviewed. We reported the clinical, renal pathology and gene mutation of a ADAS family caused by the new mutation c.3506-3528del (p.G1169Efs*13) of COL4A4 gene (One family member developed end-stage renal disease at the age of 31). We also summarized the literature reports of Chinese ADAS, and made a comprehensive analysis of the relationship between the gene, clinical phenotype and prognosis of the disease. Due to the low incidence of ADAS, this family report expands the gene mutation spectrum of AS, and helps to improve clinicians' awareness and timely diagnosis and treatment of rare-onset ADAS.

Abstract Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20–25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-β1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.

Abstract Background Gastric cancer is the third leading cause of death from cancer worldwide and has a poor prognosis. Practical risk scores and prognostic models for gastric cancer are lacking. While immunotherapy has succeeded in some cancers, few gastric cancer patients benefit from immunotherapy. Immune genes and the tumor microenvironment (TME) are essential for cancer progression and immunotherapy response. However, the roles of immune genes and the tumor microenvironment in immunotherapy remain unclear. The study aimed to construct a prognostic prediction model and identify immunotherapeutic targets for gastric cancer (GC) patients by exploring immune genes and the tumor microenvironment. Results An immune-related risk score (IRRS) model, including APOH, RNASE2, F2R, DEFB126, CXCL6, and CXCL3 genes, was constructed for risk stratification. Patients in the low-risk group, which was characterized by elevated tumor mutation burden (TMB) have higher survival rate. The risk level was remarkably correlated with tumor-infiltrating immune cells (TIICs), the immune checkpoint molecule expression, and immunophenoscore (IPS). CXCL3 and CXCL6 were significantly upregulated in gastric cancer tissues compared with normal tissues using the UALCAN database and RT-qPCR. The nomogram showed good calibration and moderate discrimination in predicting overall survival (OS) at 1-, 3-, and 5- year for gastric cancer patients using risk-level and clinical characteristics. Conclusion Our findings provided a risk stratification and prognosis prediction tool for gastric cancer patients and further the research into immunotherapy in gastric cancer.

Abstract Background Lung cross-section is one of the emphases and challenges in sectional anatomy. Identification of the complex arrangement of intrapulmonary tubes such as bronchi, arteries, and veins in the lungs requires the spatial imagination of students. Three-dimensional (3D) printing has become increasingly used in anatomy education. This study aimed to analyze the effectiveness of 3D-printed specimens used for the experimental teaching of sectional anatomy. Methods A digital thoracic dataset was obtained and input into a 3D printer to print multicolor specimens of the pulmonary segment after software processing. As research subjects, 119 undergraduate students majoring in medical imaging from classes 5–8 in the second-year were chosen. In the lung cross-section experiment course, 59 students utilized 3D printed specimens in conjunction with traditional instruction as the study group, while 60 students received traditional teaching as the control group. Preclass and postclass tests, course grading, and questionnaire surveys were used to assess instructional efficacy. Results We obtained a set of pulmonary segment specimens for teaching. The students in the study group scored better in the postclass test than those in the control group (P

Abstract Phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma (ESCC). It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kα inhibitors in an aim to improve the clinical responsive rate in ESCC. Here, ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33, a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC. Elevated level of cyclin D1, p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells. CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase, which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2. Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1, which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21. Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

BackgroundClonorchis sinensis (C. sinensis) is a epidemiologically significant food-borne parasite, causing several hepatobiliary diseases. Biliary microbiota community structure might be influenced by infection with pathogens. However, the biliary microbiome of biliary obstruction patients infected with C. sinensis is still an unexplored aspect.MethodsA total of 50 biliary obstruction patients were enrolled, including 24 infected with C. sinensis and 26 non-infected subjects. The bile samples were collected by Endoscopic Retrograde Cholangiopancretography. Biliary microbiota alteration was analyzed through high-throughput 16S ribosomal RNA (rRNA) gene sequencing.ResultsOur findings revealed that there was significant increase in both richness and diversity, as well as changes in the taxonomic composition of the biliary microbiota of C. sinensis infected patients. At the phylum level, C. sinensis infection induced Proteobacteria increased and Firmicutes reduced. At the genus level, the relative abundance of Pseudomonas and Staphylococcus increased significantly, while Enterococcus decreased prominently in infected groups (P < 0.05). The PICRUSt analysis further showed remarkably different metabolic pathways between the two groups.ConclusionC. sinensis infection could modify the biliary microbiota, increasing the abundance and changing the phylogenetic composition of bacterial in biliary obstruction patients. This study may help deepen the understanding of the host-biliary microbiota interplay with C. sinensis infection on the background of biliary obstruction and provide new insights into understanding the pathogenesis of clonorchiasis.

Cell therapy is an important topic in the field of regeneration medicine that is gaining attention within the scientific community. However, its potential for treatment in coronary heart disease (CHD) has yet to be established. Several various strategies, types of cells, routes of distribution, and supporting procedures have been tried and refined to trigger heart rejuvenation in CHD. However, only a few of them result in a real considerable promise for clinical usage. In this review, we give an update on techniques and clinical studies of cell treatment as used to cure CHD that are now ongoing or have been completed in the previous five years. We also highlight the emerging efficacy of stem cell treatment for CHD. We specifically examine and comment on current breakthroughs in cell treatment applied to CHD, including the most effective types of cells, transport modalities, engineering, and biochemical approaches used in this context. We believe the current review will be helpful for the researcher to distill this information and design future studies to overcome the challenges faced by this revolutionary approach for CHD.

ABSTRACTT cell Receptor (TCR) Fusion Construct (TRuC®) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BBζ CAR-T cells (MSLN-BBζ CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BBζ CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.

Two data-driven machine learning (ML) models were proposed for the hardness prediction of high-entropy alloys (HEA) and the composition optimization of high hardness HEAs, respectively. The hardness prediction model combined interpretable ML methods with solid solution strengthening theory, and the R2 and RMSE values of 0.9716 and 39.2525 were respectively achieved under the leave-one-out validation method. The optimization model adopted an intelligent optimization algorithm to design the optimized elemental molar ratios of high hardness HEAs and was experimentally verified. A general design framework was summarized for prediction and composition optimization of various HEA performances.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

Abstract Background Stimulator of interferon genes (STING) has emerged as a crucial and promising target in tumor immunotherapy in recent years. Its agonists play a vital role in activating both innate and adaptive immune responses to combat cancer. Currently, STING agonists are primarily administered through intratumoral or intravenous injection, with only a few could be administered by orally. Therefore, orally available STING agonists are urgently needed to be developed. Approach and results Based on previous structure‐activity relationship (SAR) studies, we made a structure modification to MSA‐2 by replacing the carbonyl group with a difluoromethylene to get a new compound 202 (C202) that exhibited better plasma exposure and oral bioavailability than MSA‐2. Thus, we conducted extensive pharmacological evaluations to understand its effects. C202 demonstrated the ability to activate various human STING isoforms and murine STING protein, showcasing a potent and specific activation of the STING signalling pathway at cellular level. In diverse immunocompetent mouse models representing both ‘cold’ and ‘hot’ tumors, C202, whether administered intratumorally or orally, displayed broad‐spectrum anti‐tumor activity. Encouragingly, it induced complete tumor regression in several tumor models of mice and stimulated immune memory effects, contributing to long‐term immune response against cancer. Additionally, our investigations into the impact of C202 on the tumor microenvironment found that it enhanced the anti‐tumor response of both innate and adaptive immune systems, bolstering the immune‐mediated fight against tumors. Furthermore, we made an intriguing observation regarding C202's synergistic effects. It was found to enhance the anti‐tumor activity of chemotherapy drug gemcitabine and the angiogenesis inhibitor AL3810, which provide potential combination therapies in future translational studies. Conclusions Our research highlights C202 as a novel STING agonist with durable anti‐tumor activity that can be administered orally, presenting a promising candidate for cancer immunotherapy.

Abstract Cellular senescence plays a pivotal role in wound healing. At the initiation of liver fibrosis regression, accumulated senescent cells were detected and genes of senescence were upregulated. Flow cytometry combined with single‐cell RNA sequencing analyses revealed that most of senescent cells were liver nonparenchymal cells. Removing senescent cells by dasatinib and quercetin (DQ), alleviated hepatic cellular senescence, impeded fibrosis regression, and disrupted liver sinusoids. Clearance of senescent cells not only decreased senescent macrophages but also shrank the proportion of anti‐inflammatory M2 macrophages through apoptotic pathway. Subsequently, macrophages were depleted by clodronate, which diminished hepatic senescent cells and impaired fibrosis regression. Mechanistically, the change of the epigenetic regulator enhancer of zeste homolog2 (EZH2) accompanied with the emergence of hepatic senescent cells while liver fibrosis regressed. Blocking EZH2 signaling by EPZ6438 reduced hepatic senescent cells and macrophages, decelerating liver fibrosis regression. Moreover, the promoter region of EZH2 was transcriptionally suppressed by Notch‐Hes1 (hairy and enhancer of split 1) signaling. Disruption of Notch in macrophages using Lyz2 (lysozyme 2) Cre‐RBP‐J (recombination signal binding protein Jκ) f/f transgenic mice, enhanced hepatic cellular senescence, and facilitated fibrosis regression by upregulating EZH2 and blocking EZH2 abrogated the above effects caused by Notch deficiency. Ultimately, adopting Notch inhibitor Ly3039478 or exosome‐mediated RBP‐J decoy oligodeoxynucleotides accelerated liver fibrosis regression by augmenting hepatic cellular senescence.