Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice.

BACKGROUND & AIMS: Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS: miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS: miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS: miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.

Performance of aerobic denitrifying fungal community for promoting nitrogen reduction and its application in drinking water reservoirs.

The effect of mix-cultured aerobic denitrifying microorganisms on the water remediation has been extensively explored, but little is known about the performance of mix-cultured low efficiency fungi on denitrification. In this study, two kinds of aerobic denitrifying fungi (Trichoderma afroharzianum H1 and Aspergillus niger C1) were isolated from reservoirs, improved the capacity by mix-cultured. The results showed a difference between northern and southern reservoirs, the dominants of genera were Cystobasidium and Acremonium. The removals of total nitrogen (TN) was 12.00%, 7.53% and 69.33% in Trichoderma afroharzianum H1, Aspergillus niger C1 and mix-cultured (C1 and H1) under the denitrification medium. The contents of ATP and electron transport system activity in mix-cultured amendment were increased by 42.54% and 67.52%, 1.72 and 2.91 times, respectively. Besides, the raw water experiment indicated that TN removals were 24.05%, 12.66% and 73.42% in Trichoderma afroharzianum H1, Aspergillus niger C1 and mix-cultured. The removals of dissolved organic carbon in mix-cultured were increased 35.02% and 50.46% compared to Trichoderma afroharzianum H1 and Aspergillus niger C1. Therefore, mix-cultured of two low efficiency aerobic denitrifying fungi has been considered as a novelty perspective for mitigation of drinking water source.

Homeobox A7 promotes esophageal squamous cell carcinoma progression through C-C motif chemokine ligand 2-mediated tumor-associated macrophage recruitment.

Homeobox A7 (HOXA7) plays essential roles in multiple malignancies and was reported to be overexpressed in esophageal squamous cell carcinoma (ESCC). However, its functions in the ESCC tumor microenvironment remain to be explored. In this study, we showed that HOXA7 was overexpressed in ESCC among HOXA family members and correlated with tumor-associated macrophage (TAM) infiltration both in The Cancer Genome Atlas database and ESCC clinical samples. Moreover, transactivation of C-C motif chemokine ligand 2 (CCL2) by HOXA7 was identified (real-time quantitative PCR [RT-qPCR], western blot analysis, ELISA, and ChIP-qPCR), which was detected to drive chemotaxis and M2 polarization of macrophages both in vitro (Transwell assay) and in vivo (xenograft tumors models). In addition, CCL2 triggers macrophage expression of epidermal growth factor (EGF) (RT-qPCR and ELISA), which promotes tumor proliferation and metastasis by activating its receptor EGFR. In addition, EGF-induced ESCC cell proliferation and migration can be abrogated by HOXA7 knockdown (CCK-8 proliferation assay, EdU fluorescence, and Transwell assay). These results indicate a novel mechanistic role of HOXA7 in the cross-talk between ESCC and TAMs, which could be an underlying therapeutic target for ESCC.

No-touch endoscopic full-thickness resection technique for gastric gastrointestinal stromal tumors.

BACKGROUND : There remain concerns regarding the technical feasibility of endoscopic resection for large gastrointestinal stromal tumors (GISTs), mainly relating to the risk of tumor rupture and the adequacy of the resection margins. This study aimed to evaluate the feasibility and therapeutic outcomes of the newly developed no-touch endoscopic full-thickness resection (NT-EFTR) technique for GISTs. METHODS : In this retrospective study, 92 patients with gastric GISTs undergoing NT-EFTR were included. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS : The median tumor size was 2.5 cm and en bloc resection was achieved in all patients with negative surgical margins. The median time of the NT-EFTR procedure was 59.5 minutes. Large tumors (> 3.0 cm), extraluminal tumor growth pattern, and large gastric defects were significant contributors to long operative times. Patients were discharged within 4 days postoperatively. During follow-up, all patients were free from local recurrence and distant metastasis. CONCLUSIONS : NT-EFTR was a feasible method for the resection of gastric GISTs and can be expected to achieve complete radical resection. Large tumors with extraluminal growth and large gastric defects impact procedural difficulty.

ETV5 overexpression promotes progression of esophageal squamous cell carcinoma by upregulating SKA1 and TRPV2.

Esophageal squamous cell carcinoma (ESCC) is notorious for the rapid progression especially early tumor metastasis due to the unclear mechanism. Recently, ETV5 attracts much attention for its potential role as an oncogenic transcription factor involved in multiple cancers. However, no one reported the mechanism behind the association between ETV5 expression and esophageal squamous cell carcinoma progression. In this study, we found that ETV5 was upregulated in ESCC both from online database and our ESCC tissues and ETV5 was associated with tumor staging and prognosis. Knockdown of ETV5 or its downstream genes SKA1 and TRPV2 significantly suppress ESCC cells migration and invasion, respectively. Additionally, in vivo study showed knockdown of ETV5 inhibited tumor metastasis. Further experiments unveiled ETV5 could transcriptionally upregulate the expression of SKA1 and TRPV2 and further activate MMPs in ESCC progression. In conclusion, ETV5 was associated with ESCC tumor staging and ESCC prognosis clinically. ETV5 promoted metastasis of ESCC by activating MMPs through augmenting the transcription of SKA1 and TRPV2. ETV5 was likely to be a novel oncogene and therapeutic target in ESCC.

Effect of allisartan on blood pressure and left ventricular hypertrophy through Kv1.5 channels in hypertensive rats.

BACKGROUND: The objective of the present work was to study the anti-hypertensive effect of allisartan on blood pressure (BP) and in facilitating left ventricular remodeling through voltage-gated potassium channels (Kv) 1.5 channels. METHODS: A total of 30 SD rats were randomly divided into sham operation group, hypertension control group, and allisartan treatment group. Hypertension was induced by renal artery stenosis. The animals of treatment group were administered with allisartan once a day at a dose of 30 mg/kg body weight through an oral gavage for 4 weeks. The heart function of animals post 4 weeks of treatment was evaluated by echocardiography, and the degree of ventricular hypertrophy and cardiomyocyte hypertrophy were evaluated by histomorphology. The expression of Kv1.5 is detected by real-time quantitative polymerase chain reaction while Western blotting was used to detect the protein expression. RESULTS: Four weeks after renal artery stenosis, a significant difference was observed in the whole heart ratio, left heart ratio, and cardiomyocyte area between allisartan treatment group and the hypertension control group (P< .01). A significant decrease in BP of allisartan treatment group compared to hypertension control group (P< .01) was observed. The expression of Kv1.5 mRNA was increased significantly (P< .01) in allisartan treatment group compared to hypertension control group. Western blot analysis also confirmed the increased expression of Kv1.5 channel. CONCLUSION: The results showed that allisartan lowers BP and improves left ventricular remodeling through increased expression of Kv1.5 mRNA.

Finite element comparative analysis of three different internal fixation methods in the treatment of Pauwels type III femoral neck fractures.

BACKGROUND: Comparison of 4 cannulated lag screws (3 inverted triangular cannulated screws + anti-rotating screws;4 CLS), dynamic hip screws + derotational screws (DHS + DS), and femoral neck fixation system (FNS) in the treatment of Biomechanical properties of middle-aged Pauwels type III femoral neck fractures. METHODS: The femur CT data of a healthy young volunteer was selected and imported into Mimics software to construct a three-dimensional model of a normal femur. Pauwels type III femoral neck fractures were simulated according to the 70° fracture line. Use Geomagic and SolidWorks software to optimize and build CLS, DHS + DS, and FNS fracture internal fixation models. Finally, Ansys software was used to analyze the stress distribution, peak value, and maximum displacement of the proximal fracture fragment and internal fixation; the displacement distribution, and peak value of the fracture surface at the fracture end. RESULTS: ① The stress peaks of the proximal fracture fragments in the three groups were concentrated near the femoral calcar. The peak stress of the FNS group was the largest, and the DHS + DS group was the smallest. ②The displacement of the fracture fragments was all located at the top of the femur. The peak displacement of the FNS group was the largest, and the DHS + DS group was the smallest. ③ The internal fixation stress of the three groups is concentrated in the middle part of the device. The stress distribution of the first two groups of models is more uniform than that of FNS. The peak stress of FNS is the largest and the CLS is the smallest. ④ The internal fixed displacements are all located at the top of the model. The peak displacement of the CLS is the largest, and the DHS + DS is the smallest. ⑤ The displacement of the fracture surface is in the upper part of the fractured end. The peak displacement of the FNS group was the largest, and the DHS + DS group was the smallest. CONCLUSION: Compared with the other two internal fixation methods, dynamic hip screw + derotational screw (DHS + DS) showed good biomechanical stability. When Pauwels type III femoral neck fracture occurs in young adults, DHS + DS can be given priority as the preferred treatment for this type of fracture.

Cow dung-derived biochars engineered as antibacterial agents for bacterial decontamination.

Disposal of the pollutants arising from farming cattle and other livestock threatens the environment and public safety in diverse ways. Herein, we report on the synthesis of engineered biochars using cow dung as raw material, and investigating these biochars as antibacterial agents for water decontamination. By coating the biochars with N-halamine polymer and loading them with active chlorine (i.e., Cl+), we were able to regulate them on demand by tuning the polymer coating and bleaching conditions. The obtained N-halamine-modified biochars were found to be extremely potent against Escherichia coli and Staphylococcus aureus. We also investigated the possibility of using these N-halamine-modified biochars for bacterial decontamination in real-world applications. Our findings indicated that a homemade filter column packed with N-halamine-modified biochars removed pathogenic bacteria from mining sewage, dairy sewage, domestic sewage, and artificial seawater. This proposed strategy could indicate a new way for utilizing livestock pollutants to create on-demand decontaminants.

Enhanced expression of asparagine synthetase under glucose-deprived conditions promotes esophageal squamous cell carcinoma development.

Background: Cancer cells survive and develop under nutrient deficient microenvironment caused by low blood supply. Although anaerobic metabolism could function through the enhanced uptake of glucose, other mechanisms of tolerance to glucose deficient conditions might be required. Materials and Methods: Expression of asparagine synthetase (ASNS) under normal glucose and glucose-deprived conditions was examined. Cancer cell proliferation and migration were evaluated by in vitro and in vivo assays. In addition, the relationship between ASNS expression and cancer stages was also analyzed. Results: Expression of ASNS was enhanced under glucose deficient conditions. In vitro assays indicated that ASNS could promote the proliferation and migration abilities of esophageal squamous cell carcinoma (ESCC) cells under glucose deficient condition. In mechanism, 2 critical effectors during nutrient deprivation, NRF2 and ATF4, were upregulated and demonstrated to promote ASNS expression. Clinically, high level of ASNS was significantly associated with ESCC with advanced stages and metastasis. In vivo, ASNS could promote tumor growth and metastasis in mouse xenograft models. Conclusion: This study uncovered that glucose deprivation induces the overexpression of ASNS in ESCC cells, which in turn causes cancer cell tolerance to nutrient stress and promotes cancer development. The illustration of the mechanism sheds deep insight on how cell biology was regulated in response to the conditions of limited nutrient availability.

Collectivism, face concern and Chinese-style lurking among university students: the moderating role of trait mindfulness.

Introduction: This study focuses on understanding the unique causes and mechanisms of "Chinese-style lurking" on WeChat among university students, within a cultural context that emphasizes collectivism and face concern. The research also looks into the moderating role of trait mindfulness. Methods: For the confirmation of these phenomena and to validate the theories, a structural equation model was constructed using the Stress-Strain-Outcome (SSO) theory and mindfulness buffering theory. The model was then tested and validated with data from 1,453 valid online surveys. These data were analyzed using the SmartPLS 4.0 software. Results: The results indicate that collectivism increases face concern, which in turn escalates online social anxiety. Face concern completely mediates between collectivism and online social anxiety, creating a serial mediation effect between face concern, online social anxiety, and lurking behavior. Additionally, trait mindfulness was found to negatively modulate the pathways from collectivism to face concern and from online social anxiety to lurking. Discussion: The findings underscore the influence of traditional Chinese culture on contemporary students' online behavior and provide a new perspective for understanding social media lurking in an Eastern context. The results suggest that a mindfulness-based approach could be used to mitigate the associated silence and anxiety.

STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is an aggressive disease with a poor prognosis, caused by the inactivation of critical cell growth regulators that lead to uncontrolled proliferation and increased malignancy. Although Serine/Threonine Kinase 3 (STK3), also known as Mammalian STE20-like protein kinase 2 (MST2), is a highly conserved kinase of the Hippo pathway, plays a critical role in immunomodulation, organ development, cellular differentiation, and cancer suppression, its phenotype and function in ESCC require further investigation. In this study, we report for the first time on the role of STK3 kinase and its activation condition in ESCC, as well as the mechanism and mediators of kinase activation. METHODS: In this study, we investigated the expression and clinical significance of STK3 in ESCC. We first used bioinformatics databases and immunohistochemistry to analyze STK3 expression in the ESCC patient cohort and conducted survival analysis. In vivo, we conducted a tumorigenicity assay using nude mouse models to demonstrate the phenotypes of STK3 kinase. In vitro, we conducted Western blot analysis, qPCR analysis, CO-IP, and immunofluorescence (IF) staining analysis to detect molecule expression, interaction, and distribution. We measured proliferation, migration, and apoptosis abilities in ESCC cells in the experimental groups using CCK-8 and transwell assays, flow cytometry, and EdU staining. We used RNA-seq to identify genes that were differentially expressed in ESCC cells with silenced STK3 or FOXO1. We demonstrated the regulatory relationship of the TP53INP1/P21 gene medicated by the STK3-FOXO1 axis using Western blotting and ChIP in vitro. RESULTS: We demonstrate high STK3 expression in ESCC tissue and cell lines compared to esophageal epithelium. Cellular ROS induces STK3 autophosphorylation in ESCC cells, resulting in upregulated p-STK3/4. STK3 activation inhibits ESCC cell proliferation and migration by triggering apoptosis and suppressing the cell cycle. STK3 kinase activation phosphorylates FOXO1Ser212, promoting nuclear translocation, enhancing transcriptional activity, and upregulating TP53INP1 and P21. We also investigated TP53INP1 and P21's phenotypic effects in ESCC, finding that their knockdown significantly increases tumor proliferation, highlighting their crucial role in ESCC tumorigenesis. CONCLUSION: STK3 kinase has a high expression level in ESCC and can be activated by cellular ROS, inhibiting cell proliferation and migration. Additionally, STK3 activation-mediated FOXO1 regulates ESCC cell apoptosis and cell cycle arrest by targeting TP53INP1/P21. Our research underscores the anti-tumor function of STK3 in ESCC and elucidates the mechanism underlying its anti-tumor effect on ESCC.

IGF-1-mediated FOXC1 overexpression induces stem-like properties through upregulating CBX7 and IGF-1R in esophageal squamous cell carcinoma.

Substantial evidence attests to the pivotal role of cancer stem cells (CSC) in both tumorigenesis and drug resistance. A member of the forkhead box (FOX) family, FOXC1, assumes significance in embryonic development and organogenesis. Furthermore, FOXC1 functions as an overexpressed transcription factor in various tumors, fostering proliferation, enhancing migratory capabilities, and promoting drug resistance, while maintaining stem-cell-like properties. Despite these implications, scant attention has been devoted to its role in esophageal squamous cell carcinoma. Our investigation revealed a pronounced upregulation of FOXC1 expression in ESCC, correlating with a poor prognosis. The downregulation of FOXC1 demonstrated inhibitory effects on ESCC tumorigenesis, proliferation, and tolerance to chemotherapeutic agents, concurrently reducing the levels of stemness-related markers CD133 and CD44. Further studies validated that FOXC1 induces ESCC stemness by transactivating CBX7 and IGF-1R. Additionally, IGF-1 activated the PI3K/AKT/NF-κB and MEK/ERK/NF-κB pathways through its binding to IGF-1R, thereby augmenting FOXC1 expression. Conversely, suppressing FOXC1 impeded ESCC stemness induced by IGF-1. The presence of a positive feedback loop, denoted by IGF-1-FOXC1-IGF-1R, suggests the potential of FOXC1 as a prognostic biomarker for ESCC. Taken together, targeting the IGF-1-FOXC1-IGF-1R axis emerges as a promising approach for anti-CSC therapy in ESCC.

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis.

Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3ß from the Wnt/ß-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven ß-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3ß, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.

Alcohol inducing macrophage M2b polarization in colitis by modulating the TRPV1-MAPK/NF-κB pathways.

BACKGROUND: Macrophages exhibit different phenotypes in inflammatory bowel disease (IBD) and promote inflammation or tissue repair depending on their polarization state. Alcohol is a widely used solvent in pharmaceutical formulations, and its consumption is associated with an increased risk of colitis; however, its effects on macrophages in IBD remain poorly understood. PURPOSE: This study aimed to investigate the effect of alcohol on macrophages in dextran sodium sulfate (DSS)-induced colitis and understand the underlying mechanisms. METHODS: DSS-treated C57BL/6 mice were exposed to varying concentrations of alcohol, transient receptor potential vanilloid 1 (TRPV1) antagonist, and 5-aminosalicylic acid. The distal colon was resected, fixed, stained, and histologically analyzed, through hematoxylin and eosin (H&E) staining and immunofluorescence staining. Ratio [Ca2+]i measurements, western blotting, quantitative polymerase chain reaction, cytokine measurements, and RNA sequencing analyses were also performed. Peritoneal macrophages and RAW264.7 cells were used for in vitro experiments, and various assays were performed to evaluate cellular responses, gene expression, and signaling pathways. RESULTS: Alcohol exacerbated DSS-treated mice colitis and promoted the secretion of various inflammatory cytokines from colonic macrophages. Alcohol enhances the calcium ion influx induced by lipopolysaccharide (LPS) in peritoneal macrophages, while the TRPV1 antagonist capsazepine (CPZ) inhibits LPS- and/or alcohol- induced calcium influx in macrophages. Alcohol and LPS activate the MAPK/P38, MAPK/ERK, and NF-κB signaling pathways and induce the macrophage M2b polarization, resulting in the increased expression level of inflammatory cytokines such as Tnf, Il1b, and Il10. Additionally, CPZ can inhibit the facilitatory effects of alcohol or LPS on the abovementioned pathways and inflammatory factors, reversing macrophage M2b polarization and promoting alcohol-induced colitis. The inhibition of nucleotide binding oligomerization domain containing 2 (NOD2) partially suppressed the alcohol and LPS effects on macrophages. CONCLUSION: Alcohol exacerbates experimental colitis and induces M2b polarization of macrophage via TRPV1-MAPK/NF-κB. Our study provides new insights into the potential therapeutic targets for IBD treatment by elucidating the role of TRPV1 in alcohol-exacerbated colitis, using CPZ as a potential therapeutic option. The identification of transient receptor potential ankyrin subtype 1 (TRPA1) as a therapeutic target expands the scope of future research.

The construction of a three-dimensional donor/acceptor interface based on a bilayered titanium dioxide nanorod array-flower for perovskite solar cells.

Recently, organic-inorganic hybrid perovskite solar cells have been considered as the new generation of photovoltaic devices due to their excellent performance. However, their finite interfacial stability limits their further commercialization. How to improve their stability is one of the important issues in current scientific research. Herein, a bilayered titanium dioxide nanorod array-flower (B-TiO2-NAF) was prepared as an electron transport material for hybrid perovskite solar cells in order to overcome this difficulty. A device based on B-TiO2-NAF exhibits an excellent power conversion efficiency (PCE) of 21.8% due to its low electron trap density (ntrap), low carrier recombination resistance (Rs), facilitated electron injection, and reduced nonradiative recombination rate. The application of B-TiO2-NAF provides a stable three-dimensional (3-D) D/A interface and shortens the internal photoexciton diffusion distance. As a result, the device shows excellent long-term stability, which is maintained at over 83% of the initial efficiency after 30 days. Our work should be beneficial for the preparation of 3-D semiconductor materials and provides new insights into highly stable perovskite solar cells.

Cost-effectiveness of camrelizumab combined with chemotherapy in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma in China.

OBJECTIVE: This study aimed to investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody camrelizumab to first-line platinum-doublet chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma (L/M NPC) from the perspective of Chinese healthcare system. DESIGN: A Markov model consisting of four health states, progression-free survival, first progression survival, second progression survival and death, was built to simulate 3-week patient transitions over a 20-year horizon. A direct comparison between first-line camrelizumab in combination with gemcitabine plus cisplatin and gemcitabine plus cisplatin was performed by calculating transition probabilities from the CAPTAIN-1st trial. Costs and utilities were collected from the local public database and literature. One-way and probabilistic sensitivity analyses were employed to evaluate the robustness of the model. SETTING: The Chinese healthcare system perspective. PARTICIPANTS: A hypothetical cohort of Chinese patients with pathologically diagnosed L/M NPC who had an Eastern Cooperative Oncology Group performance status of 0 or 1. INTERVENTIONS: First-line camrelizumab in combination with camrelizumab and gemcitabine plus cisplatin (CGP) versus gemcitabine plus cisplatin (GP). PRIMARY OUTCOME MEASURE: Cost, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER). RESULTS: The baseline analysis demonstrated that, compared with first-line GP, first-line CGP yields an effectiveness increase of 0.26 QALY, accompanied by an increment of US$6137.59 in healthcare cost. This results in an ICER of US$23 482.32/QALY. With the willingness-to-pay (WTP) threshold for a QALY set at US$37 654.50, first-line CGP proves to be cost-effective in 97.20% of the iterations. Deterministic sensitivity analyses indicated that the uncertainty in model parameters had no substantial effect on our results. Probability sensitivity analysis indicated that CGP was cost-effective at the assumed WTP threshold. CONCLUSION: For Chinese patients with L/M NPC, adding Chinese-developed anti-PD-1 antibody camrelizumab to the first-line GP chemotherapy may be cost-effective.

Refined assessment and decomposition analysis of carbon emissions in high-energy intensive industrial sectors in China.

Carbon emissions from high-energy intensive industrial sectors are the focus of this study due to the huge energy consumption of these sectors. A refined carbon emission inventory of Chinese high-energy intensive industrial sectors in 2020 was first developed at the point source level. The results showed that coal-fired power plants (CFPPs) were the leading contributors to carbon emissions, followed by iron and steel smelting (ISS) and cement production (CMP). Provinces with high carbon emission intensity were mainly concentrated in the north and northeast coasts, while exhibiting a developed economic level and a concentration of heavy industries. Additionally, the growth in China's industrial carbon emissions from 1995 to 2020 can be divided into three phases. The largest decrease in emission intensity was observed in Central, Southwest, North, and East China. Furthermore, the economic structure remained the dominant driver of carbon emissions from the 10th to 13th Five-Year Plan (FYP), playing a positive promotional role. The contribution of economic structure, energy intensity, and energy structure to carbon emissions varied substantially by region and period. With the proposal of sustainable development and energy conservation in China, the influence of economic structure on the carbon emissions of industrial sectors has gradually weakened since the 11th FYP. The reduction in industrial carbon emissions in China under three scenarios could reach up to 46.6 % from 2030 to 2050. The results indicate that industrial carbon emission control in China needs to be integrated into the refined control pathway for conventional air pollutants, considering the spatial variability of industrial carbon emissions in China.

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia.

BACKGROUND: Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application and the underlying mechanisms at play remain unclear. The aims of this study were to elucidate the role of abnormal signal transmission and metabolism in the chemoresistance of OSCC under hypoxia and to identify targeted drugs that enhance the sensitivity of DDP chemotherapy. METHODS: Upregulated genes in OSCC were determined by RNA sequencing (RNA-seq), the Cancer Genome Atlas (TCGA) database, immunohistochemistry (IHC), real-time quantitative PCR (RT-qPCR), and western blotting (WB). The clinicopathological significance of insulin-like growth factor-I receptor (IGF1R), argininosuccinate synthetase 1 (ASS1), and pyrroline-5-carboxylate reductase 1 (PYCR1) in OSCC was analysed using tissue micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP-resistance role of IGF1R, ASS1, and PYCR1 in OSCC was investigated in vitro and in vivo. RESULTS: Generally, tumour cells exist in a hypoxic microenvironment. By genomic profiling, we determined that IGF1R, as a receptor tyrosine kinase (RTK), was upregulated in OSCC under low-oxygen conditions. Clinically, enhanced IGF1R expression was associated with higher tumour stages and a poorer prognosis in OSCC patients, and its inhibitor, linsitinib, showed synergistic effects with DDP therapy in vivo and in vitro. Since oxygen-deprivation frequently lead to metabolic reprogramming, we further learned via metabolomics analysis that abnormal IGF1R pathways promoted the expression of metabolic enzymes ASS1 and PYCR1 by the transcriptional activity of c-MYC. In detail, enhanced expression of ASS1 promotes arginine metabolism for biological anabolism, whereas PYCR1 activates proline metabolism for redox balance, which maintains the proliferation ability of OSCC cells during DDP treatment under hypoxic conditions. CONCLUSION: Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under hypoxia. Linsitinib targeting IGF1R signaling may lead to promising combination therapy options for OSCC patients with DDP resistance.

Transcription factor 3 promotes migration and invasion potential and maintains cancer stemness by activating ID1 expression in esophageal squamous cell carcinoma.

Transcription factor 3 (TCF3) is a member of the basic Helix - Loop - Helix (bHLH) transcription factor (TF) family and is encoded by the TCF3 gene (also known as E2A). It has been shown that TCF3 functions as a key transcription factor in the pathogenesis of several human cancers and plays an important role in stem cell maintenance and carcinogenesis. However, the effect of TCF3 in the progression of esophageal squamous cell carcinoma (ESCC) is poorly known. In our study, TCF3 was found to express highly and correlated with cancer stage and prognosis. TCF3 was shown to promote ESCC invasion, migration, and drug resistance both from the results of in vivo and in vitro assays. Moreover, further studies suggested that TCF3 played these roles through transcriptionally regulating Inhibitor of DNA binding 1(ID1). Notably, we also found that TCF3 or ID1 was associated with ESCC stemness. Furthermore, TCF3 was correlated with the expression of cancer stemness markers CD44 and CD133. Therefore, maintaining cancer stemness might be the underlying mechanism that TCF3 transcriptionally regulated ID1 and further promoted ESCC progression and drug resistance.

TAOK3 Facilitates Esophageal Squamous Cell Carcinoma Progression and Cisplatin Resistance Through Augmenting Autophagy Mediated by IRGM.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers because of its robust aggressive phenotype and chemoresistance. TAO kinase belongs to mitogen-activated protein kinases, which mediate drug resistance in multiple cancers. However, the role of TAO kinase in ESCC progression and chemoresistance has never been explored. Here, it is reported that TAOK3 augments cell autophagy and further promotes ESCC progression and chemoresistance. Mechanistically, TAOK3 phosphorylates KMT2C at S4588 and strengthens the interaction between KMT2C and ETV5. Consequently, the nuclear translocation of KMT2C is increased, and the transcription of autophagy-relevant gene IRGM is further upregulated. Additionally, the inhibitor SBI-581 can significantly suppress cell autophagy mediated by TAOK3 and synergizes with cisplatin to treat ESCC in vitro and in vivo.