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Photoreduction of highly toxic U(VI) to less toxic U(IV) is crucial for mitigating radioactive contamination. Herein, a CoWO4/TpDD p-n heterojunction is synthesized, with TpDD serving as the n-type semiconductor substrate and CoWO4 as the p-type semiconductor grown in situ on its surface. The Fermi energy difference between TpDD and CoWO4 provides the electrochemical potential for charge-hole separation. Moreover, the Coulombic forces from the distinct carrier types between the two materials synergistically facilitate the transfer of electrons and holes. Hence, an internal electric field directed from TpDD to CoWO4 is established. Under photoexcitation conditions, charges and holes migrate efficiently along the curved band and internal electric field, further enhancing charge-hole separation. As a result, the removal capacity of CoWO4/TpDD increases from 515.2 mg/g in the dark to 1754.6 mg/g under light conditions. Thus, constructing a p-n heterojunction proves to be an effective strategy for remediating uranium-contaminated environments.
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Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.
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Linfocitos T CD8-positivos , Factores de Transcripción , Animales , Femenino , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Matriz Extracelular/metabolismo , Histona Desacetilasas/metabolismo , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Agotamiento de Células T , Factores de Transcripción/metabolismo , Microambiente Tumoral , Estrés MecánicoRESUMEN
Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14+RNASE2+ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.
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Post-translational modifications (PTMs) of the non-histone protein high-mobility group protein B1 (HMGB1) are involved in modulating inflammation and immune responses. Recent studies have implicated that the RNA-binding protein (RBP) Musashi-2 (MSI2) regulates multiple critical biological metabolic and immunoregulatory functions. However, the precise role of MSI2 in regulating PTMs and tumor immunity in colorectal cancer (CRC) remains unclear. Here, we present data indicating that MSI2 potentiates CRC immunopathology in colitis-associated colon cancer (CAC) mouse models, cell lines and clinical specimens, specifically via HMGB1-mediated dendritic cell (DC) maturation and migration, further contributes to the infiltration of CD4+ and CD8+ T cells and inflammatory responses. Under stress conditions, MSI2 can exacerbate the production, nucleocytoplasmic transport and extracellular release of damage-associated molecular patterns (DAMPs)-HMGB1 in CRC cells. Mechanistically, MSI2 mainly enhances the disulfide HMGB1 production and protein translation via direct binding to nucleotides 1403-1409 in the HMGB1 3' UTR, and interacts with the cytoplasmic acetyltransferase P300 to upregulate its expression, further promoting the acetylation of K29 residue in HMGB1, thus leading to K29-HMGB1 nucleocytoplasmic translocation and extracellular release. Furthermore, blocking HMGB1 activity with glycyrrhizic acid (Gly) attenuates MSI2-mediated immunopathology and immune infiltration in CRC in vitro and in vivo. Collectively, this study suggests that MSI2 may improve the prognosis of CRC patients by reprogramming the tumor immune microenvironment (TIME) through HMGB1-mediated PTMs, which might be a novel therapeutic option for CRC immunotherapy.
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Neoplasias Colorrectales , Proteína HMGB1 , Animales , Humanos , Ratones , Linfocitos T CD8-positivos , Neoplasias Colorrectales/metabolismo , Citosol/metabolismo , Proteína HMGB1/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas de Unión al ARN/genética , Microambiente TumoralRESUMEN
BACKGROUND: Musashi-2 (MSI2) is a critical RNA-binding protein (RBP) whose ectopic expression drives the pathogenesis of various cancers. Accumulating evidence suggests that inducing ferroptosis of tumor cells can inhibit their malignant biological behavior as a promising therapeutic approach. However, it is unclear whether MSI2 regulates cell death in colorectal cancer (CRC), especially the underlying mechanisms and biological effects in CRC ferroptosis remain elusive. METHODS: Experimental methods including qRTâPCR, immunofluorescence, flow cytometry, western blot, co-immunoprecipitation, CCK-8, colony formation assay, in vitro cell transwell migration and invasion assays, in vivo xenograft tumor experiments, liver and lung CRC metastasis models, CAC mice models, transmission electron microscopy, immunohistochemistry, histopathology, 4D label-free proteomics sequencing, bioinformatic and database analysis were used in this study. RESULTS: Here, we investigated that MSI2 was upregulated in CRC and positively correlated with ferroptosis inhibitor molecules. MSI2 deficiency suppressed CRC malignancy by inhibiting cell proliferation, viability, migration and invasion in vitro and in vivo; and MSI2 deficiency triggered CRC ferroptosis by changing the intracellular redox state (ROS levels and lipid peroxidation), erastin induced cell mortality and viability, iron homeostasis (intracellular total irons and ferrous irons), reduced glutathione (GSH) levels and mitochondrial injury. Mechanistically, through 4D-lable free proteomics analysis on SW620 stable cell lines, we demonstrated that MSI2 directly interacted with p-ERK and MSI2 knockdown downregulated the p-ERK/p38/MAPK axis signaling pathway, which further repressed MAPKAPK2 and HPSB1 phosphorylation, leading to decreased expression of PCNA and Ki67 and increased expression of ACSL4 in cancer cells. Furthermore, HSPB1 could rescue the phenotypes of MSI2 deficiency on CRC ferroptosis in vitro and in vivo. CONCLUSIONS: This study indicates that MSI2 deficiency suppresses the growth and survival of CRC cells and promotes ferroptosis by inactivating the MAPK signaling pathway to inhibit HSPB1 phosphorylation, which leads to downregulation of PCNA and Ki67 and upregulation of ACSL4 in cancer cells and subsequently induces redox imbalance, iron accumulation and mitochondrial shrinkage, ultimately triggering ferroptosis. Therefore, targeted inhibition of MSI2/MAPK/HSPB1 axis to promote ferroptosis might be a potential treatment strategy for CRC.
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The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.
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Vía de Señalización Hippo , Proteínas Serina-Treonina Quinasas , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Espectrina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Señalizadoras YAP , Factores de Transcripción/metabolismo , Carcinogénesis/genéticaRESUMEN
Plasmonic photocatalysis is an effective strategy to solve radioactive uranium hazards in wastewater. A plasmonic photocatalyst Bi/Bi2O3-x@COFs was synthesized by in-situ growth of covalent organic frameworks (COFs) on Bi/Bi2O3-x surface for the U(VI) adsorption and plasmonic photoreduction in rare earth tailings wastewater. The presence of oxygen vacancy in Bi/Bi2O3-x and Schottky potential well formed by Bi and Bi2O3-x interface increased the number of free electrons, which induced localized surface plasmon resonance (LSPR) and enhanced the light absorption performance of composites. In addition, oxygen vacancy improved the Fermi level of Bi/Bi2O3-x, leading to another potential well between Bi2O3-x and COFs interface. The electron transport direction was reversed, thus increasing the electron density of COFs layer. COFs was an N-type semiconductor with specific binding U(VI) groups and suitable band structure, which could be used as an active reaction site. Bi/Bi2O3-x@COFs had 1411.5 mg g-1 removal capacity and high separation coefficient for U(VI) due to the synergistic action of photogenerated electrons and hot electrons. Moreover, the removal rate of uranium from rare earth tailings wastewater by regenerated Bi/Bi2O3-x@COFs was over 93.9%. The scheme of introducing LSPR and Schottky potential well provides another way to improve the photocatalytic effect.
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Background: Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related death worldwide. Hepatocellular carcinoma accounts for an estimated 90% of all liver cancers. Many enzymes of the GPAT/AGPAT family are required for the synthesis of triacylglycerol. Expression of AGPAT isoenzymes has been reported to be associated with an increased risk of tumorigenesis or development of aggressive phenotypes in a variety of cancers. However, whether members of the GPAT/AGPAT gene family also influence the pathophysiology of HCC is unknown. Methods: Hepatocellular carcinoma datasets were obtained from the TCGA and ICGC databases. Predictive models related to the GPAT/AGPAT gene family were constructed based on LASSO-Cox regression using the ICGC-LIRI dataset as an external validation cohort. Seven immune cell infiltration algorithms were used to analyze immune cell infiltration patterns in different risk groups. IHC, CCK-8, Transwell assay, and Western blotting were used for in vitro validation. Results: Compared with low-risk patients, high-risk patients had shorter survival and higher risk scores. Multivariate Cox regression analysis showed that risk score was a significant independent predictor of overall survival (OS) after adjustment for confounding clinical factors (p < 0.001). The established nomogram combined risk score and TNM staging to accurately predict survival at 1, 3, and 5 years in patients with HCC with AUC values of 0.807, 0.806, and 0.795, respectively. This risk score improved the reliability of the nomogram and guided clinical decision-making. In addition, we comprehensively analyzed immune cell infiltration (using seven algorithms), response to immune checkpoint blockade, clinical relevance, survival, mutations, mRNA expression-based stemness index, signaling pathways, and interacting proteins related to the three core genes of the prognostic model (AGPAT5, LCLAT1, and LPCAT1). We also performed preliminary validation of the differential expression, oncological phenotype, and potential downstream pathways of the three core genes by IHC, CCK-8, Transwell assay, and Western blotting. Conclusion: These results improve our understanding of the function of GPAT/AGPAT gene family members and provide a reference for prognostic biomarker research and individualized treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Pronóstico , Reproducibilidad de los Resultados , Sincalida , Microambiente Tumoral/genética , Glicerol-3-Fosfato O-Aciltransferasa/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genéticaRESUMEN
Acute rejection of the transplanted heart is mediated by oxidative programmed cell death through the synergistic effects of the innate and adaptive immune systems. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been widely evaluated. Tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2), also known as TIPE2, is required for maintaining immune homeostasis. To characterize the role of TIPE2 in mediating heart allografts, BALB/c hearts were transplanted into C57BL/6 wild-type (WT) and TIPE2-/- recipient mice. In TIPE2-/- recipient mice, allograft injury in BALB/c allograft hearts was significantly reduced through the inhibition of allograft ferroptosis. On day 3 and day 6 post-transplantation, the numbers of CD3+, CD4+, and CD8+ cells among splenocytes and draining lymph node cells were significantly decreased, and the activation of CD4+ and CD8+ cells in grafts was decreased in TIPE2-/- recipient mice compared with WT mice. Moreover, CD4+ and CD8+ T cells in TIPE2-/- recipient mice were characterized by deficient capacities for interferon-γ (IFN-γ) production through the TBK1 signaling axis and increased glutathione peroxidase 4 (GPX4). In cell experiments, treatment with IFN-γ enhanced ferroptosis-specific lipid peroxidation in myocardial cells and correlated inversely with GPX4 expression. Mechanistically, IFN-γ administration decreased the expression of GPX4 by inhibiting MEK/ERK phosphorylation. In summary, our findings demonstrated that TIPE2 deficiency inhibits T-cell production of IFN-γ to reduce ferroptosis in allografts by restraining lipid peroxidation.
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Ferroptosis , Rechazo de Injerto , Trasplante de Corazón , Interferón gamma , Péptidos y Proteínas de Señalización Intracelular , Animales , Ratones , Linfocitos T CD8-positivos , Rechazo de Injerto/genética , Rechazo de Injerto/prevención & control , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Peroxidación de LípidoRESUMEN
Background: The initial dose of tacrolimus after liver transplantation (LT) is critical for rapidly achieving the steady state of the drug concentration, minimizing the potential adverse reactions and warranting long-term patient prognosis. We aimed to develop and validate a genotype-guided model for determining personalized initial dose of tacrolimus. Methods: By combining pharmacokinetic modeling, pharmacogenomic analysis and multiple statistical methods, we developed a genotype-guided model to predict individualized tacrolimus initial dose after LT in the discovery (n = 150) and validation cohorts (n = 97) respectively. This model was further validated in a prospective, randomized and single-blind clinical trial from August, 2021 to February, 2022 (n = 40, ChiCTR2100050288). Findings: Our model included donor's and recipient's genotypes, recipient's weight and total bilirubin, which achieved an area under the curve of receiver operating characteristic curve (AUC of ROC) of 0.88 and 0.79 in the discovery and validation cohorts, respectively. We found that patients who were given tacrolimus within the recommended concentration range (RCR) (4-10 ng/mL), the new-onset metabolic syndromes are lower, especially for new-onset diabetes (p = 0.043). In the clinical trial, compared to those in experience-based (EB) group, patients in the model-based (MB) group were more likely to achieving the RCR (75% vs 40%, p = 0.025) with a more variable individualized dose (0.023-0.096 mg/kg/day vs 0.045-0.057 mg/kg/day). Moreover, significantly fewer medication adjustments were required for the MB group than the EB group (2.75 ± 2.01 vs 6.05 ± 3.35, p = 0.001). Interpretation: Our genotype-based model significantly improved the initial dosing accuracy of tacrolimus and reduced the number of medication adjustments, which are critical for improving the prognosis of LT patients. Funding: National Natural Science Foundation of China, Shanghai three-year action plan, National Science and Technology Major Project of China.
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Background: Tacrolimus (FK506) is the cornerstone of immunosuppression after liver transplantation (LT), however, clinically, switching from FK506 to cyclosporine (SFTC) is common in LT patients with tacrolimus intolerance. The aim of this study was to investigate the genetic risk of patients with tacrolimus intolerance. Methods: A total of 114 LT patients were enrolled in this retrospective study. SNPs were genotyped using Infinium Human Exome-12 v1.2 BeadChip, and genome-wide gene expression levels were profiled using Agilent G4112F array. Results: SFTC was a potential risk factor of dyslipidemia (OR=4.774[1.122-20.311], p = 0.034) and insulin resistance (IR) (OR=6.25[1.451-26.916], p = 0.014), but did not affect the survival of LT patients. Differential expression analysis showed donor CYP3A5, CYP2C9, CFTR, and GSTP1, four important pharmacogenetic genes were significantly up-regulated in the tacrolimus intolerance group. Twelve SNPs of these four genes were screened to investigate the effects on tacrolimus intolerance. Regression analysis showed donor rs4646450 (OR=3.23 [1.22-8.60] per each A allele, p = 0.01), donor rs6977165 (OR=6.44 [1.09-37.87] per each C allele, p = 0.02), and donor rs776746 (OR=3.31 [1.25-8.81] per each A allele, p = 0.01) were independent risk factors of tacrolimus intolerance. Conclusions: These results suggested that SFTC was a potential risk factor for dyslipidemia and IR after LT. Besides, rs4646450, rs6977165, and rs776746 of CYP3A5 might be the underlying genetic risks of tacrolimus intolerance. This might help transplant surgeons make earlier clinical decisions about the use of immunosuppression.
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Trasplante de Hígado , Tacrolimus , Ciclosporina/efectos adversos , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/genética , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/metabolismo , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Tacrolimus/efectos adversosRESUMEN
BACKGROUND: China ranks currently as one of the top countries for organ transplantation according to types, capacity, related research, quality, and quantity of procedures. However, the management systems struggle to support these practices. This study aims to review the current situation with organ donation and transplantation in China recently. METHODS: Data about organ donation and transplantation was collected by using web crawler technology from several news sections of representative portal websites in China. A total of 3475 documents about organ donation and transplantation were analyzed after data preprocessing. The documents were analyzed using machine learning to find out the relationship among the hot topics and their social popularity as well as to explore the dominant subtopics of the hot topics. RESULTS: The results of weighted correlation network analysis and documents clustering analysis identified 9 topics about organ donation and transplantation in China with a wide discussion: transplantation ethics, donor compensation, use of the remains, transportation guarantee of living organs, organ allocation, relevant national standards of organ donation and transplantation, legislation on organ donation, penalties for violation, and the Red Cross Society of China. CONCLUSIONS: This study found out the main problems and proposed them for future discussion with organ donation and transplantation system in China: the lack of publicity and education and the difficulty of standardizing legislation about ethical issues arousing ethical problems; the need to understand the relationship and the standardization among costs, expenses, and compensation; and the lack of more support from the government and public to ensure regular organ donation and transplantation.
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Trasplante de Órganos , Obtención de Tejidos y Órganos , Humanos , Donantes de Tejidos , China , Aprendizaje AutomáticoRESUMEN
Sepsis remains the most lethal infectious disease and substantially impairs patient prognosis after liver transplantation (LT). Our previous study reported a role of the pannexin 1 (PANX1)-interleukin-33 (IL-33) axis in activating innate immunity to protect against methicillin-resistant Staphylococcus aureus infection; however, the role of PANX1 in regulating adaptive immunity in sepsis and the underlying mechanism are unclear. In this study, we examined the role of the PANX1-IL-33 axis in protecting against sepsis caused by a gram-negative bacterial infection in an independent LT cohort. Next, in animal studies, we assessed the immunological state of Panx1-/- mice with lipopolysaccharide (LPS)-induced endotoxemia and then focused on the cytokine storm and regulatory T cells (Tregs), which are crucial for the resolution of inflammation. To generate liver-specific Panx1-deficient mice and mimic clinical LT procedures, a mouse LT model was established. We demonstrated that hepatic PANX1 deficiency exacerbated LPS-induced endotoxemia and dysregulated the immune response in the mouse LT model. In hepatocytes, we confirmed that PANX1 positively regulated IL-33 synthesis after LPS administration. We showed that the adenosine triphosphate-P2X7 pathway regulated the hepatic PANX1-IL-33 axis during endotoxemia in vitro and in vivo. Recombinant IL-33 treatment rescued LPS-induced endotoxemia by increasing the numbers of liver-infiltrating ST2+ Tregs and attenuating the cytokine storm in hepatic PANX1-deficient mice. In conclusion, our findings revealed that the hepatic PANX1-IL-33 axis protects against endotoxemia and liver injury by targeting ST2+ Tregs and promoting the early resolution of hyperinflammation.
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Endotoxemia , Staphylococcus aureus Resistente a Meticilina , Sepsis , Animales , Conexinas/genética , Conexinas/metabolismo , Síndrome de Liberación de Citoquinas , Modelos Animales de Enfermedad , Endotoxemia/inducido químicamente , Humanos , Inflamación/inducido químicamente , Inflamación/complicaciones , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Lipopolisacáridos/toxicidad , Hígado/metabolismo , Staphylococcus aureus Resistente a Meticilina/metabolismo , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Sepsis/complicaciones , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: Using data from the global burden of disease (GBD) between 1990 and 2019 to report the leading etiological factors and hazards for liver cancer by HBV (LCHB), HCV (LCHC), alcoholic use (LCAL), NASH (LCNA), and other causes (LCOT). METHOD: The estimated annual percentage change (EAPC) and age-standardized incidence rate (ASR) in different districts, sex, and age are used to quantify the change of etiologies of liver cancer. Age-period-cohort models were performed to predict the primary liver cancer incidence and case numbers. RESULTS: Based on the GBD database of the whole world for the five etiologies of liver cancer in 2019, the percentage of incidence of LCAL, LCHB, LCHC, LCNA, and LCOT are 18.4%, 41%, 28.5%, 6.8%, and 5.3%, respectively. Fiver etiologies of liver cancer show gender differences, with LCHB and LCAL being more prevalent in men, and LCHC, LCNA being more prevalent in women. Besides, live cancer of males is because of alcohol using and smoking, while the reason of liver cancer of females is drug use, high BMI and high fasting plasma glucose. Interestingly, the incidence of LCHC in women over 85 years old, LCNA in women over 75 years old, and LCOT in women over 75 years old were all higher than that in men. According to the future prediction, the incidence rate of liver cancer itself, as well as the five causes of liver cancer, tends to decrease gradually after 2019, while the incidence rate of LCNA in males will continue to increase until 2025. CONCLUSIONS: The incidence of liver cancer has been increasing and its major causes vary considerably at global, regional, or national levels, also vary by gender and age group.
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Carga Global de Enfermedades , Neoplasias Hepáticas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Masculino , Factores SexualesRESUMEN
Background: The etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are generally believed to be related to immune dysfunction and intestinal microbiota disorder. However, the exact mechanism is not yet fully understood. The pathological changes associated with dextran sodium sulfate (DSS)-induced colitis are similar to those in human UC. As a subgroup of the innate immune system, group 3 innate lymphoid cells (ILC3s) are widely distributed in the lamina propria of the intestinal mucosa, and their function can be regulated by a variety of molecules. Musashi2 (MSI2) is a type of evolutionarily conserved RNA-binding protein that maintains the function of various tissue stem cells and is essential for postintestinal epithelial regeneration. The effect of MSI2 deficiency in ILC3s on IBD has not been reported. Thus, mice with conditional MSI2 knockout in ILC3s were used to construct a DSS-induced colitis model and explore its effects on the pathogenesis of IBD and the species, quantity and function of the intestinal microbiota. Methods: Msi2flox/flox mice (Msi2fl/fl ) and Msi2flox/floxRorcCre mice (Msi2ΔRorc ) were induced by DSS to establish the IBD model. The severity of colitis was evaluated by five measurements: body weight percentage, disease activity index, colon shortening degree, histopathological score and routine blood examination. The species, quantity and function of the intestinal microbiota were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples. Results: MSI2 was knocked out in the ILC3s of Msi2ΔRorc mice. The Msi2ΔRorc mice exhibited reductions in body weight loss, the disease activity index, degree of colon shortening, tissue histopathological score and immune cells in the peripheral blood compared to those of Msi2fl/fl mice after DSS administration. The 16S rRNA sequencing results showed that the diversity of the intestinal microbiota in DSS-treated Msi2ΔRorc mice changed, with the abundance of Firmicutes increasing and that of Bacteroidetes decreasing. The linear discriminant analysis effect size (LEfSe) approach revealed that Lactobacillaceae could be the key bacteria in the Msi2ΔRorc mouse during the improvement of colitis. Using PICRUST2 to predict the function of the intestinal microbiota, it was found that the functions of differential bacteria inferred by modeling were mainly enriched in infectious diseases, immune system and metabolic functions. Conclusions: MSI2 deficiency in ILC3s attenuated DSS-induced colonic inflammation in mice and affected intestinal microbiota diversity, composition, and function, with Lactobacillaceae belonging to the phylum Firmicutes possibly representing the key bacteria. This finding could contribute to our understanding of the pathogenesis of IBD and provide new insights for its clinical diagnosis and treatment.
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Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Proteínas de Unión al ARN , Animales , Ratones , Bacterias/genética , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Inmunidad Innata , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/genética , Linfocitos/metabolismo , ARN Ribosómico 16S/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Humanos , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Prospectivos , Calidad de Vida , Sirolimus/efectos adversos , Resultado del TratamientoRESUMEN
Colorectal cancer (CRC) is a common tumor that harms human health with a high recurrence rate. It has been reported that the expression of microRNA-539 (miR-539) is low in several types of cancer, including CRC. Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) is highly expressed in CRC and promotes the proliferation, migration and angiogenesis of CRC. However, the relationship between miR-539 and TIPE and the mechanisms by which they regulate the proliferation of CRC remain to be explored. We aimed to investigate the functions and mechanisms of miR-539 in CRC proliferation. Functionally, miR-539 can bind to and regulate the expression of TIPE, and miR-539 activates SAPK/JNK to downregulate the expression of glutathione peroxidase 4 (GPX4) and promote ferroptosis. Our data reveal the novel role of miR-539 in regulating ferroptosis in CRC via activation of the SAPK/JNK axis, providing new insight into the mechanism of abnormal proliferation in CRC and a novel potential therapeutic target for advanced CRC.
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Liver transplantation patients are at increased risk for methicillin-resistant Staphylococcus aureus (MRSA) infection, but the molecular mechanism remains unclear. We found that genetic predisposition to low pannexin 1 (PANX1) expression in donor livers was associated with MRSA infection in human liver transplantation recipients. Using Panx1 and Il-33-knockout mice for liver transplantation models with MRSA tail vein injection, we demonstrated that Panx1 deficiency increased MRSA-induced liver injury and animal death. We found that decreased PANX1 expression in the liver led to reduced release of adenosine triphosphate (ATP) from hepatocytes, which further reduced the activation of P2X2, an ATP-activating P2X receptor. Reduced P2X2 function further decreased the NLRP3-mediated release of interleukin-33 (IL-33), reducing hepatic recruitment of macrophages and neutrophils. Administration of mouse IL-33 to Panx1-/- mice significantly (P = 0.011) ameliorated MRSA infection and animal death. Reduced human hepatic IL-33 protein abundance also associated with increased predisposition to MRSA infection. Our findings reveal that genetic predisposition to reduced PANX1 function increases risk for MRSA infection after liver transplantation by decreasing hepatic host innate immune defense, which can be attenuated by IL-33 treatment.
Asunto(s)
Trasplante de Hígado , Staphylococcus aureus Resistente a Meticilina , Adenosina Trifosfato , Animales , Conexinas , Humanos , Interleucina-33 , Donadores Vivos , Ratones , Proteínas del Tejido Nervioso/genéticaRESUMEN
Analysis of circulating tumor cells (CTCs) is regarded as a useful diagnostic index to monitor tumor development and guide precision medicine. Although the immunoassay is a common strategy for CTC identification and heterogeneity characterization, it is challenged by poor reaction efficiency and laborious manipulations in microdevices, which hinder the sensitivity, throughput, simplification, and applicability. To meet the need for rapid, sensitive, and simple CTC analysis, we developed an efficient CTC detection system by integrating a 3D printed off-chip multisource reagent platform, a bubble retainer, and a single CTC capture microchip, which can achieve CTC capture and identification within 90 min. Compared with traditional CTC identification methods, this system decreases immunostaining time and antibody consumption by 90% and performs the on-chip immunoassay in a fully automated manner. Using this system, CTCs from the peripheral blood of 19 patients with various cancers were captured, detected, and compared with clinical data. The system shows great potential for early screening, real-time monitoring, and precision medicine for hepatocellular carcinoma (HCC). With the advantages of automation, stability, economy, and user-friendly operation, the proposed system is promising for clinical scenarios.