Single-cell immune profiling of mouse liver aging reveals Cxcl2+ macrophages recruit neutrophils to aggravate liver injury.

BACKGROUND AND AIMS: Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging. APPROACH AND RESULTS: We carried out single-cell RNA sequencing on mouse liver tissues at 4 different ages, namely, the newborn, suckling, young, and aged stages. The transcriptomic landscape, cellular classification, and intercellular communication were analyzed. We confirmed the findings by multiplex immunofluorescence staining, flow cytometry, in vitro functional experiments, and chimeric animal models. Nine subsets of 89,542 immune cells with unique properties were identified, of which Cxcl2+ macrophages within the monocyte/macrophage subset were preferentially enriched in the aged liver. Cxcl2+ macrophages presented a senescence-associated secretory phenotype and recruited neutrophils to the aged liver through the CXCL2-CXCR2 axis. Through the secretion of IL-1ß and TNF-α, Cxcl2+ macrophages stimulated neutrophil extracellular traps formation. Targeting the CXCL2-CXCR2 axis limited the neutrophils migration toward the liver and attenuated age-related liver injury. Moreover, the relationship between Cxcl2+ macrophages and neutrophils in age-related liver injury was further validated by human liver transplantation samples. CONCLUSIONS: This in-depth study illustrates that the mechanism of Cxcl2+ macrophage-driven neutrophil activation involves the CXCL2-CXCR2 axis and provides a potential therapeutic strategy for age-related liver injury.

Connexin32 gap junction channels deliver miR155-3p to mediate pyroptosis in renal ischemia-reperfusion injury.

OBJECTIVES: To explore whether the gap junction (GJ) composed by connexin32(Cx32) mediated pyroptosis in renal ischemia-reperfusion(I/R) injury via transmitting miR155-3p, with aim to provide new strategies for the prevention and treatment of acute kidney injury (AKI) after renal I/R. METHODS: 8-10 weeks of male C57BL/ 6 wild-type mice and Cx32 knockdown mice were divided into two groups respectively: control group and renal I/R group. MCC950 (50 mg/kg. ip.) was used to inhibit NLRP3 in vivo. Human kidney tubular epithelial cells (HK - 2) and rat kidney tubular epithelial cells (NRK-52E) were divided into high-density group and low-density group, and treated with hypoxia reoxygenation (H/R) to mimic I/R. The siRNA and plasmid of Cx32, mimic and inhibitor of miR155-3p were transfected into HK - 2 cells respectively. Kidney pathological and functional injuries were measured. Western Blot and immunofluorescent staining were used to observe the expression of NLRP3, GSDMD, GSDMD-N, IL - 18, and mature IL-18. The secretion of IL-18 and IL-1ß in serum, kidney tissue and cells supernatant were detected by enzyme-linked immuno sorbent assay (ELISA) kit, and the expression of NLPR3 and miR155-3p were detected by RT-qPCR and fluorescence in situ hybridization (FISH). RESULTS: Tubular pyroptosis were found to promote AKI after I/R in vivo and Cx32-GJ regulated pyroptosis by affecting the expression of miR155-3p after renal I/R injury. In vitro, H/R could lead to pyroptosis in HK-2 and NRK-52E cells. When the GJ channels were not formed, and Cx32 was inhibited or knockdown, the expression of miR155-3p was significantly reduced and the pyroptosis was obviously inhibited, leading to the reduction of injury and the increase of survival rate. Moreover, regulating the level of miR155-3p could affect survival rate and pyroptosis in vitro after H/R. CONCLUSIONS: The GJ channels composed of Cx32 regulated tubular pyroptosis in renal I/R injury by transmitting miR155-3p. Inhibition of Cx32 could reduce the level of miR155-3p further to inhibit pyroptosis, leading to alleviation of renal I/R injury which provided a new strategy for preventing the occurrence of AKI. Video Abstract.

CAF-derived exosomes transmitted Gremlin-1 promotes cancer progression and decreases the sensitivity of hepatoma cells to sorafenib.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide because of metastasis. An increasing number of studies have reported that cancer-associated fibroblasts (CAFs) have emerged as the largest component of the stroma and play a critical role in tumor-promoting processes. However, the effects of CAFs on cancer progression and the sensitivity of hepatoma cells to sorafenib are not well characterized. Here, we identified the proteome of CAF-derived exosomes, and unveiled that exosomal Gremlin-1 derived from CAFs contributes to epithelial-mesenchymal transition (EMT) of hepatoma cells and the decrease of the sorafenib sensitivity through regulating Wnt/ß-catenin and BMP signaling pathways. Compared to control subjects, the level of plasma exosomal Gremlin-1 was significantly increased in HCC patients. Further studies indicated that plasma exosomal Gremlin-1 may predict sorafenib response in HCC patients. Collectively, our findings uncover CAFs-derived Gremlin-1-rich exosomes promote EMT and decrease the sensitivity of hepatoma cells to sorafenib by Wnt/ß-catenin and BMP signaling.

Anatomical sites (Takasaki's segmentation) predicts the recurrence-free survival of hepatocellular carcinoma.

BACKGROUND: Until now, several classification staging system and treatment algorithm for hepatocelluar carcinoma (HCC) has been presented. However, anatomical location is not taken into account in these staging systems. The aim of this study is to investigate whether anatomical sites could predict the postoperative recurrence of HCC patients. METHODS: 294 HCC patients were enrolled in this retrospective study. A novel score classification based on anatomical sites was established by a Cox regression model and validated in the internal validation cohort. RESULTS: HCC patients were stratified according to the novel score classification into three groups (score 0, score 1-3 and score 4-6). The predictive accuracy of the novel recurrence score for HCC patients as determined by the area under the receiver operating characteristic curves (AUCs) at 1, 3, and 5 years (AUCs 0.703, 0.706, and 0.605) was greater than that of the other representative classification systems. These findings were supported by the internal validation cohort. For patients with Barcelona Clinic Liver Cancer (BCLC) 0 and A stage, our data demonstrated that there was no significant difference in recurrence-free survival (RFS) between patients with score 0 and liver transplantation recipients. Additionally, we introduced this novel classification system to guide anatomical liver resection for centrally located liver tumors. CONCLUSION: The novel score classification may provide a reliable and objective model to predict the RFS of HCC after hepatic resection.

A comprehensive analysis of the MAGE family as prognostic and diagnostic markers for hepatocellular carcinoma.

The Melanoma Antigen Gene (MAGE) family is a large, highly conserved group of proteins which was reported to participate in the progression of multiple cancers in humans. However, the function of distinct MAGE genes in hepatocellular carcinoma (HCC) is largely unclear. In this study, we comprehensively evaluated the expression, clinical significance, genetic alteration, interaction network and functional enrichment of MAGEs in HCC. Our research showed that many MAGE genes were dysregulated in HCC. Among them, MAGEA1, MAGEC2, MAGED1, MAGED2, MAGEF1 and MAGEL2 were significantly associated with clinical stage and differentiation of HCC. MAGED1, MAGED2, MAGEA6, MAGEA12, MAGEA10, MAGEB4, MAGEL2 and MAGEC3 significantly correlated with HCC prognosis. Further functional enrichment analysis suggested the dysregulated MAGEs may play important roles in signal transduction. These results indicate that multiple dysregulated MAGEs might play important roles in the development of HCC and can be exploited as useful biomarkers for diagnosis and treatment in HCC.

Nomogram based on blood lipoprotein for estimation of mortality in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a clinic syndrome with substantial high short-term mortality. It is very important to stratify patients according to prognosis to decide management strategy. This study aimed to formulate and validate a nomogram model based on blood lipoprotein for prediction of 3-month mortality in patients with hepatitis B virus (HBV)-related ACLF. METHODS: Data on 393 consecutive patients who were diagnosed as HBV-related ACLF at the Third Affiliated Hospital of Sun Yat-sen University between June 1, 2013, and February 1, 2015, were prospectively collected. Of these, 260 patients who were collected in an earlier period formed the training cohort for the development of nomogram, while 133 patients who were collected thereafter formed the validation cohort for confirming the performance of nomogram. RESULTS: Multivariate analysis showed that low density lipoprotein cholesterol (LDL-C), age, prothrombin time, and creatinine were independently associated with 3-month mortality of patients with HBV-related ACLF. Kaplan-Meier survival analysis revealed that the high LDL-C (LDL-C ≥ 1.0 mmol/L, cut-off value) was significantly associated with elevated overall survival (P < 0.001). All independent factors for survival were selected into the nomogram. The calibration plot for the probability of survival showed good agreement between prediction by nomogram and actual observation. CONCLUSION: This study highlighted that reduction of serum LDL-C level was an independent risk factor for the survival in patients with HBV-related ACLF, and the nomogram based on serum LDL-C was an accurate and practical model for predicting the 3-month mortality in patients with this disease.

Analysis of air quality characteristics of Beijing-Tianjin-Hebei and its surrounding air pollution transport channel cities in China.

Beijing-Tianjin-Hebei (BTH) and its surrounding areas are very important to air pollution control in China. To analyze the characteristics of BTH and its surrounding areas of China, we collected 5,641,440 air quality data from 161 air monitoring stations and 37,123,000 continuous monitoring data from air polluting enterprises in BTH and surrounding cities to establish an indicator system for urban air quality portraits. The results showed that particulate matter with aerodynamic diameters of <2.5 µm (PM2.5), particulate matter with aerodynamic diameters of <10 µm (PM10) and SO2 improved significantly in 31 cities from 2015 to 2018, but ozone deteriorated. Air quality in BTH and the surrounding areas showed obvious seasonal characteristics, among which PM2.5, PM10, SO2, and NO2 showed a "U" type distribution from January to December, while O3 had an "inverted U" distribution. The hourly changes in air quality revealed that peaks of PM2.5, PM10 and NO2 appeared from 8:00 to 10:00, while those for O3 appeared at 15:00-16:00. The exposure characteristics of the 31 cities showed that six districts in Beijing had the highest air quality population exposure, and that exposure levels in Zhengzhou, Puyang, Anyang, Jincheng were higher than the average of the 31 investigated cities. Additionally, multiple linear regression revealed a negative correlation between meteorological factors (especially wind and precipitation) and air quality, while a positive correlation existed between industrial pollution emissions and air quality in most of BTH and its surrounding cities.

Preparation of Porous Activated Carbons for High Performance Supercapacitors from Taixi Anthracite by Multi-Stage Activation.

Coal-based porous materials for supercapacitors were successfully prepared using Taixi anthracite (TXA) by multi-stage activation. The characterization and electrochemical tests of activated carbons (ACs) prepared in different stages demonstrated that the AC from the third-stage activation (ACIII) shows good porous structures and excellent electrochemical performances. ACIII exhibited a fine specific capacitance of 199 F g-1 at a current density of 1 A g-1 in the three-electrode system, with 6 mol L-1 KOH as the electrolyte. The specific capacitance of ACIII remained 190 F g-1 even despite increasing the current density to 5 A g-1, indicating a good rate of electrochemical performance. Moreover, its specific capacitance remained at 98.1% of the initial value after 5000 galvanostatic charge-discharge (GCD) cycle tests at a current density of 1 A g-1, suggesting that the ACIII has excellent cycle performance as electrode materials for supercapacitors. This study provides a promising approach for fabricating high performance electrode materials from high-rank coals, which could facilitate efficient and clean utilization of high-rank coals.

The clinical value of Fibulin-1 for prognosis and its prospective mechanism in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy arising from the liver. Fibulin-1 has been demonstrated to be involved in various cancers, however, its role in ICC remains unclear. METHODS: To study the clinical value and potential molecular mechanism of Fibulin-1 in ICC, immunohistochemistry and bioinformatic analyses were performed using data in the Gene Expression Omnibus Datasets and The Cancer Genome Atlas database. RESULTS: Fibulin-1 expression was overexpressed in ICC tissues compared with adjacent non-cancerous tissues, and was significantly associated with unfavorable overall survival. Moreover, similar genes were identified by Gene Expression Profiling Interactive Analysis and microarray data set. Next, functional and pathway enrichment analysis demonstrated that Fibulin-1 was overrepresented in the pathways of extracellular matrix organization and angiogenesis, which are associated with tumor progression and potential for metastasis. Gene set enrichment analysis indicated that the gene sets of epithelial mesenchymal transition, TGF-beta signaling pathway and angiogenesis were enriched in tissues with high Fibulin-1 level. Furthermore, Fibulin-1 silencing suppressed the ability of ICC tumor cells to form colonies and siFibulin-1 repressed the endogenous protein level of p-AKT. CONCLUSION: Collectively, this study suggests that Fibulin-1 overexpression may play key roles in the carcinogenesis and progression of ICC via regulation of tumor-related pathways.

Predictive Value of Age-Bilirubin-International Normalized Ratio-Creatinine Score in Short-Term Survival of Acute-on-Chronic Hepatitis B Liver Failure.

BACKGROUND/AIMS: The age-bilirubin-international normalized ratio-creatinine (ABIC) score, which is a predictive model commonly used for alcoholic hepatitis, has not yet been studied in acute-on-chronic hepatitis B liver failure (HBV-ACLF). We aimed to investigate the predictive value of the ABIC score in patients with HBV-ACLF. METHODS: This retrospective study involved 398 patients diagnosed with HBV-ACLF, who were divided into a training cohort of 305 patients and a validation cohort of 93 patients. Univariate and multivariate Cox regression models were used to determine risk factors for mortality. Area under the receiver operating characteristic curve (AUC) was calculated to estimate and compare the predictive values of different prognostic scores. RESULTS: The ABIC score was significantly higher in the death group of the training cohort than in its survival group. Independent risk factors for mortality identified by multivariate Cox analysis included blood urea nitrogen, ABIC score, and Chronic Liver Failure Consortium Organ Failure (CLIF-C OF) score. For predicting 1- and 3-month mortality, AUC was higher for the ABIC score than for the Model for End-stage Liver Diseases (MELD) score (0.732 vs. 0.653, P < 0.05, 0.695 vs. 0.619, P < 0.05, respectively), CLIF-C OF score (0.693, P=0.353, 0.656, P=0.341, respectively), and Child-Pugh score (0.675, P=0.189, 0.656, P=0.300, Respectively). Patients with ABIC score > 9.44 had reduced 1- and 3-month survival rates. CONCLUSION: ABIC score is superior to MELD score in predicting short-term survival in HBV-ACLF patients. ABIC score > 9.44 predicts high short-term mortality risk in HBV-ACLF patients.

Prognostic value of neutrophil-to-lymphocyte ratio associated with prognosis in HBV-infected patients.

Chronic severe hepatitis B (CSHB) is a critical clinical syndrome with a high mortality rate in China. The prognostic value of neutrophil to lymphocyte ratio (NLR) which is simple, low-cost, and useful inflammatory marker for hepatitis B virus (HBV)-infected patients is largely overlooked and without further exploration. This study assesses the association of NLR with prognosis of chronic hepatitis B (CHB) and CSHB patients. Two hundred and eighty subjects, including 79 with chronic hepatitis B (CHB) and 67 with chronic severe hepatitis B (CSHB), and 134 healthy individuals were retrospectively recruited into this study. Blood samples were collected to conduct liver function, prothrombin time activity (PTA), international normalized ratio (INR), HBV DNA measurement, and routine hematological testing. All patients were followed up for at least 3 months. NLR values in patients with CSHB (4.984 ± 3.608) and CHB (2.020 ± 1.182) were significantly higher than those in healthy control (1.638 ± 0.601) and patients with CSHB had the highest NLR values than CHB and healthy control. Increased NLR values were clinically associated with severe liver disease and higher mortality rate. NLR was found to be an independent predictor of mortality in multivariable Cox Regression models (HR = 3.912, 95%CI: 1.587-9.640, P = 0.003). NLR values are significantly increased in CHB and CSHB patients with the severity of liver disease. Moreover, NLR value is an independent predicting factor for the mortality rate in HBV-infected patients.

Down-regulation of Transducin-Like Enhancer of Split protein 4 in hepatocellular carcinoma promotes cell proliferation and epithelial-Mesenchymal-Transition.

BACKGROUND: Transducin-Like Enhancer of Split protein 4 (TLE4) has been reported to be involved in some subsets of acute myeloid leukemia and colorectal cancer. In the present study, we aimed to explore the role of TLE4 in tumorigenesis and cancer progression in hepatocellular carcinoma (HCC). METHODS: The expression pattern of TLE4 in HCC was determined by Western-blot and qRT-PCR, gain-of-function and loss-of-function was used to explore the biological role of TLE4 in HCC cells. A xenograft model was established to confirm its effects on proliferation. RESULTS: The protein expression levels of TLE4 were significantly down-regulated in HCC tissues compared to matched adjacent normal liver tissues. In vitro, down-regulation of TLE4 in Huh7 or SMMC-7721 promoted cell proliferation and ectopical expression of TLE4 in Hep3B or Bel-7404 suppressed cell proliferation. In addition, the cell colony formation ability was enhanced after down-regulation of TLE4 expression in Huh-7 but suppressed after over-expression in Hep3B. Furthermore, down-regulation of TLE4 increased the cell invasion ability, as well as increased the expression level of Vimentin and decreased that of E-cadherin, indicating a phenotype of epithelial-mesenchymal transition (EMT) in HCC cells. On the contrary, ectopical expression of TLE4 in HCC cells decreased the cell invasion ability and inhibited EMT. In vivo, compared to control group, xenograft tumor volumes were significantly decreased in TLE4 overexpression group. CONCLUSIONS: These results demonstrated that TLE4 might play important regulatory roles in cellular proliferation and EMT process in HCC.

E2F1-mediated Up-regulation of NCAPG Promotes Hepatocellular Carcinoma Development by Inhibiting Pyroptosis.

Background and Aims: As a subunit of the condensin complex, NCAPG has an important role in maintaining chromosome condensation, but its biological function and regulatory mechanism in hepatocellular carcinoma (HCC) remains undefined. Methods: The prognostic ability of NCAPG in HCC patients was examined by univariate and multivariate Cox regression analysis. ROC curves were plotted to compare the predictive ability of NCAPG and AFP. Double luciferase reporter system, and ChIP were used to investigate transcriptional potential of E2F1 to NCAPG. Pyroptosis was observed by scanning electron microscopy. Protein expression of NCAPG, E2F1, and major proteins constituting NLRP3 inflammasome was determined by western blotting and ELISA. An in vivo tumor formation assay was conducted to verify the in vitro results. Results: Up-regulated NCAPG was identified in HCC tissues compared with adjacent tissue and high NCAPG was positively correlated with poor prognosis. Serum NCAPG mRNA level was a prognostic factor in HCC patients and also a diagnostic factor with higher predictive ability compared with AFP [AUROC 0.766 (95% CI: 0.650-0.881) vs. 0.649 (95% CI 0.506-0.793)]. HBx transfection resulted in concomitant up-regulation of E2F1 and NCAPG. E2F1 significantly increased the activity of luciferase reporter fused with NCAPG reporter, and the interaction of E2F1 and NCAPG gene was confirmed by ChIP. Silencing of E2F1 resulted in significant down-regulation of NCAPG. Knockdown of NCAPG promote pyroptosis mediated by NLRP3 inflammasome activation in multiple HCC cell lines and also suppressed tumorigenesis in vitro. Conclusions: We identified a novel role of NCAPG in the regulation of NLRP3 inflammasome-mediated pyroptosis, which was regulated by its upstream transactivator, E2F1. The role of E2F1-NCAPG-NLRP3 regulation of pyroptosis network may be a potential target in HCC treatment.

Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity.

Lenvatinib is a multitargeted tyrosine kinase inhibitor capable of promoting apoptosis, suppressing angiogenesis, inhibiting tumor cell proliferation, and modulating the immune response. In multiple cancer types, lenvatinib has presented manageable safety and is currently approved as an effective first-line therapy. However, with the gradual increase in lenvatinib application, the inevitable progression of resistance to lenvatinib is becoming more prevalent. A series of recent researches have reported the mechanisms underlying the development of lenvatinib resistance in tumor therapy, which are related to the regulation of cell death or proliferation, histological transformation, metabolism, transport processes, and epigenetics. In this review, we aim to outline recent discoveries achieved in terms of the mechanisms and potential predictive biomarkers of lenvatinib resistance as well as to summarize untapped approaches available for improving the therapeutic efficacy of lenvatinib in patients with various types of cancers.

FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC.

Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation. The potential mechanism remains unclear. Here, we demonstrate older livers exhibit increased ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuates older HIRI phenotypes. Mass spectrometry reveals that fat mass and obesity-associated gene (FTO) expression is downregulated in older livers, especially during HIRI. Overexpressing FTO improves older HIRI phenotypes by inhibiting ferroptosis. Mechanistically, acyl-CoA synthetase long chain family 4 (ACSL4) and transferrin receptor protein 1 (TFRC), two key positive contributors to ferroptosis, are FTO targets. For ameliorative effect, FTO requires the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrate nicotinamide mononucleotide can upregulate FTO demethylase activity, suppressing ferroptosis and decreasing older HIRI. Collectively, these findings reveal an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO to improve graft function after older donor liver transplantation.

Regional characteristics and spatial correlation of haze pollution: Interpretative system analysis in cities of Fenwei Plain in China.

Urban agglomeration is an important model for promoting global economic development and has made important contributions to global economic integration. However, as the core area of urbanization and industrialization, urban agglomerations also contribute to air pollutant emissions primarily due to the agglomeration of population and industry. The mutual influence of air pollution between different cities in urban agglomerations has brought significant challenges to global environmental governance. The Fenwei Plain is one of the most severely polluted areas in China. We collected daily average PM2.5 concentration data of 11 cities in the Fenwei Plain, China in 2019. We then developed an interpretive structural model to statistically analyze the spatial correlation and hierarchical transmission of haze pollution between the 11 cities. The results showed that haze pollution has a strong systematic correlation between the 11 cities, and a regional haze pollution community has formed throughout the region. Haze pollution also exhibits evident transmission and spatial correlations between the cities. The transmission starts from Baoji and ends at Sanmenxia, with mutual interactions between the cities of Xi'an, Xianyang, Weinan, Tongchuan, Jinzhong, Lvliang, Linfen, Yuncheng, and Luoyang. Thus, air pollution prevention and control in the Fenwei Plain should consider the spatial correlation of haze pollution between different cities, especially in autumn and winter, and should rationally be implemented in key urban cluster areas. We recommend building a coordinated governance between cities to improve the overall air quality. Our findings shed a light for coordinated pollution management in urban agglomerations worldwide.

Classification of colorectal cancer into clinically relevant subtypes based on genes and mesenchymal cells.

BACKGROUND: Most studies on subtype identification of colorectal cancer (CRC) were based on expressions of either genes or immune cells. However, few studies have hitherto used the combination of genes with immune and stroma cells for subtype identification. METHODS: Dataset GSE17536 was obtained from the Gene Expression Omnibus (GEO) database. The xCell algorithm was used to estimate the composition and density of 64 cell types, including immune and stroma cell types. Clustering analysis was then conducted on the top 3000 most variable genes from a total of 20,174 genes for CRC subtype identification. We employed the ensemble method of Similarity network fusion and 112 Consensus Clustering (SNF-CC) for cancer subtype identification. Reactome pathway analysis was conducted to identify the impact of the representative genes on prognosis. The results were validated in independent gene expression data from dataset GSE17537. RESULTS: In this study, we identified 3 clinically relevant subtypes and their representative genes, immune and stroma cells. Moreover, we confirmed the correlation of these subtypes with their clinical characteristics. The representative genes of the subtype with poor prognosis correlated with extracellular matrix structural constituent, while the subtype with good prognosis correlated with Toll-like receptor signaling pathway or chemokine signaling pathway. However, different subtypes were associated with distinct cell subtypes; the subtype with poor prognosis had a high abundance of fibroblasts and endothelial cells; the subtype with median prognosis had a higher abundance of immune cells, such as CD4 + T-cell, Th2 cells and aDC; the subtype with good prognosis had a higher abundance of NKT. CONCLUSION: This study highlights the utility of immune and innate cells, especially during gene analysis, to provide the theoretical basis for personalized treatment in colorectal cancer patients.

Chemotherapy combined with radiotherapy can benefit more unresectable HCC patients with portal and/or hepatic vein invasion: a retrospective analysis of the SEER database.

Background: The purpose of this study is to evaluate the effects of chemotherapy and radiotherapy on the prognosis of unresectable HCC patients with portal and/or hepatic vein invasion. Methods: A retrospective analysis of unresectable HCC patients with portal and/or hepatic vein invasion registered in the Surveillance, Epidemiology, End Results (SEER) database was performed. The propensity score-matching (PSM) method was used to balance differences between groups. Overall survival (OS) and cancer-specific survival (CSS) were the interesting endpoints. OS was calculated from the date of diagnosis to the date of death caused by any cause or the last follow-up. CSS was defined as the interval between the date of diagnosis and date of death due only to HCC or last follow-up. OS and CSS were analyzed by using Kaplan-Meier analysis, Cox proportional hazards model, and Fine-Gray competing-risk model. Results: A total of 2,614 patients were included. 50.2% patients received chemotherapy or radiotherapy and 7.5% patients received both chemotherapy and radiotherapy. Compared to the untreated group, chemotherapy or radiotherapy (COR) (HR = 0.538, 95% CI 0.495-0.585, p < 0.001) and chemotherapy and radiotherapy (CAR) (HR = 0.371, 95% CI 0.316-0.436, p < 0.001) showed better OS. In the COR group, Cox analysis results showed AFP, tumor size, N stage and M stage were independent risk factor of OS. Competing-risk analysis results showed AFP, tumor size and M stage were independent risk factor of CSS. In the CAR group, AFP and M stage were independent risk factors of OS. Competing-risk analysis results showed M stage were independent risk factor of CSS. Kaplan Meier analysis showed chemotherapy combined with radiotherapy significantly improves OS (10.0 vs. 5.0 months, p < 0.001) and CSS (10.0 vs. 6.0 months, p = 0.006) than monotherapy. Conclusion: AFP positive and distant metastasis are the main risk factors affecting OS and CSS of unresectable HCC patients with portal and/or hepatic vein invasion. Chemotherapy combined with radiotherapy significantly improves OS and CSS of unresectable HCC patients with portal and/or hepatic vein invasion.

MSC-derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration.

Aging is one of the critical factors to impair liver regeneration leading to a high incidence of severe complications after hepatic surgery in the elderly population without any effective treatment for clinical administration. As cell-free nanotherapeutics, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated the therapeutic potentials on liver diseases. However, the effects of MSC-EVs on the proliferation of aged hepatocytes are largely unclear. In this study, we found MSCs could reduce the expression of senescence-associated markers in the liver and stimulate its regeneration in aged mice after receiving a two-thirds partial hepatectomy (PHx) through their secreted MSC-EVs. Using RNA-Seq and AAV9 vector, we mechanistically found that these effects of UC-MSC-EVs partially attributed to inducing Atg4B-related mitophagy. This effect repairs the mitochondrial status and functions of aged hepatocytes to promote their proliferation. And protein mass spectrum analysis uncovered that DEAD-Box Helicase 5 (DDX5) enriches in UC-MSC-EVs, which interacts with E2F1 to facilitate its nuclear translocation for activating the expression of Atg4B. Collectively, our data show that MSC-EVs act nanotherapeutic potentials in anti-senescence and promoting regeneration of aged liver by transferring DDX5 to regulate E2F1-Atg4B signaling pathway that induce mitophagy, which highlights the clinical application valuation of MSC-EVs for preventing severe complications in aged population receiving liver surgery.