Hepatocellular carcinoma (HCC), a prevalent liver malignancy, is closely associated with dysregulated lipid metabolism. Endocrine disrupting chemicals (EDCs) can bind to nuclear receptors (NRs) and potentially induce carcinogenesis, but their specific influence on HCC progression remains unclear. To investigate this relationship, we combined bioinformatic analyses with experimental validation in the present study. Differential expression analysis of public HCC datasets (GSE14323, GSE17548, and GSE25097) identified candidate genes, which were further refined via weighted gene co-expression network analysis (WGCNA) and machine learning algorithms (RF and SVM-RFE), pinpointing NPY1R and CLEC1B as key genes. Their downregulation in HCC was validated in an independent dataset (GSE54236) and in clinical liver tissues (n = 118). Molecular docking and dynamics simulations prioritized perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) as high-affinity binders to the proteins encoded by these genes. In vitro, exposure to PFOA/PFOS dose-dependently suppressed NPY1R and CLEC1B expression in HepG2 cells. Chromatin immunoprecipitation assays revealed that PFOA/PFOS inhibit the binding of estrogen receptors (ERα and ERβ) to the promoters of these genes, leading to reduced transcription and increased lipid accumulation. Knockdown of ERα/ERβ exacerbated, while their overexpression rescued, the lipid-metabolic disruption induced by PFOA/PFOS. These findings indicate that EDCs such as PFOA and PFOS may promote HCC progression by disrupting lipid metabolism via interference with NR-dependent gene regulation, highlighting a novel environmental-toxicological axis in hepatocarcinogenesis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by unresolved inflammation, yet precise mechanisms linking immune metabolism to disease progression remain elusive. Here, we identified myeloid-expressed Mas, a G protein-coupled receptor, as a critical metabolic checkpoint in MASLD. Mas expression is elevated in hepatic myeloid cells from patients and diet-induced mouse models. Myeloid-specific Mas1 deletion attenuated MASLD by restraining glycolytic reprogramming and inflammatory senescence. Single-cell RNA sequencing analyses revealed that this deletion specifically impaired the glycolytic flux and subsequent pathogenic differentiation of FN1⁺CCR2⁺ monocyte precursors. Mechanistically, Mas interacts with the glycolytic enzyme PKM2, enhancing lactate production that drives lactylation of the transcription factor Spi1 at lysine 208. Spi1-K208 lactylation promotes its nuclear localization and transcriptional activation of senescence-associated secretory phenotype (SASP) genes. Myeloid-specific Pkm2 ablation phenocopied the protective effect of Mas1 deletion, and PKM2 overexpression rescued the metabolic and transcriptional defects caused by Mas loss. Virtual screening identified theaflavin-3,3'-digallate (TFDG) as a Mas inhibitor that disrupts the Mas-PKM2 interaction. A macrophage membrane-coated nanoparticle (MM@NP-TFDG) delivered TFDG specifically to hepatic macrophages, suppressed the Mas-PKM2-Spi1 lactylation axis, and ameliorated MASLD pathology in vivo. Our findings define a novel Mas-PKM2-Spi1 lactylation axis that orchestrates glycolytic reprogramming, monocyte precursor differentiation, and macrophage-driven inflammation in MASLD, presenting a targeted nanotherapeutic strategy for its treatment.

Background:Epigenetic mechanisms, including microRNAs (miRNAs), are increasingly recognized as crucial regulators of organ fibrosis. In this study, we investigated the role of miR-24 in hepatic stellate cell (HSC) activation and liver fibrosis. Methods:miR-24 expression was analyzed in carbon tetrachloride (CCl4)-induced liver fibrosis and activated HSCs using quantitative real-time PCR (qRT-PCR). Gain- and loss-of-function experiments of miR-24 were performed in vitro. Western blotting, qRT-PCR, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, luciferase reporter assays, bioinformatics analysis, and chromatin immunoprecipitation PCR (ChIP-PCR) were performed to examine the molecular mechanisms of miR-24. Serum miR-24 levels were measured in patients with liver cirrhosis and further analyzed by subgroup. Results:We observed significant downregulation of miR-24 in CCl4-induced liver fibrosis and activated HSCs. Functional assays showed that miR-24 overexpression markedly inhibited HSC activation and migration, whereas miR-24 inhibition had the opposite effects. Mechanistically, ALK4 was identified as a direct target of miR-24: miR-24 bound the 3'UTR of ALK4 mRNA, thereby suppressing Smad3 phosphorylation and downstream fibrosis-associated signaling pathways. Furthermore, the transcription factor RUNX1 was induced during HSC activation, and it transcriptionally repressed miR-24 expression. Clinically, serum miR-24 levels were significantly lower in patients with liver cirrhosis than in healthy controls and were negatively correlated with Child-Pugh grade. Conclusion:Our findings suggest that the RUNX1/miR-24/ALK4 axis plays a crucial role in HSC activation and migration. miR-24 may serve as a biomarker for liver fibrosis screening, representing a potential therapeutic target for anti-fibrotic intervention.

BACKGROUND:Anaemia is a common complication after kidney transplantation, and the haemoglobin concentration is one of the main criteria for identifying anaemia. Moreover, artificial intelligence methods have developed rapidly in recent years, are widely used in the medical field and have achieved good results. OBJECTIVE:To optimize the process of constructing a clinical prediction model based on machine learning and improve related technologies. A classification prediction model for the haemoglobin concentration after kidney transplantation was constructed. METHODS:Real-world data from 854 kidney transplant patients in a Grade A tertiary hospital were retrospectively extracted. An imputation method combining the K-nearest neighbour algorithm and multilayer perceptron was used to fill in missing values in the dataset. Recursive feature elimination and extreme gradient boosting were used to rank and screen the importance of patient features and reduce the dimensionality of the features. Before the classification prediction model was established, the number of classification categories was determined first, and the optimal ideal cluster was approximated by the ideal cluster under each classification number and the similarity between the ideal cluster and the actual cluster. Finally, five kinds of machine learning methods, random forest, extreme gradient boosting, light gradient boosting machine, linear support vector classifier and support vector machine, were used to establish classification prediction models, and error-correcting output codes were used to optimize each model. A classification prediction model for abnormal haemoglobin concentrations after kidney transplantation was constructed, and the prediction effect was verified. RESULTS:The imputation method combining the K-nearest neighbour algorithm and multilayer perceptron has a better effect on the imputation of missing values than do the commonly used imputation methods. Among the machine learning methods used for modelling, the prediction results of the tree model are improved to a certain degree after the error-correcting output code optimization. The final model with the best effect is optimized extreme gradient boosting, and the prediction accuracies before and after model optimization are 85.98% and 87.22%, respectively. CONCLUSIONS:The accuracy of the machine learning classification prediction model established by the optimized modelling method and process reached 87.22%, which can assist doctors in preoperative risk prediction.

BACKGROUND:ACK1, a non-receptor tyrosine kinase, phosphorylates various substrates involved in cancer progression. Its oncogenic activity is driven by gene amplification, mutations, and post-translational modifications. However, additional regulatory mechanisms that govern ACK1 activity remain to be fully understood. Liquid-liquid phase separation (LLPS) has emerged as a key mechanism of cellular compartmentalization, controlling the spatiotemporal dynamics of signaling pathways. METHODS:Expression plasmids and corresponding mutants were generated using molecular cloning techniques. Protein expression and localization were assessed through western blotting, immunofluorescence, and confocal microscopy. LLPS properties were evaluated using time-lapse imaging, photobleaching, optoDroplet assays, and in vitro droplet formation assays. Cellular functions were examined through colony formation and wound-healing assays. STAT5 signaling activation was assessed by western blotting, co-immunoprecipitation (Co-IP), immunofluorescence, RNA sequencing (RNA-Seq), and Gene Set Enrichment Analysis (GSEA). RESULTS:We demonstrate that ACK1 is frequently amplified and overexpressed in lung squamous cell carcinoma (LUSC). In LUSC cells, ACK1 undergoes LLPS, a process that depends on the intrinsically disordered region (IDR, 96-156 aa) but is independent of its kinase activity. We identify that the IDR induces droplet formation, with the 143-156 aa segment being essential for this activity. Furthermore, our data reveal that ACK1 phosphorylates STAT5 in LUSC cells. ACK1 condensates recruit the non-catalytic adaptors NCK1 and NCK2 and enhance STAT5 signaling. These condensates promote STAT5 nuclear localization and transcriptional activity, thereby facilitating LUSC cell growth and migration. CONCLUSIONS:Our findings highlight the crucial role of ACK1 condensates in oncogenic STAT5 signaling and suggest that targeting the formation of ACK1 condensates could serve as a potential therapeutic strategy for LUSC.

BACKGROUND:Sodium MRI (23Na-MRI) measuring tissue sodium content may directly assess the corticomedullary gradient (CMG) in the kidney. However, it is understudied in transplanted kidneys. PURPOSE:To investigate associations between CMG in renal graft and urine concentrating ability, estimated glomerular filtration rate (eGFR), and biopsy-determined fibrosis scores, and to determine if CMG could differentiate between renal grafts with superior and inferior graft function. STUDY TYPE:Prospective. SUBJECTS:57 participants (39 males) with renal transplantation. FIELD STRENGTH/SEQUENCE:3D T2-weighted turbo spin echo sequence and 23Na-MR imaging at 3 T. ASSESSMENT:Urine specific gravity and eGFR were assessed as measures of kidney function. Thirty-eight participants underwent biopsy within 2 days of MRI, and the Banff fibrosis score was assessed. The average medulla to cortex ratio (MCR) was determined from 23Na-MRI analysis. Transplanted kidneys were divided into those with superior graft function (SGF, eGFR ≥ 45 mL/min/1.73 m2) and inferior graft function (IGF, eGFR < 45 mL/min/1.73 m2) groups. STATISTICAL TESTS:Correlation analysis (Pearson or Spearman coefficient, r), intraclass correlation coefficient, and area under the receiver-operating characteristic curve (AUC). RESULTS:MCR was 1.27 ± 0.11 and mean urine specific gravity was 1.013 ± 0.005. MCR was significantly correlated with mean urine specific gravity (r = 0.32) and with eGFR (r = 0.795). MCR distinguished IGF (n = 42) from SGF (n = 15) with an AUC of 0.851 (95% CI: 0.732, 0.931) with a cutoff of ≥ 1.295. MCR was significantly correlated with the Banff fibrosis score of tubulitis in areas of interstitial fibrosis and tubular atrophy (t-IFTA) (r = 0.347). DATA CONCLUSION:23Na-MRI has the potential to show the CMG in transplanted kidneys, with MCR being correlated with urine concentrating ability. In addition, the transplanted kidney CMG was related to eGFR and the Banff fibrosis score t-IFTA. EVIDENCE LEVEL:Level 2. TECHNICAL EFFICACY:Stage 2.

Mas, a newly identified G-protein-coupled receptor, is prevalent in myeloid-derived immune cells and plays a key role in inflammation. This study investigates Mas signaling and neutrophil extracellular traps (NETs) in acute liver failure (ALF), aiming to elucidate their mechanisms. Male Mas1-/- and wild-type mice, aged 6-8 weeks, receive intraperitoneally injected with lipopolysaccharide (LPS)/D-galactosamine (D-Gal) (L/G) to study NETs formation. Hepatic Mas expression increases in WT-L/G mice, whereas systemic Mas1 knockout significantly reduces L/G-induced NETs and hepatotoxicity. Antibiotics treatment and co-housing (Mas1-/--L/G and WT-L/G mice) experiments show that gut flora influences the disease phenotype in Mas1-/--L/G mice. Fecal metabolite analysis suggests that mice may be protected by reduced deoxycholic acid (DCA) production in Mas1-/- activated hepatic farnesoid X receptor (FXR), suppressing sphingosine-1-phosphate (S1P)-dependent NETs. Additionally, Mas1-/- also activates the FXR-S1P-NETs axis in the liver by inhibiting SHP2. Single-cell sequencing shows decreased interaction between endothelial cells and Cldn1+CD177+ senescent neutrophils through Col4a1-CD44. This inhibits S1P-induced Raf signaling pathway activation and NETs formation. Mas signaling significantly impacts NETs formation, highlighting its potential as an anti-inflammatory therapeutic target for ALF.

Postischemic acute kidney injury (AKI) is a common clinical complication and often fatal, with no effective treatment available. Little is known about the role of leukocytes trapped in renal vessels during ischemia-reperfusion injury (IRI) in the postischemic AKI. We designed a new animal model in rats with preforming renal artery lavage prior to IRI to investigate the effect of diminishing the residual circulating leukocytes on kidney damage and inflammation. Moreover, the functional changes of macrophages in hypoxia reoxygenation condition were also analyzed. We found pre-ischemic renal lavage significantly decreased the serum creatinine and blood urea nitrogen levels, and downregulated the mRNA and protein expressions in kidneys and urinary secretion of kidney injury molecule-1 of rats after IRI. The renal pathological damage caused by IRI was also ameliorated by pre-ischemic renal lavage, as evidenced by fewer cast formation, diminished morphological signs of AKI in the tissue at 24 hours after IRI. Pre-ischemic renal lavage reduced the numbers of infiltrating CD68(+)macrophages and MPO(+)neutrophils. The mRNA expression of pro-inflammatory mediator in IRI kidneys and the levels of pro-inflammatory cytokines in circulatory system and urine were also reduced due to pre-ischemic lavage. Compared with nontreated rats with IRI, pre-ischemic renal lavage significantly reduced the phosphorylation levels of ERK and p65 subunit of NF-kappa B in the kidney after IRI. In addition, we found hypoxia/reoxygenation could promote the expression of pro-inflammatory mediators and inhibit the expression of anti-inflammatory factors by regulating ERK/NF-kappa B signaling pathway. Thus, pre-ischemic renal lavage could clearly reduce the renal damage after IRI by attenuating inflammation, and macrophages trapped in renal vessels during IRI could be important pathogenic factors driving tissue injury.

Gliomas, the most prevalent and lethal form of brain cancer, are known to exhibit metabolic alterations that facilitate tumor growth, invasion, and resistance to therapies. Peroxisomes, essential organelles responsible for fatty acid oxidation and reactive oxygen species (ROS) homeostasis, rely on the receptor PEX5 for the import of metabolic enzymes into their matrix. However, the prognostic significance of peroxisomal enzymes for glioma patients remains unclear. In this study, we elucidate that PEX5 is indispensable for the cell growth, migration, and invasion of glioma cells. We establish a robust prognosis model based on the expression of peroxisomal enzymes, whose localization relies on PEX5. This PEX5-dependent signature not only serves as a robust prognosis model capable of accurately predicting outcomes for glioma patients, but also effectively distinguishes several clinicopathological features, including the grade, isocitrate dehydrogenase (IDH) mutation, and 1p19q codeletion status. Furthermore, we developed a nomogram that integrates the prognostic model with other clinicopathological factors, demonstrating highly accurate performance in estimating patient survival. Patients classified into the high-risk group based on our prognostic model exhibited an immunosuppressive microenvironment. Finally, our validation reveals that the elevated expression of GSTK1, an antioxidant enzyme within the signature, promotes the cell growth and migration of glioma cells, with this effect dependent on the peroxisomal targeting signal recognized by PEX5. These findings identify the PEX5-dependent signature as a promising prognostic tool for gliomas.

Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen-induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein-coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single-cell RNA sequencing, spatial transcriptomics, and hour-long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell-specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF-κB/TNF-α signaling pathway due to myeloid-Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets.

Introduction: Given the increase in ultra-processed food (UPF) consumption, their potential health effects have aroused concern. Whether UPF consumption is associated with cancer and cardiovascular disease mortality is debatable. This study evaluates the association of UPF consumption with mortality. Methods: A total of 108,714 U.S. adults from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (1993-2001), 208,051 UK adults from UK Biobank (2006-2010), and 41,070 U.S. adults from National Health and Nutrition Examination Survey (1999-2018) were included. Dietary data were collected by dietary questionnaire and classified using the NOVA classification. UPF consumption was expressed as the weight proportion of UPFs in total foods consumed. Cox proportional hazard models were used to calculate hazard ratios and 95% CIs. Mediation analysis was used to evaluate whether multiple metabolic pathways mediated the associations in UK Biobank. Analyses were performed in 2022-2023. Results: Combined analyses of the three cohorts showed that those with the highest quartile of UPF consumption had higher risks of all-cause mortality (hazard ratio, 1.16; 95% CI, 1.11-1.20) and cardiovascular disease mortality (hazard ratio, 1.17; 95% CI, 1.06-1.28) compared to the lowest quartile of UPF consumption. UPF consumption was not associated with cancer mortality risk. Biomarkers of liver function have the greatest mediating effects on all-cause mortality (20.3%), and biomarkers of inflammation have the greatest mediating effects on cardiovascular disease mortality (29.2%). Conclusions: Higher UPF consumption was associated with increased all-cause and cardiovascular disease mortality risk, with multiple metabolic pathways playing mediating roles. Am J Prev Med 2024;66(2):315-323. (c) 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

BACKGROUND Glioblastomas are universally lethal brain tumors containing tumor-propagating glioblastoma stem cells (GSCs). EGFR gene amplification or mutation is frequently detected in GBMs and is associated with poor prognosis. However, EGFR variants in GSCs and their role in the maintenance of GSCs and progression of GBM are unclear. METHODS EGFR variants were detected through bioinformatic HISAT-StringTie-Ballgown pipeline and verified through 5' RACE, RT-PCR, ribonuclease protection, and northern blotting assays. EGFRx function was investigated through neurosphere, cell viability, intracranial xenograft and RNA-seq assays. EGFRx-STAT5 signaling was investigated through western blotting, coimmunoprecipitation, immunofluorescence, luciferase reporter, RT-PCR and CUT&Tag assays. RESULTS We identified a novel EGFR variant (EGFRx), that is specifically expressed in GSCs. Unlike the EGFRvIII variant, which lacks exons 2-7, EGFRx is characterized by the absence of exons 2-14, and encodes an EGFR protein that does not possess the entire extracellular ligand-binding domain. We observed that EGFRx exhibits significant glycosylation, is required for GSC self-renewal, proliferation, and tumorigenesis, and highly active in glioblastomas compared to normal brain tissue. Mechanistically, EGFRx constitutively and specifically activates STAT5 in GSCs through spontaneous asymmetric dimerization of the kinase domain. CONCLUSIONS EGFRx plays essential roles in the maintenance of the GSC phenotype through constitutive activation of STAT5 and promotes GBM progression, suggesting that EGFRx-STAT5 signaling represents a promising therapeutic target for GBM.

AbstractIntron retention (IR) constitutes a less explored form of alternative splicing, wherein introns are retained within mature mRNA transcripts. This investigation demonstrates that the cell division cycle (CDC)‐like kinase 2 (CLK2) undergoes liquid–liquid phase separation (LLPS) within nuclear speckles in response to heat shock (HS). The formation of CLK2 condensates depends on the intrinsically disordered region (IDR) located within the N‐terminal amino acids 1‐148. Phosphorylation at residue T343 sustains CLK2 kinase activity and promotes overall autophosphorylation, which inhibits the LLPS activity of the IDR. These CLK2 condensates initiate the reorganization of nuclear speckles, transforming them into larger, rounded structures. Moreover, these condensates facilitate the recruitment of splicing factors into these compartments, restricting their access to mRNA for intron splicing and promoting the IR. The retained introns lead to the sequestration of transcripts within the nucleus. These findings extend to the realm of glioma stem cells (GSCs), where a physiological state mirroring HS stress inhibits T343 autophosphorylation, thereby inducing the formation of CLK2 condensates and subsequent IR. Notably, expressing the CLK2 condensates hampers the maintenance of GSCs. In conclusion, this research unveils a mechanism by which IR is propelled by CLK2 condensates, shedding light on its role in coping with cellular stress.

OBJECTIVE:Lifestyle factors after cancer diagnosis could influence cancer survival. This study aimed to investigate the joint effects of smoking, physical activity, alcohol consumption, diet and sleep duration on all-cause, cancer and non-cancer mortality of cancer survivors in UK biobank. METHODS:The follow-up period concluded in December 2021, with post-diagnostic lifestyle factors assessed at baseline. A lifestyle score ranging from 0 to 5 was assigned based on adherence to the selected lifestyle factors. The study employed Cox regression models for hazard ratios (HRs) and Kaplan-Meier for survival rates, with stratified and sensitivity analyses to assess the robustness of our findings under various assumptions. RESULTS:During a median follow-up of 12.7 years, 5652 deaths were documented from 34,184 cancer survivors. Compared to scoring 0-1, the HRs (95% CIs) for all-cause mortality with lifestyle scores of 2, 3, 4, and 5 were 0.70 (95% CI: 0.64, 0.76), 0.57 (0.52, 0.62), 0.50 (0.45, 0.54) and 0.43 (0.38, 0.48), respectively. Specific cancer types, particularly digestive, breast, female reproductive, non-solid, and skin cancers, showed notable benefits from adherence to healthy lifestyle, with the HRs of 0.55 (0.39, 0.79), 0.54 (0.42, 0.70), 0.32 (0.19, 0.53), 0.58 (0.39, 0.86), and 0.36 (0.28, 0.46) for lifestyle score of 5, respectively. Stratified analyses indicated the association was particularly significant among those with normal/lower BMI and higher Townsend Deprivation Index (Pinteraction = 0.001 and < 0.001, respectively). CONCLUSIONS:Healthier lifestyles were significantly linked with reduced mortality among cancer survivors. These findings highlight the need for adherence to healthy lifestyle habits to improve survival.

The cancer burden in China is increasing. We aimed to assess the time trends in the prevalence of 16 modifiable risk factors involved in lifestyle, diet, infection, and air pollution between 1997 and 2025 based on the China Health and Nutrition Survey, the Global Burden of Disease website, and publically available studies. The population attributable fraction (PAF) and its 95% uncertainty interval (UI) from 2007 to 2035 were calculated to quantify the attributable cancer burden in major 12 anatomic sites using the comparative risk assessment method, considering a 10-year lag effect. As a result, 1,559,476 cancer cases (PAF = 54.1%, 95% UI: 36.8%-65.8%) from the 12 anatomic sites were attributable to these modifiable risk factors in 2007, with lung, liver, and gastric cancer raging the top three. It was predicted that by 2035, the attributable cancer cases would reach 1,680,098 (PAF = 44.2%, 95% UI: 29.1%-55.5%), with the top three of lung, liver, and colorectal cancer. Smoking, physical inactivity, insufficient fruit consumption, HBV infection, and Helicobacter pylori infection were the most attributable risk factors in 2007, contributing to 480,352, 233,684, 215,009, 214,455, and 187,305 associated cancer cases, respectively. In 2035, the leading factors for cancer would be smoking, physical inactivity, insufficient fruit intake, HPV infection, and HBV infection, resulting in 427,445, 424,327, 185,144, 156,535, and 154,368 cancer cases, respectively. Intervention strategies should be swiftly established and dynamically altered in response to risk factors like smoking, physical inactivity, poor fruit intake, and infectious factors that may cause a high cancer burden in the Chinese population.

OBJECTIVES:Although portal vein thrombosis (PVT) was thought to deteriorate portal hypertension and contribute to poor prognosis, risk stratification remains unclear. This study aimed to evaluate its effect on the risk of variceal rehemorrhage and to develop a competitive risk model in cirrhotic patients with PVT. METHODS:Cirrhotic patients with and without PVT admitted for acute variceal hemorrhage were retrospectively included after matching (1:1) for age, gender and etiology of cirrhosis from two tertiary centers with 1-year follow-up. Those with PVT were subsequently divided into the training and validation cohorts. Cox regression analysis was performed to identify risk factors and develop a competitive risk model, of which the predictive performance and optimal decision threshold were evaluated by C-index, competitive risk curves, calibration curves and decision curve analysis. RESULTS:Among 398 patients, PVT significantly increased the variceal rehemorrhage risk. Multivariate Cox regression analysis identified that the Child-Turcotte-Pugh score (P = 0.013), chronic PVT (P = 0.025), C-reactive protein (P < 0.001), and aspartate aminotransferase (P = 0.039) were independently associated with variceal rehemorrhage, which were incorporated into the competitive risk model, with high C-index (0.804 and 0.742 of the training and validation cohorts, respectively), risk stratification ability, and consistency. The optimal decision range of the threshold probability was 0.2-1.0. CONCLUSION:We confirmed the adverse effect of PVT on variceal rehemorrhage and developed a competitive risk model for variceal rehemorrhage in cirrhotic patients with PVT, which might be conveniently used for clinical decision-making.

Nonalcoholic fatty liver disease (NAFLD) is a growing health problem that is closely associated with insulin resistance and hereditary susceptibility. Exercise is a beneficial approach to NAFLD. However, the relief mechanism of exercise training is still unknown. In this study, mice on a normal diet or a high-fat diet (HFD), combined with Nω-nitro-L-arginine methyl ester, hydrochloride (L-NAME) mice, were either kept sedentary or were subjected to a 12-week exercise running scheme. We found that exercise reduced liver steatosis in mice with diet-induced NAFLD. The hepatic adenosine deaminases acting on RNA 2 (ADAR2) were downregulated in NAFLD and were upregulated in the liver after 12-week exercise. Next, overexpression of ADAR2 inhibited and suppression promoted lipogenesis in HepG2 cells treated with oleic acid (OA), respectively. We found that ADAR2 could down-regulate mature miR-34a in hepatocytes. Functional reverse experiments further proved that miR-34a mimicry eliminated the suppression of ADAR2 overexpression in lipogenesis in vitro. Moreover, miR-34a inhibition and mimicry could also affect lipogenesis in hepatocytes. In conclusion, exercise-induced ADAR2 protects against lipogenesis during NAFLD by editing miR-34a. RNA editing mediated by ADAR2 may be a promising therapeutic candidate for NAFLD.

Introduction Porcine anti-human lymphocyte immunoglobulin (pALG) has been used in kidney transplantation, but its impacts on the lymphocyte cell pool remain unclear. Methods We retrospectively analyzed 12 kidney transplant recipients receiving pALG, and additional recipients receiving rabbit anti-human thymocyte immunoglobulin (rATG), basiliximab, or no induction therapy as a comparison group. Results pALG showed high binding affinity to peripheral blood mononuclear cells (PBMCs) after administration, immediately depleting blood lymphocytes; an effect that was weaker than rATG but stronger than basiliximab. Single-cell sequencing analysis showed that pALG mainly influenced T cells and innate immune cells (mononuclear phagocytes and neutrophils). By analyzing immune cell subsets, we found that pALG moderately depleted CD4+T cells, CD8+T cells, regulatory T cells, and NKT cells and mildly inhibited dendritic cells. Serum inflammatory cytokines (IL-2, IL-6) were only moderately increased compared with rATG, which might be beneficial in terms of reducing the risk of untoward immune activation. During 3 months of follow-up, we found that all recipients and transplanted kidneys survived and showed good organ function recovery; there were no cases of rejection and a low rate of complications. Discussion In conclusion, pALG acts mainly by moderately depleting T cells and is thus a good candidate for induction therapy for kidney transplant recipients. The immunological features of pALG should be exploited for the development of individually-optimized induction therapies based on the needs of the transplant and the immune status of the patient, which is appropriate for non-high-risk recipients.

Numerous studies have revealed associations between high intake of whole grains and reduced risk of various cancers. Yet, in recent decades, the traditional Chinese diets have been challenged by reduction in whole grains and increase in refined grains. To assess the impact of this dietary transition on cancer prevention, we analyzed the time trend of whole grain intake using nationally representative sampling data of over 15 thousand individuals from the China Health and Nutrition Survey. We applied the comparative risk assessment method to estimate the population attributable fraction of cancers due to insufficient whole grain intake from 1997 to 2011 and projected the trend of whole grain intake and the associated burden of cancers to 2035. We found a significant decrease of approximately 59% of whole grain intake in the Chinese population from 1997 to 2011. Compared with 1997, insufficient intake of whole grains was responsible for 9940 more cases of breast cancer, 12,903 more cases of colorectal cancer and 434 more cases of pancreatic cancer in 2011. Our projections suggest that if every Chinese would consume 125 g whole grain per day as recommended by the latest Chinese Dietary Guidelines, 0.63% bladder cancer, 8.98% breast cancer, 15.85% colorectal cancer, 3.86% esophageal cancer, 2.52% liver cancer and 2.22% pancreatic cancer (totaling 186,659 incident cases) could theoretically be averted by 2035. Even if everyone maintained the 2011 whole grain intake level, an estimated 8.38% of cancer events could still be prevented by 2035.