Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage.

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Synergistic improvement of humus formation in compost residue by fenton-like and effective microorganism composite agents.

Improving the humification of compost through a synergistic approach of biotic and abiotic methods is of great significance. This study employed a composite reagent, comprising Fenton-like agents and effective microorganisms (EM) to improve humification. This composite reagent increased humic-acid production by 37.44 %, reaching 39.82 g kg-1, surpassing the control group. The composite reagent synergistically promoted micromolecular fulvic acid and large humic acid production. Collaborative mechanism suggests that Fenton-like agents contributed to bulk residue decomposition and stimulated the evolution of microbial communities, whereas EMs promoted highly aromatic substance synthesis and adjusted the microbial community structure. Sequencing analysis indicates the Fenton-like agent initiated compost decomposition by Firmicutes, and EM reduced the abundance of Virgibacillus, Lentibacillus, and Alcanivorax. Applied as an organic fertilizer in Brassica chinensis L. plantations, the composite reagent considerably improved growth and photosynthetic pigment content. This composite reagent with biotic and abiotic components provides a learnable method for promoting humification.

CX3CR1 deficiency promotes resolution of hepatic ischemia-reperfusion injury by regulating homeostatic function of liver infiltrating macrophages.

Hepatic ischemia-reperfusion injury(HIRI) remains to be an unsolved risk factor that contributes to organ failure after liver surgery. Our clinical retrospective study showed that lower donor liver CX3-C chemokine receptor-1(CX3CR1) mRNA expression level were correlated with upregulated pro-resolved macrophage receptor MERTK, as well as promoted restoration efficiency of allograft injury in liver transplant. To further characterize roles of CX3CR1 in regulating resolution of HIRI, we employed murine liver partial warm ischemia-reperfusion model by Wt & Cx3cr1-/- mice and the reperfusion time was prolonged from 6 h to 4-7 days. Kupffer cells(KCs) were depleted by clodronate liposome(CL) in advance to focus on infiltrating macrophages, and repopulation kinetics were determined by FACS, IF and RNA-Seq. CX3CR1 antagonist AZD8797 was injected i.p. to interrogate potential pharmacological therapeutic strategies. In vitro primary bone marrow macrophages(BMMs) culture by LXR agonist DMHCA, as well as molecular and functional studies, were undertaken to dissect roles of CX3CR1 in modulating macrophages cytobiological development and resolutive functions. We observed that deficiency or pharmacological inhibition of CX3CR1 facilitated HIRI resolution via promoted macrophages migration in CCR1/CCR5 manner, as well as enhanced MerTK-mediated efferocytosis. Our study demonstrated the critical roles of CX3CR1 in progression of HIRI and identified it as a potential therapeutic target in clinical liver transplantation.

Comparative prognosis and risk assessment in gallbladder neuroendocrine neoplasms versus adenocarcinomas.

Background: Gallbladder neuroendocrine neoplasms (GB-NENs) are a rare malignant disease, with most cases diagnosed at advanced stages, often resulting in poor prognosis. However, studies regarding the prognosis of this condition and its comparison with gallbladder adenocarcinomas (GB-ADCs) have yet to yield convincing conclusions. Methods: We extracted cases of GB-NENs and GB-ADCs from the Surveillance, Epidemiology, and End Results (SEER) database in the United States. Firstly, we corrected differences in clinical characteristics between the two groups using propensity score matching (PSM). Subsequently, we visualized and compared the survival outcomes of the two groups using the Kaplan-Meier method. Next, we employed the least absolute shrinkage and selection operator (LASSO) regression and Cox regression to identify prognostic factors for GB-NENs and constructed two nomograms for predicting prognosis. These nomograms were validated with an internal validation dataset from the SEER database and an external validation dataset from a hospital. Finally, we categorized patients into high-risk and low-risk groups based on their overall survival (OS) scores. Results: A total of 7,105 patients were enrolled in the study, comprising 287 GB-NENs patients and, 6,818 GB-ADCs patients. There were substantial differences in clinical characteristics between patients, and GB-NENs exhibited a significantly better prognosis. Even after balancing these differences using PSM, the superior prognosis of GB-NENs remained evident. Independent prognostic factors selected through LASSO and Cox regression were age, histology type, first primary malignancy, tumor size, and surgery. Two nomograms for prognosis were developed based on these factors, and their performance was verified from three perspectives: discrimination, calibration, and clinical applicability using training, internal validation, and external validation datasets, all of which exhibited excellent validation results. Using a cutoff value of 166.5 for the OS nomogram score, patient mortality risk can be identified effectively. Conclusion: Patients with GB-NENs have a better overall prognosis compared to those with GB-ADCs. Nomograms for GB-NENs prognosis have been effectively established and validated, making them a valuable tool for assessing the risk of mortality in clinical practice.

Ecological and human health hazards of soil heavy metals after wildfire: A case study of Liangshan Yi autonomous prefecture, China.

Soil samples were collected in at different depths from the conflagration area in Liangshan Yi Autonomous Region, China, to investigate the distribution characteristics and ecological and human health risks of heavy metals after a wildfire. The samples collected comprise wildfire ash (WA) above the soil surface, ash soil (AS) 0-5 cm, and plain soil (PS) 5-15 cm below the soil surface. Additionally, reference soil (RS) was collected from a nearby unburned area at the same latitude as the conflagration area. The results showed that the concentrations of zinc (Zn), copper (Cu), lead (Pb), and cadmium (Cd) in the WA and AS were significantly higher than in reference soil (RS) (p < 0.05). Concentrations of Pb in the PS were 2.52 times higher than that in RS (17.9 mg kg-1) (p < 0.05). The AS and WA had the highest Index of potential ecological risks (RI > 600). In addition, The Cd in AS and WA contributed the most to the highest Improved nemerow index (INI) and RI with a contribution of more than 80%. The concentration of heavy metals was used to establish non-carcinogenic effects and cancer risks in humans via three exposure pathways: accident ingestion of soil, dermal contact with soil, and inhalation of soil particles. Hazard index (HI) values of each sample were all less than 1, indicating the non-carcinogenic risk was within the acceptable range and would not adversely affect the local population's health. The Cancer risk (CR) values of Cr, As, Cd, and Ni were all below 1 × 10-6, indicating that heavy metal pollution from this wildfire did not pose a cancer risk to residents.

Effects of different extraction methods on the structural and biological properties of Hericium coralloides polysaccharides.

In current study, polysaccharides from Hericium coralloides were extracted by heat reflux, acid-assisted, alkali-assisted, enzyme-assisted, ultrasonic-assisted, cold water, pressurized hot water, hydrogen peroxide/ascorbic acid system and acid-chlorite delignification methods, which were named as HRE-P, ACE-P, AAE-P, EAE-P, UAE-P, CWE-P, PHE-P, HAE-P, and ACD-P, respectively. Their physicochemical properties, structural characteristics, and antioxidant activities were investigated and compared. Experimental outcomes indicated notable variations in the extraction yields, chemical compositions, monosaccharide constituents and molecular weights of the obtained nine polysaccharides. HRE-P demonstrated the highest activity against ABTS and OH radicals, CWE-P against ABTS, DPPH, and superoxide radicals, and UAE-P against DPPH radicals. In addition, UAE-P, CWE-P, and HAE-P exhibited better protective effects on L929 cells, when compared to the other obtained polysaccharides. Additionally, correlation analysis indicated that monosaccharide composition and total polyphenol content were two prominent variables influencing the bioactivity of H. coralloides polysaccharides.

Development and validation of prealbumin-bilirubin score (preALBI score) for predicting long-term survival after hepatectomy for hepatocellular carcinoma: A multicenter analysis versus ALBI score.

BACKGROUND: The Albumin-Bilirubin (ALBI) score, widely used in predicting long-term prognosis for patients with hepatocellular carcinoma (HCC), has limitations due to serum albumin variability. This study aimed to develop and validate the Prealbumin-Bilirubin (preALBI) score as a reliable alternative. METHODS: A multicenter cohort of HCC patients who underwent hepatectomy was randomly divided into the training and validation cohorts. The preALBI score was developed using Cox regression models within the training cohort, incorporating serum prealbumin and bilirubin levels as crucial determinants. The survival predictive accuracy was evaluated and compared between the preALBI score with two other staging systems, including the ALBI score and the Child-Pugh grade. RESULTS: A total of 2409 patients were enrolled. In the training cohort, the preALBI score demonstrated superior performance in predicting long-term survival after hepatectomy. The preALBI score was associated with the best monotonicity of gradients (linear trend χ2: 72.84) and homogeneity (likelihood ratio χ2: 74.69), and the highest discriminatory ability (the areas under curves for 1-, 3-, and 5-year mortality: 0.663, 0.654, and 0.644, respectively). In addition, the preALBI was the most informative staging system in predicting survival (Akaike information criterion: 11325.65).The results remained consistent in both training and validation cohorts, indicating its reliable performance across different populations. CONCLUSION: The preALBI score, leveraging the stability of prealbumin, represents a promising tool for better patient stratification, providing more accurate prognostic predictions than the ALBI score and the Child-Pugh grade.

Prognostic Value of Serum α-Fetoprotein Level as an Important Characteristic of Tumor Biology for Patients Undergoing Liver Resection of Early-Stage Hepatocellular Carcinoma (BCLC Stage 0/A): A Large Multicenter Analysis.

BACKGROUND AND OBJECTIVE: According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, tumor burden and liver function, but not tumor biology, are the key factors in determining tumor staging and treatment modality, and evaluating treatment prognosis. The serum α-fetoprotein (AFP) level is an important characteristic of hepatocellular carcinoma (HCC) biology, and we aimed to evaluate its prognostic value for patients undergoing liver resection of early-stage HCC. METHODS: Patients who underwent curative liver resection for early-stage HCC were identified from a multi-institutional database. Patients were divided into three groups according to preoperative AFP levels: low (< 400 ng/mL), high (400-999 ng/mL), and extremely-high (≥ 1000 ng/mL) AFP groups. Overall survival (OS) and recurrence rates were compared among these three groups. RESULTS: Among 1284 patients, 720 (56.1%), 262 (20.4%), and 302 (23.5%) patients had preoperative low, high, and extremely-high AFP levels, respectively. The cumulative 5-year OS and recurrence rates were 71.3 and 38.9% among patients in the low AFP group, 66.3 and 48.5% in the high AFP group, and 45.7 and 67.2% in the extremely-high AFP group, respectively (both p < 0.001). Multivariate Cox regression analysis identified both high and extremely-high AFP levels to be independent risk factors of OS (hazard ratio [HR] 1.275 and 1.978, 95% confidence interval [CI] 1.004-1.620 and 1.588-2.464, respectively; p = 0.047 and p < 0.001, respectively) and recurrence (HR 1.290 and 2.050, 95% CI 1.047-1.588 and 1.692-2.484, respectively; p = 0.017 and p < 0.001, respectively). CONCLUSIONS: This study demonstrated the important prognostic value of preoperative AFP levels among patients undergoing resection for early-stage HCC. Incorporating AFP to prognostic estimation of the BCLC algorithm can help guide individualized risk stratification and identify neoadjuvant/adjuvant treatment necessity.

Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression.

BACKGROUND: With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. RESULTS: We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. CONCLUSIONS: These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.

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.

Nomogram for Estimation of Acute Liver Failure Risk in Spontaneous Ruptured Hepatocellular Carcinoma.

Purpose: Acute liver failure (ALF) is a severe complication of spontaneous ruptured hepatocellular carcinoma (SRHCC) that requires accurate prediction for effective treatment strategies. We aimed to develop a predictive nomogram to estimate the risk of ALF in patients with SRHCC undergoing treatment. Patients and Methods: We performed a retrospective analysis of historical data from 284 patients diagnosed with SRHCC at the First Hospital of Jilin University over the past decade. Variables were selected through univariate and multivariate logistic regression analyses, and a predictive nomogram was constructed. We evaluated its predictive accuracy against the Child-Pugh Score, R.MELD, and ALBI by assessing discrimination, calibration, and net clinical benefit. Results: Among the 284 patients, 65 developed ALF. The risk factors identified for model development included largest tumor size (LTS), platelet counts, prolonged prothrombin time, and elevated serum α-fetoprotein levels. The nomogram exhibited high accuracy in predicting ALF risk with a C-index of 0.91 (0.87-0.95). The Delong test showed a significant difference between the nomogram and the other three models (p<0.05). The calibration curve for the nomogram fit well, and the decision curve analysis revealed superior net benefit. The optimal cut-off point for the nomogram was determined to be 40, yielding sensitivity, specificity, positive predictive value, and negative predictive value of 83.10%, 87.20%, 65.90% and 94.60%, respectively. Conclusion: The nomogram we developed provides an optimized tool for predicting ALF in SRHCC patients. Its application can help determine individual patient's risk of ALF, enabling more rational and personalized treatment strategies.

Identification of multiple risk factors for colorectal cancer relapse after laparoscopic radical resection.

BACKGROUND: Colorectal cancer (CRC) is a common life-threatening disease that often requires surgical intervention, such as laparoscopic radical resection. However, despite successful surgeries, some patients experience disease relapse. Identifying the risk factors for CRC relapse can help guide clinical interventions and improve patient outcomes. AIM: To determine the risk factors that may lead to CRC relapse after laparoscopic radical resection. METHODS: We performed a retrospective analysis using the baseline data of 140 patients with CRC admitted to our hospital between January 2018 and January 2020. All included participants were followed up until death or for 3 years. The baseline data and laboratory indicators were compared between the patients who experienced relapse and those who did not experienced relapse. RESULTS: Among the 140 patients with CRC, 30 experienced relapse within 3 years after laparoscopic radical resection and 110 did not experience relapse. The relapse group had a higher frequency of rectal tumors with low differentiation and lymphatic vessel invasion than that of the non-relapse group. The expression of serum markers and the prognostic nutritional index were lower, whereas the neutrophil-to-lymphocyte ratio, expression of cytokeratin 19 fragment antigen 21-1, vascular endothelial growth factor, and Chitinase-3-like protein 1 were significantly higher in the relapse group than those in the non-relapse group. The groups did not differ significantly based on other parameters. Logistic regression analysis revealed that all the above significantly altered factors were independent risk factors for CRC relapse. CONCLUSION: We identified multiple risk factors for CRC relapse following surgery, which can be considered for the clinical monitoring of patients to reduce disease recurrence and improve patient survival.

Predicting lymph node metastasis in colorectal cancer: An analysis of influencing factors to develop a risk model.

BACKGROUND: Colorectal cancer (CRC) is a significant global health issue, and lymph node metastasis (LNM) is a crucial prognostic factor. Accurate prediction of LNM is essential for developing individualized treatment strategies for patients with CRC. However, the prediction of LNM is challenging and depends on various factors such as tumor histology, clinicopathological features, and molecular characteristics. The most reliable method to detect LNM is the histopathological examination of surgically resected specimens; however, this method is invasive, time-consuming, and subject to sampling errors and interobserver variability. AIM: To analyze influencing factors and develop and validate a risk prediction model for LNM in CRC based on a large patient queue. METHODS: This study retrospectively analyzed 300 patients who underwent CRC surgery at two Peking University Shenzhen hospitals between January and December 2021. A deep learning approach was used to extract features potentially associated with LNM from primary tumor histological images while a logistic regression model was employed to predict LNM in CRC using machine-learning-derived features and clinicopathological variables as predictors. RESULTS: The prediction model constructed for LNM in CRC was based on a logistic regression framework that incorporated machine learning-extracted features and clinicopathological variables. The model achieved high accuracy (0.86), sensitivity (0.81), specificity (0.87), positive predictive value (0.66), negative predictive value (0.94), area under the curve for the receiver operating characteristic (0.91), and a low Brier score (0.10). The model showed good agreement between the observed and predicted probabilities of LNM across a range of risk thresholds, indicating good calibration and clinical utility. CONCLUSION: The present study successfully developed and validated a potent and effective risk-prediction model for LNM in patients with CRC. This model utilizes machine-learning-derived features extracted from primary tumor histology and clinicopathological variables, demonstrating superior performance and clinical applicability compared to existing models. The study provides new insights into the potential of deep learning to extract valuable information from tumor histology, in turn, improving the prediction of LNM in CRC and facilitate risk stratification and decision-making in clinical practice.

PUS1 promotes hepatocellular carcinoma via mRNA pseudouridylation to enhance the translation of oncogenic mRNAs.

BACKGROUND AIMS: Pseudouridine is a prevalent RNA modification and is highly present in the serum and urine of patients with hepatocellular carcinoma (HCC). However, the role of pseudouridylation and its modifiers in HCC remains unknown. We investigated the function and underlying mechanism of pseudouridine synthase 1 (PUS1) in HCC. APPROACH RESULTS: By analyzing the TCGA data set, PUS1 was found significantly upregulated in human HCC specimens and positively correlated with tumor grade and poor prognosis of HCC. Knockdown of PUS1 inhibited cell proliferation and the growth of tumors in subcutaneous xenograft mouse model. Accordingly, increased cell proliferation, and tumor growth were observed in PUS1 overexpressing cells. Furthermore, overexpression of PUS1 significantly accelerates tumor formation in a mouse HCC model established by hydrodynamic tail vein injection, while knock-out of PUS1 decreased it. Additionally, PUS1 catalytic activity is required for HCC tumorigenesis. Mechanistically, we profiled the mRNA targets of PUS1 by utilizing Surveying Targets by APOBEC1-Mediated Profiling (STAMP) and found that PUS1 incorporated pseudouridine into mRNAs of a set of oncogenes, thereby endowing them with greater translation capacity. CONCLUSION: Our study highlights the critical role of PUS1 and pseudouridylation in HCC development, and provides new insight that PUS1 enhances the protein levels of a set of oncogenes, including IRS1 and c-MYC, via pseudouridylation-mediated mRNA translation.

Effect Of Urinary Kidney Injury Molecule-1 Levels On Short-Term Prognosis Of Chronic Heart Failure.

Objectives: To explore the influential elements of urinary kidney injury molecule-1 levels in chronic heart failure, and to judge its ability to predict 90-day rehospitalisation. METHODS: The cross-sectional case-control study was conducted from November 2020 to April 2021, at Hanzhong Central Hospital, China, and comprised adult patients having chronic heart failure with normal renal function in group A and healthy subjects in control group B. Patients in group A received anti-heart failure therapy for 1 week in hospital and were followed up for 90 days after discharge. Blood pressure (BP), kidney injury molecule-1, creatinine and serum pro- B-type natriuretic peptide levels were evaluated at baseline and 1 week after treatment in group A, while the samples were collected only at baseline in the control group B. Data was analysed using SPSS 22. RESULTS: Of the 102 subjects, 68(66.6%) were in group A; 44(64.7%) males and 24 (35.3%) females with mean age 62.38±9.51 years. The remaining 34(33.3%) subjects were in group B; 21(61.7%) males and 13(38.2%) females with mean age vs. 58.82±8.11 years. The urinary kidney injury molecule-1 level in group A was essentially on the increase compared to group B (p<0.05). After 1 week of treatment, the kidney injury molecule-1 level decreased compared to the baseline value in group A (p<0.05). Diastolic blood pressure and pro-B-type natriuretic peptide were the determinants of urinary kidney injury molecule-1 level, and urinary kidney injury molecule-1 level before discharge was significantly associated with rehospitalisation within 90 days (p<0.05). CONCLUSIONS: Urinary kidney injury molecule-1 level before discharge was a significant predictor of rehospitalisation within 90 days, and diastolic blood pressure and pro-B-type natriuretic peptide levels were the influencing factors of urinary kidney injury molecule-1. Also, urinary kidney injury molecule-1 levels were significantly raised in chronic heart failure.