Prognostic Value of Myosteatosis and Creatinine-to-Cystatin C Ratio in Patients with Pancreatic Cancer Who Underwent Radical Surgery.

BACKGROUND: Myosteatosis is correlated with poor prognosis in some malignancies. The creatinine-to-cystatin ratio (CCR) is revealed to predict gastric cancer prognosis. However, the prognostic abilities of CCR and the combination of CCR and myosteatosis in patients with pancreatic cancer (PC) who underwent radical surgery remains unclear. METHODS: The retrospective cohort study included 215 patients with PC who underwent radical surgery (January 2016-October 2021). Clinicopathological and serological data were collected on admission. Myosteatosis and other body composition indices were assessed by using computed tomography. The cutoff value of CCR was determined by using the Youden index. Risk factors responsible for poor overall survival (OS) and disease-free survival (DFS) were determined by the Cox proportional hazards model. RESULTS: The myosteatosis group included 104 patients (average age, 61.3 ± 9.1 years). The best cutoff value for CCR was 1.09. CCR ≤ 1.09 was an independent predictive biomarker inversely corelated with OS (P = 0.036). Myosteatosis was an independent risk factor associated with OS and DFS (P = 0.032 and P = 0.004, respectively). Patients with concomitant myosteatosis and CCR ≤ 1.09 had the worst OS (P = 0.016). CONCLUSIONS: Myosteatosis and CCR are prognostic biomarkers for survival in PC patients who underwent radical surgery. Patients with the coexistence of myosteatosis and CCR ≤ 1.09 deserve more attention.

Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma.

BACKGROUND: The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood. METHODS: Cells were separated from the single-cell RNA-sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell-cell communication. Flow cytometry, EDU staining, H3-Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF-NGFR promoting proliferation. RESULTS: The present study has revealed that during the process of T-cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF-NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1-mediated inhibition of unclear trans-localization of PREX1. Furthermore, PD-1 mAb acts synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF-NGFR communication was positively correlates with the PD-1/PDL-1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients. CONCLUSION: Inefficiency in NGF-NGFR communication impairs PD-1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

MicroRNA-192-5p downregulates Fat Mass and Obesity-associated Protein to aggravate renal ischemia/reperfusion injury.

Acute kidney injury (AKI) is a common disorder without effective therapy yet. Renal ischemia/reperfusion (I/R) injury is a common cause of AKI. MicroRNA miR-192-5p has been previously reported to be upregulated in AKI models. However, its functional role in renal I/R injury is not fully understood. This study aimed to investigate the effects and the underlying mechanism of miR-192-5p in renal I/R progression. Hypoxia/reoxygenation (H/R)-induced cell injury model in HK-2 cells and I/R-induced renal injury model in mice were established in this study. Cell counting kit-8 assay was performed to determine cell viability. Quantitative real-time PCR and western blot analysis were performed to detect gene expressions. Hematoxylin-eosin and periodic acid-Schiff staining were performed to observe the histopathological changes. Enzyme-linked immunosorbent assay was performed to detect the kidney markers' expression. In vivo and in vitro results showed that miR-192-5p was up-regulated in the I/R-induced mice model and H/R-induced cell model, and miR-192-5p overexpression exacerbated I/R-induced renal damage. Then, the downstream target of miR-192-5p was analyzed by combining the differentially expressed mRNAs and the predicted genes and confirmed using a dual-luciferase reporter assay. It was found that miR-192-5p was found to regulate fat mass and obesity-associated (FTO) protein expression by directly targeting the 3' untranslated region of FTO mRNA. Moreover, in vivo and in vitro studies unveiled that FTO overexpression alleviated renal I/R injury and promoted HK-2 cell viability via stimulating autophagy flux. In conclusion, miR-192-5p aggravated I/R-induced renal injury by blocking autophagy flux via down-regulating FTO.

Silica Nanoparticles Promote the Megakaryocyte Maturation and Differentiation: Potential Implications for Hematological Homeostasis.

Silica nanoparticles (SiO2 NPs) have been widely applied in diverse areas, thus causing the extensive release through multiple routes. Their toxicological effects, especially for the disturbance in hematological homeostasis, have raised public concern. Considering the detrimental role of excessive platelets in many cardiovascular diseases, the regulation of platelet formation offers a unique aspect for studying the blood compatibility of nanomaterials. In this study, the effects of SiO2 NPs with four sizes (80, 120, 200, and 400 nm) were investigated on the maturation and differentiation of the megakaryocytes into platelets. The results showed that SiO2 NPs promoted megakaryocyte development as manifested by the occurrence of irregular cell morphology, enlargement of cell size, increases in DNA content and DNA ploidy, and formation of spore-like protrusions. The expression of megakaryocyte-specific antigen (CD41a) was up-regulated, due to SiO2 NP treatments. The correlation analysis of SiO2 NP size with the above test bioindicators showed that the smaller the SiO2 NPs were, the stronger effects they induced. Moreover, exposure to SiO2 NPs induced the up-regulation of both GATA-1 and FLI-1, while the transcriptional expressions of aNF-E2 and fNF-E2 remained unchanged. The significant positive correlation of GATA-1 and FLI-1 with megakaryocytic maturation and differentiation suggested their crucial roles in the SiO2 NP-promoted effect. The finding herein provided new insight into the potential health risk of SiO2 NPs by perturbing the platelet-involved hematological homeostasis.

Differential metabolites in cirrhotic patients with hepatitis B and muscle mass loss.

Background: Sarcopenia leads to complications (infections, hepatic encephalopathy and ascites) and poor overall survival in patients with cirrhosis, in which the phenotypic presentation is loss of muscle mass. This study aimed to reveal the metabolic profile and identify potential biomarkers in cirrhotic patients with hepatitis B virus and muscle mass loss. Method: Twenty decompensated cirrhotic patients with HBV and muscle mass loss were designated Group S; 20 decompensated cirrhotic patients with HBV and normal muscle mass were designated Group NS; and 20 healthy people were designated Group H. Muscle mass loss was defined as the skeletal muscle mass index less than 46.96 cm2/m2 for males and less than 32.46 cm2/m2 for females. Gas chromatography-mass spectrometry was used to explore the distinct metabolites and pathways in the three groups. Results: Thirty-seven metabolic products and 25 associated metabolic pathways were significantly different in the Group S patients from Group NS patients. Strong predictive value of 11 metabolites (inosine-5'-monophosphate, phosphoglycolic acid, D-fructose-6-phosphate, N-acetylglutamate, pyrophosphate, trehalose-6-phosphate, fumaric acid, citrulline, creatinine, (r)-3-hydroxybutyric acid, and 2-ketobutyric acid) were selected as potential biomarkers in Group S patients compared with Group NS patients. Two pathways may be associated with loss of muscle mass in patients with liver cirrhosis: amino acid metabolism and central carbon metabolism in cancer. Conclusion: Seventy differential metabolites were identified in patients who have liver cirrhosis and loss of muscle mass compared with patients who have cirrhosis and normal muscle mass. Certain biomarkers might distinguish between muscle mass loss and normal muscle mass in HBV-related cirrhosis patients.

STX5 Inhibits Hepatocellular Carcinoma Adhesion and Promotes Metastasis by Regulating the PI3K/mTOR Pathway.

Background and Aims: Syntaxin 5 (STX5) is a member of the syntaxin or target-soluble SNAP receptor (t-SNARE) family and plays a critical role in autophagy. However, its function and molecular mechanism in tumor cell migration are still unknown. The role of STX5 in influencing hepatocellular carcinoma (HCC) is an important topic in our research. Methods: By using quantitative reverse transcription polymerase chain reaction (qPCR), western blotting, and immunohistochemical analysis of RNA and protein in tissues, we comprehensively evaluated data sets from public databases and clinical patient cohorts for STX5. The correlation of STX5 expression with the clinicopathological characteristics of HCC patients were assessed. In addition, we predicted signal pathways from differentially expressed genes (DEGs) and the Cancer Genome Atlas (TCGA) databases, and confirmed the prediction using integrated transcriptome and RNA-seq. We further investigated the underlying mechanisms of STX5 in the migration and adhesion of HCC cells both in vitro and in vivo. Results: In the TCGA dataset and our patient cohort, STX5 levels were significantly higher in HCC tissues than in adjacent normal liver tissues. At the same time, high expression of STX5 predicted worse prognosis in patients with liver cancer. High expression of STX5 indicates the decrease of adhesion and the increase of migration of HCC cells, and the conversion of epithelial-mesenchymal transition (EMT) in vitro via PI3K/mTOR pathway activation. Conversely, when Sirolimus, a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) inhibitor acts on cells simultaneously, STX5 overexpression-mediated enhancement of HCC metastasis is reversed. Double-negative regulation of STX5 and mTOR further enhanced the inhibitory effect of STX5 on HCC metastasis. In vivo, STX5 knockdown inhibited the metastasis of HCC cells. Conclusions: Our study demonstrates a novel research result that STX5 promotes HCC metastasis through PI3K/mTOR pathway. We believe that combined inhibition of STX5 and mTOR is a potential treatment for effectively prolonging patient survival and inhibiting HCC metastasis.

Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center.

BACKGROUND: Regorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment. METHODS: Ninety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant. RESULTS: The patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child-Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients. CONCLUSIONS: This real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.

Technology Invention and Mechanism Analysis of Rapid Rooting of Taxus × media Rehder Branches Induced by Agrobacterium rhizogenes.

Taxus, a vital source of the anticancer drug paclitaxel, grapples with a pronounced supply-demand gap. Current efforts to alleviate the paclitaxel shortage involve expanding Taxus cultivation through cutting propagation. However, traditional cutting propagation of Taxus is difficult to root and time-consuming. Obtaining the roots with high paclitaxel content will cause tree death and resource destruction, which is not conducive to the development of the Taxus industry. To address this, establishing rapid and efficient stem rooting systems emerges as a key solution for Taxus propagation, facilitating direct and continuous root utilization. In this study, Agrobacterium rhizogenes were induced in the 1-3-year-old branches of Taxus × media Rehder, which has the highest paclitaxel content. The research delves into the rooting efficiency induced by different A. rhizogenes strains, with MSU440 and C58 exhibiting superior effects. Transcriptome and metabolome analyses revealed A. rhizogenes' impact on hormone signal transduction, amino acid metabolism, zeatin synthesis, and secondary metabolite synthesis pathways in roots. LC-MS-targeted quantitative detection showed no significant difference in paclitaxel and baccatin III content between naturally formed and induced roots. These findings underpin the theoretical framework for T. media rapid propagation, contributing to the sustainable advancement of the Taxus industry.

Prognostic significance of the systemic immune inflammation index in patients with metastatic and unresectable pancreatic cancer.

Purpose: Systemic inflammatory markers may be predictors of the survival rate of patients with pancreatic cancer (PC). The aim of this work was to investigate the prognostic value of markers, mainly the systemic immune inflammation index (SII), in patients with metastatic and unresectable PC and to explore the relationship between markers and liver metastasis. Methods: Records of patients with metastatic and unresectable PC at the Affiliated Hospital of Qingdao University from January 2000 to December 2019 and who were followed until December 2020 were retrospectively analyzed. Clinical data and laboratory indexes were collected, and cut-off values for inflammatory markers were determined using median values. The Cox proportional hazard model was used to analyze the prognostic value of the markers through univariate and multivariate survival analysis. Results: All 253 patients met the inclusion criteria, and 102 (42.0%) patients had liver metastasis. The patients were divided into a high SII group and a low SII group, and the cut-off value was 533. In the multivariate analysis, high SII (HR = 2.151; p < 0.001), chemotherapy (HR = 0.546; p < 0.001), lymph node metastasis (HR = 4.053; p < 0.001), and distant metastasis (HR = 1.725; p = 0.001) were independent risk markers of overall survival (OS). The level of markers, mainly SII, PLR and NLR, were higher in patients with liver metastasis. Conclusions: A high level of SII is an independent risk factor for short overall survival of patients with metastatic and unresectable PC. Patients with a high level of the inflammatory markers SII, PLR, and NLR, may be more prone to early liver metastasis.

IV segment portal vein reconstruction in split-liver transplantation with extended right grafts.

BACKGROUND: Liver transplantation is one of the most effective treatments for end-stage liver disease. Split liver transplantation (SLT) can effectively improve the utilization efficiency of grafts. However, split liver transplantation still faces shortcomings and is not widely used in surgery. How to improve the effective transplantation volume of split liver transplantation and promote the postoperative recovery of patients has important clinical significance. METHODS: In our study, the donor's liver was split into the extended right graft and left lateral sector, and the IV segment occur ischemia. To guarantee the functional graft size, and avoid complications, we reconstructed the IV segment portal vein and left portal vein. And we analyzed the operation time, intraoperative bleeding, liver function, and postoperative complications. RESULTS: In our research, 14 patients underwent IV segment portal vein reconstruction, and 8 patients did not undergo vascular reconstruction. We found that the ischemic area of the IV segment decreased significantly after IV segment portal vein reconstruction. We found that there was no significant difference in operation time and postoperative complications between the patients of the groups. There were significant differences in ALT on the 1st day and albumin on the 6th day after the operation. CONCLUSION: It indicates that IV segment reconstruction in SLT surgery can alleviate the graft ischemic and promote the recovery of liver function after the operation. And, IV segment reconstruction as a novel operating procedure may be widely used in SLT.

PyCoCa:A quantifying tool of carbon content in airway macrophage for assessment the internal dose of particles.

Given the lack of a comprehensive understanding of the complex metabolism and variable exposure environment, carbon particles in macrophages have become a potentially valuable biomarker to assess the exposure level of atmospheric particles, such as black carbon. However, the tedious and subjective quantification method limits the application of carbon particles as a valid biomarker. Aiming to obtain an accurate carbon particles quantification method, the deep learning and binarization algorithm were implemented to develop a quantitative tool for carbon content in airway macrophage (CCAM), named PyCoCa. Two types of macrophages, normal and foamy appearance, were applied for the development of PyCoCa. In comparison with the traditional methods, PyCoCa significantly improves the identification efficiency for over 100 times. Consistency assessment with the gold standard revealed that PyCoCa exhibits outstanding prediction ability with the Interclass Correlation Coefficient (ICC) values of over 0.80. And a proper fresh dye will enhance the performance of PyCoCa (ICC = 0.89). Subsequent sensitivity analysis confirmed an excellent performance regarding accuracy and robustness of PyCoCa under high/low exposure environments (sensitivity > 0.80). Furthermore, a successful application of our quantitative tool in cohort studies indicates that carbon particles induce macrophage foaming and the foaming decrease the carbon particles internalization in reverse. Our present study provides a robust and efficient tool to accurately quantify the carbon particles loading in macrophage for exposure assessment.

Identification of immune infiltration-related genes as prognostic indicators for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high degree of malignancy and a poor prognosis. Immune infiltration-related genes have shown good predictive value in the prognosis of many solid tumours. In this study, we established and verified prognostic biomarkers consisting of immune infiltration-related genes in HCC. Gene expression data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differential gene expression analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm were used to screen prognostic immune infiltration-related genes and to construct a risk scoring model. Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic performance of the risk scoring model in the TCGA-HCC cohort. In addition, a nomogram model with a risk score was established, and its predictive performance was verified by ROC analysis and calibration plot analysis in the TCGA-HCC cohort. Gene set enrichment analysis (GSEA) identified pathways and biological processes that may be enriched in the high-risk group. Finally, immune infiltration analysis was used to explore the characteristics of the tumour microenvironment related to the risk score. We identified 17 immune infiltration-related genes with prognostic value and constructed a risk scoring model. ROC analysis showed that the risk scoring model can accurately predict the 1-year, 3-year, and 5-year overall survival (OS) of HCC patients in the TCGA-HCC cohort. KM analysis showed that the OS of the high-risk group was significantly lower than that of the low-risk group (P < 0.001). The nomogram model effectively predicted the OS of HCC patients in the TCGA-HCC cohort. GSEA indicated that the immune infiltration-related genes may be involved in biological processes such as amino acid and lipid metabolism, matrisome and small molecule transportation, immune system regulation, and hepatitis virus infection. Immune infiltration analysis showed that the level of immune cell infiltration in the high-risk group was low, and the risk score was negatively correlated with infiltrating immune cells. Our prognostic model based on immune infiltration-related genes in HCC could help the prognostic assessment of HCC patients and provide potential targets for HCC inhibition.

Gelation of highly entangled hydrophobic macromolecular fluid for ultrastrong underwater in situ fast tissue adhesion.

Although strong underwater bioadhesion is important for many biomedical applications, designing adhesives to perform in the presence of body fluids proves to be a challenge. To address this, we propose an underwater and in situ applicable hydrophobic adhesive (UIHA) composed of polydimethylsiloxane, entangled macromolecular silicone fluid, and a reactive silane. The hydrophobic fluid displaced the boundary water, formed an in situ gel, bonded to tissues, and achieved exceptional underwater adhesion strength. Its underwater lap shear adhesion on porcine skin was significantly higher than that of cyanoacrylate and fibrin glues, demonstrating excellent water resistance. The burst pressure of UIHA on porcine skin was 10 times higher than that of fibrin glue. The cytocompatible UIHA successfully sealed ruptured arteries, skin, and lungs in rats, pigs, rabbits, and dogs. Together, the gelation of highly entangled hydrophobic macromolecular fluid provided a means to prepare underwater bioadhesives with strong bonding to tissues and excellent water resistance.

Neutrophil extracellular traps are associated with enhanced procoagulant activity in liver cirrhosis patients with portal vein thrombosis.

OBJECTIVE: Patients with liver cirrhosis (LC) commonly exhibit hypercoagulability and tend to develop thrombosis. Neutrophil extracellular traps (NETs) are associated with a variety of thrombotic conditions, but their possible value in portal vein thrombosis (PVT) is not known. We assessed whether NETs promote thrombosis and contribute to the procoagulant state in patients with LC. METHODS: The circulating levels of NETs markers (myeloperoxidase, neutrophil elastase, citrullinated histone H3) were measured in 72 patients (median age, 55 years; 48 [66.7%] men) with LC from September 2020 to February 2021. Then they were divided into two groups: patients with or without PVT. NETs procoagulant activity was assessed based on thrombin-antithrombin complex (TAT complex) and Factor X. The levels of plasma markers were determined by ELISA. RESULTS: There were 28 patients with PVT and 44 patients without PVT. The levels of NETs markers and hypercoagulability markers in the plasma of cirrhosis patients with PVT were significantly higher than those of cirrhosis patients without PVT (p < 0.05). Additionally, the levels of the NETs markers correlated with TAT complex and Factor X (Spearman correlation rho >0.73, p < 0.0001). CONCLUSIONS: Neutrophil extracellular traps seem to enhance procoagulant activity in LC patients with PVT; thus, they may be a practical predictor of PVT as well as a rapid and easy-to-use diagnostic and treatment guide for PVT in patients with cirrhosis.

Prognostic significance of systemic immune-inflammation index and platelet-albumin-bilirubin grade in patients with pancreatic cancer undergoing radical surgery.

Background: Systemic inflammatory markers are associated with patient survival in pancreatic cancer (PC). The aim of this study was to investigate the prognostic significance of the systemic immune-inflammation index (SII) in PC patients who underwent radical surgery. Platelet-albumin-bilirubin (PALBI) grade is a composite evaluation index based on liver function. Patients with pancreatic head cancer are prone to obstructive jaundice, which leads to abnormal liver function. Based on this, we also explored the prognostic value of PALBI grade in PC patients. Methods: Patients with pathologically confirmed PC who had undergone radical surgery (with negative surgical margin) for the first time at the Affiliated Hospital of Qingdao University from January 2013 to December 2019 and followed up by December 2020 were retrospectively analyzed. Peripheral blood cell count is easily affected by infection or hematological diseases, which affects the results, so it is excluded. Clinical data and laboratory examination indexes were collected. The SII and PALBI grade were calculated. The cutoff values were determined using the Youden index. The Cox proportional hazards regression model was used to analyze the prognostic value of the SII and PALBI grade through univariate and multivariate survival analysis. Results: A total of 214 patients [median age, 60.29 years; 128 (59.8%) men] met the inclusion criteria. There were 140 patients (65.4%) with pancreatic head cancer according to the tumor location. They were divided into high and low SII or PALBI groups by cutoff values of 705 and -5.6, respectively. According to the multivariate analysis, SII (P<0.001) was an independent factor negatively associated with overall survival (OS) and disease-free survival (DFS). In patients with pancreatic head cancer, PALBI grade was associated with shorter OS (P=0.031). The combination of high SII and high PALBI grade had stronger predictive value for poor prognosis (log-rank test, P<0.001), which the OS was 11.3 months less than the combination of low two groups. Conclusions: SII was a promising prognostic biomarker in PC. And PALBI grade also showed predictive value for patients with pancreatic head cancer. Therefore, it can help predict the treatment outcomes in these patients.

A practical nomogram based on systemic inflammatory markers for predicting portal vein thrombosis in patients with liver cirrhosis.

INTRODUCTION: Immunothrombosis has recently been used to describe the responses/mechanisms in thrombosis. Systemic inflammatory markers are prognostic markers for a variety of thrombotic conditions; however, their potential value in predicting portal vein thrombosis (PVT) is unknown. This study aimed to establish an easy-to-use nomogram based on systemic inflammatory markers to predict portal vein thrombosis (PVT) in patients with liver cirrhosis. PATIENTS AND METHODS: This retrospective study included 478 patients with cirrhosis between January 2013 and January 2021. Reputed systemic inflammatory markers (systemic immune-inflammation index [SII], neutrophil-to-lymphocyte ratio [NLR], monocyte-to-lymphocyte ratio [MLR], and platelet-to-lymphocyte ratio (PLR)) were measured, and the clinical data were recorded. The independent risk factors for PVT were determined using univariate analyses and multivariate logistic regression analyses, and a nomogram to predict the occurrence of PVT was established. The concordance index, receiver operating characteristic curves, and calibration plots were used to evaluate the performance of the model. RESULTS: A total of 239 patients with PVT and 239 patients without PVT were selected. In the univariate analysis, high SII, NLR, PLR, and MLR were significantly associated with PVT. NLR and PLR were independent risk factors for PVT (P < 0.05) by multivariate analysis. The nomogram had good predictive efficiency for PVT in patients with cirrhosis, with an area under the receiver operating characteristic (AUROC) curves of 0.891 (95% CI 0.862-0.919) and the calibration curves fit as well, indicating that the nomogram had good clinical application value. CONCLUSIONS: PVT in patients with cirrhosis is associated with increased levels of systemic inflammatory markers. We successfully developed a practical nomogram based on NLR and PLR to accurately predict PVT, which is a practical method helping clinicians rapidly and conveniently diagnose and guide the treatment of PVT in patients with cirrhosis.Key MessagesThe present study is the first report on a nomogram based on systemic inflammatory markers in patients with portal vein thrombosis (PVT).The nomogram had good predictive efficiency and a good clinical application value for predicting PVT in patients with cirrhosis.

Integrated analysis of 1804 samples of six centers to construct and validate a robust immune-related prognostic signature associated with stromal cell abundance in tumor microenvironment for gastric cancer.

BACKGROUND: Stromal cells in tumor microenvironment could promote immune escape through a variety of mechanisms, but there are lacking research in the field of gastric cancer (GC). METHODS: We identified differential expressed immune-related genes (DEIRGs) between the high- and low-stromal cell abundance GC samples in The Cancer Genome Atlas and GSE84437 datasets. A risk score was constructed basing on univariate cox regression analysis, LASSO regression analysis, and multivariate cox regression analysis in the training cohort (n=772). The median value of the risk score was used to classify patients into groups with high and low risk. We conducted external validation of the prognostic signature in four independent cohorts (GSE26253, n=432; GSE62254, n=300; GSE15459, n=191; GSE26901, n=109) from the Gene Expression Omnibus (GEO) database. The immune cell infiltration was quantified by the CIBERSORT method. RESULTS: The risk score contained 6 genes (AKT3, APOD, FAM19A5, LTBP3, NOV, and NOX4) showed good performance in predicting 5-year overall survival (OS) rate and 5-year recurrence-free survival (RFS) rate of GC patients. The risk death and recurrence of GC patients growing with the increasing risk score. The patients were clustered into three subtypes according to the infiltration of 22 kinds of immune cells quantified by the CIBERSORT method. The proportion of cluster A with the worst prognosis in the high-risk group was significantly higher than that in the low-risk group; the risk score of cluster C subtype with the best prognosis was significantly lower than that of the other two subtypes. CONCLUSION: This study established and validated a robust prognostic model for gastric cancer by integrated analysis 1804 samples of six centers, and its mechanism was explored in combination with immune cell infiltration characterization.

Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes.

Small-diameter tissue-engineered vascular grafts (sdTEVGs) with hyperglycemia resistance have not been constructed. The intimal hyperplasia caused by hyperglycemia remains problem to hinder the patency of sdTEVGs. Here, inspired by bionic regulation of nerve on vascular, we found the released neural exosomes could inhibit the abnormal phenotype transformation of vascular smooth muscle cells (VSMCs). The transformation was a prime culprit causing the intimal hyperplasia of sdTEVGs. To address this concern, sdTEVGs were modified with an on-demand programmable dual-responsive system of ultrathin hydrogels. An external primary Reactive Oxygen Species (ROS)-responsive Netrin-1 system was initially triggered by local inflammation to induce nerve remolding of the sdTEVGs overcoming the difficulty of nerve regeneration under hyperglycemia. Then, the internal secondary ATP-responsive DENND1A (guanine nucleotide exchange factor) system was turned on by the neurotransmitter ATP from the immigrated nerve fibers to stimulate effective release of neural exosomes. The results showed nerve fibers grow into the sdTEVGs in diabetic rats 30 days after transplantation. At day 90, the abnormal VSMCs phenotype was not detected in the sdTEVGs, which maintained long-time patency without intima hyperplasia. Our study provides new insights to construct vascular grafts resisting hyperglycemia damage.

A Ferroptosis and Pyroptosis Molecular Subtype-Related Signature Applicable for Prognosis and Immune Microenvironment Estimation in Hepatocellular Carcinoma.

Background: Due to the heterogeneity of tumors and the complexity of the immune microenvironment, the specific role of ferroptosis and pyroptosis in hepatocellular carcinoma (HCC) is not fully understood, especially its impact on prognosis. Methods: The training set (n = 609, merged by TCGA and GSE14520) was clustered into three subtypes (C1, C2, and C3) based on the prognosis-related genes associated with ferroptosis and pyroptosis. The intersecting differentially expressed genes (DEGs) among C1, C2, and C3 were used in univariate Cox and LASSO penalized Cox regression analysis for the construction of the risk score. The median risk score served as the unified cutoff to divide patients into high- and low-risk groups. Results: Internal (TCGA, n = 370; GSE14520, n = 239) and external validation (ICGC, n = 231) suggested that the 12-gene risk score had high accuracy in predicting the OS, DSS, DFS, PFS, and RFS of HCC. As an independent prognostic indicator, the risk score could be applicable for patients with different clinical features tested by subgroup (n = 26) survival analysis. In the high-risk patients with a lower infiltration abundance of activated B cells, activated CD8 T cells, eosinophils, and type I T helper cells and a higher infiltration abundance of immature dendritic cells, the cytolytic activity, HLA, inflammation promotion, and type I IFN response in the high-risk group were weaker. The TP53 mutation rate, TMB, and CSC characteristics in the high-risk group were significantly higher than those in the low-risk group. Low-risk patients have active metabolic activity and a more robust immune response. The high- and low-risk groups differed significantly in histology grade, vascular tumor cell type, AFP, new tumor event after initial treatment, main tumor size, cirrhosis, TNM stage, BCLC stage, and CLIP score. Conclusion: The ferroptosis and pyroptosis molecular subtype-related signature identified and validated in this work is applicable for prognosis prediction, immune microenvironment estimation, stem cell characteristics, and clinical feature assessment in HCC.

Correlation Analysis of Pleural Effusion and Lung Infection After Liver Transplantation.

BACKGROUND: The aim was to probe the association of pleural effusion with lung infection in patients with liver transplantation and to provide a theoretical foundation for preventing, diagnosing, and remedying pulmonary complications after liver transplantation. METHODS: Our team harvested clinical data of patients undergoing orthotopic allogeneic liver transplantation complicated with pleural effusion after surgery in our institution from May 2018 to July 2019. Based on whether puncture drainage was needed, patients were allocated to either control group or observation group. The differences in pleural effusion depth, lung function, lung infection, serum inflammatory factor levels and 6-month survival before and after surgery were compared. Finally, ROC curves were constructed for dissecting the correlation of pleural effusion with lung infection. RESULTS: On day 3 after surgery, (1) pleural effusion depth of the observation group was 5.70 ± 1.20 cm, which was saliently greater than that of control group (p < 0.05); (2) in comparison to control group, lung function indexes FVC, FEV1.0, MVV, and PaO2 of observation group declined (all p < 0.05); (3) sputum culture evinced that the lung infection rates of the control group and observation group were 17.24% and 71.70%, respectively, and the observation group harbored brilliantly higher infection rate (p < 0.05); (4) in comparison to the control group, IL-6, IL-8, and TNF-α in observation group were increased (p < 0.05); (5) AUC of pleural effusion depth and lung infection was 0.849, 0.805, and 0.853, respectively on days 1, 2, and 3 after surgery. CONCLUSIONS: A positive correlation existed between pleural effusion and lung infection after liver transplantation. When patients have persistent pleural effusion, the incidence of lung infection should be prevented and reduced.