Intestinal IL-33 promotes microbiota-derived trimethylamine N -oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α.

BACKGROUND AND AIMS: Gut microbiota plays a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). IL-33 is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD. APPROACH AND RESULTS: In both humans and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation, and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild-type mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N -oxide-producing bacteria. Inhibition of trimethylamine N -oxide synthesis by 3,3-dimethyl-1-butanol mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia-inducible factor-1α and suppressed its activation, directly damaging the integrity of the intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2- Hif1a - Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice. CONCLUSIONS: Intestinal IL-33 enhanced gut microbiota-derived trimethylamine N -oxide synthesis and aggravated MASLD progression through dual regulation on hypoxia-inducible factor-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Deep Learning Radiomics Model of Dynamic Contrast-Enhanced MRI for Evaluating Vessels Encapsulating Tumor Clusters and Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Vessels encapsulating tumor cluster (VETC) is a critical prognostic factor and therapeutic predictor of hepatocellular carcinoma (HCC). However, noninvasive evaluation of VETC remains challenging. PURPOSE: To develop and validate a deep learning radiomic (DLR) model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of VETC and prognosis of HCC. STUDY TYPE: Retrospective. POPULATION: A total of 221 patients with histologically confirmed HCC and stratified this cohort into training set (n = 154) and time-independent validation set (n = 67). FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T; DCE imaging with T1-weighted three-dimensional fast spoiled gradient echo. ASSESSMENT: Histological specimens were used to evaluate VETC status. VETC+ cases had a visible pattern (≥5% tumor area), while cases without any pattern were VETC-. The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI and reproducibility of segmentation was evaluated. Deep neural network and machine learning (ML) classifiers (logistic regression, decision tree, random forest, SVM, KNN, and Bayes) were used to develop nine DLR, 54 ML and clinical-radiological (CR) models based on AP, PP, and DP of DCE-MRI for evaluating VETC status and association with recurrence. STATISTICAL TESTS: The Fleiss kappa, intraclass correlation coefficient, receiver operating characteristic curve, area under the curve (AUC), Delong test and Kaplan-Meier survival analysis. P value <0.05 was considered as statistical significance. RESULTS: Pathological VETC+ were confirmed in 68 patients (training set: 46, validation set: 22). In the validation set, DLR model based on peritumor PP (peri-PP) phase had the best performance (AUC: 0.844) in comparison to CR (AUC: 0.591) and ML (AUC: 0.672) models. Significant differences in recurrence rates between peri-PP DLR model-predicted VETC+ and VETC- status were found. DATA CONCLUSIONS: The DLR model provides a noninvasive method to discriminate VETC status and prognosis of HCC patients preoperatively. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Anatomical sectionectomy based on Takasaki's segmentation for solitary intrahepatic cholangiocarcinoma: a propensity-matched analysis.

BACKGROUND: Anatomical sectionectomy based on Takasaki's segmentation has shown advantages in hepatocellular carcinoma. However, whether this approach improves the survival of intrahepatic cholangiocarcinoma (ICC) remains unknown. METHODS: A series of 248 consecutive patients with solitary ICCs who underwent hepatectomy were studied retrospectively. The patients were classified into the groups of anatomical sectionectomy based on Takasaki's segmentation (TS group) and non-Takasaki's hepatectomy (NTH group). The bias between the two groups was minimized using propensity score matching (PSM). Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier analysis. The Cox proportional hazards model was performed to determine the adverse risk factors associated with survival. RESULTS: After PSM, 67 pairs of patients were compared. Both the RFS and OS rates in the TS group were significantly better than those in the NTH group (23.2 % vs. 16.5 %, and 40.4 % vs. 27.3 %, P = 0.035 and 0.032, respectively). Multivariate analysis showed that NTH was independently associated with worse RFS and OS than TS. The stratified analysis demonstrated that the RFS and OS rates in the TS group with tumor stage I and tumor size ≥3 cm were significantly better than those in the NTH group, while the survival rates for ICC with stage I and tumor size <3 cm or stage II-III showed no significant difference. CONCLUSION: TS was associated with improved RFS and OS in patients with solitary ICC even after PSM. TS may be preferred particularly in patients with tumor stage I and tumor size ≥3 cm.

The state of female hepato-pancreato-biliary (HPB) surgeons in China: see us in operation theater with great prospects.

OBJECTIVE: This study aims to investigate the proportion and distribution of female HPB surgeons in China, describe their current status, and analyze the possible barriers and challenges in their careers. METHOD: Tertiary hospitals with the division of HPB in mainland China in 2021 were enrolled and surgeon demographic information was collected through the review of official websites and/or telephone interviews. RESULTS: The majority of female HPB surgeons (72.92%) were located in the first or second-tier cities in mainland China, with an increasing number of new female HPB surgeons entering the field annually, particularly after 2005 (from 27 to 52 per 5 years). Despite no significant difference in academic backgrounds, female HPB surgeons initiated their careers at an earlier age and took a longer time to obtain chief titles (P < 0.05). Interestingly, female HPB surgeons performed laparoscopic complex HPB cases at a similar rate (95.42%) to their male counterparts and were more likely to specialize in endoscopic surgery (P = 0.021), with a similar ratio of obtaining administrative positions. CONCLUSION: Minimally invasive surgery may provide females with unprecedented opportunities in the HPB surgery field. However, despite the increasing numbers of female HPB surgeons, the proportion remains low in China.

Venous gas caused by emphysematous pyelonephritis: a case report and review of literature.

BACKGROUND: Emphysematous pyelonephritis (EPN) is a potentially life-threatening disease caused by a gas-producing necrotizing bacterial infection that involves the renal parenchyma, collecting system, and/or perinephric tissue. EPN is often complicated by a previous diagnosis of diabetes mellitus, and venous air bubbles are an uncommon complication of it. We describe a 52-year-old woman who was admitted in coma, with a history of vomiting, and was found to have EPN with air bubbles in the uterine veins. We discuss the presentation, diagnosis, and pathogenesis of this uncommon but clinically significant event, and briefly review other case reports of venous gas or thrombosis caused by EPN. CASE PRESENTATION: We report the case of a 52-year-old woman with past history of type 2 diabetes mellitus, presenting with loss of consciousness after vomiting for half a day. Abdominal computed tomography scan revealed unilateral EPN with air bubbles in the uterine veins. The blood, pus, and urine cultures were positive for extended-spectrum beta-lactamase-producing Escherichia coli. The patient's condition improved well after conservative management comprising supportive measures, broad-spectrum antibiotics, percutaneous drainage therapy, and an open operation. CONCLUSIONS: Venous air bubbles are rare but fatal complication of EPN. Early diagnosis and treatment are critical to ensure good results.

Is spinal sagittal alignment of diffuse idiopathic skeletal hyperostosis relevant to thoracolumbar pain? A controlled study.

OBJECTIVES: The extension of diffuse idiopathic skeletal hyperostosis (DISH) from the low thoracic spine to the lumbar spine result in adjustment of spinal sagittal alignment in surgical patients. The aim of this study was to investigate changes in sagittal alignment and back pain in the thoracolumbar spine in nonsurgical DISH and control participants selected from a radiological database. METHODS: Participants in the DISH and the control group were selected by searching for "DISH or degenerative changes in the thoracic spine" in the radiology database of Taizhou Hospital between 2018 and 2021 using Resnick and Niwayama's criteria. The subjects with spinal tumors, previous spinal surgery, vertebral fractures, inflammatory diseases, poor-quality radiographs, or loss of follow-up were excluded. Demographic and clinical characteristics were recorded retrospectively via the hospital information system and telephone follow-up. Segmental disc angles (SDAs), lumbar lordosis (LL), and bridge scores were analyzed using images of three-dimensional CT. RESULTS: The final participants consisted of 51 individuals with DISH (DISH group) and 102 individuals without DISH (control group). Depending on the presence of thoracolumbar pain, the DISH group was divided into the DISH group with thoracolumbar pain (DISH+Pain) and the DISH group without thoracolumbar pain (DISH-Pain). The LL and SDAs of T11-T12 and T12-L1 were significantly greater in the DISH group than in the control group. In addition, the SDA of L1-L2 was significantly smaller in the DISH+Pain group than in the DISH-Pain group, whereas there was no significant difference in lumbar lordosis between the DISH+Pain group and the DISH-Pain group. The bridge scores in DISH+Pain group was larger in T10-T11 (p = 0.01) and L1-L2 (p < 0.01) spine segments than those in DISH-Pain group. CONCLUSION: The extension of DISH from thoracic to lumbar spine may increase lumbar lordosis and SDAs in the thoracolumbar spine. The DISH patients with more bony bridging and small L1-L2 SDA may be more likely have thoracolumbar pain. Adjustment of sagittal alignment of the spine in the development of DISH may be of clinical importance.

A novel approach for monitoring TGF-ß signaling in vivo in colon cancer.

The TGF-ß receptor kinase inhibitors (TRKI) have been reported to inhibit tumorigenicity in colon cancer. However, there is no direct evidence showing that these inhibitors function through inhibiting the TGF-ß- mediated tumor-promoting effects in vivo. We established a TGF-ß inducible reporter system by inserting a luciferase reporter gene to the vector downstream of TGF-ß-inducible promoter elements, and transfected it into colon cancer cell lines. TRKIs SB431542 and LY2109761 were used to treat TGF-ß inducible cells in vitro and in vivo. The luciferase activity was induced 5.24-fold by TGF-ß in CT26 inducible cells, while it was marginally changed in MC38 inducible cells lacking Smad4 expression. Temporary treatment of mice with SB431542 inhibited the TGF-ß pathway and TGF-ß induced bioluminescence activity in vivo. Long-term treatment with LY2109761 inhibited tumorigenicity and liver metastasis in vivo in concomitant with reduced luciferase activity in the tumor. In this study, we established a model to monitor the TGF-ß pathway in vivo and to compare the antitumor effects of TRKIs. Based on this novel experimental tool, we provided direct evidences that LY2109761 inhibits tumorigenicity and liver metastasis by blocking the pro-oncogenic functions of TGF-ß in vivo.

Association of liver abnormalities with in-hospital mortality in patients with COVID-19.

BACKGROUND & AIMS: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. METHODS: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching. RESULTS: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes. CONCLUSIONS: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19. LAY SUMMARY: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes.

Intraoperative ultrasonography of robot-assisted laparoscopic hepatectomy: initial experiences from 110 consecutive cases.

BACKGROUND: To evaluate the safety and efficacy of IOUS in robotic liver surgery and propose a standard protocol of IOUS for safe robot-assisted hepatectomy. METHODS: Between February 2015 and December 2016, liver resection was performed in 110 patients with robotic approach in Tongji Hospital. In these patients, IOUS was routinely performed. All data about demographic, surgical procedure, postoperative course were collected prospectively and analyzed. RESULTS: A four steps IOUS protocol in robotic liver surgery was proposed, including exploration, verification, guidance, and confirmation. A total of 11 additional lesions in 11 patients were detected and 7 patients accepted strategic surgical modification. No patient suffered from any single or multiple organ dysfunctions, and there were no mortalities observed. CONCLUSION: IOUS is indispensable to understand lesions and vessels in robotic liver surgery. A four-step standard protocol of IOUS is essential for safe robot-assisted hepatectomy.

Plasma microRNA might as a potential biomarker for hepatocellular carcinoma and chronic liver disease screening.

Our study aims to investigate the expression signature of plasma microRNA-106b (miRNA-106b, miR-106b) in hepatocellular carcinoma (HCC) patients and chronic liver disease (CLD) patients compared with healthy controls and further evaluate the potential clinical value of miR-106b as biomarker in HCC detection. In addition, a meta-analysis was conducted to assess the diagnostic performance of miR-106a/b as a biochemical marker for cancer screening. This study was divided into two phases. In the first phase, the expression levels of plasma miR-106b obtained from 108 subjects (47 HCC patients, 25 CLD patients, and 36 healthy controls) were measured by using qRT-PCR. Areas under receiver operating characteristic (ROC) curves (AUCs) were used to evaluate the diagnostic accuracy of plasma miR-106. In the second phase, a meta-analysis based on 11 previous researches as well as our current study was conducted to assess the potential clinical value of miR-106 in cancer detection. Plasma levels of miR-106b in HCC patients were significantly higher compared with CLD patients and healthy individuals. ROC curves suggested that plasma miR-106b yielded relative high sensitivities and specificities in differentiating HCC patients from CLD patients or healthy controls with corresponding AUC values of 0.726 and 0.879, respectively. In addition, miR-106b showed a relatively high accuracy in distinguishing CLD patients from healthy controls with its AUC value of 0.703. Furthermore, the meta-analysis for diagnostic performance of miR-106a/b showed a pooled sensitivity of 0.74, specificity of 0.75, and an AUC of 0.81. Subgroup analysis based on samples types revealed a higher diagnostic performance of miR-106 for cancer detection by using non-blood samples. Similarly, miR-106 as biomarker showed a higher diagnostic accuracy for gastric cancer detection. We found that plasma miR-106b has clinical value in the detection of HCC from healthy people and CLD patients. Further large-scale study may be needed to validate our findings.

Near-infrared-light mediated ratiometric luminescent sensor for multimode visualized assays of explosives.

The development of a portable and easy-to-use device for the detection of explosives with high sensitivity and selectivity is in high demand for homeland security and public safety. In this study, we demonstrate miniaturized devices depending on the upconversion ratiometric luminescent probe for point-of-care (POC) assay of explosives with the naked-eye. When the PEI-coated upconversion nanoparticles (UCNPs) selectively bonded to 2,4,6-trinitrotoluene (TNT) explosives by the formation of Meisenheimer complex, the formed of UCNP-Meisenheimer complexes show turned visible multicolor upconversion luminescence (UCL) on account of TNT-modulating Förster resonance energy transfer process under near-infrared excitation. With UCL emission at 808 nm as internal standard and ratiometric UCL at 477 nm to that at 808 nm (I477/I808) as output signal, the probe can simultaneously meet the accuracy for TNT explosives quantitative analysis. In addition, this easy-to-use visual technique provides a powerful tool for convenient POC assay of rapid explosives identification.

Chen's U-suture technique for end-to-end invaginated pancreaticojejunostomy following pancreaticoduodenectomy.

BACKGROUND AND PURPOSE: Internationally, postoperative pancreatic fistula (POPF) remains a leading cause of morbidity and mortality after pancreaticoduodenectomy (PD). In order to reduce the incidence of POPF, a number of technical modifications for pancreato-enteric anastomosis after PD have been proposed. In 1995, we established a new technique with transpancreatic transverse U-sutures for end-to-end invaginated pancreaticojejunostomy after a PD, and the preliminary results were quite encouraging. This study aims to review a new surgical approach, the Chen's U-stitch technique, for end-to-end invaginated pancreaticojejunostomy, which involves two to four transpancreatic transverse U-sutures, and to evaluate the effectiveness of this approach with reducing the incidence of POPF formation. METHODS: To evaluate this new approach, during 2002-2012, a total of 264 patients who received the new Chen's U-stitch technique after a PD were included in this study. Postoperative morbidity and mortality, including the incidence of POPF, were analyzed. RESULTS: Postoperative morbidity was 22.3 % (59/264) and mortality was 0 % (0/264). The POPF rate was 3.4 % (9/264) for Grade A, 0.8 % (2/264) for Grade B, and 0 % (0/264) for Grade C. CONCLUSIONS: This new surgical technique (Chen's U-stitch), which involves an end-to-end invaginated pancreaticojejunostomy with two to four transpancreatic transverse U-sutures, provides excellent outcomes at reducing the incidence of POPF after PD.

Near-infrared-light-mediated imaging of latent fingerprints based on molecular recognition.

Photoluminescence is one of the most sensitive techniques for fingerprint detection, but it also suffers from background fluorescence and selectivity at the expense of generality. The method described herein integrates the advantages of near-infrared-light-mediated imaging and molecular recognition. In principle, upconversion nanoparticles (UCNPs) functionalized with a lysozyme-binding aptamer were used to detect fingerprints through recognizing lysozyme in the fingerprint ridges. UCNPs possess the ability to suppress background fluorescence and make it possible for fingerprint imaging on problematic surfaces. Lysozyme, a universal compound in fingerprints, was chosen as the target, thus simultaneously meeting the selectivity and generality criteria in photoluminescence approaches. Fingerprints on different surfaces and from different people were detected successfully. This strategy was used to detect fingerprints with cocaine powder by using UCNPs functionalized with a cocaine-binding aptamer.

Revisiting the chaperonin T-complex protein-1 ring complex in human health and disease: A proteostasis modulator and beyond.

BACKGROUND: Disrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T-complex protein-1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes. MAIN BODY: In this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC-associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment. CONCLUSION: This review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.

Prediction power of radiomics in early recurrence of hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Raiomics is an emerging auxiliary diagnostic tool, but there are still differences in whether it can be applied to predict early recurrence of hepatocellular carcinoma (HCC). The purpose of this meta-analysis was to systematically evaluate the predictive power of radiomics in the early recurrence (ER) of HCC. METHODS: Comprehensive studies on the application of radiomics to predict ER in HCC patients after hepatectomy or curative ablation were systematically screened in Embase, PubMed, and Web of Science. RESULTS: Ten studies which is involving a total of 1929 patients were reviewed. The overall estimates of radiomic models for sensitivity and specificity in predicting the ER of HCC were 0.79 (95% confidence interval [CI]: 0.68-0.87) and 0.83 (95% CI: 0.73-0.90), respectively. The area under the summary receiver operating characteristic curve (SROC) was 0.88 (95% CI: 0.85-0.91). CONCLUSIONS: The imaging method is a reliable method for diagnosing HCC. Radiomics, which is based on medical imaging, has excellent power in predicting the ER of HCC. With the help of radiomics, we can predict the recurrence of HCC after surgery more effectively and provide a useful reference for clinical practice.

A deep learning model based on MRI for prediction of vessels encapsulating tumour clusters and prognosis in hepatocellular carcinoma.

PURPOSE: This study aimed to build and evaluate a deep learning (DL) model to predict vessels encapsulating tumor clusters (VETC) and prognosis preoperatively in patients with hepatocellular carcinoma (HCC). METHODS: 320 pathologically confirmed HCC patients (58 women and 262 men) from two hospitals were included in this retrospective study. Institution 1 (n = 219) and Institution 2 (n = 101) served as the training and external test cohorts, respectively. Tumors were evaluated three-dimensionally and regions of interest were segmented manually in the arterial, portal venous, and delayed phases (AP, PP, and DP). Three ResNet-34 DL models were developed, consisting of three models based on a single sequence. The fusion model was developed by inputting the prediction probability of the output from the three single-sequence models into logistic regression. The area under the receiver operating characteristic curve (AUC) was used to compare performance, and the Delong test was used to compare AUCs. Early recurrence (ER) was defined as recurrence within two years of surgery and early recurrence-free survival (ERFS) rate was evaluated by Kaplan-Meier survival analysis. RESULTS: Among the 320 HCC patients, 227 were VETC- and 93 were VETC+ . In the external test cohort, the fusion model showed an AUC of 0.772, a sensitivity of 0.80, and a specificity of 0.61. The fusion model-based prediction of VETC high-risk and low-risk categories exhibits a significant difference in ERFS rates, akin to the outcomes observed in VETC + and VETC- confirmed through pathological analyses (p < 0.05). CONCLUSIONS: A DL framework based on ResNet-34 has demonstrated potential in facilitating non-invasive prediction of VETC as well as patient prognosis.

The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

Postoperative lenvatinib + PD-1 blockade reduces early tumor recurrence in hepatocellular carcinoma with microvascular invasion (Barcelona Clinic Liver Cancer stage 0 or A): a propensity score matching analysis.

BACKGROUND: This study aimed to determine the effectiveness of postoperative adjuvant lenvatinib + PD-1 blockade for patients with early-stage hepatocellular carcinoma (HCC) with microvascular invasion (MVI). METHODS: A total of 393 patients with HCC (Barcelona Clinic Liver Cancer stage 0 or A) who underwent curative hepatectomy with histopathologically proven MVI were enrolled according to the inclusion and exclusion criteria and assigned to 2 groups: surgery alone (surgery-alone group) and surgery with lenvatinib and PD-1 blockade (surgery + lenvatinib + PD-1 group) to compare recurrence-free survival (RFS), overall survival (OS), recurrence type, and annual recurrence rate after the application of propensity score matching (PSM). The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: Overall, 99 matched pairs were selected using PSM. Patients in the surgery + lenvatinib + PD-1 group had significantly higher 3-year RFS rates (76.8%, 65.7%, and 53.5%) than patients in the surgery-alone group (60.6%, 45.5%, and 37.4%) (P = .012). The 2 groups showed no significant difference in recurrence types and OS. Surgery alone, MVI-M2, and alpha-fetoprotein of ≥200 ng/mL were independent risk factors for RFS (P < .05), and history of alcohol use disorder was an independent risk factor for OS (P = .022). CONCLUSION: Postoperative lenvatinib + PD-1 blockade improved the RFS in patients with HCC with MVI and was particularly beneficial for specific individuals.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Preoperative MRI features for characterization of vessels encapsulating tumor clusters and microvascular invasion in hepatocellular carcinoma.

PURPOSE: This study aimed to analyze imaging features based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the identification of vessels encapsulating tumor clusters (VETC)-microvascular invasion (MVI) in hepatocellular carcinoma (HCC), VM-HCC pattern. METHODS: Patients who underwent hepatectomy and preoperative DCE-MRI between January 2015 and March 2021 were retrospectively analyzed. Clinical and imaging features related to VM-HCC (VETC + /MVI-, VETC-/MVI +, VETC + /MVI +) and Non-VM-HCC (VETC-/MVI-) were determined by multivariable logistic regression analyses. Early and overall recurrence were determined using the Kaplan-Meier survival curve. Indicators of early and overall recurrence were identified using the Cox proportional hazard regression model. RESULTS: In total, 221 patients (177 men, 44 women; median age, 60 years; interquartile range, 52-66 years) were evaluated. The multivariable logistic regression analyses revealed fetoprotein > 400 ng/mL (odds ratio [OR] = 2.17, 95% confidence interval [CI] 1.07, 4.41, p = 0.033), intratumor vascularity (OR 2.15, 95% CI 1.07, 4.31, p = 0.031), and enhancement pattern (OR 2.71, 95% CI 1.17, 6.03, p = 0.019) as independent predictors of VM-HCC. In Kaplan-Meier survival analysis, intratumor vascularity was associated with early and overall recurrence (p < 0.05). CONCLUSION: Based on DCE-MRI, intratumor vascularity can be used to characterize VM-HCC and is of prognostic significance for recurrence in patients with HCC.