Criteria and prognostic models for patients with hepatocellular carcinoma undergoing liver transplantation.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.

IMPDH2 suppression impedes cell proliferation by instigating cell cycle arrest and stimulates apoptosis in pediatric hepatoblastoma.

BACKGROUND: Hepatoblastoma (HB) is the most common pediatric liver tumor, presenting significant therapeutic challenges due to its high rates of recurrence and metastasis. While Inosine Monophosphate Dehydrogenase 2(IMPDH2) has been associated with cancer progression, its specific role and clinical implications in HB have not been fully elucidated. METHODS: This study utilized Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Tissue Microarray (TMA) for validation. Following this, IMPDH2 was suppressed, and a series of in vitro assays were conducted. Flow cytometry was employed to assess apoptosis and cell cycle arrest. Additionally, the study explored the synergistic therapeutic effects of mycophenolate mofetil (MMF) and doxorubicin (DOX) on HB cell lines. RESULTS: The study identified a marked overexpression of IMPDH2 in HB tissues, which was strongly correlated with reduced Overall Survival (OS) and Event-Free Survival (EFS). IMPDH2 upregulation was also found to be associated with key clinical-pathological features, including pre-chemotherapy alpha-fetoprotein (AFP) levels, presence of preoperative metastasis, and the pre-treatment extent of tumor (PRETEXT) staging system. Knockdown of IMPDH2 significantly inhibited HB cell proliferation and tumorigenicity, inducing cell cycle arrest at the G0/G1 phase. Notably, the combination of MMF, identified as a specific IMPDH2 inhibitor, with DOX, substantially enhanced the therapeutic response. CONCLUSION: The overexpression of IMPDH2 was closely linked to adverse outcomes in HB patients and appeared to accelerate cell cycle progression. These findings suggest that IMPDH2 may serve as a valuable prognostic indicator and a potential therapeutic target for HB. IMPACT: The present study unveiled a significant overexpression of inosine monophosphate dehydrogenase 2 (IMPDH2) in hepatoblastoma (HB) tissues, particularly in association with metastasis and recurrence of the disease. The pronounced upregulation of IMPDH2 was found to be intimately correlated with adverse outcomes in HB patients. This overexpression appears to accelerate the progression of the cell cycle, suggesting that IMPDH2 may serve as a promising candidate for both a prognostic marker and a therapeutic target in the context of HB.

Development of a deep learning model for predicting recurrence of hepatocellular carcinoma after liver transplantation.

Background: Liver transplantation (LT) is one of the main curative treatments for hepatocellular carcinoma (HCC). Milan criteria has long been applied to candidate LT patients with HCC. However, the application of Milan criteria failed to precisely predict patients at risk of recurrence. As a result, we aimed to establish and validate a deep learning model comparing with Milan criteria and better guide post-LT treatment. Methods: A total of 356 HCC patients who received LT with complete follow-up data were evaluated. The entire cohort was randomly divided into training set (n = 286) and validation set (n = 70). Multi-layer-perceptron model provided by pycox library was first used to construct the recurrence prediction model. Then tabular neural network (TabNet) that combines elements of deep learning and tabular data processing techniques was utilized to compare with Milan criteria and verify the performance of the model we proposed. Results: Patients with larger tumor size over 7 cm, poorer differentiation of tumor grade and multiple tumor numbers were first classified as high risk of recurrence. We trained a classification model with TabNet and our proposed model performed better than the Milan criteria in terms of accuracy (0.95 vs. 0.86, p < 0.05). In addition, our model showed better performance results with improved AUC, NRI and hazard ratio, proving the robustness of the model. Conclusion: A prognostic model had been proposed based on the use of TabNet on various parameters from HCC patients. The model performed well in post-LT recurrence prediction and the identification of high-risk subgroups.

Adenosinergic metabolism pathway: an emerging target for improving outcomes of solid organ transplantation.

Extracellular nucleotides are widely recognized as crucial modulators of immune responses in peripheral tissues. Adenosine triphosphate (ATP) and adenosine are key components of extracellular nucleotides, the balance of which contributes to immune homeostasis. Under tissue injury, ATP exerts its pro-inflammatory function, while the adenosinergic pathway rapidly degrades ATP to immunosuppressive adenosine, thus inhibiting excessive and uncontrolled inflammatory responses. Previous reviews have explored the immunoregulatory role of extracellular adenosine in various pathological conditions, especially inflammation and malignancy. However, current knowledge regarding adenosine and adenosinergic metabolism in the context of solid organ transplantation remains fragmented. In this review, we summarize the latest information on adenosine metabolism and the mechanisms by which it suppresses the effector function of immune cells, as well as highlight the protective role of adenosine in all stages of solid organ transplantation, including reducing ischemia reperfusion injury during organ procurement, alleviating rejection, and promoting graft regeneration after transplantation. Finally, we discuss the potential for future clinical translation of adenosinergic pathway in solid organ transplantation.

Programmable Atom-Like Nanoparticle Reporters for High-Precision Urinalysis of In Situ Membrane Proteins.

The expression of disease-specific membrane proteins (MPs) is a crucial indicator for evaluating the onset and progression of diseases. Urinalysis of in situ MPs has the potential for point-of-care disease diagnostics, yet remains challenging due to the lack of molecular reporter to transform the expression information of in situ MPs into the measurable urine composition. Herein, a series of tetrahedral DNA frameworks (TDFs) are employed as the cores of programmable atom-like nanoparticles (PANs) to direct the self-assembly of PAN reporters with defined ligand valence and spatial distribution. With the rational spatial organization of ligands, the interaction between PAN reporters and MPs exhibits superior stability on cell-membrane interface under renal tubule-mimic fluid microenvironment, thus enabling high-fidelity conversion of MPs expression level into binding events and reverse assessment of in situ MP levels via measurement of the renal clearance efficiency of PAN reporters. Such PAN reporter-mediated signal transformation mechanism empowers urinalysis of the onset of acute kidney injury at least 6 h earlier than the existing methods with an area under the curve of 100%. This strategy has the potential for urinalysis of a variety of in situ membrane proteins.

Increased Platelet Aggregation in Adults After Orthotopic Liver Transplantation Indicates Higher Probability of Early Postoperative Survival.

BACKGROUND Studies have shown that increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death, but studies on the association between platelet aggregation function and early postoperative survival in orthotopic liver transplantation (OLT) patients are rare. We conducted a retrospective study to investigate whole-blood platelet aggregation during the perioperative period of OLT patients and its association with clinical outcomes. MATERIAL AND METHODS Adult patients who underwent OLT between January 1 and April 30, 2021 were retrospectively reviewed. Laboratory test results indicating primary hemostasis were analyzed. The generalized linear model was used to investigate the association between primary hemostasis parameters and survival. RESULTS A total of 256 patients were enrolled. The median platelet count (PLT) was 61.5 (39.5-106.3)×109/L before transplantation. The median MA value was 43.1 (34.5-56.2) mm. From the 1st to the 3rd day after transplantation, PLT and MA both indicated a significant decrease. Two weeks after transplantation, PLT rose to 143.0 (85.0-209.0)×109/L, and the MA value rose to 56.7 (52.2-62.7) mm. On multivariate analysis, PLT at 1 week after transplantation (OR: 1.07; P=0.006) and MA value (OR: 1.12; P=0.003) were independently associated with outcome. The AUROC of the model combined with MA value, MELD score, and age was 0.945 (95% CI: 0.911-0.978). CONCLUSIONS The change in primary hemostasis during the early postoperative period of adult OLT is mainly characterized by the increase of platelet count and function 14 days after transplantation. Higher PLT was associated with higher survival at 14 days after transplantation, while a higher PLT ratio was associated with survival at 3 months after transplantation. Based on comprehensive consideration, the model combined with MA value, MELD score, and age more reliably indicated the associated with early survival after transplantation.

Patient-derived models facilitate precision medicine in liver cancer by remodeling cell-matrix interaction.

Liver cancer is an aggressive tumor originating in the liver with a dismal prognosis. Current evidence suggests that liver cancer is the fifth most prevalent cancer worldwide and the second most deadly type of malignancy. Tumor heterogeneity accounts for the differences in drug responses among patients, emphasizing the importance of precision medicine. Patient-derived models of cancer are widely used preclinical models to study precision medicine since they preserve tumor heterogeneity ex vivo in the study of many cancers. Patient-derived models preserving cell-cell and cell-matrix interactions better recapitulate in vivo conditions, including patient-derived xenografts (PDXs), induced pluripotent stem cells (iPSCs), precision-cut liver slices (PCLSs), patient-derived organoids (PDOs), and patient-derived tumor spheroids (PDTSs). In this review, we provide a comprehensive overview of the different modalities used to establish preclinical models for precision medicine in liver cancer.

HRG inhibits liver cancer lung metastasis by suppressing neutrophil extracellular trap formation.

BACKGROUND: Distant metastasis is a sign of poor prognosis for cancer patients. Extrahepatic liver cancer metastases commonly spread to the lung. Remodelling of the metastatic microenvironment is essential for tumour metastasis. Neutrophil-associated metastatic microenvironment contributes to the early metastatic colonisation of cancer cells in the lung. METHOD: The lung metastasis models were constructed via treated cancer cells by tail vein injection into mice. And samples of lung were harvested at the indicated time to analyze tumor growth and immune cells in the microenvironment. Tumors and lung metastasis specimens were obtained via surgical operations for research purposes. Neutrophils were obtained from peripheral blood of patients with liver cancer or healthy donors (HD). RESULTS: Hepatocellular carcinoma cells reduce the secretion of histidine-rich glycoprotein (HRG), regulate the recruitment and activation of neutrophils in the metastatic microenvironment and promote the production of neutrophil extracellular traps (NETs), thereby promoting liver cancer lung metastasis. HRG binds to FCγR1 on the neutrophil membrane while inhibiting PI3K and NF-κB activation, thereby reducing IL-8 secretion to reduce neutrophil recruitment. Meanwhile, HRG inhibited IL8-MAPK and NF-κB pathway activation and ROS production, resulting in reduced NETs formation. CONCLUSIONS: Our study reveals that liver cancer regulates neutrophil recruitment and NETs formation in the metastatic microenvironment by reducing HRG secretion, thereby promoting tumour lung metastasis. The results of this study will contribute to the development of possible strategies for treating metastases.

Single-cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single-cell level, which could facilitate a better understanding of HB at both the biological and clinical levels. APPROACH AND RESULTS: Single-cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single-cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post-neoadjuvant chemotherapy tumor samples. A single-cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic-targeted therapeutic strategy against the CSC-like HB1-Pro-like1 subpopulation and its related high-risk "Pro-like1" subtype of HB. CONCLUSIONS: Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single-cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.

Unusual Ileocecal Ulcers after Liver Transplantation for Hepatitis B Cirrhosis and Hepatocellular Carcinoma.

We presented a case demonstrating ileocecal ulcers after liver transplantation for hepatitis B cirrhosis and hepatocellular carcinoma. The patient presented 4 years post-transplant with paroxysmal right lower abdominal pain. Due to a mild increase in the leukocyte and neutrophil count, infectious diseases were initially suspected. However, probiotic treatment did not help improve the symptom. An enhanced CT scan revealed a thickening in the ileocecal region, and endoscopy later showed multiple giant and deep ulcers in the ileocecal region with polypoid hyperplasia. Histopathology of an ulcer biopsy displayed benign ulcers, and chronic inflammation with non-caseous granulomas, without signs of a fungus or parasite infection. Epithelial exfoliation with atypical hyperplasia was observed, and a tacrolimus-induced ileocecal ulcer was considered by a pathologist. Clinical manifestation, lab findings, radiology, and pathology characteristics of ulcers were not consistent with the pathogenesis of ischemia, tuberculosis, CMV, EBV, tumor, or inflammatory bowel diseases. Abdominal pain was gradually relieved and subsided with the discontinuation of tacrolimus and corticosteroid administration.

Association between Metabolic Dysfunction-associated Fatty Liver Disease and Cognitive Impairment.

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed term based on modified criteria. Although nonalcoholic fatty liver disease (NAFLD) has been well-documented as a multisystem disease, research on the correlation of MAFLD and extra-hepatic diseases is limited. This study aimed to clarify the association of MAFLD, as well as NAFLD status with cognitive function. Methods: A total of 5,662 participants 20-59 years of age who underwent cognitive tests and liver ultrasonography in the Third National Health and Nutrition Examination Survey were included in the analysis. Cognitive function was evaluated using three computer-administered tests, the serial digit learning test (SDLT), the simple reaction time test (SRTT) and the symbol digit substitution test (SDST). Results: Participants with MAFLD had significantly poorer performance on the SRTT [odds ratio (OR) 1.47, 95% confidence interval (CI): 1.14-1.89)]. MAFLD with moderate-severe liver steatosis was associated with higher risks of scoring low in the SDLT (OR 1.37, 95% CI: 1.04-1.82) and SRTT (OR 1.55, 95% CI: 1.19-2.02). NAFLD combined with metabolic dysfunction, instead of NAFLD without metabolic disorders, was associated an increased risk of a low SRTT score (OR 1.44, 95% CI: 1.10-1.82). MAFLD patients had a high probability of fibrosis, prediabetes, and diabetes and were also significantly associated with increased risks based on the SDST or SRTT score. Conclusions: MAFLD was significantly associated with increased risk of cognitive impairment, especially among MAFLD patients with a high degree of liver fibrosis, moderate-severe steatosis, or hyperglycemia.

Macrophage Notch1 inhibits TAK1 function and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin signaling in liver ischemia and reperfusion injury.

BACKGROUND: Notch signaling is highly conserved and critically involved in cell differentiation, immunity, and survival. Activation of the Notch pathway modulates immune cell functions during the inflammatory response. However, it remains unknown whether and how the macrophage Notch1 may control the innate immune signaling TAK1, and RIPK3-mediated hepatocyte necroptosis in liver ischemia and reperfusion injury (IRI). This study investigated the molecular mechanisms of macrophage Notch1 in modulating TAK1-mediated innate immune responses and RIPK3 functions in liver IRI. METHODS: Myeloid-specific Notch1 knockout (Notch1M-KO) and floxed Notch1 (Notch1FL/FL) mice (n = 6/group) were subjected to 90 min partial liver warm ischemia followed by 6 h of reperfusion. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated ß-catenin knockout (KO) vector followed by LPS (100 ng/ml) stimulation. RESULTS: IR stress-induced Notch1 activation evidenced by increased nuclear Notch intracellular domain (NICD) expression in liver macrophages. Myeloid Notch1 deficiency exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil accumulation, and proinflammatory cytokines/chemokines production compared to the Notch1FL/FL controls. Unlike in the Notch1FL/FL controls, Notch1M-KO enhanced TRAF6, TAK1, NF-κB, RIPK3, and MLKL but reduced ß-catenin activation in ischemic livers. However, adoptive transfer of lentivirus ß-catenin-modified macrophages markedly improved liver function with reduced TRAF6, p-TAK1, RIPK3 and p-MLKL in IR-challenged livers. Moreover, disruption of RIPK3 in Notch1M-KO mice with an in vivo mannose-mediated RIPK3 siRNA delivery system diminished IR-triggered hepatocyte death. In vitro studies showed that macrophage NICD and ß-catenin co-localized in the nucleus, whereby ß-catenin interacted with NICD in response to LPS stimulation. Disruption of ß-catenin with a CRISPR/Cas9-mediated ß-catenin KO in Notch1FL/FL macrophage augmented TRAF6 activation leading to enhanced TAK1 function. While CRISPR/Cas9-mediated TRAF6 KO in Notch1M-KO macrophage inhibited RIPK3-mediated hepatocyte necroptosis after co-culture with primary hepatocytes. CONCLUSIONS: Macrophage Notch1 controls TAK1-mediated innate immune responses and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin. ß-catenin is required for the macrophage Notch1-mediated immune regulation in liver IRI. Our findings demonstrate that the macrophage Notch1-ß-catenin axis is a crucial regulatory mechanism in IR-triggered liver inflammation and provide novel therapeutic potential in organ IRI and transplant recipients. Video abstract.

Two-Dimensional Shear Wave Elastography Evaluation of Post-transplantation Complications in Pediatric Receipt: A Retrospective Cohort.

Background: The 20-year survival rate in pediatric patients after liver transplantation (LT) was no more than 70%. Hepatic fibrosis is one of the principal factors affecting the long-term prognosis. Imaging evaluation was the first-line examination for pediatric liver graft assessment. However, the sensitivity and specificity were insufficient. Thus, two-dimensional shear wave elastography (2D-SWE) was performed to evaluate liver graft stiffness and complication in post-transplant pediatric receipt. Materials and Methods: In this retrospective cohort, 343 pediatric recipients who underwent liver graft biopsy in our tertiary LT center were recruited between June 2018 and December 2020. The 2D-SWE evaluation, laboratory examination, routine post-transplant biopsy, and hepatic pathological assessment were performed. Results: Ninety-eight of the 343 pediatric patients were included according to the protocol. The Liver Stiffness Measurements (LSM) value of 2D-SWE was significantly elevated in post-transplant fibrosis (p < 0.0001). The LSM value of patients with post-transplant biliary complications (p < 0.0001) and biopsy-proven rejection (BPR, p = 0.0016) also rose compared to regular recovery patients. Concerning the sensitivity and specificity of 2D-SWE in diagnosing liver graft fibrosis, the area under the ROC curve (AUC) was 88%, and the optimal cutoff value was 10.3 kPa. Conclusion: Pediatric LSM by 2D-SWE was efficient. Routine 2D-SWE evaluation could be optimal to predict significant liver graft fibrosis.

Liver-specific Mettl3 ablation delays liver regeneration in mice.

This study investigated the role of N6-methyladenosine RNA methylation in liver regeneration following partial hepatectomy in mice. We created a liver-specific knockout mouse model by the deletion of Mettl3, a key component of the N6-methyladenosine methyltransferase complex, using the albumin-Cre system. Mettl3 liver-specific knockout mice and their wild-type littermates were subjected to 2/3 partial hepatectomy. Transcriptomic changes in liver tissue at 48 h after partial hepatectomy were detected by RNA-seq. Immunohistochemistry and immunofluorescence were used to determine protein expression levels of Ki67, hepatocyte nuclear factor 4 alpha, and cytokeratin 19. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling was also performed. Liver weight/body weight ratios after partial hepatectomy were significantly lower in Mettl3 liver-specific knockout mice than in wild-type mice at 48 h after 2/3 partial hepatectomy (3.1% ± 0.11% vs. 2.7% ± 0.03%). Compared with wild-type littermates, Mettl3 liver-specific knockout mice showed reduced bromodeoxyuridine staining and reduced Ki-67 expression at 48 h after 2/3 partial hepatectomy. RNA-seq analysis showed that Mettl3 liver-specific knockout delayed the cell cycle progression in murine liver by downregulating the expression levels of genes encoding cyclins D1, A2, B1, and B2. Loss of Mettl3-mediated N6-methyladenosine function led to attenuated liver regeneration by altering the mRNA decay of suppressor of cytokine signaling 6, thereby inhibiting the phosphorylation of signal transducer and activator of transcription 3 during early liver regeneration. These results demonstrated the importance of N6-methyladenosine mRNA modification in liver regeneration and suggest that Mettl3 targeting might facilitate liver regeneration.

Added value of computed tomography venography in the identification of abnormities in veins of lower extremities.

OBJECTIVE: To investigate the efficacy of direct computed tomography venography (CTV) in early and accurate detection of lower extremity venous (LEV) abnormalities. METHODS: Cross-sectional research was conducted in Hebei General Hospital of China. A total of 211 CTV reports of both lower extremities from January 2017 to September 2019, 75 color Doppler ultrasound (DUS) examinations, and eight intravascular angiography records of these patients over the same period were collected from the hospital. Comparisons were made for the reported number and percentage of LEV abnormalities (thrombosis, stenosis including severe stenosis, and varicosities). Chi-square test and t-test were applied to compare the rates and means, respectively. Significance level α was 0.05. Individual interviews were performed to understand the perceptions of medical staff and patients on the application of CTV, and the interview results were analyzed. RESULTS: Of the 75 cases with both CTV and DUS reports, 159 abnormalities occurring in the lower extremity deep veins (LEDV) were reported, among which 125 (79%) and 18 (11%) were reported by CTV and DUS on a single basis, respectively, whereas 16 (10%) were reported by CTV and DUS simultaneously. A statistically significant greater number of abnormalities in LEDV were identified by CTV than DUS in both males and females (χ2males = 78.449, χ2females = 27.574, χ2total = 104.164, p < .05). In the 211 CTV reports, among the 383 abnormalities reported in total, the common iliac vein (CIV) had the highest number of reported abnormalities (132, 34.5%), followed by the femoral vein (93, 24.3%). The ratios between LEDV abnormality and patient numbers were 1.055 and 0.688 for left and right sides in males, and 0.892 and 0.461 for left and right sides in females, respectively, with that for the left side statistically significantly higher than the right one (tmale = 2.896, tfemale = 4.347, p < .05). The incidence of thrombosis was 10.9% (95% CI = 6.7 ∼ 15.1%). Reported abnormities in CIV by CTV were in agreement with those by intravascular angiography. The medical staff believed that CTV could guide the performance of surgeries for LEV and the patients perceived CTV acceptable. CONCLUSIONS: Application of CTV for early and accurate detection of LEDV abnormalities including thrombosis has been proven to be efficient. Corresponding benefit in early intervention and reduction of severe complications of such abnormalities is of important value. CTV earned good recognition from medical staff and patients. Hence, it could be considered as part of global health assistance cooperation with developing countries to facilitate enhanced medical services.

ABCC6 Knockdown Fuels Cell Proliferation by Regulating PPARα in Hepatocellular Carcinoma.

The ATP binding cassette (ABC) transporter family is ubiquitous in eukaryotes, specifically in vertebrates, and plays a crucial role in energy homeostasis, cell signaling, and drug resistance. Accumulating evidence indicates that some ABC transporters contribute to cancer cell proliferation and tumor progression; however, relatively little is known about the behavior of the ABC transporter family in hepatocellular carcinoma (HCC). By analyzing two public transcriptomic databases, we evaluated the effect of genes in the ABC transporter family on HCC prognostic prediction; ABCC6 was selected for further study. Notably, ABCC6 was found to be downregulated in HCC tissues and correlated with favorable outcomes in patients with HCC. Moreover, ABCC6 knockdown not only significantly promoted cell proliferation in vitro and in vivo, but also inhibited cell cycle arrest and cell apoptosis. Transcriptome analysis revealed that ABCC6 depletion enhanced the "mitotic cell cycle" and "DNA replication" pathways, and suppressed the "PPAR signaling pathway". Further investigation demonstrated that PPARα, one of the key regulators in peroxisome metabolism, is located downstream of ABCC6. In summary, our study provides profound insights into the behavior of ABC transporter family genes in various HCC cohorts, identifies ABCC6 as a biomarker for early-stage HCC diagnosis, and offers experimental basis for further investigations of targeting ABCC6 in the treatment of patients with HCC.

Neoadjuvant Programmed Cell Death 1 (PD-1) Inhibitor Treatment in Patients With Hepatocellular Carcinoma Before Liver Transplant: A Cohort Study and Literature Review.

Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.

Macrophage Polarization and Liver Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury refers to organ damage caused by the previous insufficient supply of oxygen and nutrients and the involvement of metabolic by-products after blood flow is restored. Liver ischemia-reperfusion injury (IRI) has become a hot research in recent years, because it occurs in many clinical scenarios. After the introduction of liver transplantation and vascular control techniques in liver surgery, liver ischemia-reperfusion injury is considered to be an important factor affecting postoperative mortality and morbidity. As the largest immune organ in the human body, liver contain a lot of immune cells such as resident macrophages (Kupffer cells), dendritic cells, natural killer cells, and natural killer T cells which play a key role in ischemia-reperfusion injury. Among those, macrophage-mediated excessive inflammatory response is considered to be an important factor in liver ischemia-reperfusion injury. The prominent feature of liver injury is an increase in the number of macrophages in liver due to the infiltration of blood monocytes and differentiation into monocyte-derived macrophages. Liver macrophages can be divided into M1 macrophages which can promote inflammation progress and M2 macrophages that inhibit inflammation progress according to their different phenotypes and functions. Both of them can regulate liver aseptic inflammation, and play an important role in triggering, maintaining, and improving liver ischemia-reperfusion injury. This review summarizes studies of macrophage polarization on liver ischemia-reperfusion injury in recent years, to provide potential ideas for translation application in future clinical management.