NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

Benefits of Hypothermic Oxygenated Perfusion Versus Static Cold Storage in Liver Transplant: A Comprehensive Systematic Review and Meta-analysis.

Background: The magnitude of potential benefits that hypothermic oxygenated perfusion (HOPE) may provide for liver transplantation (LT) patients compared to static cold storage (SCS) remains uncertain. In this systematic review and meta-analysis, we aimed to investigate the therapeutic effect that HOPE can offer LT recipients relative to SCS by synthesizing available evidence. Methods: A literature search was conducted in Embase, Medline, Web of Science, and the Cochrane database up to 1 June, 2023. The included studies were pooled for meta-analysis to synthesize their findings. Subgroup analysis was performed to investigate potential differences between HOPE and SCS for specific subgroups. Results: A total of 11 studies comprising 1765 patients were included. Compared with SCS, HOPE was associated with a significant reduction in the incidence of early allograft dysfunction (EAD) (OR: 0.36, 95% CI: 0.26-0.50), as well as a noteworthy decrease in graft loss rate within one year (OR: 0.57, 95% CI: 0.33-0.97) and a lower occurrence of Clavien-Dindo grade IIIa or higher complications (OR: 0.62, 95% CI: 0.43-0.89). Subgroup analysis revealed that HOPE significantly reduced the one-year mortality rate, any biliary complications incidence, and acute rejection of transplanted liver rate in patients who received organs from donation after cardiac death (DCD). Conclusions: HOPE has demonstrated efficacy in reducing the incidence of EAD after LT and shows some potential in diminishing postoperative complications such as biliary complications and acute rejection. This ultimately leads to improved patient prognosis, particularly among those receiving DCD grafts.

Comparison of different adjuvant therapy regimen efficacies in patients with high risk of recurrence after radical resection of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high recurrence rate even after radical surgery. Postoperative adjuvant transhepatic arterial chemoembolization (PA-TACE), postoperative adjuvant hepatic arterial infusion chemotherapy (PA-HAIC), postoperative adjuvant radiotherapy (PA-RT), and postoperative adjuvant molecular targeted therapy have been demonstrated to be effective in reducing the postoperative recurrence rate. The present network meta-analysis was conducted to compare the effects of PA-TACE, PA-HAIC, PA-RT and postoperative adjuvant molecular targeted therapy on the overall survival (OS) and disease-free survival (DFS) in HCC patients after radical resection and to determine the optimal treatment strategy. METHODS: Network meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane Library, and Web of Science were used to collect eligible studies up to December 25, 2022. Studies related to PA-TACE, PA-HAIC, and postoperative adjuvant molecular targeted therapy after radical HCC resection was included. The endpoints were OS and DFS, and the effect size was determined using hazard ratio with a 95% confidence interval. R software and "gemtc" package were employed to analyze the results. RESULTS: A total of 38 studies involving 7079 patients with HCC after radical resection were ultimately enrolled to be analyzed. Four postoperative adjuvant therapy measures and two oncology indicators were evaluated. In this study, OS-related investigations validated that PA-Sorafenib and PA-RT markedly enhanced the OS rates in patients after radical resection when compared to PA-TACE and PA-HAIC. However, statistical analysis revealed no significant difference between PA-Sorafenib and PA-RT, as well as PA-TACE and PA-HAIC. In the DFS-related investigations, PA-RT demonstrated superior efficacy over PA-Sorafenib, PA-TACE, and PA-HAIC. Additionally, PA-Sorafenib displayed better efficacy than PA-TACE. Nevertheless, there was no statistical significance between PA-Sorafenib and PA-HAIC, as well as PA-TACE and PA-HAIC. We also performed a subgroup analysis of studies focusing on HCC complicated by microvascular invasion after radical resection. In terms of OS, both PA-RT and PA-Sorafenib demonstrated a noteworthy improvement over PA-TACE, whereas no statistical significance was detected between PA-RT and PA-Sorafenib. Likewise, for DFS, both PA-Sorafenib and PA-RT exhibited superior efficacy compared to PA-TACE. CONCLUSION: In patients with HCC after radical resection and a high risk of recurrence, both PA-Sorafenib and PA-RT significantly improved OS and DFS when compared to PA-TACE and PA-HAIC. Notably, PA-RT exhibited superior efficacy over PA-Sorafenib, PA-TACE, and PA-HAIC in terms of DFS. Similarly, PA-Sorafenib appeared to be more effective than PA-TACE for DFS.

The combination of a prolonged treatment time window and alpha-fetoprotein benefits the tumor response of hepatocellular carcinoma patients as evaluated by the imRECIST: a single-center, retrospective study.

Background: The combined immunotargeting therapy of hepatocellular carcinoma (HCC) have brought remarkable results. There are still some drawbacks to the application of the immune-modified Response Evaluation Criteria in Solid Tumors to Immunotherapy (imRECIST). How many weeks does it take to confirm the true disease progression for HCC patients who had reported disease progression for the first time based on imRECIST. Whether alpha-fetoprotein (AFP), an important indicator in the progression and prognosis of liver cancer, has the same value in immunotherapy. This prompted more clinical data to gather evidence that the immunotherapy time window issue contradicts the potential benefit of therapy. Methods: This study retrospectively analyzed the clinical data of 32 patients who had undergone immunotherapy plus targeted therapy at the First Affiliated Hospital of Chongqing Medical University from June 2019 to June 2022. ImRECIST was used to evaluate the therapeutic efficacy among the patients. Before initial treatment and each immunotherapy cycle, each patient underwent standard abdominal computed tomography (CT) imaging and some biochemical indicators to assess physical condition and tumor response. All patients included will be divided into 8 groups. The differences in the survival outcomes of each treatment group were analysed. Results: Among the 32 advanced HCC patients, 9 patients achieved stable disease (SD), 12 patients showed progressive disease (PD), 3 patients showed a complete response (CR), and 8 patients showed a partial response (PR). There is no difference in baseline characteristics between subgroups. In relation to patients with PD, a prolonged therapeutic time window and the provision of continuous medication may lead to a PR, prolonging their overall survival (P=0.5864). Compared to the patients with continuous PD, there was no significant difference in the survival of patients with increased AFP concentrations after treatment who achieved PR or SD and ultimately showed PD (P=0.6600). Conclusions: In our study, the time window for treatment may need to be extended in the process of immunotherapy for HCC patients. An analysis of AFP may assist the imRECIST by providing a more accurate evaluation of tumor progression.

Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation.

BACKGROUND: Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. METHODS: Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. RESULTS: Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4+ T cells, CD4+CD8+ T cells, and CD4+CD25+CD127- Tregs and significantly decreased the levels of CD16+CD56+ natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. CONCLUSIONS: This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA. TRIAL REGISTRATION: ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .

Correlation between Immunohistochemical Markers in Hepatocellular Carcinoma Cells and In Vitro High-Throughput Drug Sensitivity Screening.

AIM: This study analyzed the correlation between immunohistochemical markers in hepatocellular carcinoma cells and the results of in vitro high-throughput drug sensitivity screening, to provide a reference for individualized drug treatment in patients with liver cancer. METHODS: Seventy-four patients with hepatocellular carcinoma were included in this study from December 2019 to June 2021, and their liver cancer cells were used for in vitro high-throughput drug sensitivity screening. According to the screening results, the patients were divided into relatively sensitive and insensitive groups, and the correlations between sensitivity and immunohistochemistry results were analyzed statistically. RESULTS: Alpha-fetoprotein (AFP)-positive liver cancer cells were significantly more sensitive to gemcitabine than AFP-negative cells (χ 2 = 6.102, P=0.014). AFP was also positively correlated with sensitivity of liver cancer cells to three combined regimens containing oxaliplatin (L-OHP) and epirubicin (EPI) : L-OHP + EPI + irinotecan + 5-fluorouracil (5-FU), L-OHP + irinotecan + EPI, and L-OHP + EPI (χ 2 = 8.168, P=0.004, χ 2 = 5.705, P=0.017, and χ 2 = 8.275, P=0.004, respectively). CONCLUSION: Gemcitabine and L-OHP + EPI + irinotecan + 5-FU, L-OHP + EPI, and L-OHP + irinotecan + EPI were more effective against AFP-positive compared with AFP-negative liver cancer cells according to in vitro high-throughput drug sensitivity screening. These results may guide the selection of personalized drug treatments for patients with advanced liver cancer in the future but still need further clinical studies to confirm.

Therapeutic effect of postoperative adjuvant transcatheter arterial chemoembolization based on the neutrophil-to-lymphocyte ratio.

Aim: To evaluate the feasibility of the preoperative neutrophil-to-lymphocyte ratio (NLR) as an index to guide postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with liver cancer. Methods: We recruited a total of 166 patients with liver cancer who underwent surgery alone or surgery plus PA-TACE between January 2013 and June 2017 and compared the 1, 2, and 3-year recurrence-free survival (RFS) and overall survival (OS) between patients with high and low NLRs, surgery and surgery plus PA-TACE groups, and relevant subgroups using the Kaplan-Meier method. We also evaluated the independent factors affecting the prognosis of liver cancer after surgery using a Cox risk ratio model and correlation between NLR levels and high-risk recurrence factors of liver cancer with logistic regression analysis. Results: The 1, 2, and 3-year RFS rates were all significantly higher in the low-NLR group compared to the high-NLR group (P < 0.05). However, the 1, 2, and 3-year OS rates were similar in the low- and high-NLR groups (P > 0.05). After propensity score matching, the 1, 2, and 3-year RFS and OS rates were significantly better in patients treated with surgery plus PA-TACE compared with surgery alone (P < 0.05). The 1, 2, and 3-year RFS and OS rates were also significantly better in the surgery plus PA-TACE subgroup compared with the surgery-alone subgroup in the high-NLR group (P < 0.05), but there was no significant difference in RFS or OS between the surgery plus PA-TACE and surgery-alone subgroups at 1, 2, and 3 years in the low-NLR group (P > 0.05). Multivariate analysis in the high-NLR group showed that a poorly differentiated or undifferentiated tumor was an independent risk factor for postoperative RFS. Multiple tumors were an independent risk factor for postoperative OS (P < 0.05), while PA-TACE was an independent protective factor for postoperative RFS and OS (P < 0.05). In the low-NLR group, AFP > 400 µg/L was an independent risk factor for postoperative OS (P < 0.05). Multivariate logistic regression indicated that patients with a maximum tumor diameter of >5 cm were at increased risk of having high NLR levels compared to patients with a maximum tumor diameter of <5 cm (P < 0.05). Conclusion: PA-TACE can improve the prognosis of patients with a high preoperative NLR (≥2.5), but has no obvious benefit in patients with low preoperative NLR (<2.5). This may provide a reference for clinical selection of PA-TACE.

Conversion therapy of hepatic artery ligation combined with transcatheter arterial chemoembolization for treating liver cancer: A case report.

BACKGROUND: Hepatocellular carcinoma is an aggressive tumor, and its latency and lack of clinical symptoms mean that most patients are already in the late stage when diagnosed. Large tumor volume and metastasis are the main reasons for not attempting surgery. Portal vein embolization and associated liver partition and portal vein ligation for staged hepatectomy are commonly used in clinical practice to increase the volume of remnant liver to allow surgical resection; however, research in this area is currently lacking. CASE SUMMARY: A 48-year-old male patient with a history of viral hepatitis B for at least 30 years attended our center with a hepatic space-occupying lesion detected 3 d previously. Enhanced computed tomography scanning of the upper abdomen revealed a large mass in the right lobe of the liver, centered on the right posterior lobe, with the larger section measuring about 14 cm × 10 cm × 14 cm. He successfully underwent conversion therapy for a large right liver tumor after combined hepatic artery ligation and transcatheter arterial chemoembolization, and finally had an opportunity to undergo right hemi-hepatectomy and cholecystectomy. He remained asymptomatic with no obvious abnormalities on computed tomography scanning review at 2 mo after surgery. CONCLUSION: This case highlights new ideas and provides a reference for conversion therapy of large liver tumors.

Evaluation of the Therapeutic Effect of Adjuvant Transcatheter Arterial Chemoembolization Based on Ki67 After Hepatocellular Carcinoma Surgery.

BACKGROUND AND AIMS: This study aimed to determine the relationship between Ki67 expression and the efficacy of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with hepatocellular carcinoma. METHODS: The Kaplan-Meier method was used to analyze the recurrence-free survival (RFS) and overall survival (OS) rates between the sub-groups in the ki67 low expression group and the ki67 high expression group and analyze the relationship between the expression of Ki67 and the efficacy of TACE. RESULTS: After PSM, there was no significant difference in the RFS and OS between the surgery + TACE and surgery subgroups after 1, 2, or 3 years (RFS: 63.9%, 55.6%, and 42.9% vs. 83.3%, 63.9%, and 55.6%, respectively, P = 0.279; OS: 91.7%, 83.3%, and 74.3% vs. 91.7%, 88.9%, and 71.4%, respectively, P = 0.890) in the Ki67 low-expression group. The RFS and OS were higher in the surgery + TACE subgroup than the surgery subgroup after 1, 2, and 3 years (RFS: 80.0%, 77.5%, and 69.2% vs. 53.5%, 39.5%, and 32.6%, respectively, P<0.001; OS: 97.5%, 85.0%, and 79.5% vs. 79.1%, 48.8%, and 42.9%, respectively, P = 0.001) in the Ki67 high expression group. The RFS was higher in the Ki67 high-expression subgroup than the low-expression subgroup after 1, 2, and 3 years, and OS had no significant difference (RFS: 80.0%, 79.5%, and 69.2% vs. 67.4%, 56.5%, and 46.7%, respectively, P = 0.035; OS: 97.5%, 85.0%, and 79.5% vs. 93.5%, 82.6%, and 75.6%, respectively, P = 0.665) in the surgery + TACE group. CONCLUSIONS: For patients with hepatocellular carcinoma and high expression of Ki67 (Ki67≥20%), adjuvant hepatic artery chemoembolization after radical liver tumor resection effectively reduced the probability of tumor recurrence after surgery and prolonged the OS of patients. High Ki67 expression during the post-operative follow-up evaluation of hepatocellular carcinoma patients is an indicator for adjuvant TACE therapy.

Carbapenem-resistant Klebsiella pneumoniae infection causing rupture of graft artery in solid organ recipients: Case report and review of literature.

RATIONALE: Donor-derived bacterial infection is a rare cause of morbidity after solid organ transplantation (SOT) but associated with significant morbidity and mortality, deaths caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) infection account for a considerable proportion of postoperation mortality rate in liver and kidney recipients. The arterial rupture as a result of fungal arteritis is occasionally described, while the rupture of graft vascular anastomosis after SOT due to donor-derived CRKP infection is rarely reported. PATIENTS CONCERNS: We reported 1 patient with donor-derived CRKP infection following liver transplantation and 2 patients following renal transplantation (1 liver and 2 kidneys were from the same donor), who experienced sudden abdominal pain and abdominal hemorrhage almost at the same time after organ transplantation. DIAGNOSIS: The patients were diagnosed as graft arteries rupture due to corrosion caused by CRKP infection based on computed tomography scan, blood culture, laparotomy, and pulse-field gel electrophoresis. INTERVENTIONS: Anti-shock treatment, exploratory laparotomy, broad-spectrum antibiotics, and abdominal puncture and drainage were given. OUTCOMES: The liver recipient survived as well as the liver graft, still under treatment of multiple abdominal infections. The 2 renal recipients were alive after resection of the renal grafts and underwent hemodialysis. LESSONS: Rupture of graft artery should be foreseen when donor-derived CRKP infection was confirmed and broad-spectrum antibiotics and other interventions need to be considered.

Donor safety and remnant liver volume in living donor liver transplantation.

AIM: To evaluate the relationship between donor safety and remnant liver volume in right lobe living donor liver transplantation (LDLT). METHODS: From July 2001 to January 2009, our liver transplant centers carried out 197 LDLTs. The clinical data from 151 cases of adult right lobe living donors (not including the middle hepatic vein) were analyzed. The conditions of the three groups of donors were well matched in terms of the studied parameters. The donors' preoperative data, intraoperative and postoperative data were calculated for the three groups: Group 1 remnant liver volume (RLV) < 35%, group 2 RLV 36%-40%, and group 3 RLV > 40%. Comparisons included the different remnant liver volumes on postoperative liver function recovery and the impact of systemic conditions. Correlations between remnant liver volume and post-operative complications were also analyzed. RESULTS: The donors' anthroposomatology data, operation time, and preoperative donor blood test indicators were calculated for the three groups. No significant differences were observed between the donors' gender, age, height, weight, and operation time. According to the Chengdu standard liver volume formula, the total liver volume of group 1 was 1072.88 ± 131.06 mL, group 2 was 1043.84 ± 97.11 mL, and group 3 was 1065.33 ± 136.02 mL. The three groups showed no statistically significant differences. When the volume of the remnant liver was less than 35% of the total liver volume, the volume of the remnant had a significant effect on the recovery of liver function and intensive care unit time. In addition, the occurrence of complications was closely related to the remnant liver volume. When the volume of the remnant liver was more than 35% of the total liver volume, the remnant volume change had no significant effect on donor recovery. CONCLUSION: To ensure donor safety, the remnant liver volume should be greater than the standard liver volume (35%) in right lobe living donor liver transplantation.

Management of venous stenosis in living donor liver transplant recipients.

AIM: To retrospectively evaluate the management and outcome of venous obstruction after living donor liver transplantation (LDLT). METHODS: From February 1999 to May 2009, 1 intraoperative hepatic vein (HV) tension induced HV obstruction and 5 postoperative HV anastomotic stenosis occurred in 6 adult male LDLT recipients. Postoperative portal vein (PV) anastomotic stenosis occurred in 1 pediatric left lobe LDLT. Patients ranged in age from 9 to 56 years (median, 44 years). An air balloon was used to correct the intraoperative HV tension. Emergent surgical reoperation, transjugular HV balloon dilatation with stent placement and transfemoral venous HV balloon dilatation was performed for HV stenosis on days 3, 15, 50, 55, and 270 after LDLT, respectively. Balloon dilatation followed with stent placement via superior mesenteric vein was performed for the pediatric PV stenosis 168 d after LDLT. RESULTS: The intraoperative HV tension was corrected with an air balloon. The recipient who underwent emergent reoperation for hepatic stenosis died of hemorrhagic shock and renal failure 2 d later. HV balloon dilatation via the transjugular and transfemoral venous approach was technically successful in all patients. The patient with early-onset HV stenosis receiving transjugular balloon dilatation and stent placement on the 15th postoperative day left hospital 1 wk later and disappeared, while the patient receiving the same interventional procedures on the 50th postoperative day died of graft failure and renal failure 2 wk later. Two patients with late-onset HV stenosis receiving balloon dilatation have survived for 8 and 4 mo without recurrent stenosis and ascites, respectively. Balloon dilatation and stent placement via the superior mesenteric venous approach was technically successful in the pediatric left lobe LDLT, and this patient has survived for 9 mo without recurrent PV stenosis and ascites. CONCLUSION: Intraoperative balloon placement, emergent reoperation, proper interventional balloon dilatation and stent placement can be effective as a way to manage hepatic and PV stenosis during and after LDLT.

Evaluation of standard liver volume formulae for Chinese adults.

AIM: To evaluate different standard liver volume (SLV) formula and verify the applicability of the formulae for Chinese adults. METHODS: Data from 70 cases of living donor liver transplantation (LDLT) performed at our transplantation centers between January 2008 and April 2009 were analyzed. SLV was estimated using our recently reported formula [the Chengdu formula: SLV (mL) = 11.5 x body weight (kg) + 334] and other reported formulae used for Chinese adults. Actual intraoperative liver volumes were obtained from a review of the patients' medical records. RESULTS: The actual right liver volume was not significantly different from the estimated right liver volume determined by the Chengdu formula, but was significantly smaller than estimates using the Heinemann, Urata, Vauthey, and Lee formulae (P < 0.01), and significantly larger than estimates using the Fan formula (P < 0.05). CONCLUSION: The Chengdu formula was demonstrated to be reliable by its application in LDLT.