Long-term Radiological and Pulmonary Function Abnormalities at 3-year post COVID-19 Hospitalization: A Longitudinal Cohort Study.

BACKGROUND: This study aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulations, and fibrotic-like changes) and pulmonary function, three years following coronavirus disease 2019(COVID-19). METHODS: This prospective, longitudinal cohort study enrolled COVID-19 survivors who exhibited residual lung abnormalities upon discharge from two hospitals. Follow-up assessments were conducted at 6 months, 12 months, 2 years, and 3 years post-discharge, and included pulmonary function tests, 6-minute walk distance (6MWD), chest CT scans, and symptom questionnaires. Non-COVID-19 controls were retrospectively recruited for comparative analysis. RESULTS: 728 COVID-19 survivors and 792 controls were included. From 6 months to 3 years, there was a gradual improvement in reduced diffusing capacity of the lungs for carbon monoxide (DLCO＜80% predicted, 49% versus 38%, p=0.001), 6MWD (496 m versus 510 m, p=0.002) and residual lung abnormalities(46% versus 36%, p<0.001), regardless of the disease severity. Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32% versus 16%, p<0.001), lower 6MWD (494 m versus 510 m, p=0.003), and abnormal DLCO (57% versus 27%, p<0.001) compared to those with complete resolution. Compared to the controls, the proportion of DLCO impairment (38% versus 17%, p<0.001) and respiratory symptoms (23% versus 2.2%, p<0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up. CONCLUSIONS: Most patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than one-third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.

Ginkgetin exhibits antifibrotic effects by inducing hepatic stellate cell apoptosis via STAT1 activation.

Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.

Predictors of Improvement of Sarcopenia after Transjugular Intrahepatic Portosystemic Shunt Creation in Cirrhotic Patients.

To investigate the risk factors affecting the improvement of sarcopenia after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients, this study retrospectively analyzed the data of 111 cirrhotic patients with sarcopenia who underwent TIPS creation. Computed tomography-based measurement of skeletal muscle area was used to calculate skeletal muscle index (SMI) in all patients at baseline and 6 months after TIPS creation. Multivariate logistic regression analysis was used to identify independent risk factors, which showed a significant increase in 6-month post-TIPS SMI compared with that at baseline in both men and women (for both, P < .001). Pre-TIPS SMI (odds ratio [OR], 0.93; 95% CI, 0.87-0.99; P = .031) and change in portal pressure gradient (OR, 1.13; 95% CI, 1.03-1.24; P = .009) were found to be independent risk factors for experiencing substantial improvement in post-TIPS SMI.

Reversion of liver cirrhosis after endovascular treatment in Chinese patients with Budd-Chiari syndrome.

AIMS: To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd-Chiari syndrome (BCS). METHODS: From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV-treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. RESULTS: The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3 , p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. CONCLUSIONS: BCS-induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis.

Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease. We explored simple and effective ways to improve NAFLD and investigate the mechanism of action. METHODS: NAFLD was induced in 40 rats fed a high-fat diet (HFD). Magnetic resonance imaging was used to evaluate the progression and improvement of NAFLD. The treatment-related interventions included aerobic exercise (E) and vitamin E (VE) supplementation. Expression levels of proteins related to fat metabolism were also assessed. The activities of antioxidant enzymes in the liver and serum lipid metabolism were analyzed using biochemical methods. RESULTS: Aerobic exercise and vitamin E effectively improved NAFLD in rats, resulting in decreased hepatic fat accumulation, reduced hepatocyte ballooning, and decreased triglyceride levels. Combination therapy achieved the best effect. Both aerobic exercise and vitamin E activate the AMPK pathway to phosphorylate acetyl-CoA carboxylase (ACC) and reduce fatty acid synthesis. The expression of sterol regulatory element-binding protein-1 (SREBP-1) was decreased significantly in the treated groups, particularly in the E + VE + HFD group. The expression of carnitine palmitoyl-transferase 1C (CPT1C) significantly increased in the treated groups, particularly in the E + VE + HFD group. Compared with the control group, reactive oxygen species (ROS) in the E + HFD group were slightly decreased, while that in the VE + HFD group were significantly decreased, with the even greater reduction observed in the E + VE + HFD group. CONCLUSION: Aerobic exercise and vitamin E supplementation can improve HFD-induced NAFLD in rats by regulating the AMPK pathway and reducing oxidative stress.

Sarcopenia Defined by Psoas Muscle Thickness Predicts Mortality After Transjugular Intrahepatic Portosystemic Shunt.

PURPOSE: To assess and compare the value of psoas muscle thickness at the level of the third lumbar (L3) vertebra (TPML) or umbilicus (TPMU) and skeletal muscle index (SMI) for diagnosing sarcopenia and predicting mortality in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). MATERIALS AND METHODS: Two hundred forty-nine patients undergoing TIPS were included in this retrospective study. The cut-offs of L3-SMI for sarcopenia were 42.0 cm2/m2 in men and 38.0 cm2/m2 in women. The cut-offs for TPML/height and TPMU/height to predict mortality was established using a receiver-operating characteristic analysis. The Kaplan-Meier and Cox regression were used for survival analyses. RESULTS: Compared with TPMU/height, TPML/height was more consistent with L3-SM for the diagnosis of sarcopenia (Kappa coefficient: 0.63 vs. 0.36 in men; 0.61 vs. 0.45 in women). The Cox analysis showed that both TPML/height and TPMU/height were independent risk factors for mortality. The optimal cut-off values of TPML/height and TPMU/height for mortality in men and women were 11.2 mm/m, 9.4 mm/m, 18.4 mm/m, 15.1 mm/m, respectively. There were 119 (47.8%), 87 (34.9%), and 82 (32.9%) patients diagnosed with sarcopenia in the TPMU/height, TPML/height, and L3-SMI models, respectively. Kaplan-Meier analysis showed that the overall survival was significantly lower in the sarcopenia group in all three models. CONCLUSION: TPMU/height and TPML/height have a similar survival prognostic value as L3-SMI. TPML/height has better consistency with L3-SMI in diagnosing sarcopenia and is a more stable alternative to L3-SMI for diagnosing sarcopenia in patients undergoing TIPS.

Natural History and Influence on Long-term Outcomes of Isolated Type II Endoleak after Endovascular Aneurysm Repair: A 10-year Experience at a Single Center.

BACKGROUND: The management of type II endoleaks (T2ELs) remains controversial in current literature. Hence, this study aimed to explore the natural history of isolated type II endoleak after endovascular aneurysm repair (EVAR) and its influence on long-term outcomes based on a 10-year follow-up at a tertiary medical center. METHODS: From January 2011 to April 2021, consecutive patients who underwent elective EVAR were reviewed. The demographics, clinical characteristics, treatment details, imaging information, in the event of T2ELs, and outcomes were extracted. RESULTS: A total of 287 patients were included for analysis. Isolated T2EL was identified in 79 patients (27.5%), while no endoleak was found in 208 patients (72.5%). The mean age at EVAR was 68.1 ± 8.9 years (range, 41-92 years) and the majority of patients were male (81.5%). The mean follow-up duration was 42.7 months (range, 2-119.7 months). Among the 79 patients with isolated T2ELs, 33 (41.8%, 33/79) were early and 46 (58.2%, 46/79) were late. Spontaneous resolution of T2ELs was identified in 29 patients (36.7%, 29/79). Persistent T2ELs were observed in 50 patients (63.3%, 50/79). No sac growth was seen in 33 patients (66%, 33/50) and these patients were managed conservatively. The remaining 17 patients (34%, 17/50) showed significant sac growth. Six of them declined intervention due to various reasons and the remaining 11 patients underwent interventional embolization for T2ELs. Following the embolization, 2 patients had complete resolution of T2ELs and 9 patients had persistent T2ELs. Among the patients with persistent T2ELs, 2 patients (2/9) still showed progressive sac growth, and one of them died from aneurysm rupture; the remaining 7 patients (7/9) showed no sac growth. Patients with isolated T2ELs had a higher incidence of sac growth than patients without any endoleak (21.5% vs 4.3%, p < 0.001), while no difference was found in overall survival between the two groups. In Cox regression analysis, only higher age was independently associated with worse survival. CONCLUSIONS: Type II Endoleak was significantly associated with aneurysm sac growth and no association with survival was observed.

Late combination of transarterial chemoembolization with apatinib and camrelizumab for unresectable hepatocellular carcinoma is superior to early combination.

OBJECTIVE: The purpose of this study was to explore the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab (TACE + AC) for unresectable hepatocellular carcinoma (HCC), and the impact of the timing of the combination on it. METHODS: In this single-arm retrospective study, consecutive data of patients with unresectable HCC treated to our hospital from March 2017 to September 2021 were collected. These patients were treated with TACE and started on camrelizumab and apatinib within one week of TACE. Camrelizumab 200 mg intravenously once every three weeks and apatinib 250 mg orally once daily. Repeat TACE treatment was available on an on-demand basis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The univariate and multivariate Cox regression analyses were used to assess the effect of early and late combination on OS and PFS. RESULTS: A total of 80 patients were enrolled in this study. The median OS was 22.1 months (95% confidence interval [CI]: 13.8-30.5 months) and the median PFS was 15.7 months (95% CI: 14.7-16.6 months). The ORR was 58.8% (95% CI: 47.2-69.6) and DCR reached 81.2% (95% CI: 71.0-89.1). Multivariable Cox proportional hazard regression analyses showed that TACE late combined with apatinib and camrelizumab provided better OS than early combination (HR = 0.175, 95% CI:0.060-0.509, P = 0.001), as did PFS (HR = 0.422, 95% CI:0.184-0.967, P = 0.041). All treatment-related adverse events were tolerable, and no serious adverse events were observed. CONCLUSION: TACE combined with apatinib plus camrelizumab for patients with unresectable HCC has promising antitumor activity and a manageable safety profile. For unresectable HCC with large tumor burden, late combination provides better OS and PFS compared to early combination.

Covered vs. uncovered self-expandable metal stents for palliation of malignant afferent loop obstruction: a multicenter study.

BACKGROUND AND AIMS: Endoscopic stent placement is a palliative therapy for malignant digestive tract obstruction. However, its use for malignant afferent loop obstruction (mALO) has not been adequately investigated. METHODS: From March 2009 to December 2020, 137 patients with mALO who underwent endoscopic stent placement at three tertiary care centers were retrospectively enrolled. The primary aim of this study was to compare stent dysfunction (SD) between the covered self-expandable metal stent (CSEMS) and uncovered self-expandable metal stent (UCSEMS) groups, with subgroup analysis among patients with extrinsic and intrinsic tumors separately. RESULTS: Twenty-three patients developed SD in the CSEMS group and 29 patients in the UCSEMS group (log-rank p = .974). The primary contributors to SD included a higher risk of stent migration in the CSEMS group and stent ingrowth in the UCSEMS group (p = .003; p < .001). Among patients with extrinsic tumors, the CSEMS group showed a significantly higher probability of overall SD (p = .008) and stent migration (p = .001) with a shorter time to SD (log-rank p = .006) than the UCSEMS group. Among patients with intrinsic tumors, the CSEMS group showed a significantly lower incidence of overall SD (p < .001) and stent ingrowth (p < .001) with a longer time to SD (log-rank p = .011) than the UCSEMS group. CONCLUSIONS: Our results showed no significant difference in SD between the CSEMS and UCSEMS groups for palliation of mALO. Furthermore, subgroup analysis suggested using CSEMSs for patients with intrinsic tumors, and UCSEMSs for those with extrinsic tumors.

FIPS Score for Prediction of Survival After TIPS Placement: External Validation and Comparison With Traditional Risk Scores in a Cohort of Chinese Patients With Cirrhosis.

BACKGROUND. Various prognostic scores for patients with chronic liver disease have been applied for predicting survival after TIPS placement. In 2021, the Freiburg index of post-TIPS survival (FIPS) score was developed specifically for predicting survival after TIPS placement. The score has exhibited variable performance in initial investigations conducted in German and U.S. cohorts. OBJECTIVE. The purpose of this study was to compare the utility of the FIPS score and traditional scoring systems for predicting post-TIPS survival in a cohort of Chinese patients with cirrhosis. METHODS. This retrospective validation study compared four prognostic scores (model for end-stage liver disease [MELD], sodium MELD [MELD-Na], Chronic Liver Failure Consortium acute decompensation [CLIF-C AD], and FIPS) in 383 patients (mean age, 54.9 ± 11.7 years; 249 men, 134 women) with cirrhosis who underwent TIPS placement (341 for variceal bleeding, 42 for refractory ascites) at Wuhan Union Hospital between January 2016 and August 2021. Model performance was assessed in terms of discrimination (using concordance index) and calibration (using Brier score and observed-to-predicted ratios) for 6-, 12-, and 24-month post-TIPS survival. Discrimination was further stratified by TIPS indication. Risk stratification was performed using previously proposed cutoffs for each score. RESULTS. During postprocedural follow-up, 72 (18.8%) patients died. Discriminative performance for 6-month survival was highest for FIPS score (concordance index, 0.784), followed by CLIF-C AD (0.743), MELD-Na (0.699), and MELD (0.694). FIPS score also showed the highest calibration in terms of lower Brier scores and observed-to-predicted ratios closer to 1 and showed the strongest prognostic performance for 12- and 24-month survival and in subgroups of patients who underwent TIPS placement for either variceal bleeding or refractory ascites (except for similar performance of FIPS and CLIF-C AD in the refractory ascites subgroup). When prior cutoffs were applied, further application of FIPS score was significantly associated with survival among patients classified as low risk by the other scores. CONCLUSION. FIPS score outperformed traditional risk scores in predicting post-TIPS survival in patients with cirrhosis. CLINICAL IMPACT. The findings support utility of FIPS score in differentiating patients who are optimal candidates for TIPS placement versus those at high risk who may instead warrant close monitoring and early liver transplant.

Portal flow diversion based on portography is superior than puncture site in the prediction of overt hepatic encephalopathy after TIPS creation.

BACKGROUND: Targeted puncture of an appropriate portal venous branch during transjugular intrahepatic portosystemic shunt (TIPS) procedure may reduce the risk of postprocedural overt hepatic encephalopathy (HE). This study aimed to describe blood distribution under portography and combined it with puncture site to determine portal flow diversion, and to evaluate its prognostic value in predicting post-TIPS overt HE. METHODS: In this retrospective analysis of patients with cirrhosis undergoing TIPS, we included 252 patients to describe blood distribution under portography and 243 patients to assess the association between portal flow diversion and post-TIPS overt HE. RESULTS: At the first stage, 51 (20.2%) patients were identified as type A (unilateral type with the right portal branch receives blood from splenic vein [SV]), 16 (6.4%) as type B (unilateral type with the right branch receives blood from superior mesenteric vein [SMV]) and 185 (73.4%) as type C (fully mixed type). At the second stage, 40 patients were divided into the SV group, 25 into the SMV group and 178 into the mixed group. Compared with the mixed group, the risk of post-TIPS overt HE was significantly higher in the SMV group (adjusted HR 3.70 [95% CI 2.01-6.80]; p < 0.001), whereas the SV group showed a non-significantly decreased risk (adjusted HR 0.57 [95% CI 0.22-1.48]; p = 0.25). Additionally, the SMV group showed a substantial increase in ammonia level at 3 days and 1 month after procedure. CONCLUSIONS: Our results support the clinical use of portal flow diversion for risk stratification and decision-making in the management of post-TIPS overt HE.

Microwave ablation combined with anti-PD-1 therapy enhances systemic antitumor immunity in a multitumor murine model of Hepa1-6.

BACKGROUND: To evaluate the changes of immune environment of distant tumors after combined microwave ablation (MWA) and anti- programmed death receptor - 1 (anti-PD-1) therapy, and assess the changes of systemic immune response. METHODS: Bilateral hepatocellular carcinoma model was established in mice, which were then subsequently treated with MWA, or anti-PD-1, or no treatment, or MWA + anti-PD-1. The contralateral tumor volume and mice survival time were recorded. Flow cytometry and immunohistochemistry were used for evaluation of the immune cells subgroup change of contralateral tumor. In addition, tumor rechallenge tests were conducted on unilateral tumor-bearing mice to examine the systemic immune effects of the combination therapy. RESULTS: We found that MWA treatment alone failed to produce a significant abscopal effect. In contrast, the combination group had longer survival than the MWA or anti-PD-1 group alone, with slower distant tumor growth. Moreover, the tumor-specific immune responses induced by combination therapy are stronger than anti-PD-1 or MWA alone. Combination therapy also elevated the levels of Th1-type cytokines in peripheral blood. In addition, after tumor rechallenge, the combination group showed more rejection to the reimplanted tumors (6 out of 10 mice). CONCLUSIONS: The combination of MWA and anti-PD-1 therapy resulted in the inhibition of distant tumor growth and the construction of a systemic anti-tumor immune environment that can reduce recurrence.

Impact of Sarcopenia on Prognosis in Primary Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization: A Single Center Retrospective Study.

Objective: This study aimed to investigate the prognostic effect of sarcopenia on primary hepatocellular carcinoma (HCC) patients after transcatheter arterial chemoembolization (TACE). Methods: This retrospective study enrolled 265 patients diagnosed with HCC who underwent TACE between April 2014 and February 2021. The patients were divided into two groups: the sarcopenia group (n=133) and the non-sarcopenia group (n=132). The study analyzed the differences in overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier curves. The independent risk factors for OS and PFS were determined using univariate and multivariate Cox regression analysis. Based on these factors, the study constructed a prognostic risk grading system. Results: At 3 and 6 months post-TACE, the prognoses of the sarcopenia group were worse than that of the non-sarcopenia group according to the mRECIST criteria. Kaplan-Meier curves showed that the cumulative OS and PFS rate in the non-sarcopenia group were significantly higher compared to the sarcopenia group (HR=3.319, 95%CI: 2.283-4.824, Log-rank P < 0.001; HR=0.631, 95%CI: 0.486-0.820, Log-rank P < 0.001). Sarcopenia, maximal tumor diameter, and AFP ≥ 200 ng/mL were independent risk factors for OS and PFS. The prognostic risk grading system based on sarcopenia, AFP ≥ 200 ng/mL, and maximal tumor diameter≥8.9 cm showed significant differences in prognosis between risk groups. Conclusion: Sarcopenia had excellent predictive value for OS and PFS in patients after TACE, and AFP ≥ 200 ng/mL and maximal tumor diameter were also independent risk factors for a poor prognosis. The prognostic risk grading system based on sarcopenia, AFP, and maximal tumor diameter had good guiding value for the prognosis of patients.

The time window for pre-emptive transjugular intrahepatic portosystemic shunt could be extended to 5 days.

As recommended by Baveno VII consensus, the utilization of pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) has been considered as standard therapeutic approach for the management of acute variceal bleeding (AVB) associated with cirrhosis., but the 72-h window for pTIPS is too narrow. This study aimed to compare the clinical outcomes between patients who received <72 h pTIPS and 72 h-5d pTIPS. In this study, a total of 63 cirrhotic patients with AVB who underwent pTIPS between October 2016 and December 2021 were included in this retrospective study. They were divided into <72 h group (n = 32) and 72 h-5d group (n = 31), based on the timing of the intervention. The Kaplan-Meier curves demonstrated that there were no significant differences in the cumulative incidence of death (22.3% ± 7.4% vs. 19.9% ± 7.3%, log-rank P = 0.849), variceal rebleeding (9.7% ± 5.3% vs. 17.8% ± 7.3%, log-rank P = 0.406), OHE (28.5% ± 8.0% vs. 23.9% ± 8.0%, log-rank P = 0.641) and shunt dysfunction (8.6% ± 6.0% vs. 17.4% ± 8.1%, log-rank P = 0.328) between <72 h and 72 h-5d groups. In the total cohort, sarcopenia was identified as an independent risk factor for mortality (HR = 11.268, 95% CI = 1.435-88.462, P = 0.021) and OHE(HR = 12.504, 95% CI = 1.598-97.814, P = 0.016). In conclusion, the clinical outcomes of cirrhotic patients with AVB who underwent pTIPS within the 72-h to 5-day window were found to be comparable to those treated within the 72-h window.

Recent advances in hepatocellular carcinoma-targeted nanoparticles.

In the field of medicine, we often brave the unknown like interstellar explorers, especially when confronting the formidable opponent of hepatocellular carcinoma (HCC). The global burden of HCC remains significant, with suboptimal treatment outcomes necessitating the urgent development of novel drugs and treatments. While various treatments for liver cancer, such as immunotherapy and targeted therapy, have emerged in recent years, improving their transport and therapeutic efficiency, controlling their targeting and release, and mitigating their adverse effects remains challenging. However, just as we grope through the darkness, a glimmer of light emerges-nanotechnology. Recently, nanotechnology has attracted attention because it can increase the local drug concentration in tumors, reduce systemic toxicity, and has the potential to enhance the effectiveness of precision therapy for HCC. However, there are also some challenges hindering the clinical translation of drug-loaded nanoparticles (NPs). Just as interstellar explorers must overcome interstellar dust, we too must overcome various obstacles. In future researches, the design and development of nanodelivery systems for novel drugs treating HCC should be the first attention. Moreover, researchers should focus on the active targeting design of various NPs. The combination of the interventional therapies and drug-loaded NPs will greatly advance the process of precision HCC therapy.

Synergistic Effects of Nanoscale CaO2 Combined with PD-1 Inhibitors in the Treatment of Hepatocellular Carcinoma: A Promising Combination.

Purpose: To explore the effect of calcium peroxide nanoparticles (CaO2 NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and its related mechanism. Methods: Hepa1-6 cells were cultured to construct the Hepa1-6 mouse liver cancer model. In vivo mechanism study, a unilateral tumor model was established. Eighteen tumor-bearing mice were randomly divided into the control group (intra-tumoral injection of PBS solution) and the experimental group (intra-tumoral injection of CaO2 NPs). A hypoxic probe, pH probe, and micro-CT were used to evaluate the effect of CaO2 NPs on improving hypoxia, neutralizing acidity, and inducing calcium overload within the tumor. To study the effect of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors, the bilateral tumor model was established. Forty tumor-bearing mice were randomly divided into the control group (intra-tumoral/intra-peritoneal injection of PBS solution), CaO2 NPs group (intra-tumoral injection of CaO2 NPs), PD-1 group (intra-peritoneal injection of PD-1 inhibitor), and the combination group (intra-tumoral injection of CaO2 NPs and intra-peritoneal injection of PD-1 inhibitors). The administered side was recorded as the proximal tumor. Tumor volume and body weight were measured every 2 days after treatment. On day 8, serum and tumor samples were collected. The immune factors in serum (Interferon-γ (IFN-γ), Tumour necrosis factor-α (TNF-α), Interleukin-2 (IL-2), and Interleukin-10 (IL-10)) and tumor tissue (IFN-γ and TNF-α) were detected by ELISA. H&E staining was used to detect tumor necrosis. Immunohistochemical staining was used to detect the amount of CD4+ and CD8+ T cells within the tumor. By analyzing the tumor volume, pathological indexes, and immune-related indexes, the effects of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors were evaluated, and they mediated immunomodulatory effects (including local and systemic immunity), and their effects on tumor burden were studied. In addition, a unilateral tumor model was established to study the effect of CaO2 NPs combined with PD-1 inhibitors on survival time. Results: The results of in vivo mechanism study showed that CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors. The results of the study on the effect of CaO2 NPs combined with PD-1 inhibitor on proximal and distal tumors showed that, compared with the other three groups, the bilateral tumor burden of the combination group was significantly reduced, the intra-tumoral infiltration of CD8+ and CD4+ T cells were significantly increased, the secretion of anti-tumor immune factors in tumor and serum was increased, and the secretion of pro-tumor immune factors was decreased. Mice in the combination group showed the longest survival compared with the other groups. Conclusion: CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors, so as to reduce tumor burden and realize an immunosuppressive tumor transformation to a hot tumor, and play a synergistic role with PD-1 inhibitors in anti-liver cancer.

Activation of AMPK pathway by low­dose donafenib and atorvastatin combination improves high­fat diet­induced metabolic dysfunction­associated steatotic liver disease.

Metabolic dysfunction­associated steatotic liver disease (MASLD) is an increasingly significant global health burden for which there is currently no effective treatment. The present study aimed to explore the underlying mechanisms and investigate the effects of donafenib and atorvastatin in MASLD. The effects of donafenib and atorvastatin on the activity and lipid metabolism of HepG2 cells were analyzed in vitro. A rat model of MASLD was established induced by a high­fat diet in vivo. H&E and Oil red O staining were used to observe the improvement in MASLD, western blotting analysis was used to detect the expression of proteins related to fat metabolism and immunofluorescence was used to detect reactive oxygen species (ROS) levels. In vitro, donafenib and atorvastatin inhibited lipid accumulation in HepG2 cells. In vivo, donafenib and atorvastatin activated the AMP­activated protein kinase (AMPK) pathway, downregulated the expressions of proteins related to fatty acid synthesis (sterol regulatory element­binding protein­1, 3­hydroxy­3­methylglutaryl­CoA reductase and fatty acid synthase) and upregulated the expression of proteins related to fatty acid ß­oxidation (carnitine palmitoyl­transferase 1C and acyl­CoA oxidase). The levels of free fatty acids, cholesterol and triglycerides in the liver and serum decreased in all three treatment groups. Additionally, donafenib and atorvastatin reduced oxidative stress in the liver tissue and decreased ROS levels. Low­dose donafenib combined with atorvastatin improved MASLD by regulating fatty acid metabolism and reducing oxidative stress through activation of the AMPK signaling pathway.

Comparison of specialized stent versus generic stent and bare stent combination for transjugular intrahepatic portosystemic shunt creation.

Transjugular intrahepatic portosystemic shunt (TIPS) creation using the Viatorr stent remains relatively uncommon in underdeveloped and high-burden disease regions in Asia-Pacific, and there is a lack of comparative studies regarding its prognostic effects compared with the generic stent-graft/bare stent combination. The purpose of this retrospective study is to compare the prognostic endpoints of these two treatments in patients who underwent TIPS creation. Clinical data from 145 patients were collected, including 82 in the combination group and 63 in the Viatorr group. Differences in prognostic endpoints (shunt dysfunction, death, overt hepatic encephalopathy [OHE], rebleeding) between the two groups were analyzed using Kaplan-Meier curves. The Cox proportional hazards model was used to identify independent risk factors for post-TIPS shunt dysfunction. The TIPS procedure was successful in all patients. After TIPS creation, both groups showed a significant decrease in porto-caval pressure gradient compared to that before TIPS creation. The stent patency rates at 6, 12, and 18 months were high in both the combination and Viatorr groups (93.7%, 88.5%, and 88.5% vs. 96.7%, 93.4%, and 93.4%, respectively). The stent patency rates was higher in the combination group than in the Viatorr group, although not statistically significant (HR = 2.105, 95% CI 0.640-6.922, Log-rank P = 0.259). There were no significant differences in other prognostic endpoints (death, OHE, rebleeding) between the two groups. The Cox model identified portal vein diameter (HR = 0.807, 95% CI 0.658-0.990, P = 0.040) and portal vein thrombosis (HR = 13.617, 95% CI 1.475-125.678, P = 0.021) as independent risk factors for post-TIPS shunt dysfunction. The shunt patency rates between the Viatorr stent and the generic stent-graft/bare stent combination showed no significant difference and the generic stent-graft/bare stent combination may be a viable alternative in areas where the Viatorr stent is not yet available.

Blocking TGFßR synergistically enhances anti-tumor effects of anti-PD-1 antibody in a mouse model of incomplete thermal ablation.

The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-ß (TGFß) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-ß receptor (TGFßR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFßR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFßR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFßR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFßR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.

Amorphous Albumin Gadolinium-Based Nanoparticles for Ultrahigh-Resolution Magnetic Resonance Angiography.

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 µm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.