Background: The preoperative selection of patients with intermediate-stage hepatocellular carcinoma (HCC) who are likely to have an objective response to first transarterial chemoembolization (TACE) ...remains challenging. Objective: To develop and validate a clinical-radiomic model (CR model) for preoperatively predicting treatment response to first TACE in patients with intermediate-stage HCC. Methods: A total of 595 patients with intermediate-stage HCC were included in this retrospective study. A tumoral and peritumoral (10 mm) radiomic signature (TPR-signature) was constructed based on 3,404 radiomic features from 4 regions of interest. A predictive CR model based on TPR-signature and clinical factors was developed using multivariate logistic regression. Calibration curves and area under the receiver operating characteristic curves (AUCs) were used to evaluate the model’s performance. Results: The final CR model consisted of 5 independent predictors, including TPR-signature (p < 0.001), AFP (p = 0.004), Barcelona Clinic Liver Cancer System Stage B (BCLC B) subclassification (p = 0.01), tumor location (p = 0.039), and arterial hyperenhancement (p = 0.050). The internal and external validation results demonstrated the high-performance level of this model, with internal and external AUCs of 0.94 and 0.90, respectively. In addition, the predicted objective response via the CR model was associated with improved survival in the external validation cohort (hazard ratio: 2.43; 95% confidence interval: 1.60–3.69; p < 0.001). The predicted treatment response also allowed for significant discrimination between the Kaplan-Meier curves of each BCLC B subclassification. Conclusions: The CR model had an excellent performance in predicting the first TACE response in patients with intermediate-stage HCC and could provide a robust predictive tool to assist with the selection of patients for TACE.
Telomerase reverse transcriptase (
) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of
-telomere signaling during ...hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of
gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE).
promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein-protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with
. The PPI analysis identified eight key
-interacting genes, namely
,
,
,
,
,
,
, and
. Among these,
was the most strongly differentially expressed gene.
promoter mutations were more frequent,
expression was significantly higher, and telomere length was longer in tumors versus non-tumors.
promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs.
promoter mutations were associated with higher
levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy.
expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The
-telomere network may have a crucial role in the development and progression of HCC.
-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.
In the present study, a novel oleaginous Thraustochytrid containing a high content of docosahexaenoic acid (DHA) was isolated from a mangrove ecosystem in Malaysia. The strain identified as an
...Aurantiochytrium
sp. by 18S rRNA sequencing and named KRS101 used various carbon and nitrogen sources, indicating metabolic versatility. Optimal culture conditions, thus maximizing cell growth, and high levels of lipid and DHA production, were attained using glucose (60 g l
−1
) as carbon source, corn steep solid (10 g l
−1
) as nitrogen source, and sea salt (15 g l
−1
). The highest biomass, lipid, and DHA production of KRS101 upon fed-batch fermentation were 50.2 g l
−1
(16.7 g l
−1
day
−1
), 21.8 g l
−1
(44% DCW), and 8.8 g l
−1
(40% TFA), respectively. Similar values were obtained when a cheap substrate like molasses, rather than glucose, was used as the carbon source (DCW of 52.44 g l
−1
, lipid and DHA levels of 20.2 and 8.83 g l
−1
, respectively), indicating that production of microbial oils containing high levels of DHA can be produced economically when the novel strain is used.
Although the prevalence of nonalcoholic steatohepatitis (NASH) is rapidly increasing, effective therapy is lacking. Tenofovir alafenamide (TAF) is a widely used antiviral drug for hepatitis B. In ...this study, we investigated the potential pharmacological effects of TAF on NASH.
Two different NASH mouse models were established: 1) by subcutaneous injection of streptozotocin (0.2 mg) and feeding the mice a high-fat, high-cholesterol (HFHC) diet, and 2) feeding the mice a choline-deficient, L-amino acid-defined, high-fat (CDAHF) diet.
Serum alanine aminotransferase and triglyceride levels in TAF-treated NASH mice were significantly lower than those in the mock-treated ones. The livers from the TAF-treated NASH mice showed attenuated mononuclear phagocyte (MP) infiltration compared to those from the mock-treated ones. TAF-treated NASH mice exhibited decreased liver infiltration of activated MPs (IAIE+/PD-L1+/MerTK+). In ex vivo experiments using sorted human CD14+ monocytes treated with lipopolysaccharide (LPS) and/or TAF, we confirmed the decreased level of phosphorylated AKT in TAF-treated LPS-stimulated monocytes compared to that in the mock-treated ones. Mouse liver immunoblotting showed that phosphorylation levels of AKT were significantly lower in the TAF-treated NASH group than in the mock-treated group.
TAF exerts anti-inflammatory effects in NASH livers by attenuating AKT phosphorylation in intrahepatic activated MPs. Therefore, TAF may serve as a new therapeutic option for NASH.
We report a case of a patient with Dubin-Johnson syndrome confirmed by a genetic study. A 50-year-old woman who had symptoms of intermittent right upper quadrant abdominal pain was diagnosed with ...calculous cholecystitis at another institute and was presented to our hospital for a cholecystectomy. She had no history of liver disease, and her physical examination was normal. Abdominal computed tomography showed a gallbladder stone with chronic cholecystitis. During a laparoscopic cholecystectomy for cholecystitis, a smooth, black-colored liver was noted, and a liver biopsy was performed. The biopsy specimen showed coarse, dark brown granules in centrilobular hepatocytes via hematoxylin and eosin staining. We performed a genetic study using the blood samples of the patient. In the
(
) mutation study, a missense mutation in exon 18 was noted. Based on the black-colored liver without nodularity, conjugated hyperbilirubinemia, the liver biopsy results of the coarse pigment in centrilobular hepatocytes, and the
mutation, Dubin-Johnson syndrome was diagnosed. The patient was managed with conservative care using hepatotonics. One month after follow-up, total bilirubin and direct bilirubin remained in a similar range. Another follow-up was planned a month later, and the patient maintained her use of hepatotonics.
In vitro culture (IVC) for porcine embryo development is inferior compared to in vivo development because oxidative stress can be induced by the production of excessive reactive oxygen species (ROS) ...under high oxygen tension in the in vitro environment. To overcome this problem, we investigated the effect of lycopene, an antioxidant carotenoid, on developmental competence and the mechanisms involved in mitochondria-dependent apoptosis pathways in porcine embryos. In vitro fertilized (IVF) embryos were cultured in IVC medium supplemented with 0, 0.02, 0.05, 0.1, or 0.2 μM lycopene. The results indicate that 0.1 μM lycopene significantly increased the rate of blastocyst formation and the total cell numbers, including trophectoderm cell numbers, on Day In terms of mitochondria-dependent apoptosis, IVF embryos treated with 0.1 μM lycopene exhibited significantly decreased levels of ROS, increased mitochondrial membrane potential, and decreased expression of cytochrome c on Days 2 and Furthermore, 0.1 μM lycopene significantly decreased the number and percentage of caspase 3-positive and apoptotic cells in Day-6 blastocysts. In addition, Day-2 embryos and Day-6 blastocysts treated with 0.1 μM lycopene showed significantly reduced mRNA expression related to antioxidant enzymes (
) and apoptosis (
ratio). These results indicate that lycopene supplementation during the entire period of IVC enhanced embryonic development in pigs by regulating oxidative stress and mitochondria-dependent apoptosis.
Background & Aims
Cancer metastasis is responsible for the majority of cancer-related deaths. Exosomal miRNAs have emerged as promising biomarkers for cancer, serving as signaling molecules that can ...regulate tumor growth and metastasis. This study examined circulating exosomal miRNAs that could predict hepatocellular carcinoma (HCC) metastasis.
Methods
Exosomal miRNA was measured by quantitative real-time PCR (qRT-PCR) in a large set of patients (
n
= 284). To investigate the role of exosomal miRNA in HCC, we performed a series of
in vitro
tests, such as exosome labeling, qRT-PCR, reverse transcription PCR, wound healing assay, transwell assay, and Western blot assay.
Results
Exosomal miR-125b was drastically downregulated in HCC patients with metastasis than in those without metastasis.
In vitro
, we observed the uptake of miR-125b by exosome in recipient cells. Exosome-mediated miR-125b significantly inhibited migration and invasion abilities and downregulated the mRNA expressions of MMP-2, MMP-9, and MMP-14 in recipient cells
via
intercellular communication. Further investigation revealed that miR-125b suppressed SMAD2 protein expression in recipient cells by binding to its 3′ untranslated regions. Exosome-mediated miR-125b transfer also disrupted TGF-β1–induced epithelial–mesenchymal transition and TGF-β1/SMAD signaling pathway in recipient cells by leading to a decrease of SMAD2 protein expression. Moreover, exosomal miR-125b was downregulated after metastasis compared with that at baseline in patients with serial measurements before and after metastasis.
Conclusions
The results imply that exosome-mediated miR-125b exerts anti-metastatic properties in HCC. These findings highlight that circulating exosomal miR-125b might represent a reliable biomarker with diagnostic and therapeutic implications for extrahepatic metastasis from HCC.
Objective: We aimed to assess and validate the radiologic and clinical factors that were associated with recurrence and survival after curative surgery for heterogeneous targetoid primary liver ...malignancies in patients with chronic liver disease and to develop scoring systems for risk stratification. Materials and Methods: This multicenter retrospective study included 197 consecutive patients with chronic liver disease who had a single targetoid primary liver malignancy (142 hepatocellular carcinomas, 37 cholangiocarcinomas, 17 combined hepatocellular carcinoma-cholangiocarcinomas, and one neuroendocrine carcinoma) identified on preoperative gadoxetic acid-enhanced MRI and subsequently surgically removed between 2010 and 2017. Of these, 120 patients constituted the development cohort, and 77 patients from separate institution served as an external validation cohort. Factors associated with recurrence-free survival (RFS) and overall survival (OS) were identified using a Cox proportional hazards analysis, and risk scores were developed. The discriminatory power of the risk scores in the external validation cohort was evaluated using the Harrell C-index. The Kaplan-Meier curves were used to estimate RFS and OS for the different risk-score groups. Results: In RFS model 1, which eliminated features exclusively accessible on the hepatobiliary phase (HBP), tumor size of 2-5 cm or > 5 cm, and thin-rim arterial phase hyperenhancement (APHE) were included. In RFS model 2, tumors with a size of > 5 cm, tumor in vein (TIV), and HBP hypointense nodules without APHE were included. The OS model included a tumor size of > 5 cm, thin-rim APHE, TIV, and tumor vascular involvement other than TIV. The risk scores of the models showed good discriminatory performance in the external validation set (C-index, 0.62-0.76). The scoring system categorized the patients into three risk groups: favorable, intermediate, and poor, each with a distinct survival outcome (all log-rank p < 0.05). Conclusion: Risk scores based on rim arterial enhancement pattern, tumor size, HBP findings, and radiologic vascular invasion status may help predict postoperative RFS and OS in patients with targetoid primary liver malignancies.
Idiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver ...may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI.
From January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days.
The numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days.
Activated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.
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