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Aim: We previously reported that abdominal aortic calcification is associated with poor overall and recurrence‐free survival after hepatectomy for hepatocellular carcinoma (HCC). However, the effect of abdominal aortic calcification on cancer‐specific prognosis in very old patients with several comorbidities remains unknown. This multicenter study aimed to evaluate the impact of abdominal aortic calcification on the cumulative recurrence rate and recurrence‐free survival in patients with HCC aged >80 years. Methods: We retrospectively analyzed the data of 128 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at seven hospitals belonging to Hiroshima Surgical Study Group of Clinical Oncology between January 2014 and December 2018. Patients were divided into two groups: high and low abdominal aortic calcification groups. The primary endpoints were cumulative recurrence rate and recurrence‐free survival. Results: Kaplan–Meier survival curve analysis demonstrated that the cumulative recurrence rate in the high abdominal aortic calcification group was significantly higher than that in the low abdominal aortic calcification group, and the high abdominal aortic calcification group had a significantly lower recurrence‐free survival rate. In the multivariate analysis, high abdominal aortic calcification (p = 0.03), high des‐gamma‐carboxyprothrombin score (p = 0.04), and multiple tumors (p < 0.01) were independent predictive factors for recurrent HCC, and high abdominal aortic calcification (p = 0.01) and high des‐gamma‐carboxyprothrombin (p = 0.01) were independent predictive factors for poor cancer‐specific survival. Conclusions: Our results indicate that the abdominal aortic calcification score is associated with cumulative recurrence rate and recurrence‐free survival in very old patients with HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors. [ABSTRACT FROM AUTHOR]

Abstract Aim We previously reported that abdominal aortic calcification is associated with poor overall and recurrence‐free survival after hepatectomy for hepatocellular carcinoma (HCC). However, the effect of abdominal aortic calcification on cancer‐specific prognosis in very old patients with several comorbidities remains unknown. This multicenter study aimed to evaluate the impact of abdominal aortic calcification on the cumulative recurrence rate and recurrence‐free survival in patients with HCC aged >80 years. Methods We retrospectively analyzed the data of 128 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at seven hospitals belonging to Hiroshima Surgical Study Group of Clinical Oncology between January 2014 and December 2018. Patients were divided into two groups: high and low abdominal aortic calcification groups. The primary endpoints were cumulative recurrence rate and recurrence‐free survival. Results Kaplan–Meier survival curve analysis demonstrated that the cumulative recurrence rate in the high abdominal aortic calcification group was significantly higher than that in the low abdominal aortic calcification group, and the high abdominal aortic calcification group had a significantly lower recurrence‐free survival rate. In the multivariate analysis, high abdominal aortic calcification (p = 0.03), high des‐gamma‐carboxyprothrombin score (p = 0.04), and multiple tumors (p

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors.

Hepatocellular carcinoma is a refractory tumor with poor prognosis and high mortality. Many oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma. Based on previous studies, we constructed a recombinant GM-CSF-carrying Sindbis virus, named SINV-GM-CSF, which contains a mutation (G to S) at amino acid 285 in the nsp1 protein of the viral vector. The potential of this mutated vector for liver cancer therapy was verified at the cellular level and in vivo, respectively, and the changes in the tumor microenvironment after treatment were also described. The results showed that the Sindbis virus could effectively infect hepatocellular carcinoma cell lines and induce cell death. Furthermore, the addition of GM-CSF enhanced the tumor-killing effect of the Sindbis virus and increased the number of immune cells in the intra-tumor microenvironment during the treatment. In particular, SINV-GM-CSF was able to efficiently kill tumors in a mouse tumor model of hepatocellular carcinoma by regulating the elevation of M1-type macrophages (which have a tumor-resistant ability) and the decrease in M2-type macrophages (which have a tumor-promoting capacity). Overall, SINV-GM-CSF is an attractive vector platform with clinical potential for use as a safe and effective oncolytic virus. [ABSTRACT FROM AUTHOR]

Summary: Background: Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies. Methods: To discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity. Findings: We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. Interpretation: Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment. Funding: This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).

Abstract Background Increasing evidence suggests that hepatocellular carcinoma (HCC) stem cells (LCSCs) play an essential part in HCC recurrence, metastasis, and chemotherapy and radiotherapy resistance. Multiple studies have demonstrated that stemness-related genes facilitate the progression of tumors. However, the mechanism by which stemness-related genes contribute to HCC is not well understood. Here, we aim to construct a stemness-related score (SRscores) model for deeper analysis of stemness-related genes, assisting with the prognosis and individualized treatment of HCC patients.Further, we found that the gene LPCAT1 was highly expressed in tumor tissues by immunohistochemistry, and sphere-forming assay revealed that knockdown of LPCAT1 inhibited the sphere-forming ability of hepatocellular carcinoma cells. Methods We used the TCGA-LIHC dataset to screen stemness-related genes of HCC from the MSigDB database. Prognosis, tumor microenvironment, immunological checkpoints, tumor immune dysfunction, rejection, treatment sensitivity, and putative biological pathways were examined. Random forest created the SRscores model. The anti-PD-1/anti-CTLA4 immunotherapy, tumor mutational burden, medication sensitivity, and cancer stem cell index were compared between the high- and low-risk score groups. We also examined risk scores for different cell types using single-cell RNA sequencing data and correlated transcription factor activity in cancer stem cells with SRscores genes. Finally, we tested core marker expression and biological functions. Results Patients can be divided into two subtypes (Cluster1 and Cluster2) based on the TCGA-LIHC dataset's identification of 11 stemness-related genes. Additionally, a SRscores was developed based on subtypes. Cluster2 and the group with the lowest SRscores had superior survival and immunotherapy response than Cluster1 and the group with the highest SRscores. The group with a high SRscores was significantly more enriched in classical tumor pathways than the group with a low SRscores. Multiple transcription factors and SRscores genes are correlated. The core gene LPCAT1 is highly expressed in rat liver cancer tissues and promotes tumor cell sphere formation. Conclusion A SRscores model can be utilized to predict the prognosis of HCC patients as well as their response to immunotherapy.

Background: Increasing evidence suggests that hepatocellular carcinoma (HCC) stem cells (LCSCs) play an essential part in HCC recurrence, metastasis, and chemotherapy and radiotherapy resistance. Multiple studies have demonstrated that stemness-related genes facilitate the progression of tumors. However, the mechanism by which stemness-related genes contribute to HCC is not well understood. Here, we aim to construct a stemness-related score (SRscores) model for deeper analysis of stemness-related genes, assisting with the prognosis and individualized treatment of HCC patients.Further, we found that the gene LPCAT1 was highly expressed in tumor tissues by immunohistochemistry, and sphere-forming assay revealed that knockdown of LPCAT1 inhibited the sphere-forming ability of hepatocellular carcinoma cells. Methods: We used the TCGA-LIHC dataset to screen stemness-related genes of HCC from the MSigDB database. Prognosis, tumor microenvironment, immunological checkpoints, tumor immune dysfunction, rejection, treatment sensitivity, and putative biological pathways were examined. Random forest created the SRscores model. The anti-PD-1/anti-CTLA4 immunotherapy, tumor mutational burden, medication sensitivity, and cancer stem cell index were compared between the high- and low-risk score groups. We also examined risk scores for different cell types using single-cell RNA sequencing data and correlated transcription factor activity in cancer stem cells with SRscores genes. Finally, we tested core marker expression and biological functions. Results: Patients can be divided into two subtypes (Cluster1 and Cluster2) based on the TCGA-LIHC dataset's identification of 11 stemness-related genes. Additionally, a SRscores was developed based on subtypes. Cluster2 and the group with the lowest SRscores had superior survival and immunotherapy response than Cluster1 and the group with the highest SRscores. The group with a high SRscores was significantly more enriched in classical tumor pathways than the group with a low SRscores. Multiple transcription factors and SRscores genes are correlated. The core gene LPCAT1 is highly expressed in rat liver cancer tissues and promotes tumor cell sphere formation. Conclusion: A SRscores model can be utilized to predict the prognosis of HCC patients as well as their response to immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Kinetic estimation provides fitted parameters related to blood flow perfusion and fluorine-18-fluorodeoxyglucose (18F-FDG) transport and intracellular metabolism to characterize hepatocellular carcinoma (HCC) but usually requires 60 min or more for dynamic PET, which is time-consuming and impractical in a busy clinical setting and has poor patient tolerance. Methods This study preliminarily evaluated the equivalence of liver kinetic estimation between short-term (5-min dynamic data supplemented with 1-min static data at 60 min postinjection) and fully 60-min dynamic protocols and whether short-term 18F-FDG PET-derived kinetic parameters using a three-compartment model can be used to discriminate HCC from the background liver tissue. Then, we proposed a combined model, a combination of the maximum-slope method and a three-compartment model, to improve kinetic estimation. Results There is a strong correlation between the kinetic parameters K 1 ~ k 3, HPI and $${{\varvec{V}}}_{{\varvec{b}}}$$ V b in the short-term and fully dynamic protocols. With the three-compartment model, HCCs were found to have higher k 2, HPI and k 3 values than background liver tissues, while K 1, k 4 and $${{\varvec{V}}}_{{\varvec{b}}}$$ V b values were not significantly different between HCCs and background liver tissues. With the combined model, HCCs were found to have higher HPI, K 1 and k 2, k 3 and $${{\varvec{V}}}_{{\varvec{b}}}$$ V b values than background liver tissues; however, the k 4 value was not significantly different between HCCs and the background liver tissues. Conclusions Short-term PET is closely equivalent to fully dynamic PET for liver kinetic estimation. Short-term PET-derived kinetic parameters can be used to distinguish HCC from background liver tissue, and the combined model improves the kinetic estimation. Clinical relevance statement Short-term PET could be used for hepatic kinetic parameter estimation. The combined model could improve the estimation of liver kinetic parameters. Graphical Abstract

Tobacco contains many harmful chemicals, toxins, and carcinogens which cause serious health hazards. Mycotoxins and Aflatoxins are present in all tobacco including chewing and smokeless tobacco. We detected and isolated the aflatoxins-producing fungi Aspergillus sp. by microbial and molecular-based techniques. 50 samples were collected randomly and grown on SDA media by spread plate method. Isolates of A. flavus were analyzed for Aflatoxin production by Ammonia vapor test and the DNA of isolates was extracted and subjected for further molecular identification. Different fungal genera were observed including the most common Aspergillus while the other were Penicillium, Rhizopus, candida, and Trichophyton. Aspergillus flavus was isolated and characterized as a white soft velvety surface. The diameter of colonies was observed as 50 - 70 mm. Coconut-based medium detection by UV light of 365 nm showed the production of blue-green fluorescence on the reverse of colonies on coconut agar medium. DNA extracted from all the strains producing aflatoxins was quantified by VICAM. High levels of Aflatoxin ranging from 21 - 47 ug/kg were detected in 10 different samples while the remaining samples had a range of 10 - 20 ug/kg. the study showed both quantitative and qualitative techniques for the detection of aflatoxin-producing fungi in chewing tobacco. aflR and aflS were observed as potential candidates for the detection of aflatoxigenic fungi. [ABSTRACT FROM AUTHOR]

Background: The expression level of Ribonuclease H2, subunit A (RNASEH2A) in hepatocellular carcinoma (HCC) has been reported, but the function of RNASEH2A on HCC cells development and the related molecular mechanisms remain unclear. Herein, we intend to explore the upstream regulator of RNASEH2A and its role in the HCC progression. Methods: GEPIA website was employed to determine the level of RNASEH2A in HCC tissues and get a survival analysis. After reducing RNASEH2A expression by RNA interference, cell counting kit-8, colony formation, Western blot, Transwell and wound healing assays were performed to estimate the malignant properties of HCC cells. The transcriptional factor of RNASEH2A was predicted by UCSC and JASPAR database and confirmed by dual luciferase assay and Ch-IP assay. The expression level of EMT pathway related molecules was determined by western blotting. Results: An increased expression of RNASEH2A was presented in HCC and predicted worse prognosis of HCC patients. Functionally, the results demonstrated that depletion of RNASEH2A suppressed HCC cell proliferation, cell cycle, migration and invasion. Moreover, we illustrated that SP1 targeted to the promoter of RNASEH2A and modulated its expression in HCC cell lines. RNASEH2A knockdown counteracted the function of SP1 overexpression in modulating HCC cell growth, cell cycle, and mobility. Then, our data showed that the SP1/RNASEH2A axis affected the malignant behaviors of HCC cells by regulating EMT process. Conclusions: In summary, these results demonstrated that RNASEH2A promoted HCC cells development through regulating EMT process and was transcriptionally modulated by SP1.

Background: Kinetic estimation provides fitted parameters related to blood flow perfusion and fluorine-18-fluorodeoxyglucose (18F-FDG) transport and intracellular metabolism to characterize hepatocellular carcinoma (HCC) but usually requires 60 min or more for dynamic PET, which is time-consuming and impractical in a busy clinical setting and has poor patient tolerance. Methods: This study preliminarily evaluated the equivalence of liver kinetic estimation between short-term (5-min dynamic data supplemented with 1-min static data at 60 min postinjection) and fully 60-min dynamic protocols and whether short-term 18F-FDG PET-derived kinetic parameters using a three-compartment model can be used to discriminate HCC from the background liver tissue. Then, we proposed a combined model, a combination of the maximum-slope method and a three-compartment model, to improve kinetic estimation. Results: There is a strong correlation between the kinetic parameters K1 ~ k3, HPI and V b in the short-term and fully dynamic protocols. With the three-compartment model, HCCs were found to have higher k2, HPI and k3 values than background liver tissues, while K1, k4 and V b values were not significantly different between HCCs and background liver tissues. With the combined model, HCCs were found to have higher HPI, K1 and k2, k3 and V b values than background liver tissues; however, the k4 value was not significantly different between HCCs and the background liver tissues. Conclusions: Short-term PET is closely equivalent to fully dynamic PET for liver kinetic estimation. Short-term PET-derived kinetic parameters can be used to distinguish HCC from background liver tissue, and the combined model improves the kinetic estimation. Clinical relevance statement: Short-term PET could be used for hepatic kinetic parameter estimation. The combined model could improve the estimation of liver kinetic parameters. Key points: Short-term PET could be used for hepatic kinetic parameter estimation. Short-term PET was very similar to full dynamic PET in the estimation of liver kinetic parameters. The combined models could improve the estimation of liver kinetic parameters. [ABSTRACT FROM AUTHOR]

DNA glycosylases promote genomic stability by initiating base excision repair (BER) in both the nuclear and mitochondrial genomes. Several of these enzymes have overlapping substrate recognition, through which a degree of redundancy in lesion recognition is achieved. For example, OGG1 and NEIL1 both recognize and release the imidazole-ring-fragmented guanine, FapyGua as part of a common overall pathway to cleanse the genome of damaged bases. However, these glycosylases have many differences, including their differential breadth of substrate specificity, the contrasting chemistries through which base release occurs, the subsequent steps required to complete the BER pathway, and the identity of specific protein-binding partners. Beyond these differences, the complexities and differences of their in vivo biological roles have been primarily elucidated in studies of murine models harboring a knockout of Neil1 or Ogg1, with the diversity of phenotypic manifestations exceeding what might have been anticipated for a DNA glycosylase deficiency. Pathologies associated with deficiencies in nuclear DNA repair include differential cancer susceptibilities, where Ogg1-deficient mice are generally refractory to carcinogenesis, while deficiencies in Neil1-deficient mice confer cancer susceptibility. In contrast to NEIL1, OGG1 functions as a key transcription factor in regulating inflammation and other complex gene cascades. With regard to phenotypes attributed to mitochondrial repair, knockout of either of these genes results in age- and diet-induced metabolic syndrome. The adverse health consequences associated with metabolic syndrome can be largely overcome by expression of a mitochondrial-targeted human OGG1 in both wild-type and Ogg1-deficient mice. The goal of this review is to compare the roles that NEIL1 and OGG1 play in maintaining genomic integrity, with emphasis on insights gained from not only the diverse phenotypes that are manifested in knockout and transgenic mice, but also human disease susceptibility associated with polymorphic variants. [ABSTRACT FROM AUTHOR]

Highlight 1. High BMI combined with HBV infection has a negative impact on the PFS and OS of HCC patients treated with TACE. 2. Irrespective of TACE, the average HMGB1 in hepatitis and obesity patients was higher than that in normal individuals, which was not upregulated after TACE. 3. Patients without overweight and HBV infection had a low level of serum concentration of HMGB1 before TACE that was upregulated after TACE. Compared to others, these patients have severe changes in HMGB1 in the peripheral blood after treatment, indicating a higher risk of acute liver injury. 4. Upregulated HMGB1 elevated the prognosis after TACE, but obesity and HBV infection resulted in the negative effect by inhibiting HMGB1 expression. 5. For advanced HCC, overweight combined HBV infection, PVTT, multiple lesions, and larger tumor diameter are negative factors for TACE.

Hypoxia in the tumor microenvironment (TME) is the leading cause of metastasis and chemoresistance in cancer cells. Numerous 3D in vitro models have been proposed to study hypoxic stress, but none have enabled sufficient analysis of hepatocellular carcinoma (HCC). Herein, a 3D in vitro tumor vasculature model for HCC is introduced to investigate cellular responses and drug resistance under hypoxic conditions through high‐content screening. The hypoxic TME of vascularized HCC can be established by maintaining the platform in a hypoxia chamber and is used to analyze the diverse physiological responses of the TME to normoxia, hypoxia, and drug treatment. The proposed platform also demonstrates the hypoxic status naturally induced by 3D HCC spheroids for comparison with single HCC cells cultured in the hypoxia chamber. The results show that hypoxic stress in the HCC vasculature promotes angiogenesis, hypoxia‐inducible factor 1 (HIF‐1) expression, and proliferation; it also enhances drug resistance. The hypoxic tumor vasculature of the model generates cellular responses that are also expressed in the physiological hypoxic microenvironment of HCC. These findings suggest that our high‐content microfluidic platform can be applied as a powerful tool to develop anticancer therapeutics, which have remained elusive because of hypoxia in the TME.

Background: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC.Methods: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population.Results: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE.Conclusions: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1. [ABSTRACT FROM AUTHOR]

Abstract The physical microenvironment is a critical mediator of tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of chemotherapy‐enriched CD133+ liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive cancer and functional stemness phenotype in hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of matrix metalloproteinase (MMP) activity, collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC metastasis. Interestingly, a positive feed‐forward loop is identified where a local soft spot microenvironment in the HCC tumor is enriched with CD133 expressing cells that secrete markedly less ECM‐modifying THBS2 upon histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased collagen fiber deposits and an invasive tumor front. The findings have implications for the treatment of cancer stemness and for the prevention of tumor outgrowth through disseminated tumor cells.

The physical microenvironment is a critical mediator of tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of chemotherapy‐enriched CD133+ liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive cancer and functional stemness phenotype in hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of matrix metalloproteinase (MMP) activity, collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC metastasis. Interestingly, a positive feed‐forward loop is identified where a local soft spot microenvironment in the HCC tumor is enriched with CD133 expressing cells that secrete markedly less ECM‐modifying THBS2 upon histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased collagen fiber deposits and an invasive tumor front. The findings have implications for the treatment of cancer stemness and for the prevention of tumor outgrowth through disseminated tumor cells. [ABSTRACT FROM AUTHOR]

Patients with HCC receiving TACE have various clinical outcomes. Several prognostic models have been proposed to predict clinical outcomes for patients with hepatocellular carcinomas (HCC) undergoing transarterial chemoembolization (TACE), but establishing an accurate prognostic model remains necessary. We aimed to develop a radiomics signature from pretreatment CT to establish a combined radiomics-clinic (CRC) model to predict survival for these patients. We compared this CRC model to the existing prognostic models in predicting patient survival. This retrospective study included multicenter data from 162 treatment-naïve patients with unresectable HCC undergoing TACE as an initial treatment from January 2007 and March 2017. We randomly allocated patients to a training cohort (n = 108) and a testing cohort (n = 54). Radiomics features were extracted from intra- and peritumoral regions on both the arterial phase and portal venous phase CT images. A radiomics signature (Rad-signature) for survival was constructed using the least absolute shrinkage and selection operator method in the training cohort. We used univariate and multivariate Cox regressions to identify associations between the Rad- signature and clinical factors of survival. From these, a CRC model was developed, validated, and further compared with previously published prognostic models including four-and-seven criteria, six-and-twelve score, hepatoma arterial-embolization prognostic scores, and albumin-bilirubin grade. The CRC model incorporated two variables: The Rad-signature (composed of features extracted from intra- and peritumoral regions on the arterial phase and portal venous phase) and tumor number. The CRC model performed better than the other seven well-recognized prognostic models, with concordance indices of 0.73 [95% confidence interval (CI) 0.68–0.79] and 0.70 [95% CI 0.62–0.82] in the training and testing cohorts, respectively. Among the seven models tested, the six-and-12 score and four-and-seven criteria performed better than the other models, with C-indices of 0.64 [95% CI 0.58–0.70] and 0.65 [95% CI 0.55–0.75] in the testing cohort, respectively. The CT radiomics signature represents an independent biomarker of survival in patients with HCC undergoing TACE, and the CRC model displayed improved predictive performance.

Patients with HCC receiving TACE have various clinical outcomes. Several prognostic models have been proposed to predict clinical outcomes for patients with hepatocellular carcinomas (HCC) undergoing transarterial chemoembolization (TACE), but establishing an accurate prognostic model remains necessary. We aimed to develop a radiomics signature from pretreatment CT to establish a combined radiomics-clinic (CRC) model to predict survival for these patients. We compared this CRC model to the existing prognostic models in predicting patient survival. This retrospective study included multicenter data from 162 treatment-naïve patients with unresectable HCC undergoing TACE as an initial treatment from January 2007 and March 2017. We randomly allocated patients to a training cohort (n = 108) and a testing cohort (n = 54). Radiomics features were extracted from intra- and peritumoral regions on both the arterial phase and portal venous phase CT images. A radiomics signature (Rad-signature) for survival was constructed using the least absolute shrinkage and selection operator method in the training cohort. We used univariate and multivariate Cox regressions to identify associations between the Rad- signature and clinical factors of survival. From these, a CRC model was developed, validated, and further compared with previously published prognostic models including four-and-seven criteria, six-and-twelve score, hepatoma arterial-embolization prognostic scores, and albumin-bilirubin grade. The CRC model incorporated two variables: The Rad-signature (composed of features extracted from intra- and peritumoral regions on the arterial phase and portal venous phase) and tumor number. The CRC model performed better than the other seven well-recognized prognostic models, with concordance indices of 0.73 [95% confidence interval (CI) 0.68–0.79] and 0.70 [95% CI 0.62–0.82] in the training and testing cohorts, respectively. Among the seven models tested, the six-and-12 score and four-and-seven criteria performed better than the other models, with C-indices of 0.64 [95% CI 0.58–0.70] and 0.65 [95% CI 0.55–0.75] in the testing cohort, respectively. The CT radiomics signature represents an independent biomarker of survival in patients with HCC undergoing TACE, and the CRC model displayed improved predictive performance. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the efficacy and safety of microwave ablation (MWA) in small hepatocellular carcinomas sized ≤ 3 cm, determine long-term survival, and identify prognostic factors for survival rates. Material and methods: In this study, the radiological and laboratory findings obtained from 31 consecutive patients who underwent MWA were retrospectively evaluated. The survival periods and complication rates were analysed. Results: Microwave ablation was applied to 42 hepatocellular carcinoma nodules in 31 patients. The mean age of the patients was 61 ± 7.3 (median 62, range 46-78) years. The mean overall survival (OS) was 47.4 ± 3.3 months. The rates of cumulative OS in the first, second, and third years were 95.2%, 91.8%, and 79.2%, respectively. The mean disease-free survival (DFS) rate was 24.1 ± 2.5 months. The cumulative DFS rates in the first, second, and third years were 75.6%, 52.5%, and 28.2%, respectively. The number of tumours and tumour distribution were determined as prognostic factors. No major complication was detected, but six patients (13.9%) developed minor complications after MWA. Conclusions: Microwave ablation in patients with hepatocellular carcinoma is a safety treatment modality with very low rates of complications. It offers an effective treatment with a high rate of complete response and local disease control according to the short-term results. In the long term, it prolongs the survival time of the treated patients. The number of tumours and tumour distribution were determined as prognostic factors affecting survival rates. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is very common globally prevalent cancer. Due to its poor clinical prognosis, increasing the diagnostic rate of HCC is urgently needed. Herein, we validate discovered metabolomic biomarkers to distinguish Hepatitis B virus (HBV)-related HCC, including alpha-fetoprotein (AFP) negative (AFP–) and positive (AFP+) individuals.Methods: We recruited 130 HCC subjects (independent case-control, randomized clinical cohorts) to our study. We separated the subjects randomly into two panels: (1) 58 individuals for the discovery panel; and (2) 72 individuals for the validation panel. For each panel, gender and age-matched hepatitis B group (HBG) and healthy group were included as controls. Plasma samples were collected for metabolic profiling by liquid chromatography—mass spectrometry—based metabolomics assays. We applied both non-targeted metabolomics analyses and targeted metabolomics analyses. Significantly changed metabolites (SCMs) were identified. The power of SCMs to discriminate HCC and HBG or healthy group was determined by receiver operating characteristic curve (ROC) analysis.Results: Ten SCMs were selected form the discovery panel, and further verified in the validation panel. ROC analyses indicated that 1 SCMs (LysoPC (24:0)) could discriminate HCC from HBG (AUC = 0.765). Further, 8 SCMs including (LysoPC (17:0), LysoPC (20:4(8Z,11Z,14Z,17Z)), LysoPC (22:0), LysoPC (24:0), PE (P-16:0/22:4(7Z,10Z,13Z,16Z)), SM (d18:1/22:1(13Z)), Creatinine, and L-Isoleucine) displayed a heightened ability to discriminate between HCC and healthy controls (AUC were more than 0.800). Most of these SCMs were important in lipid metabolism.Conclusions: LysoPC (24:0) could distinguished HCC from HBG, and 8 SCMs distinguished HCC from healthy controls. LysoPC and other metabolites have the potential to serve as non-invasive biomarkers for HBV related AFP– and AFP+ HCC.

Hepatocellular carcinoma (HCC) is a prototype of inflammation-related cancer, harboring M1-like and M2-like tumor-associated macrophages. M1 macrophages are thought to be tumoricidal, but some studies report its pro-tumor role. The programmed cell death-ligand (PD-L) 1 expressed in HCC cells is a critical checkpoint molecule to mediate immune escape of HCC. The PD-L1 expression in HCC cells is inducible. In the present study, we ask whether M1 macrophages induce the expression of PD-L1 in HCC cells. First, an association between M1 macrophage infiltration and PD-L1 expression in HCC tissues was determined by bioinformatics and immunohistochemistry experiments. The enrichment score of M1 macrophages was correlated to PD-L1 expression in 90 HCC samples from GEO database. Besides, infiltration of CD68+HLA-DR+ M1-like macrophages correlated with PD-L1 expression level in HCC cells. Moreover, M1-conditioned media was prepared from M1 macrophages derived from THP-1 cell, RAW264.7 cell or murine bone marrow. These supernatants induced expression of PD-L1 in HCC cells. Furthermore, inflammatory cytokine IL-1β in the supernatants was identified to account for the inducible PD-L1 expression by siRNA assay and receptor blockade assay. Additionally, transcription factor p65 and IRF1 in the HCC cells were revealed by CHIP assay to mediate the inducible PD-L1 expression. All the results demonstrate that M1 macrophages induced expression of PD-L1 in HCC cells, supporting the pro-tumor role of M1 macrophages.

Background: Hepatocellular carcinoma (HCC) is very common globally prevalent cancer. Due to its poor clinical prognosis, increasing the diagnostic rate of HCC is urgently needed. Herein, we validate discovered metabolomic biomarkers to distinguish Hepatitis B virus (HBV)-related HCC, including alpha-fetoprotein (AFP) negative (AFP–) and positive (AFP+) individuals. Methods: We recruited 130 HCC subjects (independent case-control, randomized clinical cohorts) to our study. We separated the subjects randomly into two panels: (1) 58 individuals for the discovery panel; and (2) 72 individuals for the validation panel. For each panel, gender and age-matched hepatitis B group (HBG) and healthy group were included as controls. Plasma samples were collected for metabolic profiling by liquid chromatography—mass spectrometry—based metabolomics assays. We applied both non-targeted metabolomics analyses and targeted metabolomics analyses. Significantly changed metabolites (SCMs) were identified. The power of SCMs to discriminate HCC and HBG or healthy group was determined by receiver operating characteristic curve (ROC) analysis. Results: Ten SCMs were selected form the discovery panel, and further verified in the validation panel. ROC analyses indicated that 1 SCMs (LysoPC (24:0)) could discriminate HCC from HBG (AUC = 0.765). Further, 8 SCMs including (LysoPC (17:0), LysoPC (20:4(8Z,11Z,14Z,17Z)), LysoPC (22:0), LysoPC (24:0), PE (P-16:0/22:4(7Z,10Z,13Z,16Z)), SM (d18:1/22:1(13Z)), Creatinine, and L-Isoleucine) displayed a heightened ability to discriminate between HCC and healthy controls (AUC were more than 0.800). Most of these SCMs were important in lipid metabolism. Conclusions: LysoPC (24:0) could distinguished HCC from HBG, and 8 SCMs distinguished HCC from healthy controls. LysoPC and other metabolites have the potential to serve as non-invasive biomarkers for HBV related AFP– and AFP+ HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and growing challenges of global health. In this study, for the first time in Iran, we investigated the 5-year survival rate and prognostic factors in patients with HCC. Materials and Methods: In this historical cohort study, we examined the medical records of 227 HCC patients who were registered in the central tumor registry of our institution from September 2007 to September 2017. Demographic data, clinical parameters, received treatments, and survival curves from time of diagnosis were evaluated. Kaplan-Meier was used for univariate analysis, and multivariable analysis was performed by Cox regression. Results: A total of 208 (91.63%) patients were dead. The 5-year survival rate was estimated 19 (8.37%). The average follow-up in this study was 14.3 months. Overall median survival rate was 12.1 months. Univariate analysis showed that tumor size, metastasis, number of involved lymph node, hepatitis type, and treatment were significantly related to the survival rate, and Cox regression analysis revealed that the tumor size >3 cm (hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.68-4.97; P = 0.027), involved lymph nodes >2 (HR = 4.12, 95% CI = 2.66-6.38; P = 0.001), metastasis (HR = 3.87, 95% CI = 3.13-6.54; P = 0.011), combination therapy with surgery and chemotherapy (HR = 0.4, 95% CI = 0.15-0.79; P = 0.023), and coinfection with hepatitis B virus and hepatitis C virus (HR = 2.11, 95% CI = 1.81-4.6; P = 0.036) are the most relevant prognostic factors with 5-year survival rate in patients with HCC. Conclusion: Results of this study will help estimate survival rates for patients with HCC according to their clinical status. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prototype of inflammation-related cancer, harboring M1-like and M2-like tumor-associated macrophages. M1 macrophages are thought to be tumoricidal, but some studies report its pro-tumor role. The programmed cell death-ligand (PD-L) 1 expressed in HCC cells is a critical checkpoint molecule to mediate immune escape of HCC. The PD-L1 expression in HCC cells is inducible. In the present study, we ask whether M1 macrophages induce the expression of PD-L1 in HCC cells. First, an association between M1 macrophage infiltration and PD-L1 expression in HCC tissues was determined by bioinformatics and immunohistochemistry experiments. The enrichment score of M1 macrophages was correlated to PD-L1 expression in 90 HCC samples from GEO database. Besides, infiltration of CD68+HLA-DR+ M1-like macrophages correlated with PD-L1 expression level in HCC cells. Moreover, M1-conditioned media was prepared from M1 macrophages derived from THP-1 cell, RAW264.7 cell or murine bone marrow. These supernatants induced expression of PD-L1 in HCC cells. Furthermore, inflammatory cytokine IL-1β in the supernatants was identified to account for the inducible PD-L1 expression by siRNA assay and receptor blockade assay. Additionally, transcription factor p65 and IRF1 in the HCC cells were revealed by CHIP assay to mediate the inducible PD-L1 expression. All the results demonstrate that M1 macrophages induced expression of PD-L1 in HCC cells, supporting the pro-tumor role of M1 macrophages. [ABSTRACT FROM AUTHOR]

In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids (MitoHCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH∙− and ROO∙− induced lipid peroxidation. H2O2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines (HepG2, L02 and WI38) indicated that the MitoHCAs were selective for cancer cells. Interestingly, the MitoHCAs both with or without Ca2+ triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore (mPTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that mPTP may be involved in the antiproliferative activity of MitoHCAs. Further studies focused on structural optimization of these compounds are onging.

Abstract: Hepatocellular carcinoma is the most frequent primary liver cancer worldwide. The use of antioxidants as cancer prevention and treatment agents has become a focus of research in recent years due to their limited adverse effects. Alpha lipoic acid (ɑ‐LA) is synthesized in the liver and is considered a naturally occurring antioxidant. In this study, a total of 4446 differentially expressed genes (2097 down‐regulated and 2349 up‐regulated) were identified via RNA‐Seq in HepG2 cells after exposure to α‐LA for 24 hrs. Moreover, GO and KEGG pathway analyses showed that cancer‐relevant cell membrane proteins were significantly affected. An interaction network analysis predicted that Grb2 might mediate the key target pathways activated by exposure to ɑ‐LA. Verification of the RNA‐Seq and iTRAQ results confirmed that Grb2 mediated the ɑ‐LA‐induced inhibition of cell proliferation in vitro. Furthermore, the analysis of human hepatocellular carcinoma specimens obtained from the GEO database showed that the expression of EGFR and Met correlated with that of Grb2. These findings provide a novel mechanism through which ɑ‐LA regulates cell proliferation via the down‐regulation of growth factor‐stimulated Grb2 signalling. [ABSTRACT FROM AUTHOR]

Clinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN-γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC. In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors. Furthermore, B7-H1 expression induced synergistically by TNF-α and IFN-γ in murine HCC cells facilitated tumor growth in vivo. Our findings suggest that TNF-α may enhance the adaptive immune resistance mediated by IFN-γ-induced B7-H1 in HCC cells. [ABSTRACT FROM AUTHOR]

Background & objective: It has been shown that the combined use of alcohol before radiofrequency ablation (RFA) helps to augment the therapeutic advantage of RFA. The present study was conducted to compare the outcome of treatment with RFA alone and RFA with alcohol as ablative technique in patients with small hepatocellular carcinomas (HCCs), who were not candidates for surgery. Methods: Fifty patients with chronic liver disease and concurrent HCC were enrolled in this prospective study. The patients were treated with either RFA alone (n=25) or RFA combined with alcohol (n=25). Patient outcome was evaluated, and the tumour recurrence and survival of the patients were assessed in the two groups. Results: The survival rates at six months in patients who completed at least six months of follow up were 84 and 80 per cent in patients treated with RFA alone and combination therapy, respectively. During the follow up period, 11 and four patients treated with RFA alone showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at one to 18 months of the follow up period. The distant recurrences occurred at 6-36 months of the follow up period. During the follow up period, eight and six patients treated with combination therapy showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at 1.5-15 months during the follow up period. The distant intrahepatic recurrences occurred at 6-72 months during the follow up period. Interpretation & conclusions: No significant difference was seen between the survival time of the patients treated with RFA alone and RFA with alcohol as well as in the local recurrences and distant intrahepatic recurrences in RFA compared to RFA and alcohol group patients. Combined use of RFA and alcohol did not improve the local tumour control and survival in patients with HCC compared to RFA alone. [ABSTRACT FROM AUTHOR]

Background and purpose To report the clinical usefulness of coiled fiducial markers as an internal surrogate in gated stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) using a real-time tumor-tracking radiotherapy (RTRT) system. Materials and methods Seventeen HCC patients with Child-Pugh (CP) scores of A or B received gated SBRT (45–50 Gy in 5–10 fractions) using an RTRT system and Visicoil markers. Local control (LC), progression-free (PFS), and overall survival (OS) rates were assessed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria for Adverse Events, Version 4.0. Results Of the 17 patients, 14 had a CP score A. The mean planning target volume was 54.6 cc. Only 1 patient developed pneumothorax after marker implantation. Visicoil tracking during SBRT was possible in all cases. With a median follow-up of 16 months, 1-year LC, PFS, and OS rates were 100%, 53%, and 82%, respectively. Grade ≥ 2 late toxicity was observed in 2 patients (grade 2 duodenal ulcer and grade 3 temporary transaminase elevation). Conclusions Using an RTRT system and Visicoil markers, gated SBRT was well tolerated in patients with HCC. This can be considered a safe treatment strategy with potential for delivering favorable outcomes. [ABSTRACT FROM AUTHOR]

In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids (MitoHCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH ∙− and ROO ∙− induced lipid peroxidation. H 2 O 2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines (HepG2, L02 and WI38) indicated that the MitoHCAs were selective for cancer cells. Interestingly, the MitoHCAs both with or without Ca 2+ triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore (mPTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that mPTP may be involved in the antiproliferative activity of MitoHCAs. Further studies focused on structural optimization of these compounds are onging. [ABSTRACT FROM AUTHOR]

Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high-density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha-fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC ( P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect ( P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30++/+++) had a better 5-year overall survival rate than those with low/negative (TIP30+/−) expression ( P < 0.001). TIP30+/−/HBV+ patients had the worst 5-year overall survival rate, whereas TIP30++/+++/HBV− patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV+ hepatoblastoma cell-line HepG2 2.2.15 and HCC cell-line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC. [ABSTRACT FROM AUTHOR]

Combination therapies targeting two immune checkpoint regulators (PD-1 and CTLA-4) or PD-1 concurrently with the angiogenic pathway prolong the overall survival time to nearly twice that of patients receiving monotherapy ([3]; also reviewed by He et al. below). Keywords: Hepatocellular carcinomas; biomarkers; immune-checkpoint inhibitors; PD-1; PD-L1; immunotherapies; bioinformatics EN Hepatocellular carcinomas biomarkers immune-checkpoint inhibitors PD-1 PD-L1 immunotherapies bioinformatics 1 2 2 03/14/22 20220310 NES 220310 Hepatocellular carcinomas (HCCs), made up of 75-85% of primary liver cancers, remain the leading cause of new cancer cases (>0.7 million) and cancer deaths (>0.6 million) globally according to the data collected up to 2020 before the coronavirus disease 2019 (COVID-19) pandemic ([1]). Hepatocellular carcinomas, biomarkers, immune-checkpoint inhibitors, PD-1, PD-L1, immunotherapies, bioinformatics. [Extracted from the article]

The acquisition of stemness is a hallmark of aggressive human hepatocellular carcinoma (hHCC). The stem cell marker OCT4 is frequently expressed in HCCs, and its expression correlates with those of putative cancer stem cell (CSC) markers and CSC properties. Here, we describe a novel mechanism of CSC maintenance by SRY through OCT4. We previously reported that Sry is involved in tumor malignancy in rodent HCCs. However, the oncogenic function of SRY in hHCCs is poorly understood. Ectopic expression of SRY increased multiple stem cell factors, including OCT4 and CD13. The OCT4 promoter contained SRY-binding sites that were directly activated by SRY. In HCC-derived cells, SRY knockdown decreased OCT4 expression and cancer stem-like phenotypes such as self-renewal, chemoresistance, and tumorigenicity. Conversely, OCT4 and SRY overexpression promoted cancer stem-like phenotypes. OCT4 knockdown in SRY clones downregulated the self-renewal capacity and chemoresistance. These data suggest that SRY is involved in the maintenance of cancer stem-like characteristics through OCT4. Moreover, CSCs of HCC-derived cells differentiated into Tuj1-positive neuron-like cells by retinoic acid. Noteworthily, SRY was highly expressed in some hHCC patients. Taken together, our findings imply a novel therapeutic strategy against CSCs of hHCCs. S tem C ells 2015;33:2652-2663 [ABSTRACT FROM AUTHOR]

Transcatheter arterial chemoembolization (TACE) is known to be an effective palliative treatment for unresectable hepatocellular carcinoma (HCC). Serious complications, such as neutropenic sepsis and hepatic decompensation, are well known. A HCC rupture following TACE is a rare complication: however, it can be life-threatening if it occurs. In a 75-year-old male patient who subsequently developed capsular rupture of the lipiodol laden mass and several free intraperitoneal chemoembolization agents with hemoperitoneum, we report a case of a ruptured HCC that superficially located arterial enhancing and early wash-out mass in the right hepatic dome following TACE. [ABSTRACT FROM AUTHOR]

ginine deiminase (ADI), an arginine-degrading enzyme, has been studied as a potential anti-cancer agent for inhibiting arginine-auxotrophic tumors, such as melanomas and hepatocellular carcinomas. Based on our preliminary results, it was noticed that the optimum pH of ADI from Pseudomonas plecoglossicida (PpADI) was 6.0, and less than 10% of the activity was retained at pH 7.4 (pH of human plasma). Additionally, the K value for wild-type ADI (WT-ADI) was 2.88 mM (pH 6.0), which is over 20 times of the serum arginine level (100-120 μM). These are two major limitations for PpADI as a potential anti-cancer drug. A highly sensitive and efficient high-throughput screening strategy based on a modified diacetylmonoxime-thiosemicarbazide method was established to isolate ADI mutants with higher activity and lower K under physiological pH. Three improved mutants was selected from 650 variants after one round of ep-PCR, among which mutant 314 (M314: A128T, H404R, I410L) exhibiting the highest activity. Interestingly, sequence alignment shows that three amino acid substitutes in M314 are coincident with corresponding residues in ADI from Mycoplasma arginini. The specific activity of M314 (9.02 U/mg) is over 20-fold higher than that of WT-ADI (0.44 U/mg) at pH 7.4, and the K value was reduced to 0.65 mM (pH 7.4). Noticeably, the pH optimum was shifted from 6.0 to 6.5 in M314. Homology model of M314 was constructed to understand the molecular basis of the improved enzymatic properties. This work could provide promising drug candidate for curing arginine-auxotrophic cancers. [ABSTRACT FROM AUTHOR]

Background: Malignant transformation of hepatocellular adenomas (HCAs) into hepatocellular carcinomas (HCCs) has been reported repeatedly and is considered to be one of the main reasons for surgical treatment. However, its actual risk is currently unknown. Objective: To provide an estimation of the frequency of malignant transformation of HCAs and to discuss its clinical implications. Methods: A systematic literature search was conducted using the following databases: The Cochrane Hepatobiliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE and EMBASE. Results: One hundred and fifty-seven relevant series and 17 case reports (a total of 1635 HCAs) were retrieved, reporting an overall frequency of malignant transformation of 4.2%. Only three cases (4.4%) of malignant alteration were reported in a tumour smaller than 5 cm in diameter. Discussion: Malignant transformation of HCAs into HCCs remains a rare phenomenon with a reported frequency of 4.2%. A better selection of exactly those patients presenting with an HCA with an amplified risk of malignant degeneration is advocated in order to reduce the number of liver resections and thus reducing the operative risk for these predominantly young patients. The Bordeaux adenoma tumour markers are a promising method of identifying these high-risk adenomas. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To prospectively assess the relationship between the time to peak enhancement of hepatocellular carcinomas (HCC) and that of the aorta at 64-detector computed tomography (CT). Materials and methods: The study prospectively included 43 patients with known HCC. All underwent abdominal CT imaging by using BodyPerfusion CT model. The CT data acquisition was initiated with a delay of 8–15s from the beginning of the contrast material administered. The time–density curves (TDC) of the HCC and the aorta were drawn. The times to peak enhancement of the HCC and the aorta were recorded and the correlation between the time to peak enhancement of the HCC and that of the aorta was analyzed. Results: There were three tendencies of TDC of the HCC enhancement, only 23.3% of them were similar to that of the aorta. The mean time to peak enhancement of the aorta and the HCC (86.1%) was 23.38s and 30.04s, respectively. The time to peak enhancement of most HCC was positively and linearly correlated with the time to peak aortic enhancement (r =0.662, P <0.05). Conclusion: The result may potentially allow scan delay optimization at contrast material-enhanced CT image in the detection of HCC according to interindividual variability. [Copyright &y& Elsevier]