Locoregional therapy combined with systemic therapy (LRT + ST) for unresectable and metastatic intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND: The outcome of systemic therapy (ST) for unresectable and metastatic intrahepatic cholangiocarcinoma (iCCA) is poor. This study aims to further evaluate the efficacy and safety of locoregional therapy combined with systemic therapy (LRT + ST) compared with only ST in unresectable and metastatic iCCA by performing a systematic literature review and meta-analysis. METHODS: A comprehensive search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 3, 2022. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). RESULTS: Ten retrospective cohort studies with 3,791 unresectable or metastatic iCCA patients were enrolled in this study, including 1,120 who received ablation, arterially directed therapy (ADT), or external beam radiation therapy (EBRT) combined with ST. The meta-analysis showed that the LRT + ST group had a better OS (HR = 0.51; 95% CI =0.41-0.64; p value < 0.001), PFS (HR = 0.40, 95% CI = 0.22-0.71, p value = 0.002) and ORR (RR = 1.68; 95% CI = 1.17-2.42; p value = 0.005). Subgroup analysis showed that both ST combined with ADT (HR = 0.42, 95% CI = 0.31-0.56, p value < 0.001) and EBRT (HR = 0.67, 95% CI = 0.63-0.72, p value < 0.001) could improve OS. Neutropenia, thrombocytopenia, anemia, anorexia, and vomiting did not show significant differences between the groups (p value > 0.05). CONCLUSIONS: Compared with only ST, LRT + ST improved survival outcomes for unresectable and metastatic iCCA patients without increasing severe AEs, which can further provide a basis for guidelines.

Safety and Efficacy of CT-Guided Iodine-125 Brachytherapy for Portal Vein Tumor Thrombus in Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: Portal vein tumor thrombus (PVTT) seriously reduces the survival of patients with hepatocellular carcinoma (HCC). CT-guided iodine-125 (125I) brachytherapy has the advantage of a high local control rate and is minimally invasive. This study aims to evaluate the safety and efficacy of 125I brachytherapy for treating PVTT in HCC patients. MATERIALS AND METHODS: Thirty-eight patients diagnosed with HCC complicated with PVTT and treated with 125I brachytherapy for PVTT were included in this retrospective study. The local tumor control rate, local tumor progression-free survival, and overall survival (OS) were analyzed. Cox proportional hazards regression analysis was performed to identify predictors affecting survival. RESULTS: The local tumor control rate was 78.9% (30/38). The median local tumor progression-free survival was 11.6 (95% confidence interval [CI]: 6.7, 16.5) months, and the median overall survival was 14.5 (95% CI: 9.2, 19.7) months. Multivariate Cox analysis showed that age <60 years (hazard ratio [HR] = 0.362; 95% CI: 0.136, 0.965; p = 0.042), type I+II PVTT (HR = 0.065; 95% CI: 0.019, 0.228; p < 0.001), and tumor diameter <5 cm (HR = 0.250; 95% CI: 0.084, 0.748; p = 0.013) were significant predictors of OS. There were no serious adverse events related to 125I seed implantation during the follow-up period. CONCLUSION: CT-guided 125I brachytherapy is effective and safe for treating PVTT of HCC, with a high local control rate and no severe adverse events. Patients younger than 60 years old with type I+II PVTT and a tumor diameter less than 5 cm have a more favorable OS.

Astragalus polysaccharides alleviates cardiac hypertrophy in diabetic cardiomyopathy via inhibiting the BMP10-mediated signaling pathway.

BACKGROUND: Cardiac hypertrophy can lead to cardiac dysfunction and is closely associated with mortality in diabetic cardiomyopathy (DCM). Astragalus polysaccharides (APS) is the main component extracted from Astragalus membranaceus (Fisch.) Bunge (AM), which exhibits anti-hypertrophic effects on cardiomyocytes in various diseases. However, whether APS exerts anti-hypertrophic effects in DCM remains unclear. PURPOSE: To investigate whether APS can attenuate cardiac hypertrophy in DCM and exert anti-hypertrophic effects by inhibiting the bone morphogenetic protein 10 (BMP10) pathway. METHODS: The anti-hypertrophic effects of APS were studied in high-glucose (HG)-stimulated H9c2 cardiomyocytes and streptozotocin (STZ)-induced DCM rats. BMP10 siRNA was used to inhibit BMP10 expression in H9c2 cardiomyocytes. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was evaluated using heart weight/body weight (HW/BW), RT-PCR, hematoxylin-eosin (HE), and rhodamine phalloidin staining. Changes in hypertrophic components, including BMP10 and downstream factors, were measured using western blotting. RESULTS: In vitro, HG treatment increased the relative cell surface area of H9c2 cardiomyocytes, whereas BMP10 siRNA transfection or APS treatment alleviated the increase induced by HG. APS treatment improved the general condition, increased cardiac function, and decreased the HW/BW ratio, ANP mRNA level, and cardiomyocyte cross-sectional area of DCM rats in vivo. Molecular experiments demonstrated that APS downregulated the levels of the pro-hypertrophic protein BMP10 and its downstream proteins ALK3, BMPRII, and p-Smad1/5/8 without affecting the level of total Smad1/5/8. CONCLUSIONS: Our study demonstrates that APS can alleviate cardiac hypertrophy and protect against DCM by inhibiting activation of the BMP10 pathway. APS is a promising candidate for DCM treatment.

Hepatitis B virus (HBV) codon adapts well to the gene expression profile of liver cancer: an evolutionary explanation for HBV's oncogenic role.

Due to the evolutionary arms race between hosts and viruses, viruses must adapt to host translation systems to rapidly synthesize viral proteins. Highly expressed genes in hosts have a codon bias related to tRNA abundance, the primary RNA translation rate determinant. We calculated the relative synonymous codon usage (RSCU) of three hepatitis viruses (HAV, HBV, and HCV), SARS-CoV-2, 30 human tissues, and hepatocellular carcinoma (HCC). After comparing RSCU between viruses and human tissues, we calculated the codon adaptation index (CAI) of viral and human genes. HBV and HCV showed the highest correlations with HCC and the normal liver, while SARS-CoV-2 had the strongest association with lungs. In addition, based on HCC RSCU, the CAI of HBV and HCV genes was the highest. HBV and HCV preferentially adapt to the tRNA pool in HCC, facilitating viral RNA translation. After an initial trigger, rapid HBV/HCV translation and replication may change normal liver cells into HCC cells. Our findings reveal a novel perspective on virus-mediated oncogenesis.

Retrieving the deleterious mutations before extinction: genome-wide comparison of shared derived mutations in liver cancer and normal population.

STUDY PURPOSE: Deleterious mutations would be rapidly purged from natural populations along with the extinction of their carriers. The currently observed mutations in existing species are mostly neutral. The inaccessibility of deleterious mutations impedes the functional studies on how these mutations affect the fitness at individual level. STUDY DESIGN: The connection between the deleterious genotype and the non-adaptive phenotype could be bridged by sequencing the genome before extinction. Although this approach is no longer feasible for evolutionary biologists, it is feasible for cancer biologists by profiling the mutations in tumour samples which are so deleterious that the carriers hardly live. RESULTS: By comparing the derived mutation profile between normal populations and patients with liver cancer, we found that the shared mutations, which are highly deleterious, are suppressed to low allele frequencies in normal populations and tissues, but show remarkably high frequency in tumours. The density of shared mutations is negatively correlated with gene conservation and expression levels. CONCLUSIONS: Deleterious mutations are suppressed in functionally important genes as well as in normal populations. This work deepened our understanding on how natural selection act on deleterious mutations by analogising the cancer evolution to species evolution, which are essentially the same molecular process but at different time scales.

Large-scale omics data reveal the cooperation of mutation-circRNA-miRNA-target gene network in liver cancer oncogenesis.

Aims: Clarifying the initial trigger of the differentially expressed genes in cancers helps researchers understand the cellular system as a whole network. Materials & methods: We retrieve the transcriptome and translatome of tumor and normal tissues from ten liver cancer patients and define differentially expressed genes and tumor-specific mutations. We associate the oncogenesis with the mutations by target prediction and experimental verification. Results: Upregulated genes have tumor-specific mutations in 3'UTRs that abolish the binding of miRNAs. For downregulated genes, their corresponding miRNAs are mutually targeted by two circRNAs, with mutations in base-pairing regions. Transfection experiments support the oncogenic role of these mutations. Conclusions: The tumor-specific mutations serve as the initial trigger of liver cancer. The mutation-circRNA-miRNA-target gene chain is completed.

Synonymous mutations that regulate translation speed might play a non-negligible role in liver cancer development.

BACKGROUND: Synonymous mutations do not change the protein sequences. Automatically, they have been regarded as neutral events and are ignored in the mutation-based cancer studies. However, synonymous mutations will change the codon optimality, resulting in altered translational velocity. METHODS: We fully utilized the transcriptome and translatome of liver cancer and normal tissue from ten patients. We profiled the mutation spectrum and examined the effect of synonymous mutations on translational velocity. RESULTS: Synonymous mutations that increase the codon optimality significantly enhanced the translational velocity, and were enriched in oncogenes. Meanwhile, synonymous mutations decreasing codon optimality slowed down translation, and were enriched in tumor suppressor genes. These synonymous mutations significantly contributed to the translational changes in tumor samples compared to normal samples. CONCLUSIONS: Synonymous mutations might play a role in liver cancer development by altering codon optimality and translational velocity. Synonymous mutations should no longer be ignored in the genome-wide studies.

Genome-wide expression changes mediated by A-to-I RNA editing correlate with hepatic oncogenesis.

BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing is one of the most prevalent RNA modifications in the animal kingdom. Since inosine is recognized as guanosines, the A-to-I process mimics A-to-G DNA mutations but can be controlled in a more flexible manner compared to DNA alterations. METHODS: We parsed the transcriptomes and translatomes of liver cancer and normal tissues from ten patients. We profiled the landscape of the A-to-I RNA editome in these samples and interrogated whether the A-to-I processes participated in the gene expression regulation in oncogenesis. RESULTS: Globally, editing activity was enhanced in all tumor samples compared to that in normal samples. Accordingly, expression of the gene encoding the RNA editing enzyme ADAR (adenosine deaminase acting on RNA) was elevated. Two intronic self-editing sites in ADAR mRNAs controlled its splicing pattern and may regulate its translation efficiency (TE). Moreover, the expression of oncogenes was generally upregulated in tumors, whereas tumor suppressor genes (TSG) were downregulated, possibly due to alterations to microRNA binding sites or RNA splicing defects caused by A-to-I editing. CONCLUSIONS: A-to-I RNA editing plays a crucial role in the oncogenesis of liver cancer. ADAR regulates its own expression via self-editing, and it also affects global transcriptomes and translatomes involving cancer-related genes by RNA editing and changing their expression patterns.

Effect of microRNA-133a-3p/matrix metalloproteinase-9 axis on the growth of atherosclerotic vascular smooth muscle cells.

Atherosclerosis (AS) is the leading cause of cardiovascular disease and poses a threat to human health. MicroRNAs (miRNAs/miRs) are a group of endogenous small non-coding RNAs that have been identified to serve important roles in AS. However, the expression and role of miR-133a-3p in AS remains unclear. The aim of the present study was to investigate miR-133a-3p in AS and to determine its underlying mechanism. The level of miR-133a-3p expression in the blood and vascular plaque tissue of patients with AS was detected via reverse transcription-quantitative PCR (RT-qPCR). The role of miR-133a-3p in human vascular smooth muscle cells (hVSMCs) was investigated, following upregulation and downregulation of this miR in hVSMCs. Cell proliferation and apoptosis were determined using a Cell Counting kit-8 assay and flow cytometry, respectively. The results demonstrated the downregulation of miR-133a-3p in the blood and vascular plaque tissue of patients with AS. Matrix metallopeptidase-9 (MMP-9) was revealed to be a direct target gene of miR-133a-3p, which was upregulated in the blood and vascular plaque tissue of patients with AS. Furthermore, MMP-9 was determined to be negatively regulated by miR-133a-3p in hVSMCs. In addition, significant inhibition of hVSMC proliferation and induction of cell apoptosis were observed following MMP-9 downregulation and following transfection with the miR-133a-3p mimic. The effects of the miR-133a-3p mimic on hVSMC proliferation and apoptosis were reversed by MMP-9 over-expression. Overall, the results indicated that miR-133a-3p was downregulated in AS, which results in the inhibition of hVSMC proliferation and the induction of cell apoptosis via MMP-9. miR-133a-3p may therefore be a promising therapeutic target for the treatment of AS.

MicroRNA-199a-5p aggravates primary hypertension by damaging vascular endothelial cells through inhibition of autophagy and promotion of apoptosis.

The present study investigated the expression of microRNA (miRNA or miR)-199a-5p in the peripheral blood of patients with primary hypertension, and examined its mechanism of action in vascular endothelial cell injury induced by hypertension. A total of 57 patients with primary hypertension, who were treated at the Affiliated Hospital of Qingdao University (Qingdao, China) between December 2014 and November 2015 were included in the present study. Peripheral blood was collected from all patients. The expression of miR-199a-5p was measured using reverse-transcription quantitative polymerase chain reaction analysis. Human umbilical vein endothelial cells (HUVECs) were divided into negative control, miR-199a-5p mimics and rescue (co-transfected with miR-199a-5p mimics and inhibitor) groups. After transfection, the proliferation and apoptosis of HUVECs were evaluated by a Cell Counting Kit-8 assay, a bromodeoxyuridine incorporation assay and flow cytometry. Western blot analysis was used to determine the expression of proteins involved in autophagy-associated and adenosine monophosphate kinase (AMPK)/unc-51 like autophagy activating kinase 1 (ULK1) signaling pathways. Laser scanning confocal microscopy and electron microscopy were used to observe the autophagy of HUVECs. The expression of miR-199a-5p was elevated in peripheral blood of patients with hypertension, and was correlated with the progression of hypertension. Overexpression of miR-199a-5p inhibited the proliferation and promoted the apoptosis of HUVECs. Upon expression of miR-199a-5p, the transition between microtubule-associated proteins 1A/1B light chain 3B (LC3B)I and LC3BII proteins was inhibited, the expression of p62 protein was upregulated. In addition, miR-199a-5p decreased the numbers of autophagosomes and autolysosomes in HUVECs. The present study demonstrated that expression of miR-199a-5p is positively correlated with the severity of hypertension. Expression of miR-199a-5p aggravated vascular endothelial injury by inhibiting autophagy and promoting the apoptosis of HUVECs via downregulation of the AMPK/ULK1 signaling pathway.

FoxM1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by targeting Snai1.

Forkhead box protein M1 (FoxM1) is aberrantly expressed in several types of human malignancy, and serves an important role in tumor metastasis. Epithelial­mesenchymal transition (EMT) of cancer cells has been associated cancer metastasis; however, the implication of FoxM1 in EMT and its putative roles in the regulation of cancer metastasis remain to be elucidated. In the present study, the expression of FoxM1, Snai1 and E­cadherin in hepatocellular carcinoma (HCC) cell lines with various metastatic potentials, and in normal liver cells, was investigated using western blot analysis and reverse transcription­quantitative polymerase chain reaction. The effects of FoxM1 on the invasive and migratory capabilities of HCC cells were evaluated using wound healing and Transwell migration assays. The present results demonstrated that FoxM1 expression was significantly upregulated in HCC cells compared with in normal hepatocytes (P<0.05). In addition, FoxM1 expression was significantly increased in MHCC­LM3 cells, characterized by higher metastatic potential, compared with in SMMC­7721 cells, which have a lower metastatic potential. Furthermore, overexpression of FoxM1 was demonstrated to be negatively correlated with E­cadherin (P<0.05) and positively associated with Snai1 (P<0.05) expression. These observations suggested that FoxM1 may enhance the invasion and migration of cancer cells, and thus promotes their EMT, in a mechanism that may involve the regulation of Snai1. Therefore, it may be hypothesized that FoxM1 has potential as a novel diagnostic marker and therapeutic target for the treatment of patients with HCC.

Lobaplatin combined floxuridine/pirarubicin-based transcatheter hepatic arterial chemoembolization for unresectable primary hepatocellular carcinoma.

PURPOSE: To assess the effect and safety of lobaplatin combinated floxuridine /pirarubicin in transcatheter hepatic arterial chemoembolization(TACE) of unresectable primary liver cancer. PATIENTS AND METHODS: TACE combined with the chemotherapy regimen was used to treat 34 unresectable primary liver cancer patients. DSA/ MRI/CT/blood routine examinations were used to evaluate short term activity and toxicity after 4-5 weeks, the process being repeated if necessary. RESULTS: Among the 34 cases, 1 (2.9%) showed a complete response, 21 (61.7%) a partial response, 8 (23.5%) stable disease, and 4 progressive disease, with a total effective rate of 67.6%. The content of alpha fetoprotein dropped by over 50% in 20 cases (58.8%). The rate of recovery was hepatalgia (88.2%), ascites (47.1%), appetite (55.9%), Performance Status(30.4%). The median follow-up time (MFT) was 281 days (63-558 days), and median progression-free survival was 118.5 days (95%, CI:88.8-148.2 days). Adverse reactions (III-IV grade) were not common, with only 4 cases of vomiting and 2 cases of thrombocytopenia (III grade). CONCLUSIONS: Lobaplatin-based TACE is an effective and safe treatment for primary liver cancer.