Utility of Alpha-Fetoprotein and Ultrasound in the Diagnosis and Prognosis of Patients with Hepatocellular Liver Cancer.

Objective: To investigate the utility of alpha-fetoprotein (AFP) and ultrasound in the diagnosis and prognosis of patients with hepatocellular liver cancer (HCC). Methods: Using retrospective convenience sampling, 401 patients with HCC who underwent transarterial chemoembolisation at the Department of Oncology of The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University between June 2015 and January 2020 were recruited and assigned to the case group. Simultaneously, patients matched to the case group in terms of gender and age but excluded for HCC were enrolled at a 1:1 ratio and classified as the control group. Relevant parameters were collected from both groups for comparison. Results: Both AFP levels and ultrasound results demonstrated diagnostic value for patients with HCC (P < 0.05). Their combined use exhibited the highest diagnostic accuracy for the cancer, with an area under the curve of 0.896 (95% confidence interval [CI]: 0.876, 0.923), a sensitivity of 67.65% and a specificity of 91.22%. In terms of overall survival (OS), statistically significant differences in the OS rates were observed between the low-AFP (L-AFP) group and high-AFP (H-AFP) group as well as between the low-tumour-diameter (LTD) group and high-tumour-diameter (HTD) group (81.31% vs 52.22% and 85.11% vs 63.41%, respectively; P < 0.05). Regarding the progression-free survival (PFS), significant differences in the PFS rates were also noted between the L-AFP and H-AFP groups and between the LTD and HTD groups (81.31% vs 52.22% and 85.11% vs 63.41%, respectively; P < 0.05). Conclusion: Ultrasound and AFP display notable distinctions when used in the diagnosis of HCC. The sensitivity of ultrasound as a standalone diagnostic tool surpasses that of AFP alone. However, their combined use results in much higher specificity than the use of either test individually. In addition, both techniques hold predictive value for patients' OS and PFS, enabling timely prognostic assessment.

Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma.

BACKGROUND: PR55α plays important roles in oncogenesis and progression of numerous malignancies. However, its role in hepatocellular carcinoma (HCC) is unclear. This study aims to characterize the functions of PR55α in HCC. METHODS: PR55α expressions in HCC tissues and paired healthy liver samples were evaluated using Western blot and tissue microarray immunohistochemistry. We knocked down the expression of PR55α in SMMC-7721 and LM3 cell lines via small interfering and lentivirus. In vitro cell counting, colony formation, migration and invasion assays were performed along with in vivo xenograft implantation and lung metastases experiments. The potential mechanisms involving target signal pathways were investigated by RNA-sequencing. RESULTS: PR55α expression level was suppressed in HCC tissues in comparison to healthy liver samples. Decreased PR55α levels were correlated with poorer prognosis (P = 0.0059). Knockdown of PR55α significantly promoted cell proliferation and migration, induced repression of the cell cycle progression and apoptosis in vitro while accelerating in vivo HCC growth and metastasis. Mechanistic analysis indicated that PR55α silencing was involved with MAPK/AKT signal pathway activation and resulted in increased phosphorylation of both AKT and ERK1/2. CONCLUSIONS: This study identifies PR55α to be a candidate novel therapeutic target in the treatment of HCC.

Meta-analysis of laparoscopic versus open liver resection for hepatocellular carcinoma.

AIM: The aim of this study was to evaluate the surgical safety and effectiveness of laparoscopic hepatectomy (LH) in short- and long-term outcomes compared to open hepatectomy (OH) in patients treated for hepatocellular carcinoma (HCC). METHODS: An electronic search of reports published before August 2017 was carried out to identify comparative studies evaluating LH versus OH for HCC. RESULTS: A total of 5889 patients (2421 underwent LH; 3468 underwent OH) were included in our meta-analysis from 47 studies. Laparoscopic hepatectomies were associated with favorable outcomes in terms of operative blood loss (mean difference [MD], -147.27; 95% confidence interval [CI], -217.00, -77.55), blood transfusion requirement (odds ratio [OR], 0.51; 95% CI, 0.40, 0.65), pathologic resection margins (MD, 0.07; 95% CI, 0.02, 0.12; P = 0.01), R0 resection rate (OR, 1.34; 95% CI, 0.98, 1.84; P = 0.07), and length of hospital stay (MD, -5.13; 95% confidence interval, -6.23, -4.03). There were no differences between the groups in overall survival (OS) at 1 year (OR, 1.41; 95% CI, 1.00, 1.98), 3 years (OR, 1.12; 95% CI, 0.93, 1.36), or 5 years (OR, 1.18; 95% CI, 0.94, 1.46), in disease-free survival (DFS) at 1 (OR, 1.19; 95% CI, 0.94, 1.51), 3 years (OR, 1.07; 95% CI, 0.86, 1.33), or 5 years (OR, 1.13; 95% CI, 0.92, 1.40), or in recurrence (OR, 0.90; 95% CI, 0.74, 1.08). CONCLUSION: Compared to OH, LH is superior in terms of lower intraoperative blood loss and the requirement for blood transfusion, larger pathologic resection margins, increased R0 resection rates, and shorter length of hospital stay. Laparoscopic hepatectomy and OH have similar OS, DFS, and recurrence.

Optimal adjuvant chemotherapy for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis.

Adjuvant chemotherapy improves survival in patients with resected pancreatic cancer but the optimal regimen remains unclear. We aim to compare all possible adjuvant chemotherapy in terms of overall survival and toxic effects. Pubmed, Trial registries and Cochrane library databases for randomized controlled trials were searched until November 2016. Thirteen trials were included for network analysis and the hazard ratios (HRs) for survival and odds ratios for toxic effects were assessed via Aggregate Data Drug Information System software. Only S-1 chemotherapy improved 1-year, 3-year and 5-year survival compared with observation (HR (95% CI): 3.94 (1.18-12.34); 4.08 (1.58-8.24) and 5.09 (1.16-29.83) respectively). Although not significant, gemcitabine plus uracil/tegafur was associated with poorer 1-year and 3-year survival compared with observation (HR (95% CI): 0.85 (0.16-4.03) and 0.86 (0.23-2.95)). Adding radiation to chemotherapy has no significant improvement in survival. S-1 and gemcitabine plus capecitabine are currently the most effective adjuvant therapies for pancreatic cancer. While S1 has only been validated in Asian people, higher toxicity is an issue for gemcitabine plus capecitabine.

Orexin-A promotes Glu uptake by OX1R/PKCα/ERK1/2/GLT-1 pathway in astrocytes and protects co-cultured astrocytes and neurons against apoptosis in anoxia/hypoglycemic injury in vitro.

Orexin-A, which is an endogenous neuropeptide, is reported to have a protective role in ischemic stroke. High-concentration glutamic acid (Glu) induced by hypoxia injury in ischemic stroke can be inhibited by glial glutamate transporter GLT-1 which is only expressed in astroglia cells. A previous study reported that Orexin-A may regulate GLT-1 expression. However, the role of orexin-A in the regulation of GLT-1 in ischemic stroke still remains unclear. In this study, we aimed to investigate the effect and the underlying mechanism of orexin-A on Glu uptake in astrocytes in vitro and this effect on protecting the neurons from anoxia/hypoglycemic injury. The expression of GLT-1 significantly increased in the astrocytes with orexin-A treatment under anoxia/hypoglycemic conditions, promoting the uptake of Glu and inhibiting the apoptosis of co-cultured cells of astrocytes and neurons. However, these effects were significantly weakened by treatment with orexin-A receptor 1 (OX1R) antagonist. Orexin-A significantly up-regulated the expressions of PKCα and ERK1/2 under anoxia/hypoglycemic conditions in astrocytes, whereas the OX1R antagonist markedly reversed the effect. Furthermore, PKCα or ERK1/2 inhibitor significantly constrained the GLT-1 expression in astrocytes and facilitated the apoptosis of co-cultured cells, and GLT-1 overexpression could reverse those effects of PKCα or ERK1/2 inhibitor. Taken together, orexin-A promoted the GLT-1 expression via OX1R/PKCα/ERK1/2 pathway in astrocytes and protected co-cultured cells against anoxia/hypoglycemic injury.

Overexpression of OCT4 contributes to progression of hepatocellular carcinoma.

The abnormal change of octamer transcription factor 4 (OCT4) is associated with tumor progression; however, its effect on hepatocellular carcinoma (HCC) behavior remains unclear. The purpose of this study was to determine the correlation between HCC and OCT4. In the present study, IHC, western blot analysis, and QRT-PCR were performed to identify differentially expressed OCT4 in a series of HCC tissues and adjacent non-cancerous tissues. In addition, the functions of OCT4 on HCC progression were studied in vitro. Silencing of OCT4 with siRNA was performed in HCC cell lines, and the impact on proliferation, migration, and the EMT marker of HCC was analyzed. Our results found that OCT4 levels were significantly higher in HCC tissues compared with the adjacent non-cancerous tissues. Furthermore, OCT4 siRNA significantly reduced the proliferation rate of SMMC-7721 and HepG2 cells, inhibited the migration and inversion, and could reverse EMT in HCC cells, indicating that OCT4 plays a critical role in HCC progression. Our data suggest that the pathogenesis of human HCC may be mediated by OCT4, and thus, OCT4 could represent selective targets for the molecularly targeted treatments of HCC.

Adjuvant interferon therapy after surgical treatment for hepatitis B/C virus-related hepatocellular carcinoma: A meta-analysis.

AIM: This meta-analysis aimed to determine whether interferon (IFN) therapy could improve clinical effects of patients with chronic hepatitis B virus (HBV)or hepatitis C virus (HCV) infection-related primary hepatocellular carcinoma (HCC) after surgery. METHODS: An electronic search from January 1998 to December 2012 was conducted to identify comparative studies evaluating IFN therapy on recurrence and survival after surgical treatment of HCC. RESULTS: The estimated odds ratios (OR) for the 1-, 2-, 3- and 5-year overall survival rates of HBV-related HCC were 3.37 (95% confidence interval [CI], 1.18-6.27), 2.36 (95% CI, 1.45-3.83), 1.81 (95% CI, 1.21-2.72) and 1.93 (95% CI, 1.35-2.75), respectively; and the OR for the 1-, 2-, 3- and 5-year recurrence rates were 0.63 (95% CI, 0.44-0.91), 0.84 (95% CI, 0.60-1.18), 0.88 (95% CI, 0.63-1.22) and 0.78 (95% CI, 0.56-1.07), respectively. The overall survival rates of HCV-related HCC were significantly higher in IFN groups than in control groups at 1, 2, 3 and 5 years (OR, 2.10; 95% CI, 0.96-4.55; OR, 1.71; 95% CI, 1.01-2.89; OR, 1.76; 95% CI, 1.09-2.83; and OR, 3.03; 95% CI, 1.97-4.65, respectively); and the recurrence rates of IFN groups were lower than control groups at 1, 2, 3 and 5 years (OR, 0.60; 95% CI, 0.38-0.92; OR, 0.57; 95% CI, 0.41-0.81; OR, 0.58; 95% CI, 0.41-0.80; and OR, 0.52; 95% CI, 0.36-0.75, respectively). CONCLUSION: In conclusion, IFN therapy in this meta-analysis shows a significant clinical effect in postoperative patients of HCC, particularly in HCV-related HCC.

A functional variomics tool for discovering drug-resistance genes and drug targets.

Comprehensive discovery of genetic mechanisms of drug resistance and identification of in vivo drug targets represent significant challenges. Here we present a functional variomics technology in the model organism Saccharomyces cerevisiae. This tool analyzes numerous genetic variants and effectively tackles both problems simultaneously. Using this tool, we discovered almost all genes that, due to mutations or modest overexpression, confer resistance to rapamycin, cycloheximide, and amphotericin B. Most significant among the resistance genes were drug targets, including multiple targets of a given drug. With amphotericin B, we discovered the highly conserved membrane protein Pmp3 as a potent resistance factor and a possible target. Widespread application of this tool should allow rapid identification of conserved resistance mechanisms and targets of many more compounds. New genes and alleles that confer resistance to other stresses can also be discovered. Similar tools in other systems, such as human cell lines, will also be useful.

Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy.

Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7(T287N)) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets.

Meta-analysis of surgical resection and radiofrequency ablation for early hepatocellular carcinoma.

BACKGROUND: There is no definite agreement on the better therapy (radiofrequency ablation (RFA) versus surgical resection (SR)) for early hepatocellular carcinoma (HCC) eligible for surgical treatments. The purpose of this study is to evaluate the evidence using meta-analytical techniques. METHODS: A literature search was undertaken until December 2011 to identify comparative studies evaluating survival rates, recurrence rates, and complications. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated with either the fixed or random effect model. RESULTS: Thirteen articles, comprising two randomized controlled trials(RCTs), were included in the review, with a total of 2,535 patients (1,233 treated with SR and 1,302 with RFA). The overall survival rates were significantly higher in patients treated with SR than RFA after1, 3, and 5 years (respectively: OR, 0.60 (95% CI, 0.42 to 0.86); OR, 0.49 (95% CI, 0.36 to 0.65); OR, 0.60 (95% CI, 0.43 to 0.84)). In the SR group, the 1, 3, and 5 years recurrence rates were significantly lower than the RFA group (respectively: OR, 1.48 (95% CI, 1.05 to 2.08); OR, 1.76 (95% CI, 1.49 to 2.08); OR, 1.68 (95% CI, 1.21 to 2.34)). However, local recurrence between two groups did not exhibit significant difference. For HCC ≤ 3 cm in diameter, SR was better than RFA at the 1, 3, and 5 years overall survival rates (respectively: OR, 0.34 (95% CI, 0.13 to 0.89); OR, 0.56 (95% CI, 0.37 to 0.84); OR, 0.44 (95% CI, 0.31 to 0.62)). This meta-analysis indicated that the complication of SR was higher than RFA (OR, 6.25 (95%CI, 3.12 to 12.52); P = 0.000). CONCLUSION: Although local recurrence between two groups did not exhibit significant difference, SR demonstrated significantly improved survival benefits and lower complications for patients with early HCC, especially for HCC ≤ 3 cm in diameter. These findings should be interpreted carefully, owing to the lower level of evidence.

Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma.

BACKGROUND: CD97 as a member of the EGF-TM7 family with adhesive properties plays an important role in tumor aggressiveness by binding its cellular ligand CD55, which is a complement regulatory protein expressed by cells to protect them from bystander complement attack. Previous studies have shown that CD97 and CD55 both play important roles in tumor dedifferentiation, migration, invasiveness, and metastasis. The aim of this study was to investigate CD97 and CD55 expression in primary gallbladder carcinoma (GBC) and their prognostic significance. METHODS: Immunohistochemistry was used to investigate the expression of CD97 and CD55 proteins in 138 patients with GBC. RESULTS: CD97 and CD55 were absent or only weakly expressed in the normal epithelium of the gallbladder but in 69.6% (96/138) and 65.2% (90/138) of GBC, respectively, remarkably at the invasive front of the tumors. In addition, CD97 and CD55 expressions were both significantly associated with high histologic grade (both P = 0.009), advanced pathologic T stage (P = 0.01 and 0.009, resp.) and clinical stage (both P = 0.009), and positive venous/lymphatic invasion (both P = 0.009). Multivariate analyses showed that CD97 (hazard ratio, 3.236; P = 0.02) and CD55 (hazard ratio, 3.209; P = 0.02) expressions and clinical stage (hazard ratio, 3.918; P = 0.01) were independent risk factor for overall survival. CONCLUSION: Our results provide convincing evidence for the first time that the expressions of CD97 and CD55 are both upregulated in human GBC. The expression levels of CD97 and CD55 in GBC were associated with the severity of the tumor. Furthermore, CD97 and CD55 expressions were independent poor prognostic factors for overall survival in patients with GBC.

Fascin and cortactin expression is correlated with a poor prognosis in hepatocellular carcinoma.

OBJECTIVES: The aim of this study was to investigate the relationship between fascin and cortactin protein expression and clinicopathological parameters and survival time in patients with hepatocellular carcinoma (HCC). METHODS: A total of 77 specimens of HCC and seven specimens of normal liver tissues were collected. The expressions of fascin and cortactin were examined by immunohistochemical staining. The patients from whom the HCCs were taken were also followed up. In these 74 patients, Kaplan-Meier was used to assess survival outcomes. RESULTS: The data revealed that fascin and cortactin expressions were upregulated in the HCC samples. The positive expression of fascin significantly correlated with histological differentiation and metastasis. The positive expression of cortactin significantly correlated with histological differentiation, metastasis, and T stage (International Union Against Cancer). Survival time of the patients with positive fascin expression and positive cortactin expression was significantly decreased, and the median survival duration was short. CONCLUSION: Fascin and cortactin might be important indicators of the malignancy and metastasis of liver cancer, and may have predictive value in the prognosis of HCC.

Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population.

NBS1 plays important roles in maintaining genomic stability as a key DNA repair protein in the homologous recombination repair pathway and as a signal modifier in the intra-S phase checkpoint. We hypothesized that polymorphisms of NBS1 are associated with hepatic cancer (HCC) risk. The NBS1 rs1805794 C/G polymorphism has been frequently studied in some cancers with discordant results, but its association with HCC has not been investigated. Moreover, studies of the 3'UTR variant rs2735383 have not touched upon HCC. This study examined the contribution of these two polymorphisms to the risk of developing HCC in a Chinese population. NBS1 genotypes were determined in 865 HCC patients and 900 controls and the associations with risk of HCC were estimated by logistic regression. Compared with the rs1805794 GG genotype, the GC genotype had a significantly increased risk of HCC (adjusted odds ratios [OR]=1.41; 95% confidence interval [CI]=1.11-1.80), the CC carriers had a further increased risk of HCC (OR=2.27; 95% CI=1.68-3.14), and there was a trend for an allele dose effect on risk of HCC (p<0.001). Also, we found that the risk effect of rs1805794 CC+CG was more pronounced in HCC patients that drank (OR=2.28, 95% CI=1.55-3.29 for drinkers; OR=1.31, 95% CI=1.00-1.77 for nondrinkers). However, there was no significant difference in genotype frequencies of rs2735383 G/C site between cases and controls. These findings suggest that rs1805794 C/G polymorphism in NBS1 may be a genetic modifier for developing HCC.

Sampangine inhibits heme biosynthesis in both yeast and human.

The azaoxoaporphine alkaloid sampangine exhibits strong antiproliferation activity in various organisms. Previous studies suggested that it somehow affects heme metabolism and stimulates production of reactive oxygen species (ROS). In this study, we show that inhibition of heme biosynthesis is the primary mechanism of action by sampangine and that increases in the levels of reactive oxygen species are secondary to heme deficiency. We directly demonstrate that sampangine inhibits heme synthesis in the yeast Saccharomyces cerevisiae. It also causes accumulation of uroporphyrinogen and its decarboxylated derivatives, intermediate products of the heme biosynthesis pathway. Our results also suggest that sampangine likely works through an unusual mechanism-by hyperactivating uroporhyrinogen III synthase-to inhibit heme biosynthesis. We also show that the inhibitory effect of sampangine on heme synthesis is conserved in human cells. This study also reveals a surprising essential role for the interaction between the mitochondrial ATP synthase and the electron transport chain.