HO-3867, a curcumin analog, elicits cell apoptosis and p38-mediated caspase activation in hepatocellular carcinoma.

HO-3867, a synthetic curcumin analog, has displayed various tumor-suppressive characteristics and improved bioabsorption over its parent compound. However, its influences on the development of hepatocellular carcinoma (HCC) are poorly defined. To address this, we tested the anticarcinogenic impact of HO-3867 and investigated the underlying mechanisms in fighting liver cancer. Our result demonstrated that HO-3867 reduced the viability of HCC cells, accompanied by promotion of cell cycle arrest at the sub-G1 stage and apoptotic responses. Furthermore, a distinctive profile of apoptosis associated proteins, encompassing elevated heme oxygenase-1 (HO-1) level and caspase activation, was detected in HO-3867-stimulated HCC cells. In addition, such HO-3867-mediated elevation in caspase activation was dampened by pharmacological suppression of p38 activities. Taken together, our findings unveiled that HO-3867 triggered cell cycle arrest and apoptotic events in liver cancer, involving a p38-mediated activation of caspase cascades. These data highlighted a usefulness of curcumin or its analogs on the management of hepatocarcinogenesis.

Loss of MTA2-mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK-MMP7 axis.

The expression of metastasis tumor-associated protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) is associated with hepatocellular carcinoma (HCC) progression. However, the functional effect and mechanism through which MTA2 regulates PTK7-mediated HCC progression remains unclear. Here, we found that MTA2 knockdown significantly down-regulated PTK7 expression in HCC cells (SK-Hep-1 and PLC/PRF/5). Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases show that the PTK7 expression level was higher in HCC tissues than in normal liver tissues. In HCC patients, the PTK7 expression level clearly correlated with tumor stage and grade, lower overall survival (OS) correlated positively with MTA2 level, and PTK7 expression acted as a downstream factor for MTA2 expression. In addition, matrix metalloproteinase 7 (MMP7) expression was closely regulated by PTK7, and the mRNA and protein expression levels of MTA2 and PTK7 correlated positively with lower OS. MMP7 downregulation by PTK7 knockdown clearly decreased the migration and invasion abilities of HCC cells. In HCC cells, recombinant human MMP7 reversed the PTK7 knockdown-induced suppression of migration and invasion. Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF-573228, PF) synergistically contributed to PTK7 knockdown-inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2-FAK-MMP7 axis and may be a diagnostic value for HCC patients.

Efficacy and safety of once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in kidney transplant recipients: A meta-analysis and trial sequential analysis.

BACKGROUND: Kidney transplantation is the most important treatment for end-stage renal disease. Immunosuppressive therapies can prevent acute rejection for kidney transplant recipients. Tacrolimus is usually administered to prevent graft rejection after transplantation. Previous studies have indicated that once-daily tacrolimus may improve medication adherence. Therefore, this meta-analysis aimed to compare clinical outcomes between once-daily and twice-daily tacrolimus in de novo renal transplant patients. METHODS: Eligible studies were identified from the Cochrane Library Database, PubMed, and Embase until July 2022. Those randomized controlled trials (RCTs) evaluating once-daily versus twice-daily tacrolimus formulations in de novo renal transplantation were included. A summary risk ratio (RR) and standardized mean difference (SMD) with the 95% confidence interval (CI) were estimated using a random-effects model. RESULTS: In total, nine RCTs were included. There were no differences in biopsy-confirmed acute rejection rates between patients with once-daily and those with twice-daily tacrolimus (RR, 0.91; 95% CI, 0.73-1.13) in 12 months. Regarding renal function, there was no significant difference between the once-daily and twice-daily tacrolimus groups (SMD, -0.03; 95% CI, -0.12 to 0.07). In addition, the risk of graft failure, death, and adverse events in the first year was similar for the once-daily and twice-daily tacrolimus groups. CONCLUSION: Our major findings suggest that de novo renal transplantation recipients receiving once-daily tacrolimus immediately after transplantation have comparable efficacy and safety with those recipients who received twice-daily tacrolimus. Therefore, once-daily tacrolimus medication can be an alternative for de novo renal transplantation recipients.

Survival Benefit of Experience of Liver Resection for Advanced Recurrent Hepatocellular Carcinoma Treated with Sorafenib: A Propensity Score Matching Analysis.

Several studies have shown that liver resection (LR) confers better survival outcomes in intermediate- and advanced-stage hepatocellular carcinoma (HCC) patients. However, the postoperative recurrence rate is high, and little is known about the survival benefits of LR for recurrent HCC patients who have already received systemic treatment. This study aimed to evaluate the impact of LR on recurrent advanced-stage HCC patients who received sorafenib as a systemic treatment. In this study, 147 advanced HCC patients were enrolled between 1 January 2012 and 31 December 2019. Two study groups were classified, based on whether they underwent LR or not. To reduce the possible selection bias, a propensity score matching (PSM) analysis was performed. The primary study endpoint was set as overall survival (OS), and the secondary endpoint was set as progression-free survival (PFS). Our study results revealed that advanced HCC patients who received sorafenib with LR had a longer OS than did those without LR, whether before or after PSM (15.0 months vs. 6.0 months, HR 0.45, 95% CI 0.31-0.67, p < 0.001; 15.0 months vs. 5.0 months, HR 0.46, 95% CI 0.28-0.76, p = 0.001). Similar results were obtained in PFS, before or after PSM (4.14 months vs. 2.60 months, HR 0.60, 95% CI 0.40-0.89, p = 0.01; 4.57 months vs. 2.63 months, HR 0.58, 95% CI 0.34-0.97, p = 0.037). Multivariate analysis showed that the experience of LR was independent of other factors associated with better OS and PFS, whether before or after PSM (p < 0.05). Therefore, advanced HCC patients who have undergone liver resection should be encouraged to continue sorafenib treatment to improve prognosis.

Type 2 Diabetes, PNPLA3 rs738409 Polymorphism, and the Risk of Liver Cirrhosis: Analysis of Taiwan Biobank.

Type 2 diabetes (T2D) and liver cirrhosis remain significant public health threats in Taiwan. These conditions are reported to be associated with the rs738409 polymorphism of the patatin-like phospholipase domain-containing protein three gene (PNPLA3) in European populations. We assessed the effect of T2D and PNPLA3 rs738409 polymorphism on liver cirrhosis among Taiwan Biobank (TWB) participants. In total, 17,985 participants in TWB had their health records linked to the National Health Insurance Research Database (NHIRD). Participants included those who visited the assessment centers between 2008 and 2015, with an age range between 30 and 70 years of age. We performed logistic regression analysis to investigate the odds ratios (OR) for liver cirrhosis among participants based on the T2D status and rs738409 genotypes. Genotyping was performed using the Axiom Genome-Wide TWB Array Plate. In our analysis, 150 of the 17,619 eligible participants were identified as cirrhosis cases. Based on the univariate analysis, liver cirrhosis was positively associated with T2D (OR, 1.83; 95% CI 1.23-2.70) whereas, the variant rs738409 was not (regardless of the genetic model). The variant and T2D, however, showed significant interactions in the additive, genotype, and dominant models (p values of 0.0302, 0.0395, and 0.0455, respectively). We observed a statistically significant association between T2D and liver cirrhosis and variant rs738409 with an OR of 1.71 (95% CI, 1.03-2.84) for individuals carrying a G allele compared to those with a C allele and 2.92 (95% CI 1.07-7.99) for GG compared to CC individuals. According to our study, Taiwanese adults with T2D and the rs738409 GG genotype are more likely to develop liver cirrhosis.

Using IVIM Parameters to Differentiate Prostate Cancer and Contralateral Normal Tissue through Fusion of MRI Images with Whole-Mount Pathology Specimen Images by Control Point Registration Method.

The intravoxel incoherent motion (IVIM) model may enhance the clinical value of multiparametric magnetic resonance imaging (mpMRI) in the detection of prostate cancer (PCa). However, while past IVIM modeling studies have shown promise, they have also reported inconsistent results and limitations, underscoring the need to further enhance the accuracy of IVIM modeling for PCa detection. Therefore, this study utilized the control point registration toolbox function in MATLAB to fuse T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) MRI images with whole-mount pathology specimen images in order to eliminate potential bias in IVIM calculations. Sixteen PCa patients underwent prostate MRI scans before undergoing radical prostatectomies. The image fusion method was then applied in calculating the patients' IVIM parameters. Furthermore, MRI scans were also performed on 22 healthy young volunteers in order to evaluate the changes in IVIM parameters with aging. Among the full study cohort, the f parameter was significantly increased with age, while the D* parameter was significantly decreased. Among the PCa patients, the D and ADC parameters could differentiate PCa tissue from contralateral normal tissue, while the f and D* parameters could not. The presented image fusion method also provided improved precision when comparing regions of interest side by side. However, further studies with more standardized methods are needed to further clarify the benefits of the presented approach and the different IVIM parameters in PCa characterization.

Antioxidant vitamins promote anticancer effects on low-concentration methotrexate-treated glioblastoma cells via enhancing the caspase-3 death pathway.

Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.

A PRISMA-compliant meta-analysis of apolipoprotein C3 polymorphisms and nonalcoholic fatty liver disease.

BACKGROUND: The relationship between apolipoprotein C3 (APOC3) gene polymorphisms and nonalcoholic fatty liver disease (NAFLD) risk has been investigated in many studies, with inconclusive findings. This meta-analysis evaluated the effect of APOC3 promoter region polymorphisms (-455T/C and -482C/T) on NAFLD susceptibility. METHODS: A comprehensive search of eligible studies up to October 2020 was performed on Medline, Embase, Web of Science, and Google Scholar databases. No restriction was imposed on language, publication date, or publication status. Odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated to assess the combined effect sizes. The levels of heterogeneity, sensitivity, subgroup, and publication bias were analyzed subsequently. RESULTS: This meta-analysis included eight studies, consisting of 1,511 patients with NAFLD and 1,900 controls fulfilling the inclusion criteria and exclusion criteria. The pooled analysis showed significant associations between APOC3 -455T/C polymorphism and NAFLD risk in allelic (OR = 1.33; 95% CI = 1.05-1.67), dominant (OR = 1.34; 95% CI = 1.04-1.72), and recessive (OR = 1.60; 95% CI = 1.06-2.40) models. Ethnicity-based stratification showed that -455T/C polymorphism was significantly associated with NAFLD risk in the non-Asian but not in the Asian population. No association was evident between -482C/T polymorphism and NAFLD risk. CONCLUSION: Our findings suggest that APOC3 promoter region polymorphism -455T/C may be associated with NAFLD risk in the non-Asian but not in the Asian population. Additional studies with other functional polymorphisms are needed to discover APOC3 gene effects on NAFLD.

The Diagnostic Value of p16/Ki67 Dual Immunostaining for Anal Intraepithelial Neoplasia: A Meta-Analysis.

The p16/Ki67 dual immunostaining was performed on anal cytology specimens; this is an anal cancer screening method. A literature search was performed in the BioMed Central, Cochrane Library, Embase, Google Scholar, and PubMed electronic databases for relevant articles. We included studies that discussed the efficacy of p16/Ki67 dual immunostaining for detecting anal intraepithelial neoplasia (AIN). Studies that calculated the diagnostic efficacy on a per-patient basis were included. We excluded review articles, case series, and studies that did not provide sufficient information. We extracted data on true positive, true negative, false positive, and false negative from the included studies to generate pooled sensitivity, specificity, and diagnostic odds ratio (DOR). All analyses were performed with a random-effects model using MetaDiSc 1.4 and MetaDTA. The meta-analysis produced a pooled sensitivity of 0.63 (95% CI: 0.34, 0.86) and specificity of 0.65 (95% CI: 0.46, 0.81) for p16/Ki67 dual immunostaining in detecting AIN. The pooled DOR was 3.26 (95% CI: -0.29, 6.82). A subgroup analysis of HIV-infected men who have sex with men (MSM) demonstrated a pooled sensitivity of 0.75 (95% CI: 0.28, 0.96). p16/Ki67 dual immunostaining might have a higher sensitivity for detecting AIN in HIV-infected MSM. p16/Ki67 dual immunostaining might be more sensitive in HIV-infected MSM and has higher specificity compared to human papillomavirus testing among this high-risk group. p16/Ki67 dual immunostaining might be an adjuvant and potential triage test for anal cytology in anal cancer screening.

Association of lncRNA CCAT2 and CASC8 Gene Polymorphisms with Hepatocellular Carcinoma.

The worldwide incidence of hepatocellular carcinoma (HCC), the major histological type of primary liver cancer, is heterogeneous due to the variable prevalence of etiological factors, indicating a correlation of HCC risk with genetic variations among individuals. Among long non-coding RNAs (lncRNAs) located in the chromosome 8q24 loci and involved in the carcinogenesis are colon cancer associated transcript 2 (CCAT2) and cancer susceptibility candidate 8 (CASC8). In this study, the association of CCAT2 and CASC8 gene polymorphisms with the occurrence of HCC was explored between 397 HCC patients and 1195 controls. We found that carriers of rs6983267 GG in CCAT2 were more susceptible to HCC, with the odds ratio (OR) and adjusted odds ratio (AOR) being 1.532 (95% CI, 1.103-2.129; p = 0.011) and 1.627 (95% CI, 1.120-2.265; p = 0.033), respectively. Moreover, for patients stratified by age (under 65), gender (male only), or status of drinking (habitual drinkers), a protective effect of CASC8 rs3843549 on presenting high Child-Pugh scores, metastatic vascular invasion, or large-size tumors was observed in a dominant model. Collectively, our data reveal association of CCAT2 and CASC8 gene polymorphisms with the occurrence and progression of HCC.

Association of lncRNA H19 Gene Polymorphisms with the Occurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, whose diversified occurrence worldwide indicates a connection between genetic variations among individuals and the predisposition to such neoplasms. Mounting evidence has demonstrated that long non-coding RNA (lncRNA) H19 can have both promotive and inhibitory effects on cancer development, revealing a dual role in tumorigenesis. In this study, the link of H19 gene polymorphisms to hepatocarcinogenesis was assessed between 359 HCC patients and 1190 cancer-free subjects. We found that heterozygotes for the minor allele of H19 rs2839698 (T) and rs3741219 (G) were more inclined to develop HCC (OR, 1.291; 95% CI, 1.003-1.661; p = 0.047, and OR, 1.361; 95% CI, 1.054-1.758; p = 0.018, respectively), whereas homozygotes for the polymorphic allele of rs2107425 (TT) were correlated with a decreased risk of HCC (OR, 0.606; 95% CI, 0.410-0.895; p = 0.012). Moreover, patients who bear at least one variant allele (heterozygote or homozygote) of rs3024270 were less prone to develop late-stage tumors (for stage III/IV; OR, 0.566; 95% CI, 0.342-0.937; p = 0.027). In addition, carriers of a particular haplotype of three H19 SNPs tested were more susceptible to HCC. In conclusion, our results indicate an association between H19 gene polymorphisms and the incidence and progression of liver cancer.

Coronarin D induces apoptotic cell death through the JNK pathway in human hepatocellular carcinoma.

Coronarin D, a diterpene derived from the rhizomes of Hedychium coronarium, has been used to treat inflammatory diseases. Coronarin D can exert strong anticancer effects through cell growth prevention and cell cycle arrest in many cancer cells. In this study, we investigated the molecular mechanism through which coronarin D suppresses cell proliferation and triggers cell death in human hepatocellular carcinoma (HCC) cells. Treatment of Huh7 and Sk-hep-1 cells with coronarin D resulted in a significantly increased loss of mitochondrial membrane potential, leading to the cleavage and activation of caspase-9, caspase-8, and caspase-3 and changes in Bax, Bcl-2, and Bcl-xL protein levels. Coronarin D significantly induced autophagy by increasing the expression of Beclin-1 and LC3-II and reducing the expression of p62. Moreover, Huh7 and Sk-hep-1 cells exposed to coronarin D had decreased expression of phosphorylated AKT, p38, and ERK and increased expression of phosphorylated JNK. Exposure of cells to the JNK-specific inhibitor SP600125 attenuated the apoptotic effects of coronarin D. Taken together, this is the first study to report that coronarin D may effectively inhibit cell growth through apoptosis. We have provided evidence indicating that coronarin D induces cell death through the upregulation of JNK mitogen-activated protein kinases in human HCC cells.

Nimbolide induced apoptosis by activating ERK-mediated inhibition of c-IAP1 expression in human hepatocellular carcinoma cells.

Nimbolide is one of the major compounds from the leaves and flowers of the neem tree and exhibits antitumor properties on various cancer cells. However, no report has shown that nimbolide induces apoptosis in vitro and in vivo in human hepatocellular carcinoma cells. Our results indicated that it inhibited cell growth in Huh-7 and PLC/PRF/5 cells. We also found that nimbolide induced cell death through the induction of G2/M phase arrest and mitochondrial dysfunction, accompanied by the increased expression of cleaved caspase-7, caspase-9, caspase-3, caspase-PARP, and Bax and decreased expression of Mcl-1 and Bcl-2. A human apoptosis antibody array analysis demonstrated that inhibition of the apoptosis family proteins (XIAP, c-IAP1, and c-IAP2) was one of the major targets of nimbolide. Additionally, nimbolide sustained activation of ERK expression. Moreover, pretreatment with U0126 (MEK inhibitor) markedly abolished nimbolide-inhibited cell viability, induced cell apoptosis, ERK phosphorylation, cleaved caspase-9, caspase-3, cleaved-PARP activation, and increased c-IAP1 expression in Huh-7 cells. An in vivo study showed that nimbolide significantly reduced Huh-7 tumor growth and weight in a xenograft mouse model. This study indicated the antitumor potential of nimbolide in human hepatocellular carcinoma cells.

FUT2 genetic variants as predictors of tumor development with hepatocellular carcinoma.

Lewis antigens related to the ABO blood group are fucosylated oligosaccharides and are synthesized by specific glycosyltransferases (FUTs). FUTs are involved in various biological processes including cell adhesion and tumor progression. The fucosyltransferase-2 gene (FUT2) encodes alpha (1,2) fucosyltransferase, which is responsible for the addition of the alpha (1,2)-linkage of fucose to glycans. Aberrant fucosylation occurs frequently during the development and progression of hepatocellular carcinoma (HCC). However, the association of FUT2 polymorphisms with HCC development has not been studied. Therefore, we aimed to investigate the association of FUT2 polymorphisms with demographic, etiological, and clinical characteristics and with susceptibility to HCC. In this study, a total of 339 patients and 720 controls were recruited. The genotypes of FUT2 at four single-nucleotide polymorphisms (SNPs; rs281377, rs1047781, rs601338, and rs602662) were detected by real-time polymerase chain reaction from these samples. Compared with the wild-type genotype at SNP rs1047781, which is homozygous for nucleotides AA, at least one polymorphic T allele (AT or TT) displayed significant association with clinical stage (p = 0.048) and tumor size (p = 0.022). Our study strongly implicates the polymorphic locus rs1047781 of FUT2 as being associated with HCC development.

The role of liver transplantation or resection for patients with early hepatocellular carcinoma.

Liver resection (LR) and liver transplantation (LT) are curative treatments for early hepatocellular carcinoma (HCC), although their performance remains debated. We compared the survival of patients with HCC conforming to the Milan criteria (MC) after LT and LR and analyzed factors affecting clinical outcomes. Between January 2006 and January 2013, 65 and 184 patients received LT and LR for HCCs fulfilling the MC, respectively. Overall survival (OS) and disease-free survival (DFS) rates were compared between the two groups. To investigate effects of liver function and living donor liver transplantation (LDLT) on survival, two subgroup analyses were performed and associations with OS and DFS were examined. We found that OS rates were higher after LT than after LR since 3 years postoperatively. DFS rates were significantly better after LT than after LR. Performance of LR, vascular invasion, and tumor multiplicity were associated with poor DFS, and factors affecting OS included the presence of vascular invasions, liver cirrhosis, and tumor multiplicity. In conclusion, despite of the effects of tumor characteristics on clinical outcomes, LT, including LDLT, should be considered the treatment of choice for patients with HCCs who met the MC. The role of LR is to identify poor prognostic factors through pathological examination.

Management of spontaneously ruptured hepatocellular carcinoma and hemoperitoneum manifested as acute abdomen in the emergency room.

BACKGROUND: Spontaneously ruptured hepatocellular carcinoma (HCC) with hemoperitoneum has a poor prognosis, especially in cases of cirrhosis. Patients usually present to emergency rooms (ERs) with acute abdomen. The aim of the present study was to determine the factors affecting mortality and to compare the prognosis of conservative treatment, transcatheter arterial embolization (TAE), or hepatectomy in these situations. METHODS: Fifty-four patients with spontaneously ruptured HCC diagnosed between January 2004 and August 2010 were enrolled in this retrospective review of clinical data. Grouping by survival or mortality, univariate and multivariate analyses of factors affecting 30-day mortality, and long-term survival were conducted. The outcomes of the various treatments were analyzed. RESULTS: After primary fluid resuscitation in the ER, 6 of 54 patients underwent conservative treatment. Emergency hepatectomy was performed on 19 patients; TAE was used for 29 patients, 18 of whom received staged hepatectomy thereafter. Poor liver function, prolonged international normalized ratio (INR), and conservative treatment were associated with increased 30-day mortality. Logistic regression analysis of cumulative survival revealed that INR ≥ 1.4, multiple intrahepatic HCC, and conservative treatment were related to poorer long-term survival. The patients who received hepatectomy, either immediate or staged after TAE, had higher survival rates of 85.2 % at 30 days and 62.2 % at 1 year. CONCLUSIONS: The treatment of ruptured HCC should be tailored to the individual case. Prolonged survival is possible in patients with preserved liver function through curative liver resection. Emergency physicians, radiologists, and surgeons play essential roles in managing these patients.

Pneumatosis intestinalis and pneumoperitoneum on computed tomography: Beware of non-therapeutic laparotomy.

Pneumatosis intestinalis (PI) is defined as gas within the gastrointestinal wall and is associated with a variety of disorders. As a concurrent occurrence with pneumoperitoneum, it can easily to be mistaken for bowel ischemia with perforated peritonitis. In fact, air dissection or rupture from subserosal cysts may be the cause of intraperitoneal and intraluminal free air, with clinical symptoms such as abdominal pain and fullness occurring as a result. We hereby report a case of an 82-year-old male with a history of chronic obstructive pulmonary disease who was diagnosed with bowel ischemia and received emergency laparotomy because of the appearance of PI and pneumoperitoneum on abdominal computed tomography scan. However, no perforated hollow organ or necrotic bowel segment was found, only diffusely distributed massive intraperitoneal air and PI of gastrointestinal tract. The laparotomy seemed non-therapeutic for this patient. This is significant warning for clinicians to differentiate the associated conditions of PI, and to evaluate whether or not emergency surgery is necessary.