Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Nomogram incorporating prognostic immune-inflammatory-nutritional score for survival prediction in pancreatic cancer: a retrospective study.

BACKGROUND: Prognosis prediction for pancreatic cancer has always been difficult in clinical practice because of its high heterogeneity and mortality. The aim of the study was to assess the value of prognostic immune-inflammatory-nutritional (PIIN) score on overall survival (OS) in postoperative patients with pancreatic cancer and to develop a nomogram incorporating PIIN score. METHODS: This study retrospectively analyzed the clinic pathological data of 155 patients with pancreatic cancer who underwent radical surgery. PIIN score was calculated by measuring the fibrinogen (FIB), neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), albumin-bilirubin (ALBI) score, and prognostic nutritional index (PNI). Patients were divided into two groups by PIIN score levels over a threshold of 37.2. Univariate and multivariate analysis were performed using the Cox regression analysis model. The time-dependent receiver operating characteristic (ROC) curve was plotted to compare the prognostic values of the scoring systems. Finally, a nomogram based on PIIN score was constructed and validated. RESULTS: Multivariate regression analysis showed that PIIN score (hazard ratio (HR) = 2.171, 95% confidence interval (CI) = 1.207-3.906, P = 0.010), lymphovascular invasion (HR = 1.663, 95% CI = 1.081-2.557, P = 0.021), poor tumor grade (HR = 2.577, 95% CI = 1.668-3.982, P < 0.001), bad TNM stage (I vs. II: HR = 1.791, 95% CI = 1.103-2.906, P = 0.018; I vs. III: HR = 4.313, 95% CI = 2.365-7.865, P < 0.001) and without adjuvant chemotherapy (HR = 0.552, 95% CI = 0.368-0.829, P = 0.004) were independent risk factors for OS. The time-dependent ROC curves revealed that PIIN score was better than the other scoring systems in predicting survival prognosis. And last, the nomogram established from independent factors such as PIIN score had good predictive power for OS. The ROC curve results showed that the AUC values for 1, 3 and 5 years were 0.826, 0.798 and 0.846, respectively. The calibration plots showed the superior clinical applicability of the nomogram. CONCLUSION: The nomogram model based on PIIN score can be utilized as one of the prognosis stratifications as well as postoperative follow-up for the development of individual treatment for pancreatic cancer.

The selective sponging of miRNAs by OIP5-AS1 regulates metabolic reprogramming of pyruvate in adenoma-carcinoma transition of human colorectal cancer.

RNA interactomes and their diversified functionalities have recently benefited from critical methodological advances leading to a paradigm shift from a conventional conception on the regulatory roles of RNA in pathogenesis. However, the dynamic RNA interactomes in adenoma-carcinoma sequence of human CRC remain unexplored. The coexistence of adenoma, cancer, and normal tissues in colorectal cancer (CRC) patients provides an appropriate model to address this issue. Here, we adopted an RNA in situ conformation sequencing technology for mapping RNA-RNA interactions in CRC patients. We observed large-scale paired RNA counts and identified some unique RNA complexes including multiple partners RNAs, single partner RNAs, non-overlapping single partner RNAs. We focused on the antisense RNA OIP5-AS1 and found that OIP5-AS1 could sponge different miRNA to regulate the production of metabolites including pyruvate, alanine and lactic acid. Our findings provide novel perspectives in CRC pathogenesis and suggest metabolic reprogramming of pyruvate for the early diagnosis and treatment of CRC.

The value of the preoperative Naples prognostic score in predicting prognosis in gallbladder cancer surgery patients.

PURPOSE: The Naples prognostic score (NPS) is a comprehensive prognostic model that includes inflammatory and nutrition-related indicators and is increasingly used as a prognostic score for various malignant tumors. Given its predictive effect on prognosis in patients with gallbladder cancer, it is currently unclear. This study aimed to investigate the role of preoperative NPS in predicting prognosis in gallbladder cancer surgery patients. PATIENTS AND METHODS: A retrospective analysis was performed for 135 patients who underwent radical surgery for gallbladder cancer without preoperative treatment between March 2011 and January 2020. NPS was calculated by measuring the preoperative total cholesterol value, serum albumin value, neutrophil-lymphocyte ratio (NLR), and lymphocyte-monocyte ratio (LMR). They were then divided into 3 groups (groups 0, 1, and 2) based on NPS scores. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify independent prognostic factors. Plot time-dependent receiver operating characteristic (ROC) curves to compare the prognostic value of scoring systems. Finally, a nomogram model was developed with independent prognostic factors. RESULTS: Multivariate analysis showed that NPS was an independent risk factor affecting OS (HR = 3.417, p < 0.05). The time-dependent ROC curve results showed that NPS had a better predictive value on survival prognosis than other indicators. The nomogram constructed according to independent factors such as NPS has a good predictive ability for OS. CONCLUSION: As a simple and reliable tool, the NPS has important predictive value in the survival prognosis of gallbladder cancer patients. The nomogram model constructed by NPS will help determine prognosis and make individualized treatment decisions.

Machine learning-based nomogram for 30-day mortality prediction for patients with unresectable malignant biliary obstruction after ERCP with metal stent: a retrospective observational cohort study.

BACKGROUND: This study aimed to investigate the risk factors for 30-day mortality in patients with malignant biliary obstruction (MBO) after endoscopic retrograde cholangiopancreatography (ERCP) with endobiliary metal stent placement. Furthermore, we aimed to construct and visualize a prediction model based on LASSO-logistic regression. METHODS: Data were collected from 245 patients who underwent their first ERCP with endobiliary metal stent placement for unresectable MBO between June 1, 2013, and August 31, 2021. Univariable and multivariable logistic regression analyses were conducted to identify the risk factors for 30-day mortality. We subsequently developed a logistic regression model that incorporated multiple parameters identified by LASSO regression. The model was visualized and the nomogram was plotted. Risk stratification was performed based on nomogram-derived scores. RESULTS: The 30-day mortality rate was 10.7% (23/245 patients). Distant metastasis, total bilirubin, post-ERCP complications, and successful drainage were independent risk factors of 30-day mortality. The variables screened by LASSO regression, including distant metastasis, total bilirubin, post-ERCP complications, and successful drainage, were incorporated into the logistic model. The results were visualized through a nomogram based on the model. To assess the model's performance, discrimination was evaluated using the area-under-the-curve values obtained from receiver operating characteristic analyses with 10-fold cross-validation in the training group and validated in the testing group. The calibration curve showed the good predictive ability of the model. Decision curve analysis is used to evaluate the clinical application of nomogram. Finally, we performed risk stratification based on the risk calculated using the nomogram. Patients were assigned to the low-, moderate-, and high-risk groups based on their probability scores. The Kaplan-Meier survival curves for the different nomogram-based groups were significantly different (p < 0.001). CONCLUSIONS: We developed a nomogram using the LASSO-logistic regression model to forecast the 30-day mortality rate in patients who had undergone ERCP with endobiliary metal stent placement due to MBO. This nomogram can assist in identifying individuals at high-risk of 30-day mortality following ERCP.

Intensity evaluation of bottom backscattering between high-frequency underwater acoustic instruments and its experimental validation.

Running several high-frequency underwater acoustic instruments simultaneously on board a surface or underwater platform can cause interference between the instruments. By combining ray theory and the high-frequency bistatic scattering model for water bottoms, this work presents a practical method for evaluating the relative intensities of such interference signals corresponding to different instrument-to-instrument distances. To examine this method's effectiveness, a series of lake experiments were conducted. The relative intensity of the interference signal was first evaluated by using the proposed method, and then it was measured for comparison. The experimental results showed good agreement between the evaluated and the measured intensities.

Quantitative coupled-mode model for a metal-dielectric-metal waveguide with a side-coupled cavity.

The Fabry-Perot model is proposed to analyze the wavelength-selective transmission behaviors of the metal-dielectric-metal waveguide with a rectangular side-coupled cavity. The guided modes propagating in the waveguide and the cavity are extracted by the aperiodic Fourier modal method (a-FMM). The scattering coefficients that appeared in the model are calculated by the a-FMM and the normal-mode theory. The applications of such structure in the wavelength-selective filter and the refractive index sensor are also discussed. Our model is shown to accurately predict the fully vectorial data and thus can provide reliable and quantitative analysis of this kind of device.

Motion of a rigid prolate spheroid in a sound wave field.

The motions of a rigid and unconstrained prolate spheroid subjected to plane sound waves are computed using preliminary analytic derivation and numerical approach. The acoustically induced motions are found comprising torsional motion as well as translational motion in the case of acoustic oblique incidence and present great relevance to the sound wavelength, body geometry, and density. The relationship between the motions and acoustic particle velocity is obtained through finite element simulation in terms of sound wavelengths much longer than the overall size of the prolate spheroid. The results are relevant to the design of inertial acoustic particle velocity sensors based on prolate spheroids.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

A multicenter clinical AI system study for detection and diagnosis of focal liver lesions.

Early and accurate diagnosis of focal liver lesions is crucial for effective treatment and prognosis. We developed and validated a fully automated diagnostic system named Liver Artificial Intelligence Diagnosis System (LiAIDS) based on a diverse sample of 12,610 patients from 18 hospitals, both retrospectively and prospectively. In this study, LiAIDS achieved an F1-score of 0.940 for benign and 0.692 for malignant lesions, outperforming junior radiologists (benign: 0.830-0.890, malignant: 0.230-0.360) and being on par with senior radiologists (benign: 0.920-0.950, malignant: 0.550-0.650). Furthermore, with the assistance of LiAIDS, the diagnostic accuracy of all radiologists improved. For benign and malignant lesions, junior radiologists' F1-scores improved to 0.936-0.946 and 0.667-0.680 respectively, while seniors improved to 0.950-0.961 and 0.679-0.753. Additionally, in a triage study of 13,192 consecutive patients, LiAIDS automatically classified 76.46% of patients as low risk with a high NPV of 99.0%. The evidence suggests that LiAIDS can serve as a routine diagnostic tool and enhance the diagnostic capabilities of radiologists for liver lesions.

PCSK6 mediates Th1 differentiation and promotes chronic colitis progression and mucosal barrier injury via STAT1.

This study was aimed at investigating the expression and role of proprotein convertase subtilisin/kexin type (PCSK6) in inflammatory bowel disease (IBD). DSS induced mouse colitis and mucosal barrier injury, down-regulation of TJ proteins, improvement of permeability, and increases of the proportions of Th1 and M1 macrophages. After PCSK6 knockdown, the colitis in KO mice was improved relative to WT mice, the TJ protein levels increased, and the proportions of Th1 and M1 macrophages decreased. STAT1 inhibitor treatment also inhibited chronic colitis in mice. As revealed by in-vitro experiments, PCSK6 overexpression promoted the transformation of Th0 into Th1, while PCSK6 silencing suppressed the transfection. COPI assay results revealed the presence of targeted binding relation between PCSK6 and STAT1. PCSK6 binds to STAT1 to promote STAT1 phosphorylation and regulate Th1 cell differentiation, thus promoting the M1 polarization of macrophages and aggravating colitis progression. PCSK6 is promising as the new target for the treatment of colitis.

Efficacy and safety of TACE combined with lenvatinib and PD-1 inhibitors for unresectable recurrent HCC: A multicenter, retrospective study.

BACKGROUND: There is no consensus on the optimal regimen for unresectable recurrent hepatocellular carcinoma (HCC), so this retrospective study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib and PD-1 inhibitors (T-L-P) versus TACE combined with lenvatinib (T-L) or TACE alone. METHOD: Data were collected from 204 patients with unresectable recurrent HCC who received T-L-P, T-L, or TACE alone at three medical centers from January, 2019 to December, 2020 for analysis. The survival outcomes, tumor response, and adverse events were compared between three groups, and risk factors were further investigated. RESULTS: The median overall survival in the T-L-P, T-L, and TACE alone groups were not reached, 25.6, and 15.7 months, respectively (p < 0.001). The median progression-free survival in the T-L-P, T-L, and TACE alone groups were 24.1, 17.3, and 13.7 months, respectively (p < 0.001). The best objective response rate in the T-L-P, T-L, and TACE alone groups were 70.4%, 48.9%, and 42.5%, respectively. The best disease control rate in the T-L-P, T-L, and TACE alone groups were 100.0%, 97.8%, and 87.5%, respectively. There was no significant difference between the T-L-P and T-L groups for Grade 3/4 adverse events. CONCLUSION: T-L-P regimen was safe and superior to T-L or TACE alone in improving survival for unresectable recurrent HCC patients.

Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study.

Background: Anti-programmed cell death ligand 1/vascular endothelial growth factor inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). Objectives: We investigated the efficacy and safety of atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX) in advanced BTC and explore the potential biomarkers related to the response. Design: Multicenter, single-arm, retrospective study. Methods: Advanced BTC patients, who received a triple combination therapy at three medical centers between 18 March 2020 and 1 September 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. Results: In all, 30 patients were enrolled. The best ORR was 76.7% and the DCR was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) of patients suffered from ⩾grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), increased aspartate transaminase and alanine aminotransferase levels (50.0% and 43.3%, respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. Conclusion: The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a potential predictive biomarker for the efficacy of triple combination therapy.

Intensity-modulated radiotherapy combined with systemic atezolizumab and bevacizumab in treatment of hepatocellular carcinoma with extrahepatic portal vein tumor thrombus: A preliminary multicenter single-arm prospective study.

Background and aims: The efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients. Methods: This multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety. Results: Of 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths. Conclusions: IMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study. Clinical trial registration: http://www.chictr.org.cn, Identifier ChiCTR2200061793.

A necroptosis related prognostic model of pancreatic cancer based on single cell sequencing analysis and transcriptome analysis.

Background: As a tumor type with high mortality and poor therapeutic effect, the pathogenesis of pancreatic cancer is still unclear. It is necessary to explore the significance of necroptosis in pancreatic cancer. Methods: Pancreatic cancer transcriptome data were obtained from the TCGA database, ICGC database, and GSE85916 in the GEO database. The TCGA cohort was set as a training cohort, while the ICGC and GSE85916 cohort were set as the validation cohorts. Single-cell sequencing data of pancreatic cancer were obtained from GSE154778 in the GEO database. The genes most associated with necroptosis were identified by weighted co-expression network analysis and single-cell sequencing analysis. COX regression and Lasso regression were performed for these genes, and the prognostic model was established. By calculating risk scores, pancreatic cancer patients could be divided into NCPTS_high and NCPTS_low groups, and survival analysis, immune infiltration analysis, and mutation analysis between groups were performed. Cell experiments including gene knockdown, CCK-8 assay, clone formation assay, transwell assay and wound healing assay were conducted to explore the role of the key gene EPS8 in pancreatic cancer. PCR assays on clinical samples were further used to verify EPS8 expression. Results: We constructed the necroptosis-related signature in pancreatic cancer using single-cell sequencing analysis and transcriptome analysis. The calculation formula of risk score was as follows: NCPTS = POLR3GL * (-0.404) + COL17A1 * (0.092) + DDIT4 * (0.007) + PDE4C * (0.057) + CLDN1 * 0.075 + HMGA2 * 0.056 + CENPF * 0.198 +EPS8 * 0.219. Through this signature, pancreatic cancer patients with different cohorts can be divided into NCPTS_high and NCPTS_low group, and the NCPTS_high group has a significantly poorer prognosis. Moreover, there were significant differences in immune infiltration level and mutation level between the two groups. Cell assays showed that in CAPAN-1 and PANC-1 cell lines, EPS8 knockdown significantly reduced the viability, clonogenesis, migration and invasion of pancreatic cancer cells. Clinical PCR assay of EPS8 expression showed that EPS8 expression was significantly up-regulated in pancreatic cancer (*P<0.05). Conclusion: Our study can provide a reference for the diagnosis, treatment and prognosis assessment of pancreatic cancer.

A poor prognosis in human hepatocellular carcinoma is associated with low expression of DPP4.

This study aimed to explore the prognostic role of dipeptidyl peptidase 4 (DPP4) expression in hepatocellular carcinoma (HCC). DPP4 expression was measured in formalin-fixed paraffin-embedded specimens that were gathered from 327 HCC patients. Immunohistochemistry analyses were utilized to examine DPP4 expression characteristics and prognostic values (overall survival (OS) and time to recurrence) of DDP4 in HCC tissues. In addition, a patient-derived xenograft (PDX) model was used to assess the correlation between DPP4 expression and tumor growth in vivo. DPP4 was expressed in low levels in HCC tissues in contrast to paired peritumoral tissues (38 cases were down-regulated in a total of 59 cases, 64.4%. P=0.0202). DPP4 expression was significantly correlated with TNM stage (P=0.038), tumor number (P=0.035), and vascular invasion (P=0.024), and significantly reduced in patients who were in TNM stages II and III-V, with multiple tumors, and with microvascular invasion compared to patients with TNM stage I, single tumor, and no microvascular invasion. Notably, HCC tissues with low expression of DPP4 had poor OS (P=0.016) compared with HCC tissues with high expression of DPP4, and results from PDX model showed that tumor growth was significantly faster in HCC patients that lowly expressed DPP4 compared to those with highly expressed DPP4. Our findings suggested that low levels of DPP4 could impact the aggressiveness of HCC and contribute to a poor prognosis.

Emodin enhances the demethylation by 5-Aza-CdR of pancreatic cancer cell tumor-suppressor genes P16, RASSF1A and ppENK.

5-Aza-2'-deoxycytidine (5-Aza-CdR) is currently acknowledged as a demethylation drug, and causes a certain degree of demethylation in a variety of cancer cells, including pancreatic cancer cells. Emodin, a traditional Chinese medicine (TCM), is an effective monomer extracted from rhubarb and has been reported to exhibit antitumor activity in different manners in pancreatic cancer. In the present study, we examined whether emodin caused demethylation and increased the demethylation of three tumor-suppressor genes P16, RASSF1A and ppENK with a high degree of methylation in pancreatic cancer when combined with 5-Aza-CdR. Our research showed that emodin inhibited the growth of pancreatic cancer Panc-1 cells in a dose- and time-dependent manner. Dot-blot results showed that emodin combined with 5-Aza-CdR significantly suppressed the expression of genome 5mC in PANC-1 cells. In order to verify the effect of methylation, methylation-specific PCR (MSP) and bisulfite genomic sequencing PCR (BSP) combined with TA were selected for the cloning and sequencing. Results of MSP and BSP confirmed that emodin caused faint demethylation, and 5-Aza-CdR had a certain degree of demethylation. When emodin was combined with 5-Aza-CdR, the demethylation was more significant. At the same time, fluorescent quantitative PCR and western blot analysis results confirmed that when emodin was combined with 5-Aza-CdR, the expression levels of P16, RASSF1A and ppENK were increased more significantly compared to either treatment alone. In contrast, the expression levels of DNA methyltransferase 1 (DNMT1) and DNMT3a were more significantly reduced with the combination treatment than the control or either agent alone, further proving that emodin in combination with 5-Aza-CdR enhanced the demethylation effect of 5-Aza-CdR by reducing the expression of methyltransferases. In conclusion, the present study confirmed that emodin in combination with 5-Aza-CdR enhanced the demethylation by 5-Aza-CdR of tumor-suppressor genes p16, RASSF1A and ppENK by reducing the expression of methyltransferases DNMT1 and DNMT3a.

A poor prognosis in human hepatocellular carcinoma is associated with low expression of DPP4

This study aimed to explore the prognostic role of dipeptidyl peptidase 4 (DPP4) expression in hepatocellular carcinoma (HCC). DPP4 expression was measured in formalin-fixed paraffin-embedded specimens that were gathered from 327 HCC patients. Immunohistochemistry analyses were utilized to examine DPP4 expression characteristics and prognostic values (overall survival (OS) and time to recurrence) of DDP4 in HCC tissues. In addition, a patient-derived xenograft (PDX) model was used to assess the correlation between DPP4 expression and tumor growth in vivo. DPP4 was expressed in low levels in HCC tissues in contrast to paired peritumoral tissues (38 cases were down-regulated in a total of 59 cases, 64.4%. P=0.0202). DPP4 expression was significantly correlated with TNM stage (P=0.038), tumor number (P=0.035), and vascular invasion (P=0.024), and significantly reduced in patients who were in TNM stages II and III-V, with multiple tumors, and with microvascular invasion compared to patients with TNM stage I, single tumor, and no microvascular invasion. Notably, HCC tissues with low expression of DPP4 had poor OS (P=0.016) compared with HCC tissues with high expression of DPP4, and results from PDX model showed that tumor growth was significantly faster in HCC patients that lowly expressed DPP4 compared to those with highly expressed DPP4. Our findings suggested that low levels of DPP4 could impact the aggressiveness of HCC and contribute to a poor prognosis.