PPM1G promotes cell proliferation via modulating mutant GOF p53 protein expression in hepatocellular carcinoma.

The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p < 0.0001) and disease-free survival (p = 0.004) in HCC patients. Enhanced expression of PPM1G increases the cell proliferation rate, and knockdown of PPM1G led to a significant reduction in tumor volume in vivo. Further experiments illustrated that upregulated-PPM1G expression increased the protein expression of gain-of-function (GOF) mutant p53. Besides, the immunoprecipitation analysis revealed a direct interaction between PPM1G and GOF mutant p53. Collectively, PPM1G can be a powerful prognostic predictor and potential drug-target molecule.

CD45- erythroid progenitor cells promote lymph node metastasis in gastric cancer by inducing a hybrid epithelial/mesenchymal state in lymphatic endothelial cells.

BACKGROUND AND AIMS: Specific mechanisms of lymph node (LN) metastasis in early-stage gastric cancer (GC) have not been elucidated. The role of anemia, a vital clinical feature of GC, in LN metastasis is also unclear. Since the number of erythroid progenitor cells (EPCs) is increased in chronic anemia, we investigated its association with LN metastasis in GC. METHODS: Flow cytometry and immunofluorescence analyses were performed to sort and study EPCs from the circulation and tumors of patients with stage I-III GC. The effect of these EPCs on the activation of T and B cells and on the functions of lymphatic endothelial cells (LECs) was determined, and their ability to promote LN metastasis was evaluated using a footpad-popliteal LN metastasis model based on two human adenocarcinoma GC cell lines in nude mice. The prognostic value of EPCs was also analyzed. RESULTS: The proportion of CD45- EPCs was higher in the mononuclear cells in the circulation, tumors, and LNs of GC patients with LN metastasis (N+) than in those of GC patients without LN metastasis (N0). In N+ patients, CD45- EPCs were more abundant in metastatic LNs than in non-metastatic LNs. Lymphatic vessel endothelial hyaluronan receptor 1 immunoreactivity in tumors revealed that CD45- EPCs were positively associated with nodal stages and lymph vessel density. Furthermore, CD45- EPCs increased LEC proliferation and migration through their S100A8/A9 heterodimer-induced hybrid epithelial/mesenchymal (E/M) state; however, they did not influence the invasion and tubulogenesis of LECs or T and B cell proliferation. CD45- EPCs promoted LN metastasis in vivo; the S100A8/A9 heterodimer mimicked this phenomenon. Finally, CD45- EPCs predicted the overall and disease-free survival of stage I-III GC patients after radical resection. CONCLUSIONS: The CD45- EPCs accumulated in GC tissues and metastatic LNs and promoted LN metastasis via the S100A8/9-induced hybrid E/M state of LECs, which was the specific mechanism of LN metastasis in the early stages of GC.

Multifunctional hybrid hydrogel with transparency, conductivity, and self-adhesion for soft sensors using hemicellulose-decorated polypyrrole as a conductive matrix.

Polymers with high conductivity and cross-linking ability are ideal materials for the preparation of conductive hydrogels for application in wearable electronic devices. However, the fabrication of conductive polymer-incorporated hydrogels with good synergistic properties remains a great challenge due to the hydrophobicity and opacity of conjugated π conductive polymers. In this study, a multifunctional hybrid hydrogel was prepared by incorporating hemicellulose-decorated polypyrrole (H/PPY), polyvinyl alcohol (PVA), and tannic acid (TA) into a polyacrylamide (PAM) network. The addition of excess ammonium persulfate (APS) in the process of gelation not only initiated the polymerization of PAM but also resulted in the change of the hydrogel from opaque to transparent by continuously breaking and reducing the size of the PPY particles. The hybrid hydrogel exhibited high transparency and conductivity, good adhesion ability and mechanical performance, and high resistance strain sensitivity and could accurately monitor the strain signals of the index finger and elbow flexion and pulse beat during rest and exercise, which has promising potential for use in wearable or implantable smart sensor devices, electronic skins, and artificial intelligence applications.

ebv-circRPMS1 promotes the progression of EBV-associated gastric carcinoma via Sam68-dependent activation of METTL3.

Epstein-Barr virus (EBV) is a tumor virus that is associated with a variety of neoplasms, including EBV-associated gastric carcinoma (EBVaGC). Recently, EBV was reported to generate various circular RNAs (circRNAs). CircRNAs are important regulators of tumorigenesis by modulating the malignant behaviors of tumor cells. However, to date, the functions of ebv-circRNAs in EBVaGC remain poorly understood. In the present study, we observed high ebv-circRPMS1 expression in EBVaGC and showed that ebv-circRPMS1 promoted the proliferation, migration, and invasion and inhibited the apoptosis of EBVaGC cells. In addition, METTL3 was upregulated in GC cells overexpressing ebv-circRPMS1. Mechanistically, ebv-circRPMS1 bound to Sam68 to facilitate its physical interaction with the METTL3 promotor, resulting in the transactivation of METTL3 and cancer progression. In clinical EBVaGC samples, ebv-circRPMS1 was associated with distant metastasis and a poor prognosis. Based on these findings, ebv-circRPMS1 contributed to EBVaGC progression by recruiting Sam68 to the METTL3 promoter to induce METTL3 expression. ebv-circRPMS1, Sam68, and METTL3 might serve as therapeutic targets for EBVaGC.

EBV-Induced CXCL8 Upregulation Promotes Vasculogenic Mimicry in Gastric Carcinoma via NF-κB Signaling.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.

Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway.

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.

Prognostic Value of Serum Apolipoprotein B to Apolipoprotein A-I Ratio in Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization: A Propensity Score-Matched Analysis.

INTRODUCTION: The prognosis of advanced hepatocellular carcinoma (HCC) varies in patients receiving transcatheter arterial chemoembolization (TACE). In this study, we aimed to assess the prognostic value of serum apolipoprotein B (ApoB)/apolipoprotein A-I (ApoA-I) in this group of patients. METHODS: The serum lipid levels of HCC patients undergoing TACE were obtained from routine preoperative blood lipid examination. A propensity score-matched (PSM) analysis was used to eliminate the imbalance of baseline characteristics of the high and low ApoB/ApoA-I groups. Then, univariate and multivariate analysis were conducted to evaluate the prognostic value of ApoB/ApoA-I. RESULTS: In 455 HCC patients treated with TACE, ApoB/ApoA-I was positively correlated with AFP, T stage, distant metastasis, and TNM stage (p < 0.05). Patients with high ApoB/ApoA-I had a significantly shorter overall survival (OS) than those with low ApoB/ApoA-I (median OS, 21.7 vs. 39.6 months, p < 0.001). Multivariate analysis indicated that ApoB/ApoA-I was an independent prognostic index for OS (hazard ratio [HR] = 1.42, p = 0.008). After baseline characteristics were balanced, 288 patients were included in the PSM cohort. In this cohort, high ApoB/ApoA-I still predicted inferior OS in both univariate analysis (median OS, 27.6 vs. 39.3 months, p = 0.002) and multivariate analysis (HR = 1.58, p = 0.006). CONCLUSION: Serum ApoB/ApoA-I is a useful biomarker in predicting aggressive clinicopathological characteristics and poor prognosis in HCC patients treated with TACE.

Prognostic and immunological role of CD36: A pan-cancer analysis.

CD36 plays a critical role in lipid metabolism, which is closely associated with human immunity. However, the role of CD36 in cancer remains unclear. We performed a pan-cancer analysis to elucidate the potential role of CD36 in cancer by investigating its prognostic value and current predictors for the efficacy of immune checkpoint inhibitors (ICIs) in multiple cancer types. CD36 expression in cancer cell lines, tumor tissue, and their adjacent normal tissues displayed heterogeneity among different cancers. Immunohistochemistry was used to detect CD36 expression and confirmed the results. CD36 expression significantly affects prognosis in the six cancer types. High CD36 expression was marginally associated with poorer prognosis in four of them and improved prognosis in the remaining two types. CD36 expression was significantly correlated with the 6 immune infiltrates in most cancer types. In addition, CD36 gene expression was positively correlated with Stromal score, Immune score, and ESTIMATE score. A total of 47 immune checkpoint genes were collected and their relationship with CD36 expression was analyzed. CD36 expression was significantly associated with multiple stimulatory and inhibitory checkpoint molecules with a disease-specific pattern. As to the genes reported to positively relate to the efficacy of ICIs, CD36 expression was positively correlated with most of them but negatively associated with a small proportion of cancer type-specific patterns. Concerning the genes negatively related to the efficacy of ICIs, CD36 expression was positively correlated with NRP1 and TNFSF15 in multiple cancers. CD36 expression was negatively correlated with tumor neoantigen burden in most cancer types. However, CD36 expression was negatively correlated with tumor mutation burden in most cancer types. The correlation between CD36 expression and the four methyltransferases was also significant in multiple cancers, but also with a cancer type-specific pattern. In summary, the current study found CD36 expression and its prognostic value in multiple cancer types. In addition, the expression of CD36 was significantly associated with current predictors for the efficacy of ICIs. The practical application value of CD36 is disease specific.

Efficacy of Oxaliplatin/5-Fluorouracil/Capecitabine-Cetuximab Combination Therapy and Its Effects on K-Ras Mutations in Advanced Colorectal Cancer.

BACKGROUND The aim of this study was to perform an accurate exploration on the efficacy of oxaliplatin/5-fluorouracil/capecitabine-cetuximab combination therapy and its effects on K-Ras mutations in advanced colorectal cancer. MATERIAL AND METHODS Among 96 patients who suffered metastatic colorectal cancer without mutated K-Ras, 41 patients who were receiving treatment with oxaliplatin/5-fluorouracil/capecitabine and administered cetuximab as the initial treatment comprised the observation group; the remaining 55 patients receiving cetuximab as an alternative treatment comprised the control group. RESULTS The observation group experienced significantly higher objective response rates (ORRs), and disease control rates (DCRs), than the control group (P<0.05 for both). The median progression-free survival (PFS) rates of the observation group and the control groups were 11.2 months (95% confidence interval [CI]: 10.1-12.3 months) and 7.4 months (95% CI: 6.6-8.2 months). The median overall survival (OS) rates were 16.8 months (95% CI: 15.2-18.4 months) and 12.4 months (95% CI: 11.6-13.2 months), respectively. The observation group had significantly longer PFS and OS in comparison to the control group (P<0.05). The patients who underwent cetuximab treatment for ≥10 months had a slightly higher rate of K-Ras mutations than those treated with cetuximab for <10 months (9.1% versus 7.3%). CONCLUSIONS Oxaliplatin/5-fluorouracil/capecitabine plus cetuximab exhibited better efficacy as initial treatment than the alternative treatment; it was also highly safe. Unfortunately, some patients might develop K-Ras mutations after long duration of cetuximab treatment, suggesting that K-Ras mutations are correlated with tumor progression and depend on the duration or dose of cetuximab treatment.

Synthesis of hemicellulose hydrogels with tunable conductivity and swelling behavior through facile one-pot reaction.

The conductive hemicellulose hydrogels (CHHs) were achieved by incorporating carboxyl terminated aniline pentamer (CTAP) into the hydrophilic xylan-rich hemicellulose networks with epichlorohydrin. CHHs were obtained by facile one-pot reaction in water at ambient temperature. The successful synthesis of CTAP was confirmed by FT-IR, 1H NMR, and UV-vis spectra. All the hydrogels reached their equilibrium-swollen state within 12 h. The morphology and the thermal stability of CHHs were adjusted by the addition of CTAP. The conductivities of CHHs could also be tuned from 8.92 × 10-5 to 2.11 × 10-3 S/m by adding the blending amounts of the CTAP from 0 to 50% mass ratio while simultaneously altering the equilibrium swelling ratio from 28.1 to 15.8. CHHs showed homogeneous porous structure, tunable swelling behavior, controllable conductivity, and good thermal stability. These results highlight that CHHs are attractive candidates to be used in biomedical applications.

Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a major cause of cancer-related death, with a 5-year overall survival rate being below 5%. The main causes of poor prognosis in pancreatic cancer include easy metastasis, high recurrence rate, and robust drug resistance. Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer. However, due to drug resistance, the clinical effect is not satisfactory. ADAM28 is reported as a tumor promoter in some cancers, but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated. AIM: To identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer. METHODS: RNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer. SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine, and the mRNA levels of ADAM28 were evaluated by RT-PCR. The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells. The ADAM28 expression was also assessed in TCGA and GEO databases, and the results were confirmed in the collected tumor and adjacent normal tissues. The overall survival (OS) rate and relapse-free survival (RFS) rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter. Furthermore, the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden (TMB) and low TMB. CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells. The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis. The correlations of ADAM28 with GSTP1, ABCC1, GSTM4, and BCL2 were analyzed based on TCGA data on pancreatic cancer. RESULTS: RNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells, and gemcitabine treatment could induce the expression of ADAM28. The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells. Also, the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues. Notably, ADAM28 was highly expressed in the classical type than in the basal tumor type. Furthermore, the high expression of ADAM28 was associated with low OS and RFS rates. Interestingly, the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients, but not in the low TMB patients. Moreover, overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine, and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine. The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism, and ADAM28 was significantly positively correlated with GSTP1, ABCC1, GSTM4, and BCL2. CONCLUSION: This study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcitabine resistance. Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer.

The Prognostic Value of aspartate aminotransferase to lymphocyte ratio and systemic immune-inflammation index for Overall Survival of Hepatocellular Carcinoma Patients Treated with palliative Treatments.

Background: Lymphocytes were reported to play a significant part in host anticancer immune responses and influence tumour prognosis. Few studies have focused on the prognostic values of aspartate aminotransferase (AST) to lymphocyte ratio (ALRI), aspartate aminotransferase to platelet count ratio index (APRI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) treated with palliative treatments. Methods: Five hundred and ninety-eight HCC patients treated with palliative therapies were retrospectively analysed. We randomly assigned patients into the training cohort (429 patients) and the validation cohort I (169 patients). Receiver operating characteristic (ROC) curves were used to identify the best cut-off values for the ALRI, APRI and SII in the training cohort and the values were further validated in the validation cohort I. Correlations between ALRI and other clinicopathological factors were also analysed. A prognostic nomogram including ALRI was established. We validated the prognostic value of the ALRI, SII and APRI with two independent cohorts, the validation cohort II of 82 HCC patients treated with TACE and the validation cohort III of 150 HCC patients treated with curative resection. In the training cohort and all the validation cohorts, univariate analyses by the method of Kaplan-Meier and multivariate analysis by Cox proportional hazards regression model were carried out to identify the independent prognostic factors. Results: The threshold values of ALRI, APRI and SII were 86.3, 1.37 and 376.4 respectively identified by ROC curve analysis in the training cohort. Correlation analysis showed that ALRI>86.3 was greatly associated with higher rates of Child-Pugh B&C, portal vein tumor thrombosis (PVTT) and ascites (P < 0.05). Correspondingly, ALRI level of HCC patients with Child-Pugh B&C, PVTT and ascites was evidently higher than that of HCC patients with Child-Pugh A, without PVTT and without ascites (P < 0.001). In the training cohort and the validation cohort I, II, III, the OS of patients with ALRI >86.3 was obviously shorter than patients with ALRI ≤86.3 (P <0.001). We identified ALRI as an independent prognostic factor by univariate and multivariate analyses both in training Cohort (HR=1.481, P=0.004), validation cohort I (HR=1.511, P=0.032), validation cohort II (HR=3.166, P=0.005) and validation cohort III (HR=3.921, P=0.010). The SII was identified as an independent prognostic factor in training cohort (HR=1.356, P=0.020) and the validation cohort II (HR=2.678, P=0.002). The prognostic nomogram including ALRI was the best in predicting 3-month, 6-month, 1-year, 2-year survival And OS among TNM, ALRI, ALRI-TNM and nomogram. Conclusions: The ALRI was a novel independent prognostic index for the HCC patients treated with palliative treatments.

Structure and distribution changes of Eucalyptus hemicelluloses during hydrothermal and alkaline pretreatments.

Eucalyptus wood was pretreated with an integrated process based on hydrothermal and alkaline pretreatments. The structural changes of hemicelluloses during the pretreatments and the components of the hydrolysates were comprehensively characterized. Sugar and spectral analyses indicated that the hemicelluloses remained in the residues obtained at hydrothermal pretreatment under low temperatures were mainly composed of a (1 → 4)-ß-D-Xylp backbone with 4-O-methyl-α-D-glucuronic acids attached at O-2 of the xylose together with various monosaccharides of rhamnose, arabinose, galactose, glucose, and mannose. The pretreatments resulted in serious degradation of hemicelluloses at high pretreatment temperatures. The distribution changes of the hemicelluloses in the cell walls during the integrated pretreatments were detected by Confocal Raman Microscopy, which revealed that the dissolution of hemicelluloses in different morphological regions was inhomogeneous, and the a large portion of hemicelluloses were removed from the secondary cell wall regions during the pretreatments.

The Predictive Value of Albumin-to-Alkaline Phosphatase Ratio for Overall Survival of Hepatocellular Carcinoma Patients Treated with Trans-Catheter Arterial Chemoembolization Therapy.

Background: We have previously reported the prognostic value of the albumin-to-alkaline phosphatase ratio (AAPR) for advanced hepatocellular carcinoma (HCC) patients who are not receiving any standard anticancer therapy. However, the prognostic value of the AAPR for HCC patients treated with trans-catheter arterial chemoembolization therapy (TACE) was not investigated. Methods: We retrospectively analysed 372 HCC patients treated with TACE (the training cohort) and applied receiver operating characteristic curves (ROC curves) to identify the best cut-off value for the AAPR in this cohort. Then, univariate analyses by the Kaplan-Meier method and multivariate analysis by a Cox proportional hazards regression model were conducted. Both comparisons of the ROC curves and the likelihood ratio test (LRT) were employed to evaluate the abilities of different factors in predicting the survival of patients in this cohort. Finally, the prognostic value of the AAPR was validated in two cohorts: one included 202 HCC patients treated with supportive care (validation cohort I), and the other included 82 HCC patients treated with TACE (validation cohort II). Results: We identified 0.439 as the best cut-off value of the AAPR by ROC curve analysis. An AAPR > 0.439 was significantly correlated with a lower frequency of Child-Pugh grade B, portal vein tumour thrombus (PVTT), T3-4 and lymph node metastasis (P < 0.05). The median overall survival (OS) of the patients with an AAPR > 0.439 was significantly longer than that of those with an AAPR ≤ 0.439 (58.4 m vs 17.8 m, respectively, P < 0.001). The AAPR was identified as an independent prognostic factor after univariate and multivariate analyses (HR = 0.636, P = 0.003). The independent prognostic value of the AAPR was also confirmed in validation cohorts I and II. Additionally, we substituted the AAPR for the Child-Pugh grade in the CLIP system and integrated the AAPR into the TNM system. We found that the area under the curve (AUC) of the AAPR-CLIP system was significantly larger than that of the CLIP and the TNM when predicting 3-month, 6-month, 1-year and 2-year survival (P < 0.05). There was no significant difference between the AUCs for the AAPR-CLIP and the AAPR-TNM. The LRT suggested that both AAPR-CLIP and AAPR-TNM had significantly larger χ2 values and smaller AIC values than that of their corresponding primary system (P < 0.05). Conclusions: The AAPR was an independent prognostic index for the HCC patients treated with TACE. Both AAPR-CLIP and AAPR-TNM outperformed their corresponding primary system in predicting OS in the current study.

Modified CLIP score with the albumin-bilirubin grade retains prognostic value in HBV-related hepatocellular carcinoma patients treated with trans-catheter arterial chemoembolization therapy.

Background: The Cancer of the Liver Italian Program (CLIP) score is commonly used for prognosis prediction of hepatocellular carcinoma (HCC). The CLIP includes the Child-Pugh grade, which is relatively subjective, for hepatic encephalopathy assessment. A newly developed scoring system called albumin-bilirubin grade (ALBI grade), consists of albumin and bilirubin to assess liver function reserve objectively. Here, we substituted the ALBI grade for the Child-Pugh grade to establish the ALBI-CLIP scoring system and validated its prognostic value in hepatitis B virus (HBV)-related HCC patients treated with trans-catheter arterial chemoembolization (TACE) therapy. Methods: We retrospectively analyzed HBV-related HCC patients who received TACE therapy. Baseline characteristics were collected and evaluated to classify patients according to ALBI-CLIP, CLIP and TNM systems. Univariate analyses using the Kaplan-Meier method and the log-rank test, as well as multivariate analysis using the Cox proportional hazards regression model, were conducted to detect independent prognostic factors for overall survival. Receiver operating characteristic (ROC) curves and a likelihood ratio test (LRT) were both utilized to compare the values of ALBI-CLIP, CLIP and TNM staging systems in predicting survival. Results: With a total of 389 patients included in the current study, 301 (77.4%) and 88 (22.6%) were classified as Child-Pugh grade A and B, respectively. However, 152 (39.1%), 227 (58.4%) and 10 (2.5%) patients were correspondingly classified into ALBI grade 1, 2 and 3. The areas under the curves of ALBI-CLIP, CLIP and TNM systems were 0.804, 0.778 and 0.734, respectively, for predicting 3-month survival; 0.796, 0.778 and 0.733, respectively, for 6-month survival; 0.697, 0.687 and 0.644, respectively, for 1-year survival; and 0.618, 0.612 and 0.569, respectively, for 2-year survival. The LRT indicated that the ALBI-CLIP and the CLIP had similar values of χ2 and Akaike information criterion (AIC) while the TNM system had the smallest χ2 value (χ2 = 12.1, 11.9, 10.5; AIC = 2620.2, 2620.5, 2621.1 for ALBI-CLIP, CLIP and TNM, respectively). Conclusions: In conclusion, our present study suggested that the ALBI-CLIP scoring system retained the prognostic value of the CLIP in HBV-related HCC treated with TACE therapy.

NMR and ESI-MS spectrometry characterization of autohydrolysis xylo-oligosaccharides separated by gel permeation chromatography.

Chemical structure determination of xylo-oligosaccharides obtained by common production pathway is difficult, since the products mixture must be separated and purified into individual chemicals. In the present study, gel permeation chromatography was used to efficiently separate and purify the xylo-oligosaccharides produced by biomass autohydrolysis for the chemical structural evaluation. Results showed that the separation obtained high purity (85.2-94.5%) xylo-oligosaccharides with individual component. The separated samples were further characterized by ESI-MS and NMR, which revealed that the samples were non-substituted xylobiose and acetylated xylo-oligosaccharides with degree of polymerization from 3 to 6. The combined 1H, 13C and two-dimensional proton-detected heteronuclear single quantum (2D HSQC) NMR spectra results suggested that acetyl groups only attached to the internal units of xylo-oligosaccharides after autohydrolysis, and no acetylated non-reducing ends were detected.

Comparison of five staging systems in predicting the survival rate of patients with hepatocellular carcinoma undergoing trans-arterial chemoembolization therapy.

The majority of patients with unresectable hepatocellular carcinoma (HCC) undergo trans-arterial chemoembolization (TACE). However, the prognosis of HCC remains poor. In the present study, five staging systems were compared to predict the survival rate of patients with HCC undergoing TACE treatment. A total of 220 patients with HCC were examined according to the model to estimate survival for hepatocellular carcinoma (MESH), hepatoma arterial embolization prognostic score (HAP), modified HAP (mHAP), performance status combined Japan Integrated Staging system (PSJIS) and tumor-node-metastasis (TNM) staging systems. The endpoints of the study were 3-month survival, 6-month survival, 1-year survival and overall survival (OS) rates. Receiver operating characteristic curve analysis indicated that the area under the curve of MESH, HAP, mHAP, PSJIS and TNM was 0.858, 0.728, 0.690, 0.688 and 0.699, respectively, in predicting 3-month survival rates; 0.822, 0.747, 0.720, 0.722 and 0.715, respectively, in predicting 6-month survival rates and 0.725, 0.664, 0.672, 0.645 and 0.654, respectively, in predicting 1-year survival rates. Discriminatory ability, homogeneity, monotonicity and prognostic stratification ability was evaluated using a likelihood ratio test and Akaike information criterion values among the five staging systems, and revealed that the MESH system was the optimal prognostic staging system for HCC. In conclusion, the results of the present study suggest that the MESH system is the most accurate prognostic staging system of 3-month survival, 6-month survival, 1-year survival and OS rates among the five systems analyzed in patients with HCC who have received TACE treatment.

Albumin-to-Alkaline Phosphatase Ratio as an Independent Prognostic Factor for Overall Survival of Advanced Hepatocellular Carcinoma Patients without Receiving Standard Anti-Cancer Therapies.

Background Albumin-to-Alkaline Phosphatase Ratio (ALB/ALP ratio, AAPR), a newly developed index of liver function, has been rarely discussed about its prognostic value in malignancies. The current study attempted to evaluate the prognostic prediction of AAPR in advanced HCC. Methods 237 advanced HCC patients who refused any standard anti-cancer therapies were retrospectively analyzed. The threshold value of AAPR was determined by receiver operating characteristic (ROC) curve. Univariate analyses using Kaplan-Meier method and log-rank test, and multivariate analysis using Cox proportional hazards regression model were conducted. Comparisons of ROC curves and likelihood ratio test (LRT) were utilized to compare the value of different factors in predicting survival. Results ROC curve analysis confirmed 0.38 as the optimal cutoff value of AAPR in evaluating overall survival (OS). Patients with an AAPR > 0.38 exhibited significantly lower frequencies of ascites, portal vein tumor thrombus, Child-Pugh grade B & C, and KPS < 70 (all P < 0.05). These patients also displayed a longer median survival time than those with an AAPR ≤ 0.38 (5.8 m vs 2.4 m, P < 0.01). Univariate and multivariate analyses identified AAPR as an independent prognostic indicator (HR = 0.592, P = 0.007). Furthermore, we integrated AAPR with TNM system and found that area under curve of AAPR-TNM system was significantly larger than that of TNM system when predicting 3-month survival (0.670 vs 0.611, P < 0.01). Moreover, LRT indicated that AAPR-TNM system had a significantly larger χ2 (26.4 vs 16.4, P < 0.01) and a significantly smaller Akaike information criterion value (1936 vs 1948, P < 0.01) comparing with TNM system. Conclusions Our study implied that AAPR was a potentially valuable prognostic index for advanced HCC patients without receiving any standard anti-cancer therapies. AAPR-TNM system preceded TNM system in predicting overall survival in this study.

Combination of ULK1 and LC3B improve prognosis assessment of hepatocellular carcinoma.

BACKGROUND: Autophagy involves in both prevention and promotion in cancer, and its role probably changed during tumor development. Defined the dynamic function of autophagy in cancer may advance precision diagnostics, treatment, and guide drug design. Autophagy related protein ULK1 is key regulator of autophagy, and its role in hepatocellular carcinoma (HCC) was still unclear. This study aims to investigate ULK1's capacity along with other autophagic markers in predicting prognosis of HCC and explore position of these biomarkers in dynamic function of autophagy during HCC progression. METHODS: The expression of ULK1 and other autophagic marker (LC3B) were test by Tissue microarray-based immunohistochemistry in 156 operable HCC patients. Survival analysis and correlation analysis were used to analysis influence of ULK1 and combined biomarker on clinical characteristics and prognosis. RESULTS: The expression level of ULK1 was not related to all clinicopathological features, however, high expression of the ULK1 as well as LC3B overexpression suggested large tumor size (P=0.035), high levels of serum AFP (P=0.049), more frequency of node metastasis (P=0.015), later TNM stage (P=0.009). Survival analysis showed that ULK1 expression were negatively correlated with PFS rather than OS in HCC patients (P=0.021), while LC3B were suggested to be negatively related with patients' PFS, However, Simultaneous high expression of ULK1 and LC3B had a poorer 5-year overall survival (OS) rate (P=0.002) and shorter 5-year progression free survival (PFS)(P=0.003), Further multivariate analysis revealed that the two combined biomarkers were independent factors to predict the prognosis of OS and PFS in all patients, while ULK1 alone or LC3B alone were only an independent predict factor for OS or PFS respectively. CONCLUSION: ULK1 were demonstrated to be an important prognostic factor for HCC patient, and it combined LC3B would improve prognosis assessment of the patients. Combined autophagic biomarkers would better represent dynamic stage of autophagy and It might provide a potential therapeutic way that how to interfere autophagy in HCC.