d-Penicillamine@Ag/Cu Nanocluster-Based Fluorescent Nanoneuron for Logic Screening Phosphonate-Type Organophosphate Pesticides and Steganographically Encrypting Information.

Organophosphate pesticides are used in agriculture due to their high effectiveness and low persistence in eradicating insects and pests. However, conventional detection methods encounter the limitation of undesired detection specificity. Thus, screening phosphonate-type organophosphate pesticides (OOPs) from their analogues, phosphorothioate organophosphate pesticides (SOPs), remains a challenge. Here, we reported a d-penicillamine@Ag/Cu nanocluster (DPA@Ag/Cu NCs)-based fluorescence assay to screen OOPs from 21 kinds of organophosphate pesticides, which can be used for logic sensing and information encryption. Acetylthiocholine chloride was enzymatically split by acetylcholinesterase (AChE) to produce thiocholine, which reduced the fluorescence of DPA@Ag/Cu NCs due to the transmission of electrons from DPA@Ag/Cu NCs donor to the thiol group acceptor. Impressively, OOPs acted as an AChE inhibitor and retained the high fluorescence of DPA@Ag/Cu NCs due to the stronger positive electricity of the phosphorus atom. Conversely, SOPs possessed weak toxicity to AChE, which led to low fluorescence intensity. By setting 21 kinds of organophosphate pesticides as the inputs and the fluorescence of the resulting products as the outputs, DPA@Ag/Cu NCs could serve as a fluorescent nanoneuron to construct Boolean logic tree and complex logic circuit for molecular computing. As a proof of concept, by converting the selective response patterns of DPA@Ag/Cu NCs into binary strings, molecular crypto-steganography for encoding, storing, and concealing information was successfully achieved. This study is expected to advance the progress and practical application of nanoclusters in the area of logic detection and information security while also enhancing the relationship between molecular sensors and the world of information.

Photocontrollable DNA Walker-Based Molecular Circuit for the Tunable Detection of MicroRNA-21 Using Metal-Organic Frameworks as Label-Free Fluorescence Tags.

Tunable detection of microRNA is crucial to meet the desired demand for sample species with varying concentrations in clinical settings. Herein, we present a DNA walker-based molecular circuit for the detection of miRNA-21 (miR-21) with tunable dynamic ranges and sensitivity levels ranging from fM to pM. The phosphate-activated fluorescence of UiO-66-NH2 metal-organic framework nanoparticles was used as label-free fluorescence tags due to their competitive coordination effect with the Zr atom, which significantly inhibited the ligand-to-metal charge transfer. To achieve a tunable detection performance for miR-21, the ultraviolet sensitive o-nitrobenzyl was induced as a photocleavable linker, which was inserted at various sites between the loop and the stem of the hairpin probe to regulate the DNA strand displacement reaction. The dynamic range can be precisely regulated from 700- to 67,000-fold with tunable limits of detection ranging from 2.5 fM to 36.7 pM. Impressively, a Boolean logic tree and complex molecular circuit were constructed for logic computation and cancer diagnosis in clinical blood samples. This intelligent biosensing method presents a powerful solution for converting complex biosensing systems into actionable healthcare decisions and will facilitate early disease diagnosis.

Transcriptome analysis reveals mechanism of early ripening in Kyoho grape with hydrogen peroxide treatment.

BACKGROUND: In a previous study, the early ripening of Kyoho grape following H2O2 treatment was explored at the physiological level, but the mechanism by which H2O2 promotes ripening at the molecular level is unclear. To reveal the molecular mechanism, RNA-sequencing analysis was conducted on the different developmental stages of Kyoho berry treated with H2O2. RESULTS: In the comparison of treatment and control groups, 406 genes were up-regulated and 683 were down-regulated. Time course sequencing (TCseq) analysis showed that the expression patterns of most of the genes were similar between the treatment and control, except for some genes related to chlorophyll binding and photosynthesis. Differential expression analysis and the weighted gene co-expression network were used to screen significantly differentially expressed genes and hub genes associated with oxidative stress (heat shock protein, HSP), cell wall deacetylation (GDSL esterase/lipase, GDSL), cell wall degradation (xyloglucan endotransglucosylase/ hydrolase, XTH), and photosynthesis (chlorophyll a-b binding protein, CAB1). Gene expression was verified with RT-qPCR, and the results were largely consistent with those of RNA sequencing. CONCLUSIONS: The RNA-sequencing analysis indicated that H2O2 treatment promoted the early ripening of Kyoho berry by affecting the expression levels of HSP, GDSL, XTH, and CAB1 and- photosynthesis- pathways.

Transcriptome profiling of 'Kyoho' grape at different stages of berry development following 5-azaC treatment.

BACKGROUND: 5-Azacytidine (5-azaC) promotes the development of 'Kyoho' grape berry but the associated changes in gene expression have not been reported. In this study, we performed transcriptome analysis of grape berry at five developmental stages after 5-azaC treatment to elucidate the gene expression networks controlling berry ripening. RESULTS: The expression patterns of most genes across the time series were similar between the 5-azaC treatment and control groups. The number of differentially expressed genes (DEGs) at a given developmental stage ranged from 9 (A3_C3) to 690 (A5_C5). The results indicated that 5-azaC treatment had not very great influences on the expressions of most genes. Functional annotation of the DEGs revealed that they were mainly related to fruit softening, photosynthesis, protein phosphorylation, and heat stress. Eight modules showed high correlation with specific developmental stages and hub genes such as PEROXIDASE 4, CAFFEIC ACID 3-O-METHYLTRANSFERASE 1, and HISTONE-LYSINE N-METHYLTRANSFERASE EZA1 were identified by weighted gene correlation network analysis. CONCLUSIONS: 5-AzaC treatment alters the transcriptional profile of grape berry at different stages of development, which may involve changes in DNA methylation.

A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma.

BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

Tropomodulin 3 modulates EGFR-PI3K-AKT signaling to drive hepatocellular carcinoma metastasis.

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.

Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma.

BACKGROUND & AIMS: In recent years, circular RNAs (circRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of circRNAs to hepatocellular carcinoma (HCC) remain largely unknown. METHODS: cSMARCA5 (a circRNA derived from exons 15 and 16 of the SMARCA5 gene, hsa_circ_0001445) was identified by RNA-sequencing and validated by quantitative reverse transcription PCR. The role of cSMARCA5 in HCC progression was assessed both in vitro and in vivo. circRNAs in vivo precipitation, luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridization were conducted to evaluate the interaction between cSMARCA5 and miR-17-3p/miR-181b-5p. RESULTS: The expression of cSMARCA5 was lower in HCC tissues, because of the regulation of DExH-Box Helicase 9, an abundant nuclear RNA helicase. The downregulation of cSMARCA5 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival and recurrence-free survival in patients with HCC after hepatectomy. Our in vivo and in vitro data indicated that cSMARCA5 inhibits the proliferation and migration of HCC cells. Mechanistically, we found that cSMARCA5 could promote the expression of TIMP3, a well-known tumor suppressor, by sponging miR-17-3p and miR-181b-5p. CONCLUSION: These results reveal an important role of cSMARCA5 in the growth and metastasis of HCC and provide a fresh perspective on circRNAs in HCC progression. LAY SUMMARY: Herein, we studied the role of cSMARCA5, a circular RNA, in hepatocellular carcinoma. Our in vitro and in vivo data showed that cSMARCA5 inhibits the growth and migration of hepatocellular carcinoma cells, making it a potential therapeutic target.

Antiviral Therapy Reduces Hepatocellular Carcinoma Recurrence in Patients With Low HBV-DNA Levels: A Randomized Controlled Trial.

BACKGROUND: Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. METHODS: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409-0.884; P = 0.010] and 0.509 (95% CI, 0.333-0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio [HR] = 0.316, 95% CI 0.157-0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493-1.240; P = 0.296). CONCLUSIONS: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection.

Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1.

UNLABELLED: Tumor cells with stemness (stem-cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but involvement of long noncoding RNAs (lncRNAs) remains largely unclear. Genome-wide analyses were applied to identify tumor-associated lncRNA-DANCR. DANCR expression level and prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down- and overexpression) was done to explore the role of DANCR in tumorigenesis and colonization, and tumor-bearing mice were used to determine therapeutic effects. We found that lncRNA-DANCR is overexpressed in stem-like HCC cells, and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra-/extrahepatic tumor colonization. Conversely, DANCR knockdown attenuated the stem-cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage, and improved mouse survival. Additionally, we found that the role of DANCR relied largely on an association with, and regulation of, CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, messenger RNAs, and microRNAs. CONCLUSIONS: These studies reveal a significance and mechanism of DANCR action in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HCC.

Aldolase B inhibits metastasis through Ten-Eleven Translocation 1 and serves as a prognostic biomarker in hepatocellular carcinoma.

BACKGROUND: Downregulation of Aldolase B (ALDOB) has been reported in hepatocellular carcinoma. However, its clinical significance and its role in pathogenesis of HCC remain largely unknown. METHODS: We analyzed the expression of ALDOB and its clinical features in a large cohort of 313 HCC patients using tissue microarray and immunohistochemistry. Moreover, the function of stably overexpressed ALDOB in HCC cells was explored in vitro and in vivo. Gene expression microarray analysis was performed on ALDOB-overexpressing SMMC7721 cells to elucidate its mechanism of action. RESULTS: ALDOB downregulation in HCC was significantly correlated with aggressive characteristics including absence of encapsulation, increased tumor size (>5 cm) and early recurrence. ALDOB downregulation was indicative of a shorter recurrence-free survival (RFS) and overall survival (OS) for all HCC patients and early-stage HCC patients (BCLC 0-A and TNM I stage patients). Multiple analyses revealed that ALDOB downregulation was an independent risk factor of RFS and OS. Stable expression of ALDOB in HCC cell lines reduced cell migration in vitro and inhibited lung metastasis, intrahepatic metastasis, and reduced circulating tumor cells in vivo. Mechanistically, we found that cells stably expressing ALDOB show elevated Ten-Eleven Translocation 1 (TET1) expression. Moreover, ALDOB expressing cells have higher levels of methylglyoxal than do control cells, which can upregulate TET1 expression. CONCLUSION: The downregulation of ALDOB could indicate a poor prognosis for HCC patients, and therefore, ALDOB might be considered a prognostic biomarker for HCC, especially at the early stage. In addition, ALDOB inhibits the invasive features of cell lines partly through TET1 expression.

Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial.

OBJECTIVE: A randomized controlled trial was conducted to find out whether antiviral therapy in patients with hepatitis B-related hepatocellular carcinoma (HCC) improves long-term survival after hepatic resection. BACKGROUND: Despite advances in surgery and in multidisciplinary treatment, there is still no effective adjuvant treatment to prevent HCC recurrence after R0 resection for HCC. Whether antiviral therapy is useful in reducing postoperative HCC recurrence is unclear. METHODS: Between May 2007 and April 2008, patients who received R0 hepatic resection for HBV-related HCC were randomly assigned to receive no treatment (the control group, n = 100) or antiviral therapy (adefovir 10 mg/d, the antiviral group, n = 100). RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.0%, 50.3%, 46.1% and 84.0%, 37.9%, 27.1%, respectively. The corresponding overall survival rates for the 2 groups were 96.0%, 77.6%, 63.1% and 94.0%, 67.4%, 41.5%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.026, P = 0.001). After adjusting for the confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.651 [95% confidence interval (CI): 0.451-0.938; P = 0.021] and 0.420 (95% CI: 0.271-0.651; P < 0.001). Antiviral therapy was an independent protective factor of late tumor recurrence (HR = 0.348, 95% CI: 0.177-0.687; P = 0.002) but not of early tumor recurrence [hazard ratio (HR) = 0.949, 95% CI: 0.617-1.459; P = 0.810]. CONCLUSIONS: In patients with hepatitis B-related HCC, adefovir antiviral therapy reduced late HCC recurrence and significantly improved overall survival after R0 hepatic resection.

Ligand-directed stearic acid grafted chitosan micelles to increase therapeutic efficacy in hepatic cancer.

Targeted delivery system would be an interesting platform to enhance the therapeutic effect and to reduce the side effects of anticancer drugs. In this study, we have developed lactobionic acid (LA)-modified chitosan-stearic acid (CS-SA) (CSS-LA) to deliver doxorubicin (DOX) to hepatic cancer cells. The average particle size of CSS-LA/DOX was ∼100 nm with a high entrapment efficiency of >95%. Drug release studies showed that DOX release from pH-sensitive micelles is significantly faster at pH 5.0 than at pH 7.4. The LA conjugated micelles showed enhanced cellular uptake in HepG2 and BEL-7402 liver cancer cells than free drug and unconjugated micelles. Consistently, CSS-LA/DOX showed enhanced cell cytotoxicity in these two cell lines. Annexin-V/FITC and PI based apoptosis assay showed that the number of living cells greatly reduced in this group with marked presence of necrotic and apoptotic cells. LA-conjugated carrier induced typical chromatic condensation of cells; membrane blebbing and apoptotic bodies began to appear. In vivo, CSS-LA/DOX showed an excellent tumor regression profile with no toxic side effects. The active targeting moiety, long circulation profile, and EPR effect contributed to its superior anticancer effect in HepG2 based tumor. Our results showed that polymeric micelles conjugated with LA increased the therapeutic availability of DOX in the liver cancer cell based solid tumor without any toxic side effects. The active targeting ligand conjugated nanoparticulate system could be a promising therapeutic strategy in the treatment of hepatic cancers.

Surgical treatment of hepatocellular carcinoma with inferior vena cava tumor thrombus: a new classification for surgical guidance.

BACKGROUND: Hepatic resection is the main treatment modality for hepatic tumors. Advances in diagnostic technique, preoperative preparation, surgical technique, and postoperative management increased the success rate. The present study aimed to evaluate hepatectomy and resection of inferior vena cava tumor thrombus (IVCTT) in patients with hepatocellular carcinoma, and the relationship between IVCTT classification and selection of surgical technique. METHODS: We retrospectively reviewed 13 patients with hepatocellular carcinoma who had undergone hepatectomy with IVCTT resection between May 1997 and August 2009. Age, gender, diagnosis, findings of physical examination, results of preoperative laboratory investigations, radiological examination, criteria for resection, postoperative pathological results, incisions, operative technique, intraoperative transfusion, drains, and intraoperative and postoperative complications were evaluated for all patients. RESULTS: Type I IVCTT (10 patients) was posterior to the liver and below the diaphragm; type II IVCTT (2 patients) was above the diaphragm but still outside the atrium; and type III IVCTT (1 patient) was above the diaphragm and in the right atrium. Type I was treated by radical hepatectomy and removal of IVCTT with total hepatic vascular exclusion. Type II was treated by radical hepatectomy and removal of IVCTT by incision of the diaphragm. Type III was treated by hepatectomy and resection of the thrombus from the right atrium under cardiopulmonary bypass. There were no surgical complications and one patient has been survived for 4 years with cancer-free status. The median survival time was 18.2 months, and the 1- and 2-year survival rates were 53.8% and 15.4%, respectively. CONCLUSION: Surgical treatment is safe and feasible for treatment of IVCTT in patients with hepatocellular carcinoma, and surgical resectability can be judged according to the classification of tumor thrombus.

A dual-signal fluorescent colorimetric tetracyclines sensor based on multicolor carbon dots as probes and smartphone-assisted visual assay.

The widespread presence of tetracyclines in the environment has raised concerns about the potential risks to ecosystems and human health. The ratiometric fluorescence sensor for detecting tetracyclines was developed using europium-doped carbon dots (Eu-CDs) as probes under alkaline conditions. The sensing mechanism of sensor for tetracyclines was considered as inner filter effect (IFE), antenna effect (AE), and self-quenching effect (SQE). The sensor had a wide linear detection range than the reported europium ions-based tetracyclines sensors. The linear detection ranges of oxytetracycline (OTC), tetracycline (TC), doxycycline (DC) and chlorotetracycline (CTC) were respectively 0.00-603.75 µM, 0.00-623.82 µM, 0.00-594.61 µM and 0.00-601.54 µM, and the corresponding detection limits were respectively 9.50 nM, 15.80 nM, 10.40 nM and 90.30 nM. The smartphone with RGB Color Picker was further employed to analyze the concentration of tetracyclines, which provided a new method for visual tetracyclines detection. The application of Eu-CDs test paper was also explored, and the results showed that the Eu-CDs test paper has great potential application in the visual detection of tetracyclines. In addition, the accuracy of the established tetracyclines sensor was compared with that of the China national standard method by high-performance liquid chromatography (HPLC), and the results showed that the established method in this work has similar accuracy to the China national standard method. The sensor has been employed to detect tetracyclines in the actual samples with satisfactory results, which indicated that this method has promising applications in the real-time monitoring tetracyclines of food and environment.

Efficacy and safety of Lenvatinib-based combination therapies for patients with unresectable hepatocellular carcinoma: a single center retrospective study.

Background: Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies. Methods: This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR). Results: Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE. Conclusion: Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.

N6-Methyladenosine Modification of ANLN Enhances Hepatocellular Carcinoma Bone Metastasis.

Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N6-methyladenosine (m6A) is a prominent modification involved in HCC, but the exact mechanisms on how m6A modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant m6A RNA modification-induced HCC BM was found to be the METTL3 and YTHDF1. The expression of Anillin actin-binding protein (ANLN) was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via m6A epitranscriptomic regulation by METTL3 and YTHDF1. High METTL3 and YTHDF1 expression along with nuclear ANLN protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear ANLN forming a transcriptional complex with SP1 which enhanced KIF2C transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of RANKL and disproportionated RANKL-OPG expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of ANLN m6A modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of m6A epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets.

[Hepatic vein occlusion with Satinsky clamp in hepatectomy for complicated liver tumor].

OBJECTIVE: To investigate the application of an improved method of hepatic vein occlusion with Satinsky clamp when resecting the liver tumor involving second hepatic portal. METHODS: From January 2003 to December 2010, there were totally 330 patients with liver tumor admitted, who underwent liver resection with Pringle maneuver plus hepatic vein occlusion with Satinsky clamp. Data regarding the intra-operative and post-operative course of the patients were analyzed. There were 245 male and 85 female patients, with a mean age of (50 ± 11) years. The diameter of tumor was (9 ± 6) cm. Among the 330 patients, there were 271 patients with viral hepatitis B, 215 patients with liver cirrhosis; 321 patients were in Child class A of liver function and 9 in class B. Pringle maneuver plus hepatic vein occlusion with Satinsky clamp was used to occlude the blood flow in the liver resection. The liver transection was performed with clamp-crushing technique. RESULTS: Hepatic vein occlusion with Satinsky clamp was successful in all 330 patients. The operation time was (132 ± 29) minutes, while (7 ± 3) minutes for dissecting hepatic vein and (22 ± 7) minutes for inflow blood occlusion. The blood loss in operation was (480 ± 265) ml, with 20% of patients receiving blood transfusion. No patient had large hemorrhage and air embolism due to hepatic vein laceration. No patient died in the perioperative period. The complications included 31 patients of pleural effusion, 14 patients of seroperitoneum, 10 patients of biliary fistula, 2 patients of massive blood loss during liver resection and 2 patients of re-bleeding after operation. CONCLUSION: The method of hepatic vein occlusion with Satinsky clamp was safe and effective.

Antidiabetic treatment improves prognosis after radical resection in hepatocellular carcinoma patients with diabetes mellitus: a retrospective cohort study from 2000 to 2013.

Background: It remains unclear whether diabetic medications, such as metformin and insulin, affect the post-liver resection prognosis of hepatocellular carcinoma (HCC) patients complicated with diabetes mellitus (DM). This study try to find out the prognostic factors in HCC patients with DM and provide a better antidiabetic therapy after liver resection. Methods: Patients presenting with HCC complicated with DM undergoing liver resection were enrolled in this study. They were examined and followed up every 3-6 months after surgery. Patients were divided into the antidiabetic treatment group and no antidiabetic treatment group according to whether they received medications for diabetes or not. Then patients in the antidiabetic treatment group were further divided into insulin group, metformin group, insulin plus metformin group and others group, according to the medications they received. Overall survival (OS) and recurrence-free survival (RFS) were compared among two groups and four subgoups. Comparative and multivariate analyses were performed to investigate the effects of DM medication on the prognosis of these HCC patients, using Cox proportional hazards model. Results: The 1-, 3-, 5-, and 7-year OS rates for the antidiabetic treatment group were 87.5%, 75.5%, 48.7%, and 29.1%, respectively, and for the no antidiabetic treatment group, the OS rates were 85.4%, 57.7%, 33.6%, and 19.1%, respectively (P=0.007). The 1-, 3-, 5-, 7-year RFS rates for the antidiabetic treatment group were 76.4%, 53.5%, 28.5%, and 17.5%, respectively, and for the no antidiabetic treatment group, the RFS rates were 69.5%, 32.5%, 16.5%, and 10.7%, respectively (P=0.001). In subgroup analysis, There was no significant difference in either RFS (P=0.934) nor OS (P=0.412) among the different types of antidiabetic treatment regimens. Cox proportional hazard regression analysis revealed that tumor size (HR: 1.048), tumor number (HR: 1.626), vascular invasion (HR: 2.074, P=0.003), satellite tumor (HR: 1.592), Edmondson classification (HR: 1.468) and antidiabetic treatment (HR: 0.722) were independent prognostic factors of DFS, while tumor size (HR: 1.048), tumor number (HR: 1.779), vascular invasion (HR: 2.545), Edmondson classification (HR: 1.596) and antidiabetic treatment (HR: 0.713) were independent prognostic factors of OS. Conclusions: For HCC patients with DM, antidiabetic treatment should be recommended aggressively in order to improve the surgical outcome, regardless of which antidiabetic drugs are used.

In situ encapsulation of SQDs by zinc ion-induced ZIF-8 growth strategy for fluorescent and colorimetric dual-signal detection of alkaline phosphatase.

Controllable encapsulation of sulfur quantum dots (SQDs) into metal-organic frameworks (ZIF-8) by a surface-bound zinc ion-induced growth strategy, and SQDs@ZIF-8 was successfully prepared for alkaline phosphatase (ALP) detection. The new synthesis procedure involves first binding Zn2+ to the surface of SQDs to form SQDs/Zn, and then via zinc ion-induced in situ ZIF-8 growth to obtain SQDs@ZIF-8, which greatly improved the luminous efficiency of SQDs. The specific process of detecting ALP using pH-triggered fluorescence quenching of SQDs@ZIF-8: firstly ALP hydrolyzes 2-phosphate-l-ascorbic acid trisodium salt (AAP) to ascorbic acid (AA), and then the leakage of SQDs in the SQDs@ZIF-8 leads to a decrease in fluorescence intensity based on the destruction of ZIF-8 skeleton by H+ released by AA. A linear relationship was obtained between the fluorescence intensity and the ALP concentration in the range of 0.15-50 U/L, and the detection limit was 0.044 U/L. Moreover, it was found that free SQDs can be complexed with Fe2+ to produce wine red complexes, and the obtained UV absorbance and ALP concentration have a linear relationship in the range of 10-200 U/L. The detection range of ALP is significantly broadened based on the combination of the above two detection methods. Furthermore, SQDs@ZIF-8 exhibited excellent stability in water and was successfully applied to the fluorescence and colorimetric detection of ALP in human serum.

Low CPEB1 levels may predict the benefit of 5-fluorouracil treatment in patients with colon or stomach adenocarcinoma.

Background: For patients with colon or stomach adenocarcinoma, 5-fluorouracil (5-FU) is an essential component of systemic chemotherapy in the palliative and adjuvant settings. The post-transcriptional regulatory factor cytoplasmic polyadenylation element-binding protein 1 (CPEB1) has been reported to be linked to tumor metastasis. This study aimed to investigate the relationship between CPEB1 expression and 5-FU treatment response in patients with colon and stomach adenocarcinomas. Methods: The expression of CPEB1 in stomach adenocarcinoma and colorectal cancer (CRC) tissues and in cell lines was determined by quantitative real-time PCR (qRT-PCR) and immunohistochemistry analyses. Transwell assays were employed to analyze the effects of CPEB1 on the migration and invasion abilities of gastric cancer (GC) and CRC cells. Results: The expression levels of CPEB1 were increased in colon and stomach adenocarcinoma and were negatively correlated with malignancy and poor patient survival. Data suggested that patients with CRC or GC who had strong CPEB1 expression responded poorly to 5-FU treatment. Furthermore, knockdown of CPEB1 inhibited the migration and invasion of CRC and GC cells via a mechanism involving decreased expression of matrix metalloprotein (MMP)2, 7, and 9. Finally, our methylated RNA immunoprecipitation PCR (meRIP qPCR) data suggested that the increased CPEB1 expression in colon and stomach adenocarcinomas might be mediated by FTO (FTO alpha-ketoglutarate dependent dioxygenase)-dependent m6A demethylation of CPEB1 mRNA. Conclusions: Our results indicate that the level of CPEB1 expression may be valuable for predicting the benefit of 5-FU treatment for patients with colon and stomach adenocarcinomas. We therefore propose that low CPEB1 expression may represent a novel biomarker for personalized 5-FU therapy.