A colorimetric sensing platform for azodicarbonamide detection in flour based on MnO2 nanosheets oxidative system.

Azodicarbonamide (ADA), as a dough conditioner food additive in flour, can be turned into toxic biurea and semicarbazide after high temperature processing. Hence, the using of ADA in food material should be strictly controlled, and the detection of ADA is very important for consumers' safety and health. Herein, a simple and fast colorimetric strategy has been developed for ADA detection based on the MnO2 nanosheets-3,3',5,5'-tetramethylbenzidine (TMB)-glutathione (GSH) as oxidative sensing system (MnO2-TMB-GSH). Since the ADA can selectively react with GSH via oxidizing the sulfydryl (-SH) group of GSH to disulfide bond (S-S), which makes GSH unable to reduce MnO2 nanosheets and restore its oxidase-like activity. The absorbance changes of the TMB solution depended on ADA content. The MnO2-TMB-GSH colorimetric platform can detect the ADA with a linear range of 10 µmol L-1 (11.6 ppm) to 400 µmol L-1 (464 ppm), and the limit of detection (LOD) is 3.3 µmol L-1 (3.51 ppm). Some potential interferences in real sample were tested and did not affect the MnO2-TMB-GSH colorimetric platform for ADA detection. Furthermore, the sensing platform was applied for detecting ADA in real flour sample with a recovery of 96%-105% (RSD < 5%). This colorimetric method can effectively and rapidly detect ADA additives in flour less than the prescribed standard (45 mg kg-1), which shows a great potential for visualization analysis and on-site detection of ADA in flour. A simple and fast colorimetric strategy has been developed for azodicarbonamide (ADA) detection based on the MnO2 nanosheets-3,3',5,5'-tetramethylbenzidine (TMB)-glutathione (GSH) as oxidative sensing system (MnO2-TMB-GSH).

A systematic review of the comparison of the incidence of seeding metastasis between endoscopic biliary drainage and percutaneous transhepatic biliary drainage for resectable malignant biliary obstruction.

BACKGROUND AND AIM: Endoscopic biliary drainage (EBD) and percutaneous biliary drainage (PTBD) are the two main strategies of preoperative biliary drainage (PBD) for resectable malignant biliary obstruction (MBO) worldwide, but which is better remains unclear. Seeding metastasis (SM) has been reported repeatedly in the recent decade, although it is rarely taken into consideration in the choice of PBD. Hence, a systematic review was badly warranted to evaluate the incidence of SM between PTBD and EBD in the preoperative treatment of MBO. METHODS: PubMed, MEDLINE, the Cochrane Library, and Web of Science were used to identify any potentially eligible studies comparing the incidence of SM between EBD and PTBD from Nov 1990 to Mar 2018. The effect size was determined by odds ratio (OR) with 95% confidence interval (CI). RESULTS: Ten studies were enrolled in this study, including 1379 cases in the EBD group and 1085 cases in the PTBD group. Results showed that the incidence of SM in the EBD group was significantly lower than that in the PTBD group (10.5% vs. 22.0%, OR = 0.35, 95% CI 0.23~0.53). Subgroup analysis stratified by the definition of SM showed that the pooled ORs for peritoneal metastasis and tube-related SM between EBD and PTBD were 0.42 (95% CI 0.31~0.57) and 0.17 (95% CI 0.10~0.29), respectively. Subgroup analysis stratified by the location of MBO showed that the pooled ORs for the incidence of SM between EBD and PTBD for perihilar cholangiocarcinoma, distal cholangiocarcinoma, and pancreatic cancer were 0.27 (95% CI 0.13~0.56), 0.32 (95% CI 0.17~0.60), and 0.27 (95% CI 0.19~0.40), respectively. CONCLUSION: EBD should be the optimal PBD for MBO considering the SM, but it deserved further validation.

Resection Margin Width Does Not Influence the Prognosis of Solitary Hepatocellular Carcinoma After Anatomic Resection: A Real-World Study from China.

Purpose: The influence of resection margin (RM) width on the prognosis of solitary hepatocellular carcinoma (HCC) following anatomical resection (AR) has yet to be determined. Therefore, we conducted a real-world study to identify the optimal RM width and assess its impact on the outcomes of solitary HCC patients undergoing AR. Methods: The data pertaining to patients diagnosed with solitary HCC who underwent AR between December 2012 and December 2015 were retrospectively collected. The optimal cutoff value for the width of the RM was determined using X-tile software. The Kaplan-Meier method was utilized to compare the overall survival (OS) and disease-free survival (DFS) between the narrow and wide RM groups. Additionally, propensity score matching (PSM) was performed to minimize potential bias in the data. Results: Of the 1033 patients who met the inclusion criteria, 293 (28.4%) were categorized into the narrow RM group (≤4 mm) and 740 (71.6%) into the wide RM group (> 4mm). Before and after PSM, there were no significant differences in OS and DFS between the two groups (before PSM: OS, HR=0.78, P=0.071; DFS, HR=0.95, P=0.620; after PSM: OS, HR=0.77, P=0.150; DFS, HR=0.90, P=0.470). Multivariate analysis demonstrated that RM width was not an independent risk factor for DFS and OS both before and after PSM (all P>0.05). However, subgroup analyses revealed that patients with ALBI grade 1, absence of cirrhosis, and AJCC stage II significantly benefited from wide RM in OS (all P< 0.05). Similarly, patients without HBV infection and absence of cirrhosis also exhibited significant benefits from wide RM in DFS (both P< 0.05). Conclusion: In patients with solitary HCC undergoing AR, the width of the RM does not appear to have a significant impact on their prognosis. However, in certain selected patients, a wider RM may confer benefits.

The Significance of Transarterial Chemo(Embolization) Combined With Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma in the Era of Systemic Therapy: A Systematic Review.

Background and Aims: Regardless of great progress in early detection of hepatocellular carcinoma (HCC), unresectable HCC (uHCC) still accounts for the majority of newly diagnosed HCC with poor prognosis. With the promising results of a double combination of transarterial chemo(embolization) and tyrosine kinase inhibitors (TKIs), and TKIs and immune checkpoint inhibitors (ICIs), a more aggressive strategy, a triple combination of transarterial chemo(embolization), TKIs, and ICIs has been tried in the recent years. Hence, we aimed to conduct a systematic review to verify the safety and efficacy of the triple therapy for uHCC. Methods: PubMed, MedLine, Embase, the Cochrane Library, and Web of Knowledge were used to screen the eligible studies evaluating the clinical efficacy and safety of triple therapy for patients with uHCC up to April 25th 2022, as well as Chinese databases. The endpoints were the complete response (CR), objective response rate (ORR), disease control rate (DCR), conversion rate, progression-free survival (PFS) rate, overall survival (OS) rate, and the incidence of adverse events (AEs). Results: A total of 15 studies were eligible with 741 patients receiving transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with TKIs and ICIs. The pooled rate and 95% confidence interval (CI) for CR, ORR, and DCR were 0.124 (0.069-0.190), 0.606 (0.528-0.682), and 0.885 (0.835-0.927). The pooled rates for PFS at 0.5 years and 1 year were 0.781 (0.688-0.862) and 0.387 (0.293-0.486), respectively. The pooled rates for OS at 1, 2, and 3 years were 0.690 (0.585-0.786), 0.212 (0.117-0.324), and 0.056 (0.028-0.091), respectively. In addition, the pooled rate and 95%CI for the conversion surgery was 0.359 (0.153-0.595). The subgroup analysis of control studies showed that triple therapy was superior to TACE+TKIs, TKIs+ICIs, and TKIs in CR, ORR, and DCR, conversion rate; PFS; and OS. No fatal AEs were reported, and the top three most common AEs were elevated ALT, elevated AST, and hypertension, as well as severe AEs (grading ≥3). Conclusion: With the current data, we concluded that the triple therapy of TACE/HAIC, TKIs, and ICIs would provide a clinical benefit for uHCC both in short- and long-term outcomes without increasing severe AEs, but the conclusion needs further validation. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO/, Review registry: CRD42022321970.

Corrigendum: The Significance of Transarterial Chemo(embolization) Combined With Tyrosine Kinase Inhibitors and Immune Check Point Inhibitors for Unresectable Hepatocellular Carcinoma in the Era of Systemic Therapy: A Systematic Review.

[This corrects the article DOI: 10.3389/fimmu.2022.913464.].

Tumor Microenvironment Triggered Cascade-Activation Nanoplatform for Synergistic and Precise Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade-activation nanoplatform (A-NPLap/TPZ ) is prepared based on ß-lapachone (ß-Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A-NPLap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H2 O2 -triggered disassembly to release ß-Lap and TPZ. The released ß-Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over-expressed NAD(P)H-quinone oxidoreductase-1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti-tumor effect. The studies in vitro and in vivo consistently demonstrate that the as-prepared A-NPLap/TPZ nanoplatform possesses an excellent synergistic anti-tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.

A remotely controlled NIR-II photothermal-sensitive transgene system for hepatocellular carcinoma synergistic therapy.

Photothermal therapy (PTT) exhibits an excellent therapeutic effect in cancer treatment, but some cancers are still facing rapid recurrence due to the presence of heat-resistant cells, which express heat shock proteins (HSP) to defend against hyperthermia. Inspired by optogenetics, we firstly designed a caged TNF-related apoptosis-inducing ligand (TRAIL) expressing plasmid under HSP70 protomer (HSP70-TRAIL) as the thermal-activated gene therapy agent to induce the apoptosis of heat resistant cells. Then, the caged HSP70-TRAIL was decorated on the surface of the photothermal agent (semiconducting nanoparticles, SPNs) through electrostatic adsorption to obtain SPN@HSP70-TRAIL-GFP (SPNHT). Under 1064 nm near-infrared second region (NIR-II) laser irradiation, the SPNHT acted as an emerging photothermal agent for PTT. Importantly, the caged HSP70-TRAIL could be further activated by PTT to express TRAIL on demand to concurrently kill survival cells for overcoming the problem of tumor recurrence after PTT. Both in vitro and in vivo studies demonstrated that the SPNHT nano-system with the ability of NIR-II photothermal-triggered TRAIL in situ expression possessed an admirable synergistic anti-cancer efficacy for HCC. This work offers new tactics for effective treatment of cancer, which showed a great significance for reducing the rate of cancer recurrence after PTT treatment.

Circular RNA CircEPB41L2 Functions as Tumor Suppressor in Hepatocellular Carcinoma Through Sponging miR-590-5p.

BACKGROUND: Circular RNAs (circRNAs) could interact with miRNAs to regulate gene expression, participating in hepatocellular carcinoma (HCC) initiation and development. This work aimed to determine the potential function and molecular mechanism of circEPB41L2 (hsa_circ_0077837) during HCC progression. MATERIALS AND METHODS: The expression of circEPB41L2 in HCC tissues and HCC cell lines was quantified using real-time quantitative PCR (qRT-PCR). CCK-8 assays and colony formation assays were utilized to detect the proliferation of HCC cells. Wound healing assay and transwell assay were performed to determine the capability of migration and invasion for HCC cells. Western blot was conducted to determine gene expression on protein levels. The effect of circEPB41L2 on HCC in vivo was investigated via xenograft experiment. Interaction between circEPB41L2 and miR-590-5p was predicted through bioinformatics methods and confirmed via luciferase reporter assay. RESULTS: Extensive analysis of circRNA profiles in tumor and matched para-tumor tissues collected from 61 HCC patients identified that circEPB41L2 was significantly down-regulated in HCC, which was further confirmed in another HCC group by qRT-PCR analysis. The clinicopathological analysis revealed that down-regulation of circEPB41L2 was negatively associated with tumor size, vascular invasion and alpha-fetoprotein, while positively correlated with HCC prognosis. The biological function experiments showed that overexpression of circEPB41L2 could obviously inhibit the proliferation and metastasis of HCC cells in vitro, while knockdown of circEPB41L2 induced opposite results. Moreover, we also found that circEPB41L2 inhibited HCC migration and invasion though EMT signaling pathway. Similarly, overexpression of circEPB41L2 can also significantly inhibit the proliferation of HCC cells in vivo. Bioinformatic analysis and luciferase reporter assay revealed that circEPB41L2 interacts directly with miR-590-5p and the corresponding biological functions were also verified in miRNA rescue experiments. CONCLUSION: Our results suggest that circEPB41L2 might function as a tumor suppressor during HCC progression by sponging miR-590-5p.

Does the intermittent Pringle maneuver affect the recurrence following surgical resection for hepatocellular carcinoma? A systematic review.

BACKGROUND AND AIM: To evaluate the effect of intermittent pringle maneuver (IPM) on the long-term prognosis and recurrence of hepatocellular carcinoma (HCC). METHODS: Eligible studies were identified by PubMed and other databases from Jan 1st 1990 to Mar 31st 2019. Hazard ratios (HR) with 95% confidence interval (CI) were calculated to evaluate the effects of IPM on the long-term prognosis and recurrence of patients with HCC. RESULTS: Six studies were enrolled in this meta-analysis. Results showed that there were no differences between IPM group and non-IPM group in the pooled HRs for the overall survival (OS) and disease-free survival (DFS) (HR 1.04, 95%CI 0.84~1.28, P = 0.74; HR 0.93, 95%CI 0.81~1.07, P = 0.29; respectively). However, subgroup analysis showed that the pooled Odd ratios (OR) for the 1-year OS and DFS rates of the IPM group when compared with the non-IPM group were 0.65 (95% CI 0.45~0.94, P = 0.02), 0.38 (95% CI 0.20~0.72, P = 0.003), respectively. In addition, there were no significant differences in the proportions of liver cirrhosis, HBsAg (+), Child-Pugh A class, multiple tumor, vascular invasion, and major hepatectomy between groups of IPM and non-IPM. CONCLUSION: Since IPM would increase the risk of early-recurrence, it should be used cautiously in the procedure of hepatectomy for resectable HCC. However, the current conclusion needs further validation. TRIAL REGISTRY NUMBER: CRD 42019124923.

A thieno-isoindigo derivative-based conjugated polymer nanoparticle for photothermal therapy in the NIR-II bio-window.

Photothermal therapy (PTT), a powerful tool for non-invasive cancer treatment, has been recognized as an alternative strategy for cancer therapy in the clinic, and it is promoted by optical absorbing agents (photothermal agents) that can intensively convert near-infrared (NIR) light into thermal energy for cancer ablation. Conjugated polymer nanoparticles (CPNs) have recently attracted extensive attention owing to their excellent photothermal properties. However, the absorption of typical CPNs is mostly located in the traditional near-infrared region (NIR-I, 700-900 nm), which suffers from low tissue penetration, so the penetration depth is still limited and severely restricts their further applications. Compared with the NIR-I light, the second near-infrared window light (NIR-II, 1000-1700 nm) could efficiently enhance the tissue penetration depth, however, CPNs which absorb NIR-II region light are still especially limited and need further exploration. Here, a thieno-isoindigo derivative-based Donor-Acceptor (D-A) polymer (BTPBFDTS), which exhibited excellent absorption characteristics from the NIR-I to NIR-II window, was prepared. After formation of nanoparticles and surface functionalization, the prepared nanoparticles (NPsBTPBFDTS@HA NPs) exhibited obvious targeting ability, high photothermal conversion efficiency and photoacoustic imaging effects under 1064 nm irradiation. Both in vitro and in vivo studies demonstrate that our obtained NPsBTPBFDTS@HA nanoparticles possess excellent PTT efficacy including extremely high cancer cell killing ability and admirable tumor elimination efficiency. Hence, this work developed a promising photothermal conversion agent based on CPNs for cancer ablation.

Donor-acceptor conjugated polymer-based nanoparticles for highly effective photoacoustic imaging and photothermal therapy in the NIR-II window.

We prepared novel conjugated polymer based NIR-II nanoparticles, which display extremely high photothermal conversion efficiency (65%). Both in vitro and in vivo investigations revealed that the as-prepared nanoparticles exhibit excellent theranostic properties including an extremely high cancer cell killing ability, admirable tumor elimination efficiency (100%) and a remarkable photoacoustic imaging contrast enhancing ability.

Photodynamic Therapy Combined with Antihypoxic Signaling and CpG Adjuvant as an In Situ Tumor Vaccine Based on Metal-Organic Framework Nanoparticles to Boost Cancer Immunotherapy.

Photodynamic therapy (PDT) usually aggravates tumor hypoxia, which promotes the survival and metastasis of residue cancer cells; furthermore, although PDT-induced immunogenic death of cancer cells can induce host antitumor responses, such responses are generally weak and not enough to eliminate the residue cancer cells. Here, metal-organic framework (MOF)-based nanoparticles to combine PDT, antihypoxic signaling, and CpG adjuvant as an in situ tumor vaccine to boost host anticancer responses after PDT are designed. The MOF-based nanoparticles are self-assembled from H2 TCPP and zirconium ions with hypoxia inducible factor (HIF) signaling inhibitor (ACF) and immunologic adjuvant (CpG) loading, and hyaluronic acid (HA) coating on the surface. The final nanoparticles (PCN-ACF-CpG@HA) can specifically target cancer cells overexpressing CD44 receptor though HA; the aggravated hypoxic survival signaling after PDT can be blocked by ACF to inhibit the HIF-1α induced survival and metastasis. With the help of CpG adjuvant, the tumor associated antigens generated from PDT-based cancer cell destruction can initiate strong antitumor immune responses to eliminate residue cancer cells. Taken together, a novel in situ immunostimulatory strategy is designed to synergistically enhance therapeutic effects of PDT by activating host antitumor immune-responses both in vitro and in vivo, which may have great potential for clinical translation in future.

Comparison of long-term efficacy between endoscopic and percutaneous biliary drainage for resectable extrahepatic cholangiocarcinoma with biliary obstruction: A systematic review and meta-analysis.

BACKGROUND/AIM: For resectable extrahepatic cholangiocarcinoma with biliary obstruction, it remains a controversy whether to choose percutaneous transhepatic biliary drainage (PTBD) or endoscopic biliary drainage (EBD). A systematic review was conducted to compare the long-term efficacy between the two techniques. MATERIALS AND METHODS: Eligible studies were searched from January 1990 to May 2018, comparing the long-term efficacy between EBD and PTBD for extrahepatic cholangiocarcinoma. Primary end point was overall survival (OS) rate, and secondary end points included postoperative severe complications and seeding metastasis. Effect size on outcomes was calculated using a fixed- or random-effect model, accompanied with hazard ratio (HR) and 95% confidence interval (CI). RESULT: Six studies were included in this meta-analysis. Meta-analysis showed that EBD was superior to PTBD in OS (HR = 0.70, 95% CI 0.59-0.84,P= 0.0002). But subgroup results showed that the superiority disappeared in distal cholangiocarcinoma (HR = 0.76, 95% CI 0.56-1.01,P= 0.06). Other prognostic factors such as intraoperative blood transfusion, lymphatic metastasis and seeding metastasis, were inconsistent between groups. In addition, regional disparity was obviously apparent between Japanese and non-Japanese studies. CONCLUSION: The conclusion that EBD was superior to PTBD in OS for resectable extrahepatic cholangiocarcinoma with biliary obstruction is less convincing, and more trials need to be conducted in future.

Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients with Hepatocellular Carcinoma.

PURPOSE: Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment. EXPERIMENTAL DESIGN: We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers. RESULTS: All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapse-free survival (P = 0.001) and overall survival (P = 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection. CONCLUSIONS: We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.

Metallothioneins may be a potential prognostic biomarker for tumors: A Prisma-compliant meta-analysis.

BACKGROUND: Metallothioneins (MTs) were reported to be associated with many kinds of tumors' prognosis, although MTs expression varied greatly among tumors. To assess the prognostic value of Metallothioneins (MTs) in different kinds of tumors, comprehensive literature search was conducted to perform a meta-analysis. METHODS: Eligible studies were identified by PubMed, MEDLINE, Web of Science (WOS), the Cochrane Library of Systematic Reviews, EMBASE, China National Knowledge Infrastructure (CNKI), WANFANG database and SinoMed database up to December 2017, which was designed to assess the prognostic value of MTs in different kinds of tumors. The main endpoint events were overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) and its variance were retrieved from the original studies directly or calculated using Engauge Digitizer version 4.1. Random or fixed effects model meta-analysis was employed depending on the heterogeneity. Publication bias was evaluated by funnel plots, Begg and Egger tests. RESULTS: A total of 22 studies were enrolled in this meta-analysis, including 2843 tumor tissues (1517 were MTs negative/low, and 1326 were MTs high). Results showed that there was significant association between MTs expression and tumors' OS (HR = 1.60; 95%CI 1.34∼1.92, P < .00001). Subgroup analysis showed that high level of MTs expression was associated with prolonged OS in liver cancer (HR = 0.65, 95%CI 0.48∼0.89, P = .007), but it was on the contrary in the tumor of ovary (HR = 1.47, 95%CI 1.01∼2.14, P = .04), bladder (HR = 1.71, 95%CI 1.21∼2.42, P = .002), intestine (HR = 3.13, 95%CI 1.97∼4.97, P < .00001), kidney (HR = 3.31, 95%CI 1.61∼6.79, P = .001). However, there was no significant association between MTs expression and OS in breast (HR = 1.02, 95%CI 0.69∼1.51, P = .93). CONCLUSIONS: MTs could be taken as a potential prognostic biomarker for tumors, and uniqueness of MTs prognostic value in liver cancer deserved further study.