Defensive furofuran lignans localized to the oil cells of Neocinnamomum delavayi and their metabolism by a specialist insect.

Neocinnamomum delavayi (Lauraceae) leaves with abundant oil cells are seldom attacked by insects, but their chemical constituent and biological function remain obscure. Three furofuran lignans, including (+)-eudesmin (3), (+)-magnolin (4), and demethoxyaschantin (5), were identified to be the major specialized metabolites in the oil cells of N. delavayi leaves through laser microdissection coupled with NMR analysis. Compounds 3 and 4 exhibited obvious antifeedant activity against a generalist insect Spodoptera exigua, and their natural contents in the leaves could effectively defend against generalist insects. Intriguingly, three specific metabolites 9-11, the O-demethylation derivates of compounds 3-5, were identified from a native specialist insect Dindica polyphaenaria feeding with N. delavayi leaves, implying an adaptation mechanism of specialist insects to plant defensive compounds. The results revealed a chemical connection between plants and insects, which would contribute to our understanding of plant-insect interaction and insect management.

Heterologous characterization of mechercharmycin A biosynthesis reveals alternative insights into post-translational modifications for RiPPs.

Mechercharmycin A (MCM-A) is a marine natural product belonging to a family of polyazole cyclopeptides with remarkable bioactivities and unique structures. Identification, heterologous expression, and genetic characterizations of the MCM biosynthetic gene cluster in Bacillus subtilis revealed that it is a ribosomally synthesized and post-translationally modified peptide (RiPP) possessing complex with distinctive modifications. Based on this heterologous expression system, two MCM analogs with comparable antitumor activity are generated by engineering the biosynthetic pathway. Combinatorial co-production of a precursor peptide with different modifying enzymes in Escherichia coli identifies a different timing of modifications, showing that a tRNAGlu-dependent highly regioselective dehydration is the first modification step, followed by polyazole formation through heterocyclization and dehydrogenation in an N- to C-terminal direction. Therefore, a rational biosynthetic pathway of MCMs is proposed, which unveils a subfamily of azol(in)e-containing RiPPs and sets the stage for further investigations of the enzymatic mechanism and synthetic biology.

Combined iodine-125 seed strand, portal vein stent, transarterial chemoembolization, lenvatinib and anti-PD-1 antibodies therapy for hepatocellular carcinoma and Vp4 portal vein tumor thrombus: A propensity-score analysis.

Objective: To evaluate the safety and efficacy of interventional therapy (iodine-125[125I] seed strand and portal vein stent [PVS] implantation plus transarterial chemoembolization [TACE]) combined with systemic therapy (lenvatinib plus anti-PD-1 antibody) as first-line treatment for hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT). Patients and methods: From December 2018 to October 2021, 87 HCC patients with Vp4 PVTT were included in this single-center retrospective study. Forty-seven patients underwent interventional therapy combined with lenvatinib and anti-PD-1 antibody (group A), while 40 cases underwent interventional therapy combined with lenvatinib only (group B). Overall response rate (ORR), stent occlusion rates (SOR), median overall survival (OS), median progression-free survival (PFS) and median stent patency time (SPT) were compared between the 2 groups. Results: The mean intended dose (r = 10 mm; z = 0; 240 days) was 64.9 ± 1.0 Gy and 64.5 ± 1.1 Gy in group A and B, respectively (p = 0.133). ORR and SOR were significantly different between group A and B (ORR, 55.3% vs 17.5%, p < 0.001; SOR, 12.8% vs 35.0%, p = 0.014). In the propensity-score matching (PSM) cohort, the median OS, median PFS and median SPT were significantly longer in group A compared with group B (32 PSM pairs; OS, 17.7 ± 1.7 vs 12.0 ± 0.8 months, p = 0.010; PFS, 17.0 ± 4.3 vs 8.0 ± 0.7 months, p < 0.001; SPT, not-reached vs 12.5 ± 1.1 months, p = 0.028). Conclusion: This interventional therapy combined with lenvatinib and anti-PD-1 antibody is safe and effective for HCC patients with Vp4 PVTT.

Corrigendum: Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Outcomes in Patients With Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Plus Sorafenib.

[This corrects the article DOI: 10.3389/fmolb.2021.624366.].

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Outcomes in Patients With Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Plus Sorafenib.

Objectives: To investigate the predictive value of inflammatory biomarkers in patients with unresectable hepatocellular carcinoma (HCC) for outcomes following the combination treatment of transarterial chemoembolization (TACE) plus sorafenib. Materials and Methods: A total of 314 (270 male and 44 female) treatment-naïve patients with unresectable HCC treated by TACE plus sorafenib between January 2011 and December 2018 were enrolled in the retrospective study. The primary outcome was overall survival (OS). The secondary outcome was progression-free survival (PFS). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were obtained within 3-7 days before the initial TACE and the median value of the NLR and PLR was considered as the cut-off value. Results: The median value of NLR and PLR was 2.42 and 100, respectively. The median OS and PFS of the entire cohort were 18.7 months (95% CI: 16.8-20.6) and 9.1 months (95% CI: 8.5-9.8), respectively. The low NLR and PLR group showed improved OS and PFS compared with the high NLR and PLR group [21.8 months (95% CI: 15.2-28.5) vs. 15.4 months (95% CI: 12.4-18.3), p < 0.0001; 21.6 months (95% CI: 15.8-27.5) vs. 14.9 months (95% CI: 11.9-17.8), p = 0.00027, respectively]. In addition, the low NLR and PLR group also provided a longer PFS than the high NLR and PLR group [10.4 months (95% CI: 8.9-12.0) vs. 8.1 months (95% CI: 7.1-9.2), p = 0.00022; 10.3 months (95% CI: 8.6-11.9) vs. 8.2 months (95% CI: 7.2-9.2), p < 0.0001, respectively]. High NLR and PLR at baseline were predictive factors of poor OS (p = 0.02 and p = 0.004) and PFS (p = 0.045 and p = 0.005). Conclusion: This study showed the prognostic value of quantitative inflammatory biomarkers in correlation with OS and PFS in unresectable HCC patients undergoing TACE plus sorafenib treatment.

Embolization of the Transhepatic Tract after Percutaneous Portal Vein Interventions: Single-Centre Retrospective Study Comparing n-butyl Cyanoacrylate Versus Coils.

PURPOSE: The aim of this study was to compare the safety and efficacy of transhepatic puncture tract embolization with n-butyl cyanoacrylate (n-BCA) versus coils after percutaneous transhepatic portal vein interventions in patients with hepatocellular carcinoma (HCC). It was also the aim of the study to evaluate the extent of artifacts in CT exams during FU. METHODS: Single-center retrospective study from 2017-2019 in 190 patients who underwent percutaneous transhepatic portal vein interventions. The transhepatic puncture tracts were embolized with n-BCA in 88 patients (Group A) and with coils in 102 patients (Group B). Procedure-related complications and image noise around coils and n-BCA were compared between the groups. No significant differences were noted at baseline between both groups (platelets, coagulation, liver disease, types of procedures, liver function, liver tumors). RESULTS: All patients underwent transhepatic puncture tract embolization. Procedure-related complications were only observed in patients from Group B: subcapsular hemorrhage (n = 2; 1.96%), hepatic artery hemorrhage (n = 1; 0.98%), and pseudoaneurysms combined with hemobilia occurred (n = 1; 0.98%). In Group A, the distal part of the punctured portal vein branch was embolized with n-BCA in 1 patient (1.14%). Four major complications in Group B Vs 0 in Group A were observed, respectively (p < 0.0001). The image noise around n-BCA was significantly lower than that around coils (10.7 ± 1.7 HU vs. 54.3 ± 15.0 HU, p < .001). CONCLUSIONS: n-BCA tract embolization is more effective than using coils, with fewer bleeding events, at the cost of a higher potential for unintended embolization of portal vein branches.

Prognosis Nomogram for Hepatocellular Carcinoma Patients with Portal Vein Invasion Undergoing Transarterial Chemoembolization Plus Sorafenib Treatment: A Retrospective Multicentre Study.

OBJECTIVES: To explore the outcomes of combined transarterial chemoembolization (TACE) with sorafenib in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) and to establish a prognostic prediction nomogram to differentiate target patients and stratify risk. MATERIALS AND METHODS: This multicentre, retrospective study consisted of 185 consecutive treatment-naïve patients with HCC and PVTT treated with TACE plus sorafenib from three institutions between January 1st, 2012 and December 31st, 2017. The primary outcome measurement of the study was overall survival (OS). The type of PVTT was classified by the Liver Cancer Study Group of Japan. The prognostic nomogram was established based on the predictors and was performed with interval validation. RESULTS: The median OS of the Vp1-3 and Vp4 groups was 12.4 months (11.7-18.9) and 8.5 months (7.6-11.2) (P = 0.00098), respectively, and there was a significant difference in the median OS between the Vp1-2 and Vp3 subgroups (16.4 months (12.2-27.9) vs. 10.9 months (8.4-18.1), P = 0.041). The multivariate Cox regression analysis suggested that tumour size, albumin-bilirubin grade, and PVTT type were independent prognostic factors. The C-index value of the nomogram based on these predictors in the entire cohort was 0.731 (0.628-0.833). CONCLUSIONS: After the combined therapy of TACE and sorafenib, advanced HCC patients with segmental or subsegmental PVTT showed better survival than those with main PVTT. The nomogram can be applied to identify advanced HCC patients with PVTT who may benefit most from the combination treatment and be helpful for making decision in clinical practice.

Deep Learning Predicts Overall Survival of Patients With Unresectable Hepatocellular Carcinoma Treated by Transarterial Chemoembolization Plus Sorafenib.

OBJECTIVES: To develop and validate a deep learning-based overall survival (OS) prediction model in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) plus sorafenib. METHODS: This retrospective multicenter study consisted of 201 patients with treatment-naïve, unresectable HCC who were treated with TACE plus sorafenib. Data from 120 patients were used as the training set for model development. A deep learning signature was constructed using the deep image features from preoperative contrast-enhanced computed tomography images. An integrated nomogram was built using Cox regression by combining the deep learning signature and clinical features. The deep learning signature and nomograms were also externally validated in an independent validation set of 81 patients. C-index was used to evaluate the performance of OS prediction. RESULTS: The median OS of the entire set was 19.2 months and no significant difference was found between the training and validation cohort (18.6 months vs. 19.5 months, P = 0.45). The deep learning signature achieved good prediction performance with a C-index of 0.717 in the training set and 0.714 in the validation set. The integrated nomogram showed significantly better prediction performance than the clinical nomogram in the training set (0.739 vs. 0.664, P = 0.002) and validation set (0.730 vs. 0.679, P = 0.023). CONCLUSION: The deep learning signature provided significant added value to clinical features in the development of an integrated nomogram which may act as a potential tool for individual prognosis prediction and identifying HCC patients who may benefit from the combination therapy of TACE plus sorafenib.

Serum STIP1, a Novel Indicator for Microvascular Invasion, Predicts Outcomes and Treatment Response in Hepatocellular Carcinoma.

Background: Previous studies reported that stress-induced phosphoprotein 1 (STIP1) can be secreted by hepatocellular carcinoma (HCC) cells and is increased in the serum of HCC patients. However, the therapy-monitoring and prognostic value of serum STIP1 in HCC remains unclear. Here, we aimed to systemically explore the prognostic significance of serum STIP1 in HCC. Methods: A total of 340 HCC patients were recruited to this study; 161 underwent curative resection and 179 underwent transcatheter arterial chemoembolization (TACE). Serum STIP1 was detected by enzyme-linked immunosorbent assay (ELISA). Optimal cutoff values for serum STIP1 in resection and TACE groups were determined by receiver operating characteristic (ROC) analysis. Prognostic value was assessed by Kaplan-Meier, log-rank, and Cox regression analyses. Predictive values of STIP1 for objective response (OR) to TACE and MVI were evaluated by ROC curves and logistic regression. Results: Serum STIP1 was significantly increased in HCC patients when compared with chronic hepatitis B patients or health donors (both P < 0.05). Optimal cutoff values for STIP1 in resection and TACE groups were 83.43 and 112.06 ng/ml, respectively. High pretreatment STIP1 was identified as an independent prognosticator. Dynamic changes in high STIP1 status were significantly associated with long-term prognosis, regardless of treatment approaches. Moreover, post-TACE STIP1 was identified as an independent predictor for OR, with a higher area under ROC curve (AUC-ROC) than other clinicopathological features. Specifically, pretreatment STIP1 was significantly increased in patients with microvascular invasion (MVI), and was confirmed as a novel, powerful predictor for MVI. Conclusions: Serum STIP1 is a promising biomarker for outcome evaluation, therapeutic response assessment, and MVI prediction in HCC. Integration serum STIP1 detection into HCC management might facilitate early clinical decision making to improve the prognosis of HCC.

Prognostic Performance of Albumin-Bilirubin Grade With Artificial Intelligence for Hepatocellular Carcinoma Treated With Transarterial Chemoembolization Combined With Sorafenib.

PURPOSE: To establish albumin-bilirubin (ALBI) grade-based and Child-Turcotte-Pugh (CTP) grade-based nomograms, as well as to develop an artificial neural network (ANN) model to compare the prognostic performance and discrimination of these two grades for hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) combined with sorafenib as an initial treatment. METHODS: This multicenter retrospective study included patients from three hospitals between January 2013 and August 2018. In the training cohort, independent risk factors associated with overall survival (OS) were identified by univariate and multivariate analyses. The nomograms and ANN were established and then validated in two validation cohorts. RESULTS: A total of 504 patients (319, 61, and 124 patients from hospitals A, B, and C, respectively) were included. The median OS was 15.2, 26.9, and 14.8 months in the training cohort and validation cohorts 1 and 2, respectively (P = 0.218). In the training cohort, both ALBI grade and CTP grade were identified as independent risk factors. The ALBI grade-based and CTP grade-based nomograms were established separately and showed similar prognostic performance and discrimination when validated in the validation cohorts (C-index in validation cohort 1: 0.799 vs. 0.779, P = 0.762; in validation cohort 2: 0.700 vs. 0.693, P = 0.803). The ANN model showed that the ALBI grade had higher importance in survival prediction than the CTP grade. CONCLUSIONS: The ALBI grade and CTP grade have comparable prognostic performance for HCC patients treated with TACE combined with sorafenib. ALBI grades 1 and 2 have the potential to act as a stratification factor for clinical trials on the combination therapy of TACE and systemic therapy.

Transradial access chemoembolization for hepatocellular carcinoma in comparation with transfemoral access.

BACKGROUND: This study aimed to compare the safety and efficacy of transradial access (TRA) with transfemoral access (TFA) chemoembolization in treatment of hepatocellular carcinoma (HCC). METHODS: HCC patients who were late for curative treatment on initial diagnosis or HCC patients who had undergone one or several rounds of transarterial chemoembolization (TACE) were enrolled. The clinical and angiographic characteristics, the procedure related details, and the follow-up data from patients who underwent TRA and TFA were analyzed and compared. RESULTS: In total, 112 patients undergoing 160 TRA-TACE and 107 patients undergoing 163 TFA-TACE were included. The technical success rate of TRA was 95.0% and that of TFA was 98.8% (P=0.102). In the TFA-TACE group, 5.5% of cases suffered access site-related complications, including 6 with minor bleeding and 3 with severe bleeding or pseudoaneurysm. In the TRA-TACE group, 1.9% of cases underwent crossover to femoral access for selective cannulation failure. The rate of radial artery occlusion (RAO) was 2.7% (3 of 112 patients), and none of the RAO patients suffered paresthesia, pain at the site of occlusion, hand function loss or distal ischemia. Comparing patients with/without access site-related complications in the TFA-TACE group, there was a statistical difference in patient age and in the percentage of patient with a PT time >15 s (72.6% vs. 57.1%, P<0.001; 44.4% vs. 11.7%, P=0.022). CONCLUSIONS: TRA is a safe and effective method for patients undergoing TACE. Compared with TFA, TRA may reduce the occurrence of access site-related bleeding and vascular complications. TRA-TACE may especially benefit older patients or those with a longer prothrombin time (PT).

Directed production of aurantizolicin and new members based on a YM-216391 biosynthetic system.

Using a highly effective heterologous expression system, the YM-216391 (1) biosynthetic gene cluster was engineered to yield aurantizolicin (2) and the hybrid compound 3. Both of these compounds were isolated and fully structurally characterised and the bioactivity was evaluated. The results indicate that compound 3 exhibits significantly improved antitumor activity.

Radiofrequency Ablation Combined With Transarterial Chemoembolization for Specially Located Small Hepatocellular Carcinoma.

OBJECTIVE: To investigate the safety and efficacy of radiofrequency ablation combined with transarterial chemoembolization in patients with specially located small hepatocellular carcinoma. MATERIALS AND METHODS: Between March 2014 and March 2017, a total of 26 patients with 26 lesions (10 perivascular, 6 subdiaphragmatic, 5 subcapsular, 5 perivascular, and subdiaphragmatic location; mean diameter 2.12 (0.62) cm), who received radiofrequency ablation-transarterial chemoembolization treatment, were retrospectively analyzed. Local tumor response was assessed by computed tomography/magnetic resonance imaging 1 month after the procedure. Tumor-free survival was also assessed according to the modified Response Evaluation Criteria in Solid Tumors. Complications were evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.0). RESULTS: Complete response was achieved in all patients 1 month after the procedure. During a median follow-up duration of 16.76 months (95% confidence interval: 7.78-25.73 months), local tumor recurrence occurred in 2 patients and new intrahepatic lesions developed in 7 patients. The 1-, 2-, and 3-year cumulative local tumor progression rates were 3.84%, 7.69%, and 7.69%, respectively. The median tumor-free survival duration was 21.96 months (95% confidence interval: 17.58-26.34 months). The 1-, 2-, and 3-year tumor-free survival rates were 67.4%, 46.1%, and 39.3%, respectively. CONCLUSION: The radiofrequency ablation-transarterial chemoembolization combination therapy appears to be safe and effective and might be a treatment option for specially located small hepatocellular carcinoma lesions that have a risk of incomplete ablation or major complications.

Endovascular brachytherapy combined with portal vein stenting and transarterial chemoembolization improves overall survival of hepatocellular carcinoma patients with main portal vein tumor thrombus.

Hepatocellular carcinoma (HCC) patients with main portal vein tumor thrombus have a median survival time of only about 4 months. We therefore compared the safety and efficacy of endovascular brachytherapy (EVBT) and sequential three-dimensional conformal radiotherapy (3-DCRT). From a cohort of 176 patients, we treated 123 with EVBT using iodine-125 seed strands (group A) and the remaining 53 with sequential 3-DCRT (group B). Overall survival, progression free survival and stent patency characteristics were compared between the two groups. Our analysis demonstrated a median survival of 11.7 ± 1.2 months in group A versus 9.5 ± 1.8 months in group B (p = 0.002). The median progression free survival was 5.3 ± 0.7 months in groupA versus 4.4 ± 0.4 months in group B (p = 0.010). The median stent patency period was 10.3 ± 1.1 months in group A versus 8.7 ± 0.7 months in group B (p = 0.003). Therefore, as compared to sequential 3-DCRT, EVBT combined with portal vein stenting and TACE improved overall survival of HCC patients with main portal vein tumor thrombus.

Arsenic trioxide: marked suppression of tumor metastasis potential by inhibiting the transcription factor Twist in vivo and in vitro.

PURPOSE: Arsenic trioxide (ATO) has been found effective in several types of cancer cells, including acute promyelocytic leukemia, and recently in hepatocellular carcinoma (HCC). In this study, we investigated the role of ATO in regulating the invasive activity of HCC after transarterial embolization (TAE). METHODS: Cell migration and invasion were observed using Transwell and wound-healing assay. The molecular changes in E-cadherin, N-cadherin, and Vimentin of surviving tumor cells were determined by Western blotting. The effects of ATO on Twist activity of the tumor cells were further analyzed. In animal study, 40 male buffalo rats implanted with McA-RH7777 tumor in the liver were randomly divided into four groups: control, TAE, ATO, and TAE + ATO. TAE procedures were performed on the 14th day after implantation. Lung metastases were observed using fluorescence imaging, and the molecular changes in residual tumor cells were evaluated by Western blotting or immunohistochemistry. Tumor growth and survival analysis were also evaluated. RESULTS: Arsenic trioxide markedly reduced cell migration and invasiveness, which were enhanced by hypoxia after TAE. Western blot analysis revealed ATO inhibited the expression of epithelial-mesenchymal transition (EMT) markers by suppressing Twist. The marked suppression effect of ATO on invasiveness and metastatic potential related to EMT was also shown in tissue. CONCLUSION: The results of this study demonstrated that ATO is an effective anticancer agent in combination with TAE in the treatment of HCC, by suppressing tumor progression and metastasis via selectively inducing tumor cell apoptosis and arresting EMT by inhibiting the Twist activation.

Common and unusual CT and MRI manifestations of pancreatic adenocarcinoma: a pictorial review.

Pancreatic adenocarcinoma is the most common malignancy of the pancreas with high death rate. Preoperative imaging is crucial for the assessment of the disease and the planning of treatment. In this review, we discussed the common and unusual findings of pancreatic carcinoma. The common CT and MR findings include hypovascular mass, dilataion of upstream biliary and pancreatic ducts, invasion to adjacent structures and metastasis. The uncommon CT and MR findings include: a cystic mass, a mass without dilataion of upstream ducts, multiple masses or a lesion diffusively infiltrating most parts of the pancreas without distorting its configuration.