Pentacyclic triterpenoids as potential ACL inhibitors from the rare medicinal plant Semiliquidambar cathayensis.

An extensive phytochemical investigation on the rare medicinal plant Semiliquidambar cathayensis (family: Hamamelidaceae) led to the isolation of four new (1-4, named semiliquidacids A-D, respectively) and 25 related known pentacyclic triterpenoids. The new structures with absolute configurations were elucidated by spectroscopic methods, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Compound 1 represents the first naturally occurring ursane-type triterpenoid featuring an uncommon C-25 formyl group. Compound 4 and oleanolic acid (13) exhibited remarkable inhibitory effects against the ATP-citrate lyase (ACL, an emerging drug target for hyperlipidemia and related metabolic disorders) with IC50 values of 6.5 and 11.9 µM, respectively. The molecular interaction and binding mode between the bioactive triterpenoids and ACL were elaborated by conducting a molecular docking study. Meanwhile, the chemotaxonomic significance of the isolated triterpenoids has been briefly discussed.

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.

Chemical investigation of Buddleja officinalis leaves and localization of defensive triterpenoids to its glandular trichomes.

Buddleja officinalis is a traditional Chinese medicinal plant covered with glandular and non-glandular trichomes on leaves. Phytochemical investigation of its leaves led to the identification of one undescribed tetranorcycloartane 3-oxo-25,26,27,29-tetranorcycloartan-24-oic acid (1) and one first identified natural product tetranorcycloartane 3-oxo-25,26,27,29-tetranorcycloartan-24-oic methyl ester (2), along with an undescribed megastigmane glucoside (3) and 14 known constituents (4-17). Structures of undescribed chemicals were elucidated by comprehensive 1D and 2D NMR, MS and CD analysis. Further chemical investigation resulted in six triterpenoids (4-9) being localized to the trichomes of B. officinalis. The major trichome components cycloeucalenone (4) and 24-oxo-29-norcycloartan-3-one (5) showed potent antifeedant activity against a generalist insect cotton bollworm (Helicoverpa armigera), but no obvious activity against the specialist herbivore Hyphasis inconstans. Compounds 4 and 7 also displayed inhibitory effects on seed germination of Arabidopsis thaliana. In addition, 1 and 4 exhibited moderate antibacterial activity toward three gram-positive bacteria.

Sequence Type 5 (ST5) as a Possible Predictor of Bacterial Persistence in Adult Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia Treated with Vancomycin.

Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC0-24) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose (P = 0.045), peak concentration (P = 0.020), and sdrC (P = 0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose (P = 0.009), cardiovascular disease (P = 0.043), sequence type 5 (ST5; P = 0.017), tst (P = 0.050), and sec gene (P = 0.044) associated with bacteriological failure. Although the AUC0-24/MIC was higher in the groups with bacterial eradication, the difference was not statistically significant (P = 0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P = 0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB, tst, and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB, tst, and sec.

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.

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.

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.

Protective effect of microinjection of glutamate into hypothalamus paraventricular nucleus on chronic visceral hypersensitivity in rats.

Chronic visceral hypersensitivity (CVH) is a major pathophysiological feature of patients experiencing in irritable bowel syndrome (IBS) and other disorders with visceral pain. However, little is known about its regulation of the central nucleus. In this research, we investigated the protective effect of microinjection of glutamate into hypothalamus paraventricular nucleus (PVN) on CVH and its possible regulatory mechanism in rats. Visceral sensitivity was assessed by pain threshold, abdominal withdrawal reflex (AWR) score, and the abdominal external oblique muscle electromyography (EMG) amplitude. Pathological changes in colorectal mucosa were assessed using immunohistochemical, biochemical analysis and Western blot. Results showed that microinjection of different doses of glutamate into PVN reduced the visceral sensitivity in a dose-dependent manner. This effect can be reversed after chemical ablation of PVN or nucleus tractus solitarius (NTS) or pretreatment with the arginine vasopressin (AVP)-V1 receptor antagonist ([Deamino-pen1,val4,D-Arg8]-vasopressin) DPVDAV into NTS. The vagus discharge frequency was significantly reduced after the glutamate microinjection into PVN. Additionally, oxidation, proliferation and apoptosis in colorectal mucosa were related to the CVH regulations. These findings suggested that PVN and NTS are involved in the regulatory process of CVH and exert the protective effect on CVH, providing new ideas and therapeutic targets for CVH research.

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.

The Efficacy and Safety of Transcatheter Arterial Embolization to Treat Renal Hemorrhage after Percutaneous Nephrolithotomy.

PURPOSE: The aim of this study was to evaluate the safety and efficacy of transcatheter arterial embolization (TAE) in patients with renal hemorrhage after percutaneous nephrolithotomy (PCNL) and evaluate the risk factors that may result in severe bleeding requiring TAE. METHODS: We retrospectively reviewed 121 patients with post-PCNL renal hemorrhage. Thirty-two patients receiving endovascular embolization were compared with 89 patients only receiving conservative treatment. The demographic and clinical data were recorded and compared between the two groups. The values of estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) were recorded preoperatively, postoperatively, and at last follow-up and analyzed to evaluate the safety and efficiency of TAE. RESULTS: The successful hemostasis rate of conservative therapy was 73.6% (89/121) and that of TAE was 100% (32/32). SCr and eGFR were not significantly different before PCNL and after the last follow-up of TAE (SCr: 0.95 vs. 0.95 mg/dl, P=0.857; eGFR: 86.77 vs. 86.18 ml/min/1.73m2, P=0.715). The univariate analysis demonstrated that advanced age, urinary tract infection, and diabetes mellitus were significantly associated with severe bleeding during PCNL. Multivariate analysis further identified that diabetes mellitus was an independent risk factor for severe bleeding needing TAE [odds ratio (OR): 3.778, 95% confidence interval (CI):1.276-11.190, and P=0.016]. CONCLUSION: TAE is a safe and effective procedure to treat renal hemorrhage that cannot be resisted by conservative treatment after PCNL. Diabetes mellitus was associated with high risks of severe bleeding needing TAE after PCNL.

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.

A Geranylfarnesyl Diphosphate Synthase Provides the Precursor for Sesterterpenoid (C25) Formation in the Glandular Trichomes of the Mint Species Leucosceptrum canum.

Plant sesterterpenoids, an important class of terpenoids, are widely distributed in various plants, including food crops. However, little is known about their biosynthesis. Here, we cloned and functionally characterized a plant geranylfarnesyl diphosphate synthase (Lc-GFDPS), the enzyme producing the C25 prenyl diphosphate precursor to all sesterterpenoids, from the glandular trichomes of the woody plant Leucosceptrum canum. GFDPS catalyzed the formation of GFDP after expression in Escherichia coli. Overexpressing GFDPS in Arabidopsis thaliana also gave an extract catalyzing GFDP formation. GFDPS was strongly expressed in glandular trichomes, and its transcript profile was completely in accordance with the sesterterpenoid accumulation pattern. GFDPS is localized to the plastids, and inhibitor studies indicated its use of isoprenyl diphosphate substrates supplied by the 2-C-methyl-D-erythritol 4-phosphate pathway. Application of a jasmonate defense hormone induced GFDPS transcript and sesterterpenoid accumulation, while reducing feeding and growth of the generalist insect Spodoptera exigua, suggesting that these C25 terpenoids play a defensive role. Phylogenetic analysis suggested that GFDPS probably evolved from plant geranylgeranyl diphosphate synthase under the influence of positive selection. The isolation of GFDPS provides a model for investigating sesterterpenoid formation in other species and a tool for manipulating the formation of this group in plants and other organisms.