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Background: The incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced. However, non-classic radiation-induced liver disease (ncRILD) remains a major concern following radiotherapy in patients with hepatocellular carcinoma (HCC). This study evaluated the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) for Child–Pugh grade B (CP-B) patients with locally advanced HCC and established a nomogram for predicting ncRILD probability. Methods: Seventy-five CP-B patients with locally advanced HCC treated with IMRT between September 2014 and July 2021 were included. The max tumor size was 8.39 cm ± 5.06, and the median prescribed dose was 53.24 Gy ± 7.26. Treatment-related hepatotoxicity was evaluated within three months of completing IMRT. A nomogram model was formulated to predict the probability of ncRILD, using univariate and multivariate analysis. Results: Among CP-B patients with locally advanced HCC, ncRILD occurred in 17 (22.7%) patients. Two patients (2.7%) exhibited a transaminase elevation of ≥ G3, fourteen (18.7%) exhibited a Child–Pugh score increase of ≥ 2, and one (1.3%) demonstrated both a transaminase elevation of ≥ G3 and a Child–Pugh score increase of ≥ 2. No cRILD cases were observed. A mean dose to the normal liver of ≥ 15.1 Gy was used as the cutoff for ncRILD. Multivariate analysis revealed that the prothrombin time before IMRT, tumour number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram established on the basis of these risk factors displayed exceptional predictive performance (AUC = 0.800, 95% CI 0.674–0.926). Conclusions: The incidence of ncRILD following IMRT for CP-B patients with locally advanced HCC was acceptable. A nomogram based on prothrombin time before IMRT, tumour number, and mean dose to the normal liver accurately predicted the probability of ncRILD in these patients. [ABSTRACT FROM AUTHOR]

Background: For patients with unresectable hepatocellular carcinoma (uHCC), intensity-modulated radiotherapy (IMRT) has become one of the options for clinical local treatment. Immune parameters, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and systemic immune inflammatory (SII), predict survival in various cancers. This study aimed to determine whether peripheral immune parameters can predict survival in patients with uHCC undergoing IMRT and establish a clinically useful prognostic nomogram for survival prediction. Methods: The clinical data of 309 HCC patients were retrospectively analyzed and randomly divided into training (n = 216) and validation (n = 93) cohorts. PLR, NLR and SII were collected before and after IMRT. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors affecting survival, which were used to generate a nomogram. Results: The median survival was 16.3 months, and significant increases in PLR, NLR, and SII were observed after IMRT (P < 0.001). High levels of immune parameters were associated with poor prognosis (P < 0.001); enlarged spleen, Barcelona clinic liver cancer stage (B and C), post-SII, and delta-NLR were independent risk factors for survival and were included in the nomogram, which accurately predicted 3- and 5-year survival. The nomogram was well verified in the validation cohort. Conclusions: High levels of immune parameters are associated with poor prognosis in uHCC patients receiving IMRT. Our nomogram accurately predicts the survival of patients with uHCC receiving IMRT. [ABSTRACT FROM AUTHOR]

Background: The combination of transcatheter arterial chemoembolization (TACE) plus sorafenib prolonged progression-free survival (PFS) and overall survival (OS) than sorafenib or TACE monotherapy for patients with hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of radiotherapy (RT) plus monoclonal antibody against programmed cell death 1 (anti-PD1) versus TACE plus sorafenib for patients with advanced HCC.Methods: Patients with advanced HCC who treated with RT plus anti-PD1 and TACE plus sorafenib were enrolled. Objective response rate (ORR), PFS, disease control rate (DCR) and OS were calculated to assess the antitumor response and the treatment-related adverse events to the safety.Results: Between January 2018 to March 2021, 37 patients underwent RT plus anti-PD1 and 41 patients underwent TACE plus sorafenib. The baseline characteristics between the two groups were comparable. The ORR and DCR were significantly higher in the RT + PD1 group than the TACE plus sorafenib group according to RECIST 1.1 (54.05% vs. 12.20%, P < 0.001; 70.27% vs. 46.37%, P = 0.041; respectively) and according to mRECIST (56.76% vs. 31.71%, P = 0.039; 70.27% vs. 46.37%, P = 0.041; respectively). RT plus anti-PD1 provided significantly better PFS (HR, 0.51; 95% CI 0.30-0.86; P = 0.017) than TACE plus sorafenib. Moreover, patients with RT plus anti-PD1 had significantly higher 3-, 6-, and 9-month OS rates than those with TACE plus sorafenib(97.3% vs. 92.30%, P < 0.001; 91.89% vs. 68.60%, P < 0.001; 75.5% vs. 60.60%, P < 0.001; respectively). The median OS was more favorable 17.4 months for the RT + PD1 group and 11.9 months for the TACE plus sorafenib group. No treatment-related death was observed. Grade 3 or more treatment-related adverse events (TRAEs) occurred significantly less in patients in the RT + PD1 group than the TACE plus sorafenib group (29.7% vs. 75.6%, P < 0.001), and all TRAEs were manageable.Conclusions: In this real-world study, RT plus anti-PD1 showed significantly promising efficacy and manageable safety than TACE plus sorafenib in patients with advanced HCC. Toxicities were manageable, with no unexpected safety signals. The study provides evidence on a new therapeutic method in the treatment of advanced HCC. [ABSTRACT FROM AUTHOR]

Plants of Artemisia annua produce artemisinin, a sesquiterpene lactone widely used in malaria treatment. Amorpha-4,11-diene synthase (ADS), a sesquiterpene synthase, and CYP71AV1, a P450 monooxygenase, are two key enzymes of the artemisinin biosynthesis pathway. Accumulation of artemisinin can be induced by the phytohormone jasmonate (JA). Here, we report the characterization of two JA-responsive AP2 family transcription factors—AaERF1 and AaERF2—from A. annua L. Both genes were highly expressed in inflorescences and strongly induced by JA. Yeast one-hybrid and electrophoretic mobility shift assay (EMSA) showed that they were able to bind to the CRTDREHVCBF2 (CBF2) and RAV1AAT (RAA) motifs present in both ADS and CYP71AV1 promoters. Transient expression of either AaERF1 or AaERF2 in tobacco induced the promoter activities of ADS or CYP71AV1, and the transgenic A. annua plants overexpressing either transcription factor showed elevated transcript levels of both ADS and CYP71AV1, resulting in increased accumulation of artemisinin and artemisinic acid. By contrast, the contents of these two metabolites were reduced in the RNAi transgenic lines in which expression of AaERF1 or AaERF2 was suppressed. These results demonstrate that AaERF1 and AaERF2 are two positive regulators of artemisinin biosynthesis and are of great value in genetic engineering of artemisinin production. [ABSTRACT FROM PUBLISHER]

Summary: The medicinal plant Scutellaria baicalensis Georgi is rich in specialized 4′‐deoxyflavones, which are reported to have many health‐promoting properties. We assayed Scutellaria flavones with different methoxyl groups on human cancer cell lines and found that polymethoxylated 4′‐deoxyflavones, like skullcapflavone I and tenaxin I have stronger ability to induce apoptosis compared to unmethylated baicalein, showing that methoxylation enhances bioactivity as well as the physical properties of specialized flavones, while having no side‐effects on healthy cells. We investigated the formation of methoxylated flavones and found that two O‐methyltransferase (OMT) families are active in the roots of S. baicalensis. The Type II OMTs, SbPFOMT2 and SbPFOMT5, decorate one of two adjacent hydroxyl groups on flavones and are responsible for methylation on the C6, 8 and 3′‐hydroxyl positions, to form oroxylin A, tenaxin II and chrysoeriol respectively. The Type I OMTs, SbFOMT3, SbFOMT5 and SbFOMT6 account mainly for C7‐methoxylation of flavones, but SbFOMT5 can also methylate baicalein on its C5 and C6‐hydroxyl positions. The dimethoxylated flavone, skullcapflavone I (found naturally in roots of S. baicalensis) can be produced in yeast by co‐expressing SbPFOMT5 plus SbFOMT6 when the appropriately hydroxylated 4′‐deoxyflavone substrates are supplied in the medium. Co‐expression of SbPFOMT5 plus SbFOMT5 in yeast produced tenaxin I, also found in Scutellaria roots. This work showed that both type I and type II OMT enzymes are involved in biosynthesis of methoxylated flavones in S. baicalensis. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Díaz‐González et al and Sanduzzi‐Zamparelli et al papers. To view these articles, visit https://doi.org/10.1111/apt.15088 and https://doi.org/10.1111/apt.15572. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we aimed to compare the radiation-induced hepatic toxicity (RIHT) outcomes of radiotherapy (RT) plus antibodies against programmed cell death protein 1 (anti-PD1) versus RT alone in patients with hepatocellular carcinoma (HCC), evaluate prognostic factors of non-classic radiation-induced liver disease (ncRILD), and establish a nomogram for predicting the probability of ncRILD. Patients and methods: Patients with unresectable HCC treated with RT and anti-PD1 (RT + PD1, n = 30) or RT alone (n = 66) were enrolled retrospectively. Patients (n = 30) in each group were placed in a matched cohort using propensity score matching (PSM). Treatment-related hepatotoxicity was evaluated and analyzed before and after PSM. The prognostic factors affecting ncRILD were identified by univariable logistic analysis and Spearman's rank test in the matched cohort to generate a nomogram. Results: There were no differences in RIHT except for increased aspartate aminotransferase (AST) ≥ grade 1 and increased total bilirubin ≥ grade 1 between the two groups before PSM. After PSM, AST ≥ grade 1 occurred more frequently in the RT + PD1 group (p = 0.020), and there were no significant differences in other hepatotoxicity metrics between the two groups. In the matched cohort, V25, tumor number, age, and prothrombin time (PT) were the optimal prognostic factors for ncRILD modeling. A nomogram revealed a good predictive performance (area under the curve = 0.82). Conclusions: The incidence of RIHT in patients with HCC treated with RT + PD1 was acceptable and similar to that of RT treatment. The nomogram based on V25, tumor number, age, and PT robustly predicted the probability of ncRILD. [ABSTRACT FROM AUTHOR]

The key enzymes involved in the flavonoid biosynthesis pathway have been extensively studied in seed plants, but relatively less in ferns. In this study, two 4‐Coumarate: coenzyme A ligases (Sc4CL1 and Sc4CL2) and one novel chalcone synthase (ScCHS1) were functionally characterized by mining the Stenoloma chusanum transcriptome database. Recombinant Sc4CLs were able to esterify various hydroxycinnamic acids to corresponding acyl‐coenzyme A (CoA). ScCHS1 could catalyze p‐coumaroyl‐CoA, cinnamoyl‐CoA, caffeoyl‐CoA, and feruloyl‐CoA to form naringenin, pinocembrin, eriodictyol, and homoeriodictyol, respectively. Moreover, enzymatic kinetics studies revealed that the optimal substrates of ScCHS1 were feruloyl‐CoA and caffeoyl‐CoA, rather than p‐coumaroyl‐CoA, which was substantially different from the common CHSs. Crystallographic and site‐directed mutagenesis experiments indicated that the amino acid residues, Leu87, Leu97, Met165, and Ile200, located in the substrate‐binding pocket near the B‐ring of products, could exert a significant impact on the unique catalytic activity of ScCHS1. Furthermore, overexpression of ScCHS1 in tt4 mutants could partially rescue the mutant phenotypes. Finally, ScCHS1 and Sc4CL1 were used to synthesize flavanones and flavones with multi‐substituted hydroxyl and methoxyl B‐ring in Escherichia coli, which can effectively eliminate the need for the cytochrome P450 hydroxylation/O‐methyltransferase from simple phenylpropanoid acids. In summary, the identification of these important Stenoloma enzymes provides a springboard for the future production of various flavonoids in E. coli. [ABSTRACT FROM AUTHOR]

Abstract: Terpenoids serve as both constitutive and inducible defense chemicals in many plant species, and volatile terpenes participate in plant a indirect defense by attracting natural enemies of the herbivores. The rice (Oryza sativa L.) genome contains about 50 genes encoding putative terpene synthases (TPSs). Here we report that two of the rice sesquiterpene synthase genes, OsTPS3 and OsTPS13, encode (E)-β-caryophyllene synthase and (E,E)-farnesol synthase, respectively. In vitro, the recombinant protein of OsTPS3 catalyzed formation of (E)-β-caryophyllene and several other sesquiterpenes, including β-elemene and α-humulene, all being components of inducible volatiles of rice plants. The transcript levels of OsTPS3 exhibit a circadian rhythm of fluctuation, and its expression was also greatly induced by methyl jasmonate (MeJA). In addition, expression of OsTPS3 in transgenic plants of Arabidopsis thaliana resulted in emitting high quantities of OsTPS3 products. We also overexpressed OsTPS3 in rice plants which then produced more (E)-β-caryophyllene after MeJA treatment. Finally, we found that the MeJA-treated transgenic rice plants attracted more parasitoid wasps of Anagrus nilaparvatae than the wild-type. These results demonstrate that OsTPS3, an enzyme catalyzing the formation of volatile sesquiterpenes, plays a role in indirect defense of rice plants. [Copyright &y& Elsevier]