A Single-Cell Analysis of the NK-Cell Landscape Reveals That Dietary Restriction Boosts NK-Cell Antitumor Immunity via Eomesodermin.

Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cells, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. NK cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. In this study, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. First, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through nontumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.

Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively.

Eomesodermin (Eomes) is a critical factor in the development of natural killer (NK) cells, but its precise role in temporal and spatial coordination during this process remains unclear. Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development. Specifically, the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2, another important transcription factor. ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence (CNS) of Klf2. Utilizing the CHimeric IMmune Editing (CHIME) technique, we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest. Moreover, constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency. Conversely, Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27+CD11b+ phenotype to the CD27-CD11b+ phenotype. Late-stage deficiency of Eomes led to a significant increase in T-bet expression, which subsequently increased the expression of the transcription factor Zeb2. Genetic deletion of one allele of Tbx21, encoding T-bet, effectively reversed the aberrant differentiation of Eomes-deficient NK cells. In summary, we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.

Angeliticin B, a new chromone isolated from Angelica polymorpha Maxim.

A new chromone, angeliticin B (1) together with nine known compounds, psoralene (2), isoimperatorin (3), (S)-(-)-2'-methoxypeucedanin hydrate (4), (S)-(-)-oxypeucedanin (5), xanthotoxin (6), isopimpinellin (7), 1'-O-ß-D-glucopyranosyl-(2'S, 3'R)-3'-hydroxymarmesin (8), sec-O-glucosylhamaudol (9) and vanillin (10) were isolated from the methanol extract of Angelica polymorpha Maxim. The structures of these compounds were elucidated through a comprehensive analysis of standard spectral data (MS, IR, and NMR). Compound 1 exhibited antioxidant activity with IC50 = 198.57 µM in DPPH experiment and 31.71 µM in ABTS experiment. Compound 2, 6, 7 exhibited ABTS radical scavenging activity with IC50 ranging from 105.96 µM to 167.67 µM. Compound 3 demonstrated a synergistic induction effect on nigericin-activated NLRP3 inflammasome in THP-1 cell by LDH release method.

Scalable co-cured polyimide/poly(p-phenylene benzobisoxazole) all-organic composites enabling improved energy storage density, low leakage current and long-term cycling stability.

The all-organic high-temperature polymer dielectrics with promising scale-up potential have witnessed much progress in the energy storage area, etc. However, the electron suppression trap mechanisms behind many all-organic dielectrics are still unclear, especially for high temperature resistant poly(p-phenylene benzobisoxazole) (PBO) polymers. To resolve this tough issue, we herein innovatively prepared PBO-based all-organic thin films containing sulfone-based polyimide (P(DSDA-ODA)) functioning as an electron trap phase using a facile and scalable co-curing method. The great linear dielectric properties of the prepared P(DSDA-ODA)/PBO films hold high dielectric thermal stability over the temperature range from 25 °C to 200 °C. The 60 wt% P(DSDA-ODA) systems yield the lowest leakage current (3.8 × 10-8 A cm-2). The tight structure and reduced leakage current enable an enhanced breakdown strength of 60 wt% P(DSDA-ODA)/PBO (470 kV mm-1), which is 1.7 times that of pure PBO. Meanwhile, it can reach 4.16 J cm-3 of energy density, which is 257% higher than that for pure PBO thin films while concurrently maintaining a long stable charge-discharge cycle (at least 5000 times) and high charge-discharge efficiency at 85.10%. Moreover, P(DSDA-ODA)/PBO still exhibits excellent energy storage performance at high temperature compared to PBO. This innovative strategy is further verified by replacing P(DSDA-ODA) with P(6FDA-ODA), and therefore lays a solid foundation for more investigation on scalable all-organic dielectrics.

Adjustable Plane Curvature of Covalent Organic Framework Enabling Outstanding Dielectric, Electret, and High-Temperature Processing Properties.

With the rapid development of integrated circuits towards miniaturization and complexity, there is an urgent need for materials with low dielectric constant/loss and high processing temperatures to effectively prevent signal delay and crosstalk. With high porosity, thermal stability, and easy structural modulation, covalent organic frameworks have great potential in the field of low dielectric materials. However, the optimization of dielectric properties by modulating the conjugated/plane curvature structure of covalent organic frameworks (COFs) has rarely been reported. Accordingly, we herein innovatively prepare COF films with adjustable planar curvature, hence possessing ultralow dielectric constant (1.9 at 1 kHz), ultralow dielectric loss at 1 kHz (0.0029 at room temperature, 0.0052 at 200 °C), high thermal decomposition temperature (5 % weight loss temperature, 473 °C) and good hydrophobicity (water contact angle, 105.3°). Also, to the best of our knowledge, we are the first to report that the resulting COF film enables high surface potential (≈320 V) for one week, attributing to its intrinsic high porosity, thus presenting great potential in electret applications. Accordingly, this innovative work provides a readily available and scalable idea to prepare materials with comprehensively excellent dielectric and electret properties as well as high processing temperatures simultaneously for advanced electronic device applications.

Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors.

Targeting mitochondrial complex I (CI) is emerging as an attractive anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated. Among them, the maximum tolerated dose (MTD) values of SCAL-255 (compound 5q) and SCAL-266 (compound 6f) were 68 mg/kg, which was nearly 10 times that of IACS-010759 (6 mg/kg), showing good safety. In addition, SCAL-255 and SCAL-266 significantly inhibited the proliferation of HCT116 and KG-1 cells in vitro and exerted satisfactory inhibitory activity against KG-1 cells in vivo. These results suggested that the optimized compounds might serve as promising CI inhibitors against oxidative phosphorylation (OXPHOS)-dependent cancer, which merits further study.

Enhanced Interfacial and Dielectric Performance for Polyetherimide Nanocomposites through Tailoring Shell Polarities.

Polyimide (PI) and its derivative polyetherimide (PEI) have been widely investigated as promising candidates for dielectric energy storage due to their excellent intrinsic features. However, most of the current research for PI- or PEI-based dielectric nanocomposites only focuses on a certain polar group contained in a dianhydride monomer, while there are very few studies on exploring the effect of a series of polar groups derived from various dianhydride monomers on the dielectric properties of nanocomposites. To fill this gap, we herein fabricated and investigated a series of novel hyperbranched polyimides grafted on barium titanate nanoparticles (HBPI@BT) using different dianhydride monomers and their nanocomposites with the PEI matrix. The results showed that sophisticated hyperbranched structures effectively alleviated the incompatibility between fillers and the matrix, thus significantly improving the bonding energy of nanocomposites, especially for HBPI-S@BT/PEI (797.7 kJ/mol). The Ud of HBPI-S@BT/PEI reached 8.38 J/cm3, which is 3.3 times higher than that of pure PEI. The HBPI-F@BT/PEI nanocomposites achieved high breakdown strength (∼500 MV/m) and low dielectric loss (0.008) simultaneously. The dielectric constants of HBPI@BT/PEI nanocomposites remained at a stable level from 25 to 150 °C. This work provides us promising hyperbranched structured materials for potentially advanced dielectric applications such as field effect transistors.

Seven New Phenylhexanoids with Antioxidant Activity from Saxifraga umbellulata var. pectinata.

Seven new phenylhexanoids, (S)-(+)-3,4-dihydroxy-11-methoxyphenylhex-9-one (1), (E) 3,4-dihydroxy-phenylhex-10-en-9-one (2), (E)-4-hydroxyphenylhex-10-en-9-one (3), (R)-(-)-3,4,11-trihydroxyphenylhex-9-one 11-O-ß-d-glucopyranoside (4), (R)-(-)-4,11-dihydroxyphenylhex-9-one 11-O-ß-d-glucopyranoside (5), phenylhex-4,9,11-triol 11-O-ß-d-glucopyranoside (6), and 9-O-acetyl-phenylhex-4,9,11-triol 11-O-ß-d-glucopyranoside (7), were isolated and identified from Tibetan medicine Saxifraga umbellulata var. pectinate. The antioxidant activities of these compounds were evaluated using the DPPH and ABTS radical scavenging experiments. In the ABTS experiment, compounds 1 (IC50 13.99 ± 2.53 µM) and 2 (IC50 13.11 ± 0.94 µM) exhibited significantly better antioxidant activity than L-ascorbic acid (IC50 23.51 ± 0.44 µM).

New lignans and phenylethanoid with antioxidant activity from aerial parts of Forsythia suspensa (Thunb.) Vahl.

Two new lignans, phillyroside A(1) and phillyroside B(2), together with three new phenylethanoid glycoside, forsythoside K(3), forsythoside L(5) and forsythol L (4), while compounds 4 was an aglycon of forsythoside L(5), were isolated from the aerial parts of Forsythia suspensa (Thunb.) Vahl. Their structures were elucidated by comprehensive analyses of standard spectroscopic data (MS, IR, and NMR) and the in vitro antioxidant activity of five new compounds were evaluated in DPPH and ABTS radical scavenging experiment and ferric reducing ability of plasma (FRAP) experiment. Compounds 4 and 5 exhibited antioxidant activity with IC50 values ranging from 112.49 to 153.58 µM in DPPH experiment and 45.43 to 64.09 µM in ABTS experiment.

HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress.

Diabetic cardiomyopathy (DCM) is a diabetic mellitus-related complications and progression of DCM may eventually lead to heart failure, while mechanisms related to DCM pathophysiology remain unclear. The study was undertaken to identify possible hub genes associated with DCM progression through bioinformatics analysis and to validate the role of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in DCM progression using a cellular model of high glucose (HG)-induced DCM. The common differentially expressed genes (DEGs) between GSE173884 and GSE161827 were used for PPI network analysis. Our results identified 17 common DEGs between GSE173384 and GSE161827. Further analysis of the protein-protein interaction network identified nine hub genes and HMGCS2. The in vitro functional assays showed that HG induced up-regulation of HMGCS2, suppressed cardiomyocyte viability, enhanced apoptosis, inflammation, and oxidative stress of cardiomyocytes. Gain-of-function assays showed that HMGCS2 overexpression reduced cell viability, increased apoptosis, caspase-3/-9 activity, up-regulated interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) expression, decreased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase expression, increased malondialdehyde (MDA) content, and reactive oxygen species (ROS) level but inhibited total antioxidant activity, SOD activity, CAT activity, and glutathione content in cardiomyocytes. Rescue experiments demonstrated HMGCS2 silence attenuated HG-induced decrease in cardiomyocyte viability and increase in cardiomyocyte apoptosis, inflammation, and oxidative stress. All in all, our study identified HMGCS2 as a hub gene in DCM pathophysiology and further functional studies indicated that HMGCS2 may aggravate DCM progression by reducing cardiomyocyte viability, increasing cardiomyocyte apoptosis, and promoting inflammation and oxidative stress in cardiomyocytes.

A new alkaloid with cytotoxic activity from Fritillaria thunbergii Miq.

A new alkaloid named zhebeisine (1), together with four known compounds, eduardine (2), zhebeirine (3), isoverticine (4), and verticine (5), was isolated from the bulbs of Fritillaria thunbergii Miq. The structure of the new compound was elucidated on the basis of extensive spectroscopic methods and the in vitro biological activities of it were evaluated as well. Compound 1 features a veratramine skeleton with a rare 6/6/5/6/6/6 fused-ring system, representing the first reported veratramine-type alkaloid with a new oxazinane ring (ring-F) in Fritillaria genus. The cytotoxic activities study revealed that compound 1 inhibited the cell proliferation of HT29 and DLD1 (IC50 values of 25.1 and 48.8 µM, respectively) and also induced apoptosis of the above-mentioned two cancer cell lines.[Formula: see text].

Investigating the biochemical effects of heat stress and sample quenching approach on the metabolic profiling of abalone (Haliotis iris).

INTRODUCTION: Ocean temperatures have been consistently increasing due to climate change, and the frequency of heatwave events on shellfish quality is a growing concern worldwide. Typically, shellfish growing areas are in remote or difficult to access locations which makes in-field sampling and sample preservation of shellfish heat stress difficult. As such, there is a need to investigate in-field sampling approaches that facilitate the study of heat stress in shellfish. OBJECTIVES: This study aims to apply a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach to examine molecular mechanisms of heat stress responses in shellfish using abalone as a model, and compare the effects of different quenching protocols on abalone metabolic profiles. METHODS: Twenty adult Haliotis iris abalone were exposed to two temperatures (14 °C and 24 °C) for 24 h. Then, haemolymph and muscle tissues of each animal were sampled and quenched with 4 different protocols (liquid nitrogen, dry ice, cold methanol solution and normal ice) which were analyzed via GC-MS for central carbon metabolites. RESULTS: The effects of different quenching protocols were only observed in muscle tissues in which the cold methanol solution and normal ice caused some changes in the observed metabolic profiles, compared to dry ice and liquid nitrogen. Abalone muscle tissues were less affected by thermal stress than haemolymph. There were 10 and 46 compounds significantly influenced by thermal stress in muscle and haemolymph, respectively. The changes of these metabolite signatures indicate oxidative damage, disturbance of amino acid and fatty acid metabolism, and a shift from aerobic metabolism to anaerobic pathways. CONCLUSIONS: The study provided insights into the heat response of abalone, which could be useful for understanding the effects of marine heatwaves and summer mortality events on abalone. Dry ice appeared to be a suitable protocol, and safer in-field alternative to liquid nitrogen, for quenching of abalone tissues.

Facile synthesis of amine-crosslinked starch as an efficient biosorbent for adsorptive removal of anionic organic pollutants from water.

Developing applicable biosorbents for adsorptive removal of organic pollutants from water is highly demanded. However, most biosorbents suffer poor adsorption capability for anionic organic pollutants due to their negatively charged surface. Herein, we present a facile method to synthesize amine-crosslinked starch (ACS) biosorbent for removing anionic organic pollutants. The adsorption properties of ACS were thoroughly evaluated by selecting anionic brilliant blue (BB), amaranth (ART), diclofenac sodium (DS) as representatives. The results show that the ACS can selectively adsorb anionic molecules with large adsorption capacity and fast removal rate. The adsorption kinetic and isotherm behaviors can be well described by the pseudo-second-order and Langmuir models, respectively. The maximum uptake capacity of ACS for BB, ART and DS is as high as 1287.7, 724.6 and 595.2 mg g-1, respectively. Moreover, the ACS can be easily regenerated and still exhibits favorable adsorption performance even after reusing for five times.

Isosteroidal alkaloids from Fritillaria hupehensis Hsiao et K.C.Hsia: Synthesis and biological evaluation of alkaloid derivatives as potential cytotoxic agents.

One new cevanine isosteroidal alkaloid named 5,6-anhydrohupehenine (1), together with five known alkaloids (2-6) were isolated from Fritillaria hupehensis Hsiao et K.C.Hsia, among which 5,6-anhydrohupehenine (1) exhibited strong inhibitory activity against HepG2 (IC50 = 12.21 µM) and MCF-7 (IC50 = 22.05 µM) cancer cells. Therefore, a total of 33 5,6-anhydrohupehenine derivatives (9a-9s, 10a-10f, 11a-11b, and 12a-12f) were synthesized and evaluated for their cytotoxic activity. The cytotoxicity evaluation of all 5,6-anhydrohupehenine derivatives against HepG2 and MCF-7 human cancer cells revealed that 9s displayed best activity against HepG2 cells with IC50 at 1.27 µM. Further biological evaluations on 9s showed that it inhibited the proliferation of HepG2 cells and induced apoptosis of the HepG2 cells by activating cleaved caspase-3. Moreover, 9s exhibited strong antimetastatic potential. These results suggest that 5,6-anhydrohupehenine is a promising compound to be designed as novel cytotoxic agents.

Programmed cell death-ligand 1 expression in hepatocellular carcinoma and its correlation with clinicopathological characteristics.

BACKGROUND AND AIM: Programmed cell death-ligand 1 (PD-L1) immunohistochemistry score has been approved as the predictive biomarker for anti-PD1/PD-L1 therapy in several advanced malignancies. Although its predictive role remained inconclusive in hepatocellular carcinoma, ongoing study of anti-PD1/PD-L1 therapy showed promising results. However, less is known about the PD-L1 immunohistochemistry score and factors correlated with it in hepatocellular carcinoma. We investigated PD-L1 immunohistochemistry scores in a large cohort of hepatocellular carcinoma, as well as its correlation with various clinical and genomic factors. METHODS: Immunohistochemistry was performed to detect the expression of PD-L1 protein in 315 hepatocellular carcinoma tissues. All slides were independently reviewed by three senior pathologists. Next-generation YS panel (450 genes) sequencing was performed on 309 patients. RESULTS: Higher PD-L1 expression as measured by combined positive score (CPS) was associated with increased Edmondson-Steiner grade (grade III vs II, P = 0.041) and TP53 mutations (P = 0.021). PD-L1 CPS had no correlation with tumor mutational burden (Spearman's correlation coefficient 0.067). PD-L1 CPS was not significantly associated with hepatitis B virus infection. CONCLUSIONS: Our data indicated that patients with higher Edmondson-Steiner grade (grade III) had significantly higher PD-L1 CPS than patients with lower Edmondson-Steiner grade (grade II). Patients with TP53 mutations had significantly higher PD-L1 expression.

Pharmacokinetics and tissue distribution study of hupehenenine in rats: A novel isosteroid alkaloid isolated from Bulbus Hupehensis Fritillariae.

Hupehenenine is a novel isosteroid alkaloid that was first isolated from Bulbus Hupehensis Fritillariae. The inhibitory proliferation effect of hupehenenine and its three related alkaloid derivatives, including o-caproyl-hupehenenine, o-(2-furanoyl)-hupehenenine, and Δ5(6) -isopeimine on human lung cancer cell line, human chronic myeloid leukemia cell line, and human thyroid duct cancer cell line in vitro, has been identified. This study first developed a sensitive HPLC-MS/MS method for the simultaneous quantification of hupehenenine and three alkaloid derivatives in rat plasma and tissues. The developed method was validated, and it was linear over the concentration range of 1-800 ng/mL for all analytes with R2 ≥ 0.9939 and 0.9972, respectively, in rat plasma and rat liver homogenate. The lower limit of quantitation was 1 ng/mL for all analytes. The intra-day and inter-day precision and accuracy were satisfactory. This validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of hupehenenine in rats. In pharmacokinetic study, the maximum plasma concentration of rats exists gender difference. Tissue distribution study showed that hupehenenine has good affinity for multiple tissues but is unable to cross the blood-brain barrier. These results may provide a useful reference for further research of hupehenenine and its three related alkaloid derivatives.

Simulated aging processes of black carbon and its impact during a severe winter haze event in the Beijing-Tianjin-Hebei region.

Black carbon (BC) can mitigate or worsen air pollution by perturbing meteorological conditions. BC aging processes strongly influence the evolution of the particle size, concentration, and optical properties of BC, which determine its influence on meteorology. Here, we use the online coupled Weather Research and Forecasting-Chemistry (WRF-Chem) model to quantify the role of BC aging processes, including physical processes (PP) and absorption enhancement (AE), in causing BC-induced meteorological changes and their associated feedbacks to PM2.5 (particulate matter less than 2.5 µm in diameter) and O3 concentrations during a severe haze event in the Beijing-Tianjin-Hebei (BTH) region during 21-27 February 2014. Our results show that, compared to those from the simulation without PP, the simulated near-surface BC concentration and BC mass loading in the BTH region decreased by 6.6% and 12.1%, respectively, when PP were included. PP increased the proportion of large BC (particle diameter greater than 0.312 µm) below 1000 m from 28 to 33% to 59-64% in the BTH region. When both PP and AE were included in the simulation, the reduction in PBL height due to the BC-PBL interaction was 116.3 m (20.7%), compared to reductions of 75.7 m (13.5%) without AE and 66.6 m (11.9%) without PP and AE. However, during this haze event, anomalous northeasterly winds were produced by the direct radiative effect of BC, which further affected aerosol mixing and transport. Due to their combined impacts on multiple meteorological factors, the direct radiative effects of BC without PP and AE, without AE, and with PP and AE increased the surface concentrations of PM2.5 by 8.3 µg m-3 (by 6.1% relative to the mean value), 6.1 µg m-3 (4.5%) and 9.6 µg m-3 (7.0%), respectively, but decreased the surface O3 concentrations by 2.8 ppbv (7.4%), 4.0 ppbv (9.0%) and 5.0 ppbv (10.8%) on average in the BTH region during 21-27 February 2014.

NFE2L2/KEAP1 Mutations Correlate with Higher Tumor Mutational Burden Value/PD-L1 Expression and Potentiate Improved Clinical Outcome with Immunotherapy.

BACKGROUND: Abnormalities in the KEPA1-NRF2 pathway have a role in cancer progression, metastasis, and resistance to chemo- and radiotherapies. Persistent activation of NRF2 associates with poor prognosis across different cancer types. However, the beneficial therapeutic strategy to harness this pathway in cancer remains unclear. This study aimed to investigate the clinical outcome with immunotherapy in NFE2L2/KEAP1 mutant population. MATERIALS AND METHODS: We investigated the correlation between NFE2L2/KEAP1 mutations and tumor mutational burden (TMB) and programmed death-ligand 1 (PD-L1) expression status to identify the therapeutic vulnerability. For this purpose, relevance analysis with TMB value was performed in 9,040 patients with cancer, and relevance analysis with PD-L1 expression was performed in 3,457 patients. The Memorial Sloan Kettering Cancer Center (MSKCC) database and real-world evidence were used to assess the immunotherapy response in NFE2L2/KEAP1 mutant subsets. RESULTS: NFE2L2/KEAP1 mutations occurred in various cancers, and the highest mutation incidences occurred in lung squamous cell carcinoma (LUSC) at 19.16% (NFE2L2) and 10.31% (KEAP1). We confirmed that higher TMB value and PD-L1 expression were associated with NFE2L2/KEAP1 mutations compared with wild-type, especially in non-small lung cancer. MSKCC database analysis showed the improved survival of patients with NFE2L2/KEAP1 mutant with immunotherapy compared with other treatments (median overall survival 22.52 VS 12.89, p = .0034). Real-world evidence further confirmed the efficacy of immunotherapy in the mutant population. CONCLUSION: Our study revealed that patients with NFE2L2/KEAP1 mutant could achieve improved outcomes from immunotherapy than the other treatments. These findings may broaden the application of immune checkpoint blockade to patients harboring NFE2L2/KEAP1 mutations. IMPLICATIONS FOR PRACTICE: NFE2L2/KEAP1 alterations occur frequently in multiple cancer types and are associated with poor prognosis; however, the efficacious strategy to inhibit this pathway in cancer is poorly understood. This study was designed to analyze the mutational characteristics of NFE2L2/KEAP1 alterations in 9,243 Chinese patients. The highest mutation incidences occurred in lung squamous cell carcinoma at 19.16% (NFE2L2) and 10.31% (KEAP1). Relevance analysis showed the NFE2L2/KEAP1 mutant subsets were associated with higher tumor mutational burden value and programmed death-ligand 1 expression. Clinical data further confirmed NFE2L2/KEAP1 mutations correlate with improved outcome with immunotherapy. These findings suggest the clinical application of immunotherapy in the NFE2L2/KEAP1 mutant population.

Characterization of phenolic compounds and aroma active compounds in feijoa juice from four New Zealand grown cultivars by LC-MS and HS-SPME-GC-O-MS.

The phenolic compounds and aroma active compounds in feijoa (Acca sellowiana (O.Berg) Burret) juice from four New Zealand grown cultivars (Apollo, Unique, Opal Star, and Wiki Tu) were investigated. A high total phenolic content (maximum 1.89 mg GAE/mL juice) and significant antioxidant activities (maximum 14.66 mM Trolox/mL juice) were determined in feijoa juices. A total of 7 phenolic compounds from the screening of 29 standards were identified and quantified by LC-MS, with procyanidin B1 (209.78-511.07 µg/mL) and (+)-catechin (121.80-472.75 µg/mL) being the most abundant. Procyanidin B2 and quercetin-3-galactoside were reported in feijoa samples for the first time. The volatile compounds in feijoa juice were identified by HS-SPME-GC-MS, and 17 of the 63 identified compounds were not previously reported in feijoa samples. A total of 25 aroma active compounds were further identified by the olfactory test, and the esters and terpenes were the dominant compounds contributing to the aroma of feijoa juice. Methyl benzoate showed the characteristic "feijoa-like" aroma with a concentration of 13.62-52.62 µg/g juice. The aroma profile of feijoa juice from the four selected cultivars was established, and the "fruity" and "green, grassy & herbal" notes were the predominant attributes. Among the four selected cultivars, the Unique cultivar had the highest total phenolic content and antioxidant activities, while the Wiki Tu was the most aroma intensive. This study, first report on the phenolics and aroma compounds in feijoa juice with comparison of four cultivars, could be fundamental and essential to natural fruit juice industry and feijoa fruit investigation, as well as provided scientific evidence to local feijoa market and growers regarding cultivar selection.