Bulk Trapping Organic Semiconductor with Amino-Additive Enabling Ultrasensitive NO2 Sensors.

Organic semiconductor (OSC) gas sensors have garnered considerable attention due to their promising selectivity and inherent flexibility. Introducing a functional group or modification layer is an important route to modulate the doping/trapping state of the active layer and the gas absorption/desorption process. However, the majority of the functionalization lies in the surface/interface assembling process, which is difficult to control the functional group density. This in turn brings challenges for precise modulation of the charge transport and the doping/trapping density, which will affect the repeatability and reproducibility of sensing performance. Herein, we propose a facile bulk trapping strategy incorporating amino-terminated additive molecules via the vacuum deposition process, achieving ultrahigh sensitivity of ∼2000%/ppm at room temperature to NO2 gas and approaching ∼3000%/ppm at 50 °C. Additionally, the device exhibits commendable reproducibility, stability, and low concentration detection ability, reaching down to several ppb, indicating promising potential for future applications. Comprehensive analysis of electrical properties and density functional theory calculations reveals that these exceptional properties arise from the favorable electrical characteristics of the bulk trapping structure, the high mobility of C8-BTBT, and the elevated adsorption energy of NO2. This approach enables the construction of stable and reproducible sensitive sensors and helps to understand the sensing mechanism in OSC gas sensors.

Ultrathin Al2O3 film modification on waterborne epoxy coatings by atomic layer deposition for augmenting the corrosion resistance.

The polar channels formed by the curing of waterborne anticorrosive coatings compromise their water resistance, leading to coating degradation and metal corrosion. To enhance the anticorrosive performance of waterborne coatings, this study proposed a novel method of depositing ultrathin Al2O3 films on the surface of waterborne epoxy coatings by atomic layer deposition (ALD), a technique that can modify the surface properties of polymer materials by depositing functional films. The Al2O3-modified coatings exhibited improved sealing and barrier properties by closing the polar channels and surface defects and cracks. The surface structure and morphology of the modified coatings were characterized by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). The hydrophilicity and corrosion resistance of the modified coatings were evaluated by water contact angle measurement, Tafel polarization curve, and electrochemical impedance spectroscopy. The results indicated that the water contact angle of the Al2O3-modified coating increased by 48° compared to the unmodified coating, and the protection efficiency of the modified coating reached 99.81%. The Al2O3-modified coating demonstrated high anticorrosive efficiency and potential applications for metal anticorrosion in harsh marine environments. .

Impact of relative and absolute values on orienting attention in time.

Reward has been known to render the reward-associated stimulus more salient to block effective attentional orienting in space. However, whether and how reward influences goal-directed attention in time remains unclear. Here, we used a modified attentional cueing paradigm to explore the effect of reward on temporal attention, in which the valid targets were given a low monetary reward and invalid targets were given a high monetary reward. The results showed that the temporal cue validity effect was significantly smaller when the competitive reward structure was employed (Experiment 1), and we ruled out the possibility that the results were due to the practice effect (Experiment 2a) or a reward-promoting effect (Experiment 2b). When further strengthening the intensity of the reward from 1:10 to 1:100 (Experiment 3), we found a similar pattern of results to those in Experiment 1. These results suggest that reward information which was based on relative instead of absolute values can weaken, but not reverse, the orienting attention in time.

Attenuation of inflammatory bowel disease by oral administration of mucoadhesive polydopamine-coated yeast ß-glucan via ROS scavenging and gut microbiota regulation.

Treatment for inflammatory bowel disease (IBD) is challenging since current anti-inflammatory and immunosuppressive therapies do not address the underlying causes of the illness, which include increased levels of reactive oxygen species (ROS) and dysbiosis of the gut commensal microbiota. Additionally, these treatments often have systemic off-target effects and adverse side effects. In this study, we have developed a prebiotic yeast ß-glucan nanocomplex coated with bio-adhesive polydopamine (YBNs@PDA) to effectively prolong their retention time in the gastrointestinal (GI) tract. The oral administration of YBNs@PDA restored the epithelium barriers, reduced ROS levels, and minimized systemic drug exposure while improved therapeutic efficacy in an acute colitis mouse model. Furthermore, 16S ribosomal RNA genes sequencing demonstrated a higher richness and diversity in gut microflora composition following the treatments. In particular, YBNs@PDA markedly augmented the abundance of Lachnospiraceae NK4A136 and Bifidobacterium, both of which are probiotics with crucial roles in relieving colitis via retaining gut homeostasis. Cumulatively, these results demonstrate that the potential of YBNs@PDA as a novel drug-free, ROS-scavenging and gut microbiota regulation nanoplatform for the treatment of GI disorders.

Daily Associations between Salivary Cortisol and EEG-Assessed Sleep: A 15-Day Intensive Longitudinal Study.

STUDY OBJECTIVES: Current evidence suggests that cortisol levels are bi-directionally associated with sleep. However, the daily, naturalistic cortisol-sleep associations remain unclear, as current evidence is mostly cross-sectional. This study tested whether pre-sleep cortisol predicts sleep duration and quality, and whether these sleep parameters predict the following day's diurnal cortisol slope using a 15-day intensive longitudinal design with electroencephalographic measures and saliva sampling. METHODS: Ninety-five young adults (Mage=20.48±1.59 years) provided saliva samples at awakening and pre-sleep over 14 consecutive days, providing 2,345 samples (85% viable). The Z-Machine Insight+ was used to record over 900 nights of total sleep time (TST) and sleep efficiency (SE). Multilevel models tested these data at the between- and within-person levels. RESULTS: Higher pre-sleep cortisol predicted shorter TST (p<.001) and lower SE (p<.001) at the within-person level. Individuals with shorter average TST (p =.007) or lower average SE (p<.001) had flatter diurnal cortisol slope, compared to those with longer average TST or higher average SE. Follow up analyses showed that individuals with shorter average TST (vs. longer average TST) had higher pre-sleep cortisol levels (p=.01). CONCLUSION: Our findings provide evidence that pre-sleep cortisol is associated with sleep duration and quality at the within-individual level. Furthermore, individuals with short or poor sleep had flatter diurnal cortisol slope. Although the effect sizes are small, these findings show the naturalistic associations between sleep and cortisol in a relatively healthy sample. These findings suggest that sleep maintains the regulation of the stress-response system, which is protective against mental and physical disorders.

Activation of polyimide by oxygen plasma for atomic layer deposition of highly compact titanium oxide coating.

Titanium oxide (TiO2) coated polyimide has broad application prospects under extreme conditions. In order to obtain a high-quality ultra-thin TiO2coating on polyimide by atomic layer deposition (ALD), the polyimide was activated byin situoxygen plasma. It was found that a large number of polar oxygen functional groups, such as carboxyl, were generated on the surface of the activated polyimide, which can significantly promote the preparation of TiO2coating by ALD. The nucleation and growth of TiO2were studied by x-ray photoelectron spectroscopy monitoring and scanning electron microscopy observation. On the polyimide activated by oxygen plasma, the size of TiO2nuclei decreased and the quantity of TiO2nuclei increased, resulting in the growth of a highly uniform and dense TiO2coating. This coating exhibited excellent resistance to atomic oxygen. When exposed to 3.5 × 1021atom cm-2atomic oxygen flux, the erosion yield of the polyimide coated with 100 ALD cycles of TiO2was as low as 3.0 × 10-25cm3/atom, which is one order less than that of the standard POLYIMIDE-ref Kapton®film.

Highly catalytic Prussian blue analogues and their application on the three-dimensional origami paper-based sweat sensors.

Prussian blue analogues (PBAs) are promising materials due to their rich active sites and straightforward synthesis. However, their limited conductivity and electron transfer inefficiency hinder practical applications. This study utilizes a simple one-pot synthesis approach to produce a tungsten-disulfide (WS2) and iron-cobalt Prussian blue analogue composite (WS2-PBA), enhancing conductivity and electron transfer rate performance. Through the inclusion of sodium citrate into the solution, the S-edge site concentration of WS2 increases. This augmentation introduces additional active sites and defects into the catalyst, enhancing its catalytic activity. The effectiveness of the WS2-PBA 3D-Origami paper device for lactate detection in sweat is also evaluated for biomedical applications. The device demonstrated a robust relationship between the lactate concentration and current intensity (R2 = 0.997), with a detection limit of 1.83 mM. Additionally, this platform has successfully detected lactate in clinical sweat, correlating with the high-performance liquid chromatography test results, suggesting promising prospects for clinical diagnosis. In the future, the excellent catalytic and Rct performance of the WS2-PBA will enable its use in biomedical applications.

Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC.

Triple-negative breast cancer (TNBC) is a heterogeneous and challenging-to-treat breast cancer subtype. The clinical introduction of immune checkpoint inhibitors (ICI) for TNBC has had mixed results, and very few patients achieved a durable response. The PI3K/AKT pathway is frequently mutated in breast cancer. Given the important roles of the PI3K pathway in immune and tumor cell signaling, there is an interest in using inhibitors of this pathway to increase the response to ICI. This study sought to determine if AKT inhibition could enhance the response to ICI in murine TNBC models. We further sought to understand underlying mechanisms of response or non-response to AKT inhibition in combination with ICI. Using four murine TNBC-like cell lines and corresponding orthotopic mouse tumor models, we found that hyperactivity of the PI3K pathway, as evidenced by levels of phospho-AKT rather than PI3K pathway mutational status, was associated with response to AKT inhibition alone and in combination with ICI. Additional mutations in other growth regulatory pathways could override the response of PI3K pathway mutant tumors to AKT inhibition. Furthermore, we observed that AKT inhibition enhanced the response to ICI in an already sensitive model. However, AKT inhibition failed to convert ICI-resistant tumors, to responsive tumors. These findings suggest that analysis of both the mutational status and phospho-AKT protein levels may be beneficial in predicting which TNBC tumors will respond to AKT inhibition in combination with ICI.

Acetylcholine Analog-Modified Albumin Nanoparticles for the Enhanced and Synchronous Brain Delivery of Saponin Components of Panax Notoginseng.

BACKGROUND: Panax notoginseng saponins (PNS) are commonly used first-line drugs for treating cerebral thrombosis and stroke in China. However, the synchronized and targeted delivery of active ingredients in traditional Chinese medicine (TCM) poses a significant challenge for modern TCM formulations. METHODS: Bovine serum albumin (BSA) was modified using 2-methacryloyloxyethyl phosphorylcholine (MPC), an analog of acetylcholine, and subsequently adsorbed the major PNS onto the modified albumin to produce MPC-BSA@PNS nanoparticles (NPs). This novel delivery system facilitated efficient and synchronized transport of PNS across the blood-brain barrier (BBB) through active transport mediated by nicotinic acetylcholine receptors. RESULTS: In vitro experiments demonstrated that the transport rates of R1, Rg1, Rb1, and Rd across the BBB were relatively synchronous in MPC-BSA@PNS NPs compared to those in the PNS solution. Additionally, animal experiments revealed that the brain-targeting efficiencies of R1 + Rg1 + Rb1 in MPC-BSA@PNS NPs were 2.02 and 7.73 times higher than those in BSA@PNS NPs and the free PNS group, respectively. CONCLUSIONS: This study presents a simple and feasible approach for achieving the targeted delivery of complex active ingredient clusters in TCM.

Protocatechuic acid alleviates TMAO-aggravated atherosclerosis via mitigating inflammation, regulating lipid metabolism, and reshaping gut microbiota.

Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study investigated the effect of PCA on TMAO-aggravated atherosclerosis in ApoE-/- mice. The mice were randomly divided into five groups and fed one of the following five diets for 12 weeks: namely a low-fat diet (LFD), a western diet (WD), a WD + 0.2% TMAO diet (WDT), a WDT + 0.5% PCA diet (WDT + LPCA), and a WDT + 1.0% PCA diet (WDT + HPCA). Results demonstrated that dietary TMAO exacerbated the development of atherosclerosis by eliciting inflammation and disturbing lipid metabolism. The diet with PCA at 1% reduced TMAO-induced aortic plaque by 30% and decreased the levels of plasma pro-inflammatory cytokines. PCA also improved lipid metabolism by up-regulating the hepatic gene expression of peroxisome proliferator-activated receptor alpha (PPARα). In addition, PCA supplementation enhanced fecal excretion of fatty acids and decreased hepatic fat accumulation. PCA supplementation favorably modulated gut microbiota by increasing the α-diversity with an increase in the abundance of beneficial genera (Rikenella, Turicibacter, Clostridium_sensu_stricto and Bifidobacterium) and a decrease in the abundance of the harmful Helicobacter genus. In summary, PCA could alleviate the TMAO-exacerbated atherosclerosis and inflammation, improve the lipid metabolism, and modulate gut microbiota.

Harnessing the potential of CD40 agonism in cancer therapy.

CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily of receptors expressed on a variety of cell types. The CD40-CD40L interaction gives rise to many immune events, including the licensing of dendritic cells to activate CD8+ effector T cells, as well as the facilitation of B cell activation, proliferation, and differentiation. In malignant cells, the expression of CD40 varies among cancer types, mediating cellular proliferation, apoptosis, survival and the secretion of cytokines and chemokines. Agonistic human anti-CD40 antibodies are emerging as an option for cancer treatment, and early-phase clinical trials explored its monotherapy or combination with radiotherapy, chemotherapy, immune checkpoint blockade, and other immunomodulatory approaches. In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them.

Cholesterol Oxidation Products: Potential Adverse Effect and Prevention of Their Production in Foods.

Cholesterol oxidation products (COPs) are a group of substances formed during food processing. COPs in diet is a health concern because they may affect human health in association with the risk of various diseases including atherosclerosis, Alzheimer's disease, age-related macular degeneration, diabetes, and chronic gastrointestinal inflammatory colitis. Production of COPs in foods can be affected by many factors such as temperature, pH, light, oxygen, water, carbohydrates, fatty acids, proteins, and metal cations. The key issue is preventing its generation in foods. Some COPs can also be produced in vivo by both nonenzymatic and enzymatic-catalyzed oxidation reactions. Currently, a number of natural antioxidants such as catechins, flavonoids, and other polyphenols have been proven to inhibit the generation of COPs. In addition, measures taken during food processing can also minimize the production of COPs, such as the Maillard reaction and marinating food with plant polyphenol-rich seasonings. In conclusion, a comprehensive approach encompassing the suppression on COPs generation and implementation of processing measures is imperative to safeguard human health against the production of COPs in the food chain.

Dose-response formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine in liver and urine correlates with micronucleated reticulocyte frequencies in mice administered safrole oxide.

Safrole oxide (SAFO), a metabolite of naturally occurring hepatocarcinogen safrole, is implicated in causing DNA adduct formation. Our previous study first detected the most abundant SAFO-induced DNA adduct, N7-(3-benzo[1,3] dioxol-5-yl-2-hydroxypropyl)guanine (N7γ-SAFO-G), in mouse urine using a well-developed isotope-dilution high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (ID-HPLC-ESI-MS/MS) method. This study further elucidated the genotoxic mode of action of SAFO in mice treated with SAFO 30, 60, 90, or 120 mg/kg for 28 days. The ID-HPLC-ESI-MS/MS method detected N7γ-SAFO-G with excellent sensitivity and specificity in mouse liver and urine of SAFO-treated mice. Our data provide the first direct evidence of SAFO-DNA adduct formation in rodent tissues. N7γ-SAFO-G levels in liver were significantly increased by SAFO 120 mg/kg compared with SAFO 30 mg/kg, suggesting rapid spontaneous or enzymatic depurination of N7γ-SAFO-G in tissue DNA. Urinary N7γ-SAFO-G exhibited a sublinear dose response. Moreover, the micronucleated peripheral reticulocyte frequencies increased dose-dependently and significantly correlated with N7γ-SAFO-G levels in liver (r = 0.8647; p < 0.0001) and urine (r = 0.846; p < 0.0001). Our study suggests that safrole-mediated genotoxicity may be caused partly by its metabolic activation to SAFO and that urinary N7γ-SAFO-G may serve as a chemically-specific cancer risk biomarker for safrole exposure.

Structural-guided design to improve the catalytic performance of aldo-keto reductase KdAKR.

Aldo-keto reductases (AKRs) are important biocatalysts that can be used to synthesize chiral pharmaceutical alcohols. In this study, the catalytic activity and stereoselectivity of a NADPH-dependent AKR from Kluyveromyces dobzhanskii (KdAKR) toward t-butyl 6-chloro (5S)-hydroxy-3-oxohexanoate ((5S)-CHOH) were improved by mutating its residues in the loop regions around the substrate-binding pocket. And the thermostability of KdAKR was improved by a consensus sequence method targeted on the flexible regions. The best mutant M6 (Y28A/L58I/I63L/G223P/Y296W/W297H) exhibited a 67-fold higher catalytic efficiency compared to the wild-type (WT) KdAKR, and improved R-selectivity toward (5S)-CHOH (dep value from 47.6% to >99.5%). Moreover, M6 exhibited a 6.3-fold increase in half-life (t1/2 ) at 40°C compared to WT. Under the optimal conditions, M6 completely converted 200 g/L (5S)-CHOH to diastereomeric pure t-butyl 6-chloro-(3R, 5S)-dihydroxyhexanoate ((3R, 5S)-CDHH) within 8.0 h, with a space-time yield of 300.7 g/L/day. Our results deepen the understandings of the structure-function relationship of AKRs, providing a certain guidance for the modification of other AKRs.

Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma.

Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

Adverse effect of oxidized cholesterol exposure on colitis is mediated by modulation of gut microbiota.

Both cholesterol and oxidized cholesterol (OXC) are present in human diets. The incidence of inflammatory bowel diseases (IBDs) is increasing in the world. The present study was to investigate the mechanism by which OXC promotes colitis using C57BL/6 mice as a model. Results shown that more severe colitis was developed in OXC-treated mice with the administration of dextran sulfate sodium (DSS) in water. Direct effects of short-term OXC exposure on gut barrier or inflammation were not observed in healthy mice. However, OXC exposure could cause gut microbiota dysbiosis with a decrease in the relative abundance of short-train fatty acids (SCFAs)-producing bacteria (Lachnospiraceae_NK4A136_group and Blautia) and an increase in the abundance of some potential harmful bacteria (Bacteroides). OXC-induced symptoms of colitis were eliminated when mice were administered with antibiotic cocktails, indicating the promoting effect of OXC on DSS-induced colitis was mediated by its effect on gut microbiota. Moreover, bacteria-depleted mice colonized with gut microbiome from OXC-DSS-exposed mice exhibited a severe colitis, further proving the gut dysbiosis caused by OXC exposure was the culprit in exacerbating the colitis. It was concluded that dietary OXC exposure increased the susceptibility of colitis in mice by causing gut microbiota dysbiosis.

Coping strategies predict daily emotional reactivity to stress: An ecological momentary assessment study.

BACKGROUND: Emotional reactivity predicts poor health and psychopathology. Despite its theoretical importance, little research has tested whether coping predicts emotional reactivity to stressors. We analyse three studies to test this hypothesis for negative (NA) and positive affect (PA) reactivity to daily stressors. METHODS: 422 Participants (72.5 % females, Mage = 22.79 ± 5.36) came from three longitudinal, ecological momentary assessment (EMA) studies across 7-15 days (ACES N = 190; DESTRESS N = 134; SHS N = 98). Coping was measured at baseline. NA, PA, and daily stressors were assessed via EMA. Mixed effects linear models tested whether coping predicted NA and PA reactivity, defined as their slope on within- and between-person daily stressors. RESULTS: Behavioural disengagement and mental disengagement coping predicted greater within-person NA reactivity across all studies (all p < .01, all f2 = 0.01). Denial coping predicted greater within-person NA reactivity in ACES and DESTRESS (both p < .01, f2 from 0.02-0.03) and between-person in ACES and SHS (both p < .01, f2 from 0.02 to 0.03). For approach-oriented coping, only active planning coping predicted lower within-person NA reactivity and only in DESTRESS (p < .01, f2 = 0.02). Coping did not predict PA reactivity (all p > .05). LIMITATIONS: Our findings cannot be generalised to children or older adults. Emotional reactivity to daily stressors may differ from severe or traumatic stressors. Although data were longitudinal, the observational design precludes establishing causality. CONCLUSIONS: Avoidance-oriented coping strategies predicted greater NA reactivity to daily stressors with small effect sizes. Few and inconsistent results emerged for approach-oriented coping and PA reactivity. Clinically, our results suggest that reducing reliance on avoidance-oriented coping may reduce NA reactivity to daily stressors.

Effect of tea catechins on gut microbiota in high fat diet-induced obese mice.

BACKGROUND: Tea catechins have been shown to have beneficial effects on the alleviation of obesity, the prevention of diabetes, and the amelioration of metabolic syndrome. The purpose of the present work is to explore the underlying mechanisms linking the intestinal microbiota and anti-obesity benefits of green tea, oolong tea, and black tea catechins in C57BL/6J mice fed with a high-fat diet (HFD). RESULTS: The results indicated that, after the dietary intake of three tea catechins, obesity and low-grade inflammation were significantly alleviated. Hepatic steatosis was prevented, and this was accompanied by the upregulation of the mRNA and protein expressions of hepatic peroxisome proliferator-activated receptor α (PPARα). Metagenomic analysis of fecal samples suggested that the three tea catechins similarly changed the microbiota in terms of overall structure, composition, and protein functions by regulating the metabolites, facilitating the generation of short-chain fatty acids (SCFAs), and repressing lipopolysaccharides. CONCLUSION: The anti-obese properties of three tea catechins were partially mediated by their positive effect on gut microbiota, hepatic steatosis alleviation, and anti-inflammatory activity. © 2023 Society of Chemical Industry.

Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients.

OBJECTIVE: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB. DESIGN: We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models. RESULTS: We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models. CONCLUSION: Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.

Simultaneous determination of eleven volatile components in Cinnamomi Oleum by GC-MS / 中国中药杂志

A gas chromatography-triple quadrupole mass spectrometry(GC-MS) method was established for the simultaneous determination of eleven volatile components in Cinnamomi Oleum and the chemical pattern recognition was utilized to evaluate the quality of essential oil obtained from Cinnamomi Fructus medicinal materials in various habitats. The Cinnamomi Fructus medicinal materials were treated by water distillation, analyzed using GC-MS, and detected by selective ion monitoring(SIM), and the internal standards were used for quantification. The content results of Cinnamomi Oleum from various batches were analyzed by hierarchical clustering analysis(HCA), principal component analysis(PCA), and orthogonal partial least squares-discriminant analysis(OPLS-DA) for the statistic analysis. Eleven components showed good linear relationships within their respective concentration ranges(R~2>0.999 7), with average recoveries of 92.41%-102.1% and RSD of 1.2%-3.2%(n=6). The samples were classified into three categories by HCA and PCA, and 2-nonanone was screened as a marker of variability between batches in combination with OPLS-DA. This method is specific, sensitive, simple, and accurate, and the screened components can be utilized as a basis for the quality control of Cinnamomi Oleum.