Metabolomics integrated with mass spectrometry imaging reveals novel action of tetramethylpyrazine in migraine.

Migraine as a common neurological disorder still lacks effective therapies. Tetramethylpyrazine (TMP) is the main bioactive component from Ligusticum chuanxiong hort., a traditional edible-medicinal herb. This study aimed to investigate the action of TMP on migraine by metabolomics with mass spectrometry imaging (MSI) analysis and molecular exploring, including random forest model analysis, KEGG enrichment analysis and metabolite-metabolite interaction network analysis. The results indicated that 26 key representative metabolic biomarkers were identified, especially γ-glu-cys, which were highly related to glutathione (GSH) metabolism. MSI found the abundance of eleven endogenous metabolites were modulated by TMP, particularly glucose, the most important energy metabolism molecule, and GSH were increased that maintains intracellular redox balance, which was consistent with activation of Nrf2 signals by TMP. These findings provide insights into the effectiveness of metabolomics integrated with MSI in explaining the metabolic mechanisms of TMP, and afford valuable information for healthy development of TMP in migraine.

The mining of thermostable ß-glucosidase for tea aroma enhancement under brewing conditions.

The ß-glucosidases known to improve tea aroma are all mesothermal enzymes, limiting their use under brewing conditions. Based on the properties analysis and molecular docking, the thermostable ß-glucosidase (TPG) from Thermotoga petrophlia showed potential to enhance tea aroma. Treatment by recombinant TPG at 90 °C, the floral, sweet and grassy notes of instant Oolong tea were increased, while the roasted, caramel and woody notes were decreased. The improved floral, sweet and grassy notes were related to increase releasing of benzyl alcohol (floral), geraniol (floral), (Z)-3-hexen-1-ol (grassy), benzaldehyde (sweet) and 1-hexanol (grassy) by TPG hydrolyzing of (Z)-3-hexenyl-ß-D-glucopyranoside, hexanyl-ß-D-glucopyranoside (HGP), benzyl-ß-D-glucopyranoside, prunasin and geranyl-ß-D-glucopyranoside (GGP), respectively. Although the catalytic efficiency of TGP to GGP was about twice that to HGP, HPG was more competitive than GGP when they mixed. Combined with microstructure analysis, the structure-function relationship of TPG-influencing tea aroma were understood. This study provided the method of how to mining new function of characterized ß-glucosidases, as well as a theoretical basis for the development of new tea products.

Leonurine: a comprehensive review of pharmacokinetics, pharmacodynamics, and toxicology.

Leonurine is an alkaloid unique to the Leonurus genus, which has many biological activities, such as uterine contraction, anti-inflammation, anti-oxidation, regulation of cell apoptosis, anti-tumor, angiogenesis, anti-platelet aggregation, and inhibition of vasoconstriction. This paper summarizes the extraction methods, synthetic pathways, biosynthetic mechanisms, pharmacokinetic properties, pharmacological effects in various diseases, toxicology, and clinical trials of leonurine. To facilitate a successful transition into clinical application, intensified efforts are required in several key areas: structural modifications of leonurine to optimize its properties, comprehensive pharmacokinetic assessments to understand its behavior within the body, thorough mechanistic studies to elucidate how it works at the molecular level, rigorous safety evaluations and toxicological investigations to ensure patient wellbeing, and meticulously conducted clinical trials to validate its efficacy and safety profile.

Development and Validation of a Stromal-Immune Signature to Predict Prognosis in Intrahepatic Cholangiocarcinoma.

Background: Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC. Patients and methods: We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time. Results: We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort. Conclusion: We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.

Metal-organic frameworks for organic transformations by photocatalysis and photothermal catalysis.

Organic transformation by light-driven catalysis, especially, photocatalysis and photothermal catalysis, denoted as photo(thermal) catalysis, is an efficient, green, and economical route to produce value-added compounds. In recent years, owing to their diverse structure types, tunable pore sizes, and abundant active sites, metal-organic framework (MOF)-based photo(thermal) catalysis has attracted broad interest in organic transformations. In this review, we provide a comprehensive and systematic overview of MOF-based photo(thermal) catalysis for organic transformations. First, the general mechanisms, unique advantages, and strategies to improve the performance of MOFs in photo(thermal) catalysis are discussed. Then, outstanding examples of organic transformations over MOF-based photo(thermal) catalysis are introduced according to the reaction type. In addition, several representative advanced characterization techniques used for revealing the charge reaction kinetics and reaction intermediates of MOF-based organic transformations by photo(thermal) catalysis are presented. Finally, the prospects and challenges in this field are proposed. This review aims to inspire the rational design and development of MOF-based materials with improved performance in organic transformations by photocatalysis and photothermal catalysis.

Causal relationship between gut microbiota and diabetic complications: a two-sample Mendelian randomization study.

BACKGROUND: Imbalances in gut microbiota (GM) have been proposed as a potential contributing factor to diabetic complications; however, the causal relationship remains incompletely understood. METHODS: Summary statistics were obtained from genome-wide association studies (GWAS) of 196 gut microbial taxa, including 9 phyla, 16 classes, 20 orders, 32 families, and 119 genera. These data were then analyzed using mediation Mendelian randomization (MR) analyses to explore the potential mediating effect of diabetes complications risk factors on the relationship between gut microbiota and specific diabetic complications such as diabetic kidney disease (DKD), ketoacidosis, and diabetic retinopathy (DR). RESULTS: In our Mendelian analysis, we observed negative associations between Bifidobacterial order and Actinomycete phylum with DKD in type 1 diabetes (T1D) as well as early DKD in T1D. Conversely, these taxa showed positive associations with ketoacidosis in type 2 diabetes (T2D). In reverse Mendelian analysis, we found that DR in both T1D and T2D as well as ketoacidosis in T2D affected the abundance of Eubacterium fissicaten genus and LachnospiraceaeUCG010 family within the gut microbiota. CONCLUSIONS: Our findings provide compelling evidence for causal relationships between specific GM taxa and various diabetes complications. These insights contribute valuable knowledge for developing treatments targeting diabetes-related complications.

Rapid progress of an iris metastasis from esophageal cancer: a case report and review of literature.

This case report details a rare instance of rapid iris metastasis from esophageal cancer in a 59-year-old man. A literature review was conducted to explore recent advances in detecting, diagnosing, and treating intraocular metastatic malignancies. Positron emission tomography-computed tomography played a crucial role in identifying primary sites and systemic metastases. Local treatment combined with systemic therapy effectively reduced tumor size, preserved useful vision, and improved the patient's survival rate. A comparison was made of the characteristics of iris metastases from esophageal cancer and lung cancer, including age, gender, tumor characteristics, and treatment. The challenges associated with diagnosis and treatment are discussed, highlighting the implications for clinical practice.

Cooperative Sulfur Transformations at a Dinickel Site: A Metal Bridging Sulfur Radical and Its H-Atom Abstraction Thermochemistry.

Starting from the dinickel(II) dihydride complex [ML(Ni-H)2] (1M), where L3- is a bis(tridentate) pyrazolate-bridged bis(ß-diketiminato) ligand and M+ is Na+ or K+, a series of complexes [KLNi2(S2)] (2K), [MLNi2S] (3M), [LNi2(SMe)] (4), and [LNi2(SH)] (5) has been prepared. The µ-sulfido complexes 3M can be reversibly oxidized at E1/2 = -1.17 V (in THF; vs Fc+/Fc) to give [LNi2(S•)] (6) featuring a bridging S-radical. 6 has been comprehensively characterized, including by X-ray diffraction, SQUID magnetometry, EPR and XAS/XES spectroscopies, and DFT calculations. The pKa of the µ-hydrosulfido complex 5 in THF is 30.8 ± 0.4, which defines a S-H bond dissociation free energy (BDFE) of 75.1 ± 1.0 kcal mol-1. 6 reacts with H atom donors such as TEMPO-H and xanthene to give 5, while 5 reacts with 2,4,6-tri(tert-butyl)phenoxy radical in a reverse H atom transfer to generate 6. These findings provide the first full characterization of a genuine M-(µ-S•-)-M complex and provide insights into its proton-coupled electron transfer (PCET) reactivity, which is of interest in view of the prominence of M-(µ-SH/µ-S)-M units in biological systems and heterogeneous catalysis.

Unveiling an anoikis-related risk model and the role of RAD9A in colon cancer.

OBJECTIVE: Colorectal cancer (CRC), specifically colon adenocarcinoma, is the third most prevalent and the second most lethal form of cancer. Anoikis is found to be specialized form of programmed cell death (PCD), which plays a pivotal role in tumor progression. This study aimed to investigate the role of the anoikis related genes (ARGs) in colon cancer. METHODS: Consensus unsupervised clustering, differential expression analysis, tumor mutational burden analysis, and analysis of immune cell infiltration were utilized in the study. For the analysis of RNA sequences and clinical data of COAD patients, data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were obtained. A prognostic scoring system for overall survival (OS) prediction was developed using Cox regression and LASSO regression analysis. Furthermore, loss-of-function assay was utilized to explore the role of RAD9A played in the progression of colon cancer. RESULTS: The prognostic value of a risk score composed of NTRK2, EPHA2, RAD9A, CDC25C, and SNAI1 genes was significant. Furthermore, these findings suggested potential mechanisms that may influence prognosis, supporting the development of individualized treatment plans and management of patient outcomes. Further experiments confirmed that RAD9A could promote proliferation and metastasis of colon cancer cells. These effects may be achieved by affecting the phosphorylation of AKT. CONCLUSION: Differences in survival time and the tumor immune microenvironment (TIME) were observed between two gene clusters associated with ARGs. In addition, a prognostic risk model was established and confirmed as an independent risk factor. Furthermore, our data indicated that RAD9A promoted tumorigenicityby activating AKT in colon cancer.

Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display.

Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalization─installation of a covalent warhead─with mRNA display and showcases its application in targeted covalent ligand discovery.

Learning curve stratified outcomes after robotic pancreatoduodenectomy: International multicenter experience.

BACKGROUND: Robotic pancreatoduodenectomy is increasingly being implemented worldwide, with good results reported from individual expert centers. However, it is unclear to what extent outcomes will continue to improve during the learning curve, as large international studies are lacking. METHODS: An international retrospective multicenter case series, including consecutive patients after robotic pancreatoduodenectomy from 18 centers in 8 countries in Europe, Asia, and South America until December 31, 2019, was conducted. A cumulative sum analysis was performed to determine the inflection points for the feasibility (operative time and blood loss) and proficiency (postoperative pancreatic fistula grade B/C and major morbidity) learning curves. Outcomes were compared in 3 groups on the basis of the learning curve inflection points. RESULTS: Overall, 2,186 patients after robotic pancreatoduodenectomy were included. The feasibility learning curve was reached after 30-45 robotic pancreatoduodenectomy procedures and the proficiency learning curve after 90 robotic pancreatoduodenectomy procedures. These inflection points created 3 phases, which were associated with major morbidity (24.7%, 23.4%, and 12.3%, P < .001) but not 30-day mortality (2.1%, 2.0%, and 1.5%, P = .670). Other outcomes mostly continued to improve, including median operative time 432, 390, and 300 minutes (P < .0001), conversion 6.0%, 4.7%, and 2.7% (P = .002), bile leakage 7.2%, 4.1%, and 2.4% (P < .001), postpancreatectomy hemorrhage 6.5%, 6.1%, and 1.8% (n = 21) but not R0 resection (pancreatic ductal adenocarcinoma only) 78.5%, 73.9%, and 82.8% (P = .35), and 90-day mortality rate 3.1%, 3.5%, and 2.1% (P = .191). Centers performing >20 robotic pancreatoduodenectomies annually had lower rates of conversion, reoperation, and shorter median operative time as compared with centers performing 10-20 robotic pancreatoduodenectomies annually. CONCLUSION: This international multicenter study demonstrates that most outcomes of robotic pancreatoduodenectomy continued to improve during 3 learning curve phases without a negative effect on 90-day mortality. Randomized studies are needed in high-volume centers that have surpassed the first learning curves, to compare these outcomes with the open approach.

Contamination of the traditional medicine Radix Dipsaci with aflatoxin B1 impairs hippocampal neurogenesis and cognitive function in a mouse model of osteoporosis.

BACKGROUND: Aflatoxin B1, which can penetrate the blood-brain barrier and kill neural cells, can contaminate traditional herbal medicines, posing a significant risk to human health. The present study examined cellular, cognitive and behavioral consequences of aflatoxin B1 contamination of the anti-osteoporotic medicine Radix Dipsaci. METHODS: A mouse model of osteoporosis was created by treating the animals with all-trans-retinoic acid. Then the animals were treated intragastically with water decoctions of Radix Dipsaci that contained detectable aflatoxin B1 or not. The animals were compared in terms of mineral density and mineral salt content of bone, production of pro-inflammatory factors, neurogenesis and microglial activation in hippocampus, as well as behavior and cognitive function. RESULTS: Contamination of Radix Dipsaci with aflatoxin B1 significantly reduced the medicine's content of bioactive saponins. It destroyed the ability of the herbal decoction to improve mineral density and mineral salt content in the bones of diseased mice, and it induced the production of the oxidative stress marker malondialdehyde as well as the pro-inflammatory cytokines interleukin-1ß and tumor necrosis factor-α. Aflatoxin B1 contamination inhibited formation of new neurons and increased the proportion of activated microglia in the hippocampus. These neurological changes were associated with anhedonia, behavioral despair, and deficits in short-term memory and social memory. CONCLUSION: Contamination of Radix Dipsaci with aflatoxin B1 not only eliminates the herbal decoction's anti-osteoporotic effects, but it also induces neurotoxicity that can lead to cognitive decline and behavioral abnormalities. Such contamination should be avoided through tightly regulated production and quality control of medicinal herbs.

Biased receptor signalling and intracellular trafficking profiles of structurally distinct formylpeptide receptor 2 agonists.

BACKGROUND: There is increasing interest in developing FPR2 agonists (compound 43, ACT-389949 and BMS-986235) as potential pro-resolving therapeutics, with ACT-389949 and BMS-986235 having entered phase I clinical development. FPR2 activation leads to diverse downstream outputs. ACT-389949 was observed to cause rapid tachyphylaxis, while BMS-986235 and compound 43 induced cardioprotective effects in preclinical models. We aim to characterise the differences in ligand-receptor engagement and downstream signalling and trafficking bias profile. EXPERIMENTAL APPROACH: Concentration-response curves to G protein dissociation, ß-arrestin recruitment, receptor trafficking and second messenger signalling were generated using FPR2 ligands (BMS-986235, ACT-389949, compound 43 and WKYMVm), in HEK293A cells. Log(τ/KA) was obtained from the operational model for bias analysis using WKYMVm as a reference ligand. Docking of FPR2 ligands into the active FPR2 cryoEM structure (PDBID: 7T6S) was performed using ICM pro software. KEY RESULTS: Bias analysis revealed that WKYMVm and ACT-389949 shared a very similar bias profile. In comparison, BMS-986235 and compound 43 displayed approximately 5- to 50-fold bias away from ß-arrestin recruitment and trafficking pathways, while being 35- to 60-fold biased towards cAMP inhibition and pERK1/2. Molecular docking predicted key amino acid interactions at the FPR2 shared between WKYMVm and ACT-389949, but not with BMS-986235 and compound 43. CONCLUSION AND IMPLICATIONS: In vitro characterisation demonstrated that WKYMVm and ACT-389949 differ from BMS-986235 and compound 43 in their signalling and protein coupling profile. This observation may be explained by differences in the ligand-receptor interactions. In vitro characterisation provided significant insights into identifying the desired bias profile for FPR2-based pharmacotherapy.

The first ER-targeting flavone-based fluorescent probe for Cys: Applications in real-time tracking in an epilepsy model and food analysis.

Epilepsy is one of the most commonly-seen neurological disorders, and both endoplasmic reticulum stress (ERS) and oxidative stress (OS) have been demonstrated to be associated with epileptic seizures. As one of the three endogenous thiol-containing amino acids, cysteine (Cys) is recognized not only as an important biomarker of various biological processes but also widely used as a significant additive in the food industry. However, the exact role that Cys plays in ERS has not been well answered up to now. In this paper, we reported the first flavone-based fluorescent probe (namely BFC) with nice endoplasmic reticulum (ER)-targeting ability, which was capable of monitoring Cys in a fast response (3.0 min), large stokes shift (130 nm) and low detection limit (10.4 nM). The recognition mechanism of Cys could be attributed to the addition-cyclization reaction involving a Cys residue and an acrylate group, resulting in the release of the strong excited-state intramolecular proton transfer (ESIPT) emission molecule of benzoflavonol (BF). The low cytotoxicity and good biocompatibility of the probe BFC allowed for monitoring the fluctuation of endogenous Cys levels under both ERS and OS processes, as well as in zebrafish models of epilepsy. Quantitative determination of Cys with the probe BFC was also achieved in three different food samples. Additionally, a probe-immersed test strips integrated with a smartphone device was successfully constructed for on-site colorimetric detection of Cys. Undoubtedly, our work provided a valuable tool for tracking Cys levels in both an epilepsy model and real food samples.

Natural harmaline acts as novel fluorescent probe for hypochlorous acid and promising therapeutic candidate for rheumatoid arthritis.

Endogenous hypochlorous acid (HOCl) is one of the most important reactive oxygen species (ROS) and acts as a distinct biomarker that is involved in various inflammatory responses including rheumatoid arthritis (RA). Therefore, it's crucial to develop an efficient method for the tracking and analysis of HOCl levels in vivo. Natural products continue to be compounds of interest, because they not only offer diverse and specific molecular scaffolds but also provide invaluable sources for new drug discovery. Herein, we firstly demonstrated harmaline (HML), a natural alkaloid mainly found in Peganum harmala L, could be acted as a novel fluorescent probe for HOCl with exceptional precision and responsiveness. Remarkably, this probe not only specifically tracked HOCl levels in cells and inflammatory RA mouse models, but also exhibited effective anti-inflammatory effects on RAW264.7 cells and anti-proliferative effects on fibroblast-like synoviocytes. Furthermore, HML has the potential to alleviate LPS-induced inflammation by inhibiting the NF-κB signaling pathway. This study represents the first example of a natural product that can simultaneously act as a fluorescent probe for specific ROS and a promising therapeutic candidate for a specific disease, which will undoubtedly extend the application of fluorophore-rich natural products.

Production of Martian fiber by in-situ resource utilization strategy.

Many countries and commercial organizations have shown great interest in constructing a Martian base. In situ resource utilization (ISRU) provides a cost-effective way to achieve this ambitious goal. In this article, we proposed to use Martian soil simulant to produce a fiber to satisfy material requirement for the construction of Martian base. The composition, melting behavior, and fiber forming process of the soil simulant was studied, and continuous fiber with maximum strength of 1320 MPa and elastic modulus of 99 GPa was obtained on a spinning facility. The findings of this study demonstrate the feasibility of ISRU to prepare Martian fiber from the soil on the Mars, offering a new way to obtain key materials for the construction of a Martian base.

Genome-wide CRISPR/Cas9 screen identifies SLC39A9 and PIK3C3 as crucial entry factors for Ebola virus infection.

The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOVΔVP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection.

Eco-friendly and highly efficient PM0.3 air filter made from nonwoven basalt fiber and electrospun nanocellulose fiber.

This study addresses the need for high-performance and sustainable air filters by developing a bio-based, high-efficiency particulate air (HEPA) filter. Current HEPA filters often rely on non-biodegradable materials, creating environmental burdens. In this paper, we presented a HEPA filter fabricated from natural basalt fiber (BF) and nanocellulose fiber. The developed filter featured a sandwich structure with electrospun nanocellulose fiber deposited onto a base BF layer, followed by a second BF layer and heat treatment. Various techniques were employed to characterize the obtained sample, and the results showed that the nonwoven BF fabric significantly reduced the pressure drop of the filter by up to 60 %. The nanocellulose fiber played a crucial role in achieving a remarkable filtration efficiency of 99.99 % for PM0.3. BF-based filter demonstrated exceptional fire resistance, hydrophobia, durability, and ease of cleaning, maintaining its effectiveness at temperatures up to 150 °C. Notably, it exhibited significantly better biodegradability than commercially available HEPA filters. By employing a hierarchical structure of sustainable basalt and cellulose fibers, this study paved the way for the development of next-generation hazardous particulate matter filters with exceptional performance in harsh conditions and reduced environmental impact.

Baseline viral load and on-treatment hepatocellular carcinoma risk in chronic hepatitis B: A multinational cohort study.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk persists in chronic hepatitis B (CHB) patients despite antiviral therapy. The relationship between pre-treatment baseline hepatitis B virus (HBV) viral load and HCC risk during antiviral treatment remains uncertain. METHODS: This multinational cohort study aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in 20,826 noncirrhotic, hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with baseline HBV DNA levels ≥2,000 IU/mL (3.30 log10 IU/mL) who initiated entecavir or tenofovir treatment. The primary outcome was on-treatment HCC incidence, stratified by baseline HBV viral load as a categorical variable. RESULTS: In total, 663 patients developed HCC over a median follow-up of 4.1 years, with an incidence rate of 0.81 per 100 person-years (95% confidence interval [CI], 0.75-0.87). Baseline HBV viral load was significantly associated with HCC risk in a non-linear parabolic pattern, independent of other factors. Patients with baseline viral load between 6.00 and 7.00 log10 IU/mL had the highest on-treatment HCC risk (adjusted hazard ratio, 4.28; 95% CI, 2.15-8.52; P < .0001) compared to those with baseline viral load ≥8.00 log10 IU/mL, who exhibited the lowest HCC risk. CONCLUSION: Baseline viral load showed a significant, non-linear, parabolic association with HCC risk during antiviral treatment in noncirrhotic CHB patients. Early initiation of antiviral treatment based on HBV viral load may help prevent irreversible HCC risk accumulation in CHB patients.

Identification of critical genes associated with oxidative stress pathways in benzene-induced hematotoxicity.

Background and aims: Bone marrow failure (BMF) is chronic benzene-induced hematotoxicity, which is associated with differential gene expression abnormality. Benzene-induced BMF is characterized by irreversible bone marrow depression. Despite extensive studies have been conducted, there is a lack of reliable, useful and simple diagnostic method for BMF. Previous studies have shown that the aberrant gene expression changes and reactive oxygen species production in bone marrow cells related to the development of BMF. Early detection of differentially expressed genes (DEGs) as potential biomarkers is important for diagnosis and treatment. However, the validation of effective biomarker through DEGs analysis in benzene-induced BMF still deserve to be clarified. This study aimed to identify target genes as potential biomarkers with benzene-induced BMF based on DEGs analysis. Methods: First, we developed a benzene-induced BMF mouse model and obtained the DEGs in bone marrow cells of benzene-exposed CD1 mice. Next, after obtaining the DEGs via RNA-Sequencing (RNA-seq) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also used, key genes associated with benzene-induced BMF were identified. Additionally, the key markers for benzene poisoning was evaluated using qRT-PCR technique. Results: We identified DEGs for further KEGG functional analysis. Ten statistically significantly (up or down) regulated genes, namely Mapk11, Foxo1, Lefty1, Ren1, Bank1, Fgf3, Cdc42ep2, Rasgrf1, P2rx7, and Shank3 were found mainly associated with mitogen-activated protein kinases (MAPK) oxidative stress pathway . Further analysis using qRT-PCR identified that eight statistically significant DEGs associated with signaling pathways such as MAPK. We found that the level of mRNA expression of Mapk11, Foxo1, Bank1, Lefty1, Ren1, P2rx7, and Fgf3 genes were increased and Cdc42ep2 gene was decreased in BMF mice compared to control mice. Additionally, we validated the eight candidate genes for potential biomarkers in peripheral blood mononuclear cells of benzene poisoning patients by qRT-PCR. Conclusion: Our results indicated that Mapk11 and Fgf3 were predominantly candidate genes linked to novel biomarkers for benzene hematotoxicity in human beings. Our study will provide new candidate genes as useful biomarkers involved in benzene-induced hematotoxicity.