Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.

KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.

Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice.

Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial-to-mesenchymal transition, reduces the production of pro-fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254-388aa interacts with Yes-associated protein (YAP) at WW2 domain (231-263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3',4'-Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4-dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

A novel structurally modified isophorone fluorescent probe for H2S detection.

Hydrogen sulfide (H2S) has a comprehensive contribution to the normal operation and stability of organisms and is also present in environmental water samples and food deterioration. Thus, it is exceedingly promising and significant to develop a highly sensitive detection technique for tracing H2S. Inspired by this, we designed and synthesized a new fluorescent probe 2-[3-[2-[3-bromo-4-(2,4- dinitrobenzenesulfonate)] ethenyl]-5,5-dimethyl-2-cyclohexen-1-ylidene]propanedinitrile (SP-Br) for hydrosulfide ion detection by introducing bromine atom. Compared with reported H2S probes based on the same fluorescent parent, SP-Br has longer fluorescence emission (λem = 670 nm), shorter response time (3 min), lower detection limit (149 nM), and wider detection range (0-30 nM). SP-Br can emit weak yellow fluorescence, and the emission intensity at 670 nm is considerably enhanced in the presence of hydrosulfide ions. The identification mechanism of hydrosulfide ion by SP-Br was verified by high-resolution mass spectrometry, fluorescence, and UV-vis absorption spectroscopy. In addition, SP-Br has been successfully applied to the monitoring of actual water samples and beer samples and has certain development prospects and value in the fields of environmental pollution and food quality analysis.

Harnessing chemical functionality of xylan hemicellulose towards carbohydrate polymer-based pH/magnetic dual-responsive nanocomposite hydrogel for drug delivery.

This study reports a pH/magnetic dual-responsive hemicellulose-based nanocomposite hydrogel with nearly 100 % carbohydrate polymer-based and biodegradable polymer compositions for drug delivery. We synthesized pure Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) using a co-precipitation method, then engineering xylan hemicellulose (XH), acrylic acid, poly(ethylene glycol) diacrylate, and Fe3O4 to synthesize the pH/magnetic dual-responsive hydrogel (Fe3O4@XH-Gel), through graft polymerization on XH with in-situ doping Fe3O4 MNPs initiated by the ammonium persulfate/tetramethylethylenediamine redox system. Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (1H NMR), X-ray diffractometry (XRD), scanning electron microscopy and energy dispersive spectrometer (SEM-EDS), high-resolution transmission electron microscopy (HRTEM), Brunauer-Emmett-Teller (BET), swelling gravimetric analysis, vibrating sample magnetometer (VSM) were employed to analyze the hydrogel's chemical structures, morphologies, pH-responsive behaviors, and magnetic responsiveness characteristics, mechanical and rheological properties, as well as cytotoxicity and biodegradability. The results indicate that the Fe3O4@XH-Gel exhibited excellent dual responsiveness to pH and magnetism. Furthermore, an emphasis was placed on the in-depth analysis of the pH response mechanism. Finally, we utilized this cutting-edge hydrogel to investigate the controlled-release behavior of two model drugs, Acetylsalicylic acid and Theophylline. The hydrogel demonstrated exceptional controlled release attributes, positioning it as a potential carrier for targeted drug delivery, particularly to the gastrointestinal conditions.

Ecological risk assessment methods for oxidative by-products in the oxidation degradation process of emerging pollutants: A review.

The inherent toxicity and persistence of emerging contaminants such as antibiotics and endocrine disruptors pose substantial threats to the environment. Advanced oxidation processes (AOPs) employed for oxidative degradation could yield toxic oxidation by-products (OBPs), including organic acids and aromatic hydrocarbons. Despite their typically low concentrations, OBPs require scrutiny owing to their potential health risks. Although effective assessment methodologies are available, a comprehensive review focusing on the ecological and environmental effects of these pollutants is lacking. This study offers a succinct overview of existing ecotoxicological exposure assessments for emerging organic pollutants. Further, it encapsulates principal dose-response assessment techniques and provides a comparative analysis of several methods. The straightforward assessment factor method evaluates risk based on exposure and species sensitivity and is suitable for preliminary assessments of single pollutants; Species Sensitivity Distribution (SSD) compares species sensitivities to OBPs, emphasizing the importance of species-specific toxicological responses; microcosm and mesocosm methods simulate and predict the effects of OBPs on aquatic life by considering environmental diversity and biological community structures and are ideal for assessing the toxicity of multiple OBPs; the ecological risk analysis model employs mathematical and probabilistic approaches to comprehensively and accurately assess exposures and effects, accounting for the complexities and uncertainties inherent in ecotoxicological evaluations. Different risk characterization techniques are outlined in this study, including the risk quotient (RQ), which is ideal for quantifying and comparing risks; probabilistic ecological risk assessment (PERA), suitable for managing significant uncertainty; and the Environmental Pollution Index (EPI), the preferred method for quantitative assessment of OBP pollution levels. The merits and limitations of each of these quantitative assessment tools are evaluated, providing a comprehensive view of their applications in risk analysis. In addition, pressing contemporary challenges are identified and trajectories and pivotal issues suggested for future research.

Comprehensive and deep evaluation of structural variation detection pipelines with third-generation sequencing data.

BACKGROUND: Structural variation (SV) detection methods using third-generation sequencing data are widely employed, yet accurately detecting SVs remains challenging. Different methods often yield inconsistent results for certain SV types, complicating tool selection and revealing biases in detection. RESULTS: This study comprehensively evaluates 53 SV detection pipelines using simulated and real data from PacBio (CLR: Continuous Long Read, CCS: Circular Consensus Sequencing) and Nanopore (ONT) platforms. We assess their performance in detecting various sizes and types of SVs, breakpoint biases, and genotyping accuracy with various sequencing depths. Notably, pipelines such as Minimap2-cuteSV2, NGMLR-SVIM, PBMM2-pbsv, Winnowmap-Sniffles2, and Winnowmap-SVision exhibit comparatively higher recall and precision. Our findings also show that combining multiple pipelines with the same aligner, like pbmm2 or winnowmap, can significantly enhance performance. The individual pipelines' detailed ranking and performance metrics can be viewed in a dynamic table: http://pmglab.top/SVPipelinesRanking . CONCLUSIONS: This study comprehensively characterizes the strengths and weaknesses of numerous pipelines, providing valuable insights that can improve SV detection in third-generation sequencing data and inform SV annotation and function prediction.

[Evolution Trend of Water Quality in the Inner Mongolia Section of the Yellow River from 2003 to 2020].

The aim of this study was to comprehensively understand the water environment quality status and its change trend in the Inner Mongolia section of the Yellow River Basin. To analyze the water quality in recent years,the water quality data in the Yellow River basin from 2003 to 2020 were firstly collected from five typical monitoring stations．Various data analysis methods, including principal component analysis, cluster analysis, and a long short-term memory model, were used along with an improved comprehensive water quality identification index to explore the spatiotemporal characteristics of water quality in the Yellow River Basin. The results showed that the overall water quality in the basin has improved and stabilized over time. In terms of temporal variation, there was a distinction between the wet season and dry season, with a better status observed during the wet season due to increased agricultural irrigation and higher water volume. Spatially, the five monitoring sections could be divided into three categories based on strong natural factors that maintained their temporal characteristics during the wet season； however, significant differences were observed during the dry season due to urban water usage patterns. Analysis using LSTM models revealed that ammonia nitrogen will continue to decline and have a decreasing impact on the comprehensive water quality. These findings provide valuable insights for the comprehensive management of water quality in Inner Mongolia's Yellow River Basin.

Two new species of Paraphlomis (Lamiales, Lamiaceae) from limestone karsts in Guangdong Province, China.

Paraphlomisqingyuanensis and P.baiwanensis (Lamiaceae), two new species from the limestone area in Guangdong Province, China, are described. Morphologically, both species belong to P.ser.Subcoriaceae C.Y. Wu & H.W. Li. A close relationship between the two new and P.subcoriacea was revealed by molecular phylogenetic analyses based on ETS and ITS. Further morphological and population genetic evidence indicated that they are distinct species in Paraphlomis. According to the IUCN Red List Categories and Criteria, P.qingyuanensis and P.baiwanensis were assessed as Endangered (EN) and Deficient (DD), respectively.

Myricetin mitigates motor disturbance and decreases neuronal ferroptosis in a rat model of Parkinson's disease.

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.

Alterations of mouse gut microbiome in alveolar echinococcosis.

Alveolar echinococcosis (AE) may affect the composition of the host's gut microbiota, potentially disrupting the balance between the gut microbiota and metabolites. Metagenomics and untargeted metabolomics were employed to characterize changes in the gut microbiota and metabolites in mouse models infected with E. multilocularis. Pearson correlation coefficients were calculated to compare the distribution of microbiota and metabolites, revealing synergistic or mutually exclusive relationships. Functional outputs of the gut microbiota were explored using the CAZy database and six enzymes involved in carbohydrate metabolism were identified with statistically significant differential expression between infected and control groups. The resistome was characterized by identifying antibiotic resistance genes annotated in the Comprehensive Antibiotic Resistance Database from the metagenomes of the groups. Firmicutes are the main carrier of ARGs in the host gut with tetQ being most prevalent. Antibiotic efflux, inactivation and target modification were the principal mechanisms of resistance. Comparison and analysis of two sets of antibiotic metabolic pathways allowed the identification of enzyme reactions unique to infected mice. KEGG pathway overview shows phenazine biosynthesis involving phzG to be one of them. In conclusion, infection with AE in mice leads to an overall disruption of gut microbiota and metabolites with the involvement of enzymes related to carbohydrate metabolism. Furthermore, antibiotic-resistance genes may play a role in disease progression, offering potential insights into the relationship between antibiotic use in AE and treatment outcomes.

Beneficial effects of Dendrobium officinale National Herbal Drink on metabolic immune crosstalk via regulate SCFAs-Th17/Treg.

BACKGROUND: The development of gut-liver axis metabolic immune crosstalk is intimately associated with intestinal barrier disorder, intestinal SCFAs-Th17/Treg immunological imbalance, and disorders of the gut microbiota. Prior research has discovered that Dendrobium officinale National Herbal Drink (NHD), a traditional Chinese medicine drink with enhanced immunity, may enhance the immunological response in animals with impaired immune systems brought on by cyclophosphamide by repairing intestinal barrier function and controlling turbulence in the gut microbiota. However, whether NHD can further improve the gut-liver axis metabolic immune crosstalk and its related mechanisms need to be systematically studied. OBJECTIVES: The purpose of this study is to clarify the function and mechanism of NHD in enhancing the gut-liver axis metabolic immunological crosstalk brought on by excessive alcohol intake. METHODS: In this work, we set up a mouse model to analyze the metabolic and immunological crosstalk involving the gut-liver axis across 7 weeks of continuous, excessive drinking. At the same time, high and low doses (20,10 ml/kg) of NHD were given by gavage. The effect of NHD on improving the metabolism of gut-liver axis was evaluated by blood lipid, liver lipid deposition, liver function and intestinal pathophysiology. By measuring serum immunological indices, intestinal barrier, and intestinal immune barrier, the impact of NHD on enhancing immune and intestinal barrier function was assessed. Furthermore, immunohistochemistry, immunofluorescence, 16S rRNA, Western blot, q-PCR and other methods were used to detect gut microbiota, SCFAs-GPR41/43 pathway, intestinal Th17/Treg immune cells and PPAR-α-NPC1L1/SREBP1 pathway to elucidate the mechanism by which NHD enhances the gut-liver axis' metabolic immune crosstalk. RESULTS: Our study demonstrated that NHD has the potential to improve the pathophysiological damage caused by gut-liver axis in model mice. NHD also ameliorated the disorder of lipid metabolism. In addition, it regulated the levels of peripheral blood T cell immunity and serum immune factors. And NHD can restore intestinal mechanical and immune barrier damage. NHD has a favorable impact on the quantity of beneficial bacteria, including uncultured_bacterium_g__norank_f__muribaculacea and uncultured_bacterium_g__Turicibacter. Additionally, it raised the model mice's levels of SCFAs (n-butyric acid, isovaleric acid, etc.). This resulted in the promotion of intestinal GPR41/43-ERK1/2 expression and the reshaping of intestinal CD4+T cell Th17/Treg homeostasis. As a consequence, colon IL-22 and IL-10 levels increased, while colon IL-17A levels decreased. Lastly, NHD raised the amount of intestinal IAP/LPS, regulated the development of PPAR-α-NPC1L1/SREBP1 pathway in gut-liver axis, and improve lipid metabolism disorder. CONCLUSIONS: Our study found that NHD can improve the gut-liver axis metabolic immune crosstalk in model mice caused by excessive drinking. The mechanism might be connected to how NHD controls gut microbiota disorders in model mice, the activation of intestinal SCFAs-GPR41/43 pathway, the remodeling of Th17/Treg immune homeostasis of intestinal CD4+T cells, the improvement of IAP/LPS abnormality, and further mediating the PPAR-α-NPC1L1/SREBP1 pathway of lipid metabolism in gut-liver axis.

Comprehensive identification of pathogenic variants in retinoblastoma by long- and short-read sequencing.

Retinoblastoma (RB) is the most common intraocular malignancy in childhood. The causal variants in RB are mostly characterized by previously used short-read sequencing (SRS) analysis, which has technical limitations in identifying structural variants (SVs) and phasing information. Long-read sequencing (LRS) technology has advantages over SRS in detecting SVs, phased genetic variants, and methylation. In this study, we comprehensively characterized the genetic landscape of RB using combinatorial LRS and SRS of 16 RB tumors and 16 matched blood samples. We detected a total of 232 somatic SVs, with an average of 14.5 SVs per sample across the whole genome in our cohort. We identified 20 distinct pathogenic variants disrupting RB1 gene, including three novel small variants and five somatic SVs. We found more somatic SVs were detected from LRS than SRS (140 vs. 122) in RB samples with WGS data, particularly the insertions (18 vs. 1). Furthermore, our analysis shows that, with the exception of one sample who lacked the methylation data, all samples presented biallelic inactivation of RB1 in various forms, including two cases with the biallelic hypermethylated promoter and four cases with compound heterozygous mutations which were missing in SRS analysis. By inferring relative timing of somatic events, we reveal the genetic progression that RB1 disruption early and followed by copy number changes, including amplifications of Chr2p and deletions of Chr16q, during RB tumorigenesis. Altogether, we characterize the comprehensive genetic landscape of RB, providing novel insights into the genetic alterations and mechanisms contributing to RB initiation and development. Our work also establishes a framework to analyze genomic landscape of cancers based on LRS data.

Circular RNA-based therapy provides sustained and robust neuroprotection for retinal ganglion cells.

Ocular neurodegenerative diseases like glaucoma lead to progressive retinal ganglion cell (RGC) loss, causing irreversible vision impairment. Neuroprotection is needed to preserve RGCs across debilitating conditions. Nerve growth factor (NGF) protein therapy shows efficacy, but struggles with limited bioavailability and a short half-life. Here we explore a novel approach to address this deficiency by utilizing circular RNA (circRNA)-based therapy. We show that circRNAs exhibit an exceptional capacity for prolonged protein expression and circRNA-expressed NGF protects cells from glucose deprivation. In a mouse optic nerve crush model, lipid nanoparticle (LNP)-formulated circNGF administered intravitreally protects RGCs and axons from injury-induced degeneration. It also significantly outperforms NGF protein therapy without detectable retinal toxicity. Furthermore, single-cell transcriptomics revealed LNP-circNGF's multifaceted therapeutic effects, enhancing genes related to visual perception while reducing trauma-associated changes. This study signifies the promise of circRNA-based therapies for treating ocular neurodegenerative diseases and provides an innovative intervention platform for other ocular diseases.

Accurate Identification of Spatial Domain by Incorporating Global Spatial Proximity and Local Expression Proximity.

Accurate identification of spatial domains is essential in the analysis of spatial transcriptomics data in order to elucidate tissue microenvironments and biological functions. However, existing methods only perform domain segmentation based on local or global spatial relationships between spots, resulting in an underutilization of spatial information. To this end, we propose SECE, a deep learning-based method that captures both local and global relationships among spots and aggregates their information using expression similarity and spatial similarity. We benchmarked SECE against eight state-of-the-art methods on six real spatial transcriptomics datasets spanning four different platforms. SECE consistently outperformed other methods in spatial domain identification accuracy. Moreover, SECE produced spatial embeddings that exhibited clearer patterns in low-dimensional visualizations and facilitated a more accurate trajectory inference.

Sodium thiosulfate: A donor or carrier signaling molecule for hydrogen sulfide?

Sodium thiosulfate has been used for decades in the treatment of calciphylaxis and cyanide detoxification, and has recently shown initial therapeutic promise in critical diseases such as neuronal ischemia, diabetes mellitus, heart failure and acute lung injury. However, the precise mechanism of sodium thiosulfate remains incompletely defined and sometimes contradictory. Although sodium thiosulfate has been widely accepted as a donor of hydrogen sulfide (H2S), emerging findings suggest that it is the executive signaling molecule for H2S and that its effects may not be dependent on H2S. This article presents an overview of the current understanding of sodium thiosulfate, including its synthesis, biological characteristics, and clinical applications of sodium thiosulfate, as well as the underlying mechanisms in vivo. We also discussed the interplay of sodium thiosulfate and H2S. Our review highlights sodium thiosulfate as a key player in sulfide signaling with the broad clinical potential for the future.

RDLR: A Robust Deep Learning-Based Image Registration Method for Pediatric Retinal Images.

Retinal diseases stand as a primary cause of childhood blindness. Analyzing the progression of these diseases requires close attention to lesion morphology and spatial information. Standard image registration methods fail to accurately reconstruct pediatric fundus images containing significant distortion and blurring. To address this challenge, we proposed a robust deep learning-based image registration method (RDLR). The method consisted of two modules: registration module (RM) and panoramic view module (PVM). RM effectively integrated global and local feature information and learned prior information related to the orientation of images. PVM was capable of reconstructing spatial information in panoramic images. Furthermore, as the registration model was trained on over 280,000 pediatric fundus images, we introduced a registration annotation automatic generation process coupled with a quality control module to ensure the reliability of training data. We compared the performance of RDLR to the other methods, including conventional registration pipeline (CRP), voxel morph (WM), generalizable image matcher (GIM), and self-supervised techniques (SS). RDLR achieved significantly higher registration accuracy (average Dice score of 0.948) than the other methods (ranging from 0.491 to 0.802). The resulting panoramic retinal maps reconstructed by RDLR also demonstrated substantially higher fidelity (average Dice score of 0.960) compared to the other methods (ranging from 0.720 to 0.783). Overall, the proposed method addressed key challenges in pediatric retinal imaging, providing an effective solution to enhance disease diagnosis. Our source code is available at https://github.com/wuwusky/RobustDeepLeraningRegistration .

[Research advances in trait-based approaches in soil animal community ecology]. / åŸºäºŽåŠŸèƒ½æ€§çŠ¶çš„åœŸå£¤åŠ¨ç‰©ç¾¤è½ç”Ÿæ€å­¦ç ”ç©¶è¿›å±•.

Functional traits are indicators of the responses and adaptation of organisms to environmental changes and cascade to a series of ecosystem functions. The functional traits of soil animals are sensitive to environmental factors and may characterize and predict the changes of ecosystem functions. Multiple dimensions of biodiversity that combing species, phylogenetic, and functional diversity improves the understanding of distribution patterns, community assembly mechanisms and ecosystem functions of soil animals. In this review, we listed the categories of soil animal functional traits and their ecological significance, and summarized current researches on the responses of soil animal communities to environmental changes and the community assembly processes based on trait-based approaches. We proposed to strengthen the study on the impacts of eco-evolution processes of biotic interactions to soil animal functional traits, establish the database of soil animal functional traits, and apply trait-based approaches in the ecological restoration in the future, which would benefit soil biodiversity conservation and sustainability of soil ecosystems.

Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.

The effect of modified Qiyuan paste on mice with low immunity and sleep deprivation by regulating GABA nerve and immune system.

BACKGROUND: Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction. METHODS: Indicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin-eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD4+ and CD8+ proteins in the thymus and spleen tissues. RESULTS: The findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD4+ content, decreased CD8+ content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood. CONCLUSIONS: LJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions.

The novel HLA-DPB1*05:01:20 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*05:01:20 differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.