Inflammation in Steatotic Liver Diseases: Pathogenesis and Therapeutic Targets.

Alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), two main types of steatotic liver disease (SLDs), are characterized by a wide spectrum of several different liver disorders, including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Multiple immune cell-mediated inflammatory responses not only orchestrate the killing and removal of infected/damaged cells but also exacerbate the development of SLDs when excessive or persistent inflammation occurs. In recent years, single-cell and spatial transcriptome analyses have revealed the heterogeneity of liver-infiltrated immune cells in ALD and MASLD, revealing a new immunopathological picture of SLDs. In this review, we will emphasize the roles of several key immune cells in the pathogenesis of ALD and MASLD and discuss inflammation-based approaches for effective SLD intervention. In conclusion, the study of immunological mechanisms, especially highly specific immune cell population functions, may provide novel therapeutic opportunities for this life-threatening disease.

Endophyte-mediated enhancement of salt resistance in Arachis hypogaea L. by regulation of osmotic stress and plant defense-related genes.

Introduction: Soil salinization poses a significant environmental challenge affecting plant growth and agricultural sustainability. This study explores the potential of salt-tolerant endophytes to mitigate the adverse effects of soil salinization, emphasizing their impact on the development and resistance of Arachis hypogaea L. (peanuts). Methods: The diversity of culturable plant endophytic bacteria associated with Miscanthus lutarioriparius was investigated. The study focused on the effects of Bacillus tequilensis, Staphylococcus epidermidis, and Bacillus siamensis on the development and germination of A. hypogaea seeds in pots subjected to high NaCl concentrations (200 mM L-1). Results: Under elevated NaCl concentrations, the inoculation of endophytes significantly (p < 0.05) enhanced seedling germination and increased the activities of enzymes such as Superoxide dismutase, catalase, and polyphenol oxidase, while reducing malondialdehyde and peroxidase levels. Additionally, endophyte inoculation resulted in increased root surface area, plant height, biomass contents, and leaf surface area of peanuts under NaCl stress. Transcriptome data revealed an augmented defense and resistance response induced by the applied endophyte (B. tequilensis, S. epidermidis, and B. siamensis) strain, including upregulation of abiotic stress related mechanisms such as fat metabolism, hormones, and glycosyl inositol phosphorylceramide (Na+ receptor). Na+ receptor under salt stress gate Ca2+ influx channels in plants. Notably, the synthesis of secondary metabolites, especially genes related to terpene and phenylpropanoid pathways, was highly regulated. Conclusion: The inoculated endophytes played a possible role in enhancing salt tolerance in peanuts. Future investigations should explore protein-protein interactions between plants and endophytes to unravel the mechanisms underlying endophyte-mediated salt resistance in plants.

Identification of cachexia in lung cancer patients with an ensemble learning approach.

Objective: Nutritional intervention prior to the occurrence of cachexia will significantly improve the survival rate of lung cancer patients. This study aimed to establish an ensemble learning model based on anthropometry and blood indicators without information on body weight loss to identify the risk factors of cachexia for early administration of nutritional support and for preventing the occurrence of cachexia in lung cancer patients. Methods: This multicenter study included 4,712 lung cancer patients. The least absolute shrinkage and selection operator (LASSO) method was used to obtain the key indexes. The characteristics excluded weight loss information, and the study data were randomly divided into a training set (70%) and a test set (30%). The training set was used to select the optimal model among 18 models and verify the model performance. A total of 18 machine learning models were evaluated to predict the occurrence of cachexia, and their performance was determined using area under the curve (AUC), accuracy, precision, recall, F1 score, and Matthews correlation coefficient (MCC). Results: Among 4,712 patients, 1,392 (29.5%) patients were diagnosed with cachexia based on the framework of Fearon et al. A 17-variable gradient boosting classifier (GBC) model including body mass index (BMI), feeding situation, tumor stage, neutrophil-to-lymphocyte ratio (NLR), and some gastrointestinal symptoms was selected among the 18 machine learning models. The GBC model showed good performance in predicting cachexia in the training set (AUC = 0.854, accuracy = 0.819, precision = 0.771, recall = 0.574, F1 score = 0.658, MCC = 0.549, and kappa = 0.538). The abovementioned indicator values were also confirmed in the test set (AUC = 0.859, accuracy = 0.818, precision = 0.801, recall = 0.550, F1 score = 0.652, and MCC = 0.552, and kappa = 0.535). The learning curve, decision boundary, precision recall (PR) curve, the receiver operating curve (ROC), the classification report, and the confusion matrix in the test sets demonstrated good performance. The feature importance diagram showed the contribution of each feature to the model. Conclusions: The GBC model established in this study could facilitate the identification of cancer cachexia in lung cancer patients without weight loss information, which would guide early implementation of nutritional interventions to decrease the occurrence of cachexia and improve the overall survival (OS).

Integrating IASLC grading and radiomics for predicting postoperative outcomes in stage IA invasive lung adenocarcinoma.

BACKGROUND: The International Association for the Study of Lung Cancer (IASLC) Pathology Committee introduced a histologic grading system for invasive lung adenocarcinoma (LUAD) in 2020. The IASLC grading system, hinging on the evaluation of predominant and high-grade histologic patterns, has proven to be practical and prognostic for invasive LUAD. However, there are still limitations in evaluating the prognosis of stage IA LUAD. Radiomics may serve as a valuable complement. PURPOSE: To establish a model that integrates IASLC grading and radiomics, aimed at predicting the prognosis of stage IA LUAD. METHODS: We conducted a retrospective analysis of 628 patients diagnosed with stage IA LUAD who underwent surgical resection between January 2015 and December 2018 at our institution. The patients were randomly divided into the training set (n = 439) and testing set (n = 189) at a ratio of 7:3. Overall survival (OS) and disease-free survival (DFS) were taken as the end points. Radiomics features were obtained by PyRadiomics. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO). The prediction models for OS and DFS were developed using multivariate Cox regression analysis, and the models were visualized through nomogram plots. The model's performance was evaluated using area under the curves (AUC), concordance index (C-index), calibration curves, and survival decision curve analysis (DCA). RESULTS: In total, nine radiomics features were selected for the OS prediction model, and 15 radiomics features were selected for the DFS prediction model. Patients with high radiomics scores were associated with a worse prognosis (p < 0.001). We built separate prediction models using radiomics or IASLC alone, as well as a combined prediction model. In the prediction of OS, we observed that the combined model (C-index: 0.812 ± 0.024, 3 years AUC: 0.692, 5 years AUC: 0.792) achieved superior predictive performance than the radiomics (C-index: 0.743 ± 0.038, 3 years AUC: 0.633, 5 years AUC: 0.768) and IASLC grading (C-index: 0.765 ± 0.042, 3 years AUC: 0.658, 5 years AUC: 0.743) models alone. Similar results were obtained in the models for DFS. CONCLUSION: The combination of radiomics and IASLC pathological grading proves to be an effective approach for predicting the prognosis of stage IA LUAD. This has substantial clinical relevance in guiding treatment decisions for early-stage LUAD.

Development and validation of a nomogram to predict postoperative delirium in older patients after major abdominal surgery: a retrospective case-control study.

BACKGROUND: Postoperative delirium is a common complication in older patients, with poor long-term outcomes. This study aimed to investigate risk factors and develop a predictive model for postoperative delirium in older patients after major abdominal surgery. METHODS: This study retrospectively recruited 7577 patients aged ≥ 65 years who underwent major abdominal surgery between January 2014 and December 2018 in a single hospital in Beijing, China. Patients were divided into a training cohort (n = 5303) and a validation cohort (n = 2224) for univariate and multivariate logistic regression analyses and to build a nomogram. Data were collected for 43 perioperative variables, including demographics, medical history, preoperative laboratory results, imaging, and anesthesia information. RESULTS: Age, chronic obstructive pulmonary disease, white blood cell count, glucose, total protein, creatinine, emergency surgery, and anesthesia time were associated with postoperative delirium in multivariate analysis. We developed a nomogram based on the above 8 variables. The nomogram achieved areas under the curve of 0.731 and 0.735 for the training and validation cohorts, respectively. The discriminatory ability of the nomogram was further assessed by dividing the cases into three risk groups (low-risk, nomogram score < 175; medium-risk, nomogram score 175~199; high-risk, nomogram score > 199; P < 0.001). Decision curve analysis revealed that the nomogram provided a good net clinical benefit. CONCLUSIONS: We developed a nomogram that could predict postoperative delirium with high accuracy and stability in older patients after major abdominal surgery.

Paleo-geomorphic features of pre-Jurassic and its oil-controlling effect in Wuqi-Dingbian area.

The Fuxian-Yan10 layers are the main oil-producing reservoirs of Jurassic in Wuqi-Dingbian area of Ordos Basin. However, due to the lack of understanding of the pattern and distribution characteristics of oil reservoirs, the benefits of exploration and development are restricted. In order to provide theoretical guidance for the study of similar geological features, based on the analysis of paleogeomorphic features and evolution, the analysis focuses on the influence of palaeo-geomorphology on oil reservoir distribution, and summarizes the main types of reservoir models in the study area. The results show that there are four types of palaeo-geomorphic units in the Wuding area: palaeo-river, slope, highland and interriver hill. In the study area, the Jurassic paleogeomorphology controls the sedimentary development and distribution from Fuxian Formation to Yan 9 Formation. The compacted structure and lithologic barrier provide good trapping conditions for the paleogeomorphic oil. Moreover, the swampy coal measures and mudstone at the top of Yan 9 play a sealing role for oil accumulation, and the bottom water was obviously driven. In addition, the pre-Jurassic deep valley was the main channels for oil migration. On this basis, it is concluded that there are four reservoir-forming models in Wuding area: slope type, river hill type, ancient river type and highland type.

A novel protein FNDC3B-267aa encoded by circ0003692 inhibits gastric cancer metastasis via promoting proteasomal degradation of c-Myc.

BACKGROUND: Gastric cancer (GC) ranks fifth in global cancer incidence and third in mortality rate among all cancer types. Circular RNAs (circRNAs) have been extensively demonstrated to regulate multiple malignant biological behaviors in GC. Emerging evidence suggests that several circRNAs derived from FNDC3B play pivotal roles in cancer. However, the role of circFNDC3B in GC remains elusive. METHODS: We initially screened circFNDC3B with translation potential via bioinformatics algorithm prediction. Subsequently, Sanger sequencing, qRT-PCR, RNase R, RNA-FISH and nuclear-cytoplasmic fractionation assays were explored to assess the identification and localization of circ0003692, a circRNA derived from FNDC3B. qRT-PCR and ISH were performed to quantify expression of circ0003692 in human GC tissues and adjacent normal tissues. The protein-encoding ability of circ0003692 was investigated through dual-luciferase reporter assay and LC/MS. The biological behavior of circ0003692 in GC was confirmed via in vivo and in vitro experiments. Additionally, Co-IP and rescue experiments were performed to elucidate the interaction between the encoded protein and c-Myc. RESULTS: We found that circ0003692 was significantly downregulated in GC tissues. Circ0003692 had the potential to encode a novel protein FNDC3B-267aa, which was downregulated in GC cells. We verified that FNDC3B-267aa, rather than circ0003692, inhibited GC migration in vitro and in vivo. Mechanistically, FNDC3B-267aa directly interacted with c-Myc and promoted proteasomal degradation of c-Myc, resulting in the downregulation of c-Myc-Snail/Slug axis. CONCLUSIONS: Our study revealed that the novel protein FNDC3B-267aa encoded by circ0003692 suppressed GC metastasis through binding to c-Myc and enhancing proteasome-mediated degradation of c-Myc. The study offers the potential applications of circ0003692 or FNDC3B-267aa as therapeutic targets for GC.

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

[Inaugural Scalp Metastasis of Pulmonary Squamous Cell Carcinoma: 
A Rare Case Report and Literature Review].

Distant cutaneous metastasis of primary lung squamous cell carcinoma is an exceedingly rare event, with scalp metastasis as the initial clinical presentation even rarer. Scalp skin metastases are prone to be misdiagnosed as other scalp disorders, yet their appearance signifies the deterioration and poor prognosis of lung cancer. This case report documents a female patient presenting initially with scalp folliculitis in dermatology, who was subsequently diagnosed with malignant lung tumor through radiological imaging and referred to Department of Thoracic Surgery. Pathological examination of the excised lesion from the scalp revealed distant metastasis of lung cancer. A review of similar cases reported in literature was conducted. This article aims to enhance understanding and awareness of skin metastasis in lung cancer, to emphasize the importance of this condition, and to improve early recognition and precise diagnosis. It is crucial to prevent clinical misdiagnosis and ensure appropriate treatment, finally leading to improve the prognosis of the patients.
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Metabolic characterization of sphere-derived prostate cancer stem cells reveals aberrant urea cycle in stemness maintenance.

Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem-like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline-5-carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem-like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer.

Discovery of ganoderic acid A (GAA) PROTACs as MDM2 protein degraders for the treatment of breast cancer.

Breast cancer is one of the most common female malignant tumors, with triple-negative breast cancer (TNBC) being the most specific, highly invasive, metastatic and associated with a poor prognosis. Our previous study showed that the natural product ganoderic acid A (GAA) has a certain affinity for MDM2. In this study, two series of novel GAA PROTACs C1-C10 and V1-V10 were designed and synthesized for the treatment of breast cancer. The antitumor activity of these compounds was evaluated against four human tumor cell lines (MCF-7, MDA-MB-231, SJSA-1, and HepG2). Among them, V9 and V10 showed stronger anti-proliferative effects against breast cancer cells, and V10 showed the best selectivity in MDA-MB-231 cells (TNBC), which was 5-fold higher than that of the lead compound GAA. Preliminary structure-activity analysis revealed that V-series GAA PROTACs had better effects than C-series, and the introduction of 2O-4O PEG linkers could significantly improve the antitumor activity. Molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and Western blot researches showed that both V9 and V10 could bind with MDM2, and degrade the protein through the ubiquitin-proteasome system. Molecular dynamics simulation (MD) revealed that V10 is a bifunctional molecule that can bind to von Hippel-Lindau (VHL) at one end and target MDM2 at the other. In addition, V10 promoted the upregulation of p21 in p53-mutant MDA-MB-231 cells, and induced apoptosis via down-regulation of the bcl-2/bax ratio and the expression of cyclin B1. Finally, in vivo experiments showed that, V10 also exhibited good tumor inhibitory activity in xenografted TNBC zebrafish models, with an inhibition rate of 27.2% at 50 µg/mL. In conclusion, our results suggested that V10 has anti-tumor effects on p53-mutant breast cancer in vitro and in vivo, and may be used as a novel lead compound for the future development of TNBC.

Reservoir Characteristics and Formation Model of the Bauxite Gas Reservoir: The Benxi Formation in the LX Block, Northeast of Ordos Basin, China.

Recently, horizontal well L47-1CH in the Longdong area of the southwestern Ordos Basin made a significant breakthrough in bauxite natural gas exploration, changing the traditional geological understanding that bauxite could not form effective reservoirs. To further explore the exploration and development potential of bauxite natural gas reservoirs in the northeast of the Ordos Basin, it is urgent to carry out basic geological studies. This paper discusses the sedimentary environment, reservoir characteristics, and formation patterns of the bauxite gas reservoirs in the LX Block using trace elements, thin sections, X-ray diffraction, scanning electron microscopy, conventional physical properties, constant pressure mercury, etc. Then, the distribution pattern of bauxite was studied according to the restoration of the karst paleogeomorphology, and the formation model of bauxite was ultimately established. The results show that bauxite developed a clear triple-segment structure vertically, characterized by rich iron at the bottom, high aluminum at the middle, and low iron at the top. The mineral composition of the bauxite section mainly includes diaspore, iron minerals, titanium minerals, and birnessite. The types of pores mainly include intra- and intergranular dissolved pores, matrix-dissolved pores, intercrystalline pores, and microfractures. The porosity ranges from 1.51 to 9.90%, with a relatively good sorting and connectivity of the pore and throat. The bauxite was formed in a hot and humid climate, deposited in a shallow-water tidal flat and lagoon sedimentary environment with oxygen depleted, and experienced oscillatory regression during the deposition process. The thickness of bauxite is significantly controlled by karst paleogeomorphology, and it is mainly distributed at the negative terrain positions of karat pits and karst terraces. The above results can provide a geological basis for the exploration and development of bauxite in the Ordos Basin and similar basins worldwide.

Analysis of morphology, histology characteristics, and circadian clock gene expression of Onychostoma macrolepis at the overwintering period and the breeding period.

Fish typically adapt to their environment through evolutionary traits, and this adaptive strategy plays a critical role in promoting species diversity. Onychostoma macrolepis is a rare and endangered wild species that exhibits a life history of overwintering in caves and breeding in mountain streams. We analyzed the morphological characteristics, histological structure, and expression of circadian clock genes in O. macrolepis to elucidate its adaptive strategies to environmental changes in this study. The results showed that the relative values of O. macrolepis eye diameter, body height, and caudal peduncle height enlarged significantly during the breeding period. The outer layer of the heart was dense; the ventricular myocardial wall was thickened; the fat was accumulated in the liver cells; the red and white pulp structures of the spleen, renal tubules, and glomeruli were increased; and the goblet cells of the intestine were decreased in the breeding period. In addition, the spermatogenic cyst contained mature sperm, and the ovaries were filled with eggs at various stages of development. Throughout the overwintering period, the melano-macrophage center is located between the spleen and kidney, and the melano-macrophage center in the cytoplasm has the ability to synthesize melanin, and is arranged in clusters to form cell clusters or white pulp scattered in it. Circadian clock genes were identified in all organs, exhibiting significant differences between the before/after overwintering period and the breeding period. These findings indicate that the environment plays an important role in shaping the behavior of O. macrolepis, helping the animals to build self-defense mechanisms during cyclical habitat changes. Studying the morphological, histological structure and circadian clock gene expression of O. macrolepis during the overwintering and breeding periods is beneficial for understanding its unique hibernation behavior in caves. Additionally, it provides an excellent biological sample for investigating the environmental adaptability of atypical cavefish species.

Advancing musculoskeletal tumor diagnosis: Automated segmentation and predictive classification using deep learning and radiomics.

OBJECTIVES: Musculoskeletal (MSK) tumors, given their high mortality rate and heterogeneity, necessitate precise examination and diagnosis to guide clinical treatment effectively. Magnetic resonance imaging (MRI) is pivotal in detecting MSK tumors, as it offers exceptional image contrast between bone and soft tissue. This study aims to enhance the speed of detection and the diagnostic accuracy of MSK tumors through automated segmentation and grading utilizing MRI. MATERIALS AND METHODS: The research included 170 patients (mean age, 58 years ±12 (standard deviation), 84 men) with MSK lesions, who underwent MRI scans from April 2021 to May 2023. We proposed a deep learning (DL) segmentation model MSAPN based on multi-scale attention and pixel-level reconstruction, and compared it with existing algorithms. Using MSAPN-segmented lesions to extract their radiomic features for the benign and malignant classification of tumors. RESULTS: Compared to the most advanced segmentation algorithms, MSAPN demonstrates better performance. The Dice similarity coefficients (DSC) are 0.871 and 0.815 in the testing set and independent validation set, respectively. The radiomics model for classifying benign and malignant lesions achieves an accuracy of 0.890. Moreover, there is no statistically significant difference between the radiomics model based on manual segmentation and MSAPN segmentation. CONCLUSION: This research contributes to the advancement of MSK tumor diagnosis through automated segmentation and predictive classification. The integration of DL algorithms and radiomics shows promising results, and the visualization analysis of feature maps enhances clinical interpretability.

Detoxification and Activating Blood Circulation Decoction Promotes Reendothelialization of Damaged Blood Vessels via VEGF Signaling Pathway Activation by miRNA-126.

The occurrence of in-stent restenosis (ISR) poses a significant challenge for percutaneous coronary intervention (PCI). Thus, the promotion of vascular reendothelialization is essential to inhibit endothelial proliferation. In this study, we clarified the mechanism by which Detoxification and Activating Blood Circulation Decoction (DABCD) promotes vascular reendothelialization to avoid ISR by miRNA-126-mediated modulation of the vascular endothelial growth factor (VEGF) signaling pathway. A rat model of post-PCI restenosis was established by balloon injury. The injured aortic segment was collected 14 and 28 d after model establishment. Our findings indicate that on the 14th and 28th days following balloon injury, DABCD reduced intimal hyperplasia and inflammation and promoted vascular reendothelialization. Additionally, DABCD markedly increased nitric oxide (NO) expression and significantly decreased ET-1 production in rat serum. DABCD also increased the mRNA level of endothelial nitric oxide synthase (eNOS) and the protein expression of VEGF, p-Akt, and p-extracellular signal-regulated kinase (ERK)1/2 in vascular tissue. Unexpectedly, the expression of miR-126a-5p mRNA was significantly lower in the aortic tissue of balloon-injured rats than in the aortic tissue of control rats, and higher miR-126a-5p levels were observed in the DABCD groups. The results of this study indicated that the vascular reendothelialization effect of DABCD on arterial intimal injury is associated with the inhibition of neointimal formation and the enhancement of vascular endothelial activity. More specifically, the effects of DABCD were mediated, at least in part, through miR-126-mediated VEGF signaling pathway activation.

Identification and validation of tryptophan metabolism-related lncRNAs in lung adenocarcinoma prognosis and immune response.

BACKGROUND: Tryptophan (Trp) is an essential amino acid. Increasing evidence suggests that tryptophan metabolism plays a complex role in immune escape from Lung adenocarcinoma (LUAD). However, the role of long non-coding RNAs (lncRNAs) in tryptophan metabolism remains to be investigated. METHODS: This study uses The Cancer Genome Atlas (TCGA)-LUAD dataset as the training cohort, and several datasets from the Gene Expression Omnibus (GEO) database are merged into the validation cohort. Genes related to tryptophan metabolism were identified from the Molecular Signatures Database (MSigDB) database and further screened for lncRNAs with Trp-related expression. Subsequently, a prognostic signature of lncRNAs related to tryptophan metabolism was constructed using Cox regression analysis, (Least absolute shrinkage and selection operator regression) and LASSO analysis. The predictive performance of this risk score was validated by Kaplan-Meier (KM) survival analysis, (receiver operating characteristic) ROC curves, and nomograms. We also explored the differences in immune cell infiltration, immune cell function, tumor mutational load (TMB), tumor immune dysfunction and exclusion (TIDE), and anticancer drug sensitivity between high- and low-risk groups. Finally, we used real-time fluorescence quantitative PCR, CCK-8, colony formation, wound healing, transwell, flow cytometry, and nude mouse xenotransplantation models to elucidate the role of ZNF8-ERVK3-1 in LUAD. RESULTS: We constructed 16 tryptophan metabolism-associated lncRNA prognostic models in LUAD patients. The risk score could be used as an independent prognostic indicator for the prognosis of LUAD patients. Kaplan-Meier survival analysis, ROC curves, and risk maps validated the prognostic value of the risk score. The high-risk and low-risk groups showed significant differences in phenotypes, such as the percentage of immune cell infiltration, immune cell function, gene mutation frequency, and anticancer drug sensitivity. In addition, patients with high-risk scores had higher TMB and TIDE scores compared to patients with low-risk scores. Finally, we found that ZNF8-ERVK3-1 was highly expressed in LUAD tissues and cell lines. A series of in vitro experiments showed that knockdown of ZNF8-ERVK3-1 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. In vivo experiments with xenografts have shown that knocking down ZNF8-ERVK3-1 can significantly inhibit tumor size and tumor proliferation. CONCLUSION: We constructed a new prognostic model for tryptophan metabolism-related lncRNA. The risk score was closely associated with common clinical features such as immune cell infiltration, immune-related function, TMB, and anticancer drug sensitivity. Knockdown of ZNF8-ERVK3-1 inhibited LUAD cell proliferation, migration, invasion, and G0/G1 phase blockade and promoted apoptosis.

Intratumoral CXCR4hi neutrophils display ferroptotic and immunosuppressive signatures in hepatoblastoma.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

Association of systemic inflammatory markers with postoperative arrhythmias in esophageal cancer: a propensity score matching.

BACKGROUND: The severity and prognosis of an array of inflammatory diseases have been predicted using systemic inflammatory indices, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), derived neutrophil-to-lymphocyte ratio (dNLR), and systemic immune inflammation index (SII). The purpose of this study was to examine the association between systemic inflammatory markers and postoperative arrhythmias (PA) in esophageal cancer patients. METHODS: In the study, laboratory-related parameters were gathered and examined in 278 patients (non-PA = 221, PA = 57). Fit separate propensity score matching (PSM) within subgroup strata (surgery approaches); match within strata, and aggregate for main analysis. Finally, we established a 1:1(57:57) model. The ability of inflammatory makers on the first post-esophagectomy day to distinguish PA from postoperative non-arrhythmia (non-PA) by receiver operating characteristic (ROC) analysis. RESULTS: On the first post-esophagectomy day, there was a greater difference between PA and non-PA in terms of white blood cell (WBC) and neutrophil (NE), Neutrophil percentage (NE%), NLR, dNLR, LMR, and SII. After PSM, the following variables were substantially different between non-PA and PA: NE%, NLR, dNLR, and SII. It was found that WBC, NE, NE%, NLR, dNLR, LMR, and SII had the area under the curve (AUC) that was higher than 0.500 in ROC analysis, with NLR and SII having the highest AUC (AUC = 0.661). The indicators were subjected to binary logistic regression analysis, which increased the indicators' predictive ability (AUC = 0.707, sensitivity = 0.877). CONCLUSION: On the first post-esophagectomy day, systemic inflammatory indicators were significantly correlated with both PA and non-PA, and high SII and NLR are reliable markers of PA.