Sirt1 inhibits macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway.

OBJECTIVE AND DESIGN: To elucidate Sirt1's role in gouty arthritis inflammation and its potential mechanisms. MATERIAL: Constructed murine models of gouty arthritis and conducted THP-1 cell experiments. TREATMENT: 1 mg of MSU crystals injected into mice ankle joints for a 72-h intervention. After a 3-h pre-treatment with Sirt1-specific inhibitor (EX527) and agonist (SRT2104), inflammation was induced for 21 h using lipopolysaccharide (LPS) plus MSU crystals. METHODS: We assessed gouty arthritis severity through joint inflammation index, swelling, and hematoxylin and eosin (H&E) staining, and measured CD68 mononuclear macrophages and Sirt1 expression in synovial tissue via immunohistochemistry. ELISA, NO assay, RT-qPCR, Flow cytometry, and Western blot were utilized to examine macrophage inflammatory factors, polarization, reactive oxygen species(ROS), MAPK/NF-κB/AP-1 and Nrf2/HO-1 pathways proteins. RESULTS: Significant joint swelling, synovial tissue edema, and inflammatory cell infiltration were observed. CD68 mononuclear macrophages and Sirt1 expression were elevated in synovium. Sirt1 activation decreased inflammatory factors, M1 polarization, and ROS generation. Sirt1 activation reduced p38/JNK phosphorylation, thereby inhibiting downstream NF-κB p65/AP-1 and enhancing Nrf2/HO-1, thus suppressing inflammation. CONCLUSIONS: Sirt1 alleviates M1 macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway. Thus, activating Sirt1 may provide a new therapeutic target for gouty arthritis.

Methylparaben changes the community composition, structure, and assembly processes of free-living bacteria, phytoplankton, and zooplankton.

Parabens are common contaminants in river and lake environments. However, few studies have been conducted to determine the effects of parabens on bacteria, phytoplankton, and zooplankton communities in aquatic environments. In this study, the effect of methylparaben (MP) on the diversity and community structure of the aquatic plankton microbiome was investigated by incubating a microcosm with MP at 0.1, 1, 10, and 100 µg/L for 7 days. The results of the Simpson index showed that MP treatment altered the α-diversity of free-living bacteria (FL), phytoplankton, and zooplankton but had no significant effect on the α-diversity of particle-attached bacteria (PA). Further, the relative abundances of the sensitive bacteria Chitinophaga and Vibrionimonas declined after MP addition. Moreover, the relative abundances of Desmodesmus sp. HSJ717 and Scenedesmus armatus, of the phylum Chlorophyta, were significantly lower in the MP treatment group than in the control group. In addition, the relative abundance of Stoeckeria sp. SSMS0806, of the Dinophyta phylum, was higher than that in the control group. MP addition also increased the relative abundance of Arthropoda but decreased the relative abundance of Rotifera and Ciliophora. The ß-diversity analysis showed that FL and phytoplankton communities were clustered separately after treatment with different MP concentrations. MP addition changed community assembly mechanisms in the microcosm, including increasing the stochastic processes for FL and the deterministic processes for PA and phytoplankton. Structural equation modeling analysis showed a significant negative relationship between bacteria richness and phytoplankton richness, and a significant positive relationship between phytoplankton (richness and community composition) and zooplankton. Overall, this study emphasizes that MP, at environmental concentrations, can change the diversity and structure of plankton microbial communities, which might have a negative effect on ecological systems.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

M2 macrophage-secreted exosomes promote metastasis and increase vascular permeability in hepatocellular carcinoma.

BACKGROUND: Metastasis is a key feature of malignant tumors and significantly contributes to their high mortality, particularly in hepatocellular carcinoma (HCC). Therefore, it is imperative to explore the mechanism of tumor metastasis. Recently, tumor-associated macrophages (TAMs) have been demonstrated to promote tumor progression, while TAM-derived molecules involved in HCC metastasis warrant further investigation. METHODS: THP-1 was treated with IL-4 (Interleukin-4) and IL-13 (Interleukin-13) for M2 polarized macrophages. Exosomes derived from M2 macrophages were characterized. Then, HCC cells or human umbilical vein endothelial cells (HUVECs) were co-cultured with M2 macrophages or treated with M2 macrophage-secreted exosomes. Next, Transwell®, Scratch assay, tube formation, and endothelial permeability assays were performed. Moreover, RT-PCR, western blotting, immunofluorescence, and ELISA were used to assess mRNA and protein expression levels. Finally, the miRNA expression profiles of exosomes derived from M2 and M0 macrophages were analyzed. RESULTS: M2 macrophage infiltration was correlated with metastasis and a poor prognosis in HCC patients. M2-derived exosomes were absorbed by HCC and HUVEC cells and promoted the epithelial-mesenchymal transition (EMT), vascular permeability, and angiogenesis. Notably, MiR-23a-3p levels were significantly higher in M2-derived exosomes and hnRNPA1 mediated miR-23a-3p packaging into exosomes. Phosphatase and tensin homolog (PTEN) and tight junction protein 1 (TJP1) were the targets of miR-23a-3p, as confirmed by luciferase reporter assays. Lastly, HCC cells co-cultured with M2-derived exosomes secreted more GM-CSF, VEGF, G-CSF, MCP-1, and IL-4, which in turn further recruited M2 macrophages. CONCLUSIONS: Our findings suggest that M2 macrophage-derived miR-23a-3p enhances HCC metastasis by promoting EMT and angiogenesis, as well as increasing vascular permeability. Video Abstract.

The role of the target language culture on Arabic learners' fondness for Arabic poetry.

As an important carrier of culture, poetry plays a significant role in deepening language learners' understanding of the target language culture as well as enhancing their language skills; however, the effect of the target language culture on language learners' enjoyment of poetry remains unclear. The study served as an attempt to shed light on the point of whether the target language culture has different effects on high- and low-level Chinese Arabic learners' fondness for Arabic poetry with the use of pictures related to Arabic culture and those not related to Arabic culture. In the current study, 40 Arabic learners (20 high-level and 20 low-level) scored the Arabic poem line based on their fondness for it after viewing two kinds of picture with electroencephalogram (EEG) recording. Frontal alpha asymmetry index as a correlate of approach and avoidance related motivation measured by EEG power in the alpha band (8-13 Hz) was calculated for examining whether the behavioral results of Arabic learners' fondness for poetry are in line with the results of changes in the related EEG components. Behavioral results illustrated that low-level subjects showed significantly less liking for Arabic poetry after viewing pictures related to Arabic culture compared to those not related to Arabic culture. The high-level subjects did not show a significant difference in the level of liking for Arabic poetry between the two cases. FAA results demonstrated that low-level subjects presented a significant avoidance-related responses to Arabic poetry after viewing pictures related to Arabic culture in comparison to viewing pictures not related to Arabic culture; while the FAA values did not differ significantly between the two cases in high-level subjects, which is in line with behavioral results. The findings of this research can benefit teachers in motivating students to learn poetry in foreign language curriculum and also contribute to the literature on the effect of target language culture on language learners' enjoyment of poetry.

Anterior decompression and posterior total laminectomy with fusion for ossification of the cervical posterior longitudinal ligament.

Aims: Surgical approaches to cervical ossification of the posterior longitudinal ligament (OPLL) remain controversial. The purpose of the present study was to analyze and compare the long-term neurological recovery following anterior decompression with fusion (ADF) and posterior laminectomy and fusion with bone graft and internal fixation (PLF) based on > ten-year follow-up outcomes in a single centre. Methods: Included in this retrospective cohort study were 48 patients (12 females; mean age 55.79 years (SD 8.94)) who were diagnosed with cervical OPLL, received treatment in our centre, and were followed up for 10.22 to 15.25 years. Of them, 24 patients (six females; mean age 52.88 years (SD 8.79)) received ADF, and the other 24 patients (five females; mean age 56.25 years (SD 9.44)) received PLF. Clinical data including age, sex, and the OPLL canal-occupying ratio were analyzed and compared. The primary outcome was Japanese Orthopaedic Association (JOA) score, and the secondary outcome was visual analogue scale neck pain. Results: Compared with the baseline, neurological function improved significantly after surgery in all patients of both groups (p < 0.001). The JOA recovery rate in the ADF group was significantly higher than that in the PLF group (p < 0.001). There was no significant difference in postoperative cervical pain between the two groups (p = 0.387). The operating time was longer and intraoperative blood loss was greater in the PLF group than the ADF group. More complications were observed in the ADF group than in the PLF group, although the difference was not statistically significant. Conclusion: Long-term neurological function improved significantly after surgery in both groups, with the improvement more pronounced in the ADF group. There was no significant difference in postoperative neck pain between the two groups. The operating time was shorter and intraoperative blood loss was lower in the ADF group; however, the incidence of perioperative complications was higher.

Sensitive and specific detection of Listeria monocytogenes in food samples using imprinted upconversion fluorescence probe prepared by emulsion polymerization method.

Listeria monocytogenes (L. monocytogenes) is a foodborne pathogen with high morbidity and mortality rates, necessitating rapid detection methods. Current techniques, while reliable, are labor-intensive and not amenable to on-site testing. We report the design and synthesis of a novel imprinted upconversion fluorescence probe through Pickering emulsion polymerization for the specific detection of L. monocytogenes. The probe employs trimethylolpropane trimethacrylate and divinylbenzene as cross-linkers, acryloyl-modified chitosan as a functional monomer, and the bacterium itself as the template. The developed probe demonstrated high specificity and sensitivity in detecting L. monocytogenes, with a limit of detection of 72 CFU/mL. It effectively identified the pathogen in contaminated salmon and chicken samples, with minimal background interference. The integration of molecular imprinting and upconversion fluorescence materials presents a potent and reliable approach for the rapid and specific detection of L. monocytogenes, offering considerable potential for on-site food safety testing.

Identification and Validation of Novel Metastasis-Related Immune Gene Signature in Breast Cancer.

Background: Distant metastasis remains the leading cause of death among patients with breast cancer (BRCA). The process of cancer metastasis involves multiple mechanisms, including compromised immune system. However, not all genes involved in immune function have been comprehensively identified. Methods: Firstly 1623 BRCA samples, including transcriptome sequencing and clinical information, were acquired from Gene Expression Omnibus (GSE102818, GSE45255, GSE86166) and The Cancer Genome Atlas-BRCA (TCGA-BRCA) dataset. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed using the GSE102818 dataset to identify the most relevant module to the metastasis of BRCA. Besides, ConsensusClusterPlus was applied to divide TCGA-BRCA patients into two subgroups (G1 and G2). In the meantime, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a metastasis-related immune genes (MRIGs)_score to predict the metastasis and progression of cancer. Importantly, the expression of vital genes was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Results: The expression pattern of 76 MRIGs screened by WGCNA divided TCGA-BRCA patients into two subgroups (G1 and G2), and the prognosis of G1 group was worse. Also, G1 exhibited a higher mRNA expression level based on stemness index score and Tumor Immune Dysfunction and Exclusion score. In addition, higher MRIGs_score represented the higher probability of progression in BRCA patients. It was worth mentioning that the patients in the G1 group had a high MRIGs_score than those in the G2 group. Importantly, the results of RT-qPCR and IHC demonstrated that fasciculation and elongation protein zeta 1 (FEZ1) and insulin-like growth factor 2 receptor (IGF2R) were risk factors, while interleukin (IL)-1 receptor antagonist (IL1RN) was a protective factor. Conclusion: Our study revealed a prognostic model composed of eight immune related genes that could predict the metastasis and progression of BRCA. Higher score represented higher metastasis probability. Besides, the consistency of key genes in BRCA tissue and bioinformatics analysis results from mRNA and protein levels was verified.

A Study on the Field Emission Characteristics of High-Quality Wrinkled Multilayer Graphene Cathodes.

Field emission (FE) necessitates cathode materials with low work function and high thermal and electrical conductivity and stability. To meet these requirements, we developed FE cathodes based on high-quality wrinkled multilayer graphene (MLG) prepared using the bubble-assisted chemical vapor deposition (B-CVD) method and investigated their emission characteristics. The result showed that MLG cathodes prepared using the spin-coating method exhibited a high field emission current density (~7.9 mA/cm2), indicating the excellent intrinsic emission performance of the MLG. However, the weak adhesion between the MLG and the substrate led to the poor stability of the cathode. Screen printing was employed to prepare the cathode to improve stability, and the influence of a silver buffer layer was explored on the cathode's performance. The results demonstrated that these cathodes exhibited better emission stability, and the silver buffer layer further enhanced the comprehensive field emission performance. The optimized cathode possesses low turn-on field strength (~1.5 V/µm), low threshold field strength (~2.65 V/µm), high current density (~10.5 mA/cm2), and good emission uniformity. Moreover, the cathode also exhibits excellent emission stability, with a current fluctuation of only 6.28% during a 4-h test at 1530 V.

FatPlants: a comprehensive information system for lipid-related genes and metabolic pathways in plants.

FatPlants, an open-access, web-based database, consolidates data, annotations, analysis results, and visualizations of lipid-related genes, proteins, and metabolic pathways in plants. Serving as a minable resource, FatPlants offers a user-friendly interface for facilitating studies into the regulation of plant lipid metabolism and supporting breeding efforts aimed at increasing crop oil content. This web resource, developed using data derived from our own research, curated from public resources, and gleaned from academic literature, comprises information on known fatty-acid-related proteins, genes, and pathways in multiple plants, with an emphasis on Glycine max, Arabidopsis thaliana, and Camelina sativa. Furthermore, the platform includes machine-learning based methods and navigation tools designed to aid in characterizing metabolic pathways and protein interactions. Comprehensive gene and protein information cards, a Basic Local Alignment Search Tool search function, similar structure search capacities from AphaFold, and ChatGPT-based query for protein information are additional features. Database URL: https://www.fatplants.net/.

Low but highly geographically structured genomic diversity of East Asian Eurasian otters and its conservation implications.

Populations of Eurasian otters Lutra lutra, one of the most widely distributed apex predators in Eurasia, have been depleted mainly since the 1950s. However, a lack of information about their genomic diversity and how they are organized geographically in East Asia severely impedes our ability to monitor and conserve them in particular management units. Here, we re-sequenced and analyzed 20 otter genomes spanning continental East Asia, including a population at Kinmen, a small island off the Fujian coast, China. The otters form three genetic clusters (one of L. l. lutra in the north and two of L. l. chinensis in the south), which have diverged in the Holocene. These three clusters should be recognized as three conservation management units to monitor and manage independently. The heterozygosity of the East Asian otters is as low as that of the threatened carnivores sequenced. Historical effective population size trajectories inferred from genomic variations suggest that their low genomic diversity could be partially attributed to changes in the climate since the mid-Pleistocene and anthropogenic intervention since the Holocene. However, no evidence of genetic erosion, mutation load, or high level of inbreeding was detected in the presumably isolated Kinmen Island population. Any future in situ conservation efforts should consider this information for the conservation management units.

Lymphopaenia, anti-Ro/anti-RNP autoantibodies, renal involvement and cyclophosphamide use correlate with increased risk of herpes zoster in patients with systemic lupus erythematosus.

Herpes zoster occurs with increased frequency in patients with systemic lupus erythematosus (SLE). The aim of this study was to identify and evaluate clinical and laboratory risk factors associated with development of herpes zoster in patients with SLE. A retrospective case-control study was performed in a population of patients with SLE. Patients were identified as cases if their first episode of herpes zoster occurred after diagnosis of SLE. Patients with SLE who never developed herpes zoster were enrolled as controls. Medical charts and laboratory data for both cases and control patients were comprehensively reviewed. A total of 65 cases and 105 controls were included. Risk factors associated with the development of herpes zoster in patients with SLE were found to be lymphopaenia, anti-Ro antibodies, anti-RNP antibodies, neuropsychiatric manifestations, renal involvement and cyclophosphamide use. Therefore, the presence of certain disease manifestations in patients with SLE represents risk factors for the development of herpes zoster.

Arthritis as an important determinant for psoriatic patients to develop severe vascular events in Taiwan: a nation-wide study.

BACKGROUND: Psoriasis is an important systemic inflammatory disease that often leads to severe vascular diseases. This study was launched to determine if joint involvement affects incidence of vascular comorbidities in psoriatic patients. In addition, potential vasculo-protective effects of methotrexate in psoriatic patients were also evaluated. METHOD: A population-based retrospective cohort study was conducted using the Taiwanese National Health Insurance database spanning from 1996 to 2006. Accordingly, 7648 and 284 psoriatic patients without or with arthritis, respectively, were identified. To ensure the temporal relationship between different events, those with date of first diagnosis psoriasis during the year of 1996 were excluded from subsequent analyses. In addition, those with diagnosis of cerebrovascular or cardiovascular diseases prior to onset of psoriasis were also excluded from relevant subsequent analyses. RESULT: Taking psoriatic patients without arthritis as the referent group, the hazard ratio for incident cerebrovascular disease was 1.82 (95% CI = 1.17-2.82) for psoriatic patient with arthritis. In addition, psoriatic patients without arthritis who had methotrexate treatment showed reduced risks for incident cerebrovascular disease as compared with those with no arthritis and had received no methotrexate/retinoid treatment. Similar analyses were performed on cardiovascular diseases, and equivalent results were obtained. CONCLUSION: Our study indicated that arthritis is a potential determinant for psoriatic patients in terms of incident vascular comorbidities. In addition, methotrexate treatment may be associated with reduced risks for development of severe vascular diseases in psoriatic patients without arthritis. Further studies should focus on the clinical complications associated with psoriatic patients with or without arthritis.

The Effects of Deregulated Ribosomal Biogenesis in Cancer.

Ribosomes are macromolecular ribonucleoprotein complexes assembled from RNA and proteins. Functional ribosomes arise from the nucleolus, require ribosomal RNA processing and the coordinated assembly of ribosomal proteins (RPs), and are frequently hyperactivated to support the requirement for protein synthesis during the self-biosynthetic and metabolic activities of cancer cells. Studies have provided relevant information on targeted anticancer molecules involved in ribosome biogenesis (RiBi), as increased RiBi is characteristic of many types of cancer. The association between unlimited cell proliferation and alterations in specific steps of RiBi has been highlighted as a possible critical driver of tumorigenesis and metastasis. Thus, alterations in numerous regulators and actors involved in RiBi, particularly in cancer, significantly affect the rate and quality of protein synthesis and, ultimately, the transcriptome to generate the associated proteome. Alterations in RiBi in cancer cells activate nucleolar stress response-related pathways that play important roles in cancer-targeted interventions and immunotherapies. In this review, we focus on the association between alterations in RiBi and cancer. Emphasis is placed on RiBi deregulation and its secondary consequences, including changes in protein synthesis, loss of RPs, adaptive transcription and translation, nucleolar stress regulation, metabolic changes, and the impaired ribosome biogenesis checkpoint.

Unexpected enrichment of antibiotic resistance genes and organic remediation genes in high-altitude lakes at Eastern Tibetan Plateau.

Elevation has a strong effect on aquatic microbiome. However, we know little about the effects of elevation on functional genes, especially antibiotic resistance genes (ARGs) and organic remediation genes (ORGs) in freshwater ecosystems. In this study, we analyzed five classes of functional genes including ARGs, metal resistance genes (MRGs), ORGs, bacteriophages, and virulence genes between two high-altitude lakes (HALs) and two low-altitude lakes (LALs) in Mountain Siguniang at Eastern Tibetan Plateau by means of GeoChip 5.0. No differences (Student's t-test, p > 0.05) of gene richness including ARGs, MRGs, ORGs, bacteriophages, and virulence genes in HALs and LALs were found. The abundance of most ARGs and ORGs was higher in HALs than in LALs. For MRGs, the abundance of macro metal resistance genes of potassium, calcium, and aluminum was higher in HALs than in LALs (Student's t-test, p < 0.05; all Cohen's d > 0.8). The abundance of some heavy metal resistance genes of lead and mercury was lower in HALs than in LALs (Student's t-test, p < 0.05; all Cohen's d < -0.8). The composition of these functional genes in HALs differed significantly from in LALs. The functional gene network in HALs was also more complex than that in LALs. We speculate that enrichment of ARGs and ORGs in HALs is related to different microbial communities, exogenous ARGs, and enriched persistent organic pollutants through long-range atmospheric transport driven by the Indian monsoon. This study highlights the unexpected enrichment of ARGs, MRGs, and ORGs in remote lakes at high elevations.

Association between non-atopic hand eczema and interleukin-13 gene polymorphism in Taiwanese nursing population.

Chronic hand eczema is an important occupational skin disease with atopic dermatitis (AD) and wet work being the most important risk factors. This study was launched to analyse the potential association between AD-related inflammation genes and development of non-atopic hand eczema among nurses in University Hospital. Atopic eczema, non-atopic hand dermatitis and control groups were identified. The association between occurrence of non-atopic hand eczema and interleukin (IL)-13, IL-4 and IL-5 gene variants was analysed. IL13 rs20541 A allele [assuming recessive model; odds ratio (OR) = 3.38, 95% CI: (1.63-7.00)] showed association with development of non-atopic hand eczema. Additive score analyses showed combination of this gene variant with previously identified risk factors including certain SPINK5 polymorphism and more than 10 years of work experience conferred highest risk for development of non-atopic hand eczema. As non-atopic hand eczema made up significant portion of occupational skin diseases, further studies should be focused on this commonly encountered skin condition.

Methotrexate reduces the occurrence of cerebrovascular events among Taiwanese psoriatic patients: a nationwide population-based study.

Psoriasis is a chronic inflammatory disease. The aim of this study was to evaluate the effects of methotrexate and retinoid on risks for developing cerebrovascular disease among psoriatic patients. A population-based nested case-control study was conducted using the Taiwanese National Health Insurance database. Cox proportional hazards models were adopted. The hazard ratio (HR) of newly developed cerebrovascular disease was 1.28 (95% confidence interval (CI) = 1.162-1.413; p < 0.0001) for psoriatic vs. non-psoriatic subjects. In terms of the effects of methotrexate or retinoid on the occurrence of cerebrovascular disease, a significant protection effect (HR = 0.50; 95% CI = 0.27-0.92; p = 0.0264) was found for patients with methotrexate prescription. Retinoid prescription showed no protective effect. Further analyses revealed that a low cumulative methotrexate dose is associated with significant protective effect (HR = 0.53; 95% CI = 0.28-1.00; p = 0.0486) while a high cumulative dose was not (HR 0.80; 95% CI = 0.11-5.68; p = 0.8214). These results suggest that psoriatic patients receiving low-dose methotrexate treatment may have reduced risk for developing cerebrovascular disease. Further prospective study should be performed to validate the vasculoprotective effect of this treatment strategy.

E2F1-mediated GINS2 transcriptional activation promotes tumor progression through PI3K/AKT/mTOR pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has high morbidity and mortality rates. It is therefore imperative to study the underlying mechanism of HCC to identify potential prognostic biomarkers and therapeutic targets. Recently, GINS2 has been identified to be a cancer-promoting gene in different cancer types. Nevertheless, the exact mechanism of GINS2 in HCC remains to be elucidated. To systematically explore the significance of GINS2, we first assessed the relative expression of GINS2 in pan-cancers based on data obtained from the HCCDB, TIMER, and TCGA databases. Then, we explored the clinical significance of GINS2 in HCC through Kaplan-Meier method as well as univariate and multivariate cox regression analysis. Additionally, functional enrichment analysis of GINS2 was done through GO, KEGG, PPI network, and immune cell infiltration analyses. Functional experiments were also conducted to investigate the biological significance of GINS2 in HCC cell lines. Our research revealed that GINS2 is involved in HCC progression and highlighted its potential value as a crucial diagnostic and therapeutic target for HCC.

Development and Validation of a Novel Model to Predict Regional Lymph Node Metastasis in Patients With Hepatocellular Carcinoma.

BACKGROUND: The evaluation of the nodal status of hepatocellular carcinoma (HCC) is a classic but controversial topic. This study aimed to investigate the incidence of lymph node metastasis (LNM), explore the role of lymph node dissection (LND), and develop and validate a novel model to predict LNM in patients with HCC, not other specified (NOS). METHODS: The study cohort was taken from the Surveillance, Epidemiology, and End Results database. The annual percent change (APC) was calculated using the Joinpoint regression. Survival analyses adopted the competing risk model. The nomogram was constructed based on the least absolute shrinkage and selection operator (LASSO) logistic regression algorithm and validated by calibration curves. The area under the receiver operating characteristic curve (AUROC) was obtained to compare prognostic performance. Decision curve and clinical impact curve analyses were introduced to examine the clinical value of the models. RESULTS: A total of 8,829 patients were finally enrolled in this study, and 1,346 (15.2%) patients received LND. The LND rate showed no noticeable fluctuation in the last decade, with an APC of 0.5% (P=0.593). LNM was identified in 56 (4.2%) patients and confirmed an independent prognostic factor of HCC patients (P=0.005). There were 2,497 lymph nodes retrieved, and 93 (3.7%) of them were positive. After propensity score matching, LND indicated no direct oncologic benefit and did not worsen competing risks. Moreover, an increased number of lymph nodes retrieved could not improve prognoses. 1,346 patients with LND were further randomly divided into the training and validation sets with the ratio of 1:1. Race, tumor size, clinical T stage, extrahepatic bile duct invasion, and tumor grade were independent risk factors for LNM. The constructed model was well calibrated and showed good discrimination power and net benefits in clinical practice. CONCLUSION: LNM is an independent prognostic factor in HCC, but routine LND seems to be unnecessary in HCC patients. The constructed model could predict the presence of LNM in HCC patients with good performance, which is meaningful to patient stratification and individual treatment strategies optimization.

Epidemiological and Clinical Characteristics of Five Rare Pathological Subtypes of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor with several rare pathological subtypes and which is still poorly understood. This study aimed to describe the epidemiological and clinical spectrum of five rare HCC subtypes and develop a competing risk nomogram for cancer-specific survival prediction. Methods: The study cohort was recruited from the Surveillance, Epidemiology, and End Results database. The clinicopathological data of 50,218 patients histologically diagnosed with classic HCC and five rare subtypes (ICD-O-3 Histology Code = 8170/3-8175/3) between 2004 and 2018 were reviewed. The annual percent change (APC) was calculated utilizing Joinpoint regression. The nomogram was developed based on multivariable competing risk survival analyses. Akaike information criterion, Bayesian information criterion, C-index, calibration curve, and area under the receiver operating characteristic curve were obtained to evaluate the prognostic performance. A decision curve analysis was introduced to examine the clinical value of the models. Results: Despite scirrhous carcinoma, which showed a decreasing trend (APC = -6.8%, P = 0.025), the morbidity of other rare subtypes remained stable from 2004 to 2018. The incidence-based mortality was plateau in all subtypes during the period. Clear cell carcinoma is the most common subtype (n = 551, 1.1%), followed by subtypes of fibrolamellar (n = 241, 0.5%), scirrhous (n = 82, 0.2%), spindle cell (n = 61, 0.1%), and pleomorphic (n = 17, ~0%). The patients with fibrolamellar carcinoma were younger and more likely to have a non-cirrhotic liver and better prognoses. Scirrhous carcinoma shared almost the same macro-clinical characteristics and outcomes as the classic HCC. Clear cell carcinoma tended to occur in the Asia-Pacific elderly male population, and more than half of them were large HCC (Size>5cm). Sarcomatoid (including spindle cell and pleomorphic) carcinoma was associated with a larger tumor size, poorer differentiation, and more dismal prognoses. The pathological subtype, T stage, M stage, surgery, alpha-fetoprotein, and cancer history were confirmed as the independent predictors in patients with rare subtypes. The nomogram showed good calibration, discrimination, and net benefits in clinical practice. Conclusion: The rare subtypes had unique clinicopathological features and biological behaviors compared with the classic HCC. Our findings could provide a valuable reference for clinicians. The constructed nomogram could predict the prognoses with good performance, which is meaningful to individualized management.