Recent and recurrent autopolyploidization fueled diversification of snow carp on the Tibetan Plateau.

Whole-genome duplication (WGD), or polyploidization, is a major contributor to biodiversity. However, the establishment and survival of WGDs are often considered to be stochastic, since elucidating the processes of WGD establishment remains challenging. In the current study, we explored the processes leading to polyploidy establishment in snow carp (Cyprinidae: Schizothoracinae), a predominant component of the ichthyofauna of the Tibetan Plateau and its surrounding areas. Using large-scale genomic data from isoform sequencing, we analyzed ohnolog genealogies and divergence in hundreds to thousands of gene families across major snow carp lineages. Our findings demonstrated that independent autopolyploidization subsequent to speciation was prevalent, while autopolyploidization followed by speciation also occurred in the diversification of snow carp. This was further supported by matrilineal divergence and drainage evolution evidence. Contrary to the long-standing hypothesis that ancient polyploidization preceded the diversification of snow carp, we determined that polyploidy in extant snow carp was established by recurrent autopolyploidization events during the Pleistocene. These findings indicate that the diversification of extant snow carp resembles a coordinated duet: first, the uplift of the Tibetan Plateau orchestrated the biogeography and diversification of their diploid progenitors; then, the extensive Pliocene-Pleistocene climate changes acted as relay runners, further fueling diversification through recurrent autopolyploidization. Overall, this study not only reveals a hitherto unrecognized recent WGD lineage in vertebrates but also advances current understanding of WGD processes, emphasizing that WGD establishment is a non-stochastic event, emerging from numerous adaptations to environmental challenges and recurring throughout evolutionary history rather than merely in plants.

Identification of a pyroptosis-related long noncoding RNA signature for determining the prognosis and immune status of hepatocellular carcinoma patients.

BACKGROUND: Despite improvements in cancer screening and diagnosis, hepatocellular carcinoma (HCC) is still diagnosed at an advanced stage, and the prognosis is worse than that of early HCC patients. Therefore, better molecular markers and therapeutic targets in HCC are required. OBJECTIVES: We investigated the predictive value of pyroptosis-related long noncoding RNAs (lncRNAs) in HCC and the effects of these lncRNAs on the immune microenvironment of HCC. MATERIAL AND METHODS: RNA sequencing data of HCC patients were extracted from The Cancer Genome Atlas (TCGA) database to identify differentially expressed pyroptosis-related lncRNAs related to overall survival (OS). A model was established to verify the character of pyroptosis-associated lncRNAs in the tumor microenvironment, and their prognostic value was evaluated. RESULTS: A total of 721 PR lncRNAs were identified based on the analysis of the TCGA database. Univariate Cox analysis revealed 37 survival-related PRlncRNAs with prognostic values. As a result of least absolute shrinkage and selection operator (LASSO) regression analysis, 'ELFN-AS1', AC099850.3, AC073389.3, 'HPN-AS1', AC009283.1, and AL139289.1 showed prognostic value. Kaplan-Meier analysis indicated that the OS of the high-risk set was worse than those of the low-risk set in both the training and testing cohorts. Univariate and multivariate analyses revealed that the risk score was a better independent prognostic factor than the stage. The precision of the lncRNA signature was confirmed using receiver operating characteristic curve (ROC) analysis. Immuneand metabolism-related pathways were enriched in both the lowand high-risk groups. Gene set enrichment analysis suggested that the identified lncRNAs regulate HCC tumorigenesis and prognosis by modulating metabolism. Various algorithms were used to confirm the significant differences in immune cells between these 2 groups. CONCLUSIONS: These findings could contribute to the development and validation of favorable biomarkers, improve the prognosis and survival of HCC, and help in developed individualized treatment plans for HCC.

Latexin deficiency limits foam cell formation and ameliorates atherosclerosis by promoting macrophage phenotype differentiation.

Latexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.

Dual Role of Necroptosis in Cervical Cancer: Promoting Tumor Aggression and Modulating the Immune Microenvironment via the JAK2-STAT3 Pathway.

In the dynamic landscape of cervical cancer (CC) pathophysiology, this study aimed to elucidate the role of necroptosis in modulating tumor proliferation, invasion, and the immune microenvironment in CC. In this study, the impact of necroptosis on CC was evaluated through a series of bioinformatical analyses and experimental approaches. The impact of necroptosis on CC was illustrated by analyzing its effects on tumor aggression, immune responses, and the JAK2-STAT3 signaling pathway. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), was also evaluated for its potential induction of necroptosis in CC cells and its interaction with necroptosis inhibitors. Additionally, the study assessed the influence of necroptosis on the immune microenvironment, particularly in T-cell-related pathways and the expression of tumor suppressor genes in CC. Necroptosis was found to enhance VEGFA expression through the activation of the JAK2-STAT3 pathway, promoting tumor proliferative and invasive capabilities in CC. Bevacizumab induced necroptosis in CC cells, potentially leading to resistance to therapy. The combination of bevacizumab with necroptosis inhibitors attenuated VEGFA expression, suggesting a novel therapeutic strategy. Additionally, necroptosis activated T-cell-related pathways and promoted the infiltration and activation of Jurkat T cells. CD3D-a tumor suppressor gene in CC-was identified as a critical marker and its expression could be upregulated by necroptosis via the JAK2-STAT3 pathway in Jurkat T cells. Treatment of CC cells with supernatants from necroptosis-induced Jurkat cells resulted in reduced tumor cell proliferation and invasion. This study reveals a complex interaction between necroptosis, tumor progression, and the immune response in CC. The findings propose a nuanced approach to leveraging necroptosis for therapeutic interventions, highlighting the potential of combining necroptosis inhibitors with existing therapies to improve treatment outcomes in CC.

Efficacy and safety of Tongxin formula in the treatment of coronary microvascular disease: A randomized, double-blind, placebo-controlled clinical trial study.

Objective: The objective of this study was to evaluate the efficacy and safety of Tongxin Formula in the treatment of coronary microvascular disease. Methods: We conducted a randomized, double-blind, placebo-controlled study simultaneously in two hospitals, consisting of 80 participants. Using a random number table, we assigned patients to the treatment and control groups. Patients in both groups received conventional Western medicine for coronary microvascular disease. In addition, those in the treatment group received Tongxin formula granules, while those in the control group received a placebo. The treatment course for both groups was three months, and the follow-up duration was six months. The primary efficacy indicators were coronary blood flow reserve and cardiovascular adverse events; the secondary efficacy indicators were the traditional Chinese medicine (TCM) syndrome score, the angina symptom score, the Seattle Angina Questionnaire (SAQ) score, left ventricular function, and adverse reactions. Results: After treatment, patients in the treatment group showed significantly higher variation in the coronary flow reserve (CFR) levels (CFR >2) and improvement of diastolic function (peak filling rate, or PFR >2.5) than those in the control group (P < 0.05). After 6 months of follow-up, the incidence of cardiovascular events in the treatment group was significantly lower than that in the control group (P < 0.05). After 3 months of treatment and 6 months of follow-up, the total effective rates of TCM symptoms and angina symptoms, as well as the total SAQ standard scores, in the treatment group were higher than those in the control group (P < 0.05). There were no serious adverse reactions in either group before or after treatment, and there was no significant change (P > 0.05). Conclusion: We found that Tongxin Formula combined with conventional Western medicine can significantly improved the level of coronary blood flow reserve, reduced the occurrence of cardiovascular adverse events, improved the clinical symptoms of patients, and enhanced the quality of life of patients with coronary microvascular disease with favorable safety.

Differential performance regarding the relationship of C3-epi-25(OH)D3 levels and %C3-epi-25(OH)D3 with common pediatric diseases: a case control study.

BACKGROUND: Recently, the C3-epimer of 25-hydroxyvitamin D [C3-epi-25(OH)D] has become a topic of interest among 25-hydroxyvitamin D [25(OH)D] metabolites. Although it can lead to an overestimation of vitamin D storage, its relationship with disease occurrence remains controversial, possibly related to the great extent of tracking of 25(OH)D by C3-epi-25(OH)D over time. This study aimed to investigate the differential performance of C3-epi-25(OH)D3 and its percentage [%C3-epi-25(OH)D3] with respect to 20 common paediatric diseases. METHODS: This study involved 805 healthy children and adolescents and 2962 patients with common paediatric diseases. We investigated sex, age, and seasonal differences in C3-epi-25(OH)D3 and %C3-epi-25(OH)D3 levels; their variations on 20 common paediatric diseases; and their degree of correlation with 25(OH)D3 levels and various diseases. RESULTS: Among the healthy underage participants, C3-epi-25(OH)D3 and %C3-epi-25(OH)D3 changed similarly, with no sex differences. Moreover, their levels were higher in the infant period than in the other periods (t = 5.329-5.833, t = 4.640-5.711, all Padj < 0.001), and in spring and summer than in autumn and winter (t = 3.495-6.061, t = 3.495-5.658, all Padj < 0.01). Under healthy and disease conditions, C3-epi-25(OH)D3 was positively correlated with 25(OH)D3 (ρ = 0.318 ~ 0.678, all P < 0.017), whereas %C3-epi-25(OH)D3 was not, except in patients with nephrotic syndrome (ρ=-0.393, P = 0.001). Before and after adjusting for 25(OH)D3, the relationship of C3-epi-25(OH)D3 with the diseases was notably different. However, it was almost consistent for %C3-epi-25(OH)D3. Our results indicated that %C3-epi-25(OH)D3 was associated with short stature, nephrotic syndrome, lymphocytic leukaemia, rickets, paediatric malnutrition, and hypovitaminosis D (OR = 0.80 ~ 1.21, all P < 0.05). CONCLUSIONS: The %C3-epi-25(OH)D3 can correct the properties of C3-epi-25(OH)D3 to better track 25(OH)D3 and may be more suitable for exploring its pathological relevance. Further detailed studies of each disease should be conducted.

[Effect of Linggui Zhugan Decoction on myocardial fibrosis and Lats1/Yap signaling pathway in mice after myocardial infraction].

This study aims to investigate the effects of Linggui Zhugan Decoction(LGZGD) on myocardial fibrosis(MF) and the Lats1/Yap signaling pathway in mice after myocardial infarction(MI), exploring its role and mechanism in inhibiting MF. The MI-induced ischemic mouse model was established by left anterior descending coronary artery ligation, followed by continuous intervention for six weeks. Doppler ultrasound imaging-system of small animals was used to detect left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), left ventricular internal diameter at end-systole(LVIDs), and left ventricular internal diameter at end-diastole(LVIDd). Pathological changes in myocardial tissue were observed by HE and Masson staining. Serum levels of creatine kinase isoenzyme MB(CK-MB) and lactate dehydrogenase(LDH) were detected by using ELISA. Myocardial tissue mRNA levels of Lats1, Yap, and connective tissue growth factor(CTGF) were determined by RT-qPCR. Protein expression of alpha-smooth muscle actin(α-SMA), collagen Ⅰ(Col Ⅰ), collagen Ⅲ(Col Ⅲ), tissue inhibitor of metal protease 1(TIMP1), matrix metallopeptidase 2(MMP2), Yap, p-Yap, and n-Yap was determined by Western blot. Compared with the sham group, the model group showed significantly decreased LVEF and LVFS levels, increased LVIDd and LVIDs levels(P<0.01), disordered arrangement of myocardial cells, partial fracture of myocardial fibers, and massive deposition of collagen fibers. Moreover, serum levels of CK-MB and LDH were significantly increased(P<0.01), while myocardial tissue mRNA levels of Lats1 were significantly decreased(P<0.01), and mRNA levels of Yap and CTGF were significantly increased(P<0.01). Protein expression of α-SMA, Col Ⅰ, Col Ⅲ, MMP2, Yap, and n-Yap was significantly increased(P<0.01), while protein expression of Lats1, TIMP1, p-Yap, and the ratio of p-Yap/Yap were significantly decreased(P<0.01). Compared with the model group, after intervention with LGZGD(9.36 g·kg~(-1)), mice showed significantly increased LVEF and LVFS levels, decreased LVIDd and LVIDs levels(P<0.01), more orderly arrangement of myocardial cells, significantly reduced myocardial fiber fracture and collagen fiber deposition. Serum levels of CK-MB and LDH were significantly decreased(P<0.01), while myocardial tissue mRNA levels of Lats1 were significantly increased(P<0.01), and mRNA levels of Yap and CTGF were significantly decreased(P<0.01). Protein expression of α-SMA, Col Ⅰ, Col Ⅲ, MMP2, Yap, and n-Yap was significantly decreased(P<0.01), while protein expression of Lats1, TIMP1, p-Yap, and the ratio of p-Yap/Yap were significantly increased(P<0.01). LGZGD can inhibit MF in mice after MI and improve mouse cardiac function, which is closely related to the activation of the Lats1/Yap signaling pathway.

Integrating machine learning for the optimization of polyacrylamide/alginate hydrogel.

Hydrogels are highly promising due to their soft texture and excellent biocompatibility. However, the designation and optimization of hydrogels involve numerous experimental parameters, posing challenges in achieving rapid optimization through conventional experimental methods. In this study, we leverage machine learning algorithms to optimize a dual-network hydrogel based on a blend of acrylamide (AM) and alginate, targeting applications in flexible electronics. By treating the concentrations of components as experimental parameters and utilizing five material properties as evaluation criteria, we conduct a comprehensive property assessment of the material using a linear weighting method. Subsequently, we design a series of experimental plans using the Bayesian optimization algorithm and validate them experimentally. Through iterative refinement, we optimize the experimental parameters, resulting in a hydrogel with superior overall properties, including heightened strain sensitivity and flexibility. Leveraging the available experimental data, we employ a classification algorithm to separate the cutoff data. The feature importance identified by the classification model highlights the pronounced impact of AM, ammonium persulfate, and N,N-methylene on the classification outcomes. Additionally, we develop a regression model and demonstrate its utility in predicting and analyzing the relationship between experimental parameters and hydrogel properties through experimental validation.

Plant reproduction: Mangroves use 'child-care' in extreme environments.

Using population genomics and molecular biological methods, a recent study reveals the molecular mechanisms of vivipary in mangroves, a term designating all woody plants of the tropical intertidal zones.

Carboxypeptidase inhibitor Latexin (LXN) regulates intestinal organogenesis and intestinal remodeling involved in intestinal injury repair in mice.

The self-renewal and regeneration of intestinal epithelium are mainly driven by intestinal stem cells resided in crypts, which are crucial for rapid recovery intestinal tissue following injury. Latexin (LXN) is a highly expressed stem cell proliferation and differentiation related gene in intestinal tissue. However, it is still ambiguous whether LXN participates in intestine regeneration by regulating intestinal stem cells (ISCs). Here, we report that LXN colocalizes with Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) in intestinal crypts, and deletion of LXN upregulates the expression of Lgr5 in intestinal crypts. LXN deficiency promotes the proliferation of ISCs, thereby enhances the development of intestinal organoids. Mechanically, we show that LXN deficiency enhances the expression of Lgr5 in ISCs by activating the Yes-associated protein (YAP) and wingless (Wnt) signal pathways, thus accelerating intestinal normal growth and regeneration post-injury. In summary, these findings uncover a novel function of LXN in intestinal regeneration post-injury and intestinal organogenesis, suggesting the potential role of LXN in the treatment of inflammatory bowel diseases.

A m6A regulators-related classifier for prognosis and tumor microenvironment characterization in hepatocellular carcinoma.

Background: Increasing evidence have highlighted the biological significance of mRNA N6-methyladenosine (m6A) modification in regulating tumorigenicity and progression. However, the potential roles of m6A regulators in tumor microenvironment (TME) formation and immune cell infiltration in liver hepatocellular carcinoma (LIHC or HCC) requires further clarification. Method: RNA sequencing data were obtained from TCGA-LIHC databases and ICGC-LIRI-JP databases. Consensus clustering algorithm was used to identify m6A regulators cluster subtypes. Weighted gene co-expression network analysis (WGCNA), LASSO regression, Random Forest (RF), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) were applied to identify candidate biomarkers, and then a m6Arisk score model was constructed. The correlations of m6Arisk score with immunological characteristics (immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), and immune checkpoints) were systematically evaluated. The effective performance of nomogram was evaluated using concordance index (C-index), calibration plots, decision curve analysis (DCA), and receiver operating characteristic curve (ROC). Results: Two distinct m6A modification patterns were identified based on 23 m6A regulators, which were correlated with different clinical outcomes and biological functions. Based on the constructed m6Arisk score model, HCC patients can be divided into two distinct risk score subgroups. Further analysis indicated that the m6Arisk score showed excellent prognostic performance. Patients with a high m6Arisk score was significantly associated with poorer clinical outcome, lower drug sensitivity, and higher immune infiltration. Moreover, we developed a nomogram model by incorporating the m6Arisk score and clinicopathological features. The application of the m6Arisk score for the prognostic stratification of HCC has good clinical applicability and clinical net benefit. Conclusion: Our findings reveal the crucial role of m6A modification patterns for predicting HCC TME status and prognosis, and highlight the good clinical applicability and net benefit of m6Arisk score in terms of prognosis, immunophenotype, and drug therapy in HCC patients.

A case of treatment for pulmonary infection caused by multidrug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is a major pathogen in hospital-acquired infections notorious for its strong acquired resistance and complex drug resistance mechanisms. Owing to the lack of effective drugs, the mortality rate of extensively drug-resistant A. baumannii pneumonia can reach as high as 65%. This article analyzes a case where a combination of cefoperazone-sulbactam, polymyxin B, and minocycline with rifampicin successfully treated XDR-AB pulmonary infection. Combination therapy is effective and has a particular clinical value.

Equisetin protects from atherosclerosis in vivo by binding to STAT3 and inhibiting its activity.

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid metabolism disorder and lipid accumulation. Equisetin (EQST) is a hemiterpene compound isolated from fungus of marine sponge origin, which has antibacterial, anti-inflammatory, lipid-lowering, and weight loss effects. Whether EQST has anti-atherosclerotic activity has not been reported. In this study, we revealed that EQST displayed anti- atherosclerosis effects through inhibiting macrophage inflammatory response, lipid uptake and foam cell formation in vitro, and finally ameliorated high-fat diet (HFD)-induced atherosclerosis in AopE-/- mice in vivo. Mechanistically, EQST directly bound to STAT3 with high-affinity by forming hydrophobic bonds at GLN247 and GLN326 residues, as well as hydrogen bonds at ARG325 and THR346 residues. EQST interacted with STAT3 physically, and functionally inhibited the transcription activity of STAT3, thereby regulating atherosclerosis. Therefore, these results supports EQST as a candidate for developing anti-atherosclerosis therapeutic agent.

HES6 Mediates Oxidative Phosphorylation Pathway to Promote Immune Infiltration of CD8 + T Cells in Lung Adenocarcinoma.

Tumor immunotherapy has recently gained popularity as a cancer treatment strategy. The molecular mechanism controlling immune infiltration in lung adenocarcinoma (LUAD) cells, however, is not well characterized. Investigating the immune infiltration modulation mechanism in LUAD is crucial. LUAD patient samples were collected, and HES6 expression and immune infiltration level of CD8 + T cells in patient tissues were analyzed. Bioinformatics was utilized to identify binding relationship between E2F1 and HES6, and enrichment pathway of HES6. The binding of E2F1 to HES6 was verified using dual-luciferase and ChIP experiments. HES6 and E2F1 expression in LUAD cells was detected. LUAD cells were co-cultured with CD8 + T cells, and the CD8 + T cell killing level, IFN-γ secretion, and CD8 + T-cell chemotaxis level were measured. Expression of key genes involved in oxidative phosphorylation was detected, and the oxygen consumption rate of LUAD cells was assessed. A mouse model was constructed to assay Ki67 expression and apoptosis in tumor tissue. High expression of HES6 promoted CD8 + T-cell infiltration and enhanced T-cell killing ability through oxidative phosphorylation. Further bioinformatics analysis, molecular experiments, and cell experiments verified that E2F1 negatively regulated HES6 by oxidative phosphorylation, which suppressed CD8 + T-cell immune infiltration. In addition, in vivo assays illustrated that silencing HES6 repressed tumor cell immune evasion. E2F1 inhibited HES6 transcription, thereby mediating oxidative phosphorylation to suppress immune infiltration of CD8 + T cells in LUAD. The biological functions and signaling pathways of these genes were analyzed, which may help to understand the possible mechanisms regulating immune infiltration in LUAD.

Learning metabolic dynamics from irregular observations by Bidirectional Time-Series State Transfer Network.

Modeling microbial metabolic dynamics is important for the rational optimization of both biosynthetic systems and industrial processes to facilitate green and efficient biomanufacturing. Classical approaches utilize explicit equation systems to represent metabolic networks, enabling the quantification of pathway fluxes to identify metabolic bottlenecks. However, these white-box models, despite their diverse applications, have limitations in simulating metabolic dynamics and are intrinsically inaccurate for industrial strains that lack information on network structures and kinetic parameters. On the other hand, black-box models do not rely on prior mechanistic knowledge of strains but are built upon observed time-series trajectories of biosynthetic systems in action. In practice, these observations are typically irregular, with discontinuously observed time points across multiple independent batches, each time point potentially containing missing measurements. Learning from such irregular data remains challenging for existing approaches. To address this issue, we present the Bidirectional Time-Series State Transfer Network (BTSTN) for modeling metabolic dynamics directly from irregular observations. Using evaluation data sets derived from both ideal dynamic systems and a real-world fermentation process, we demonstrate that BTSTN accurately reconstructs dynamic behaviors and predicts future trajectories. This approach exhibits enhanced robustness against missing measurements and noise, as compared to the state-of-the-art methods.IMPORTANCEIndustrial biosynthetic systems often involve strains with unclear genetic backgrounds, posing challenges in modeling their distinct metabolic dynamics. In such scenarios, white-box models, which commonly rely on inferred networks, are thereby of limited applicability and accuracy. In contrast, black-box models, such as statistical models and neural networks, are directly fitted or learned from observed time-series trajectories of biosynthetic systems in action. These methods typically assume regular observations without missing time points or measurements. If the observations are irregular, a pre-processing step becomes necessary to obtain a fully filled data set for subsequent model training, which, at the same time, inevitably introduces errors into the resulting models. BTSTN is a novel approach that natively learns from irregular observations. This distinctive feature makes it a unique addition to the current arsenal of technologies modeling metabolic dynamics.

Exploration and prognostic analysis of two types of high-risk ovarian cancers: clear cell vs. serous carcinoma: a population-based study.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare pathological histotype in ovarian cancer, while the survival rate of advanced OCCC (Stage III-IV) is substantially lower than that of the advanced serous ovarian cancer (OSC), which is the most common histotype. The goal of this study was to identify high-risk OCCC by comparing OSC and OCCC, with investigating potential risk and prognosis markers. METHODS: Patients diagnosed with ovarian cancer from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) Program. Logistic and Cox regression models were used to identify risk and prognostic factors in high-risk OCCC patients. Cancer-specific survival (CSS) and overall survival (OS) were assessed using Kaplan-Meier curves. Furthermore, Cox analysis was employed to build a nomogram model. The performance evaluation results were displayed using the C-index, calibration plots, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Immunohistochemically approach was used to identify the expression of the novel target (GPC3). RESULTS: In the Cox analysis for advanced OCCC, age (45-65 years), tumor numbers (total number of in situ/malignant tumors for patient), T3-stage, bilateral tumors, and liver metastases could be defined as prognostic variables. Nomogram showed good predictive power and clinical practicality. Compared with OSC, liver metastases had a stronger impact on the prognosis of patients with OCCC. T3-stage, positive distant lymph nodes metastases, and lung metastases were risk factors for developing liver metastases. Chemotherapy was an independent prognostic factor for patient with advanced OCCC, but had no effect on CSS in patients with liver metastases (p = 0.0656), while surgery was significantly related with better CSS in these patients (p < 0.0001) (p = 0.0041). GPC3 expression was detected in all tissue sections, and GPC3 staining was predominantly found in the cytoplasm and membranes. CONCLUSION: Advanced OCCC and OCCC with liver metastases are two types of high-risk OCCC. The constructed nomogram exhibited a satisfactory survival prediction for patients with advanced OCCC. GPC3 immunohistochemistry is expected to accumulate preclinical evidence to support the inclusion of GPC3 in OCCC targeted therapy.

Recent developments and new directions in the use of natural products for the treatment of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD. PURPOSE: This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment. METHODS: This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed. RESULTS: This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges. CONCLUSION: This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD.

Immunoreactive Microenvironment Modulator GBP5 Suppresses Ovarian Cancer Progression by Inducing Canonical Pyroptosis.

Ovarian cancer has the highest mortality among gynecological malignancies, and exploring effective strategies to reverse the immunosuppressive tumor microenvironment in patients remains a pressing scientific challenge. In this study, we identified a pyroptosis-related protective factor, GBP5, which significantly inhibits the growth of ovarian cancer cells and patient-derived ovarian cancer organoids, impeding the invasion and migration of ovarian cancer cells. Results of immunohistochemistry and external single-cell data verification were consistent. Further research confirmed that GBP5 in ovarian cancer cell can induce canonical pyroptosis through JAK2/STAT1 pathway, thereby restraining the progression of ovarian cancer. Interestingly, in this study, we also discovered that ovarian cancer cells with high GBP5 expression exhibit increased expressions of CXCL9/10/11 in a co-culture assay. Subsequent immune cell infiltration analyses revealed the remodeling of immunosuppressive microenvironment in ovarian cancer patients, characterized by increased infiltration and polarization of M1 macrophages. External immunotherapy database analysis showed profound potential for the application of GBP5 in immunotherapy strategies for ovarian cancer. Overall, our study demonstrates that the protective factor GBP5 significantly inhibits ovarian cancer progression, triggering canonical pyroptosis through the JAK2-STAT1 pathway. Driven by its pro-inflammatory nature, it can also enhance M1 macrophages polarization and reverse immunosuppressive microenvironment, thus providing new insights for ovarian cancer treatment.

LncRNA IL21-AS1 facilitates tumour progression by enhancing CD24-induced phagocytosis inhibition and tumorigenesis in ovarian cancer.

CD24 is overexpressed in various tumours and considered a regulator of cell migration, invasion, and proliferation. Recent studies have found that CD24 on ovarian cancer (OC) and triple-negative breast cancer cells interacts with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10) on tumour-associated macrophages (TAMs) to inhibit phagocytosis by macrophages. Because of its multiple roles in regulating the immune response and tumorigenesis, CD24 is a very promising therapeutic target. However, the regulatory mechanism of CD24 in OC remains unclear. Here, we found that the long noncoding RNA (lncRNA) IL21-AS1, which was upregulated in OC, inhibited macrophage-mediated phagocytosis and promoted OC cell proliferation and apoptosis inhibition. More importantly, after IL21-AS1 knockdown, a significant survival advantage was observed in mice engrafted with tumours. Mechanistically, we identified IL21-AS1 as a hypoxia-induced lncRNA. Moreover, IL21-AS1 increased HIF1α-induced CD24 expression under hypoxic conditions. In parallel, we found that IL21-AS1 acted as a competing endogenous RNA (ceRNA) for miR-561-5p to regulate CD24 expression. Finally, IL21-AS1 increased CD24 expression in OC and facilitated OC progression. Our findings provide a molecular basis for the regulation of CD24, thus highlighting a potential strategy for targeted treatment of OC.

Integration of Single-Cell RNA Sequencing and Bulk RNA Sequencing to Identify an Immunogenic Cell Death-Related 5-Gene Prognostic Signature in Hepatocellular Carcinoma.

Introduction: Immunogenic cell death (ICD) can enhance the potency of immunotherapy in cancer treatment. Nevertheless, it is ambiguous how ICD-related genes (ICDRGs) contribute to hepatocellular carcinoma (HCC). Methods: Single-cell RNA sequencing (scRNA-seq) data were used to distinguish malignant cells from normal cells in the HCC tumor microenvironment(TME). Bulk RNA sequencing data was employed to acquire the landscape of the 33 ICDRGs. Unsupervised clustering identified two ICD molecular subtypes. The cellular infiltration characteristics and biological behavior in different subtypes were analyzed by ssGSEA. Subsequently, differentially expressed genes (DEGs) between the two subtypes were determined, based on which patients were classified into three gene clusters. Then, the prognostic model was constructed by Lasso-Cox analysis. Finally, we investigated the expression of risk genes in cancer cell line encyclopedia (CCLE) and validated the function of NKX3-2 in vitro experiments. Results: ICD scores and ICDRGs expression in malignant cells were significantly lower than in normal cells by scRNA-seq analysis. ICD-high subtype was characterized by ICD-related gene overexpression and high levels of immune infiltration abundance and immune checkpoints; Three DEGs-related gene clusters were likewise strongly linked to stromal and immunological activation. In the ICD-related prognostic model consisting of NKX3-2, CHODL, MMP1, NR0B1, and CTSV, the low-risk group patients had a better endpoint and displayed increased susceptibility to immunotherapy and chemotherapeutic drugs like 5-Fluorouracil, afatinib, bortezomib, cediratinib, lapatinib, dasatinib, gefitinib and crizotinib. Moreover, NKX3-2 amplification in HCC samples has been verified by experiments, and its disruption suppressed the proliferation and invasion of tumor cells. Conclusion: Our study highlighted the potential of the ICDRGs risk score as a prognostic indicator to aid in the accurate diagnosis and immunotherapy sensitivity of HCC.