Effect of Exogenous γ-aminobutyric acid on Physiological Property, Antioxidant Activity, and Cadmium Uptake of quinoa Seedlings under Cadmium Stress.

Increasing cadmium (Cd) pollution has negative effects on quinoa growth and production. Gamma-aminobutyric acid (GABA) confers plants with stress resistance to heavy metals; however, the mechanism remains unclear. We explored the effects of exogenous GABA on the physiological characteristics, antioxidant capacity, and Cd accumulation of quinoa seedlings under Cd stress using hydroponic experiments. Partial least-squares regression was used to identify key physical and chemical indices of seedlings affecting Cd accumulation. Compared with those of the CK group, exposure to 10 µmol·L-1 and 25 µmol·L-1 Cd significantly reduced the photosynthetic pigment contents, photosynthesis, and biomass accumulation of quinoa seedlings; resulted in shorter and thicker roots; decreased the length of the lateral roots; decreased the activities of superoxide dismutase (SOD) and peroxide (POD); and increased H2O2 and malondialdehyde (MDA) contents. Exogenous GABA reduced the Cd content in the stem/leaves and roots of quinoa seedlings under Cd stress by 13.22-21.63% and 7.92-28.32%, decreased Cd accumulation by 5.37-6.71% and 1.91-4.09%, decreased the H2O2 content by 38.21-47.46% and 45.81-55.73%, and decreased the MDA content by 37.65-48.12% and 29.87-32.51%, respectively. GABA addition increased the SOD and POD activities in the roots by 2.78-5.61% and 13.81-18.33%, respectively, under Cd stress. Thus, exogenous GABA can reduce the content and accumulation of Cd in quinoa seedlings by improving the photosynthetic characteristics and antioxidant enzyme activity and reducing the degree of lipid peroxidation in the cell membrane to alleviate the toxic effect of Cd stress on seedling growth.

Clinical Features and Genomic Epidemiology of Bloodstream Infections due to Enterococcal Species Other Than Enterococcus faecalis or E. faecium in Patients With Cancer.

Background: Non-Enterococcus faecium, non-E. faecalis (NFF) enterococci are a heterogeneous group of clinically pathogenic enterococci that include species with intrinsic low-level vancomycin resistance. Patients with cancer are at increased risk for bacteremia with NFF enterococci, but their clinical and molecular epidemiology have not been extensively described. Methods: We conducted a retrospective review of all patients (n = 70) with NFF bacteremia from 2016 to 2022 at a major cancer center. The main outcomes assessed were 30-day mortality, microbiological failure (positive blood cultures for ≥4 days), and recurrence of bacteremia (positive blood culture <14 days after clearance). Whole-genome sequencing was performed on all available NFF (n = 65). Results: Patients with hematological malignancies made up 56% of the cohort (77% had leukemia). The majority of solid malignancies (87%) were gastrointestinal in origin. The majority of infections (83%) originated from an intra-abdominal source. The most common NFF species were E. gallinarum (50%) and E. casseliflavus (30%). Most (61%) patients received combination therapy. Bacteremia recurred in 4.3% of patients, there was a 30-day mortality of 23%, and 4.3% had microbiological failure. E. gallinarum and E. casseliflavus isolates were genetically diverse with no spatiotemporal clustering to suggest a single strain. Frequencies of ampicillin resistance (4.3%) and daptomycin resistance (1.9%) were low. Patients with hematologic malignancy had infections with NFF enterococci that harbored more resistance genes than patients with solid malignancy (P = .005). Conclusions: NFF bacteremia is caused by a heterogeneous population of isolates and is associated with significant mortality. Hematological malignancy is an important risk factor for infection with NFF resistant to multiple antibiotics.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis.

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

Multi-institutional validation of a radiomics signature for identification of postoperative progression of soft tissue sarcoma.

BACKGROUND: To develop a magnetic resonance imaging (MRI)-based radiomics signature for evaluating the risk of soft tissue sarcoma (STS) disease progression. METHODS: We retrospectively enrolled 335 patients with STS (training, validation, and The Cancer Imaging Archive sets, n = 168, n = 123, and n = 44, respectively) who underwent surgical resection. Regions of interest were manually delineated using two MRI sequences. Among 12 machine learning-predicted signatures, the best signature was selected, and its prediction score was inputted into Cox regression analysis to build the radiomics signature. A nomogram was created by combining the radiomics signature with a clinical model constructed using MRI and clinical features. Progression-free survival was analyzed in all patients. We assessed performance and clinical utility of the models with reference to the time-dependent receiver operating characteristic curve, area under the curve, concordance index, integrated Brier score, decision curve analysis. RESULTS: For the combined features subset, the minimum redundancy maximum relevance-least absolute shrinkage and selection operator regression algorithm + decision tree classifier had the best prediction performance. The radiomics signature based on the optimal machine learning-predicted signature, and built using Cox regression analysis, had greater prognostic capability and lower error than the nomogram and clinical model (concordance index, 0.758 and 0.812; area under the curve, 0.724 and 0.757; integrated Brier score, 0.080 and 0.143, in the validation and The Cancer Imaging Archive sets, respectively). The optimal cutoff was - 0.03 and cumulative risk rates were calculated. DATA CONCLUSION: To assess the risk of STS progression, the radiomics signature may have better prognostic power than a nomogram/clinical model.

Identification of molecular subtypes based on chromatin regulator-related genes and experimental verification of the role of ASCL1 in conferring chemotherapy resistance to breast cancer.

Objective: The aim of this study was to identify the molecular subtypes of breast cancer based on chromatin regulator-related genes. Methods: The RNA sequencing data of The Cancer Genome Atlas-Breast Cancer cohort were obtained from the official website, while the single-cell data were downloaded from the Gene Expression Omnibus database (GSE176078). Validation was performed using the Molecular Taxonomy of Breast Cancer International Consortium dataset. Furthermore, the immune characteristics, tumor stemness, heterogeneity, and clinical characteristics of these molecular subtypes were analyzed. The correlation between chromatin regulators and chemotherapy resistance was examined in vitro using the quantitative real-time polymerase chain reaction (qRT-PCR) and Cell Counting Kit-8 (CCK8) assays. Results: This study identified three stable molecular subtypes with different prognostic and pathological features. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction analyses revealed that the differentially expressed genes were associated with disease processes, such as mitotic nuclear division, chromosome segregation, condensed chromosome, and specific chromosome region. The T stage and subtypes were correlated with the clinical features. Tumor heterogeneity (mutant-allele tumor heterogeneity, tumor mutational burden, purity, and homologous recombination deficiency) and tumor stemness (RNA expression-based stemness score, epigenetically regulated RNA expression-based stemness score, DNA methylation-based stemness score, and epigenetically regulated DNA methylation-based stemness score) significantly varied between the three subtypes. Furthermore, Western blotting, qRT-PCR, and CCK8 assays demonstrated that the expression of ASCL1 was positively correlated with chemotherapy resistance in breast cancer. Conclusion: This study identified the subtypes of breast cancer based on chromatin regulators and analyzed their clinical features, gene mutation status, immunophenotype, and drug sensitivity. The results of this study provide effective strategies for assessing clinical prognosis and developing personalized treatment strategies.

Investigating the Relationship between Birthweight and Breast Cancer from A Non-Linear and Mediation Perspective.

Background: Epidemiological studies have shown a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations emerged. We re-explored the association between them in the UK Biobank cohort. Methods: Relying on the UK Biobank cohort data of white British volunteers recruited between 2006 and 2010 (5,760 cases and 162,778 controls), we evaluated the causal mediation between birthweight and breast cancer, with age of menarche and age at menopause as two potential mediators under the traditional mediation analysis framework. The non-linear relationship between birthweight and breast cancer was also investigated by including the square of birthweight or discretized birthweight categories (<2.5, 2.5~4.0, or >4.0). Furthermore, we performed a stratification analysis in terms of the menopause status. Results: Birthweight can indirectly influence breast cancer risk in adulthood via the path of age of menarche or age at menopause, and found statistical evidence supporting the existence of suggestive non-linear association between birthweight and breast cancer (ß=0.062 and P=0.004 for the square of birthweight) although failing to discover a linear relationship (P=0.230). We also demonstrated such non-linear association seemed more pronounced and robust for premenopausal women compared with postmenopausal ones (27.5% vs. 19.5% increase in breast cancer risk). Conclusion: This study provided an in-depth insight into the observed relationship between birthweight and breast cancer and revealed that non-linear impact and causal mediation commonly drive the connection between the two traits.

Neoadjuvant targeted immunotherapy followed by surgical resection versus upfront surgery for hepatocellular carcinoma with macrovascular invasion: A multicenter study.

Background: This study aimed to investigate the safety and efficacy of preoperative targeted immunotherapy followed by surgical resection for hepatocellular carcinoma (HCC) patients with macrovascular invasion. Method: Clinical information of HCC patients with macrovascular invasion was collected from four medical centers. These patients were divided into two cohorts: the upfront surgery group (n=40) and the neoadjuvant group (n=22). Comparisons between the two groups were made with appropriate statistical methods. Results: HCC Patients with macrovascular invasion in the neoadjuvant group were associated with increased incidence of postoperative ascites (72.73% vs. 37.5%, P=0.008), but shorter postoperative hospital stay (10 days vs. 14 days, P=0.032). Furthermore, targeted immunotherapy followed by surgical resection significantly reduced the postoperative recurrence rate at both 3 months and 1 year (9% versus 28.9%, 32.1% versus 67.9%, respectively; P=0.018), but increased the postoperative nononcologic mortality rate within 1 year (20.1% vs. 2.8%; P= 0.036). Conclusion: For HCC patients with macrovascular invasion, preoperative targeted immunotherapy significantly decreased the postoperative tumor recurrence rate while maintaining relative safety, but such a treatment may also result in chronic liver damage and increased risk of nononcologic mortality.

Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity.

Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.

Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis.

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.

Efficacy of cross-line anti-programmed death 1/programmed cell death-ligand 1 antibody in the treatment of advanced nonsmall cell lung cancer: A retrospective study.

Background and Aims: Immune checkpoint inhibitors (ICIs) across multiple treatment lines have not yet been evaluated comprehensively. The purpose of this research was to investigate whether or not continuous cross-line ICIs therapy is effective in treating non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective investigation into the medical histories of 47 patients diagnosed with advanced NSCLC and treated with ICIs at the Peking University First Hospital between January 2018 and June 2022. Results: Due to the progression of their disease, 14 patients were given the same ICIs, 5 patients were given different ICIs, and 6 patients discontinued taking ICIs altogether. The objective response rates were 7.140% in the ICIs cross-line treatment group, 0% in the replacement of ICIs treatment group, and 0% in the discontinuation of ICIs treatment group. The disease control rates were 64.260% in the ICIs cross-line treatment group, 60% in the replacement of ICIs treatment group, and 0% in the discontinuation of ICIs treatment group. The average overall survival durations of the three groups were 24.020 (95% confidence interval [CI]: 17.061-30.979), 31.643 (95% CI: 23.513-39.774), and 7.997 (95% CI: 3.746-12.247) months, respectively (p = 0.003). The median second progression-free survival (PFS2) durations of the three groups were 4.570 (95% CI: 3.276-5.864), 3.530 (95% CI: 0.674-6.386), and 1.570 (95% CI: 0-4.091) months, respectively (p = 0.091). Conclusions: Cross-line ICIs cannot improve the prognosis and PFS2 of patients with NSCLC, but compared to discontinuing ICIs, OS may be prolonged. A few patients may benefit from prolonged ICIs therapy.

Interaction Between Hypoxia-Inducible Factor 1-alpha Gene Polymorphism and Helicobacter pylori Infection on Gastric Cancer in a Chinese Tibetan Population.

To investigate the impact of four single nucleotide polymorphisms (SNPs) of the HIF1α gene and its interaction with Helicobacter pylori (H. pylori) infection on susceptibility to gastric cancer (GC).Logistic regression was used to test the relationship between four SNPs of HIF1α gene and the susceptibility of GC. A generalized multifactor dimensionality reduction (GMDR) model was used to assess the HIF1α gene-H. pylori infection interaction.Logistic regression analysis indicated that both the rs11549465-CT genotype and the T allele were associated with an increased risk of GC, adjusted OR (95% CI) were 1.63 (1.09-2.20) (CT vs. CC) and 1.70 (1.13-2.36) (T vs. C), respectively. We also found that both the rs11549467-A allele and rs11549467-GA genotype were associated with an increased risk of GC, and adjusted OR (95% CI) were 2.21 (1.61-2.86) (GA vs. GG), 2.13 (1.65-2.65) (A vs. G), respectively. However, no statistically significant impact of rs2057482 or rs1957757 on risk of GC was found. The GMDR model indicated a statistically significant two-dimensional model combination (including rs11549467 and H. pylori infection). The selected model had testing balanced accuracy of 0.60 and the best cross-validation consistencies of 10/10 (p = 0.0107). Compared with H. pylori infection negative participants with rs11549467-GG genotype, H. pylori positive participants with the rs11549467-GA genotype had the highest GC risk, the OR (95% CI) was 3.04 (1.98-4.12).The rs11549467-A allele and rs11549467-GA genotype was associated with increased GC risk. Additionally, the gene-environment interaction between HIF-1α-rs11549467 and H. pylori infection was also correlated with an increased risk of GC.

Identification of disease-specific genes related to immune infiltration in nonalcoholic steatohepatitis using machine learning algorithms.

To identify disease signature genes associated with immune infiltration in nonalcoholic steatohepatitis (NASH), we downloaded 2 publicly available gene expression profiles, GSE164760 and GSE37031, from the gene expression omnibus database. These profiles represent human NASH and control samples and were used for differential genes (DEGs) expression screening. Two machine learning methods, the Least Absolute Shrinkage and Selection Operator regression model and Support Vector Machine Recursive Feature Elimination, were used to identify candidate disease signature genes. The CIBERSORT deconvolution algorithm was employed to analyze the infiltration of 22 immune cell types in NASH. Additionally, we constructed a NASH cell model using HepG2 cells treated with oleic acid and free fatty acids. The construction of the cell model was verified using oil red O staining, and Western blotting was used to detect the protein expression of the disease signature genes in both control and model groups. As a result, a total of 262 DEGs were identified. These DEGs were primarily associated with metal ion transmembrane transporter activity, sodium ion transmembrane transporter protein activity, calcium ion, and neuroactive ligand-receptor interactions. FOS, IGFBP2, dual-specificity phosphatase 1 (DUSP1), and IKZF3 were identified as disease signature genes of NASH by the least absolute shrinkage and selection operator and Support Vector Machine Recursive Feature Elimination algorithms for DEGs analysis. The receiver operating characteristic curves showed that FOS, IGFBP2, DUSP1, and IKZF3 had good diagnostic value (area under receiver operating characteristic curve > 0.8). These findings were validated in the GSE89632 dataset and through cellular assays. Immunocyte infiltration analysis revealed that NASH was associated with CD8 T cells, CD4 T cells, follicular helper T cells, resting NK cells, eosinophils, regulatory T cells, and γδ T cells. The FOS, IGFBP2, DUSP1, and IKZF3 genes were specifically associated with follicular helper T cells. Lipid droplet aggregation significantly increased in HepG2 cells treated with oleic acid and free fatty acids, indicating successful construction of the cell model. In this model, the expression of FOS, IGFBP2, and DUSP1 was significantly decreased, while that of IKZF3 was significantly elevated (P < .01, P < .001) compared with the control group. Therefore, FOS, IGFBP2, DUSP1, and IKZF3 can be considered as disease signature genes associated with immune infiltration in NASH.

Synergistic promotion of microalgal growth and copper removal from synthetic wastewater by nanoscale zero-valent iron particles.

The increasing concentrations of heavy metals in livestock wastewater pose a serious threat to the environmental safety and human health, limiting its resource utilisation. In the present study, microalgae and nanoscale zero-valent iron were selected to construct a coupled system for copper-containing wastewater treatment. The addition of 50 mg·L-1 nanoscale zero-valent iron (50 nm) was the optimal value for the experiment, which could significantly increase the biomass of microalgae. In addition, nanoscale zero-valent iron stimulated microalgal secretion of extracellular polymeric substances, increasing the contents of binding sites, organic ligands, and functional groups on the microalgal surfaces and ultimately promoting the settling of microalgae and binding of heavy metals. The coupled system could quickly adapt to copper-containing wastewater of 10 mg·L-1, and the copper removal rate reached 94.99%. Adsorption and uptake by organisms, together with the contribution of zero-valent iron nanoparticles, are the major copper removal pathways. Overall, this work offers a novel technical solution for enhanced treatment of copper-containing livestock wastewater, which will help improve the efficiency and quality of wastewater treatment.

Doxorubicin induces deglycosylation of cancer cell-intrinsic PD-1 by NGLY1.

Tumor cells can express the immune checkpoint protein programmed death-1 (PD-1), but how cancer cell-intrinsic PD-1 is regulated in response to cellular stresses remains largely unknown. Here, we uncover a unique mechanism by which the chemotherapy drug doxorubicin (Dox) regulates cancer cell-intrinsic PD-1. Dox upregulates PD-1 mRNA while reducing PD-1 protein levels in tumor cells. Although Dox shortens the PD-1 half-life, it fails to directly induce PD-1 degradation. Instead, we observe that Dox promotes the interaction between peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1) and PD-1, facilitating NGLY1-mediated PD-1 deglycosylation and destabilization. The maintenance of PD-1 sensitizes tumor cells to Dox-mediated antiproliferative effects. Our study unveils a regulatory mechanism of PD-1 in response to Dox and highlights a potential role of cancer cell-intrinsic PD-1 in Dox-mediated antitumor effects.

Gapless biosynthetic pathway enables sustainable paclitaxel production.

A recent leading-edge study by Jiang et al. identified two enzymes that are responsible for key reactions in the biosynthesis of baccatin III. The authors successfully reconstructed the baccatin III synthesis pathway with a minimal number of synthetic enzymes in tobacco leaves, laying the foundation for industrial-scale sustainable production of the anticancer drug paclitaxel.

Feature Matching of Microsecond-Pulsed Magnetic Fields Combined with Fe3O4 Particles for Killing A375 Melanoma Cells.

The combination of magnetic fields and magnetic nanoparticles (MNPs) to kill cancer cells by magneto-mechanical force represents a novel therapy, offering advantages such as non-invasiveness, among others. Pulsed magnetic fields (PMFs) hold promise for application in this therapy due to advantages such as easily adjustable parameters; however, they suffer from the drawback of narrow pulse width. In order to fully exploit the potential of PMFs and MNPs in this therapy, while maximizing therapeutic efficacy within the constraints of the narrow pulse width, a feature-matching theory is proposed, encompassing the matching of three aspects: (1) MNP volume and critical volume of Brownian relaxation, (2) relaxation time and pulse width, and (3) MNP shape and the intermittence of PMF. In the theory, a microsecond-PMF generator was developed, and four kinds of MNPs were selected for in vitro cell experiments. The results demonstrate that the killing rate of the experimental group meeting the requirements of the theory is at least 18% higher than the control group. This validates the accuracy of our theory and provides valuable guidance for the further application of PMFs in this therapy.

Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice.

BACKGROUND: Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. METHODS: Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. RESULTS: Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1ß release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. CONCLUSIONS: Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.

Proteo-genomic characterization of cirrhosis-associated liver cancers reveals potential subtypes and therapeutic targets.

BACKGROUND: This study aimed to identify potential subtypes of hepatocellular carcinoma (HCC) associated with cirrhosis and to investigate key markers using bioinformatic analysis of gene expression datasets-0. METHODS: Three data sets (GSE17548, GSE56140, and GSE87630) were extracted from the Gene Expression Omnibus (GEO) database and normalized using the Limma package in R. Principal component analysis (PCA) and cluster analysis was performed to examine data distribution and identify subtypes. Differential gene expression analysis was performed using the Limma software package. Protein-protein interaction analysis and functional annotation were performed using the STRING database and Cytoscape software. Important signaling pathways and processes were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Analysis. RESULTS: The analysis revealed different subtypes of HCC associated with cirrhosis and identified several key genes, including CCNB2, MCM4, and CDC20, with strong binding power and prognostic value. Functional annotation indicated involvement in cell cycle regulation and metabolic pathways. ROC analysis showed high sensitivity and specificity of these genes in predicting HCC prognosis. CONCLUSION: These results suggest that CCNB2, MCM4, and CDC20 may serve as potential biomarkers for predicting HCC prognosis in patients with cirrhosis and provide insights into the molecular mechanisms of HCC progression.

Regulation of TAK-TAB Complex Activation through Ubiquitylation.

Transforming growth factor-ß (TGF-ß) activated kinase 1 (TAK1), also named mitogen-activated protein kinase 7 (MAPK7), forms a pivotal signaling complex with TAK1-binding proteins (TAB1, TAB2, and TAB3), orchestrating critical biological processes, including immune responses, cell growth, apoptosis, and stress responses. Activation of TAK1 by stimuli, such as tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and Toll-like receptors (TLRs), underscores its central role in cellular signaling. Given the critical role of the TAK1-binding protein (TAK1-TAB) complex in cellular signaling and its impact on various biological processes, this review seeks to understand how ubiquitination thoroughly regulates the TAK1-TAB complex. This understanding is vital for developing targeted therapies for diseases where this signaling pathway is dysregulated. The exploration is significant as it unveils new insights into the activity, stability, and assembly of the complex, underscoring its therapeutic potential in disease modulation.

Comprehensive analysis of immune-related lncRNAs in AML patients uncovers potential therapeutic targets and prognostic biomarkers.

Purpose: The objective of this study was to provide theoretically feasible strategies by understanding the relationship between the immune microenvironment and the diagnosis and prognosis of AML patients. To this end, we built a ceRNA network with lncRNAs as the core and analyzed the related lncRNAs in the immune microenvironment by bioinformatics analysis. Methods: AML transcriptome expression data and immune-related gene sets were obtained from TCGA and ImmPort. Utilizing Pearson correlation analysis, differentially expressed immune-related lncRNAs were identified. Then, the LASSO-Cox regression analysis was performed to generate a risk signature consisting immune-related lncRNAs. Accuracy of signature in predicting patient survival was evaluated using univariate and multivariate analysis. Next, GO and KEGG gene enrichment and ssGSEA were carried out for pathway enrichment analysis of 183 differentially expressed genes, followed by drug sensitivity and immune infiltration analysis with pRRophetic and CIBERSORT, respectively. Cytoscape was used to construct the ceRNA network for these lncRNAs. Results: 816 common lncRNAs were selected to acquire the components related to prognosis. The final risk signature established by multivariate Cox and stepwise regression analysis contained 12 lncRNAs engaged in tumor apoptotic and metastatic processes: LINC02595, HCP5, AC020934.2, AC008770.3, LINC01770, AC092718.4, AL589863.1, AC131097.4, AC012368.1, C1RL-AS1, STARD4-AS1, and AC243960.1. Based on this predictive model, high-risk patients exhibited lower overall survival rates than low-risk patients. Signature lncRNAs showed significant correlation with tumor-infiltrating immune cells. In addition, significant differences in PD-1/PD-L1 expression and bleomycin/paclitaxel sensitivity were observed between risk groups. Conclusion: LncRNAs related to immune microenvironment were prospective prognostic and therapeutic options for AML.