Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.

Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.

Radiotherapy with S-1 for the treatment of esophageal squamous cell carcinoma 75 years or older.

OBJECTIVE: Explore the efficacy and safety of involved-field irradiation (IFI) combined with S-1 as definitive concurrent chemoradiotherapy (dCRT) for locally advanced elderly esophageal squamous cell carcinoma (ESCC), under the premise of intensity-modulated radiotherapy (IMRT). METHODS: We designed a prospective single-arm phase II study. The study enrolled 91 patients aged 75 to 92 years. Eligible participants had histologically confirmed squamous cell carcinoma, stage II to IV disease based on the 8th edition of the American Joint Committee on Cancer (AJCC). All elderly patients (EPs) received dCRT with S-1. which was administered orally twice daily for 28 days. The radiotherapy dose was 61.2 Gy delivered in 34 fractions or 50.4 Gy delivered in 28 fractions. The primary endpoint was 2-year overall survival (OS), and the secondary endpoints were progression-free survival (PFS), local control rate (LCR), and safety. RESULTS: From July 2017 to July 2021, we enrolled EPs with ESCC who were treated at the Jiangsu Cancer hospital. As of August 1, 2023, the median follow-up of surviving EPs was 31.4 months (IQR: 25.2 to 72.6 months). 83 patients (91.2%) completed the whole course of treatment. The 2-year OS rate was 59.2%, and the PFS rate was 43.7%. The most common grade 1 to 2 adverse effects (AEs) were radiation esophagitis (79.1%), and then were radiation pneumonia (46.2%). Anemia (41.8%) was the most common of grade 1 to 2 hematologic toxicity. The incidence of grade 3 or above AEs was 24.2%, and the incidence of leukopenia was the highest (11.0%). There was not one death due to treatment-related toxicity. In a subgroup analysis of radiotherapy doses, we found no statistically significant differences in PFS (P = 0.465) and OS (P = 0.345) in EPs with ESCC who received 50.4 Gy and 61.2 Gy, and that patients in the 50.4 Gy group had lower dermatitis (P = 0.045) and anemia (P = 0.004). CONCLUSIONS: IF-IMRT combined with S-1 is a promising regimen for elderly ESCC. And the radiotherapy dose of 50.4 Gy remains the standard dose for EPs with ESCC undergoing CCRT.

Arabidopsis Histone Variant H2A.X Functions in the DNA Damage-Coupling Abscisic Acid Signaling Pathway.

Environmental variations initiate chromatin modifications, leading to the exchange of histone subunits or the repositioning of nucleosomes. The phosphorylated histone variant H2A.X (γH2A.X) is recognized for the formation of foci that serve as established markers of DNA double-strand breaks (DSBs). Nevertheless, the precise roles of H2A.X in the cellular response to genotoxic stress and the impact of the plant hormone abscisic acid (ABA) remain incompletely understood. In this investigation, we implemented CRISPR/Cas9 technology to produce loss-of-function mutants of AtHTA3 and AtHTA5 in Arabidopsis. The phenotypes of the athta3 and athta5 single mutants were nearly identical to those of the wild-type Col-0. Nevertheless, the athta3 athta5 double mutants exhibited aberrant embryonic development, increased sensitivity to DNA damage, and higher sensitivity to ABA. The RT-qPCR analysis indicates that AtHTA3 and AtHTA5 negatively regulate the expression of AtABI3, a fundamental regulator in the ABA signaling pathway. Subsequent investigation demonstrated that AtABI3 participates in the genotoxic stress response by influencing the expression of DNA damage response genes, such as AtBRCA1, AtRAD51, and AtWEE1. Our research offers new insights into the role of H2A.X in the genotoxic and ABA responses of Arabidopsis.

Risk factors for bronchiolitis obliterans complicating adenovirus pneumonia in children: a meta-analysis.

Objective: To preliminarily explore the risk factors for post-infectious bronchiolitis obliterans (PIBO) complicating adenovirus pneumonia (ADVP) in children through a meta-analysis. Methods: A systematic search was conducted on three English-language databases (PubMed, Web of Science and The National Library of Medicine) and two Chinese-language databases (China National Knowledge Infrastructure and the Wanfang Database) between database inception and 1 January 2023. Data analysis was conducted using Stata 15.1 software. Results: A total of 10 articles, reporting 14 risk factors, were included in the analysis, with 8 risk factors taken into consideration. Through the meta-analysis, 5 risk factors were identified for PIBO complicating ADVP in paediatric patients: hypoxaemia [odds ratio (OR) = 9.37, 95% CI: 4.22, 20.77, p < 0.001], persistent wheezing (OR = 4.65, 95% CI: 2.20, 9.82, p < 0.001), mechanical ventilation (OR = 3.87, 95% CI: 2.37, 6.33, p < 0.001), length of hospital stay (LoHS) (OR = 1.25, 95% CI: 1.09, 1.43, p < 0.001) and fever duration (OR = 1.08, 95% CI: 1.02, 1.14, p = 0.009). Conclusion: Existing evidence suggests that hypoxaemia, persistent wheezing, mechanical ventilation, LoHS and fever duration are risk factors for PIBO complicating ADVP in children. These findings underscore the need for enhanced assessment and management in clinical practice. This study may provide such a clinical prediction model from the identified 5 risk factors for PIBO and offer valuable insights for preventing bronchiolitis obliterans in children with ADVP.

Sirt1 m6A modification-evoked Leydig cell senescence promotes Cd-induced testosterone decline.

Diminished testosterone levels have been documented as a key factor in numerous male health disorders. Both human and animal studies have consistently demonstrated that cadmium (Cd), a pervasive environmental heavy metal, results in decreased testosterone levels. However, the exact mechanism through which Cd interferes with testosterone synthesis remains incompletely elucidated. This research sought to examine the impact of cellular senescence on Cd-suppressed testosterone synthesis. We also investigated the related m6A modification mechanism. The results demonstrated that Cd (100 mg/L) led to a decrease in testosterone levels, along with downregulated expression of testosterone synthase in C57BL/6 N male mice. Furthermore, Cd significantly increased ß-galactosidase staining intensity, senescence-related proteins, and senescence-related secretory phenotypes in mouse testicular Leydig cells. Subsequent investigations revealed that Cd decreased the mRNA and protein levels of NAD-dependent deacetylase Sirtuin-1 (SIRT1) in Leydig cells. Mechanistically, mice treated with resveratrol (50 mg/kg), a specific SIRT1 activator, mitigated Leydig cell senescence and reversed Cd-reduced testosterone levels in mouse testes. These effects were also restored by SIRT1 overexpression in Leydig cells. Additionally, we found that Cd increased the level of methyltransferase enzyme METTL3 and Sirt1 m6A modification in Leydig cells. Mettl3 siRNA effectively restored Cd-enhanced Sirt1 m6A level and reversed Cd-downregulated Sirt1 mRNA expression in Leydig cells. Overall, our findings suggest that Cd exposure inhibits testosterone synthesis via Sirt1 m6A modification-mediated senescence in mouse testes. These results offer an experimental basis for investigating the causes and potential treatments of hypotestosteronemia induced by environmental factors.

Efficient photocatalytic decomposition of PFOA over BiOI1-x with low power LED light.

In recent years, the academic community has shown significant interest in per- or polyfluoroalkyl compounds (PFAS) due to their challenging degradation and potential health risks. Photocatalysis has been investigated for PFAS decomposition due to its environmentally friendly nature. In this study, BiOI with abundant iodine vacancies was synthesized through solvothermal and calcination methods (referred to as BiOI1-x), and was used for PFAS degradation with a low power UV light source. Compared to pure BiOI, BIOI1-x showed higher photocatalytic activity towards PFOA (perfluorooctanoic acid). Within 5 h under 5 W LED light irradiation, the degradation rate of PFOA reached 51.9 % with BiOI1-x calcined at 440 °C (No significant degradation of PFAS was observed with pure BiOI). Capture experiments, electron paramagnetic resonance spectroscopy, and electrochemical experiments revealed that the main active species in the system were photogenerated holes, followed by hydroxyl radicals. Furthermore, the presence of iodine vacancies significantly improved the efficiency of charge carrier separation and enhanced the photocatalytic performance. Finally, a hypothetical degradation pathway for PFOA in this system was suggested. This study achieved efficient degradation of PFAS under low power LED light (5 W), emphasizing its significant practical importance in terms of energy conservation.

Continuous batch synthesis with atmospheric-pressure microwave plasmas.

Plasmas under atmospheric pressure offer a high-temperature environment for material synthesis, but electrode ablation compromises purity. Here, we introduce an atmospheric-pressure microwave plasma (AMP) operated without electrodes to overcome the existing limitations in pure material synthesis. The distribution of the electrostatic field intensity inside a waveguide during AMP excitation was examined via electrostatic field simulations. The lateral and radial gas temperature distributions were also studied using optical emission spectroscopy. The AMP exhibited a uniform ultrahigh temperature (9,000 K), a large volume (102-104 cm3), and a response time on the millisecond level. AMP efficiently synthesized silicon nanoparticles, graphene, and graphene@Si-Fe core-shell nanoparticles within tens of milliseconds, ensuring purity and size control. We propose the "heat impulse" metric for evaluating the plasma characteristics (n a, T g, and t) in material synthesis, extended to other high-temperature plasmas. AMP is compact, cost-effective, and easy to assemble, promising for eco-friendly mass production of pure materials.

Synthesis and optical properties of tyramine-functionalized boron dipyrromethene dyes for cell bioimaging.

Tyramine signaling amplification (TSA) technology is generally applied in immunofluorescence, enzyme-linked immunoassays, in situ hybridization techniques, etc. Successful amplification of fluoresence signals cannot be achieved without excellent fluorescent dyes. BODIPY fluorophore is an ideal probe for cell fluorescence imaging, but pristine BODIPY cannot be direct used in the TSA system. In the paper, the new red-shifted tyramide-conjugated BODIPY (BDP-B/C/D) was synthesized via the Knoevenagel condensation reaction, which based on the tyramide-conjugated BODIPY (BDP-A). The synthesized dyes were combined with tyramine to obtain which could be used as a fluorescent substrate for enzymatic reaction of TSA. By using the selected substrate (BDP-C) in TSA, we found it to be more sensitive than the commercial dye 594 styramide for the detection of low-abundance antigen proteins.

On the FT-ICR mass spectrometry analysis of dissolved organic matter released by adsorbent during coal chemical wastewater treatment.

This study analyzed the dissolved organic matter (DOM) released by adsorbent during wastewater treatment. It was found that the adsorption method resulted in an organic removal efficiency of over 97 % for coal-to-olefin (CTO) wastewater, with the lowest value of 15.7 mg/L. The Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS) detected 4111 DOM in the wastewater, 4052 remaining DOM after first-stage anthracite (ANC) adsorption, and 1013 after second-stage macroporous adsorption resin (MAR). The removal degree of lipids in wastewater was the highest, followed by aliphatic/amino-acid/mini-peptides and lignin. During the adsorption process, the proportion of halogenated compounds (HCs) declined from 59.86 % to 38.63 % and 21.67 %. Additionally, freshly produced 2035 and 311 DOMs were found in the adsorption effluent of ANC and MAR, respectively, with HCs accounting for 34.71 % and 67.96 %. Upon flowing ultra-pure water through ANC and MAR, the effluent dissolved organic carbon (DOC) ranges were 1.118-3.574 mg/L and 1.014-2.557 mg/L, respectively. There were 159 and 131 species of DOM detected, respectively, with HCs content of 59.06 % and 45.02 %. Comparative experiments revealed the complex components of the wastewater promoting the release of organic matter on the adsorbent surface that further reacted to generate organic matter. However, fewer substances were released by the adsorbent.

Identification of diagnostic biomarkers of rheumatoid arthritis based on machine learning-assisted comprehensive bioinformatics and its correlation with immune cells.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammatory cell infiltration, which can lead to chronic disability, joint destruction and loss of function. At present, the pathogenesis of RA is still unclear. The purpose of this study is to explore the potential biomarkers and immune molecular mechanisms of rheumatoid arthritis through machine learning-assisted bioinformatics analysis, in order to provide reference for the early diagnosis and treatment of RA disease. Methods: RA gene chips were screened from the public gene GEO database, and batch correction of different groups of RA gene chips was performed using Strawberry Perl. DEGs were obtained using the limma package of R software, and functional enrichment analysis such as gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), disease ontology (DO), and gene set (GSEA) were performed. Three machine learning methods, least absolute shrinkage and selection operator regression (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest tree (Random Forest), were used to identify potential biomarkers of RA. The validation group data set was used to verify and further confirm its expression and diagnostic value. In addition, CIBERSORT algorithm was used to evaluate the infiltration of immune cells in RA and control samples, and the correlation between confirmed RA diagnostic biomarkers and immune cells was analyzed. Results: Through feature screening, 79 key DEGs were obtained, mainly involving virus response, Parkinson's pathway, dermatitis and cell junction components. A total of 29 hub genes were screened by LASSO regression, 34 hub genes were screened by SVM-RFE, and 39 hub genes were screened by Random Forest. Combined with the three algorithms, a total of 12 hub genes were obtained. Through the expression and diagnostic value verification in the validation group data set, 7 genes that can be used as diagnostic biomarkers for RA were preliminarily confirmed. At the same time, the correlation analysis of immune cells found that γδT cells, CD4+ memory activated T cells, activated dendritic cells and other immune cells were positively correlated with multiple RA diagnostic biomarkers, CD4+ naive T cells, regulatory T cells and other immune cells were negatively correlated with multiple RA diagnostic biomarkers. Conclusions: The results of novel characteristic gene analysis of RA showed that KYNU, EVI2A, CD52, C1QB, BATF, AIM2 and NDC80 had good diagnostic and clinical value for the diagnosis of RA, and were closely related to immune cells. Therefore, these seven DEGs may become new diagnostic markers and immunotherapy markers for RA.

Response of anammox to organics with different degradation characteristics and exposure time: Performance, sludge characteristics and bacterial community.

The effects of typical organic compounds including easily degradable organic matters sodium acetate, yeast and methanol, and refractory organic matter (ROM) humic acid on anaerobic ammonium oxidation (anammox) systems in short-term and medium-term exposure time were studied. During short-term experiments, nitrogen removal activity (NRA) was inhibited at sodium acetate level of 150 mg L-1 total organic carbon (TOC) and methanol level of 30-150 mg L-1 TOC, but humic acid and yeast (≤150 mg L-1 TOC) enhanced nitrogen removal in anammox systems. The greatest NRA of 30.10 mg TN g-1 VSS h-1 was recorded at yeast level of 90 mg L-1 TOC. In medium-term experiments, organics significantly inhibited the nitrogen removal ability. As a ROM, humic acid enhanced sludge aggregation and biological diversity, but decreased the bioactivity and extracellular polymeric substances levels. Due to the endogenous denitrification, the relative abundance of anammox bacteria (AnAOB) was decreased. Candidatus Kuenenia is still dominant in sludge with methanol and humid acid, but AnAOB are not dominant due to the addition of sodium acetate and yeast. This research would be beneficial for the full-scale application of the anammox process in treating real wastewater with organics and ammonia.

Core-Shell Interface Engineering Strategies for Modulating Energy Transfer in Rare Earth-Doped Nanoparticles.

Rare earth-doped nanoparticles (RENPs) are promising biomaterials with substantial potential in biomedical applications. Their multilayered core-shell structure design allows for more diverse uses, such as orthogonal excitation. However, the typical synthesis strategies-one-pot successive layer-by-layer (LBL) method and seed-assisted (SA) method-for creating multilayered RENPs show notable differences in spectral performance. To clarify this issue, a thorough comparative analysis of the elemental distribution and spectral characteristics of RENPs synthesized by these two strategies was conducted. The SA strategy, which avoids the partial mixing stage of shell and core precursors inherent in the LBL strategy, produces RENPs with a distinct interface in elemental distribution. This unique elemental distribution reduces unnecessary energy loss via energy transfer between heterogeneous elements in different shell layers. Consequently, the synthesis method choice can effectively modulate the spectral properties of RENPs. This discovery has been applied to the design of orthogonal RENP biomedical probes with appropriate dimensions, where the SA strategy introduces a refined inert interface to prevent unnecessary energy loss. Notably, this strategy has exhibited a 4.3-fold enhancement in NIR-II in vivo imaging and a 2.1-fold increase in reactive oxygen species (ROS)-related photodynamic therapy (PDT) orthogonal applications.

Arginine-Modified Hemin Enhances G-Quadruplex DNAzyme Peroxidase Activity for High Sensitivity Detection.

Hemin/G-quadruplex (hG4) complexes are frequently used as artificial peroxidase-like enzymatic systems (termed G4 DNAzymes) in many biosensing applications, in spite of a rather low efficiency, notably in terms of detection limits. To tackle this issue, we report herein a strategy in which hemin is chemically modified with the amino acids found in the active site of parent horseradish peroxidase (HRP), with the aim of recreating an environment conducive to high catalytic activity. When hemin is conjugated with a single arginine, it associates with G4 to create an arginine-hemin/G4 (R-hG4) DNAzyme that exhibits improved catalytic performances, characterized by kinetic analysis and DFT calculations. The practical relevance of this system was demonstrated with the implementation of biosensing assays enabling the chemiluminescent detection of G4-containing DNA and colorimetry detection of the flap endonuclease 1 (FEN1) enzyme with a high efficiency and sensitivity. Our results thus provide a guide for future enzyme engineering campaigns to create ever more efficient peroxidase-mimicking DNA-based systems.

Modeling, applications and challenges of inner ear organoid.

More than 6% of the world's population is suffering from hearing loss and balance disorders. The inner ear is the organ that senses sound and balance. Although inner ear disorders are common, there are limited ways to intervene and restore its sensory and balance functions. The development and establishment of biologically therapeutic interventions for auditory disorders require clarification of the basics of signaling pathways that control inner ear development and the establishment of endogenous or exogenous cell-based therapeutic methods. In vitro models of the inner ear, such as organoid systems, can help identify new protective or regenerative drugs, develop new gene therapies, and be considered as potential tools for future clinical applications. Advances in stem cell technology and organoid culture offer unique opportunities for modeling inner ear diseases and developing personalized therapies for hearing loss. Here, we review and discuss the mechanisms for the establishment and the potential applications of inner ear organoids.

Heparanase accelerates the angiogenesis and inhibits the ferroptosis of p53-mutant non-small cell cancers in VEGF-dependent manner.

The aim of this study is to explore the effects and specific mechanisms of heparanase on angiogenesis and iron deficiency anemia in TP53 mutant cancer. For this purpose, we conducted in vitro cell experiments and in vivo animal experiments respectively. In this study, we first analyzed the differential expression of heparanase in TP53 wild-type and mutant cells, and analyzed its effects on iron removal and angiogenesis in two types of CALU-1 and NCI-H358 cells. Secondly, we validated whether the mechanism of action of heparanase on TP53 mutant cells for iron removal and angiogenesis is related to VEGF. We applied the iron removal agonist erastin and VEGF inhibitor bevacizumab in both in vitro and in vivo experiments to validate the relationship between heparanase and VEGF in the mechanisms of iron removal and angiogenesis. The experimental results show that heparanase is highly expressed in TP53 mutated cancer cells, and has anti-ferroptosis and pro-angiogenic effects. Our experiment also confirmed that the effect of heparanase on TP53 mutant cancer's iron removal and angiogenesis is related to VEGF. In short, heparanase is highly expressed in p53 mutated lung cancer, and the mechanism of ferroptosis tolerance to TP53 mutated cancer is related to VEGF.

Functional co-delivery nanoliposomes based on improving hypoxia for increasing photoimmunotherapy efficacy of cold tumors.

Cold tumors lack T cells infiltration and have low immunogenicity, resulting insufficient immunotherapy response. Therefore, how to realize the transformation from cold tumor to hot tumor is an urgent problem to be solved. Photodynamic therapy can induce immunogenic death of tumor cells (ICD) and activate T lymphocytes to produce tumor immune response. However, hypoxia in the cold tumor microenvironment limits the effectiveness of photodynamic therapy. So in this article, MET-HMME/CAT-HMME@Nlip as a functional co-delivery nanoliposomes was constructed based on overcoming the above problems. Firstly, the oxygen-deficient state could be improved by the following two ways, one is catalase loaded in CAT-HMME@Nlip can decompose high concentration hydrogen peroxide to produce oxygen, and the other is metformin loaded in MET-HMME@Nlip can decrease oxygen consumption by inhibiting of mitochondrial respiration. And then with the increase of substrate oxygen concentration, the sensitivity of photodynamic therapy can be greatly improved and the anti-tumor immune response by PDT-induced ICD can also be enhanced obviously. In addition, metformin could act as a small molecule immune checkpoint inhibitor to reduce the expression of PD-L1 on the surface of tumor cells, thereby effectively improving the specific killing ability of cytotoxic T cells to tumor cells which could not only erasing the primary tumor, but also inhibiting the growth of simulated distant tumors through the immune memory function. This study provides a new idea for improving the clinical treatment effect of hypoxic cold tumors, especially for tumors that could not benefit from immunotherapy due to low or no expression of PD-L1 protein on the surface of tumor cells.

Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication.

Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and epidermal growth factor receptor (EGFR), which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR co-inhibition using a multifaceted approach to analyze the global phosphoproteome and chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a highly synergistic antitumor effect. Notably, the combined inhibition strategy activated the DNA damage response, induced G1 cell cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6 (CDC6), a crucial initiator of DNA replication. Together, this study offers preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer that disrupts DNA synthesis by impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes.

Enhancement of gemcitabine sensitivity in intrahepatic cholangiocarcinoma through Saikosaponin-a mediated modulation of the p-AKT/BCL-6/ABCA1 axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches. METHODS: This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms. RESULTS: SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles. CONCLUSION: This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC.

Too much social media? Unveiling the effects of determinants in social media fatigue.

Introduction: With the boom in social media, many people spend a lot of time on these platforms. Among them, some developed negative emotions, such as fatigue, depression, or disinterest in communicating, and used social media temporarily or permanently. Therefore, this study aims to explore the antecedents of social media fatigue, including social media helpfulness, social media self-efficacy, online subjective well-being, social comparison, compulsive social media use, privacy concerns, fear of missing out, and information overload, and to further discuss the determinants of social media fatigue on social anxiety and lurking. Methods: An online questionnaire was distributed to social media users, and 659 valid samples were obtained with the help of a purposive sampling strategy. The data was analyzed by the partial least square (PLS) method. Results: The study found that social media self-efficacy had a significant negative effect on social media fatigue; compulsive social media use, fear of missing out, and information overload had a significant positive effect on social media fatigue; and social media fatigue had a significant positive effect on social anxiety and lurking. Discussion: The research results can be used as a reference for social media marketers and internet service providers in developing business strategies.

Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.