Intrinsic ADRB2 inhibition improves CAR-T cell therapy efficacy against prostate cancer.

Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in patients with solid tumors. Recent in vitro and in vivo data have shown that adrenoceptor beta-2 (ADRB2) is a novel checkpoint receptor that inhibits T cell-mediated anti-tumor responses. To inhibit ADRB2-mediated inhibitory signaling, we downregulated ADRB2 in CAR-T (shß2-CAR-T) cells via RNA interference, assessed different parameters, and compared them with conventional second-generation CAR-T cells. ADRB2 knockdown CAR-T cells exhibited enhanced cytotoxicity against prostate cancer cell lines in vitro, by increasing CD69, CD107a, GzmB, IFN-γ, T-bet, and GLUT-1. Additionally, ADRB2 deficiency led to improved proliferation, increased CD8/CD4 T cell ratio, and decreased apoptosis in CAR-T cells. shß2-CAR-T cells expressed more Bcl-2 and led to the generation of more significant proportions of T central memory cells. Finally, the ZAP-70/NF-κB signaling axis was shown to be responsible for the improved functions of novel CAR-T cells. In tumor-bearing mice, shß2-CAR-T cells performed better than conventional CAR-T cells in eradicating prostate tumors. The study provides the basis for future clinical and translational CAR-T cell research to focus on adrenergic stress-mediated challenges in the tumor microenvironment of stressed tumors.

Clinical characteristics of idiopathic inflammatory myopathies patients with anti-PM/Scl antibodies.

OBJECTIVES: To analyze the clinical features of idiopathic inflammatory myopathies (IIMs) patients with anti-PM/Scl antibodies. METHODS: In this retrospective cohort study, we compared the clinical manifestations between patients who were solely positive for anti-PM/Scl antibodies (isolated anti-PM/Scl group) and those with a coexistence of anti-PM/Scl antibodies and myositis-specific antibodies (MSAs) (double-positive group). RESULTS: Sixty-five IIMs patients positive for anti-PM/Scl antibodies were included, among whom 51 (78.5 %) were females, with a mean age of 49.1 years. Thirty-four (52.3 %) patients coexisted with MSAs. Compared to the double-positive group, the isolated anti-PM/Scl group demonstrated a higher proportion of women (90.3 % vs 67.6 %, p = 0.026) and a higher incidence of sclerodactyly (16.1 % vs 0, p = 0.021). Although there were no differences in the incidence of muscular weakness, dysphagia, or creatine kinase levels, thigh magnetic resonance imaging (MRI) revealed less muscle edema, atrophy, and fatty replacement in the isolated anti-PM/Scl group (p < 0.05). Interstitial lung disease (ILD) occurred in 80 % of patients, more frequently in the double-positive group (90.6 % vs 67.9 %, p = 0.028). According to HRCT, non-specific interstitial pneumonia (NSIP) was the most common pattern among anti-PM/Scl antibodies positive IIMs patients. The double-positive group exhibited higher ferritin levels, and a lower peripheral lymphocyte count (p < 0.05). The mortality rate in the double-positive group was higher than that in the isolated anti-PM/Scl group (20.6 % vs 0, p = 0.034). CONCLUSION: Among IIMs patients who tested positive for anti-PM/Scl antibodies, ILD emerged as the predominant clinical feature, particularly when combined with MSA. Notably, patients with isolated anti-PM/Scl antibodies exhibited a favorable prognosis following immunotherapy.

Dissect the association between per- and polyfluoroalkyl substances (PFAS) and kidney function from the perspective of lipid molecules.

Per- and polyfluoroalkyl substances (PFAS) have been linked to kidney function. Studies have shown that PFAS can cause changes in lipid metabolism and that lipids play an important role in regulating kidney function. However, few studies have explored the overall impact of PFAS mixture on kidney function. Moreover, the mechanisms by which PFAS influences kidney function remain unclear. This study was performed to investigate the overall impact of PFAS mixture on kidney function indexes, dissect the mechanism by which PFAS affect kidney function by analyzing lipid molecule profiles, and analyze the associations between different subclasses of lipids and kidney function indexes. We measured blood PFAS levels and kidney function indexes in a community population containing 278 males. Metabolomic analysis detected 332 lipid molecules. A quantile-based g-computation model was applied to assess the overall effect of PFAS mixture on kidney function index, and revealed that PFAS mixture were associated with a higher level of uric acid (UA). Linear regression analysis demonstrated a positive association between PFOA and UA, and logistic regression analysis indicated a positive association between PFOA and hyperuricemia odds. Notably, none of the PFAS were associated with the estimated glomerular filtration rate, indicating that PFAS didn't have an obvious effect on glomerular filtration. Further analysis identified 20 lipid molecules associated with both PFOA and UA. High-dimensional mediation effect analysis showed that seven lipid molecules (one glycerophospholipid, three fatty acyls, and three prenol lipids) mediated the association between PFOA and UA. Additionally, quantile-based g-computation analysis revealed positive associations between specific lipid subclasses-mainly fatty acid esters, fatty acids and conjugates, and sesquiterpenoids-and kidney function indexes. Our findings provide insights into the renal toxicity of PFAS and may also lead to more in-depth investigations using animal models and other population studies.

Based on SIRT1/NF-κB/NLRP3 Signal Pathway to Explore the Effect of Yiqi Huatan Huoxue Recipe on Inflammatory Injury in AIT Mice by Pyroptosis.

OBJECTIVE: Autoimmune thyroiditis (AIT) is the most common autoimmune thyroid disease. In recent decades, its incidence and prevalence have sharply increased. Yiqi Huatan Huoxue recipe is a traditional Chinese medicine formula we use to treat AIT. Its clinical efficacy is clear, but the specific mechanism remains unclear. This study aims to explore whether pyroptosis mediated by the SIRT1/NF-κB/NLRP3 signaling pathway is one of the therapeutic mechanisms of Yiqi Huatan Huoxue recipe. METHODS: Forty 8-week-old female NOD.H-2h4 mice were randomly divided into four groups: the normal group (NG), model group (MG), Yiqi Huatan Huoxue recipe group (YG), and western medicine group (selenium yeast tablet, SeG). The normal group was gavaged with distilled water, while the remaining groups were gavaged with 0.05% sodium iodide (NaI) solution for 8 weeks. After the AIT animal model formed naturally, the mice were euthanized by gavage after 8 weeks. Hematoxylin-eosin staining was used to observe thyroid tissue changes, and enzymelinked immunosorbent assay (ELISA) was used to detect serum anti-thyroglobulin antibodies (TGAb) and mouse anti-thyroid peroxidase antibodies (TPOAb). Real-time quantitative PCR (qRT-PCR), Western blot, and immunohistochemistry were used to detect the expression of sirtuin 1 (SIRT1), nuclear factor κB p65 (NF-κB p65), nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase- 1, gasdermin D (GSDMD), and interleukin (IL)-1ß in thyroid tissue. RESULTS: Compared with the NG group, the thyroid structure of rats in the MG group was severely damaged, with significant lymphocyte infiltration, significantly increased serum TGAb and TPOAb levels, and significantly increased expression levels of SRIT1, NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD, IL-1ß mRNA, and protein. Compared with the MG group, the thyroid structure damage and lymphocyte infiltration in rats of each treatment group were improved, and the serum TGAb, TPOAb, SRIT1, NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD, IL-1ß mRNA, and protein expression levels were significantly reduced. CONCLUSION: Yiqi Huatan Huoxue recipe can alleviate thyroid structural damage in AIT mice, and its mechanism may be related to the upregulation of SIRT1, NF-κB deacetylation, and inhibition of NLRP3-mediated pyroptosis.

Functionalized cellulose-based adhesive with epoxy groups having high humidity resistance performance.

Sustainable and environment friendly natural-based adhesive has been considered as an optimum alternative of industrial adhesive which is non-renewable and harmful to health. Cellulose is the most abundant natural polymer in nature and has potential applications in the field of adhesives. However, the inherent hydrophilic nature of cellulose-based adhesive significantly challenges its use in high humidity environments. In this paper, a highly hydrophobic and anti-swelling cellulose-based adhesive was prepared by epoxy modification of microcrystalline cellulose (MCC). The simultaneous enhancement of adhesive and cohesive properties is achieved through the reaction of epoxy groups with the hydroxyl groups from the wood and adhesive during the hot-pressing process. Prepared adhesive has excellent properties in extremely humid environments. The dry bonding strength of the prepared adhesive reached 6.02 ± 0.26 MPa, while the wet bonding strength was 4.78 ± 0.21 MPa after immersed in water at 63 °C for 3 h. Furthermore, the bonding strength remained largely stable in 90 % atmospheric humidity. The adhesive has a certain universality, which can bond to substrates such as aluminium, iron, and glass. This study presents an innovative approach to the manufacturing of cellulose-based adhesive with enhanced bonding performance and exceptional water resistance.

Downregulation of malic enzyme 3 facilitates progression of gastric carcinoma via regulating intracellular oxidative stress and hypoxia-inducible factor-1α stabilization.

BACKGROUND: Gastric cancer (GC) is one of the most malignant cancers worldwide. Metabolism disorder is a critical characteristic of malignant tumors related to tumor progression and metastasis. However, the expression and molecular mechanism of malic enzyme 3 (ME3) in GC are rarely reported. In this study, we aim to investigate the molecular mechanism of ME3 in the development of GC and to explore its potential value as a prognostic and therapeutic target in GC. METHOD: ME3 mRNA and protein expression were evaluated in patients with GC using RT-qPCR, WB, and immunohistochemistry, as well as their correlation with clinicopathological indicators. The effect of ME3 on proliferation and metastasis was evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU) assay, transwell assay, wound healing assay, and subcutaneous injection or tail vein injection of tumor cells in mice model. The effects of ME3 knockdown on the level of metabolites and hypoxia-inducible factor-1α (HIF-1α) protein were determined in GC cells. Oxidative phosphorylation was measured to evaluate adenosine triphosphate (ATP) production. RESULTS: ME3 was downregulated in human GC tissues (P < 0.001). The decreased ME3 mRNA expression was associated with younger age (P = 0.02), pathological staging (P = 0.049), and lymph node metastasis (P = 0.001), while low ME3 expression was associated with tumor size (P = 0.048), tumor invasion depth (P < 0.001), lymph node metastasis (P = 0.018), TNM staging (P < 0.001), and poor prognosis (OS, P = 0.0206; PFS P = 0.0453). ME3 knockdown promoted GC cell malignancy phenotypes. Moreover, α-ketoglutarate (α-KG) and NADPH/NADP+ ratios were reduced while malate was increased in the ME3 knockdown group under normoxia. When cells were incubated under hypoxia, the NADPH/NADP+ ratio and α-KG decreased while intracellular reactive oxygen species (ROS) increased significantly. The ME3 knockdown group exhibited an increase in ATP production and while ME3 overexpression group exhibited oppositely. We discovered that ME3 and HIF-1α expression were negatively correlated in GC cells and tissues, and proposed the hypothesis: downregulation of ME3 promotes GC progression via regulating intracellular oxidative stress and HIF-1α. CONCLUSION: We provide evidence that ME3 downregulation is associated with poor prognosis in GC patients and propose a hypothesis for the ME3 regulatory mechanism in GC progression. The present study is of great scientific significance and clinical value for exploring the prognostic and therapeutic targets of GC, evaluating and improving the clinical efficacy of patients, reducing recurrence and metastasis, and improving the prognosis and quality of life of patients.

Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma.

BACKGROUND: Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS: We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS: Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS: We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.

Time-varying similarity of neural responses to musical tension is shaped by physical features and musical themes.

The similarity of understanding is important for music experience and communication, but little is understood about the sources of this common knowledge. Although neural responses to the same piece of music are known to be similar across listeners, it remains unclear whether this neural response similarity is linked to musical understanding and the role of dynamic musical attributes in shaping it. Our study addresses this gap by investigating the relationship between neural response similarity, musical tension, and dynamic musical attributes. Using electroencephalography-based inter-subject correlation (EEG-ISC), we examined how the neural response similarity among listeners varies throughout the evaluation of musical tension in the first movement of Beethoven's Piano Sonata No. 8. Participants continuously rated the degree of alignment between musical events and their expectations, while neural activity was recorded using electroencephalography (EEG). The results showed that neural response similarity fluctuated in tandem with musical tension, with increased similarity observed during moments of heightened tension. This time-varying neural response similarity was influenced by two dynamic attributes contributing to musical tension: physical features and musical themes. Specifically, its fluctuation was driven by physical features, and the patterns of its variation were modulated by musical themes, with similar time-varying patterns observed across similar thematic materials. These findings offer valuable insight into the role of dynamic musical attributes in shaping neural response similarity, and reveal an important source and mechanism of shared musical understandings.

Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis.

Coffee, a widely consumed beverage, has shown benefits for human health but lacks sufficient basic and clinical evidence to fully understand its impacts and mechanisms. Here, we conducted a cross-sectional observational study of coffee consumption and a 1-month clinical trial in humans. We found that coffee consumption significantly reshaped the immune system and metabolism, including reduced levels of inflammatory factors and a reduced frequency of senescent T cells. The frequency of senescent T cells and the levels of the senescence-associated secretory phenotype were lower in both long-term coffee consumers and new coffee consumers than in coffee nondrinking subjects, suggesting that coffee has anti-immunosenescence effects. Moreover, coffee consumption downregulated the activities of the The Janus kinase/signal transduction and activator of transcription (JAK/STAT) and mitogen-activated protein kinases (MAPK) signaling pathways and reduced systemic proinflammatory cytokine levels. Mechanistically, coffee-associated metabolites, such as 1-methylxanthine, 3-methylxanthine, paraxanthine, and ceramide, reduced the frequency of senescent CD4+CD57+ T cells in vitro. Finally, in vivo, coffee intake alleviated inflammation and immunosenescence in imiquimod-induced psoriasis-like mice. Our results provide novel evidence of the anti-inflammatory and anti-immunosenescence effects of coffee, suggesting that coffee consumption could be considered a healthy habit.

Epidemiology of malignant tumors in patients with pemphigus: an analysis of trends from 1955 to 2021.

BACKGROUND: The incidence of malignant tumors has increased in patients with non-paraneoplastic pemphigus, although there has been no systematic analysis of global epidemiology. OBJECTIVE: To explore the epidemiology of various types of non-paraneoplastic pemphigus associated with malignant tumors. METHODS: Five databases from establishment through October 20, 2023, were searched. STATA SE 17 was used for the data analysis. Subgroup, meta-regression, and sensitivity analyses were used to evaluate the heterogeneity of pooled studies. RESULTS: A total of 6679 participants were included in our meta-analysis from 16 studies. The aggregated prevalence of tumors in patients diagnosed with pemphigus was 8%. The prevalence was 7% in patients with pemphigus vulgaris, 10% in those with pemphigus foliaceus, and 12% in individuals diagnosed with other types of pemphigus. The prevalence was 8% in Asia, 11% in Europe, and 8% in North America. From a country-specific perspective, patients with pemphigus from Israel, Greece, and Germany exhibited a higher prevalence of tumors at 11%. Furthermore, when categorized by the duration of the study period, the highest prevalence was observed in studies spanning 10 to 20 years, at 11%. CONCLUSION: These findings demonstrate the incidence and prevalence of malignant tumors in patients with non-paraneoplastic pemphigus, which may achieve early detection and intervention, and then reduce mortality rates.

Dissociated contributions of working memory and inhibitory control to children's and adults' analogical reasoning: Analogical strategies matter.

This study investigated whether and how each component of working memory (WM) and inhibitory control (IC) is related to analogical reasoning. Specifically, the mediating roles of analogical strategies were examined and compared across children and adults. In total, 79 children (50 girls; M ± SD = 8.43 ± 0.59 years old) and 77 adults (35 female; 19.44 ± 0.82 years old) were administered tests of WM, IC, and analogical reasoning. In addition, participants' eye movement data during the analogical reasoning task were collected to classify the analogical strategies. The results showed that the semantic-constraint strategy completely mediated the relationship between WM (rather than IC) and analogical reasoning for children. However, for adults, the project-first strategy partially mediated the association between IC (rather than WM) and analogical reasoning. These findings reveal the dissociated roles of WM and IC in analogical reasoning through analogical strategies for children and adults and highlight the importance of analogical strategies.

Physiological and transcriptomic analyses reveal the cadmium tolerance mechanism of Miscanthus lutarioriparia.

Miscanthus lutarioriparia is a promising energy crop that is used for abandoned mine soil phytoremediation because of its high biomass yield and strong tolerance to heavy metals. However, the biological mechanism of heavy metal resistance is limited, especially for applications in the soil restoration of mining areas. Here, through the investigation of soil cadmium(Cd) in different mining areas and soil potted under Cd stress, the adsorption capacity of Miscanthus lutarioriparia was analyzed. The physiological and transcriptional effects of Cd stress on M. lutarioriparia leaves and roots under hydroponic conditions were analyzed. The results showed that M. lutarioriparia could reduce the Cd content in mining soil by 29.82%. Moreover, different Cd varieties have different Cd adsorption capacities in soils with higher Cd concentration. The highest cadmium concentrations in the aboveground and belowground parts of the plants were 185.65 mg/kg and 186.8 mg/kg, respectively. The total chlorophyll content, superoxide dismutase and catalase activities all showed a trend of increasing first and then decreasing. In total, 24,372 differentially expressed genes were obtained, including 7735 unique to leaves, 7725 unique to roots, and 8912 unique to leaves and roots, which showed differences in gene expression between leaves and roots. These genes were predominantly involved in plant hormone signal transduction, glutathione metabolism, flavonoid biosynthesis, ABC transporters, photosynthesis and the metal ion transport pathway. In addition, the number of upregulated genes was greater than the number of downregulated genes at different stress intervals, which indicated that M. lutarioriparia adapted to Cd stress mainly through positive regulation. These results lay a solid foundation for breeding excellent Cd resistant M. lutarioriparia and other plants. The results also have an important theoretical significance for further understanding the detoxification mechanism of Cd stress and the remediation of heavy metal pollution in mining soil.

A multilevel investigation to reveal the regulatory mechanism of lignin accumulation in juice sac granulation of pomelo.

Granulation of juice sacs is a physiological disorder, which affects pomelo fruit quality. Here, the transcriptome and ubiquitinome of the granulated juice sacs were analyzed in Guanxi pomelo. We found that lignin accumulation in the granulated juice sacs was regulated at transcription and protein modification levels. In transcriptome data, we found that the genes in lignin biosynthesis pathway and antioxidant enzyme system of the granulated juice sacs were significantly upregulated. However, in ubiquitinome data, we found that ubiquitinated antioxidant enzymes increased in abundance but the enzyme activities decreased after the modification, which gave rise to reactive oxygen species (ROS) contents in granulated juice sacs. This finding suggests that ubiquitination level of the antioxidant enzymes is negatively correlated with the enzyme activities. Increased H2O2 is considered to be a signaling molecule to activate the key gene expressions in lignin biosynthesis pathway, which leads to the lignification in granulated juice sacs of pomelo. This regulatory mechanism in juice sac granulation of pomelo was further confirmed through the verification experiment using tissue culture by adding H2O2 or dimethylthiourea (DMTU). Our findings suggest that scavenging H2O2 and other ROS are important for reducing lignin accumulation, alleviating juice sac granulation and improving pomelo fruit quality.

Outcomes of secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer progressed after prior poly (adenosine diphosphate-ribose) polymerase inhibitors: A retrospective cohort study.

OBJECTIVE: To evaluate the impact of previous poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy on the effectiveness of secondary cytoreductive surgery (SCS) in patients with platinum-sensitive recurrent ovarian cancer (PSROC). METHODS: We identified patients with PSROC who underwent SCS at the Cancer Hospital, Chinese Academy of Medical Science, between January 2010 and December 2022. Postoperative complications within 30 days were categorized using the Accordion Severity Grading System. The Kaplan‒Meier method was used to estimate both overall survival (OS) and progression-free survival (PFS), and multivariate analysis was used to identify independent prognostic factors. RESULTS: Of the 265 patients included, 39 received prior PARP inhibitor therapy (Group A), and 226 did not (Group B). The rates of complete resection after SCS did not significantly differ between the two groups (79.5 % for Group A vs. 81.0 % for Group B; p = 0.766). As of December 2023, Group A exhibited a significantly shorter median PFS (14.2 months) than Group B (22.5 months; p = 0.002). Furthermore, the 3-year OS rate was lower in Group A (72.5 %) than in Group B (82.7 %; p = 0.015). The incidence of severe postoperative complications was comparable between Groups A and B (7.7 % vs. 1.8 %; p = 0.061). Multivariate analysis revealed that prior PARP inhibitor therapy significantly reduced the median PFS (hazard ratio (HR) = 4.434; p = 0.021) and OS (HR = 2.076; p = 0.010). CONCLUSIONS: SCS for PSROC demonstrated reduced efficacy in patients previously treated with PARP inhibitors compared to those without prior PARP inhibitor treatment.

Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics.

BACKGROUND: Gastric Cancer (GC) characteristically exhibits heterogeneous responses to treatment, particularly in relation to immuno plus chemo therapy, necessitating a precision medicine approach. This study is centered around delineating the cellular and molecular underpinnings of drug resistance in this context. METHODS: We undertook a comprehensive multi-omics exploration of postoperative tissues from GC patients undergoing the chemo and immuno-treatment regimen. Concurrently, an image deep learning model was developed to predict treatment responsiveness. RESULTS: Our initial findings associate apical membrane cells with resistance to fluorouracil and oxaliplatin, critical constituents of the therapy. Further investigation into this cell population shed light on substantial interactions with resident macrophages, underscoring the role of intercellular communication in shaping treatment resistance. Subsequent ligand-receptor analysis unveiled specific molecular dialogues, most notably TGFB1-HSPB1 and LTF-S100A14, offering insights into potential signaling pathways implicated in resistance. Our SVM model, incorporating these multi-omics and spatial data, demonstrated significant predictive power, with AUC values of 0.93 and 0.84 in the exploration and validation cohorts respectively. Hence, our results underscore the utility of multi-omics and spatial data in modeling treatment response. CONCLUSION: Our integrative approach, amalgamating mIHC assays, feature extraction, and machine learning, successfully unraveled the complex cellular interplay underlying drug resistance. This robust predictive model may serve as a valuable tool for personalizing therapeutic strategies and enhancing treatment outcomes in gastric cancer.

Acetyl-CoA metabolic accumulation promotes hepatocellular carcinoma metastasis via enhancing CXCL1-dependent infiltration of tumor-associated neutrophils.

High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels.

A memristive all-inclusive hypernetwork for parallel analog deployment of full search space architectures.

In recent years, there has been a significant advancement in memristor-based neural networks, positioning them as a pivotal processing-in-memory deployment architecture for a wide array of deep learning applications. Within this realm of progress, the emerging parallel analog memristive platforms are prominent for their ability to generate multiple feature maps in a single processing cycle. However, a notable limitation is that they are specifically tailored for neural networks with fixed structures. As an orthogonal direction, recent research reveals that neural architecture should be specialized for tasks and deployment platforms. Building upon this, the neural architecture search (NAS) methods effectively explore promising architectures in a large design space. However, these NAS-based architectures are generally heterogeneous and diversified, making it challenging for deployment on current single-prototype, customized, parallel analog memristive hardware circuits. Therefore, investigating memristive analog deployment that overrides the full search space is a promising and challenging problem. Inspired by this, and beginning with the DARTS search space, we study the memristive hardware design of primitive operations and propose the memristive all-inclusive hypernetwork that covers 2×1025 network architectures. Our computational simulation results on 3 representative architectures (DARTS-V1, DARTS-V2, PDARTS) show that our memristive all-inclusive hypernetwork achieves promising results on the CIFAR10 dataset (89.2% of PDARTS with 8-bit quantization precision), and is compatible with all architectures in the DARTS full-space. The hardware performance simulation indicates that the memristive all-inclusive hypernetwork costs slightly more resource consumption (nearly the same in power, 22%∼25% increase in Latency, 1.5× in Area) relative to the individual deployment, which is reasonable and may reach a tolerable trade-off deployment scheme for industrial scenarios.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.