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Objective. Immunotherapy has proven effective in treating advanced gastric cancer (AGC), yet its benefits are limited to a subset of patients. Our aim is to swiftly identify prognostic biomarkers using cytokines to improve the precision of clinical guidance and decision-making for PD-1 inhibitor-based cancer immunotherapy in AGC. Materials and Methods. The retrospective study compared 36 patients with AGC who received combined anti-PD-1 immunotherapy and chemotherapy (immunochemotherapy) with a control group of 20 patients who received chemotherapy alone. The concentrations of TNF-α, IL-1β, IL-2R, IL-6, IL-8, IL-10, and IL-17 in the serum were assessed using chemiluminescence immunoassay at three distinct time intervals following the commencement of immunochemotherapy. Results. When compared to controls, patients undergoing immunochemotherapy demonstrated a generalized rise in cytokine levels after the start of treatment. However, patients who benefited from immunochemotherapy showed a decrease in IL-6 or IL-8 concentrations throughout treatment (with varied trends observed for IL-1β, IL-2R, IL-10, IL-17, and TNF-α) was evident in patients benefiting from immunochemotherapy but not in those who did not benefit. Among these markers, the combination of IL-6, IL-8, and CEA showed optimal predictive performance for short-term efficacy of immunochemotherapy in AGC patients. Conclusion. Reductions in IL-6/IL-8 levels observed during immunochemotherapy correlated with increased responsiveness to treatment effectiveness. These easily accessible blood-based biomarkers are predictive and rapid and may play a crucial role in identifying individuals likely to derive benefits from PD-1 blockade immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The detection rate of Salmonella enterica serovar 1,4,[5], 12: i: - (S. 1,4,[5], 12: i: -) has increased as the most common serotype globally. A S. 1,4,[5], 12: i: - strain named ST3606 (sequence type 34), isolated from a fecal specimen of a child with acute diarrhea hospitalized in a tertiary hospital in China, was firstly reported to be resistant to carbapenem and ceftazidime-avibactam. The aim of this study was to characterize the whole-genome sequence of S. 1,4,[5], 12: i: - isolate, ST3606, and explore its antibiotic resistance genes and their genetic environments. Methods: The genomic DNA of S. 1,4,[5], 12: i: - ST3606 was extracted and performed with single-molecule real-time sequencing. Resistance genes, plasmid replicon type, mobile elements, and multilocus sequence types (STs) of ST3606 were identified by ResFinder 3.2, PlasmidFinder, OriTfinder database, ISfinder database, and MLST 2.0, respectively. The conjugation experiment was utilized to evaluate the conjugation frequency of pST3606-2. Protein expression and enzyme kinetics experiments of CTX-M were performed to analyze hydrolytic activity of a novel CTX-M-261 enzyme toward several antibiotics. Results: Single-molecule real-time sequencing revealed the coexistence of a 109-kb IncI1-Iα plasmid pST3606-1 and a 70.5-kb IncFII plasmid pST3606-2. The isolate carried resistance genes, including blaNDM-5, sul1, qacE, aadA2, and dfrA12 in pST3606-1, blaTEM-1B, aac(3)-lld, and blaCTX-M-261, a novel blaCTX-M-1 family member, in pST3606-2, and aac(6')-Iaa in chromosome. The blaCTX-M-261 was derived from blaCTX-M-55 by a single-nucleotide mutation 751G>A leading to amino acid substitution of Val for Met at position 251 (Val251Met), which conferred CTX-M increasing resistance to ceftazidime verified by antibiotics susceptibility testing of transconjugants carrying pST3606-2 and steady-state kinetic parameters of CTX-M-261. pST3606-1 is an IncI1-α incompatibility type that shares homology with plasmids of pC-F-164_A-OXA140, pE-T654-NDM-5, p_dm760b_NDM-5, and p_dmcr749c_NDM-5. The conjugation experiment demonstrated that pST3606-2 was successfully transferred to the Escherichia coli recipient C600 with four modules of OriTfinder. Conclusion: Plasmid-mediated horizontal transfer plays an important role in blaNDM-5 and blaCTX-M-261 dissemination, which increases the threat to public health due to the resistance to most β-lactam antibiotics. This is the first report of blaCTX-M-261 and blaNDM-5 in S. 1,4,[5], 12: i: -. The work provides insights into the enzymatic function and demonstrates the ongoing evolution of CTX-M enzymes and confirms urgency to control resistance of S. 1,4,[5], 12: i: -. [ABSTRACT FROM AUTHOR]

Bilobalide has shown strong anti-inflammatory activity. Colorectal cancer (CRC) is closely associated with inflammation. However, no studies have reported on the use of bilobalide for treating CRC. This study aims to evaluate the effect of bilobalide on CRC prevention. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, and immunofluorescence showed that bilobalide significantly inhibits the M2 polarization of macrophages dependent on phorbol 12-myristate 13-acetate (PMA) and interleukin-4 (IL-4). Analysis of signaling pathways showed that the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) was regulated. In particular, human CRC organoids were established. Western blotting, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), and analysis of cell viability and morphology further supported the hypothesis that the anti-CRC effects of bilobalide could be explained by its ability to suppress M2 macrophage polarization and promote M1 transformation. C57BL/6 mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS) were divided into three groups, i.e., control, AOM/DSS, low (2.5 mg/kg), and high (5 mg/kg). High-dose bilobalide markedly inhibited the progression of CRC, as evidenced by the increased body weight, decrease in disease activity index (DAI) death rate, and alleviation of colon length reduction and tumorigenesis. According to the in vivo results, reduced levels of inflammatory cytokines in the serum included tumor necrosis factor (TNF-α), IL-6, IL-1β, and IL-10. Bilobalide reduced oxidative stress indices, lipid peroxide (LPO), and malondialdehyde (MDA) and increased reduced glutathione (GSH). In addition, the expression of proliferating cell nuclear antigen (PCNA), Ki67, cellular Myc (c-Myc), and CD206 was downregulated in the drug-treated groups, as confirmed by the immunohistochemical staining. Collectively, these results indicated that bilobalide administration improve experimental CRC by inhibiting M2 macrophage polarization and oxidative stress. Thus, bilobalide may prevent CRC and serve as a potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

The sensitivity and accuracy of nanopore sensors are severely hindered by the high noise associated with solid-state nanopores. To mitigate this issue, the deposition of organic polymer materials onto silicon nitride ( S i N x ) membranes has been effective in obtaining low-noise measurements. Nonetheless, the fabrication of nanopores sub-10 nm on thin polymer membranes remains a significant challenge. This work proposes a method for fabricating nanopores on polymethyl methacrylate (PMMA) membrane by the local high electrical field controlled breakdown, exploring the impact of voltage and current on the breakdown of PMMA membranes and discussing the mechanism underlying the breakdown voltage and current during the formation of nanopores. By improving the electric field application method, transient high electric fields that are one–seven times higher than the breakdown electric field can be utilized to fabricate nanopores. A comparative analysis was performed on the current noise levels of nanopores in PMMA- S i N x composite membranes and S i N x nanopores with a 5 nm diameter. The results demonstrated that the fast fabrication of nanopores on PMMA- S i N x membranes exhibited reduced current noise compared to S i N x nanopores. This finding provides evidence supporting the feasibility of utilizing this technology for efficiently fabricating low-noise nanopores on polymer composite membranes. [ABSTRACT FROM AUTHOR]

Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer. [ABSTRACT FROM AUTHOR]

Background: Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. Methods: Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. Results: CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. Conclusions: CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers. [ABSTRACT FROM AUTHOR]

[Display omitted] • First characterization of unimolecular integrin with solid-state nanopore approach. • Modulation and preference of divalent metal ions on the conformation of integrin αLβ2 and αVβ3. • Proof of specific binding of c-RGD and its derivatives on integrin via SSN device. Integrins are a large family of heterodimeric mammalian transmembrane receptors that connect extracellular matrix (ECM) and the cytoskeleton. Integrin-mediated adhesion governs the cellular adhesion, mobility, and cell mechanobiology. Investigations on different integrins in cellular and the conformation change regulated by divalent metal ions and oligopeptides have been documented, they mainly adopted the cellular assays or surface manipulation to achieve the information of ensemble integrins with proteins and small molecules. This work presents the nanopore approach for the characterization of unimolecular integrin via resistive pulse sensing. The orientation selection in distinct nanopore in size and pH condition discloses the tiny disparity of the conformation and the local surface charge distribution. The divalent metal ions could efficiently modulate the conformation alteration of integrin, in which Ca2+ and Mn2+ could activate integrin αLβ2 to take larger physical dimension than Mg2+, and Ca2+ is superior to Mn2+ in the activation when integrin αLβ2 is treated in the mixed metal ions. The oligopeptide cRGD (cyclic Arg-Gly-Asp) and its derivatives cRGDfk and cRGDyk show specific binding with integrin αVβ3 and the complex of αVβ3-cRGD exhibits largest geometry upon Ca2+-mediation with characteristic nanopore translocation feature. This work provides a platform for unimolecular integrin sensing and the modulation of the local conformation transition regulated by divalent metal ions and oligopeptides, which will be valuable for the representation of integrin-related cellular behavior and bio-function. [ABSTRACT FROM AUTHOR]

[Display omitted] • Reviews the latest advances in solid-state nanopore technology and its challenges. • Exploring methodology to fabricate high precision nanopores to improve resolution. • Providing insights in the preferable technique for solid-state nanopore DNA sequencing. • The potential of solid-state nanopore DNA sequencing for single biomolecule applications. Solid-state nanopore technology has been widely used for the analysis of a variety of biomolecules and will be applied to more aspects of analysis in life sciences and clinical applications. Providing a label-free, polymerase chain reaction-free approach, solid-state nanopore DNA sequencing is anticipated to become a promising next-generation technology for deciphering DNA sequences, alongside attributes such as longer read lengths, high throughput, and cost-effectiveness. It could also play a significant role in the future of disease diagnosis and treatment, and genetic disease prevention applications. This paper reviews the latest advances in the field of solid-state nanopore technology, and discusses its challenges and prospects in DNA sequencing applications. We explore methodologies to fabricate high precision nanopores, as well as to improve spatial and temporal resolution for solid-state nanopores. We also explore the potential for optimizing and improving the feasibility of solid-state nanopore DNA sequencing, with a view toward the use of these devices for single biomolecule detection and single nucleotide recognition applications. This paper aims to provide insights into the preferable technique for researching on solid-state nanopore DNA sequencing technology and its clinical applications, even for RNA and protein sequencing applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design, synthesis and characterization of multiple helix. • Construction of helical foldamers-based hybrid channel with high ion transport activities. • Proof of the good translocation properties of helix with high capture rate. • Good sensitivity in the detection of unimolecular amino acids and enantiomers with hybrid nanochannels. Nanopore platform has been explored for wide applications in various domain. However, the intrinsic properties of the pore-carrier materials limit the scaled practical usage. Some hybrid systems combined the advantages of each material have been promoted, most of which are based on the fragile lipid bilayer-supported transmembrane proteins or DNA origami on the solid-state channel. We herein provide a lipid-free construction of hybrid nanochannel equipped with helical molecule embedding in SiN x nanopore. The mechanical robustness and the physiochemical stability of SiN x and designable biocompatible helix supply a superior integrated device for stable durable sensing with good reliability. The hybrid nanochannels display a good conduction in distinct ionic solutions with both hydrophilic and hydrophobic multiplex helix. The identification of different amino acids as well as the enantiomers reveal the potential capability of the hybrid nanochannel in the peptide and protein sensing at single amino acid level. Our work paves a way on the solid-state nanopore sequencing with sub-nanometer-sized organic/inorganic hybrid ionic channel. [ABSTRACT FROM AUTHOR]

• Electrochemical, nanopore and field-effect transistors biosensor has been developed. • Aptamer, DNAzyme, DNA origami and nanomaterials has been used for amplification. • The biosensor exhibits an excellent performance for amplification detection. • We discussed the challenges of detection strategies in clinical application. Due to the wide range of electrochemical devices available, DNA nanostructures and material-based technologies have been greatly broadened. They have been actively used to create a variety of beautiful nanostructures owing to their unmatched programmability. Currently, a variety of electrochemical devices have been used for rapid sensing of biomolecules and other diagnostic applications. Here, we provide a brief overview of recent advances in DNA-based biomolecular assays. Biosensing platform such as electrochemical biosensor, nanopore biosensor, and field-effect transistor biosensors (FET), which are equipped with aptamer, DNA walker, DNAzyme, DNA origami, and nanomaterials, has been developed for amplification detection. Under the optimal conditions, the proposed biosensor has good amplification detection performance. Further, we discussed the challenges of detection strategies in clinical applications and offered the prospect of this field. [ABSTRACT FROM AUTHOR]

Our previous studies have highlighted the pivotal role of gastric cancer mesenchymal stem cells (GCMSCs) in tumor initiation, progression, and metastasis. In parallel, it is well-documented that endothelial cells (ECs) undergo functional alterations in response to challenging tumor microenvironment. This study aims to elucidate whether functional changes in ECs might be induced by GCMSCs and thus influence cancer progression. Cell proliferation was assessed through CCK-8 and colony formation assays, while cell migration and invasion capabilities were evaluated by wound-healing and Transwell assays. Immunohistochemistry was employed to examine protein distribution and expression levels. Additionally, quantitative analysis of protein and mRNA expression was carried out through Western blotting and qRT-PCR respectively, with gene knockdown achieved using siRNA. Our findings revealed that GCMSCs effectively stimulate cell proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), both in vitro and in vivo. GCMSCs promote the migration and invasion of gastric cancer cells by inducing the expression of Slit2 in HUVECs. Notably, the inhibition of phosphorylated AKT partially mitigates the aforementioned effects. In conclusion, GCMSCs may exert regulatory control over Slit2 expression in ECs via the AKT signaling pathway, thereby inducing functional changes in ECs that promote tumor progression.Graphical Abstract: Our previous studies have highlighted the pivotal role of gastric cancer mesenchymal stem cells (GCMSCs) in tumor initiation, progression, and metastasis. In parallel, it is well-documented that endothelial cells (ECs) undergo functional alterations in response to challenging tumor microenvironment. This study aims to elucidate whether functional changes in ECs might be induced by GCMSCs and thus influence cancer progression. Cell proliferation was assessed through CCK-8 and colony formation assays, while cell migration and invasion capabilities were evaluated by wound-healing and Transwell assays. Immunohistochemistry was employed to examine protein distribution and expression levels. Additionally, quantitative analysis of protein and mRNA expression was carried out through Western blotting and qRT-PCR respectively, with gene knockdown achieved using siRNA. Our findings revealed that GCMSCs effectively stimulate cell proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), both in vitro and in vivo. GCMSCs promote the migration and invasion of gastric cancer cells by inducing the expression of Slit2 in HUVECs. Notably, the inhibition of phosphorylated AKT partially mitigates the aforementioned effects. In conclusion, GCMSCs may exert regulatory control over Slit2 expression in ECs via the AKT signaling pathway, thereby inducing functional changes in ECs that promote tumor progression. [ABSTRACT FROM AUTHOR]

Ternary refrigerants surpass traditional single-component and binary refrigerants in performance, efficiency, and environmental impact in refrigeration systems, but the abundance of combination possibilities makes it challenging to experimentally determine the optimal mixture for a specific system. This research proposes a mechanism model for screening ternary refrigerants, which selects the composition of mixed refrigerants from 24 types of refrigerants and realizes simultaneous optimization of the composition and process parameters of mixed refrigerants. The model is applied to a new ORC-VCR-CCHP (Organic Rankine Cycle- Vapor Compression Refrigeration- Combined cooling, heating and power) system. This system can effectively recover solar energy and convert it into cooling, heat and electricity to meet the energy demand of the university campus to a great extent. Taking the highest exergoeconomic efficiency as the objective function and satisfying excellent economy, environmental protection, thermodynamic stability, and low toxicity at the same time, a mixed integer nonlinear programming (MINLP) model was established. The optimization results show that the optimal exergoeconomic efficiency can reach 42.49 %. The optimal composition with safety and environmental protection in the ORC system and VCR system are R245fa/R41/R1336mzz (z) and R1234ze/R1234yf/R32, with mass fractions of 0.5339/0.4310/0.0351 and 0.2202/0.2073/0.5725 respectively. The article concludes with an Exergoeconomic analysis. • Propose a mechanism model for screening ternary mixed refrigerants. • Complex solar-powered ORC-VCR-CCHP system applied to a university. • Exergoeconomic efficiency is considered the objective function of optimization. • Joint optimization of process parameters and refrigerant compositions is carried out. • Exergoeconomic evaluation and factors affecting system efficiency are analyzed. [ABSTRACT FROM AUTHOR]

Nanopore electrochemical sensors have been developed to detect various emerging pollutants at the single-molecule level with high sensitivity and specificity due to their high resolution in past three decades, which is of great significance for emerging hazardous pollutants control. Electrochemical detection methods based on nanopore technology are primarily divided into two categories: resistive-pulse and rectification sensing. The main detection mechanism of the resistive-pulse method is based on the volume exclusion effect generated when the analyte enters through the nanopore, and it involves three primary detection strategies. The first approach involves nanopore technology for direct pollutant detection, where pollutant structure and concentration information is assessed based on nanopore-generated ionic current's blockade strength, duration, and frequency. The second strategy relies on weak intermolecular interactions when direct detection of pollutants is challenging. Molecular probes interact with target molecules to enhance detection sensitivity and achieve specific recognition. The third strategy is based on the biological/chemical reaction of pollutant molecules, through indirect detection method to achieve specific detection of target pollutant molecules. Additionally, relies on changes in surface charge polarity or nanopore spatial structure induced by the analyte molecules to achieve the detection of target molecules within the nanopore. This work demonstrates the research progress achieved in the application of nanopore electrochemical sensing technology to high-sensitivity detection of hazardous pollutants, utilizing the unique confined spatial characteristics of nanopores, combined with biorecognition techniques and principles of electrochemical reactions. [ABSTRACT FROM AUTHOR]