Quantifying T cell receptor mechanics at membrane junctions using DNA origami tension sensors.

The T cell receptor (TCR) is thought to be a mechanosensor, meaning that it transmits mechanical force to its antigen and leverages the force to amplify the specificity and magnitude of TCR signalling. Although a variety of molecular probes have been proposed to quantify TCR mechanics, these probes are immobilized on hard substrates, and thus fail to reveal fluid TCR-antigen interactions in the physiological context of cell membranes. Here we developed DNA origami tension sensors (DOTS) which bear force sensors on a DNA origami breadboard and allow mapping of TCR mechanotransduction at dynamic intermembrane junctions. We quantified the mechanical forces at fluid TCR-antigen bonds and observed their dependence on cell state, antigen mobility, antigen potency, antigen height and F-actin activity. The programmability of DOTS allows us to tether these to microparticles to mechanically screen antigens in high throughput using flow cytometry. Additionally, DOTS were anchored onto live B cells, allowing quantification of TCR mechanics at immune cell-cell junctions.

Configurational Isomerization-Induced Orientation Switching: Non-Fused Ring Dipodal Phosphonic Acids as Hole-Extraction Layers for Efficient Organic Solar Cells.

Phosphonic acid (PA) self-assembled molecules have recently emerged as efficient hole-extraction layers (HELs) for organic solar cells (OSCs). However, the structural effects of PAs on their self-assembly behaviors on indium tin oxide (ITO) and thus photovoltaic performance remain obscure. Herein, we present a novel class of PAs, namely "non-fused ring dipodal phosphonic acids" (NFR-DPAs), featuring simple and malleable non-fused ring backbones and dipodal phosphonic acid anchoring groups. The efficacy of configurational isomerism in modulating the photoelectronic properties and switching molecular orientation of PAs atop electrodes results in distinct substrate surface energy and electronic characteristics. The NFR-DPA with linear (C2h symmetry) and brominated backbone exhibits favorable face-on orientation and enhanced work function modification capability compared to its angular (C2v symmetry) and non-brominated counterparts. This makes it versatile HELs in mitigating interfacial resistance for energy barrier-free hole collection, and affording optimal active layer morphology, which results in an impressive efficiency of 19.11% with a low voltage loss of 0.52 V for binary OSC devices and an excellent efficiency of 19.66% for ternary OSC devices. This study presents a new dimension to design PA-based HELs for high-performance OSCs.

Design of a high-performance NIR-II nanoprobe by steric regulation for in vivo vasculature and tumor imaging.

A novel NIR-II nanoprobe was developed through regulating the steric effect of an A-DA'D-A dye. The probe features the properties of strong fluorescence, high stability, and a large Stokes shift, thereby serving as a remarkable contrast agent for the fluorescence imaging of hindlimb vasculature and tumors in live mice.

Nomograms incorporating hsa_circ_0029325 highly expressed in exosomes of hepatocellular carcinoma predict the postoperative outcomes.

BACKGROUND: Liquid biopsies, for example, exosomal circular RNA (circRNA) can be used to assess potential predictive markers for hepatocellular carcinoma (HCC) in patients after curative resection. This study aimed to search for effective prognostic biomarkers for HCC in patients after surgical resection based on exosomal circRNA expression profiles. We developed two nomograms incorporating circRNAs to predict the postoperative recurrence-free survival (RFS) and overall survival (OS) of HCC patients. METHOD: Plasma exosomes isolated from HCC patients and healthy individuals were used for circRNA microarray analysis to explore differentially expressed circRNAs. Pearson correlation analysis was used to evaluate the correlation between circRNAs and clinicopathological features. Cox regression analysis was used to explore the correlation between circRNA and postoperative survival time as well as recurrence time. A nomogram based on circRNA and clinicopathological characteristics was established and further evaluated to predict prognosis and recurrence. RESULT: Among 60 significantly upregulated circRNAs and 25 downregulated circRNAs, hsa_circ_0029325 was selected to verify its power for predicting HCC outcomes. The high expression level of exosomal hsa_circ_0029325 was significantly correlated with OS (P = 0.001, HR = 2.04, 95% CI 1.41-3.32) and RFS (P = 0.009, HR = 1.62, 95% CI 1.14-2.30). Among 273 HCC patients, multivariate regression analysis showed that hsa_circ_0029325 (HR = 1.96, 95% CI 1.21-3.18), tumor size (HR = 2.11, 95% CI 1.33-3.32), clinical staging (HR = 2.31, 95% CI 1.54-3.48), and tumor thrombus (HR = 1.74, 95% CI 1.12-2.7) were independent risk factors for poor prognosis in HCC patients after radical resection. These independent predictors of prognosis were incorporated into the two nomograms. The AUCs under the 1-year, 3-year, and 5-year survival and recurrence curves of the OS and RFS nomograms were 0.755, 0.749, and 0.742 and 0.702, 0.685, and 0.642, respectively. The C-index, calibration curves, and clinical decision curves showed that the two prediction models had good predictive performance. These results were verified in the validation cohort with 90 HCC patients. CONCLUSION: Our study established two reliable nomograms for predicting recurrence and prognosis in HCC patients. We also show that it is feasible to screen potential predictive markers for HCC after curative resection through exosomal circRNA expression profile analysis.

MA-MIL: Sampling point-level abnormal ECG location method via weakly supervised learning.

BACKGROUND AND OBJECTIVE: Current automatic electrocardiogram (ECG) diagnostic systems could provide classification outcomes but often lack explanations for these results. This limitation hampers their application in clinical diagnoses. Previous supervised learning could not highlight abnormal segmentation output accurately enough for clinical application without manual labeling of large ECG datasets. METHOD: In this study, we present a multi-instance learning framework called MA-MIL, which has designed a multi-layer and multi-instance structure that is aggregated step by step at different scales. We evaluated our method using the public MIT-BIH dataset and our private dataset. RESULTS: The results show that our model performed well in both ECG classification output and heartbeat level, sub-heartbeat level abnormal segment detection, with accuracy and F1 scores of 0.987 and 0.986 for ECG classification and 0.968 and 0.949 for heartbeat level abnormal detection, respectively. Compared to visualization methods, the IoU values of MA-MIL improved by at least 17 % and at most 31 % across all categories. CONCLUSIONS: MA-MIL could accurately locate the abnormal ECG segment, offering more trustworthy results for clinical application.

Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements.

The roles of γδ T cells in liver cancer, especially in the potential function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines, have aroused research interest. This review briefly describes the basic characteristics of γδ T cells, focusing on their diverse effects on liver cancer. In particular, different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. We provide a detailed description of the immune regulatory network of γδ T cells in liver cancer from two aspects: immune components and nonimmune components. The interactions between various components in this immune regulatory network are dynamic and pluralistic, ultimately determining the biological effects of γδ T cells in liver cancer. We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment, emphasizing the potential of these cells in liver cancer immunotherapy.

Heteromultivalency enables enhanced detection of nucleic acid mutations.

Detecting genetic mutations such as single nucleotide polymorphisms (SNPs) is necessary to prescribe effective cancer therapies, perform genetic analyses and distinguish similar viral strains. Traditionally, SNP sensing uses short oligonucleotide probes that differentially bind the SNP and wild-type targets. However, DNA hybridization-based techniques require precise tuning of the probe's binding affinity to manage the inherent trade-off between specificity and sensitivity. As conventional hybridization offers limited control over binding affinity, here we generate heteromultivalent DNA-functionalized particles and demonstrate optimized hybridization specificity for targets containing one or two mutations. By investigating the role of oligo lengths, spacer lengths and binding orientation, we reveal that heteromultivalent hybridization enables fine-tuned specificity for a single SNP and dramatic enhancements in specificity for two non-proximal SNPs empowered by highly cooperative binding. Capitalizing on these abilities, we demonstrate straightforward discrimination between heterozygous cis and trans mutations and between different strains of the SARS-CoV-2 virus. Our findings indicate that heteromultivalent hybridization offers substantial improvements over conventional monovalent hybridization-based methods.

The immune response of hepatocellular carcinoma after locoregional and systemic therapies: The available combination option for immunotherapy.

Hepatocellular carcinoma (HCC) is associated with a highly heterogeneous immune environment that produces an immune response to various locoregional treatments (LRTs), which in turn affects the effectiveness of immunotherapy. Although LRTs still dominate HCC therapies, 50-60% of patients will ultimately be treated with systemic therapies and might receive those treatments for the rest of their life. TACE, SIRT, and thermal ablation can dramatically increase the immunosuppressive state of HCC, a condition that can be addressed by combination with immunotherapy to restore the activity of lymphocytes and the secretion of cellular immune factors. Immune treatment with locoregional and systemic treatments has dramatically changed the management of HCC. In this review, we examine the research on the changes in the immune microenvironment after locoregional or systemic treatment. We also summarize the regulation of various immune cells and immune factors in the tumor microenvironment and discuss the different infiltration degrees of immune cells and factors on the prognosis of HCC to better compare the efficacy between different treatment methods from the perspective of the tumor microenvironment. This information can be used to help develop treatment options for the upcoming new era of HCC treatment in the future.

Prevalence of intestinal colonization and nosocomial infection with carbapenem-resistant Enterobacteriales in children: a retrospective study.

Objective: We investigated the epidemiological surveillance of the intestinal colonization and nosocomial infection of carbapenem-resistant Enterobacteriales (CRE) isolates from inpatients, which can provide the basis for developing effective prevention. Methods: A total of 96 CRE strains were collected from 1,487 fecal samples of hospitalized children between January 2016 and June 2017, which were defined as the "CRE colonization" group. In total, 70 CRE clinical isolates were also randomly selected for the comparison analysis and defined as the "CRE infection" group. The antimicrobial susceptibility of all strains was determined by the microdilution broth method. Polymerase chain reaction (PCR) was used to analyze carbapenemase genes, plasmid typing, and integrons. Multilocus sequence typing was further used to determine clonal relatedness. Results: In the "CRE colonization" group, Klebsiella pneumoniae was mostly detected with a rate of 42.7% (41/96), followed by Escherichia coli (34.4%, 33/96) and Enterobacter cloacae (15.6%, 15/96). The ST11 KPC-2 producer, ST8 NDM-5 producer, and ST45 NDM-1 producer were commonly present in carbapenem-resistant K. pneumoniae (CRKPN), carbapenem-resistant E. coli (CRECO), and carbapenem-resistant E. cloacae (CRECL) isolates, respectively. In the "CRE infection" group, 70% (49/70) of strains were K. pneumoniae, with 21.4% E. cloacae (15/70) and 5.7% E. coli (4/70). The ST15 OXA-232 producer and ST48 NDM-5 producer were frequently observed in CRKPN isolates, while the majority of NDM-1-producing CRECL isolates were assigned as ST45. Phylogenetic analysis showed that partial CRE isolates from intestinal colonization and nosocomial infection were closely related, especially for ST11 KPC-2-producing CRKPN and ST45 NDM-1-producing CRECL. Furthermore, plasmid typing demonstrated that IncF and IncFIB were the most prevalent plasmids in KPC-2 producers, while IncX3/IncX2 and ColE were widely spread in NDM producer and OXA-232 producer, respectively. Then, class 1 integron intergrase intI1 was positive in 74.0% (71/96) of the "CRE colonization" group and 52.9% (37/70) of the "CRE infection" group. Conclusion: This study revealed that CRE strains from intestinal colonization and nosocomial infection showed a partial correlation in the prevalence of CRE, especially for ST11 KPC-2-producing CRKPN and ST45 NDM-1-producing CRECL. Therefore, before admission, long-term active screening of rectal colonization of CRE isolates should be emphasized.

Detection of cellular traction forces via the force-triggered Cas12a-mediated catalytic cleavage of a fluorogenic reporter strand.

Molecular forces generated by cell receptors are infrequent and transient, and hence difficult to detect. Here we report an assay that leverages the CRISPR-associated protein 12a (Cas12a) to amplify the detection of cellular traction forces generated by as few as 50 adherent cells. The assay involves the immobilization of a DNA duplex modified with a ligand specific for a cell receptor. Traction forces of tens of piconewtons trigger the dehybridization of the duplex, exposing a cryptic Cas12-activating strand that sets off the indiscriminate Cas12-mediated cleavage of a fluorogenic reporter strand. We used the assay to perform hundreds of force measurements using human platelets from a single blood draw to extract individualized dose-response curves and half-maximal inhibitory concentrations for a panel of antiplatelet drugs. For seven patients who had undergone cardiopulmonary bypass, platelet dysfunction strongly correlated with the need for platelet transfusion to limit bleeding. The Cas12a-mediated detection of cellular traction forces may be used to assess cell state, and to screen for genes, cell-adhesion ligands, drugs or metabolites that modulate cell mechanics.

Moderating effects of perceived social support on self-efficacy and psychological well-being of Chinese nurses: a cross-sectional study.

Introduction: Nurses experience significant physical and psychological stress that negatively influences their psychological well-being. The objective of this study was to explore the association between self-efficacy and psychological well-being among Chinese nurses and to assess the moderating effects of perceived social support (PSS). Methods: In 2020, a hospital-based cross-sectional study using a multistage random sampling approach was performed in five regions of Liaoning, China. Of the 1,200 surveyed nurses, 1,010 completed questionnaires that evaluated the demographic information, 14-item Hospital Anxiety and Depression Scale, General Self-Efficacy Scale, and Multidimensional Scale of Perceived Social Support. To examine the factors associated with mental health parameters, hierarchical multiple regression analysis was performed. The interactions were visualized using a simple slope analysis. Results: The mean depression and anxiety scores for Chinese nurses were 8.74 ± 3.50 and 6.18 ± 3.26, respectively. The association between self-efficacy and depression differed between the low perceived social support (PSS) group (1 SD below the mean, ß = -0.169, p < 0.01) and high PSS group (1 SD above the mean, ß = -0.077, p < 0.01). Similarly, the association between self-efficacy and anxiety differed between the low PSS group (1 SD below the mean, ß = -0.155, p < 0.01) and high PSS group (1 SD above the mean, ß = -0.044, p < 0.01). Conclusion: We found that Chinese nurses experienced high levels of anxiety and depression. Furthermore, PSS moderates the relationship between self-efficacy and psychological well-being. Therefore, interventions targeting self-efficacy and PSS should be implemented to improve the psychological well-being of nurses.

DNA Origami Tension Sensors (DOTS) to study T cell receptor mechanics at membrane junctions.

The T cell receptor (TCR) is thought to be a mechanosensor, meaning that it transmits mechanical force to its antigen and leverages the force to amplify the specificity and magnitude of TCR signaling. The past decade has witnessed the development of molecular probes which have revealed many aspects of receptor mechanotransduction. However, most force probes are immobilized on hard substrates, thus failing to reveal mechanics in the physiological context of cell membranes. In this report, we developed DNA origami tension sensors (DOTS) which bear force sensors on a DNA origami breadboard and allow mapping of TCR mechanotransduction at dynamic intermembrane junctions. We demonstrate that TCR-antigen bonds experience 5-10 pN forces, and the mechanical events are dependent on cell state, antigen mobility, antigen potency, antigen height and F-actin activity. We tethered DOTS onto a microparticle to mechanically screen antigen in high throughput using flow cytometry. Finally, DOTS were anchored onto live B cell membranes thus producing the first quantification of TCR mechanics at authentic immune cell-cell junctions.

DNA Nanotechnology for Investigating Mechanical Signaling in the Immune System.

Immune recognition occurs at specialized cell-cell junctions when immune cells and target cells physically touch. In this junction, groups of receptor-ligand complexes assemble and experience molecular forces that are ultimately generated by the cellular cytoskeleton. These forces are in the range of piconewton (pN) but play crucial roles in immune cell activation and subsequent effector responses. In this minireview, we will review the development of DNA based molecular tension sensors and their applications in mapping and quantifying mechanical forces experienced by immunoreceptors including T-cell receptor (TCR), Lymphocyte function-associated antigen (LFA-1), and the B-cell receptor (BCR) among others. In addition, we will highlight the use of DNA as a mechanical gate to manipulate mechanotransduction and decipher how mechanical forces regulate antigen discrimination and receptor signaling.

Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation.

BACKGROUND: Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. METHODS: Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. RESULTS: Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4+ T cells, CD4+CD8+ T cells, and CD4+CD25+CD127- Tregs and significantly decreased the levels of CD16+CD56+ natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. CONCLUSIONS: This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA. TRIAL REGISTRATION: ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .

The combination of a prolonged treatment time window and alpha-fetoprotein benefits the tumor response of hepatocellular carcinoma patients as evaluated by the imRECIST: a single-center, retrospective study.

Background: The combined immunotargeting therapy of hepatocellular carcinoma (HCC) have brought remarkable results. There are still some drawbacks to the application of the immune-modified Response Evaluation Criteria in Solid Tumors to Immunotherapy (imRECIST). How many weeks does it take to confirm the true disease progression for HCC patients who had reported disease progression for the first time based on imRECIST. Whether alpha-fetoprotein (AFP), an important indicator in the progression and prognosis of liver cancer, has the same value in immunotherapy. This prompted more clinical data to gather evidence that the immunotherapy time window issue contradicts the potential benefit of therapy. Methods: This study retrospectively analyzed the clinical data of 32 patients who had undergone immunotherapy plus targeted therapy at the First Affiliated Hospital of Chongqing Medical University from June 2019 to June 2022. ImRECIST was used to evaluate the therapeutic efficacy among the patients. Before initial treatment and each immunotherapy cycle, each patient underwent standard abdominal computed tomography (CT) imaging and some biochemical indicators to assess physical condition and tumor response. All patients included will be divided into 8 groups. The differences in the survival outcomes of each treatment group were analysed. Results: Among the 32 advanced HCC patients, 9 patients achieved stable disease (SD), 12 patients showed progressive disease (PD), 3 patients showed a complete response (CR), and 8 patients showed a partial response (PR). There is no difference in baseline characteristics between subgroups. In relation to patients with PD, a prolonged therapeutic time window and the provision of continuous medication may lead to a PR, prolonging their overall survival (P=0.5864). Compared to the patients with continuous PD, there was no significant difference in the survival of patients with increased AFP concentrations after treatment who achieved PR or SD and ultimately showed PD (P=0.6600). Conclusions: In our study, the time window for treatment may need to be extended in the process of immunotherapy for HCC patients. An analysis of AFP may assist the imRECIST by providing a more accurate evaluation of tumor progression.

Diazabicyclic Electroactive Ionenes for Efficient and Stable Organic Solar Cells.

Electroactive ionenes combining caged-shaped diazabicyclic cations and aromatic diimides were developed as interlayers in organic solar cells (OSCs). These ionenes reduce the work-function of air-stable metal electrodes (e.g., Ag, Cu and Au) by generating strong interfacial dipoles, and their optoelectronic and morphological characters can be modulated by aromatic diimides, leading to high conductivity and good compatibility with active layers. The optimal ionene exhibits superior charge-transport, desirable crystallinity, and weak visible-absorption, boosting the efficiency of benchmark PM6 : Y6-based OSCs up to 17.44 %. The corresponding normal devices show excellent stability at maximum power point test under one sun illumination for 1000 h. Replacing Y6 with L8-BO promotes the efficiency to 18.43 %, one of the highest in binary OSCs. Notably, high efficiencies >16 % are maintained as the interlayer thickness increasing to 105 nm, the best result with interlayer-thickness over 100 nm.

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases.

Hepatic stellate cells (HSCs) play an essential role in various liver diseases, and exosomes are critical mediators of intercellular communication in local and distant microenvironments. Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. Substantial evidence has revealed that HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSC-derived exosomes are underpinned by vehicle molecules, such as mRNAs and microRNAs, that function in, and significantly affect, the processes of various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer. As such, numerous exosomes derived from HSCs or HSC-associated exosomes have attracted attention because of their biological roles and translational applications as potential targets for therapeutic targets. Herein, we review the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.

Drinking water behavior and willingness to use filters by middle-aged and elderly residents in rural areas: A cross-sectional study in Tengchong, China.

Access to safe drinking water is critical to health and development issues, and residents' drinking behavior reflects their awareness of health and water hygiene. Random sampling and face-to-face questionnaires were used to investigate the drinking water behavior, sanitation and perceptions of drinking water among middle-aged and elderly residents in Tengchong, southwest Yunnan from July 1 to July 28, 2021. Differences between groups were assessed using the Chi-square test and t-test. Two binary logistic regression analyses were conducted to explore the influencing factors of drinking unboiled tap water and willingness to use filters. Results show that 35% of residents drink unboiled tap water, and 29.8% of respondents indicated a willingness to use filters. The model results showed a strong correlation between 60 and 79 years old (OR: 0.510, 95% CI: 0.303-0.858), 80 and above years old (OR: 0.118, 95% CI: 0.038-0.365), drinking water at a regular interval (OR: 0.397, 95% CI: 0.257-0.612), wanting to gain knowledge about drinking water (OR: 0.198, 95% CI: 0.099-0.395), Perceived health risks (PHR) (OR: 0.847, 95% CI: 0.771-0.929), having kidney stones (OR: 2.975, 95% CI: 1.708-5.253) and drinking unboiled tap water (p < 0.05). 60-79 years old (OR: 0.446, 95% CI: 0.244-0.815), 80 and above years old (OR: 0.228, 95% CI: 0.064-0.812), water storage (OR: 0.088, 95% CI: 0.026-0.300), middle school and above (OR: 2.238, 95% CI: 1.289-3.883), household water treatment (HWT) (OR: 33.704, 95% CI: 9.726-116.791), Perceived health risks (PHR) (OR:1.106, 95% CI: 1.009-1.213), water authority satisfaction (WAT) (OR:0.857, 95% CI: 0.769-0.956) and willingness to use filters were correlated (p < 0.05). Our findings suggested that a certain proportion of permanent middle-aged and elderly residents in rural areas still drink unboiled tap water, and residents are less willing to use filters. Residents' perception of drinking water can reflect residents' drinking water behavior and willingness to a certain extent. It is recommended that the government and Centers for Disease Control (CDC) should strengthen relevant measures such as knowledge popularization and health education, and regulate the water use behavior of middle-aged and elderly residents. Promote safe, economical and effective household water filtration facilities to ensure public health safety.

A well-matched marriage of immunotherapy and radiofrequency ablation to reduce the relapse and progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a health challenge with increasing incidence worldwide. Radiofrequency ablation (RFA) is a potentially curative option for patients with early-stage HCC. However, the high rate of tumor recurrence limits long-term survival when the tumors are larger than 2 cm and undergoing insufficient RFA (iRFA). Notably, in situ tumor necrosis due to thermal ablation is assumed to be a source of antigens that induce antitumor immunity. Therefore, mounting studies and trials have attempted to provide a rational and effective therapeutic strategy combining RFA and immunotherapy to treat HCC. Nowadays, many controversies and challenges with this combined therapeutic strategy remain to be resolved, such as the indications for adjuvant immunotherapy along with RFA in early HCC, the sequence of the two treatments in advanced HCC, and the optimal timing of immunotherapy before or after RFA. In addition, individualized treatment strategies need to be perfected for patients with HCC.

Hepatic stellate cell exosome-derived circWDR25 promotes the progression of hepatocellular carcinoma via the miRNA-4474-3P-ALOX-15 and EMT axes.

Recently, the emerging role of circular RNAs (circRNAs) in tumor development and progression has been a topic of great interest. Nevertheless, the effects of hepatic stellate cell (HSC)-derived exosomes in hepatocellular carcinoma (HCC) remain unclear. Here, we aim to explore the potential effect of HSC exosome-derived circWDR25 on the aggressiveness of HCC. Firstly, a microarray analysis of circRNAs was performed to profile and identify the differentially expressed circRNAs derived from HSC exosomes activated by HCC cells. Subsequently, the roles of circWDR25 in HCC tumor growth and aggressiveness were confirmed through in vitro and in vivo functional experiments. Moreover, RNA pull-down, dual-luciferase reporter assays, and fluorescent in situ hybridization (FISH) were performed to determine interactions in the circWDR25-miR-4474-3p-ALOX15 loop. Immunohistochemical analysis was also performed on a microarray of HCC tissues and peritumoral tissues. We found that overexpressed peritumoral circWDR25 was associated with survival and recurrence in patients with HCC and promoted the progression of HCC cells both in vitro and in vivo. Mechanistically, both exogenous and HSC exosomal-derived circWDR25 regulated the expression of ALOX15 by sponging miR-4474-3p and ultimately inducing an epithelial-to-mesenchymal transition (EMT) in HCC cells. Moreover, exogenous and HSC exosomal-derived circWDR25 promoted the expression of CTLA-4 in HSCs and PD-L1 in HCC cells. In conclusion, circWDR25 facilitated HCC cell proliferation and invasion via the circWDR25/miR-4474-3p/ALOX15 and EMT axes and it promoted the expression of CTLA-4 in HSCs and PD-L1 in HCC cells, thus providing insights into the mechanism of tumor aggressiveness mediated by HSC-derived exosomal circWDR25.