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Acute Myocardial Infarction (AMI) has seen rising cases, particularly in younger people, leading to public health concerns. Standard treatments, like coronary artery recanalization, often don't fully repair the heart's microvasculature, risking heart failure. Advances show that Mesenchymal Stromal Cells (MSCs) transplantation improves cardiac function after AMI, but the harsh microenvironment post-AMI impacts cell survival and therapeutic results. MSCs aid heart repair via their membrane proteins and paracrine extracellular vesicles that carry microRNA-125b, which regulates multiple targets, preventing cardiomyocyte death, limiting fibroblast growth, and combating myocardial remodeling after AMI. This study introduces ultrasound-responsive phase-change bionic nanoparticles, leveraging MSCs' natural properties. These particles contain MSC membrane and microRNA-125b, with added macrophage membrane for stability. Using Ultrasound Targeted Microbubble Destruction (UTMD), this method targets the delivery of MSC membrane proteins and microRNA-125b to AMI's inflamed areas. This aims to enhance cardiac function recovery and provide precise, targeted AMI therapy.

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Phthalate esters (PAEs), recognized as endocrine disruptors, are released into the environment during usage, thereby exerting adverse ecological effects. This study investigates the occurrence, sources, and risk assessment of PAEs in surface water obtained from 36 sampling points within the Yellow River and Yangtze River basins. The total concentration of PAEs in the Yellow River spans from 124.5 to 836.5 ng/L, with Dimethyl phthalate (DMP) (75.4 ± 102.7 ng/L) and Diisobutyl phthalate (DiBP) (263.4 ± 103.1 ng/L) emerging as the predominant types. Concentrations exhibit a pattern of upstream (512.9 ± 202.1 ng/L) > midstream (344.5 ± 135.3 ng/L) > downstream (177.8 ± 46.7 ng/L). In the Yangtze River, the total concentration ranges from 81.9 to 441.6 ng/L, with DMP (46.1 ± 23.4 ng/L), Diethyl phthalate (DEP) (93.3 ± 45.2 ng/L), and DiBP (174.2 ± 67.6 ng/L) as the primary components. Concentration levels follow a midstream (324.8 ± 107.3 ng/L) > upstream (200.8 ± 51.8 ng/L) > downstream (165.8 ± 71.6 ng/L) pattern. Attention should be directed towards the moderate ecological risks of DiBP in the upstream of HH, and both the upstream and midstream of CJ need consideration for the moderate ecological risks associated with Di-n-octyl phthalate (DNOP). Conversely, in other regions, the associated risk with PAEs is either low or negligible. The main source of PAEs in Yellow River is attributed to the release of construction land, while in the Yangtze River Basin, it stems from the accumulation of pollutants in lakes and forests discharged into the river. These findings are instrumental for pinpointing sources of PAEs pollution and formulating control strategies in the Yellow and Yangtze Rivers, providing valuable insights for global PAEs research in other major rivers.

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Stroke has emerged as the primary cause of disability and death globally in recent years. Intracerebral hemorrhage (ICH), a particularly severe kind of stroke, is occurring in an increasing number of people. The two main clinical treatments for ICH now in use are conservative pharmaceutical therapy and surgical intervention, both of which have risks and drawbacks. Consequently, it is crucial to look into the pathophysiology of ICH and consider cutting-edge therapeutic approaches. Recent research has revealed that pyroptosis is a newly identified type of cell death distinguished by the break of the cell membrane and the discharge of pro-inflammatory substances through different routes. Following ICH, glial cells experience pyroptosis, which worsens neuroinflammation. Hence, the onset and progression of ICH are strongly linked to pyroptosis, which is facilitated by different inflammasomes. It is essential to conduct a comprehensive investigation of ICH damage processes and uncover new targets for treatment. The impact and function of pyroptosis in ICH, as well as the activation and regulation of inflammasomes and their mediated pyroptosis pathways will be fully discussed in this review.

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Chimeric antigen receptor (CAR) T cell therapy is a powerful adoptive immunotherapy against blood cancers, but the therapeutic effect was not efficient enough on solid tumors. B cells have been reported to play a critical role in regulating memory T differentiation and cytotoxic T development. However, as of yet the influence of such B cells on CAR T cells has not been discussed. In this study, using ephrin type-A receptor 2 (EphA2) specific CAR T cells, we cultured B cells successfully to stimulate CAR T cells in vitro, and investigated the cell differentiation and anti-tumor efficiency. We observed that EphA2-CAR T cells stimulated by B cells performed increased interferon γ (IFN γ) production and upregulated OX40 expression, as well as the enhanced anti-tumor activity and reduced PD-1 expression. The persistence of CAR T cells was enhanced after B cells stimulation for more than 7 days with the increased subset of central memory T cells (TCM). In addition, next generation sequencing was performed to explore the underlying mechanisms. The up-regulated genes clustered in, immune response activation, chemokine signaling pathway, calcium signaling pathway, cGMP-PKG signaling pathway and et al. which contributed to the upregulated anti-glioblastoma (GBM) activity of CAR T cells stimulated by B cell. Furthermore, MEF2C, CD40, SYK and TNFRSF13B were upregulated in CAR T cells after co-culturing with B cells. These genes functionally enriched in promoting lymphocytes proliferation and may contribute to the enhanced persistence of CAR T cells. In conclusion, these results indicated the critical role of B cells in prolonging CAR T cells longevity and enhancing anti-tumor activity, which paves the way for the therapeutic exploitation of EphA2-CAR T cells against GBM in the future.

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Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.

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Objective: To investigate the pathogenesis of Primary Angle-Closure Glaucoma (PACG) and its relationship with the anatomical structure of the anterior segment by obtaining biometric parameters using the IOL-Master 700. Methods: A retrospective case-control study was conducted. Clinical data from 39 PACG patients and 40 normal controls treated at the Aier Eye Hospital affiliated with Wuhan University from January to December 2022 were collected. Anterior chamber depth (AC), white-to-white (WTW), lens thickness (LT), central corneal thickness (CCT), axial length (AL), corneal curvature (K1), corneal curvature (K2), and lens position (LP) were measured using the IOL-Master 700 to analyze the characteristics and differences in the anterior segment structure of both groups. Statistical methods included independent sample t-tests and logistic regression analysis. Results: Significant differences were found in the anterior segment biometric parameters between PACG patients and normal controls (p < 0.05). Anterior chamber depth, white-to-white, lens thickness, central corneal thickness, axial length, and K2 were all related to the occurrence of PACG (p < 0.05). The occurrence of PACG was negatively correlated with ACD, CCT, and AL (OR = 0.12-0.64, p < 0.05), and positively correlated with LT. Conclusion: Compared to the normal control group, PACG patients in the Hubei region have a smaller anterior segment space, narrower angles, thicker lens, thinner cornea, shorter axial length, flatter cornea, and more anteriorly positioned lens.

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Introduction: Monoclonal antibodies (mAbs) play a pivotal role in disease diagnosis as well as immunotherapy interventions. Traditional monoclonal antibody generation relies on animal immunization procedures predominantly involving mice; however, recent advances in in-vitro expression methodologies have enabled large-scale production suitable for both industrial applications as well as scientific investigations. Methods: In this study, two mAbs against H7 subtype avian influenza viruses (AIV) were sequenced and analyzed, and the DNA sequences encoding heavy chain (HC) and light chain (LC) were obtained and cloned into pCHO-1.0 expression vector. Then, the HC and LC expression plasmids were transfected into CHO-S cells to establish stable cell lines expressing these mAbs using a two-phase selection scheme with different concentrations of methotrexate and puromycin. Recombinant antibodies were purified from the cell culture medium, and their potential applications were evaluated using hemagglutination inhibition (HI), western blotting (WB), confocal microscopy, and enzyme-linked immunosorbent assay (ELISA). Results: The results indicated that the obtained recombinant antibodies exhibited biological activity similar to that of the parent antibodies derived from ascites and could be used as a replacement for animal-derived mAbs. A kinetic analysis of the two antibodies to the AIV HA protein, conducted using surface plasmon resonance (SPR), showed concordance between the recombinant and parental antibodies. Discussion: The data presented in this study suggest that the described antibody production protocol could avoid the use of experimental animals and better conform to animal welfare regulations, and provides a basis for further research and development of mAbs-based diagnostic products.

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KRAS mutations play a critical role in the development and progression of several cancers, including non-small cell lung cancer and pancreatic cancer. Despite advancements in targeted therapies, the management of KRAS-mutant tumors remains challenging. This study leverages bibliometric analysis and a comprehensive review of clinical trials to identify emerging immunotherapies and potential treatments for KRAS-related cancers. Using the Web of Science Core Collection and Citespace, we analyzed publications from January 2008 to March 2023 alongside 52 clinical trials from ClinicalTrials.gov and WHO's registry, concentrating on immune checkpoint blockades (ICBs) and novel therapies. Our study highlights an increased focus on the tumor immune microenvironment and precision therapy. Clinical trials reveal the effectiveness of ICBs and the promising potential of T-cell receptor T-cell therapy and vaccines in treating KRAS-mutant cancers. ICBs, particularly in combination therapies, stand out in managing KRAS-mutant tumors. Identifying the tumor microenvironment and gene co-mutation profiles as key research areas, our findings advocate for multidisciplinary approaches to advance personalized cancer treatment. Future research should integrate genetic, immunological, and computational studies to unveil new therapeutic targets and refine treatment strategies for KRAS-mutant cancers.

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Background: Glioblastoma (GBM) is the most common primary malignant brain tumor. The aim of this study was to elucidate the role of microenvironment and intrinsic T-type calcium channels (Cav3) in regulating tumor growth and progression. Methods: We grafted syngeneic GBM cells into Cav3.2 knockout mice to assess the role of microenvironment T-Type calcium channels on GBM tumor growth. We performed single-cell RNA-seq (scRNA-seq) of tumors from WT and Cav3.2 KO mice to elucidate the regulation of tumors by the microenvironment. We used neurons from WT and Cav3.2 KO mice in co-culture with GBM stem cells (GSC) to assess the effects of Cav3.2 on neuron/GSC synaptic connections and tumor cell growth. Results: Cav3.2 KO in the microenvironment led to significant reduction of GBM growth and prolongation of animal survival. scRNA-seq showed that microenvironment Cav3.2 regulates neuronal and glial biological processes. Microenvironment Cav3.2 downregulated numerous genes associated with regulating the OPC cell state in GBM tumors such as SOX10 and Olig2. Neuronal Cav3.2 promoted neuron/GSC synaptic connections and GSC growth. Treatment of GSCs with the Cav3 blocker mibefradil downregulated genes associated with neuronal processes. The Cav3 blocker drug mibefradil synergized with temozolomide (TMZ) and radiation to reduce in vivo tumor growth and prolong animal survival. Conclusions: Together these data reveal a role for microenvironment Cav3 in promoting GBM tumor progression through regulating neuronal and glial processes particularly associated with the OPC-cell state. Targeting both intrinsic and microenvironment Cav3 with the inhibitor mibefradil significantly enhanced the anti-GBM effects of TMZ and radiation.

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OBJECTIVE: To explore the effectiveness of HPV 16/18 E7 oncoprotein in detecting high-grade cervical intraepithelial neoplasia (CIN) and predicting disease outcomes in HPV 16/18-positive patients. METHODS: The present study was a cross-sectional study with a 2-year follow up. We collected 915 cervical exfoliated cell samples from patients who tested positive for HPV 16/18 in gynecologic clinics of three tertiary hospitals in Beijing from March 2021 to October 2022 for HPV 16/18 E7 oncoprotein testing. Subsequently, 2-year follow up of 408 patients with baseline histologic CIN1 or below were used to investigate the predictive role of HPV 16/18 E7 oncoprotein in determining HPV persistent infection and disease progression. RESULTS: The positivity rate of the HPV 16/18 E7 oncoprotein assay was 42.06% (249/592) in the inflammation/CIN 1 group and 85.45% (277/324) in the CIN2+ group. For CIN2+ detection, using the HPV 16/18 E7 oncoprotein assay combined with HPV 16/18 testing, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.45%, 57.94%, 52.57%, and 87.95%, respectively. During the 2-year follow up, the sensitivity, specificity, PPV, and NPV for predicting persistent HPV infection were 48.44%, 58.21%, 34.64%, and 71.18% in the baseline inflammation and CIN1 group. CONCLUSIONS: As a triage method for high-grade CIN screening in HPV 16/18-positive patients, HPV 16/18 E7 oncoprotein demonstrated a relatively high NPV, making it suitable for clinical use in triaging HPV 16/18-positive cases and potentially reducing the colposcopic referral rate. HPV 16/18 E7 oncoprotein exhibited a preferably predictive value in determining HPV infection outcomes and disease progression.

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The increasing chemical pollution of the drinking water is widely concerned. Large number of organic contaminants cannot be removed by conventional water treatment technology due to their low concentration, and long-term exposure may pose significant risks to human health. Which organic contaminants in drinking water should be given more attention has been a topic of great concern in recent years. To identify the organic contaminants that need attention, this research proposes an improved health risk screening method to quantitatively analyze the risks of accumulation, persistence, toxicity, and antibiotic resistance. Compared with conventional method, 26 compounds were added to the improved screening list, including 9 DBPs (e.g., NDMA), 3 antibiotics (e.g., oxytetracycline), PFNA and other compounds. Overall, antibiotics and plasticizers rose in the risk rankings. From the perspective of the proportion of total risk value, a single risk plays a decisive role (more than 99%) in the ranking. This change suggests that antibiotic resistance and the accumulation of organic matter are as important as their toxic risks to humans. 58 compounds were recommended for the priority control organic contaminants list in drinking water. This list provides the necessary information for authoritative regulations to monitor, control, assess, and manage the risks of environmentally relevant compounds in drinking water in China.

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Cancer therapeutic resistance as a common hallmark of cancer is often responsible for treatment failure and poor patient survival. Cancer stem-like cells (CSCs) are one of the main contributors to therapeutic resistance, cancer relapse and metastasis. Through screening from our in-house library of natural products, we found polyphyllin II (PPII) as a potent anti-CSC compound for triple-negative breast cancer (TNBC). To enhance anti-CSC selectivity and improve druggability of PPII, we leverage the liposome-mediated delivery technique for increasing solubility of PPII, and more significantly, attaining broader therapeutic window. Liposomal PPII demonstrates its marked potency to inhibit tumor growth, post-surgical recurrence and metastasis compared to commercial liposomal chemotherapeutics in the mouse models of CSC-enriched TNBC tumor. We further identify PPII as an inhibitor of the Ras-related nuclear (RAN) protein whose upregulated expression is correlated with poor clinical outcomes. The direct binding of PPII to RAN reduces TNBC stemness, thereby suppressing tumor progression. Our work offers a significance from drug discovery to drug delivery benefiting from liposome technique for targeted treatment of high-stemness tumor.

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OBJECTIVE: This study harnesses the power of text mining to quantitatively investigate the causative factors of falls in adult inpatients, offering valuable references and guidance for fall prevention measures within hospitals. METHODS: Employing KH Coder 3.0, a cutting-edge text mining software, we performed co-occurrence network analysis and text clustering on fall incident reports of 2,772 adult patients from a nursing quality control platform in a particular city in Jiangsu Province, spanning January 2017 to December 2022. RESULTS: Among the 2,772 patients who fell, 80.23% were aged above 60, and 73.27% exhibited physical frailty. Text clustering yielded 16 distinct categories, with four clusters implicating patient factors, four linking falls to toileting processes, four highlighting dynamic interplays between patients, the environment, and objects, and another four clusters revealing the influence of patient-caregiver interactions in causing falls. CONCLUSION: This study highlights the complex, multifactorial nature of falls in adult inpatients. Effective prevention requires a collaborative effort among healthcare staff, patients, and caregivers, focusing on patient vulnerabilities, environmental factors, and improved care coordination. By strengthening these aspects, hospitals can significantly reduce fall risks and promote patient safety.

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PURPOSE: Bloodstream infections (BSIs) are associated with significant morbidity, mortality and costs, while prolonged blood culture (BC) diagnosis may delay the initiation of targeted therapy. This study evaluates the impact of an optimized microbiology laboratory process on turnaround times, antibiotic use, clinical outcomes and economics for hospitalized BSI patients. METHODS: A pre-post study was conducted in a Chinese hospital in which BSI derived BC results before (Oct. 2020- Sep. 2021) and after (Oct. 2021- Sep. 2022) newly implemented microbiology diagnostics and workflow changes were analyzed. Turnaround times, antibiotic initiation, length of stay and in-hospital costs were compared. RESULTS: From 213 included patients, 134 were pre-optimization (pre-op) and 79 were post-optimization (post-op) cases. The median time from blood sample collection (BSC) to pathogen identification (ID) decreased from 70.12 to 47.43 h post-op (P < 0.001). The median time from BSC to the first ID report related initiation of pathogen-directed antibiotic use decreased from 88.48 to 47.85 h post-op (P < 0.001). The average hospital stay decreased from 19.54 to 16.79 days and 30-day readmissions declined from 18.7 to 13.9%, while the mean total antimicrobial drug usage costs decreased by 3,889 CNY per patient (P = 0.022) after optimization. CONCLUSIONS: Implementing new diagnostics technologies and optimizing laboratory workflows significantly reduced antimicrobial drug usage costs, shortened the time to ID results and improved the timeliness of appropriate antibiotic choices to treat BSIs. Investments in faster testing and process improvements were clearly beneficial for patient outcomes and healthcare economics.

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PURPOSE: The current commonly-used metrics for evaluating the quality of auto-segmented contours have limitations and do not always reflect the clinical usefulness of the contours. This work aims to develop a novel contour quality classification (CQC) method by combining multiple quantitative metrics for clinical usability-oriented contour quality evaluation for deep learning-based auto-segmentation (DLAS). METHODS: The CQC was designed to categorize contours on slices as acceptable, minor edit, or major edit based on the expected editing effort/time with supervised ensemble tree classification models using seven quantitative metrics. Organ-specific models were trained for five abdominal organs (pancreas, duodenum, stomach, small and large-bowels) using 50 MRI datasets. Twenty additional MRI and nine CT datasets were employed for testing. Inter-observer variation (IOV) was assessed among six observers and consensus labels were established through majority vote for evaluation. The CQC was also compared with a threshold-based baseline approach. RESULTS: For the five organs, the average AUC was 0.982±0.01 and 0.979±0.01, the mean-accuracy was 95.8±1.7% and 94.3±2.1%, and the mean risk-rate was 0.8±0.4% and 0.7±0.5% for MRI and CT testing dataset, respectively. The CQC results closely matched the IOV results (mean-accuracy of 94.2±0.8% and 94.8±1.7%) and were significantly higher than those obtained using the threshold-based method (mean-accuracy of 80.0±4.7%, 83.8±5.2%, and 77.3±6.6% using one, two, and three metrics). CONCLUSION: The CQC models demonstrated high performance in classifying the quality of contour slices. This method can address the limitations of existing metrics and offers an intuitive and comprehensive solution for clinically oriented evaluation and comparison of DLAS systems.

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Myeloid-derived suppressor cells (MDSCs) are reported to be responsible for the negative prognosis of colorectal cancer (CRC) patients due to the mediated immunosuppressive tumor microenvironment (TME). The selective and chronic circumvention of tumor-infiltrated MDSCs has potential clinical significance for CRC treatment, which unluckily remains a technical challenge. Because tumor hypoxia makes a significant contribution to the recruitment of MDSCs in tumor sites, a dual oxygen-supplied immunosuppression-inhibiting nanomedicine (DOIN) is demonstrated for overcoming tumor hypoxia, which achieves selective and long-term inhibition of intratumoral recruitment of MDSCs. The DOIN is constructed by the encasement of perfluorooctyl bromide (PFOB) and 4-methylumbelliferone (4-MU) into a TME-responsive amphiphilic polymer. This nanoplatform directly carries oxygen to the tumor region and simultaneously loosens the condensed tumor extracellular matrix for the normalization of tumor vasculature, which selectively remodels the TME toward one adverse to the intratumoral recruitment of MDSCs. Importantly, this nanoplatform offers a long-acting alleviation of the hypoxic TME, chronically avoiding the comeback of tumor-infiltrated MDSCs. Consequently, the immunosuppressive TME is relieved, and T cells are successfully proliferated and activated into cytotoxic T lymphocytes, which boosts a systemic immune response and contributes to lasting inhibition of tumor growth with a prolonged survival span of xenograft.

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BACKGROUND: Coral reefs experience frequent and severe disturbances that can overwhelm their natural resilience. In such cases, ecological restoration is essential for coral reef recovery. Sexual reproduction has been reported to present the simplest and most cost-effective means for coral reef restoration. However, larval settlement and post-settlement survival represent bottlenecks for coral recruitment in sexual reproduction. While bacteria play a significant role in triggering coral metamorphosis and settlement in many coral species, the underlying molecular mechanisms remain largely unknown. In this study, we employed a transcriptome-level analysis to elucidate the intricate interactions between bacteria and coral larvae that are crucial for the settlement process. RESULTS: High Metabacillus indicus strain cB07 inoculation densities resulted in the successful induction of metamorphosis and settlement of coral Pocillopora damicoris larvae. Compared with controls, inoculated coral larvae exhibited a pronounced increase in the abundance of strain cB07 during metamorphosis and settlement, followed by a significant decrease in total lipid contents during the settled stage. The differentially expressed genes (DEGs) during metamorphosis were significantly enriched in amino acid, protein, fatty acid, and glucose related metabolic pathways. In settled coral larvae induced by strain cB07, there was a significant enrichment of DEGs with essential roles in the establishment of a symbiotic relationship between coral larvae and their symbiotic partners. The photosynthetic efficiency of strain cB07 induced primary polyp holobionts was improved compared to those of the negative controls. In addition, coral primary polyps induced by strain cB07 showed significant improvements in energy storage and survival. CONCLUSIONS: Our findings revealed that strain cB07 can promote coral larval settlement and enhance post-settlement survival and fitness. Manipulating coral sexual reproduction with strain cB07 can overcome the current recruitment bottleneck. This innovative approach holds promise for future coral reef restoration efforts.

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