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BACKGROUND: Verbascoside, a compound classified as a phenylethanol glycoside in Dihuang, has been the subject of modern pharmacological investigations. These studies have revealed its noteworthy antioxidant, anti-inflammatory, memory-enhancing, neuroprotective, antitumor, and various other pharmacological properties. While verbascoside exhibits favorable antioxidant effects, its precise mechanism of action in ameliorating osteoporosis through the treatment of oxidative stress remains unclear. METHODS: This study employed CCK8, ALP, ELISA, and ROS staining techniques to examine the osteoporotic effects of verbascoside on zebrafish and MC3T3-E1 cells. Additionally, this study aimed to investigate the molecular mechanism by which verbascoside improves osteoporosis by mitigating oxidative stress. To identify the common targets of verbascoside in relation to oxidative stress and osteoporosis, network pharmacology and molecular dynamics simulation were employed. The construction of the verbascoside - oxidative stress - osteoporosis - potential target gene network aimed to identify the core targets, while the mechanism of action was elucidated through KEGG analysis, and the accuracy was confirmed by assessing the mRNA expression of the targets. RESULTS: In vivo experiments demonstrated that verbascoside exhibited therapeutic effects on osteoporosis and reduced ROS production in zebrafish. In vitro experiments further revealed that verbascoside enhanced the proliferation and differentiation of MC3T3-E1 cells, thereby improving the oxidative stress status of osteoblasts. Thirteen core targets and estrogen signaling pathways were identified through the application of network pharmacology. The pivotal role of the estrogen signaling pathway in facilitating the ability of verbascoside to mitigate oxidative stressinduced osteoporosis was substantiated by the modulation of target protein mRNA expression. CONCLUSION: The findings underscore the considerable therapeutic potential of verbascoside in ameliorating osteoporosis through the alleviation of oxidative stress, thus establishing it as a promising compound for the treatment of this condition.
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In this work, a proton-conductive inorganic filler based on polyoxovanadate (NH4)7[MnV13O38] (AMV) and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide (EMIM TFSI) was synthesized for hybridization with sulfonated poly(aryl ether ketone sulfone) (SPAEKS) to address the "trade-off" between high proton conductivity and mechanical strength. The novel inorganic filler AMV-EMIM TFSI (AI) was uniformly dispersed and stable within the polymer matrix due to the enhanced ionic interaction. AI provided additional proton transport sites, leading to an elevated ion exchange capacity (IEC) and improved proton conductivity, even at low swelling ratios. The optimized SPAEKS-50/AI-5 (50 for degree of sulfonation of SPAEKS and 5 for weight percentage of AI filler) membrane exhibited the highest proton conductivity of 0.188 S·cm-1 at 80 °C with an IEC of 2.38 mmol·g-1. The enhancement of intermolecular forces improved the mechanical strength from 35 to 55 MPa and improved the elongation at break from 17 to 45%, indicating excellent mechanical properties. The hybrid membrane also demonstrated reinforced methanol resistance due to the hydrogen bonding network and blocking effect, making it suitable for direct methanol fuel cell (DMFC) applications, which exhibited a power density of 15.1 mW·cm-2 at 80 °C. The possibility of further functionalizing these hybrid membranes to tailor their properties for specific applications presents exciting new avenues for research and development. By modification of the type and distribution of fillers or incorporation of additional functional groups, the membranes could be customized to meet the unique demands of various energy storage and conversion systems, enhancing their performance and broadening their application scope. This work provides new insights into the design of polymer electrolyte membranes through inorganic filler hybridization.
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Purpose: As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer. Patients and Methods: This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored. Conclusion: As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders.
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Endometrial cancer (EC) is one of the predominant tumors of the female reproductive system. In this current study, we investigated the functions and related mechanisms of NAP1L1/DDX5 in EC. This retrospective study analyzed the medical records of EC patients, collected tissue samples for NAP1L1 and DDX5 staining, and conducted survival analysis using the Kaplan-Meier method. To evaluate the impact of NAP1L1 and/or DDX5 on cellular processes in EC cells, several techniques were employed. These included CCK-8 assay, wound healing assay, Transwell assay, as well as overexpression or knockdown of target gene expression. Additionally, ChIP, dual luciferase reporter gene, Co-IP assay were utilized to confirm the interaction between NAP1L1, EP300 and DDX5. Furthermore, qRT-PCR, western blot and Co-IP assay were performed to analyze the modulation of NAP1L1/DDX5 in Wnt/ß-catenin. NAP1L1 and DDX5 expression were upregulated in EC tissues, and correlated with poor prognosis. NAP1L1/DDX5 promoted EC cell proliferation, migration and invasion. NAP1L1 promotes acetylation and transcription by recruiting EP300 to the DDX5 promoter. DDX5 could activate Wnt/ß-catenin signal by binding to ß-catenin. In animal models, knockdown of NAP1L1 inhibits EC tumor growth and lung metastasis. To sum up, our study demonstrated that NAP1L1 promoted the malignant phenotypes of EC cells via recruiting EP300 to promote DDX5 acetylation, thus activating the Wnt/ß-catenin signaling pathway. Implications: Our research findings indicate that targeting the NAP1L1/EP300/DX5 axis might be a new potential treatment option for endometrial cancer.
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BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. METHODS AND DESIGN: The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. CONCLUSIONS: As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT05311072.
Subject(s)
Angioplasty, Balloon , Endarterectomy , Hypertension, Pulmonary , Pulmonary Embolism , Humans , Hypertension, Pulmonary/therapy , China , Pulmonary Embolism/complications , Pulmonary Embolism/therapy , Chronic Disease , Quality of Life , Treatment Outcome , Female , Combined Modality Therapy , Male , East Asian PeopleABSTRACT
BACKGROUND: Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. METHODS: Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. RESULTS: Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. CONCLUSIONS: Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.
Subject(s)
Chemokine CCL5 , Familial Primary Pulmonary Hypertension , Killer Cells, Natural , RNA-Seq , Single-Cell Analysis , T-Lymphocytes , Animals , Humans , Chemokine CCL5/metabolism , Chemokine CCL5/genetics , Killer Cells, Natural/metabolism , Killer Cells, Natural/immunology , Familial Primary Pulmonary Hypertension/genetics , Familial Primary Pulmonary Hypertension/pathology , Familial Primary Pulmonary Hypertension/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/immunology , Male , Cell Communication/genetics , Rats, Sprague-Dawley , Lung/pathology , Rats , Gene Regulatory Networks , Monocrotaline , Protein Interaction Maps/genetics , Computational BiologyABSTRACT
Long non-coding RNAs (lncRNAs) have emerged as influential contributors to diverse cellular processes, which regulate gene function and expression via multiple mechanistic pathways. Therefore, it is essential to exploit the structures and interactions of lncRNAs to comprehend their mechanistic functions within cells. A growing body of evidence has revealed that deregulated lncRNAs are involved in multiple regulations of malignant events including cell proliferation, growth, invasion, and metabolism. SRY-related high mobility group box (SOX)2, a well-recognized member of the SOX family, is commonly overexpressed in various types of cancer, contributing to tumor progression and maintenance of stemness. Emerging studies have shown that lncRNAs interact with SOX2 to remarkably contribute to carcinogenesis and disease states. This review elaborates on the crosstalk between the intricate and complicated functions of lncRNAs and SOX2 in the context of malignant diseases. We elucidate distinct molecular mechanisms that contribute to the onset/advancement of cancer, indicating that lncRNAs/SOX2 axes hold immense promise for potential therapeutic targets. Furthermore, we delve into the modalities of emerging feasible treatment options for targeting lncRNAs, highlighting the limitations of such therapies and providing novel insights into further ameliorations of targeted strategies of lncRNAs to promote the clinical implications. Translating current discoveries into clinical applications could ultimately boost improved survival and prognosis of cancer patients.
Subject(s)
Neoplasms , RNA, Long Noncoding , SOXB1 Transcription Factors , Humans , Biomarkers, Tumor/genetics , Carcinogenesis , Gene Expression Regulation, Neoplastic , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolismABSTRACT
Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p < 0.05). The CTEPH patients treated by balloon pulmonary angioplasty had significantly lower HPSE levels. The study demonstrates that HPSE may be a promising biomarker for noninvasive detection of CTEPH.
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Patients with venous thromboembolism (VTE) comorbid renal insufficiency (RI) are at higher risk of bleeding and thrombosis. Recommendations in guidelines on anticoagulation therapy for those patients remain ambiguous. The goal of this study is to compare the efficacy and safety between different anticoagulant regimens in VTE patients comorbid RI at different stages of treatment and prophylaxis. We performed English-language searches of Pubmed, EMBASE, and Web of Science (inception to Nov 2022). RCTs evaluated anticoagulants for VTE treatment at the acute phase, extension phase, and prophylaxis in patients with RI and reported efficacy and safety outcomes were selected. The methodological quality of the studies was assessed at the outcome level using the risk-of-bias assessment tool developed by the Cochrane Bias Methods Group. A meta-analysis of twenty-five RCTs was conducted, comprising data from twenty-three articles, encompassing a total of 9,680 participants with RI. In the acute phase, the risk of bleeding was increased with novel oral anticoagulants (NOACs) compared to LMWH (RR 1.29, 95% CI 1.04-1.60). For the prophylaxis of VTE, NOACs were associated with an elevated risk of bleeding compared with placebo (RR 1.31, 95%CI 1.02-1.68). In comparison to non-RI patients, both NOACs and vitamin K antagonists (VKA) could increase the risk of bleeding among RI patients (RR 1.45, 95%CI 1.14-1.84 and RR 1.53, 95%CI 1.25-1.88, respectively) during acute phase, while NOACs may increase the incidence of VTE in RI population (RR 1.74, 95%CI 1.29-2.34). RI patients who are under routine anticoagulation have a significantly higher risk of adverse outcomes. LMWH is the most effective and safe option for VTE treatment or prophylaxis in patients with RI.
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Balloon pulmonary angioplasty (BPA) has been proven effective for addressing technically inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the effectiveness of BPA in technically operable CTEPH patients who, for various reasons, did not undergo the procedure remains an area requiring exploration. This study sought to assess the safety and efficacy of BPA in such cases. We collected and reviewed data from CTEPH patients who underwent BPA in a consecutive manner. Following multidisciplinary team (MDT) decisions, patients were classified into two groups: technically inoperable (group A) and operable (group B). Group B comprised patients deemed technically suitable for pulmonary endarterectomy (PEA) but who did not undergo the procedure for various reasons. All patients underwent a comprehensive diagnostic work-up, including right heart categorization at baseline and the last intervention. This study compared changes in hemodynamic parameters, functional capacity, and quality of life between the two groups. In total, 161 patients underwent 414 procedures at our center, with Group A comprising 112 patients who underwent 282 BPA sessions and group B comprising 49 patients who underwent 132 BPA sessions. Significantly, both groups exhibited improvements in hemodynamics, functional capacity, and quality of life. The occurrence rate of complications, including hemoptysis and lung injury, was similar [12 (63.2%) vs. 7 (36.8%), p = 0.68]. BPA demonstrated favorable outcomes in patients with proximal CTEPH who did not undergo pulmonary endarterectomy. However, the clinical impact of BPA in technically operable CTEPH was found to be less significant than in inoperable cases.
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Anyons, exotic quasiparticles in two-dimensional space exhibiting nontrivial exchange statistics, play a crucial role in universal topological quantum computing. One notable proposal to manifest the fractional statistics of anyons is the toric code model; however, scaling up its size through quantum simulation poses a serious challenge because of its highly entangled ground state. In this Letter, we demonstrate that a modular superconducting quantum processor enables hardware-pragmatic implementation of the toric code model. Through in-parallel control across separate modules, we generate a 10-qubit toric code ground state in four steps and realize six distinct braiding paths to benchmark the performance of anyonic statistics. The path independence of the anyonic braiding statistics is verified by correlation measurements in an efficient and scalable fashion. Our modular approach, serving as a hardware embodiment of the toric code model, offers a promising avenue toward scalable simulation of topological phases, paving the way for quantum simulation in a distributed fashion.
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BACKGROUND: Multiple studies have highlighted a potential link between gut microbes and the onset of Pulmonary Arterial Hypertension (PAH). Nonetheless, the precise cause-and-effect relationship remains uncertain. OBJECTIVES: In this investigation, we utilized a two-sample Mendelian randomization (TSMR) approach to probe the presence of a causal connection between gut microbiota and PAH. METHODS: Genome-wide association (GWAS) data for gut microbiota and PAH were sourced from MiBioGen and FinnGen research, respectively. Inverse variance weighting (IVW) was used as the primary method to explore the causal effect between gut flora and PAH, supplemented by MR-Egger, weighted median (WM). Sensitivity analyses examined the robustness of the MR results. Reverse MR analysis was used to rule out the effect of reverse causality on the results. RESULTS: The results indicate that Genus Ruminococcaceae UCG004 (OR = 0.407, P = 0.031) and Family Alcaligenaceae (OR = 0.244, P = 0.014) were protective factors for PAH. Meanwhile Genus Lactobacillus (OR = 2.446, P = 0.013), Class Melainabacteria (OR = 2.061, P = 0.034), Phylum Actinobacteria (OR = 3.406, P = 0.010), Genus Victivallis (OR = 1.980, P = 0.010), Genus Dorea (OR = 3.834, P = 0.024) and Genus Slackia (OR = 2.622, P = 0.039) were associated with an increased Prevalence of PAH. Heterogeneity and pleiotropy were not detected by sensitivity analyses, while there was no reverse causality for these nine specific gut microorganisms. CONCLUSIONS: This study explores the causal effects of eight gut microbial taxa on PAH and provides new ideas for early prevention of PAH.
Subject(s)
Gastrointestinal Microbiome , Pulmonary Arterial Hypertension , Humans , Pulmonary Arterial Hypertension/epidemiology , Pulmonary Arterial Hypertension/genetics , Gastrointestinal Microbiome/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Familial Primary Pulmonary HypertensionABSTRACT
The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL. SIGNIFICANCE: Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient.
Subject(s)
Hodgkin Disease , Humans , Hodgkin Disease/genetics , Reed-Sternberg Cells/metabolism , Mutation/genetics , High-Throughput Nucleotide Sequencing , RNA, Small Nuclear/metabolismABSTRACT
Hematopoietic stem cells (HSCs) sustain hematopoiesis during homeostasis and regeneration. However, their limited availability poses a challenge for protein analysis. Here, we present a protocol for performing high-sensitivity western blot on HSCs using two techniques that enhance HSC isolation from mice and boost sensitivity for low cell numbers. We describe steps for isolating murine bone marrow cells, antibody staining, and cell sorting and post-sort analysis. We then detail a western blot procedure suitable for low numbers of HSCs. For complete details on the use and execution of this protocol, please refer to Li et al (2022).1,2.
Subject(s)
Hematopoiesis , Hematopoietic Stem Cells , Animals , Mice , Hematopoietic Stem Cells/metabolism , Cell Separation , Bone Marrow Cells , Blotting, WesternABSTRACT
Topological quantum computation (TQC) is one of the most striking architectures that can realize fault-tolerant quantum computers. In TQC, the logical space and the quantum gates are topologically protected, i.e., robust against local disturbances. The topological protection, however, requires complicated lattice models and hard-to-manipulate dynamics; even the simplest system that can realize universal TQC-the Fibonacci anyon system-lacks a physical realization, let alone braiding the non-Abelian anyons. Here, we propose a disk model that can simulate the Fibonacci anyon system and construct the topologically protected logical spaces with the Fibonacci anyons. Via braiding the Fibonacci anyons, we can implement universal quantum gates on the logical space. Our disk model merely requires two physical qubits to realize three Fibonacci anyons at the boundary. By 15 sequential braiding operations, we construct a topologically protected Hadamard gate, which is to date the least-resource requirement for TQC. To showcase, we implement a topological Hadamard gate with two nuclear spin qubits, which reaches 97.18% fidelity by randomized benchmarking. We further prove by experiment that the logical space and Hadamard gate are topologically protected: local disturbances due to thermal fluctuations result in a global phase only. As a platform-independent proposal, our work is a proof of principle of TQC and paves the way toward fault-tolerant quantum computation.
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Background: With the continuous development of machine vision and imaging technology and its application in computer-aided diagnosis, it is clinically important to use computer technology to assist physicians in accurate cataract surgery. The capsulorhexis directly affects the outcome of cataract surgery, therefore, we design a method to automatically determine the virtual boundary of capsulorhexis for cataract surgery planning and tracking in-vivo to help surgeons achieve a more ideal capsulotomy geometry. Methods: In this study, an effective method was proposed to detect and display the location of capsulorhexis in cataract videos in-vivo. The initial step was locating the entire eye area by analyzing the connected components of the mirror reflective points in the image in the cataract surgery video. Then, an operator was designed for ridge edge variation and used to extract pupil edge features. Lastly, circular Hough transform was used to detect the pupillary margin and calculate the boundary between the scleral limbus and the virtual capsulorhexis border in accordance with the pupillary margin and finally displayed it in-vivo during cataract surgery. Results: The method was tested on eight videos of cataract surgery and the results showed that 98.52% accuracy was achieved in the localization of the specular reflection point. We compared the proposed operator with the Sobel, Scharr, Laplace and Canny operators and the results showed that our operator achieved the smallest mean square error with the greatest structural similarity. Conclusions: The analysis demonstrated that the proposed operator outperformed other operators in detection and achieved satisfactory results in the videos of actual cataract surgeries.
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P2ry12 is a microglial marker gene. Recently, increasing evidence has demonstrated that its expression levels can vary in response to different CNS disorders and can affect microglial functions, such as polarization, plasticity, and migration. However, the expression and function of P2ry12 in microglia during ischemia-reperfusion injury (IRI) remain unclear. Here, we developed a computational method to obtain microglia-specific P2ry12 genes (MSPGs) using sequencing data associated with IRI. We evaluated the change in comprehensive expression levels of MSPGs during IRI and compared it to the expression of P2ry12 to determine similarity. Subsequently, the MSPGs were used to explore the P2ry12 functions in microglia through bioinformatics. Moreover, several animal experiments were also conducted to confirm the reliability of the results. The expression of P2ry12 was observed to decrease gradually within 24 h post injury. In response, microglia with reduced P2ry12 expression showed an increase in the expression of one receptor-encoding gene (Flt1) and three ligand-encoding genes (Nampt, Igf1, and Cxcl2). Furthermore, double-labeling immunofluorescence staining revealed that inhibition of P2ry12 blocked microglial migration towards vessels during IRI. Overall, we employ a combined computational and experimental approach to successfully explore P2ry12 expression and function in microglia during IRI.
Subject(s)
Microglia , Reperfusion Injury , Animals , Microglia/metabolism , Reproducibility of Results , Reperfusion Injury/genetics , Reperfusion Injury/metabolismABSTRACT
BACKGROUND AND AIM: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor with high prevalence of KIT and PDGFRA mutations. Few effective treatments can be exploited in imatinib or sunitinib resistant cases. While in immunotherapy, application of the highly individualized cancer neoantigen vaccines is hampered due to high economic and time cost. In this study we identified the most frequent mutation in Chinese GIST patients and predicted candidate neopeptide by next generation sequencing (NGS). METHODS: Tumor tissues and matched blood samples of 116 Chinese GIST patients were collected. Genomic profile was detected through NGS, and 450 cancer genes were deeply sequenced. KIT mutations were identified, and long peptides containing the mutation were queried in NetMHCpan 4.0 tools to predict MHC class I binding of mutant peptides. RESULTS: The most frequent mutated genes in detected GIST patients were KIT (81.9%, 95/116), CDKN2A (18.97%, 22/116), and CDKN2B (15.52%, 18/116) in this cohort. The most common mutation of KIT was A502_Y503 duplication (15.93%, 18/113) in exon 9. Among the 116 cases, 103 were HLA I genotyped, and 101 were HLA II genotyped. In total, 16 samples with the mutation of KIT p.A502_Y503dup were identified to produce neoantigens with qualified HLA affinity. CONCLUSIONS: KIT hotspot mutation (p.A502_Y503dup) has the highest incidence, which may further eliminate the need for whole genome sequencing and patient-specific neoantigen prediction and synthesis. Therefore, for those carrying such mutation, accounting for around 16% of Chinese GIST patients and are usually less sensitive to imatinib, effective immunotherapies are in prospect.
Subject(s)
Antineoplastic Agents , Gastrointestinal Stromal Tumors , Humans , Antineoplastic Agents/therapeutic use , East Asian People , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Imatinib Mesylate/therapeutic use , Mutation , Proto-Oncogene Proteins c-kit/genetics , Sunitinib/therapeutic use , Cyclin-Dependent Kinase Inhibitor p15/geneticsABSTRACT
Owing to unique physiochemical and biological properties as well as the ability to be combined with a wide variety of materials for both biocompatibility and hydrophilia, carboxymethyl cellulose (CMC) is an excellent choice as a carrier. Loading Chlorine dioxide (ClO2) into biodegradable carrier for its good disinfection performance and high safety factors has attracted significantattention. Therefore, in this study, we used ClO2 as a model drug, and a sustained-ClO2-gas-release gel was developed from degradable materials, such as carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), and ß-cyclodextrin (ßCD), through a simple and benign crosslinking strategy. Notably, the gel had sustained-release property in a wide temperature range of 4-35 â and released ClO2 gas effectively for more than 30 days. Furthermore, a loss factor was proposed based on the incomplete release of the drug in the sustained release process to a chieve a good fit with the gas diffusion process. A new diffusion model was designed based on the Korsmeyer-Peppas model, and an excellent fit was obtained. This sustained-ClO2-gas-release gel provides theoretical and technical guidance for the development of sustained-disinfectant-release agents for use in space and offers new insights into the sustained release model of skeleton-soluble hydrogels. Supplementary Information: The online version contains supplementary material available at 10.1007/s10570-023-05070-6.
ABSTRACT
Chimeric antigen receptor (CAR)-T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR-T cells become out of artificial control, and fierce response to CAR-T therapy may cause severe adverse events, represented by cytokine-release syndrome and on-target/off-tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise "on-tumor only" activation of CAR-T cells. Here, original gelatinase-responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The "NanoSwitch" is tumor-specific, thus inactivated switchable CAR-T cells do little harm to normal cells, even if the normal cells express the target of CAR-T. Owing to the sustained-release effect of NPs, the CAR-T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR-T therapy regardless of the target.