RESUMO
Dysfunctional CD8+ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8+ T cell antitumor function. Susd2-/- effector CD8+ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we found that SUSD2 interacted with interleukin (IL)-2 receptor α through sushi domain-dependent protein interactions and that this interaction suppressed the binding of IL-2, an essential cytokine for the effector functions of CD8+ T cells, to IL-2 receptor α. SUSD2 was not expressed on regulatory CD4+ T cells and did not affect the inhibitory function of these cells. Adoptive transfer of Susd2-/- chimeric antigen receptor T cells induced a robust antitumor response in mice, highlighting the potential of SUSD2 as an immunotherapy target for cancer.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Animais , Camundongos , Linhagem Celular Tumoral , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Receptores de Interleucina-2/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Deciphering the intricate relationships between transcription factors (TFs), enhancers, and genes through the inference of enhancer-driven gene regulatory networks (eGRNs) is crucial in understanding gene regulatory programs in a complex biological system. This study introduces STREAM, a novel method that leverages a Steiner forest problem model, a hybrid biclustering pipeline, and submodular optimization to infer eGRNs from jointly profiled single-cell transcriptome and chromatin accessibility data. Compared to existing methods, STREAM demonstrates enhanced performance in terms of TF recovery, TF-enhancer linkage prediction, and enhancer-gene relation discovery. Application of STREAM to an Alzheimer's disease dataset and a diffuse small lymphocytic lymphoma dataset reveals its ability to identify TF-enhancer-gene relations associated with pseudotime, as well as key TF-enhancer-gene relations and TF cooperation underlying tumor cells.
Assuntos
Elementos Facilitadores Genéticos , Redes Reguladoras de Genes , RNA-Seq , Análise de Célula Única , Análise de Célula Única/métodos , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Sequenciamento de Cromatina por Imunoprecipitação , Algoritmos , Biologia Computacional/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Análise da Expressão Gênica de Célula ÚnicaRESUMO
Sequence motif discovery algorithms enhance the identification of novel deoxyribonucleic acid sequences with pivotal biological significance, especially transcription factor (TF)-binding motifs. The advent of assay for transposase-accessible chromatin using sequencing (ATAC-seq) has broadened the toolkit for motif characterization. Nonetheless, prevailing computational approaches have focused on delineating TF-binding footprints, with motif discovery receiving less attention. Herein, we present Cis rEgulatory Motif Influence using de Bruijn Graph (CEMIG), an algorithm leveraging de Bruijn and Hamming distance graph paradigms to predict and map motif sites. Assessment on 129 ATAC-seq datasets from the Cistrome Data Browser demonstrates CEMIG's exceptional performance, surpassing three established methodologies on four evaluative metrics. CEMIG accurately identifies both cell-type-specific and common TF motifs within GM12878 and K562 cell lines, demonstrating its comparative genomic capabilities in the identification of evolutionary conservation and cell-type specificity. In-depth transcriptional and functional genomic studies have validated the functional relevance of CEMIG-identified motifs across various cell types. CEMIG is available at https://github.com/OSU-BMBL/CEMIG, developed in C++ to ensure cross-platform compatibility with Linux, macOS and Windows operating systems.
Assuntos
Algoritmos , Sequenciamento de Cromatina por Imunoprecipitação , Benchmarking , Evolução Biológica , Linhagem CelularRESUMO
Automated guard cell detection and measurement are vital for understanding plant physiological performance and ecological functioning in global water and carbon cycles. Most current methods for measuring guard cells and stomata are laborious, time-consuming, prone to bias, and limited in scale. We developed StoManager1, a high-throughput tool utilizing geometrical, mathematical algorithms, and convolutional neural networks to automatically detect, count, and measure over 30 guard cell and stomatal metrics, including guard cell and stomatal area, length, width, stomatal aperture area/guard cell area, orientation, stomatal evenness, divergence, and aggregation index. Combined with leaf functional traits, some of these StoManager1-measured guard cell and stomatal metrics explained 90% and 82% of tree biomass and intrinsic water use efficiency (iWUE) variances in hardwoods, making them substantial factors in leaf physiology and tree growth. StoManager1 demonstrated exceptional precision and recall (mAP@0.5 over 0.96), effectively capturing diverse stomatal properties across over 100 species. StoManager1 facilitates the automation of measuring leaf stomatal and guard cells, enabling broader exploration of stomatal control in plant growth and adaptation to environmental stress and climate change. This has implications for global gross primary productivity (GPP) modeling and estimation, as integrating stomatal metrics can enhance predictions of plant growth and resource usage worldwide. Easily accessible open-source code and standalone Windows executable applications are available on a GitHub repository (https://github.com/JiaxinWang123/StoManager1) and Zenodo (https://doi.org/10.5281/zenodo.7686022).
Assuntos
Botânica , Biologia Celular , Células Vegetais , Estômatos de Plantas , Software , Estômatos de Plantas/citologia , Estômatos de Plantas/crescimento & desenvolvimento , Células Vegetais/fisiologia , Botânica/instrumentação , Botânica/métodos , Biologia Celular/instrumentação , Processamento de Imagem Assistida por Computador/normas , Algoritmos , Folhas de Planta/citologia , Redes Neurais de Computação , Ensaios de Triagem em Larga Escala/instrumentação , Ensaios de Triagem em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/normas , Software/normasRESUMO
Chronic inflammation and dysregulated repair mechanisms after epithelial damage have been implicated in chronic obstructive pulmonary disease (COPD). However, the lack of ex vivo-models that accurately reflect multicellular lung tissue hinders our understanding of epithelial-mesenchymal interactions in COPD. Through a combination of transcriptomic and proteomic approaches applied to a sophisticated in vitro iPSC-alveolosphere with fibroblasts model, epithelial-mesenchymal crosstalk was explored in COPD and following SARS-CoV-2 infection. These experiments profiled dynamic changes at single-cell level of the SARS-CoV-2-infected alveolar niche that unveiled the complexity of aberrant inflammatory responses, mitochondrial dysfunction, and cell death in COPD, which provides deeper insights into the accentuated tissue damage/inflammation/remodeling observed in patients with SARS-CoV-2 infection. Importantly, this 3D system allowed for the evaluation of ACE2-neutralizing antibodies and confirmed the potency of this therapy to prevent SARS-CoV-2 infection in the alveolar niche. Thus, iPSC-alveolosphere cultured with fibroblasts provides a promising model to investigate disease-specific mechanisms and to develop novel therapeutics.
Assuntos
COVID-19 , Células-Tronco Pluripotentes Induzidas , Doença Pulmonar Obstrutiva Crônica , Humanos , SARS-CoV-2 , Proteômica , Imunoterapia , InflamaçãoRESUMO
BACKGROUND: NOTCH1 pathogenic variants are implicated in multiple types of congenital heart defects including hypoplastic left heart syndrome, where the left ventricle is underdeveloped. It is unknown how NOTCH1 regulates human cardiac cell lineage determination and cardiomyocyte proliferation. In addition, mechanisms by which NOTCH1 pathogenic variants lead to ventricular hypoplasia in hypoplastic left heart syndrome remain elusive. METHODS: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 genome editing was utilized to delete NOTCH1 in human induced pluripotent stem cells. Cardiac differentiation was carried out by sequential modulation of WNT signaling, and NOTCH1 knockout and wild-type differentiating cells were collected at day 0, 2, 5, 10, 14, and 30 for single-cell RNA-seq. RESULTS: Human NOTCH1 knockout induced pluripotent stem cells are able to generate functional cardiomyocytes and endothelial cells, suggesting that NOTCH1 is not required for mesoderm differentiation and cardiovascular development in vitro. However, disruption of NOTCH1 blocks human ventricular-like cardiomyocyte differentiation but promotes atrial-like cardiomyocyte generation through shortening the action potential duration. NOTCH1 deficiency leads to defective proliferation of early human cardiomyocytes, and transcriptomic analysis indicates that pathways involved in cell cycle progression and mitosis are downregulated in NOTCH1 knockout cardiomyocytes. Single-cell transcriptomic analysis reveals abnormal cell lineage determination of cardiac mesoderm, which is manifested by the biased differentiation toward epicardial and second heart field progenitors at the expense of first heart field progenitors in NOTCH1 knockout cell populations. CONCLUSIONS: NOTCH1 is essential for human ventricular-like cardiomyocyte differentiation and proliferation through balancing cell fate determination of cardiac mesoderm and modulating cell cycle progression. Because first heart field progenitors primarily contribute to the left ventricle, we speculate that pathogenic NOTCH1 variants lead to biased differentiation of first heart field progenitors, blocked ventricular-like cardiomyocyte differentiation, and defective cardiomyocyte proliferation, which collaboratively contribute to left ventricular hypoplasia in hypoplastic left heart syndrome.
Assuntos
Síndrome do Coração Esquerdo Hipoplásico , Células-Tronco Pluripotentes Induzidas , Humanos , Células Endoteliais/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Diferenciação Celular/fisiologia , Miócitos Cardíacos/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMO
The unprecedented silylene-supported dibenzodiboraoxepin 2 and 9,10-diboraphenanthrene complexes 6 and 8 were synthesized. The (NHSi)2B2(xanthene) [NHSi = PhC(NtBu)2(Me2N)Si:] 2 results from debromination of the bis(NHSi)-stabilized bis(dibromoboryl)xanthene 1 with potassium graphite (KC8); 2 is capable of activating white phosphorus and ammonia to form the B2P4 cage compound 3 and H2N-B-B-H diborane species 4, respectively. The thermal rearrangement of 2 affords the 9,10-dihydro-9,10-diboraphenanthrene 5 through a bis(NHSi)-assisted intramolecular reductive C-O-C deoxygenation process. Notably, the 9,10-diboraphenanthrene derivatives 6 and 8 could be generated by deoxygenation of 2 with KC8 and 1,3,4,5-tetramethylimidazol-2-ylidene, respectively. The aromaticity of 6 and 8 was confirmed by computational studies. Strikingly, the NHSi ligand in 8 engenders the monodeoxygenation of carbon dioxide in toluene at room temperature to form the CO-stabilized 9,10-diboraphenanthrene derivative 9 via the silaoxadiborinanone intermediate 10.
RESUMO
OBJECTIVE: Ketogenic diets (KD) have been shown to alleviate insulin resistance (IR) by exerting anti-lipogenic and insulin sensitizing effects in the liver through a variety of pathways. The present study sought to investigate whether a ketogenic diet also improves insulin sensitization in skeletal muscle cells through alleviating endoplasmic reticulum stress. METHODS: High-fat diet-induced IR mice were allowed to a 2-week ketogenic diet. Insulin resistance and glucose tolerance were evaluated through GTT, ITT, and HOMA-IR. The C2C12 myoblasts exposed to palmitic acid were used to evaluate the insulin sensitization effects of ß-hydroxybutyric acid (ß-OHB). Molecular mechanisms concerning ER stress signaling activation and glucose uptake were assessed. RESULTS: The AKT/GSK3ß pathway was inhibited, ER stress signaling associated with IRE1, PERK, and BIP was activated, and the number of Glut4 proteins translocated to membrane decreased in the muscle of HFD mice. However, all these changes were reversed after 2 weeks of feeding on a ketogenic diet. Consistently in C2C12 myoblasts, the AKT/GSK3ß pathway was inhibited by palmitic acid (PA) treatment. The endoplasmic reticulum stress-related proteins, IRE1, and BIP were increased, and the number of Glut4 proteins on the cell membrane decreased. However, ß-OHB treatment alleviated ER stress and improved the glucose uptake of C2C12 cells. CONCLUSION: Our data reveal that KD ameliorated HFD-induced insulin resistance in skeletal muscle, which was partially mediated by inhibiting endoplasmic reticulum stress. The insulin sensitization effect of ß-OHB is associated with up regulation of AKT/GSK3ß pathway and the increase in the number of Glut4 proteins on the cell membrane.
Assuntos
Dieta Cetogênica , Resistência à Insulina , Camundongos , Animais , Resistência à Insulina/fisiologia , Dieta Hiperlipídica/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácido Palmítico/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Estresse do Retículo Endoplasmático , Insulina/metabolismo , Músculo Esquelético/metabolismo , Glucose/metabolismo , Camundongos Endogâmicos C57BLRESUMO
INTRODUCTION: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. MATERIALS AND METHODS: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. CONCLUSION: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.
Assuntos
Inibidores de Checkpoint Imunológico , Imunoterapia , Animais , Camundongos , Carcinogênese , Ácidos Graxos , Macrófagos , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
The metabolic heterogeneity and metabolic interplay between cells are known as significant contributors to disease treatment resistance. However, with the lack of a mature high-throughput single-cell metabolomics technology, we are yet to establish systematic understanding of the intra-tissue metabolic heterogeneity and cooperative mechanisms. To mitigate this knowledge gap, we developed a novel computational method, namely, single-cell flux estimation analysis (scFEA), to infer the cell-wise fluxome from single-cell RNA-sequencing (scRNA-seq) data. scFEA is empowered by a systematically reconstructed human metabolic map as a factor graph, a novel probabilistic model to leverage the flux balance constraints on scRNA-seq data, and a novel graph neural network-based optimization solver. The intricate information cascade from transcriptome to metabolome was captured using multilayer neural networks to capitulate the nonlinear dependency between enzymatic gene expressions and reaction rates. We experimentally validated scFEA by generating an scRNA-seq data set with matched metabolomics data on cells of perturbed oxygen and genetic conditions. Application of scFEA on this data set showed the consistency between predicted flux and the observed variation of metabolite abundance in the matched metabolomics data. We also applied scFEA on five publicly available scRNA-seq and spatial transcriptomics data sets and identified context- and cell group-specific metabolic variations. The cell-wise fluxome predicted by scFEA empowers a series of downstream analyses including identification of metabolic modules or cell groups that share common metabolic variations, sensitivity evaluation of enzymes with regards to their impact on the whole metabolic flux, and inference of cell-tissue and cell-cell metabolic communications.
Assuntos
Análise de Célula Única , Transcriptoma , Perfilação da Expressão Gênica/métodos , Redes Neurais de Computação , RNA-Seq , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Sequenciamento do ExomaRESUMO
BACKGROUND: AP2/ERF is a large family of plant transcription factor proteins that play essential roles in signal transduction, plant growth and development, and responses to various stresses. The AP2/ERF family has been identified and verified by functional analysis in various plants, but so far there has been no comprehensive study of these factors in Chinese prickly ash. Phylogenetic, motif, and functional analyses combined with transcriptome analysis of Chinese prickly ash fruits at different developmental stages (30, 60, and 90 days after anthesis) were conducted in this study. RESULTS: The analysis identified 146 ZbAP2/ERF genes that could be classified into 15 subgroups. The motif analysis revealed the presence of different motifs or elements in each group that may explain the functional differences between the groups. ZbERF13.2, ZbRAP2-12, and ZbERF2.1 showed high levels of expression in the early stages of fruit development. ZbRAP2-4, and ZbERF3.1 were significantly expressed at the fruit coloring stage (R2 and G2). ZbERF16 were significantly expressed at fruit ripening and expression level increased as the fruit continued to develop. Relative gene expression levels of 6 representative ZbAP2/ERFs assessed by RT-qPCR agreed with transcriptome analysis results. CONCLUSIONS: These genes identified by screening can be used as candidate genes that affect fruit development. The results of the analysis can help guide future genetic improvement of Chinese prickly ash and enrich our understanding of AP2/ERF transcription factors and their regulatory functions in plants.
Assuntos
Frutas , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Plantas , Fatores de Transcrição , Frutas/genética , Frutas/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Perfilação da Expressão Gênica , Genoma de Planta , Genes de Plantas , População do Leste AsiáticoRESUMO
Identifying cis-regulatory motifs from genomic sequencing data (e.g. ChIP-seq and CLIP-seq) is crucial in identifying transcription factor (TF) binding sites and inferring gene regulatory mechanisms for any organism. Since 2015, deep learning (DL) methods have been widely applied to identify TF binding sites and predict motif patterns, with the strengths of offering a scalable, flexible and unified computational approach for highly accurate predictions. As far as we know, 20 DL methods have been developed. However, without a clear and systematic assessment, users will struggle to choose the most appropriate tool for their specific studies. In this manuscript, we evaluated 20 DL methods for cis-regulatory motif prediction using 690 ENCODE ChIP-seq, 126 cancer ChIP-seq and 55 RNA CLIP-seq data. Four metrics were investigated, including the accuracy of motif finding, the performance of DNA/RNA sequence classification, algorithm scalability and tool usability. The assessment results demonstrated the high complementarity of the existing DL methods. It was determined that the most suitable model should primarily depend on the data size and type and the method's outputs.
Assuntos
Aprendizado Profundo , Algoritmos , Sequência de Bases , Sítios de Ligação/genética , Imunoprecipitação da Cromatina , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
MOTIVATION: Identifying the functional sites of a protein, such as the binding sites of proteins, peptides, or other biological components, is crucial for understanding related biological processes and drug design. However, existing sequence-based methods have limited predictive accuracy, as they only consider sequence-adjacent contextual features and lack structural information. RESULTS: In this study, DeepProSite is presented as a new framework for identifying protein binding site that utilizes protein structure and sequence information. DeepProSite first generates protein structures from ESMFold and sequence representations from pretrained language models. It then uses Graph Transformer and formulates binding site predictions as graph node classifications. In predicting protein-protein/peptide binding sites, DeepProSite outperforms state-of-the-art sequence- and structure-based methods on most metrics. Moreover, DeepProSite maintains its performance when predicting unbound structures, in contrast to competing structure-based prediction methods. DeepProSite is also extended to the prediction of binding sites for nucleic acids and other ligands, verifying its generalization capability. Finally, an online server for predicting multiple types of residue is established as the implementation of the proposed DeepProSite. AVAILABILITY AND IMPLEMENTATION: The datasets and source codes can be accessed at https://github.com/WeiLab-Biology/DeepProSite. The proposed DeepProSite can be accessed at https://inner.wei-group.net/DeepProSite/.
Assuntos
Peptídeos , Proteínas , Ligação Proteica , Proteínas/química , Sítios de Ligação , SoftwareRESUMO
Single-cell RNA sequencing (scRNA-seq) data has been widely used for cell trajectory inference, with the assumption that cells with similar expression profiles share the same differentiation state. However, the inferred trajectory may not reveal clonal differentiation heterogeneity among T cell clones. Single-cell T cell receptor sequencing (scTCR-seq) data provides invaluable insights into the clonal relationship among cells, yet it lacks functional characteristics. Therefore, scRNA-seq and scTCR-seq data complement each other in improving trajectory inference, where a reliable computational tool is still missing. We developed LRT, a computational framework for the integrative analysis of scTCR-seq and scRNA-seq data to explore clonal differentiation trajectory heterogeneity. Specifically, LRT uses the transcriptomics information from scRNA-seq data to construct overall cell trajectories and then utilizes both the TCR sequence information and phenotype information to identify clonotype clusters with distinct differentiation biasedness. LRT provides a comprehensive analysis workflow, including preprocessing, cell trajectory inference, clonotype clustering, trajectory biasedness evaluation, and clonotype cluster characterization. We illustrated its utility using scRNA-seq and scTCR-seq data of CD8+ T cells and CD4+ T cells with acute lymphocytic choriomeningitis virus infection. These analyses identified several clonotype clusters with distinct skewed distribution along the differentiation path, which cannot be revealed solely based on scRNA-seq data. Clones from different clonotype clusters exhibited diverse expansion capability, V-J gene usage pattern and CDR3 motifs. The LRT framework was implemented as an R package 'LRT', and it is now publicly accessible at https://github.com/JuanXie19/LRT. In addition, it provides two Shiny apps 'shinyClone' and 'shinyClust' that allow users to interactively explore distributions of clonotypes, conduct repertoire analysis, implement clustering of clonotypes, trajectory biasedness evaluation, and clonotype cluster characterization.
Assuntos
Algoritmos , Análise da Expressão Gênica de Célula Única , Análise de Sequência de RNA , Perfilação da Expressão Gênica , Diferenciação Celular/genética , Receptores de Antígenos de Linfócitos T/genética , Células Clonais , Análise de Célula Única , Análise por Conglomerados , SoftwareRESUMO
Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.
Assuntos
Estudo de Associação Genômica Ampla , Esclerose Múltipla , Humanos , Herança Multifatorial/genética , Esclerose Múltipla/genética , Epigênese Genética , População Europeia , Fatores de Risco , Predisposição Genética para Doença/genética , FenótipoRESUMO
BACKGROUND: With advancements in chronic total coronary occlusion (CTO) recanalization techniques and concepts, the success rate of recanalization has been steadily increasing. However, the current data are too limited to draw any reliable conclusions about the efficacy and safety of drug-coated balloons (DCBs) in CTO percutaneous coronary intervention (PCI). Herein, we conducted a meta-analysis to confirm the efficacy of DCB in CTO PCI. METHODS: We systematically searched PubMed, Web of Science and Embase from inception to July 25, 2023. The primary outcome was major advent cardiovascular events (MACE), including cardiac death, nonfatal myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR). The follow-up angiographic endpoints were late lumen enlargement (LLE), reocclusion and restenosis. RESULTS: Five studies with a total of 511 patients were included in the meta-analysis. Across studies, patients were predominantly male (72.9-85.7%) and over fifty years old. The summary estimate rate of MACE was 13.0% (95% CI 10.1%-15.9%, I2 = 0%, p = 0.428). The summary estimate rates of cardiac death and MI were 2.2% (95% CI 0.7%-3.7%, I2 = 0%, p = 0.873) and 1.2% (95% CI -0.2-2.6%, I2 = 13.7%, p = 0.314), respectively. Finally, the pooled incidences of TLR and TVR were 10.1% (95% CI 5.7%-14.5%, I2 = 51.7%, p = 0.082) and 7.1% (95% CI 3.0%-11.2%, I2 = 57.6%, p = 0.070), respectively. Finally, the summary estimate rates of LLE, reocclusion and restenosis were 59.4% (95% CI 53.5-65.3%, I2 = 0%, p = 0.742), 3.3% (95% CI 1.1-5.4%, I2 = 0%, p = 0.865) and 17.5% (95% CI 12.9-22.0%, I2 = 0%, p = 0.623), respectively. CONCLUSION: Accordingly, DCB has the potential to be used as a treatment for CTO in suitable patients.
Assuntos
Angioplastia Coronária com Balão , Cateteres Cardíacos , Materiais Revestidos Biocompatíveis , Oclusão Coronária , Humanos , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/mortalidade , Oclusão Coronária/terapia , Resultado do Tratamento , Doença Crônica , Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/mortalidade , Fatores de Risco , Idoso , Feminino , Pessoa de Meia-Idade , Masculino , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Idoso de 80 Anos ou mais , Medição de Risco , Fatores de Tempo , Desenho de Equipamento , Reestenose Coronária/etiologia , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/mortalidadeRESUMO
BACKGROUND: Metastasis is one of the main factors leading to the high mortality rate of gastric cancer. The current monitoring methods are not able to accurately monitor gastric cancer metastasis. METHODS: In this paper, we constructed a new type of hollow Mn 3 O 4 nanocomposites, Mn 3 O 4 @HMSN-Cy7.5-FA, which had a size distribution of approximately 100 nm and showed good stability in different liquid environments. The in vitro magnetic resonance imaging (MRI) results show that the nanocomposite has good response effects to the acidic microenvironment of tumors. The acidic environment can significantly enhance the contrast of T 1 -weighted MRI. The cellular uptake and endocytosis results show that the nanocomposite has good targeting capabilities and exhibits good biosafety, both in vivo and in vitro. In a gastric cancer nude mouse orthotopic metastatic tumor model, with bioluminescence imaging's tumor location information, we realized in vivo MRI/fluorescence imaging (FLI) guided precise monitoring of the gastric cancer orthotopic and metastatic tumors with this nanocomposite. RESULTS: This report demonstrates that Mn 3 O 4 @HMSN-Cy7.5-FA nanocomposites is a promising nano-diagnostic platform for the precision diagnosis and therapy of gastric cancer metastasis in the future. CONCLUSIONS: In vivo MRI/FLI imaging results show that the nanocomposites can achieve accurate monitoring of gastric cancer tumors in situ and metastases. BLI's tumor location information further supports the good accuracy of MRI/FLI dual-modality imaging. The above results show that the MHCF NPs can serve as a good nano-diagnostic platform for precise in vivo monitoring of tumor metastasis. This nanocomposite provides more possibilities for the diagnosis and therapy of gastric cancer metastases.
Assuntos
Ácido Fólico , Imageamento por Ressonância Magnética , Nanocompostos , Metástase Neoplásica , Neoplasias Gástricas , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Animais , Nanocompostos/química , Camundongos , Linhagem Celular Tumoral , Humanos , Ácido Fólico/química , Compostos de Manganês/química , Imagem Óptica , Camundongos Nus , ÓxidosRESUMO
Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.