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BACKGROUND: This study aims to address challenges in dental pulp regeneration therapy. The heterogeneity of DPSCs poses challenges, especially in stem cell transplantation for clinical use, particularly when sourced from donors of different ages and conditions. METHODS: Pseudotime analysis was employed to analyze single-cell sequencing data, and immunohistochemical studies were conducted to investigate the expression of fibronectin 1 (FN1). We performed in vitro sorting of PDGFRß+ DPSCs using flow cytometry. A series of functional assays, including cell proliferation, scratch, and tube formation assays, were performed to experimentally validate the vasculogenic capabilities of the identified PDGFRß+ DPSC subset. Furthermore, gene-edited mouse models were utilized to demonstrate the importance of PDGFRß+ DPSCs. Transcriptomic sequencing was conducted to compare the differences between PDGFRß+ DPSCs and P1-DPSCs. RESULTS: Single-cell sequencing analysis unveiled a distinct subset, PDGFRß+ DPSCs, characterized by significantly elevated FN1 expression during dental pulp development. Subsequent cell experiments demonstrated that this subset possesses remarkable abilities to promote HUVEC proliferation, migration, and tube formation. Gene-edited mouse models confirmed the vital role of PDGFRß+ DPSCs in dental pulp development. Transcriptomic sequencing and in vitro experiments demonstrated that the PDGFR/PI3K/AKT signaling pathway is a crucial factor mediating the proliferation rate and pro-angiogenic properties of PDGFRß+ DPSCs. CONCLUSION: We defined a new subset, PDGFRß+ DPSCs, characterized by strong proliferative activity and pro-angiogenic capabilities, demonstrating significant clinical translational potential.
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Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND: An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. METHODS: Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. RESULTS: Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, TIGIT, LAG-3 or CD38) and ICEP2 (CD8+ T cells solely expressing NKG2A or co-expressing with other immune checkpoints), reflecting the co-occurrence pattern of PD-1 and the mutual exclusivity of NKG2A. Further, these two ICEP CD8+ T cell subsets represented distinct CD8+ T cell differentiation fates governed by MSC and RUNX3. Notably, ICEP2 CD8+ T cells were associated with anti-PD-1 therapy resistance in gastric cancer. This phenomenon may be attributed to the recruitment of LGMN+ macrophages mediated by the CXCL16-CXCR6 signaling pathway. CONCLUSION: This study unveiled two distinct ICEPs and the mutually exclusivity and co-occurrence characteristics of CD8+ T cells in gastric cancer. The ICEP2 CD8+ T cell subset, highly expressed in gastric cancer patients resistant to anti-PD-1 therapy, may be recruited by LGMN+ macrophages through CXCL16-CXCR6 axis. These findings provide evidence for NKG2A as a novel immunotherapeutic target in gastric cancer and offer new insights into combination strategies for immune checkpoint inhibitors in gastric cancer.
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Linfócitos T CD8-Positivos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Neoplasias Gástricas , Humanos , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Regulação Neoplásica da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas de Checkpoint Imunológico/metabolismo , Proteínas de Checkpoint Imunológico/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
Atomically thin materials (ATMs) with thicknesses in the atomic scale (typically <5 nm) offer inherent advantages of large specific surface areas, proper crystal lattice distortion, abundant surface dangling bonds, and strong in-plane chemical bonds, making them ideal 2D platforms to construct high-performance electrode materials for rechargeable metal-ion batteries, metal-sulfur batteries, and metal-air batteries. This work reviews the synthesis and electronic property tuning of state-of-the-art ATMs, including graphene and graphene derivatives (GE/GO/rGO), graphitic carbon nitride (g-C3N4), phosphorene, covalent organic frameworks (COFs), layered transition metal dichalcogenides (TMDs), transition metal carbides, carbonitrides, and nitrides (MXenes), transition metal oxides (TMOs), and metal-organic frameworks (MOFs) for constructing next-generation high-energy-density and high-power-density rechargeable batteries to meet the needs of the rapid developments in portable electronics, electric vehicles, and smart electricity grids. We also present our viewpoints on future challenges and opportunities of constructing efficient ATMs for next-generation rechargeable batteries.
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INTRODUCTION: In China, standard smoking cessation practices are rarely used by healthcare service providers (HSPs). WeChat, a popular social media app, has been widely used in China. METHODS: In this single-blind, randomized trial, undertaken in China with 8-week interventions and follow-up to 34 weeks, 1887 HSPs were randomly selected to the intervention (n=942) or control group (n=945) from Oct 2020 to Oct 2021. The intervention group received regular smoking cessation training program messages from the professional team for 8 weeks and followed for 34 weeks. The control group received thanks messages for 8 weeks, and follow-up to 34 weeks. Both groups received a hard copy of the manual after randomization. The primary outcome measure was the utilization rate of behavioral and pharmacotherapy interventions for smoking patients from 9 to 34 weeks. This trial is registered at ClinicalTrials.gov (number NCT03556774). RESULTS: HSPs in the intervention group demonstrated a better overall utilization rate of smoking cessation at 20-week follow-up compared to the control group (35.54% vs 31.41%, p=0.036). Additionally, both groups showed a significant increase in the adoption of various components of the 5A's model - including "Assess", "Assist: set a quit date", "Assist: recommend cessation program", "Assist: provide information", "Assist: recommend medication", and "Arrange" - at the 9-week follow-up relative to baseline. Notably, at the 20-week follow-up, the intervention group reported significantly enhanced utilization rates for all these components, except "Assist: set a quit date". CONCLUSIONS: The "Wechat Wequit" training program effectively enhanced smoking cessation intervention adoption among Chinese HSPs. IMPLICATION: 'WeChat WeQuit' training program was effective in increasing the provision of effective tobacco cessation interventions by Chinese-speaking HSPs to patients with cigarette smoking, which could provide valuable insights into bridging the gap between need and services for smoking cessation in China.
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Metal-Organic Polymers (MOPs) have attracted growing attention for lithium-ion battery (LIB) applications due to their merits in orderly ionic transportation and robust structure stability in electrochemical reactions. However, they suffer from poor electronic conductivity. In this work, we apply first-principles density functional theory to explore the potential of three one-dimensional (1D) electrically conductive C6H2S4TM (TM = Fe, Co, and Ni) MOPs with the π-d conjugated coordination as anode materials for Li+ ions storage. Our theoretical results reveal that these 1D MOPs possess a superior theoretical capacity of over 748 mA h g-1. In particular, the 1D C6H2S4Ni MOP shows an exceptional theoretical specific capacity of 1110 mA h g-1 based on the three-electron transferring reaction, which significantly outperforms the traditional graphite-based anode material in LIBs. Moreover, the resonant charge transfer between Ni metal and ligand within the 1D C6H2S4Ni MOP reduces the diffusion energy barrier of the Li atoms when they migrate on the surface of the MOP. The ultrahigh theoretical specific capacity of the C6H2S4Ni MOP predicts that it can be a promising anode material for LIBs.
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OBJECTIVE: This study aimed to evaluate and explore the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) peeling and gas tamponade in treating myopic foveoschisis (MF) through a meta-analysis. METHODS: Systematic searches were conducted on the PubMed, Web of Science and National Library of Medicine (NLM) English-language databases and the China National Knowledge Infrastructure (CNKI) and Wanfang Chinese-language databases. The primary outcome measures were postoperative best-corrected visual acuity (BCVA) and central foveal thickness (CFT), with the secondary outcome being the postoperative complication rate. Data analysis was performed using RevMan5.3 software. RESULTS: A total of 10 studies involving 234 eyes were included. The meta-analysis results showed the following: (1) The average postoperative BCVA improved compared with preoperative levels, with an average improvement in the logarithm of the minimum angle of resolution of 0.40, a statistically significant difference (95% CI: -0.44, - 0.20, p < 0.001); (2) the rate of postoperative BCVA improvement was 77% (95% CI: 65%, 90%, p < 0.001); (3) the postoperative CFT significantly decreased by an average of 385.92 µm, a statistically significant difference (95% CI: -437.85, - 333.98, p < 0.001); (4) the postoperative macular retinal complete reattachment rate was 90% (95% CI: 83%, 97%, p < 0.001); (5) the most common postoperative complication was a cataract, with an incidence of 55.9%. CONCLUSION: Using PPV combined with ILM peeling and gas tamponade to treat MF is reliable.
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Membrana Basal , Tamponamento Interno , Retinosquise , Acuidade Visual , Vitrectomia , Humanos , Vitrectomia/métodos , Retinosquise/cirurgia , Tamponamento Interno/métodos , Acuidade Visual/fisiologia , Membrana Basal/cirurgia , Miopia Degenerativa/cirurgia , Miopia Degenerativa/complicações , Miopia Degenerativa/fisiopatologia , Miopia/cirurgia , Miopia/fisiopatologiaRESUMO
Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative πâσ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.
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Primary Sjögren's syndrome (pSS) is an autoimmune disease that targets exocrine glands, leading to exocrine dysfunction. Due to its propensity to infect epithelial and B cells, Epstein-Barr virus (EBV) is hypothesized to be related with pSS. Through molecular mimicry, the synthesis of specific antigens, and the release of inflammatory cytokines, EBV contributes to the development of pSS. Lymphoma is the most lethal outcome of EBV infection and the development of pSS. As a population-wide virus, EBV has had a significant role in the development of lymphoma in people with pSS. In the review, we will discuss the possible causes of the disease.
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Doenças Autoimunes , Infecções por Vírus Epstein-Barr , Linfoma , Síndrome de Sjogren , Humanos , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Doenças Autoimunes/complicaçõesRESUMO
INTRODUCTION: Tofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety. DISCUSSION: This study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD. ETHICS AND DISSEMINATION: Before starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn ; ID ChiCTR2000031389.
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Doenças Pulmonares Intersticiais , Síndrome de Sjogren , Humanos , Azatioprina , Ciclofosfamida/uso terapêutico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/complicações , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Sjogren/complicações , Síndrome de Sjogren/tratamento farmacológicoRESUMO
OBJECTIVE: Systematic evaluation of the efficacy and safety of robotic-assisted laparoscopic myomectomy (RALM) versus laparoscopic myomectomy (LM). METHODS: PubMed, Embase, The Cochrane Library, and Web of Science database were searched by computer to seek relevant literature in order to compare the efficacy and safety of RALM with that of LM from the establishment of the databases to January 2023, and Review Manager 5.4 software was utilized to perform a meta-analysis on the literature. RESULTS: A total of 15 retrospective clinical controlled studies were included. There exists a total of 45,702 patients, among 11,618 patients in the RALM group and the remaining 34,084 patients in the LM group. Meta-analysis results revealed that RALM was associated with lesser intraoperative bleeding (MD = - 32.03, 95%CI - 57.24 to - 6.83, P = 0.01), lower incidence of blood transfusions (OR = 0.86, 95%CI 0.77 to 0.97, P = 0.01), shorter postoperative hospital stay (MD = - 0.11, 95%CI - 0.21 to - 0.01, P = 0.03), fewer transitions to open stomach (OR = 0.82, 95%CI 0.73 to 0.92, P = 0.0006), and lower incidence of postoperative complications (OR = 0.58, 95%CI 0.40 to 0.86, P = 0.006) than LM, whereas LM is more advantageous in terms of operative time (MD = 38.61, 95%CI 19.36 to 57.86, P < 0.0001). There was no statistical difference between the two surgical methods in terms of maximum myoma diameter (MD = 0.26, 95%CI - 0.17 to 0.70, P = 0.24). CONCLUSION: In the aspects of intraoperative bleeding, lower incidence of blood transfusions, postoperative hospital stay, transit open stomach rate, and postoperative complications, RALM has a unique advantage than that of LM, while LM has advantages over RALM in terms of operative time.
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Laparoscopia , Leiomioma , Robótica , Miomectomia Uterina , Neoplasias Uterinas , Feminino , Humanos , Miomectomia Uterina/efeitos adversos , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Estudos Retrospectivos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Resultado do TratamentoRESUMO
Lithium-air batteries (LABs) have attracted tremendous attention since the proposal of the LAB concept in 1996 because LABs have a super high theoretical/practical specific energy and an infinite supply of redox-active materials, and are environment-friendly. However, due to the lack of critical electrode materials and a thorough understanding of the chemistry of LABs, the development of LABs entered a germination period before 2010, when LABs research mainly focused on the development of air cathodes and carbonate-based electrolytes. In the growing period, i.e., from 2010 to the present, the investigation focused more on systematic electrode design, fabrication, and modification, as well as the comprehensive selection of electrolyte components. Nevertheless, over the past 25 years, the development of LABs has been full of retrospective steps and breakthroughs. In this review, the evolution of LABs is illustrated along with the constantly emerging design, fabrication, modification, and optimization strategies. At the end, perspectives and strategies are put forward for the development of future LABs and even other metal-air batteries.
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Fontes de Energia Elétrica , Lítio , Eletrodos , Íons , Estudos RetrospectivosRESUMO
Organic electrode materials (OEMs), valued for their sustainability and structural tunability, have been attracting increasing attention for wide application in sodium-ion batteries (SIBs) and other rechargeable batteries. However, most OEMs are plagued with insufficient specific capacity or poor cycling stability. Therefore, it's imperative to enhance their specific capacity and cycling stability through molecular design. Herein, we designed and synthesized a heteroaromatic molecule 2,3,8,9,14,15-hexanol hexaazatrinaphthalene (HATN-6OH) by the synergetic coupling of catechol (the precursor of ortho-quinone)/ortho-quinone functional groups and HATN conjugated core structures. The abundance of catechol/ortho-quinone and imine redox-active moieties delivers a high specific capacity of nine-electron transfer for SIBs. Most notably, the π-π interactions and intermolecular hydrogen bond forces among HATN-6OH molecules secure the stable long-term cycling performance of SIBs. Consequently, the as-prepared HATN-6OH electrode exhibited a high specific capacity (554â mAh g-1 at 0.1â A g-1 ), excellent rate capability (202â mAh g-1 at 10â A g-1 ), and stable long-term cycling performance (73 % after 3000 cycles at 10â A g-1 ) in SIBs. Additionally, the nine-electron transfer mechanism is confirmed by systematic density functional theory (DFT) calculation, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), and Raman analysis. The achievement of the synergetic coupling of the redox-active sites on OEMs could be an important key to the enhancement of SIBs and other metal-ion batteries.
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Not only high efficiency but also high selectivity of the electrocatalysts is crucial for high-performance, low-cost, and sustainable energy storage applications. Herein, we systematically investigate the edge effect of carbon-supported single-atom catalysts (SACs) on oxygen reduction reaction (ORR) pathways (two-electron (2 e- ) or four-electron (4 e- )) and conclude that the 2 e- -ORR proceeding over the edge-hosted atomic Co-N4 sites is more favorable than the basal-plane-hosted ones. As such, we have successfully synthesized and tuned Co-SACs with different edge-to-bulk ratios. The as-prepared edge-rich Co-N/HPC catalyst exhibits excellent 2 e- -ORR performance with a remarkable selectivity of ≈95 % in a wide potential range. Furthermore, we also find that oxygen functional groups could saturate the graphitic carbon edges under the ORR operation and further promote electrocatalytic performance. These findings on the structure-property relationship in SACs offer a promising direction for large-scale and low-cost electrochemical H2 O2 production via the 2 e- -ORR.
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BACKGROUND: The genus Rhododendron L. has been widely cultivated for hundreds of years around the world. Members of this genus are known for great ornamental and medicinal value. Owing to advances in sequencing technology, genomes and transcriptomes of members of the Rhododendron genus have been sequenced and published by various laboratories. With increasing amounts of omics data available, a centralized platform is necessary for effective storage, analysis, and integration of these large-scale datasets to ensure consistency, independence, and maintainability. RESULTS: Here, we report our development of the Rhododendron Plant Genome Database (RPGD; http://bioinfor.kib.ac.cn/RPGD/ ), which represents the first comprehensive database of Rhododendron genomics information. It includes large amounts of omics data, including genome sequence assemblies for R. delavayi, R. williamsianum, and R. simsii, gene expression profiles derived from public RNA-Seq data, functional annotations, gene families, transcription factor identification, gene homology, simple sequence repeats, and chloroplast genome. Additionally, many useful tools, including BLAST, JBrowse, Orthologous Groups, Genome Synteny Browser, Flanking Sequence Finder, Expression Heatmap, and Batch Download were integrated into the platform. CONCLUSIONS: RPGD is designed to be a comprehensive and helpful platform for all Rhododendron researchers. Believe that RPGD will be an indispensable hub for Rhododendron studies.
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Rhododendron , Bases de Dados Genéticas , Genoma de Planta , Genômica , Humanos , Plantas , Rhododendron/genética , TranscriptomaRESUMO
BACKGROUND: Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Although exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers. METHODS: In this study, the gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database, IMvigor210 cohorts, and six independent Gene Expression Omnibus datasets. A TEXs-associated signature named TEXscore was established to predict overall survival in multiple cancer types and in patients undergoing immune checkpoint blockade therapies. RESULTS: Based on exosome-associated genes, we first constructed a tumor-derived exosome signature named TEXscore using a principal component analysis algorithm. In single-cell RNA-sequencing data analysis, ascending TEXscore was associated with disease progression and poor clinical outcomes. In the TCGA Pan-Cancer cohort, TEXscore was elevated in tumor samples rather than in normal tissues, thereby serving as a reliable biomarker to distinguish cancer from non-cancer sources. Moreover, high TEXscore was associated with shorter overall survival across 12 cancer types. TEXscore showed great potential in predicting immunotherapy response in melanoma, urothelial cancer, and renal cancer. The immunosuppressive microenvironment characterized by macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells was associated with high TEXscore in the TCGA and immunotherapy cohorts. Besides, TEXscore-associated miRNAs and gene mutations were also identified. Further experimental research will facilitate the extending of TEXscore in tumor-associated exosomes. CONCLUSIONS: TEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.
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Exossomos , Melanoma , Biomarcadores Tumorais/genética , Humanos , Imunoterapia , Melanoma/genética , Melanoma/terapia , Prognóstico , Análise de Célula Única , Microambiente TumoralRESUMO
Compound epidermal growth factor receptor (EGFR) mutations are defined as double or multiple independent mutations of the EGFR tyrosine kinase domain (TKD), in which an EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutation is identified together with a mutation of unclarified clinical significance. Lung adenocarcinoma with compound EGFR mutation shows poor clinical response to EGFR-TKIs. Kobayashi et al. reported a non-small-cell lung cancer (NSCLC) patient whose tumor had EGFR exon21 L858R/A871G mutation presented rapid disease progression to erlotinib. However, in this case, we present an EGFR exon21 L858R/A871G mutation patient exerted significant benefit to icotinib, another first-generation EGFR-TKI, indicating that different EGFR-TKIs have diversiform sensitive sites and therapeutic effects, consistent mutation sites might achieve heterogeneous benefits from different EGFR-TKIs. Our case report provides promising EGFR-TKI for clinical treatment with EGFR exon21 L858R/A871G mutation in NSCLC. More dedicated efforts are needed to clarify their biologic effects on disease course and drug responsiveness.
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Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Éteres de Coroa , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , QuinazolinasRESUMO
BACKGROUND: The epigenetic regulator additional sex combs-like 1 (ASXL1) is an adverse prognostic factor in acute myeloid leukemia (AML). However, the mutational spectrum and prognostic factors of ASXL1-mutated (ASXL1+) AML are largely unknown. We aim to evaluate the risk factors influencing the prognosis of ASXL1+ AML. METHODS: We performed next-generation sequencing (NGS) in 1047 cases of de novo AML and discovered 91 ASXL1+ AML (8.7%). The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. RESULTS: In a total of 91 ASXL1+ AML, 86% had one or more co-mutations. The factors that had adverse impact on overall survival (OS) and event-free survival (EFS) are defined as high risk factors, including age ≥ 60 years, WBC count ≥ 50 × 109/L, FLT3-ITD mutations, RUNX1 mutations, and absence of AML1-ETO fusion gene. ASXL1 mutations without any risk factor were classified as single-hit ASXL1+ AML; ASXL1 mutations accompanied with one of the risk factors was referred to as double-hit ASXL1+ AML; ASXL1 mutations with two or more of the risk factors were designated as triple-hit ASXL1+ AML. The combination of these risk factors had a negative influence on the prognosis of ASXL1+ AML. The median OS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 6.67 months in triple-hit ASXL1+ AML (P = 0.003). The median EFS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 5.47 months in triple-hit ASXL1+ AML (P = 0.002). Allogenic hematopoietic stem cell transplantation (allo-HSCT) improved the prognosis of double/triple-hit ASXL1+ AML patients. CONCLUSIONS: Our study provided new insights into the mutational spectrum and prognostic factors of ASXL1+ AML patients. Our primary data suggest that the risk factors in ASXL1+ AML contribute to the poor outcome of these patients. The management of ASXL1+ AML patients should be based on the risk factors and allo-HSCT is highly recommended for consolidation.
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A novel kind of solid-state lithium electrolyte was fabricated by impregnating organic ionic plastic crystals (OIPCs) into the pores of covalent organic frameworks (COFs). The liquid-like phase of confined N,N-dimethylpyrrolidinium iodide (P1,1 I) and the ordered nanochannels of COFs simultaneously stimulated the lithium ion conduction.
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Immoral behaviors make individuals abominate and punish transgressors. Inspired by the associations between the Val66Met polymorphism of brain-derived neurotropic factor (BDNF) gene and emotional responses following negative events, we investigated whether this polymorphism was also associated moral emotions such as punishment and forgiveness following interpersonal transgression. To do so, we categorized 340 individuals according to the BDNF Val66Met and assessed moral emotions by using 12 hypothetic scenarios in different conditions of intention and interpersonal consequence. The results indicated that this polymorphism was significantly associated with moral aversion and punishment towards transgressors. Victims with the Val/Val genotype expressed less aversion and punishment than the Met carriers, regardless of intention and interpersonal consequence. Moreover, this polymorphism was associated with forgiveness. Victims with the Val/Val genotype expressed more forgiveness than the Met carriers. Taken together, these findings highlight the importance of the BDNF Val66Met to moral emotions.