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BACKGROUND: Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. METHODS: Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. RESULTS: We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-ß signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-ß-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. CONCLUSION: By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Análisis de la Célula Individual , Microambiente Tumoral , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Regulación Neoplásica de la Expresión Génica , Transición Epitelial-Mesenquimal/genética , Animales , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Heterogeneidad Genética , Ratones , Línea Celular Tumoral , Pronóstico , Perfilación de la Expresión Génica , Transcriptoma , Biología Computacional/métodos , Metástasis de la NeoplasiaRESUMEN
The use of protein biomarkers in blood for clinical settings is limited by the cost and accessibility of traditional venipuncture sampling. The dried blood spot (DBS) technique offers a less invasive and more accessible alternative. However, protein stability in DBS has not been well evaluated. Herein, we deployed a quantitative LC-MS/MS system to construct proteomic atlases of whole blood, DBSs, plasma, and blood cells. Approximately 4% of detected proteins' abundance was significantly altered during blood drying into blood spots, with overwhelming disturbances in cytoplasmic fraction. We also reported a novel finding suggesting a decrease in the level of membrane/cytoskeletal proteins (SLC4A1, RHAG, DSC1, DSP, and JUP) and an increase in the level of proteins (ATG3, SEC14L4, and NRBP1) related to intracellular trafficking. Furthermore, we identified 19 temporally dynamic proteins in DBS samples stored at room temperature for up to 6 months. There were three declined cytoskeleton-related proteins (RDX, SH3BGRL3, and MYH9) and four elevated proteins (XPO7, RAN, SLC2A1, and SLC29A1) involved in cytoplasmic transport as representatives. The instability was governed predominantly by hydrophilic proteins and enhanced significantly with an increasing storage time. Our analyses provide comprehensive knowledge of both short- and long-term storage stability of DBS proteins, forming the foundation for the widespread use of DBS in clinical proteomics and other analytical applications.
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Pruebas con Sangre Seca , Estabilidad Proteica , Proteómica , Espectrometría de Masas en Tándem , Humanos , Pruebas con Sangre Seca/métodos , Espectrometría de Masas en Tándem/métodos , Proteómica/métodos , Cromatografía Liquida , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/química , Biomarcadores/sangre , Factores de Tiempo , Proteínas del Citoesqueleto/sangreRESUMEN
Imbalanced Sirtuin 1 (SIRT1) levels may lead to liver diseases through abnormal regulation of autophagy, but the roles of SIRT1-regulated autophagy in hepatocellular carcinoma are still controversial. In this study, we found that SIRT1 mRNA and protein levels were upregulated in hepatocellular carcinoma, and high SIRT1 expression hinted an advanced stage and a poor prognosis. The differentially expressed proteins were significantly elevated in autophagy, cellular response to stress, and immune signaling pathways. In a thioacetamide-induced hepatocellular carcinoma mouse model, we found that SIRT1 expression was highly increased with increased autophagy and excessive macrophage inflammatory response. Next, we established a Hepa 1-6 cells and macrophage co-culture system in vitro to model the alteration of tumor microenvironment, and found that the medium from CCl4-treated or SIRT1-overexpressing Hepa 1-6 cells triggered the polarization of macrophage M1, and the culture medium derived from M1 macrophage promoted Hepa 1-6 cells growth and intracellular oxidative stress. The progression of liver fibrosis in the CCl4-induced liver fibrosis mouse model showed that inhibition of SIRT1 alleviated inflammatory response and ameliorated liver fibrosis. These findings suggest that SIRT1-regulated autophagy and inflammation are oncogenic in hepatocarcinogenesis.
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Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
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Encéfalo , Redes Reguladoras de Genes , Trastornos Mentales , Análisis de la Célula Individual , Humanos , Envejecimiento/genética , Encéfalo/metabolismo , Comunicación Celular/genética , Cromatina/metabolismo , Cromatina/genética , Genómica , Trastornos Mentales/genética , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS: A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS: Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.
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Carcinoma Hepatocelular , Metilación de ADN , Detección Precoz del Cáncer , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Femenino , Masculino , Metilación de ADN/genética , Persona de Mediana Edad , Pronóstico , Detección Precoz del Cáncer/métodos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Estudios de Cohortes , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Anciano , AdultoRESUMEN
Restructuring is an important phenomenon in catalytic reactions. Conversion-type materials with suitable redox potential may undergo in situ electrochemically driven restructurings and induce highly active catalytic sites in a working lithium-sulfur battery. Herein, driven by the electrochemical conversion reaction of BiVO4, a reversible catalytic cycle of Bi/amorphous Li3VO4 (a-Li3VO4) and Bi2S3/a-Li3VO4 heterojunctions is constructed, which targets the oxidation of Li2S and the conversion of polysulfide, respectively. The heterostructures and electrochemically driven size confinement provide abundant sites for shuttle restraining and sulfur conversion. Especially, the p-block Bi and Bi2S3 could dramatically reduce the conversion energy barriers of Li2S and polysulfide by virtue of the p-p orbital hybridization, promoting bidirectional reactions of the sulfur cathode. As a result, the corresponding sulfur cathode possesses a high reversible capacity of 7.5 mAh cm-2 after 120 cycles under a high sulfur loading of 10.3 mg cm-2 with a current density of 0.38 mA cm-2. This study furnishes a feasible scheme to obtain highly effective catalysts for bidirectional sulfur redox by utilizing the electrochemically induced restructuring.
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The suppressor of cytokine signaling 2 (SOCS2) has been identified to act as a tumor suppressor in breast cancer (BC) progression. However, the action of SOCS2 in macrophage polarization in BC cells has not been reported yet. The qRT-PCR and western blotting were adopted for detecting the levels of mRNAs and proteins. The macrophage M2 polarization was analyzed by flow cytometry. Analyses of cell oncogenic phenotypes and tumor growth were conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, scratch, Transwell, tube formation assays in vitro, and tumor xenograft assay in vivo, respectively. The interaction between CEBPA (CCAAT Enhancer Binding Protein Alpha) and SOCS2 was confirmed using bioinformatics analysis and dual-luciferase reporter assay. SOCS2 was lowly expressed in BC tissues and cells. Functionally, overexpression of SOCS2 inhibited macrophage M2 polarization, and impaired BC cell proliferation, angiogenesis, and metastasis. Mechanistically, CEBPA bound to the promoter region of SOCS2, and promoted its transcription. A low CEBPA expression was observed in BC tissues and cells. Forced expression of CEBPA also suppressed macrophage M2 polarization, BC cell proliferation, angiogenesis, and metastasis. Moreover, the anticancer effects mediated by CEBPA were abolished by SOCS2 knockdown. In addition, CEBPA overexpression impeded BC growth in nude mice by regulating SOCS2. CEBPA suppressed macrophage M2 polarization, BC cell proliferation, angiogenesis, and metastasis by promoting SOCS2 transcription in a targeted manner.
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Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
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BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma. METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy. RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway. CONCLUSION: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.
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Antineoplásicos , Imidazoles , Inmunoconjugados , Melanoma , Oximas , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Neoplasias Cutáneas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Fosfatidilinositol 3-Quinasas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inmunoconjugados/genética , Inmunoconjugados/uso terapéutico , MutaciónRESUMEN
Bis(2-ethylhexyl)phthalate (DEHP), an endocrine disruptor, shows carcinogenic, teratogenic, mutagenic and estrogenic effects. It is easy to release from plastic materials and migrate to soil environment, causing serious pollution and posing a great threat to human health. In our work, a photoelectrochemical (PEC) sensing platform for DEHP detection was constructed using BiOI/ZnO nanoarrays (NRs) as the transducer species and the DEHP aptamers as the biological recognition elements. ZnO NRs with three-dimensional and large diameter area were prepared by hydrothermal method to increase the light absorption capacity. Coupling BiOI in a narrow band gap with ZnO NRs strengthened visible-light absorption, while promoting charge carrier separation and transportation. This was attributed to the generation of an internal electric field between BiOI and ZnO NRs, exhibiting obvious photocurrent response. The as-developed PEC sensing platform demonstrated great sensing performance for detection of DEHP. Furthermore, the photocurrent varied and the logarithm of DEHP concentration showed a linear relationship from 1.0 × 10-11 to 5.0 × 10-7 mol/L, and the limit of detection was estimated to be 3.8 × 10-12 mol/L. In the meantime, while evaluating its usage in real soil samples, satisfying outcomes were realized. Thus, the as-proposed PEC sensing platform provided a potential device to monitor DEHP in the environment.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Dietilhexil Ftalato , Óxido de Zinc , Humanos , Técnicas Biosensibles/métodos , SueloRESUMEN
Bioactive scaffolds accurately mimicking the structure and composition of the extracellular matrix have garnered significant interest in tissue engineering. In this study, we developed a platform utilizing natural silk nanofibrils, hyaluronic acid, and basic fibroblast growth factor for the purpose of promoting spinal cord regeneration by creating an optimal microenvironment. The bioactive scaffold exhibited notable characteristics such as high porosity and hydrophilicity, attributed to its unique nanostructure, high connectivity, and polysaccharide composition. Furthermore, the pore size of the scaffold can be adjusted within the range of 90 µm to 120 µm by varying the content of hyaluronic acid. In vitro, human umbilical vein endothelial cells were seeded into the scaffold, demonstrating enhanced cell viability. The scaffold facilitated cell proliferation and migration. In vivo experiments on rats indicated that the scaffold had a beneficial impact on spinal cord regeneration, creating a conducive environment for motor function recovery of the rats. This effect may be attributed to the scaffold's ability to stimulate axon growth and neuronal survival, as well as inhibit the formation of glial scars, as evidenced by the decreased expression of growth associated protein-43, microtubule-associated protein 2, and neurofilament-200. This study presents a promising method to develop a feasible bioscaffold for the treatment of spinal cord injury.
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Fibroínas , Regeneración de la Medula Espinal , Ratas , Animales , Humanos , Seda/química , Andamios del Tejido/química , Ácido Hialurónico/farmacología , Fibroínas/farmacología , Fibroínas/química , Ingeniería de Tejidos/métodos , Células Endoteliales de la Vena Umbilical HumanaRESUMEN
Monozygotic (MZ) twins are theoretically genetically identical. Although they are revealed to accumulate mutations after the zygote splits, discriminating between twin genomes remains a formidable challenge in the field of forensic genetics. Single-nucleotide variants (SNVs) are responsible for a substantial portion of genetic variation, thus potentially serving as promising biomarkers for the identification of MZ twins. In this study, we sequenced the whole genome of a pair of female MZ twins when they were 27 and 33 years old to approximately 30 × coverage using peripheral blood on an Illumina NovaSeq 6000 Sequencing System. Potentially discordant SNVs supported by whole-genome sequencing were validated extensively by amplicon-based targeted deep sequencing and Sanger sequencing. In total, we found nine bona fide post-twinning SNVs, all of which were identified in the younger genomes and found in the older genomes. None of the SNVs occurred within coding exons, three of which were observed in introns, supported by whole-exome sequencing results. A double-blind test was employed, and the reliability of MZ twin discrimination by discordant SNVs was endorsed. All SNVs were successfully detected when input DNA amounts decreased to 0.25 ng, and reliable detection was limited to seven SNVs below 0.075 ng input. This comprehensive analysis confirms that SNVs could serve as cost-effective biomarkers for MZ twin discrimination.
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Nucleótidos , Gemelos Monocigóticos , Adulto , Femenino , Humanos , Biomarcadores , Mutación , Reproducibilidad de los Resultados , Gemelos Monocigóticos/genéticaRESUMEN
Endometrial carcinoma (EC) is a prevalent gynecological tumor in women, and its treatment and prevention are significant global health concerns. The mutations in DNA polymerase ε (POLE) are recognized as key features of EC and may confer survival benefits in endometrial cancer patients undergoing anti-PD-1/PD-L1 therapy. However, the anti-tumor mechanism of POLE mutations remains largely elusive. This study demonstrates that the hot POLE P286R mutation impedes endometrial tumorigenesis by inducing DNA breakage and activating the cGAS-STING signaling pathway. The POLE mutations were found to inhibit the proliferation and stemness of primary human EC cells. Mechanistically, the POLE mutants enhance DNA damage and suppress its repair through the interaction with DNA repair proteins, leading to genomic instability and the upregulation of cytoplasmic DNA. Additionally, the POLE P286R mutant also increases cGAS level, promotes TBK1 phosphorylation, and stimulates inflammatory gene expression and anti-tumor immune response. Furthermore, the POLE P286R mutation inhibits tumor growth and facilitates the infiltration of cytotoxic T cells in human endometrial cancers. These findings uncover a novel mechanism of POLE mutations in antagonizing tumorigenesis and provide a promising direction for effective cancer therapy.
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ADN Polimerasa II , Neoplasias Endometriales , Femenino , Humanos , Carcinogénesis/genética , Transformación Celular Neoplásica , ADN , ADN Polimerasa II/genética , ADN Polimerasa II/metabolismo , Neoplasias Endometriales/genética , Mutación/genética , Proteínas de Unión a Poli-ADP-Ribosa/genéticaRESUMEN
Designing photocatalysts with efficient charge separation and electron transport capabilities to achieve efficient visible-driven hydrogen production remains a challenge. Herein, 2D-2D conductive metal-organic framework/g-C3N4 heterojunctions were successfully prepared by an in situ assembly. Compared to pristine g-C3N4, the ratio-optimized Ni-CAT-1/g-C3N4 exhibits approximately 3.6 times higher visible-light H2 production activity, reaching 14 mmol g-1. Through investigations using time-resolved photoluminescence, surface photovoltage, and wavelength-dependent photocurrent action spectroscopies, it is determined that the improved photocatalytic performance is attributed to enhanced charge transfer and separation, specifically the efficient transfer of excited high-energy-level electrons from g-C3N4 to Ni-CAT in the heterojunctions. Furthermore, the high electrical conductivity of Ni-CAT enables rapid electron transport, contributing to the overall enhanced performance. This work provides a feasible strategy to construct efficient dimension-matched g-C3N4-based heterojunction photocatalysts with high-efficiency charge separation for solar-driven H2 production.
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BACKGROUND: Minimal residual disease (MRD) is proposed to be responsible for tumor recurrence. The role of circulating tumor DNA (ctDNA) to detect MRD, monitor recurrence, and predict prognosis in liver cancer patients undergoing liver transplantation (LT) remains unrevealed. METHODS: Serial blood samples were collected to profile ctDNA mutational changes. Baseline ctDNA mutational profiles were compared with those of matched tumor tissues. Correlations between ctDNA status and recurrence rate (RR) and recurrence-free survival (RFS) were analyzed, respectively. Dynamic change of ctDNA was monitored to predict tumor recurrence. RESULTS: Baseline mutational profiles of ctDNA were highly concordant with those of tumor tissues (median, 89.85%; range 46.2-100%) in the 74 patients. Before LT, positive ctDNA status was associated with higher RR (31.7% vs 11.5%; p = 0.001) and shorter RFS than negative ctDNA status (17.8 vs 19.4 months; p = 0.019). After LT, the percentage of ctDNA positivity decreased (17.6% vs 47.0%; p < 0.001) and patients with positive ctDNA status had higher RR (46.2% vs 21.3%; p < 0.001) and shorter RFS (17.2 vs 19.2 months; p = 0.010). Serial ctDNA profiling demonstrated patients with decreased or constant negative ctDNA status had lower RR (33.3% vs 50.0%; p = 0.015) and favorable RFS (18.2 vs 15.0 months, p = 0.003) than those with increased or constant positive ctDNA status. Serial ctDNA profiling predicted recurrence months ahead of imaging evidence and serum tumor biomarkers. CONCLUSIONS: ctDNA could effectively detect MRD and predict tumor recurrence in liver cancer patients undergone LT.
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ADN Tumoral Circulante , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , ADN Tumoral Circulante/genética , Recurrencia Local de Neoplasia/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Biomarcadores de Tumor/genéticaRESUMEN
Using a prospective, observational cohort study during the post-"dynamic COVID-zero" wave in China, we estimated short-term relative effectiveness against Omicron BA.5 infection of inhaled aerosolized adenovirus type 5-vectored ancestral strain coronavirus disease 2019 (COVID-19) vaccine as a second booster dose approximately 1 year after homologous boosted primary series of inactivated COVID-19 vaccine compared with no second booster. Participants reported nucleic acid or antigen test results weekly until they tested positive or completed predesignated follow-up. After excluding participants infected <14 days after study entry, relative effectiveness among the 6576 participants was 61% in 18- to 59-year-olds and 38% in ≥60-year-olds and was sustained for 12 weeks.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , COVID-19/prevención & control , Estudios Prospectivos , Eficacia de las Vacunas , China/epidemiología , Adenoviridae/genéticaRESUMEN
OBJECTIVE: To identify factors affecting the efficacy of steroid-eluting sinus stents implanted after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: We performed a post-hoc analysis of a randomized self-controlled clinical trial on post-operative implantation of bioabsorbable steroid-eluting stents in patients with CRSwNP. Univariate logistic regression analysis was conducted to identify which of the following factors affect the response to post-operative stent implantation: sex, serum eosinophil levels, history of prior surgery, endoscopic scores, and comorbid conditions (asthma and allergic rhinitis). The primary outcome was the rate of post-operative intervention on day 30, and the secondary outcome was the rate of polypoid tissue formation (grades 2-3) on days 14, 30, and 90. RESULTS: A total of 151 patients with CRSwNP were included in the post-hoc analysis. Asthma was identified as the only risk factor for a poor response to steroid-eluting sinus stents on post-operative day 30, with an odds ratio of 23.71 (95% CI, 2.81, 200.16; P=0.004) for the need for post-operative intervention and 19 (95% CI, 2.20, 164.16; P=0.003) for moderate-to-severe polypoid tissue formation. In addition, the asthmatic group showed higher rates of post-operative intervention and polypoid tissue formation than the non-asthmatic group on post-operative day 30. Blood eosinophil levels were not identified as a risk factor for poor outcomes after stent implantation. CONCLUSION: Comorbid asthma, but not blood eosinophil level, impairs the efficacy of steroid-eluting sinus stents in the short term after ESS in patients with CRSwNP.
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Asma , Pólipos Nasales , Sinusitis , Humanos , Implantes Absorbibles , Pólipos Nasales/complicaciones , Pólipos Nasales/cirugía , Resultado del Tratamiento , Sinusitis/complicaciones , Sinusitis/cirugía , Esteroides/uso terapéutico , Stents , Asma/complicaciones , Asma/cirugíaRESUMEN
Background: Various immune cell types in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) have been identified as important parameters associated with prognosis and responsiveness to immunotherapy. However, how various factors influence immune cell infiltration remains incompletely understood. Hence, we investigated the single cell multi-omics landscape of immune infiltration in HCC, particularly key gene and cell subsets that influence immune infiltration, thus potentially linking the immunotherapy response and immune cell infiltration. Methods: We grouped patients with HCC according to immune cell infiltration scores calculated by single sample gene set enrichment analysis (ssGSEA). Differential expression analysis, functional enrichment, clinical trait association, gene mutation analysis, tumor immune dysfunction and exclusion (TIDE) and prognostic model construction were used to investigate the immune infiltration landscape through multi-omics. Stepwise regression was further used to identify key genes regulating immune infiltration. Single cell analysis was performed to explore expression patterns of candidate genes and investigate associated cellular populations. Correlation analysis, ROC analysis, Immunotherapy cohorts were used to explore and confirm the role of key gene and cellular population in predicting immune infiltration state and immunotherapy response. Immunohistochemistry and multiplexed fluorescence staining were used to further validated our results. Results: Patients with HCC were clustered into high and low immune infiltration groups. Mutations of CTNNB1 and TTN were significantly associated with immune infiltration and altered enrichment of cell populations in the TME. TIDE analysis demonstrated that T cell dysfunction and the T cell exclusion score were elevated in the high and low infiltration groups, respectively. Six risk genes and five risk immune cell types were identified and used to construct risk scores and a nomogram model. CXCR6 and LTA, identified by stepwise regression, were highly associated with immune infiltration. Single cell analysis revealed that LTA was expressed primarily in tumor infiltrating T lymphocytes and partial B lymphocytes, whereas CXCR6 was enriched predominantly in T and NK cells. Notably, CXCR6+ CD8 T cells were characterized as tumor enriched cells that may be potential predictors of high immune infiltration and the immune-checkpoint blockade response, and may serve as therapeutic targets. Conclusion: We constructed a comprehensive single cell and multi-omics landscape of immune infiltration in HCC, and delineated key genes and cellular populations regulating immune infiltration and immunotherapy response, thus providing insights into the mechanisms of immune infiltration and future therapeutic control.
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The tumor microenvironment is a highly heterogeneous circumstance composed of multiple components, while tumor-associated macrophages (TAMs) are major innate immune cells with highly plastic and are always educated by tumor cells to structure an advantageous pro-tumor immune microenvironment. Despite emerging evidence focalizing the role of autophagy in other immune cells, the regulatory mechanism of autophagy in macrophage polarization remains poorly understood. Herein, we demonstrated that hepatocellular carcinoma (HCC) cells educated macrophages toward M2-like phenotype polarization under the condition of coculture. Moreover, we observed that inhibition of macrophage autophagy promoted M2-like macrophage polarization, while the tendency was impeded when autophagy was motivated. Mechanistically, macrophage autophagy inhibition inactivates the NF-κB pathway by increasing the instability of TAB3 via ubiquitination degradation, which leads to the M2-like phenotype polarization of macrophages. Both immunohistochemistry staining using human HCC tissues and experiment in vivo verified autophagy inhibition is correlated with M2 macrophage polarization. Altogether, we illustrated that macrophage autophagy was involved in the process of HCC cells domesticating M2 macrophage polarization via the NF-κB pathway. These results provide a new target to interfere with the polarization of macrophages to M2-like phenotype during HCC progression.