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Introduction: This study investigates the role of Fibroblast Activation Protein (FAP)-positive cancer-associated fibroblasts (FAP+CAF) in shaping the tumor immune microenvironment, focusing on its association with immune cell functionality and cytokine expression patterns. Methods: Utilizing immunohistochemistry, we observed elevated FAP+CAF density in metastatic versus primary renal cell carcinoma (RCC) tumors, with higher FAP+CAF correlating with increased T cell infiltration in RCC, a unique phenomenon illustrating the complex interplay between tumor progression, FAP+CAF density, and immune response. Results: Analysis of immune cell subsets in FAP+CAF-rich stromal areas further revealed significant correlations between FAP+ stroma and various T cell types, particularly in RCC and non-small cell lung cancer (NSCLC). This was complemented by transcriptomic analyses, expanding the range of stromal and immune cell subsets interrogated, as well as to additional tumor types. This enabled evaluating the association of these subsets with tumor infiltration, tumor vascularization and other components of the tumor microenvironment. Our comprehensive study also encompassed cytokine, angiogenesis, and inflammation gene signatures across different cancer types, revealing heterogeneous cellular composition, cytokine expressions and angiogenic profiles. Through cytokine pathway profiling, we explored the relationship between FAP+CAF density and immune cell states, uncovering potential immunosuppressive circuits that limit anti-tumor activity in tumor-resident immune cells. Conclusions: These findings underscore the complexity of tumor biology and the necessity for personalized therapeutic and patient enrichment approaches. The insights gathered from FAP+CAF prevalence, immune infiltration, and gene signatures provide valuable perspectives on tumor microenvironments, aiding in future research and clinical strategy development.
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Fibroblastos Asociados al Cáncer , Inmunoterapia , Serina Endopeptidasas , Microambiente Tumoral , Microambiente Tumoral/inmunología , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/inmunología , Inmunoterapia/métodos , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Citocinas/metabolismo , Endopeptidasas , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Gelatinasas/metabolismo , Gelatinasas/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/metabolismo , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismoRESUMEN
Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability were associated with the performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumor evolution.
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Demand is strong for sensitive, reliable, and cost-effective diagnostic tools for cancer detection. Accordingly, bead-based biosensors have emerged in recent years as promising diagnostic platforms based on wide-ranging cancer biomarkers owing to the versatility, high sensitivity, and flexibility to perform the multiplexing of beads. This comprehensive review highlights recent trends and innovations in the development of bead-based biosensors for cancer-biomarker detection. We introduce various types of bead-based biosensors such as optical, electrochemical, and magnetic biosensors, along with their respective advantages and limitations. Moreover, the review summarizes the latest advancements, including fabrication techniques, signal-amplification strategies, and integration with microfluidics and nanotechnology. Additionally, the challenges and future perspectives in the field of bead-based biosensors for cancer-biomarker detection are discussed. Understanding these innovations in bead-based biosensors can greatly contribute to improvements in cancer diagnostics, thereby facilitating early detection and personalized treatments.
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Biomarcadores de Tumor , Técnicas Biosensibles , Neoplasias , Técnicas Biosensibles/métodos , Técnicas Biosensibles/instrumentación , Humanos , Neoplasias/diagnóstico , Biomarcadores de Tumor/análisis , Técnicas Electroquímicas/métodos , Nanotecnología/tendencias , Nanotecnología/métodos , Nanotecnología/instrumentación , Microfluídica/métodos , Microfluídica/instrumentación , Microfluídica/tendenciasRESUMEN
Inorganic solid-state electrolytes have attracted enormous attention due to their potential safety, increased energy density, and long cycle-life benefits. However, their application in solid-state batteries is limited by unstable electrode-electrolyte interface, poor point-to-point physical contact, and low utilization of metallic anodes. Herein, interfacial engineering based on sodium (Na)-conductive polymeric solid-state interfacial adhesive is studied to improve interface stability and optimize physical contacts, constructing a robust organic-rich solid electrolyte interphase layer to prevent dendrite-induced crack propagation and security issues. The interfacial adhesive strategy significantly increases the room-temperature critical current density of inorganic Na-ion conductors from 0.8 to 3.2 mA cm-2 and markedly enhances the cycling performance of solid-state batteries up to 500 cycles, respectively. Particularly, the Na3V2(PO4)3-based full solid-state batteries with high cathode loading of 10.16 mg cm-2 also deliver an excellent cycling performance, further realizing the stable operation of solid-state laminated pouch cells. The research provides fundamental perspectives into the role of interfacial chemistry and takes the field a step closer to realizing practical solid-state batteries.
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Introduction: Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues. Methods: We analyzed FAP across 1216 tissue samples covering 23 tumor types and 70 subtypes. Results: Elevated FAP levels were notable in breast, pancreatic, esophageal, and lung cancers. Using immunohistochemistry and RNAseq, a correlation between FAP gene and protein expression was found. Evaluating FAP's clinical significance, we assessed 29 cohorts from 12 clinical trials, including both mono and combination therapies with the PD-L1 inhibitor atezolizumab and chemotherapy. A trend links higher FAP expression to poorer prognosis, particularly in RCC, across both treatment arms. However, four cohorts showed improved survival with high FAP, while in four others, FAP had no apparent survival impact. Conclusions: Our results emphasize FAP's multifaceted role in therapy response, suggesting its potential as a cancer immunotherapy biomarker.
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Neoplasias Pulmonares , Serina Endopeptidasas , Humanos , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Inmunoterapia , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Fibroblastos/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. SIGNIFICANCE: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteoma , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Glicosiltransferasas , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Biomarcadores , Proteínas de la MembranaRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine-to-inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post-transcriptional modification of genome-encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity-associated NAFLD and sarcopenia remains unclear. METHODS: ADAR2+/+/GluR-BR/R mice (wild type [WT]) and ADAR2-/-/GluR-BR/R mice (ADAR2 knockout [KO]) were subjected to feeding with standard chow or high-fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross-sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated. RESULTS: ADAR2 KO mice fed with HFD exhibited lower body weight (-7.7%, P < 0.05), lower liver tissue weight (-20%, P < 0.05), reduced liver lipid droplets in concert with a decrease in hepatic triglyceride content (-24%, P < 0.001) and liver injury (P < 0.01). ADAR2 KO mice displayed protection against HFD-induced glucose intolerance, insulin resistance and dyslipidaemia. Skeletal muscle mass (P < 0.01), muscle strength (P < 0.05), muscle endurance (P < 0.001) and fibre size (CSA; P < 0.0001) were improved in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. Muscle atrophy-associated transcripts, such as forkhead box protein O1, muscle atrophy F-box/atrogin-1 and muscle RING finger 1/tripartite motif-containing 63, were decreased in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. ADAR2 deficiency attenuates HFD-induced local liver and skeletal muscle tissue inflammation. ADAR2 deficiency abolished HFD-induced systemic (P < 0.01), hepatic (P < 0.0001) and muscular (P < 0.001) SAA1 levels. C2C12 myotubes treated with recombinant SAA1 displayed a decrease in myotube length (-37%, P < 0.001), diameter (-20%, P < 0.01), number (-39%, P < 0.001) and fusion index (-46%, P < 0.01). Myogenic markers (myosin heavy chain and myogenin) were decreased in SAA1-treated myoblast C2C12 cells. CONCLUSIONS: These results provide novel evidence that ADAR2 deficiency may be important in obesity-associated sarcopenia and NAFLD. Increased SAA1 might be involved as a regulatory factor in developing sarcopenia in NAFLD.
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Adenosina Desaminasa , Ratones Noqueados , Atrofia Muscular , Enfermedad del Hígado Graso no Alcohólico , Proteínas de Unión al ARN , Proteína Amiloide A Sérica , Animales , Adenosina Desaminasa/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratones , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Atrofia Muscular/metabolismo , Proteína Amiloide A Sérica/metabolismo , Modelos Animales de Enfermedad , Masculino , Dieta Alta en Grasa , Músculo Esquelético/patología , Músculo Esquelético/metabolismoRESUMEN
Estuda-se a incidência de cesáreas no total de partos ocorridos nos hospitais de Ribeiräo Preto (SP) antes e depois da instituiçäo da equiparaçäo da remuneraçäo ao parto por via baixa e cesariano pela Previdência Social. Esta medida da Previdência Social näo alterou a tendência à elevaçäo da incidência de cesáreas no período do estudo (1978-1981). Observou-se a existência de um gradiente na taxa de cesáreas, sendo mais baixa a incidência média de cesáreas entre as pacientes näo-pagantes e a mais elevada nas pacientes particulares, ficando a incidência de cesáreas entre as pacientes previdenciárias em uma posicäo intermediária. Atribui-se este gradiente a diferenças na modalidade de assistência segundo a classe social das pacientes
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Embarazo , Humanos , Femenino , Seguridad Social , Cesárea/economía , Honorarios Médicos , BrasilRESUMEN
Os autores estudam a incidência de cesáreas no total de partos ocorridos nos hospitais de Ribeiräo Preto (SP), antes e depois da instituiçäo da equiparaçäo da remuneraçäo ao parto por via baixa e por cesariana pela Previdência Social. Esta medida da Previdência Social näo alterou a tendência à elevaçäo da incidência de cesáreas no período do estudo (1978-1981). Observou-se a existência de um gradiente na taxa de cesáreas, sendo mais baixa a incidência média de cesáreas entre as pacientes näo-pagantes e a mais elevada nas pacientes particulares, ficando a incidência de cesáreas entre as pacientes previdenciárias em uma posiçäo intermediária. Atribuiu-se este gradiente a diferenças na modalidade de assistência, segundo a classe social das pacientes