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Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.
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Tecido Adiposo Marrom/metabolismo , Eosinófilos/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Adipócitos Marrons/metabolismo , Animais , Catecolaminas/metabolismo , Temperatura Baixa , Interleucina-13/genética , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Obesidade/metabolismo , Receptores CCR2/metabolismo , Fator de Transcrição STAT6/metabolismo , TermogêneseRESUMO
Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells (Il6ra(Δmyel) mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra(Δmyel) mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.
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Endotoxemia/imunologia , Resistência à Insulina , Interleucina-6/metabolismo , Ativação de Macrófagos , Macrófagos/imunologia , Obesidade/imunologia , Animais , Células Cultivadas , Humanos , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Interleucina-4/imunologia , Interleucina-6/genética , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Receptores de Interleucina-6/genética , Transdução de Sinais/genéticaRESUMO
Antibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles' propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first investigate these scenarios in simulations: when germline-encoded fitness differences are large relative to the rate and effect size variation of somatic mutations, the same germline alleles persistently dominate the response of different individuals. In contrast, if germline-encoded advantages can be easily overcome by subsequent mutations, allele usage becomes increasingly divergent over time, a pattern we then observe in mice experimentally infected with influenza virus. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest that although germline-encoded specificities can lead to similar immune responses between individuals, diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination.
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COVID-19 , Animais , Camundongos , COVID-19/genética , SARS-CoV-2/genética , Anticorpos , Alelos , Células GerminativasRESUMO
Renal ciliopathies are the leading cause of inherited kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), mutations in the ciliary gene PKD1 lead to the induction of CCL2, which promotes macrophage infiltration in the kidney. Whether or not mutations in genes involved in other renal ciliopathies also lead to immune cells recruitment is controversial. Through the parallel analysis of patients' derived material and murine models, we investigated the inflammatory components of nephronophthisis (NPH), a rare renal ciliopathy affecting children and adults. Our results show that NPH mutations lead to kidney infiltration by neutrophils, macrophages and T cells. Contrary to ADPKD, this immune cell recruitment does not rely on the induction of CCL2 in mutated cells, which is dispensable for disease progression. Through an unbiased approach, we identified a set of inflammatory cytokines that are upregulated precociously and independently of CCL2 in murine models of NPH. The majority of these transcripts is also upregulated in NPH patient renal cells at a level exceeding those found in common non-immune chronic kidney diseases. This study reveals that inflammation is a central aspect in NPH and delineates a specific set of inflammatory mediators that likely regulates immune cell recruitment in response to NPH genes mutations.
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Ciliopatias , Doenças Renais Policísticas , Rim Policístico Autossômico Dominante , Adulto , Animais , Criança , Ciliopatias/genética , Fibrose , Humanos , Rim , Camundongos , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genéticaRESUMO
Luminescent coupling (LC) is a key phenomenon in monolithic tandem solar cells. This study presents a nondestructive technique to quantitatively evaluate the LC effect, addressing a gap in the existing predictions made by optical modeling. The method involves measuring the ratio of photons emitted from the high bandgap top cell that escape through the rear, contributing additional current to the bottom cell, and to those escaping from the front side of top cell. The findings indicate that in the analyzed monolithic perovskite/silicon tandem solar cells, more than 85% of the emitted photons escaping from the perovskite top cell are used to generate additional current in the bottom cell. This process notably reduces the mismatch in the generated current between each subcell, particularly when the current is limited by the low bandgap subcell. The presented method is applicable to a variety of monolithic tandem structures, providing vital information for subcell characterization, providing vital information for predicting energy output and optimization for outdoor applications.
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We report the high-yielding, large-scale, one-pot synthesis of two versatile building blocks (1-Cl and 1-Br) for the regioselective synthesis of a variety of 2,3,5-trisubstituted pyridines from inexpensive materials. These molecules are readily derivatized at positions 2, 3, and 5. These building blocks can also be used for the synthesis of fused pyrido-oxazines and for the synthesis of 2,3,4,5-tetrasubstituted pyridines.
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Herein we report a method for affording 2-benzyl benzoxazoles from substituted styrenes and 2-nitrophenols. The success of this method relies on the use of simple reagents, namely elemental sulfur and DABCO. A combination of identical reagents was utilized for the annulation of styrenes with N,N-dialkyl-3-nitroanilines to afford 2-benzyl benzothiazoles. Overall, benzoxazoles and benzothiazoles bearing useful functionalities such as halogens, amines, and heterocyclic groups were isolated in moderate to good yields. Our methods are a rare example of divergent transformations of substituted nitroarenes towards 2-benzyl benzoxazoles and benzothiazoles.
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OBJECTIVE: To investigate the neurodevelopmental outcomes for preterm infants born < 29 weeks gestation with/without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Preterm infants < 29 weeks' gestation born 2007-2018 in New South Wales and the Australian Capital Territory, Australia, were included. Infants who died < 36 weeks' postmenstrual age and those with major congenital anomalies were excluded. Subjects were assessed at 18-42 months corrected age using the Bayley Scales of Infant Development, 3rd edition. RESULTS: 1436 infants without BPD (non-BPD) and 1189 infants with BPD were followed. The BPD group, 69 % infants were discharged without respiratory support (BPD1), 29 % on oxygen (BPD2) and 2 % on pressure support/tracheostomy (BPD3). Moderate neurodevelopmental impairment (NDI) was evident in 5.7 % of non-BPD infants, 11 % BPD1, 15 % BPD2, 15 % BPD3 infants. Severe NDI was seen in 1.7 % non-BPD infants, 3.4 % BPD1, 7.3 % BPD2, 35 % BPD3 infants. After adjusting for confounders, infants with BPD2 (OR 2.24, 99.9 % CI 1.25 to 5.77) or BPD3 (OR 5.99, 99.9 % CI 1.27 to 46.77) were more likely to have moderate-severe NDI compared to non-BPD infants. CONCLUSION: The majority of infants with BPD were discharged home without respiratory support and had better neurocognitive outcomes in early childhood compared to those that required home-based oxygen or respiratory support.
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Displasia Broncopulmonar , Lactente Extremamente Prematuro , Humanos , Displasia Broncopulmonar/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Recém-Nascido , New South Wales/epidemiologia , Lactente , Pré-Escolar , Território da Capital Australiana/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Idade Gestacional , Desenvolvimento InfantilRESUMO
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Neoplasias da Mama , Neoplasias Colorretais , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Neoplasias da Mama/patologia , Carcinogênese/patologia , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Humanos , Masculino , Obesidade/complicações , Obesidade/metabolismo , Células Estromais/metabolismo , Microambiente TumoralRESUMO
The liver is a major organ that is involved in essential biological functions such as digestion, nutrient storage, and detoxification. Furthermore, it is one of the most metabolically active organs with active roles in regulating carbohydrate, protein, and lipid metabolism. Hepatocellular carcinoma is a cancer of the liver that is associated in settings of chronic inflammation such as viral hepatitis, repeated toxin exposure, and fatty liver disease. Furthermore, liver cancer is the most common cause of death associated with cirrhosis and is the 3rd leading cause of global cancer deaths. LKB1 signaling has been demonstrated to play a role in regulating cellular metabolism under normal and nutrient deficient conditions. Furthermore, LKB1 signaling has been found to be involved in many cancers with most reports identifying LKB1 to have a tumor suppressive role. In this review, we use the KMPlotter database to correlate RNA levels of LKB1 signaling genes and hepatocellular carcinoma patient survival outcomes with the hopes of identifying potential biomarkers clinical usage. Based on our results STRADß, CAB39L, AMPKα, MARK2, SIK1, SIK2, BRSK1, BRSK2, and SNRK expression has a statistically significant impact on patient survival.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismoRESUMO
Immune checkpoint inhibitors and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential in cancers with high tumor mutational burden (TMB), such as melanoma, but not in cancers with low TMB, such as mutant epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma. Precision immunotherapy is an unmet need for most cancers, particularly for cancers that respond inadequately to immune checkpoint inhibitors. Here, we employed large-scale MS-based proteogenomic profiling to identify potential immunogenic human leukocyte antigen (HLA) class I-presented peptides in melanoma and EGFR-mutant lung adenocarcinoma. Similar numbers of peptides were identified from both tumor types. Cell line and patient-specific databases (DBs) were constructed using variants identified from whole-exome sequencing. A de novo search algorithm was used to interrogate the HLA class I immunopeptidome MS data. We identified 12 variant peptides and several classes of tumor-associated antigen-derived peptides. We constructed a cancer germ line (CG) antigen DB with 285 antigens. This allowed us to identify 40 class I-presented CG antigen-derived peptides. The class I immunopeptidome comprised more than 1000 post-translationally modified (PTM) peptides representing 58 different PTMs, underscoring the critical role PTMs may play in HLA binding. Finally, leveraging de novo search algorithm and an annotated long noncoding RNA (lncRNA) DB, we developed a novel lncRNA-encoded peptide discovery pipeline to identify 44 lncRNA-derived peptides that are presented by class I. We validated tandem MS spectra of select variant, CG antigen, and lncRNA-derived peptides using synthetic peptides and performed HLA class I-binding assays to demonstrate binding to class I proteins. In summary, we provide direct evidence of HLA class I presentation of a large number of variant and tumor-associated peptides in both low and high TMB cancer. These results can potentially be useful for precision immunotherapies, such as vaccine or adoptive cell therapies in melanoma and EGFR-mutant lung cancers.
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Adenocarcinoma de Pulmão/metabolismo , Antígenos de Neoplasias/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pulmonares/metabolismo , Melanoma/metabolismo , Peptídeos/metabolismo , Adenocarcinoma de Pulmão/genética , Idoso , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Receptores ErbB/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Melanoma/genética , Mutação , Peptídeos/genética , ProteogenômicaRESUMO
Focal dermal hypoplasia (FDH) is a rare X-linked dominant syndrome characterized by streaky cutaneous atrophy in a blaschkoid distribution, skeletal dysplasias, and ocular abnormalities. Here, we report hypospadias and chordee identified in a male patient with molecularly confirmed FDH. This report highlights a new clinical manifestation of male patients with FDH.
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Hipoplasia Dérmica Focal , Humanos , Masculino , Hipoplasia Dérmica Focal/complicações , Hipoplasia Dérmica Focal/diagnóstico , Hipoplasia Dérmica Focal/genética , AtrofiaRESUMO
Recently, federated learning (FL) has been receiving great attention as an effective machine learning method to avoid the security issue in raw data collection, as well as to distribute the computing load to edge devices. However, even though wireless communication is an essential component for implementing FL in edge networks, there have been few works that analyze the effect of wireless networks on FL. In this paper, we investigate FL in small-cell networks where multiple base stations (BSs) and users are located according to a homogeneous Poisson point process (PPP) with different densities. We comprehensively analyze the effects of geographic node deployment on the model aggregation in FL on the basis of stochastic geometry-based analysis. We derive the closed-form expressions of coverage probability with tractable approximations and discuss the minimum required BS density for achieving a target model aggregation rate in small-cell networks. Our analysis and simulation results provide insightful information for understanding the behaviors of FL in small-cell networks; these can be exploited as a guideline for designing the network facilitating wireless FL.
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AIM: The accuracy of 3D images produced by an intraoral scanner (IOS) is affected by the optical characteristics of restorative materials such as metal, ceramic, and composite resin. The present in vitro study aimed to investigate the impact of core buildup composite resin translucency on IOS accuracy. MATERIALS AND METHODS: A core buildup procedure was performed on a proprietary 3D-printed model using injectable composite resins in four groups with different levels of translucency (highest to lowest: AE, A3, AO3, and EX). Ten experimental scans per group were performed using a Medit i700 IOS on a phantom head-mounted model. Reference scans were obtained using an industrial scanner (Solutionix C500). Values of accuracy (trueness and precision) for the respective groups were evaluated using mean deviation values following 3D superimposition. RESULTS: Composite resin translucency caused the scale reduction of the optical impressions. Values of trueness showed the highest scale reduction in AE, significantly, followed by A3, AO3, and EX. Considering 50 µm as the cut-off value of deviations for clinical acceptability, the analysis showed most deviations in AE and A3. Similar results were found with precision, where AE showed the highest deviation value statistically, followed by A3, AO3, and EX. CONCLUSIONS: Composite resin translucency affects the accuracy of optical impressions, causing a fitting error of CAD/CAM prostheses. The more translucent the composite resin, the less accurate the optical impression. This suggests the need for proper compensation during prosthesis designing for an optimal clinical result. In addition, practitioners should indicate in the digital workflow the proper restorative materials regarding not only the mechanical properties and esthetics, but also the optical characteristics.
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Resinas Compostas , Técnica de Moldagem Odontológica , Humanos , Modelos Dentários , Estética Dentária , Materiais Dentários , Imageamento Tridimensional , Desenho Assistido por ComputadorRESUMO
Agent-Based Modelling (ABM) is a computer modelling technique that simulates the behaviour and interactions of autonomous agents within a virtual environment. Applied to health equity, this technique allows for a better understanding of the complex social and economic determinants that contribute to health inequities and enables the evaluation of the potential effects of public policies on the latter. Despite some limitations related to the accessibility and quality of health data and the complexity of the models, ABM appears to be a promising tool in the field of health equity, both for researchers in public or community health and for policy makers.
L'Agent-Based Modelling (ABM) est une technique de modélisation informatique qui simule le comportement et les interactions d'agents autonomes au sein d'un environnement virtuel. Appliquée à l'équité en santé, cette technique permet de mieux comprendre les déterminants sociaux et économiques complexes qui contribuent aux iniquités de santé et d'évaluer les effets potentiels de politiques publiques sur ces dernières. Malgré quelques limitations liées notamment à l'accessibilité et la qualité des données de santé et la complexité des modèles, l'ABM apparaît comme un outil prometteur dans le domaine de l'équité en santé, tant pour les chercheurs en santé publique et communautaire que pour les décideurs politiques.
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Equidade em Saúde , Humanos , Inteligência Artificial , Política Pública , Saúde Pública , Análise de Sistemas , Política de SaúdeRESUMO
BACKGROUND: Metabolic stress resulting from nutrient deficiency is one of the hallmarks of a growing tumour. Here, we tested the hypothesis that metabolic stress induces breast cancer stem-like cell (BCSC) phenotype in triple-negative breast cancer (TNBC). METHODS: Flow cytometry for GD2 expression, mass spectrometry and Ingenuity Pathway Analysis for metabolomics, bioinformatics, in vitro tumorigenesis and in vivo models were used. RESULTS: Serum/glucose deprivation not only increased stress markers but also enhanced GD2+ BCSC phenotype and function in TNBC cells. Global metabolomics profiling identified upregulation of glutathione biosynthesis in GD2high cells, suggesting a role of glutamine in the BCSC phenotype. Cueing from the upregulation of the glutamine transporters in primary breast tumours, inhibition of glutamine uptake using small-molecule inhibitor V9302 reduced GD2+ cells by 70-80% and BCSC characteristics in TNBC cells. Mechanistic studies revealed inhibition of the mTOR pathway and induction of ferroptosis by V9302 in TNBC cells. Finally, inhibition of glutamine uptake significantly reduced in vivo tumour growth in a TNBC patient-derived xenograft model using NSG (non-obese diabetic/severe combined immunodeficiency with a complete null allele of the IL-2 receptor common gamma chain) mice. CONCLUSION: Here, we show metabolic stress results in GD2+ BCSC phenotype in TNBC and glutamine contributes to GD2+ phenotype, and targeting the glutamine transporters could complement conventional chemotherapy in TNBC.
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Glicemia/análise , Gangliosídeos/metabolismo , Glutamina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Feminino , Ferroptose/efeitos dos fármacos , Humanos , Metabolômica/métodos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Fenótipo , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a "precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells ± PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Lesões Pré-Cancerosas , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Queratinócitos/metabolismo , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Receptores de Fatores de Crescimento de Fibroblastos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Microambiente TumoralRESUMO
Breast cancer is a complex disease exhibiting a great degree of heterogeneity due to different molecular subtypes. Notch signaling regulates the differentiation of breast epithelial cells during normal development and plays a crucial role in breast cancer progression through the abnormal expression of the Notch up-and down-stream effectors. To date, there are only a few patient-centered clinical studies using datasets characterizing the role of Notch signaling pathway regulators in breast cancer; thus, we investigate the role and functionality of these factors in different subtypes using publicly available databases containing records from large studies. High-throughput genomic data and clinical information extracted from TCGA were analyzed. We performed Kaplan-Meier survival and differential gene expression analyses using the HALLMARK_NOTCH_SIGNALING gene set. To determine if epigenetic regulation of the Notch regulators contributes to their expression, we analyzed methylation levels of these factors using the TCGA HumanMethylation450 Array data. Notch receptors and ligands expression is generally associated with the tumor subtype, grade, and stage. Furthermore, we showed gene expression levels of most Notch factors were associated with DNA methylation rate. Modulating the expression levels of Notch receptors and effectors can be a potential therapeutic approach for breast cancer. As we outline herein, elucidating the novel prognostic and regulatory roles of Notch implicate this pathway as an essential mediator controlling breast cancer progression.
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Neoplasias da Mama , Transcriptoma , Humanos , Feminino , Prognóstico , Neoplasias da Mama/genética , Epigênese Genética , Perfilação da Expressão Gênica , Transdução de Sinais/genética , Receptores Notch/genéticaRESUMO
PURPOSE OF REVIEW: Early revascularization, invasive hemodynamic profiling, and initiation of temporary mechanical circulatory support (MCS) have all become routine components of cardiogenic shock (CS) management. Despite this evolution in clinical practice, patient selection and timing of treatment initiation remain a significant barrier to achieving sustained improvement in CS outcomes. Recent efforts to standardize CS management, through the development of treatment algorithms, have relied heavily on surrogate endpoints to drive therapeutic decisions. The present review aims to provide an overview of the basis of evidence for those surrogate endpoints commonly employed in clinical trials and CS management algorithms. RECENT FINDINGS: Recent publications from both observational and randomized cohorts have demonstrated the utility of surrogate endpoints in risk stratifying patients with CS. In particular, invasive hemodynamics using pulmonary artery catheters to guide initiation and weaning of MCS, biochemical markers that portend imminent end-organ failure, and clinical risk scores that combine multiple hemodynamic and laboratory parameters have demonstrated an ability to prognosticate outcomes in patients with CS. SUMMARY: Although further validation is necessary, multiple clinical, hemodynamic, and biochemical markers have demonstrated utility as surrogate endpoints in CS, and will undoubtedly assist physicians in clinical decision-making.
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Coração Auxiliar , Choque Cardiogênico , Biomarcadores , Tomada de Decisão Clínica , Hemodinâmica , Humanos , Fatores de Risco , Choque Cardiogênico/terapiaRESUMO
PURPOSE: To conduct a systematic review to identify studies that assessed the association between CYP2C19 polymorphisms and clinical outcomes in peripheral artery disease (PAD) patients who took clopidogrel. METHODS: We systematically searched Ovid EMBASE, PubMed, and Web of Science from November 1997 (inception) to September 2020. We included observational studies evaluating how CYP2C19 polymorphism is associated with clopidogrel's effectiveness and safety among patients with PAD. We extracted relevant information details from eligible studies (e.g., study type, patient population, study outcomes). We used the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) Tool to assess the risk of bias for included observational studies. RESULTS: The outcomes of interest were the effectiveness and safety of clopidogrel. The effectiveness outcomes included clinical ineffectiveness (e.g., restenosis). The safety outcomes included bleeding and death related to the use of clopidogrel. We identified four observational studies with a sample size ranging from 50 to 278. Outcomes and comparison groups of the studies varied. Three studies (75%) had an overall low risk of bias. All included studies demonstrated that carrying CYP2C19 loss of function (LOF) alleles was significantly associated with reduced clinical effectiveness and safety of clopidogrel. CONCLUSIONS: Our systematic review showed an association between CYP2C19 LOF alleles and reduced functions of clopidogrel. The use of CYP2C19 testing in PAD patients prescribed clopidogrel may help improve the clinical outcomes. However, based on the limited evidence, there is a need for randomized clinical trials in PAD patients to test both the effectiveness and safety outcomes of clopidogrel.