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OBJECTIVE: Chronic nonspecific low back pain (CNLBP) is a serious medical and social problem resulting in functional decline and decreased work ability. Tuina, a form of manual therapy, has been sparsely used to treat patients with CNLBP. To systematically assess the efficacy and safety of Tuina for patients with CNLBP. METHODS: Multiple English and Chinese literature databases were searched until September 2022 for randomized controlled trials (RCTs) of Tuina in the treatment of CNLBP. The methodological quality was assessed using the Cochrane Collaboration's tool, and certainty of the evidence was determined with the online Grading of Recommendations, Assessment, Development and Evaluation tool. RESULTS: Fifteen RCTs with 1390 patients were included. Tuina demonstrated a significant effect on pain (SMD: -0.82; 95% CI -1.12 to -0.53; P < .001; I2 = 81%) and physical function (SMD: -0.91; 95% CI -1.55 to -0.27; P = .005; I2 = 90%) when compared to control. However, Tuina resulted in no significant improvement for quality of life (QoL) (SMD: 0.58; 95% CI -0.04 to 1.21; P = .07; I2 = 73%;) compared to control. The Grading of Recommendations, Assessment, Development and Evaluation evidence quality was determined to be low level for pain relief, physical function, and QoL measurements. Only six studies reported adverse events; none were serious. CONCLUSION: Tuina might be an effective and safe strategy for treating CNLBP in terms of pain and physical function, but not for QoL. The study results should be interpreted with caution for their low-level evidence. More multicenter, large-scale RCTs with a rigorous design are required to further confirm our findings.
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Dor Lombar , Massagem , Humanos , Bases de Dados Factuais , Dor Lombar/terapia , Estudos Multicêntricos como Assunto , Manejo da Dor , Cooperação do PacienteRESUMO
Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy-candidiasis-ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases.
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Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Poliendocrinopatias Autoimunes , Síndrome de Sjogren , Humanos , Autoanticorpos , Doenças Autoimunes/genética , Doenças Autoimunes/complicações , Autoantígenos , Receptores de Antígenos de Linfócitos BRESUMO
Cancer nanotechnologies possess immense potential as therapeutic and diagnostic treatment modalities and have undergone significant and rapid advancement in recent years. With this emergence, the complexities of data standards in the field are on the rise. Data sharing and reanalysis is essential to more fully utilize this complex, interdisciplinary information to answer research questions, promote the technologies, optimize use of funding, and maximize the return on scientific investments. In order to support this, various data-sharing portals and repositories have been developed which not only provide searchable nanomaterial characterization data, but also provide access to standardized protocols for synthesis and characterization of nanomaterials as well as cutting-edge publications. The National Cancer Institute's (NCI) caNanoLab is a dedicated repository for all aspects pertaining to cancer-related nanotechnology data. The searchable database provides a unique opportunity for data mining and the use of artificial intelligence and machine learning, which aims to be an essential arm of future research studies, potentially speeding the design and optimization of next-generation therapies. It also provides an opportunity to track the latest trends and patterns in nanomedicine research. This manuscript provides the first look at such trends extracted from caNanoLab and compares these to similar metrics from the NCI's Nanotechnology Characterization Laboratory, a laboratory providing preclinical characterization of cancer nanotechnologies to researchers around the globe. Together, these analyses provide insight into the emerging interests of the research community and rise of promising nanoparticle technologies.
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Nanoestruturas , Neoplasias , Estados Unidos , Humanos , National Cancer Institute (U.S.) , Inteligência Artificial , Nanotecnologia/métodos , Nanomedicina/métodos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVE: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. METHODS: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. RESULTS: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.
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Interferon Tipo I , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Anticorpos Antinucleares , Humanos , Lectinas Tipo C , Nefrite Lúpica/patologia , Glicoproteínas de Membrana , Receptores ImunológicosRESUMO
OBJECTIVE: To use probe oscillation shear wave elastography (PROSE) with two vibration sources to generate two shear waves in the imaging plane to quantitatively assess the shear wave speeds (SWSs) of muscles with and without the diagnosis of taut bands (TB) and/or myofascial trigger points (MTrPs). METHODS: Thirty-three patients were scanned with the PROSE technique. Shear waves were generated through continuous vibration of the ultrasound probe, while the shear wave motions were detected using the same probe. SWSs for the sides with and without TBs and/or MTrPs were computed and compared. The pressure pain thresholds (PPTs) were measured as an indicator of maximum pain tolerance of patients. The statistical differences between the SWSs with and without TBs and/or MTrPs with different PPT values were analyzed using the nonparametric Wilcoxon rank-sum test. RESULTS: The mean SWSs for the sides with TBs and/or MTrPs are faster than that of the contralateral side without TBs and/or MTrPs. A significant difference was observed between mean SWSs with and without TBs and/or MTrPs without any information of PPT, with rank-sum test P < .005. Additionally, with the information of PPT, a significant difference was observed between mean SWSs for the sides with and without TBs and/or MTrPs, for PPT values between 0 and 50 N/cm2 (P < .005), but for PPT values between 50 and 90 N/cm2 , it was difficult to differentiate mean SWSs with and without TBs and/or MTrPs. CONCLUSION: Our preliminary results show that SWSs measured from patients had a significant difference between the mean SWSs with and without TBs and/or MTrPs.
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Técnicas de Imagem por Elasticidade , Síndromes da Dor Miofascial , Técnicas de Imagem por Elasticidade/métodos , Humanos , Músculo Esquelético , Síndromes da Dor Miofascial/diagnóstico por imagem , Projetos Piloto , Pontos-Gatilho/diagnóstico por imagem , UltrassonografiaRESUMO
BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.
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Lúpus Eritematoso Sistêmico , Locos de Características Quantitativas , Alelos , Predisposição Genética para Doença/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Monócitos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND: Chronic nonspecific low back pain (CNLBP) is one of the most common complex pain conditions, and it is strongly associated with high rates of disability. Even though several studies on Tui na for CNLBP have been reported, to our knowledge there has been no systematic review of the currently available publications. OBJECTIVE: This study aims to develop a protocol for a systematic review and meta-analysis that will evaluate the effectiveness and safety of Tui na therapy for patients with CNLBP. METHODS: An electronic literature search of PubMed, Embase, MEDLINE, Cochrane Library, Springer, Scopus, World Health Organization International Clinical Trials Registry Platform, Physiotherapy Evidence Database (PEDro), Clarivate Analytics, and Chinese biomedical databases (the China National Knowledge Infrastructure, Wan-fang database, Chinese Scientific Journals Database, and Chinese Biomedical Literature Databases) will be conducted. Studies will be screened by two reviewers independently based on titles and abstracts, followed by a full-text reading with eligibility criteria. Randomized controlled trials involving Tui na for patients with CNLBP will be reviewed. The primary outcomes of the study are improvement of pain, analgesic medication reduction, improvement of functional disability, and degree of satisfaction with the intervention. A secondary outcome is any adverse event of Tui na intervention. Methodological quality and risk of bias will be assessed with the Cochrane Collaboration Risk of Bias Tool. If studies are sufficient, a meta-analysis of the effectiveness will be performed. If possible, we will evaluate publication bias using funnel plots. If substantial heterogeneity between studies is present, and there are sufficient studies, subgroup analyses will be conducted to explain the study findings. RESULTS: The review database searches will be initiated in December 2020, with findings expected by January 2021. CONCLUSIONS: This protocol will establish a framework of a high-quality literature synthesis on the impact of Tui na treatment in patients with CNLBP. The proposed review will determine whether Tui na is effective and safe for CNLBP patients. TRIAL REGISTRATION: PROSPERO CRD42020166731; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166731. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/20615.
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Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFNß/α activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: "T1IFN undetectable (T1IFN ND) or IFNß/α >1.3" (n = 9) and "T1IFN detectable but IFNß/α ≤ 1.3" (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: "T1IFN ND," "T1IFN detected and IFNß/α ≤ 1.3," and "IFNß/α >1.3." Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFNß/α >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ≤ 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFNß/α>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFNß/α >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.
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Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Interferon Tipo I/sangue , Monócitos/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Feminino , Humanos , Interferon Tipo I/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Análise de Célula Única , TranscriptomaRESUMO
TLR7 and TLR8 are pattern recognition receptors that reside in the endosome and are activated by ssRNA molecules. TLR7 and TLR8 are normally part of the antiviral defense response, but they have also been implicated as drivers of autoimmune diseases such as lupus. The receptors have slightly different ligand-binding specificities and cellular expression patterns that suggest they have nonredundant specialized roles. How the roles of TLR7 and TLR8 differ may be determined by which cell types express each TLR and how the cells respond to activation of each receptor. To provide a better understanding of the effects of TLR7/8 activation, we have characterized changes induced by TLR-specific agonists in different human immune cell types and defined which responses are a direct consequence of TLR7 or TLR8 activation and which are secondary responses driven by type I IFN or cytokines produced subsequent to the primary response. Using cell sorting, gene expression analysis, and intracellular cytokine staining, we have found that the IFN regulatory factor (IRF) and NF-κB pathways are differentially activated downstream of the TLRs in various cell types. Studies with an anti-IFNAR Ab in human cells and lupus mice showed that inhibiting IFN activity can block secondary IFN-induced gene expression changes downstream of TLR7/8 activation, but not NF-κB-regulated genes induced directly by TLR7/8 activation at earlier timepoints. In summary, these results elucidate the different roles TLR7 and TLR8 play in immunity and inform strategies for potential treatment of autoimmune diseases driven by TLR7/8 activation.
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Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , NF-kappa B/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Animais , Autoanticorpos/sangue , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação , Interferon-alfa/farmacologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos DBA , Modelos Biológicos , Células Mieloides/classificação , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistasRESUMO
OBJECTIVE: Type I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll-like receptor (TLR) agonists in high- and low-IFN SLE patient subgroups. METHODS: SLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine-guanine repeats, Resiquimod, IFN-α, and IFN-α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay. RESULTS: Circulating plasmacytoid dendritic cell numbers were specifically reduced in high-IFN SLE patients and not in low-IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high- and low-IFN groups (P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high-IFN patients had less cytokine production in response to TLR ligation than the low-IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed. CONCLUSION: We find striking differences in resting and stimulated cytokine patterns in high- vs. low-IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection.
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Renal artery stenosis (RAS) caused by narrowing of arteries is characterized by microvascular damage. Macrophages are implicated in repair and injury, but the specific populations responsible for these divergent roles have not been identified. Here, we characterized murine kidney F4/80+CD64+ macrophages in three transcriptionally unique populations. Using fate-mapping and parabiosis studies, we demonstrate that CD11b/cint are long-lived kidney-resident (KRM) while CD11chiMÏ, CD11cloMÏ are monocyte-derived macrophages. In a murine model of RAS, KRM self-renewed, while CD11chiMÏ and CD11cloMÏ increased significantly, which was associated with loss of peritubular capillaries. Replacing the native KRM with monocyte-derived KRM using liposomal clodronate and bone marrow transplantation followed by RAS, amplified loss of peritubular capillaries. To further elucidate the nature of interactions between KRM and peritubular endothelial cells, we performed RNA-sequencing on flow-sorted macrophages from Sham and RAS kidneys. KRM showed a prominent activation pattern in RAS with significant enrichment in reparative pathways, like angiogenesis and wound healing. In culture, KRM increased proliferation of renal peritubular endothelial cells implying direct pro-angiogenic properties. Human homologs of KRM identified as CD11bintCD11cintCD68+ increased in post-stenotic kidney biopsies from RAS patients compared to healthy human kidneys, and inversely correlated to kidney function. Thus, KRM may play protective roles in stenotic kidney injury through expansion and upregulation of pro-angiogenic pathways.
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Rim/patologia , Monócitos/patologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno CD11c/metabolismo , Ácido Clodrônico/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Rim/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Fosfolipídeos/metabolismoRESUMO
OBJECTIVES: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. METHODS: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. RESULTS: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. CONCLUSIONS: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.
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OBJECTIVE: We describe a 38-year-old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally. METHODS: NET formation by neutrophils was assessed by scanning electron microscopy. Neutrophil activation and neutrophil elastase production were evaluated by flow cytometry and fluorescent substrate-based functional assay, respectively. A multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PyMOL software was used to generate 3-dimensional models of mutant elastase. RESULTS: Activated neutrophils from the patient demonstrated a significantly decreased ability to form NETs on scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils showed altered levels of interleukin-12 (IL-12) and IL-8, which are key cytokines for antiviral immunity and neutrophil chemotaxis. Three-dimensional mapping revealed that the mutation could alter protein folding and surface charge distribution, potentially perturbing protein trafficking. Thus, the mutation could affect neutrophil function by decreasing NETosis and altering key antiviral activities of neutrophils. CONCLUSION: This is the first report of a human pathogenic ELANE mutation associated with a defect in NETosis and a distinct syndrome of recurrent viral infection and chronic inflammation.
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Artrite/genética , Artrite/virologia , Armadilhas Extracelulares/fisiologia , Elastase de Leucócito/genética , Neutrófilos/fisiologia , Infecções por Parvoviridae/genética , Adulto , Artrite/imunologia , Doença Crônica , Armadilhas Extracelulares/virologia , Feminino , Humanos , Interleucina-12/metabolismo , Interleucina-8/metabolismo , Mutação , Neutrófilos/virologia , Infecções por Parvoviridae/complicações , Infecções por Parvoviridae/imunologia , RecidivaRESUMO
OBJECTIVE: Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single-nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow-up of this polymorphism in human cells. METHODS: Type I IFN was measured in patient sera, using a reporter cell assay. Structural modeling of the PNP variant was performed using PyMOL software. PNP messenger RNA (mRNA) and protein levels and type I IFN-induced gene expression were measured in lymphoblastoid cell lines with known PNP rs1049564 genotypes. The cell cycle was assayed using flow cytometry. RESULTS: Structural modeling indicated no major disruption in folding related to rs1049564. We observed that homozygous rs1049564 TT lymphoblastoid cells had decreased PNP mRNA expression and protein levels, and that cells with the TT genotype had reduced PNP enzymatic activity even when the amount of PNP was controlled. Cells with the TT genotype had a 2-fold increase in S-phase block as compared with cells with the homozygous CC phenotype. The S-phase block could be pharmacologically reversed with hypoxanthine and adenosine, supporting the notion that relative PNP deficiency is the cause of the S-phase block. Type I IFN-induced transcripts were increased in a dose-response manner related to the rs1049564 T allele, at both baseline and after type I IFN stimulation. CONCLUSION: The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment.
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Ciclo Celular/genética , Interferon-alfa/fisiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Purina-Núcleosídeo Fosforilase/genética , Alelos , Ciclo Celular/imunologia , Expressão Gênica , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Fenótipo , Purina-Núcleosídeo Fosforilase/sangue , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
The National Cancer Institute Genomic Data Commons (GDC) is an information system for storing, analyzing, and sharing genomic and clinical data from patients with cancer. The recent high-throughput sequencing of cancer genomes and transcriptomes has produced a big data problem that precludes many cancer biologists and oncologists from gleaning knowledge from these data regarding the nature of malignant processes and the relationship between tumor genomic profiles and treatment response. The GDC aims to democratize access to cancer genomic data and to foster the sharing of these data to promote precision medicine approaches to the diagnosis and treatment of cancer.
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Bases de Dados Genéticas , Neoplasias/genética , Medicina de Precisão , Software , Humanos , National Cancer Institute (U.S.) , Estados UnidosRESUMO
The Cancer Genome Atlas (TCGA) is one of the most ambitious and successful cancer genomics programs to date. The TCGA program has generated, analyzed, and made available genomic sequence, expression, methylation, and copy number variation data on over 11,000 individuals who represent over 30 different types of cancer. This chapter provides a brief overview of the TCGA program and detailed instructions and tips for investigators on how to find, access, and download this data.
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Biologia Computacional/métodos , Bases de Dados Genéticas , Genômica/métodos , Neoplasias/genética , Animais , Humanos , Neoplasias/metabolismo , Software , NavegadorRESUMO
OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14â weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12â weeks. Total serum type I IFN activity, IFN-α and IFN-ß activity were measured using a functional reporter cell assay. RESULTS: In the test set, an increased ratio of IFN-ß to IFN-α (IFN-ß/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-ß/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-ß/α activity ratio (p=0.005). CONCLUSIONS: Increased pretreatment serum IFN-ß/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Interferon-alfa/sangue , Interferon beta/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto JovemRESUMO
The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial, and the interferon regulatory factors (IRFs) play an important role. Autoantibodies formed in SLE target nuclear antigens, and immune complexes formed by these antibodies contain nucleic acid. These immune complexes can activate antiviral pattern recognition receptors (PRRs), resulting in the downstream activation of IRFs, which can induce type I interferon (IFN-I) and other inflammatory mediators. Genetic variations in IRFs have been associated with susceptibility to SLE, and current evidence supports the idea that these polymorphisms are gain of function in humans. Recent studies suggest that these genetic variations contribute to the break in humoral tolerance that allows for nucleic acid binding autoantibodies, and that the same polymorphisms also augment IFN-I production in the presence of these autoantibody immune complexes, forming a feed-forward loop. In this review, we will outline major features of the PRR/IRF systems and describe the role of the IRFs in human SLE pathogenesis.