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Importance: Egg introduction in infants at age 4 to 6 months is associated with a lower risk of immunoglobulin E-mediated egg allergy (EA). However, whether their risk of EA at age 12 months is affected by maternal intake of eggs at birth is unknown. Objective: To determine the effect of maternal egg intake during the early neonatal period (0-5 days) on the development of EA in breastfed infants at age 12 months. Design, Setting, and Participants: This multicenter, single-blind (outcome data evaluators), randomized clinical trial was conducted from December 18, 2017, to May 31, 2021, at 10 medical facilities in Japan. Newborns with at least 1 of 2 parents having an allergic disease were included. Neonates whose mothers had EA or were unable to consume breast milk after the age of 2 days were excluded. Data were analyzed on an intention-to-treat basis. Interventions: Newborns were randomized (1:1) to a maternal egg consumption (MEC) group, wherein the mothers consumed 1 whole egg per day during the first 5 days of the neonate's life, and a maternal egg elimination (MEE) group, wherein the mothers eliminated eggs from their diet during the same period. Main Outcomes and Measures: The primary outcome was EA at age 12 months. Egg allergy was defined as sensitization to egg white or ovomucoid plus a positive test result in an oral food challenge or an episode of obvious immediate symptoms after egg ingestion. Results: Of the 380 newborns included (198 [52.1%] female), 367 (MEC: n = 183; MEE: n = 184) were followed up for 12 months. On days 3 and 4 after delivery, the proportions of neonates with ovalbumin and ovomucoid detection in breast milk were higher in the MEC group than in the MEE group (ovalbumin: 10.7% vs 2.0%; risk ratio [RR], 5.23; 95% CI, 1.56-17.56; ovomucoid: 11.3% vs 2.0%; RR, 5.55; 95% CI, 1.66-18.55). At age 12 months, the MEC and MEE groups did not differ significantly in EA (9.3% vs 7.6%; RR, 1.22; 95% CI, 0.62-2.40) or sensitization to egg white (62.8% vs 58.7%; RR, 1.07; 95% CI, 0.91-1.26). No adverse effects were reported. Conclusions and Relevance: In this randomized clinical trial, EA development and sensitization to eggs were unaffected by MEC during the early neonatal period. Trial Registration: UMIN Clinical Trials Registry: UMIN000027593.
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Hipersensibilidad al Huevo , Lactante , Recién Nacido , Humanos , Femenino , Masculino , Hipersensibilidad al Huevo/epidemiología , Lactancia Materna , Ovalbúmina , Madres , Ovomucina , Método Simple Ciego , Leche HumanaRESUMEN
BACKGROUND: This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F. METHODS: Healthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2-6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12-15 months of age. Adverse events (AEs) were collected on Days 1-14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 µg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3. RESULTS: Overall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > -10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI -10.6). CONCLUSION: In Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04384107; EudraCT 2019-003644-68.
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Infecciones Neumocócicas , Humanos , Lactante , Vacunas Conjugadas , Pueblos del Este de Asia , Anticuerpos Antibacterianos , Inmunoglobulina G , Vacunas Neumococicas , Inmunogenicidad VacunalRESUMEN
Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C. elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase. We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual's sleep.
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Caenorhabditis elegans , Proteostasis , Animales , Ratones , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Respuesta de Proteína Desplegada , Estrés del Retículo Endoplásmico/fisiología , Transducción de Señal , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Mamíferos/metabolismoRESUMEN
Embryonic diapause is a reproductive strategy in which embryo development and growth is temporarily arrested within the uterus to ensure the survival of neonates and mothers during unfavorable conditions. Pregnancy is reinitiated when conditions become favorable for neonatal survival. The mechanism of how the uterus enters diapause in various species remains unclear. Mice with uterine depletion of Foxa2, a transcription factor, are infertile. In this study, we show that dormant blastocysts are recovered from these mice on day 8 of pregnancy with persistent expression of uterine Msx1, a gene critical to maintaining the uterine quiescent state, suggesting that these mice enter embryonic diapause. Leukemia inhibitory factor (LIF) can resume implantation in these mice. Although estrogen is critical for implantation in progesterone-primed uterus, our current model reveals that FOXA2-independent estrogenic effects are detrimental to sustaining uterine quiescence. Interestingly, progesterone and anti-estrogen can prolong uterine quiescence in the absence of FOXA2. Although we find that Msx1 expression persists in the uterus deficient in Foxa2, the complex relationship of FOXA2 with Msx genes and estrogen receptors remains to be explored.
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Diapausa , Progesterona , Animales , Blastocisto/metabolismo , Implantación del Embrión , Desarrollo Embrionario , Estrógenos/metabolismo , Femenino , Factor Nuclear 3-beta del Hepatocito/genética , Factor Nuclear 3-beta del Hepatocito/metabolismo , Ratones , Embarazo , Progesterona/metabolismo , Útero/metabolismoRESUMEN
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.
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Encéfalo/metabolismo , Metabolómica/métodos , Mitocondrias/metabolismo , Peptidil-Prolil Isomerasa F/genética , Sepsis/metabolismo , Animales , Temperatura Corporal , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Glutatión/metabolismo , Disulfuro de Glutatión/metabolismo , Masculino , Ratones , Poro de Transición de la Permeabilidad Mitocondrial , Especies Reactivas de Oxígeno/metabolismo , Sepsis/etiología , Sepsis/genética , Sepsis/mortalidadRESUMEN
PURPOSE: The goal of this study is to clarify the underlying mechanisms of metastasis suppression by carbon-ion radiotherapy combined with immature dendritic cell immunotherapy (CiDC), which was shown previously to suppress pulmonary metastasis in an NR-S1-bearing C3H/He mouse model. METHODS AND MATERIALS: Mouse carcinoma cell lines (LLC, LM8, Colon-26, and Colon-26MGS) were grafted into the right hind paw of syngeneic mice (C57BL/6J, C3H/He, and BALB/c). Seven days later, the tumors on the mice were locally irradiated with carbon ions (290 MeV/n, 6 cm spread-out Bragg peak, 1 or 2 Gy). At 1.5 days after irradiation, bone marrow-derived immature dendritic cells (iDCs) were administrated intravenously into a subset of the mice. The number of lung metastases was evaluated within 3 weeks after irradiation. In vitro-cultured cancer cells were irradiated with carbon ions (290 MeV/n, mono-energy, LET approximately 70-80 keV/µm), and then cocultured with iDCs for 3 days to determine the DC maturation. RESULTS: CiDC effectively repressed distant lung metastases in cancer cell (LLC and LM8)-bearing C57BL/6J and C3H/He mouse models. However, Colon-26- and Colon-26MGS-bearing BALB/c models did not show enhancement of metastasis suppression by combination treatment. This result was evaluated further by comparing LM8-bearing C3H/He and LLC-bearing C57BL/6J models with a Colon-26-bearing BALB/c model. In vitro coculture assays demonstrated that all irradiated cell lines were able to activate C3H/He- or C57BL/6J-derived iDCs into mature DCs, but not BALB/c-derived iDCs. CONCLUSIONS: The genetic background of the host could have a strong effect on the potency of combination therapy. Future animal and clinical testing should evaluate host genetic factors when evaluating treatment efficacy.
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Inmunoterapia , Neoplasias Pulmonares , Animales , Carbono , Células Dendríticas , Antecedentes Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BLRESUMEN
Rheumatoid arthritis (RA) is one of the most critical articular diseases, which is characterized by synovial hyperplasia and impaired quality of life. The clinical features of RA include chronic inflammation of the joints associated with synovial cell overgrowth. However, the mechanism regulating the outgrowth of fibroblastlike synoviocytes (FLS) is not fully understood. The present study reported that grap2 cyclin D interacting protein (GCIP), an inhibitor of DNA binding/differentiation (ID)like helixloophelix protein, interacted with cAMPresponse elementbinding protein (CREB)binding protein (CBP). Furthermore, GCIP repressed CREB and NFκBdependent gene expression by inhibiting CBP binding to RNA polymerase II complexes. GCIP depletion via small interfering RNA enhanced FLS growth, whereas stable GCIP expression suppressed the growth of 293 cells. In addition, GCIP depletion in FLS induced the expression of cyclin D1, a CREB target gene. The present study identified a novel inhibitory mechanism in which an ID protein may functionally target the transcriptional coactivator CBP. These results suggested that GCIP downregulation may be pivotal in FLS outgrowth.
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Proteína de Unión a CREB/genética , Proliferación Celular/genética , Fibroblastos/metabolismo , Sinoviocitos/metabolismo , Factores de Transcripción/genética , Anciano , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Proteína de Unión a CREB/metabolismo , Movimiento Celular/genética , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Regulación hacia Abajo , Femenino , Fibroblastos/citología , Regulación de la Expresión Génica , Células HEK293 , Humanos , Persona de Mediana Edad , Unión Proteica , Interferencia de ARN , Sinoviocitos/citología , Factores de Transcripción/metabolismoRESUMEN
Obesity is currently a major medical and societal issue. Synoviolin (SYVN1) is an E3 ubiquitin ligase involved in endoplasmic reticulum (ER) stress. Overexpression of Syvn1 has been found in genetically obese mice (ob/ob and db/db), and treatment with a Syvn1 inhibitor suppresses weight gain in some mouse models (C57BL/6J and db/db). However, SYVN1 expression in humans has not yet been elucidated. In the present study, 35 human volunteers were analyzed, and the expression level of SYVN1 mRNA in peripheral blood mononuclear cells (PBMCs) was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Expression of SYVN1 mRNA was significantly increased in PBMCs from volunteers with a BMI ≥25.0, compared with volunteers with a BMI <25.0. In addition, PCR array and RT-qPCR of ER stress-responsive genes revealed that the expression of activating transcription factor 6 (ATF6), which plays an important role in the transcriptional activation of SYVN1, was increased in PBMCs from volunteers with a BMI ≥25.0. These results suggest that the ATF6-SYVN1 axis might be an important pathway in the progression of obesity.
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Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 µg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 µg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.
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Agentes Anticonceptivos Hormonales/farmacología , Implantación del Embrión/efectos de los fármacos , Factor Inhibidor de Leucemia/metabolismo , Levonorgestrel/farmacología , Útero/efectos de los fármacos , Animales , Blastocisto/efectos de los fármacos , Femenino , Masculino , Ratones Endogámicos C57BL , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Útero/metabolismoAsunto(s)
Anafilaxia/diagnóstico , Hipersensibilidad al Huevo/diagnóstico , Administración Oral , Alérgenos/inmunología , Anafilaxia/terapia , Niño , Preescolar , Cálculo de Dosificación de Drogas , Hipersensibilidad al Huevo/terapia , Proteínas del Huevo/inmunología , Femenino , Calor , Humanos , Tolerancia Inmunológica , Inmunización , Inmunoglobulina E/metabolismo , Masculino , Guías de Práctica Clínica como Asunto , Estudios ProspectivosRESUMEN
Synoviolin (Syvn1), an E3 ubiquitin ligase in endoplasmic reticulumassociated protein degradation, is involved in rheumatoid arthritis, fibrosis, liver cirrhosis and obesity. We previously demonstrated that Syvn1 negatively regulates the function of peroxisome proliferatoractivated receptor gamma coactivator1ß (PGC1ß). In addition, treatment with a Syvn1 inhibitor suppressed weight gain in a mouse model of obesity by activating PGC1ß via Syvn1 inhibition. It has been suggested that the Syvn1 inhibitors may have therapeutic benefits in obese patients. The present study tested the inhibitory activity of walnut extract, a natural product, on Syvn1 activity. Walnut extract inhibited the effect of Syvn1 on the cell proliferation of rheumatoid synovial cells and repressed the interaction between PGC1ß and Syvn1 in an in vitro binding assay. Polyubiquitination of PGC1ß by Syvn1 was suppressed by walnut extract in a concentrationdependent manner, but walnut extract did not have an inhibitory effect on the autoubiquitination of Syvn1. Treatment with walnut extract in mouse embryonic fibroblasts increased the number of mitochondria, suggesting that exposure to the extract recovered PGC1ß function. These results demonstrated that constituents of walnut extract may serve as lead compounds in drug development efforts aiming to produce drugs to treat patients with obesity and obesityassociated metabolic diseases.
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Inhibidores Enzimáticos/farmacología , Juglandaceae/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Animales , Línea Celular , Expresión Génica , Ratones , Ratones Noqueados , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Unión Proteica/efectos de los fármacos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Although it has been reported that hypoxia inducible factor 2 α (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2α in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2α regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2α allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Implantación del Embrión/fisiología , Útero/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Blastocisto/fisiología , Decidua/efectos de los fármacos , Decidua/fisiología , Modelos Animales de Enfermedad , Epitelio/fisiología , Femenino , Fertilidad/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/deficiencia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Infertilidad Femenina/etiología , Infertilidad Femenina/patología , Infertilidad Femenina/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Ratones Transgénicos , Embarazo , Progesterona/administración & dosificación , Transducción de SeñalRESUMEN
Sepsisassociated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLPinduced septic mice. Notably, KYN was not detected in CLPinduced septic Syvn1deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1deficient mice compared to that in wildtype mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dosedependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NFE2related factor 2 and peroxisome proliferatoractivated receptor coactivator 1ß, which are targets of Syvn1induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLPinduced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.
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Inflamación/genética , Factor 2 Relacionado con NF-E2/genética , Proteínas Nucleares/genética , Sepsis/genética , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Ciego/metabolismo , Ciego/patología , Modelos Animales de Enfermedad , Humanos , Inflamación/metabolismo , Inflamación/patología , Quinurenina/genética , Quinurenina/metabolismo , Ratones , Sepsis/metabolismo , Sepsis/patología , Transaminasas/genéticaRESUMEN
This corrects the article DOI: 10.1038/srep36943.
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Rheumatoid arthritis (RA) is a chronic inflammatory articular disease that is characterized by synovial hyperplasia. A number of signaling pathways are associated with the development and induced symptoms of RA. Notably, patients with RA have increased protein citrullination and generation of autoantibodies against citrullinated proteins. Genome wide association studies have revealed that peptidylarginine deiminase 4 (PADI4) is an enzyme implicated in citrullination in the RA synovium. Autoantibodies targeting citrullinated proteins are used as diagnostic markers in patients with RA. The functions associated with citrullinated proteins are thought to induce autoimmunity, however, the regulatory mechanisms of citrullination via PADI4 are unclear. The group has previously cloned an E3 ubiquitin ligase, synoviolin (SYVN1), from the RA synovium, demonstrating that SYVN1 serves critical roles in synovial hyperplasia. The data indicated that the endoplasmic reticulum (ER) associated degradation system, which involves SYVN1, may have important roles in the proliferation of synoviocytes. In addition, ubiquitination by SYVN1 is associated with fibrosis, inflammation and cytokine production via the regulation of ER stress signals and quality control of proteins. The present study investigated the crosstalk between the representative posttranslational signaling processes, citrullination and ubiquitination. The results revealed that PADI4 interacted with SYVN1 directly and that overexpression of PADI4 suppressed the ubiquitination of proteins. Thus, a reduction in ER stress induced by PADI4 may abrogate the initiation of chronic RA by suppressing the proliferative signals of RA synoviocytes.
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Desiminasas de la Arginina Proteica/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Expresión Génica , Humanos , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Arginina Deiminasa Proteína-Tipo 4 , Desiminasas de la Arginina Proteica/genética , Sinoviocitos/metabolismo , UbiquitinaciónRESUMEN
Carbon-ion radiotherapy (CIRT) is an advanced radiotherapy and has achieved good local control, even in tumors that are resistant to conventional photon beam radiotherapy (PBRT). However, distant metastasis control is an important issue. Recently, the combination of radiotherapy and immunotherapy has attracted the attention. In immunotherapy, dendritic cells (DCs) play a pivotal role in the anti-tumor immune system. However, the mechanisms underlying the combination therapy of DCs and radiotherapy have been unclear. In the present study, we evaluated anti-metastatic effects of this combination therapy, focused on the irradiation type and the route of DC administration, using a mouse model. C3H/He mice bearing NR-S1 cells were treated with CIRT or PBRT, using biologically equivalent doses. Subsequently, DCs were administered intratumorally (IT) or intravenously (IV). IV and IT DC administrations combined with CIRT to the local tumor, but not alone, significantly suppressed pulmonary metastasis, whereas the combination of DCs with PBRT suppressed metastasis at a relatively higher dose. Additionally, the anti-metastatic effect was greater in IV DC administration compared with in IT DC administration in both CIRT and PBRT. The expression levels of CD40 and IL-12 in DCs were significantly increased after co-culturing with CIRT-treated NR-S1 cells. In addition, IV administration of those co-cultured DCs significantly suppressed pulmonary metastasis. Furthermore, ecto-calreticulin levels from CIRT-treated NR-S1 cells significantly increased compared with those of a PBRT-treated tumor. Taken together, these results suggest that local CIRT combined with IV DCs augments an immunogenicity of the tumor cells by ecto-calreticulin expression and the maturation of DCs to stimulate anti-tumor immunity to decrease lung metastases.
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Células Dendríticas/metabolismo , Radioterapia de Iones Pesados , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Administración Intravenosa , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Células Clonales , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Femenino , Rayos gamma , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Ratones Endogámicos C3H , Metástasis de la Neoplasia , Fenotipo , FotonesRESUMEN
PURPOSE: The aim of the present study was to determine the brain regions with altered metabolism in patients with treatment-naïve fibromyalgia (FM). METHODS: We used [18F] fluoro-d-glucose positron emission tomography to examine a total of 18 treatment-naïve FM patients and 18 age- and sex-matched healthy controls not suffering from pain. A voxel-by-voxel group analysis was performed using statistical parametric mapping. RESULTS: No significant voxel (peak)-level results were detected in this study; however, some regions were detected as significant-size clusters. There were no significant differences in brain metabolism between FM patients and controls. However, the right thalamus and left lentiform nucleus were hypermetabolic areas in FM patients with poor prognosis compared to the healthy controls. In contrast, the left insula and left lentiform nucleus were hypometabolic areas in FM patients with good prognosis compared to the healthy controls. Compared to FM patients with good prognosis, FM patients with poor prognosis showed significant hypermetabolism in the left thalamus, bilateral lentiform nucleus, and right parahippocampal gyrus. CONCLUSION: The present findings suggest an association between the metabolism in the thalamus, lentiform nucleus, and parahippocampal gyrus and prognosis in FM patients. Further study with a larger number of patients is required to confirm this association.
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Mapeo Encefálico , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Fibromialgia/patología , Glucosa/metabolismo , Tomografía de Emisión de Positrones , Adulto , Anciano , Femenino , Fibromialgia/diagnóstico por imagen , Fluorodesoxiglucosa F18/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Escala Visual Analógica , Adulto JovenRESUMEN
OBJECTIVE: Approximately 8-10% of newborns with asymptomatic congenital cytomegalovirus (cCMV) infection develop sensorineural hearing loss (SNHL). However, the relationship between CMV load, SNHL and central nervous system (CNS) damage in cCMV infection remains unclear. This study aimed to examine the relationship between urinary CMV load, SNHL and CNS damage in newborns with cCMV infection. STUDY DESIGN: The study included 23â 368 newborns from two maternity hospitals in Saitama Prefecture, Japan. Urine screening for cCMV infection (quantitative real-time PCR) and newborn hearing screening (automated auditory brainstem response (AABR) testing) were conducted within 5â days of birth to examine the incidence of cCMV infection and SNHL, respectively. CNS damage was assessed by MRI of cCMV-infected newborns. RESULTS: The incidence of cCMV infection was 60/23â 368 (0.257%; 95% CI 0.192% to 0.322%). The geometric mean urinary CMV DNA copy number in newborns with cCMV was 1.79×106 copies/mL (95% CI 7.97×105 to 4.02×106). AABR testing revealed abnormalities in 171 of the 22â 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%). Newborns with both cCMV and SNHL had a higher urinary CMV DNA copy number than newborns with cCMV without SNHL (p=0.036). MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV. Moreover, newborns with CNS damage had a significantly greater urinary CMV load than newborns without CNS damage (p=0.013). CONCLUSIONS: We determined the incidence of cCMV infection and urinary CMV DNA copy number in seemingly healthy newborns from two hospitals in Saitama Prefecture. SNHL and CNS damage were associated with urinary CMV DNA copy number. Quantification of urinary CMV load may effectively predict the incidence of late-onset SNHL and neurodevelopmental disorders.
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Sistema Nervioso Central/anomalías , Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus , ADN Viral/orina , Pérdida Auditiva Sensorineural , Audición , Tamizaje Neonatal , Sistema Nervioso Central/virología , Anomalías Congénitas/orina , Anomalías Congénitas/virología , Citomegalovirus/genética , Citomegalovirus/crecimiento & desarrollo , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/virología , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Sensorineural/virología , Humanos , Incidencia , Recién Nacido , Japón/epidemiología , Imagen por Resonancia Magnética , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa , Sustancia BlancaRESUMEN
Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.