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OBJECTIVE: To assess the financial non-medical out-of-pocket costs of hospital admissions for children with a febrile illness. DESIGN: Single-centre survey-based study conducted between March and November 2022. SETTING: Tertiary level children's hospital in the North East of England. PARTICIPANTS: Families of patients with febrile illness attending the paediatric emergency department MAIN OUTCOME MEASURES: Non-medical out-of-pocket costs for the admission were estimated by participants including: transport, food and drinks, child care, miscellaneous costs and loss of earnings. RESULTS: 83 families completed the survey. 79 families (95.2%) reported non-medical out-of-pocket costs and 19 (22.9%) reported financial hardship following their child's admission.Total costs per day of admission were median £56.25 (IQR £32.10-157.25). The majority of families reported incurring transport (N=75) and food and drinks (N=71) costs. CONCLUSIONS: A child's hospital admission for fever can incur significant financial costs for their family. One in five participating families reported financial hardship following their child's admission. Self-employed and single parents were disadvantaged by unplanned hospital admissions and at an increased risk of financial hardship. Local hospital policies should be improved to support families in the current financial climate.
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Fiebre , Hospitalización , Humanos , Inglaterra/epidemiología , Masculino , Femenino , Fiebre/economía , Fiebre/epidemiología , Fiebre/terapia , Preescolar , Niño , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Gastos en Salud/estadística & datos numéricos , Lactante , Costo de Enfermedad , Adulto , Encuestas y Cuestionarios , Adolescente , Hospitales Pediátricos/economía , Hospitales Pediátricos/estadística & datos numéricos , Servicio de Urgencia en Hospital/economía , Servicio de Urgencia en Hospital/estadística & datos numéricosRESUMEN
Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung-brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers.
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Ácidos Grasos Omega-3 , Síndrome de Dificultad Respiratoria , Animales , Ratones , Encéfalo , Cromatografía Liquida , Inflamación , Lipopolisacáridos/toxicidad , Pulmón , Ratones Noqueados , Receptores de Leucotrieno B4 , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/genética , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: To externally validate and update the Feverkids tool clinical prediction model for differentiating bacterial pneumonia and other serious bacterial infections (SBIs) from non-SBI causes of fever in immunocompromised children. DESIGN: International, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM). SETTING: Fifteen teaching hospitals in nine European countries. PARTICIPANTS: Febrile immunocompromised children aged 0-18 years. METHODS: The Feverkids clinical prediction model predicted the probability of bacterial pneumonia, other SBI or no SBI. Model discrimination, calibration and diagnostic performance at different risk thresholds were assessed. The model was then re-fitted and updated. RESULTS: Of 558 episodes, 21 had bacterial pneumonia, 104 other SBI and 433 no SBI. Discrimination was 0.83 (95% CI 0.71 to 0.90) for bacterial pneumonia, with moderate calibration and 0.67 (0.61 to 0.72) for other SBIs, with poor calibration. After model re-fitting, discrimination improved to 0.88 (0.79 to 0.96) and 0.71 (0.65 to 0.76) and calibration improved. Predicted risk <1% ruled out bacterial pneumonia with sensitivity 0.95 (0.86 to 1.00) and negative likelihood ratio (LR) 0.09 (0.00 to 0.32). Predicted risk >10% ruled in bacterial pneumonia with specificity 0.91 (0.88 to 0.94) and positive LR 6.51 (3.71 to 10.3). Predicted risk <10% ruled out other SBIs with sensitivity 0.92 (0.87 to 0.97) and negative LR 0.32 (0.13 to 0.57). Predicted risk >30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25). CONCLUSION: Discrimination and calibration were good for bacterial pneumonia but poorer for other SBIs. The rule-out thresholds have the potential to reduce unnecessary investigations and antibiotics in this high-risk group.
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Infecciones Bacterianas , Enfermedades Transmisibles , Neumonía Bacteriana , Niño , Humanos , Lactante , Modelos Estadísticos , Pronóstico , Fiebre/etiología , Fiebre/microbiología , Infecciones Bacterianas/diagnóstico , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/complicaciones , Servicio de Urgencia en HospitalRESUMEN
Carotenoids are determinants of reproductive fitness and egg quality. Here we studied the accumulation of astaxanthin (AX), canthaxanthin (CA) zeaxanthin (ZX), lutein (LU), retinol (RX) and dehydroretinol (DR) during vitellogenesis comparing previtellogenic and vitellogenic pikeperch (Sander lucioperca) eggs (n = 5 each), as well as selected tissues (liver, fat and muscles) in first süawning females (1176-1450 g). Futhermore, we compared egg batches with high (88-99% hatching rate, n = 5) or low (40-67% hatching rate, n= 5) egg quality. Vitellogenic follicles revealed higher concentrations of DR, RX, ZX and LU compared to previtellogenic follicles. Neither CA nor AX was detectable. In parallel, DR and RX were mobilized in the liver. In adipose and muscle tissue, comparing previtellogenic and vitellogenic females, no significant differences in carotenoid/retinoid content were observed. In high quality egg batches, both DR and RX were increased. LU was lower in high quality than in low quality eggs. In a conclusion, the amount of retinoids seems suboptimal in low quality egg batches and increased DR and RX are desirable in pikeperch. Since hypervitaminosis of retinoids can be problematic though, supplementation of the food with carotenoids, which can serve as precursors for retinoids, has to be carried out carefully.
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Sensory circumventricular organs (sCVOs) are pivotal brain structures involved in immune-to-brain communication with a leaky blood-brain barrier that detect circulating mediators such as lipopolysaccharide (LPS). Here, we aimed to investigate the potential of sCVOs to produce n-3 and n-6 oxylipins after LPS-stimulation. Moreover, we investigated if norepinephrine (NE) co-treatment can alter cytokine- and oxylipin-release. Thus, we stimulated rat primary neuroglial sCVO cultures under n-3- or n-6-enriched conditions with LPS or saline combined with NE or vehicle. Supernatants were assessed for cytokines by bioassays and oxylipins by HPLC-MS/MS. Expression of signaling pathways and enzymes were analyzed by RT-PCR. Tumor necrosis factor (TNF)α bioactivity and signaling, IL-10 expression, and cyclooxygenase (COX)2 were increased, epoxide hydroxylase (Ephx)2 was reduced, and lipoxygenase 15-(LOX) was not changed by LPS stimulation. Moreover, LPS induced increased levels of several n-6-derived oxylipins, including the COX-2 metabolite 15d-prostaglandin-J2 or the Ephx2 metabolite 14,15-DHET. For n-3-derived oxylipins, some were down- and some were upregulated, including 15-LOX-derived neuroprotectin D1 and 18-HEPE, known for their anti-inflammatory potential. While the LPS-induced increase in TNFα levels was significantly reduced by NE, oxylipins were not significantly altered by NE or changes in TNFα levels. In conclusion, LPS-induced oxylipins may play an important functional role in sCVOs for immune-to-brain communication.
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Órganos Circunventriculares , Ácidos Grasos Omega-3 , Animales , Ciclooxigenasa 2 , Citocinas/metabolismo , Ácidos Grasos Omega-3/farmacología , Lipopolisacáridos/farmacología , Norepinefrina , Oxilipinas/metabolismo , Ratas , Espectrometría de Masas en Tándem , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.
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Adipoquinas/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Biglicano/farmacología , Citocinas/metabolismo , Proteína HMGB1/farmacología , Lipopolisacáridos/farmacología , Receptores Toll-Like/agonistas , Tejido Adiposo Pardo/inmunología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/inmunología , Tejido Adiposo Blanco/metabolismo , Factores de Edad , Animales , Masculino , Ratas Wistar , Receptor para Productos Finales de Glicación Avanzada/agonistas , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Vías Secretoras , Transducción de Señal , Técnicas de Cultivo de Tejidos , Receptores Toll-Like/metabolismoRESUMEN
Lipids, including omega-3 polyunsaturated fatty acids (n-3-PUFAs), modulate brain-intrinsic inflammation during systemic inflammation. The vascular organ of the lamina terminalis (OVLT) is a brain structure important for immune-to-brain communication. We, therefore, aimed to profile the distribution of several lipids (e.g., phosphatidyl-choline/ethanolamine, PC/PE), including n-3-PUFA-carrying lipids (esterified in phospholipids), in the OVLT during systemic lipopolysaccharide(LPS)-induced inflammation. We injected wild type and endogenously n-3-PUFA producing fat-1 transgenic mice with LPS (i.p., 2.5 mg/kg) or PBS. Brain samples were analyzed using immunohistochemistry and high-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization orbital trapping mass spectrometry imaging (AP-SMALDI-MSI) for spatial resolution of lipids. Depending on genotype and treatment, several distinct distribution patterns were observed for lipids [e.g., lyso(L)PC (16:0)/(18:0)] proposed to be involved in inflammation. The distribution patterns ranged from being homogeneously disseminated [LPC (18:1)], absent/reduced signaling within the OVLT relative to adjacent preoptic tissue [PE (38:6)], either treatment- and genotype-dependent or independent low signal intensities [LPC (18:0)], treatment- and genotype-dependent [PC 38:6)] or independent accumulation in the OVLT [PC (38:7)], and accumulation in commissures, e.g., nerve fibers like the optic nerve [LPE (18:1)]. Overall, screening of lipid distribution patterns revealed distinct inflammation-induced changes in the OVLT, highlighting the prominent role of lipid metabolism in brain inflammation. Moreover, known and novel candidates for brain inflammation and immune-to-brain communication were detected specifically within this pivotal brain structure, a window between the periphery and the brain. The biological significance of these newly identified lipids abundant in the OVLT and the adjacent preoptic area remains to be further analyzed.
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Cadherinas/genética , Inflamación/metabolismo , Lípidos/análisis , Organum Vasculosum/metabolismo , Animales , Cadherinas/metabolismo , Inflamación/inducido químicamente , Metabolismo de los Lípidos , Lipopolisacáridos , Masculino , Ratones , Ratones Transgénicos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Immune-to-brain communication has been studied in a variety of experimental models. Crucial insights into signalling and mechanisms were previously revealed in studies investigating fever induction pathways. The scientific community has primarily focused on neuronal and humoral pathways in the manifestation of this response. Emerging evidence has now shown that immune-to-brain signalling via immune cells is pivotal for normal brain function and brain pathology. The present manuscript aims to provide a brief overview on the current understanding of how immune cells signal to the brain. Insights are summarized on the potential physiological significance of some immune cells signalling from the periphery to the brain. A particular focus is laid on the role of neutrophil granulocytes. As such, IL-1ß expressing neutrophil granulocytes have been shown to transfer inflammatory information to the brain and contribute to prolonged behavioural changes due to septic encephalopathy in rats during severe systemic inflammation induced by the bacterial component and TLR4 agonist lipopolysaccharide. Modulation of immune cell recruitment to the brain is discussed by various confounding factors including sleep, exercise, the nutritional status e.g. obesity, leptin and omega 3 fatty acids, and psychological or inflammatory stressors. The physiological significance of immune cell mediated communication between the immune system and the brain is highlighted by the fact that systemic inflammatory insults can exacerbate ongoing brain pathologies via immune cell trafficking. New insights into mechanisms and mediators of immune cell mediated immune-to-brain communication are important for the development of new therapeutic strategies and the better understanding of existing ones. Abbreviations: ACTH: adrenocorticotropic hormone; BBB: blood-brain barrier; BBI: blood-brain interface; CD: cluster of differentiation; CINC: cytokine-induced neutrophil chemoattractant; CRH: corticotropin releasing hormone; CVOs: circumventricular organs; CXCR: chemokine receptor; DAPI: 40:6-diamidino-2-phenylindole dilactate; DHA: docosahexaenoid acid; ICAM: intracellular adhesion molecule; IL: interleukin; i.p.: intraperitoneal; i.v.: intravenous; KC: keratinocytes-derived chemokine; LPS: lipopolysaccharide; MIP: macrophage inflammatory protein; MS: multiple sclerosis; NFκB: nuclear factor kappa B; NF-IL6: nuclear factor IL-6; PCTR: protectin conjugates in tissue regeneration; PG: prostaglandin; p.i.: post injection; PVN: paraventricular nucleus; ra: receptor antagonist; STAT3: signal transducer and activator of transcription 3; TIMP: tissue inhibitors of metalloproteinases; TLR: toll-like receptor; TNFα: tumor necrosis factor alpha.
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The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3-6 µM PCI-34051 or 10 µM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05 µM (ALK-amplified) to 0.8 µM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n = 88) and the German Neuroblastoma Trial cohort (n = 649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma.
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Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/farmacología , Neuroblastoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , Proteínas Represoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/metabolismo , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Crizotinib/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Neuroblastoma/metabolismo , Neuroblastoma/patología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Células Tumorales Cultivadas , Pez CebraRESUMEN
The number of long-term survivors of high-risk neuroblastoma remains discouraging, with 10-year survival as low as 20%, despite decades of considerable international efforts to improve outcome. Major obstacles remain and include managing resistance to induction therapy, which causes tumor progression and early death in high-risk patients, and managing chemotherapy-resistant relapses, which can occur years after the initial diagnosis. Identifying and validating novel therapeutic targets is essential to improve treatment. Delineating and deciphering specific functions of single histone deacetylases in neuroblastoma may support development of targeted acetylome-modifying therapeutics for patients with molecularly defined high-risk neuroblastoma profiles. We show here that HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs. Genes necessary for mitotic cell cycle progression and cell division were most prominently enriched in at least two of three time points in whole-genome expression data combined from two cell systems, and all nine genes in these functional categories were strongly repressed, including CENPA, KIF14, KIF23 and RACGAP1. Enforced expression of one selected candidate, RACGAP1, partially rescued the induction of apoptosis caused by HDAC11 depletion. High-level expression of all nine genes in primary neuroblastomas significantly correlated with unfavorable overall and event-free survival in patients, suggesting a role in mediating the more aggressive biological and clinical phenotype of these tumors. Our study identified a group of cell cycle-promoting genes regulated by HDAC11, being both predictors of unfavorable patient outcome and essential for tumor cell viability. The data indicate a significant role of HDAC11 for mitotic cell cycle progression and survival of MYCN-amplified neuroblastoma cells, and suggests that HDAC11 could be a valuable drug target.
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Ciclo Celular/genética , Supervivencia Celular/genética , Histona Desacetilasas/metabolismo , Mitosis/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Supervivencia sin Enfermedad , Expresión Génica/genética , Genes cdc/genética , Humanos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismoRESUMEN
The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.
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Regulación Neoplásica de la Expresión Génica/fisiología , Histona Desacetilasas/metabolismo , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/patología , Tetraspanina 29/biosíntesis , Animales , Histona Desacetilasas/genética , Humanos , Ratones , Ratones Transgénicos , Proteína Proto-Oncogénica N-Myc/genética , Invasividad Neoplásica/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Tetraspanina 29/genéticaRESUMEN
MRL/lpr mice develop a spontaneous autoimmune disease that closely resembles human systemic lupus erythematosus (SLE) with DNA autoantibodies, hypergammaglobulinemia, immune complex glomerulonephritis, and systemic vasculitis. Little is known about the role of IL-3 in SLE. In order to study this we analyzed the expression of IL-3 in murine lupus and determined whether blockade of IL-3 with a monoclonal antibody or injection of recombinant IL-3 affects lupus nephritis in MRL/lpr mice. During disease progression IL-3 levels were increased in the plasma and in the supernatant of cultured splenocytes from MRL/lpr mice. Administration of IL-3 aggravated the disease with significantly higher renal activity scores, more renal fibrosis, and more glomerular leukocyte infiltration and IgG deposition. Blockade of IL-3 significantly improved acute and chronic kidney damage, reduced the glomerular infiltration of leukocytes and the glomerular deposition of IgG, and decreased the development of renal fibrosis. Furthermore, DNA autoantibody production, proteinuria, and serum creatinine levels were significantly lower in the anti-IL-3 group. Thus, IL-3 plays an important role in the pathogenesis of SLE and the progression of lupus nephritis. Hence, blockade of IL-3 may represent a new strategy for treatment of lupus nephritis.
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Anticuerpos/farmacología , Interleucina-3/sangre , Interleucina-3/inmunología , Nefritis Lúpica/metabolismo , Nefritis Lúpica/patología , Animales , Anticuerpos Antinucleares/sangre , Células Cultivadas , Creatinina/sangre , Progresión de la Enfermedad , Fibrosis , Inmunoglobulina G/análisis , Interleucina-3/antagonistas & inhibidores , Interleucina-3/farmacología , Glomérulos Renales/química , Glomérulos Renales/patología , Nefritis Lúpica/sangre , Recuento de Linfocitos , Ratones , Proteinuria/etiología , Índice de Severidad de la Enfermedad , Bazo/citologíaRESUMEN
Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here, we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as histone deacetylase (HDAC) inhibitors. Grainyhead-like 1 (GRHL1), a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genome-wide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN colocalized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation, and retarded xenograft growth in mice. GRHL1 knockdown in MYCN single-copy cells with high endogenous GRHL1 levels promoted colony formation. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell-cell adhesion, cell spreading, and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma.
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Histona Desacetilasas/fisiología , Neuroblastoma/genética , Proteínas Nucleares/fisiología , Proteínas Oncogénicas/fisiología , Proteínas Represoras/genética , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Genes Supresores de Tumor , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Lactante , Estimación de Kaplan-Meier , Ratones , Ratones SCID , Proteína Proto-Oncogénica N-Myc , Trasplante de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/mortalidad , Neuroblastoma/patología , Panobinostat , Proteínas Represoras/metabolismo , Transcripción Genética , Carga TumoralRESUMEN
A retrospective multicenter study has been conducted to evaluate domino liver transplantations (DLTs) in Germany. The study provides insight into survival and features having an impact on the assessment of neuropathy after DLT. In addition, a neurologic follow-up program with a scheme to estimate the likelihood of de novo amyloidosis is presented. A series of 61 DLTs at seven transplant centers in Germany was enrolled. The mean age of domino recipients at the time of transplantation was 58 years, 46 of them being men, and 15 being women. The median follow-up was 46 months. The overall 1-, 3-, and 5-year survival of domino recipients was 81.6%, 70.8% and 68.8%, respectively. Causes of death were primarily not related to familial amyloidosis. The main indication of DLT was hepatocellular carcinoma. Two of the reported domino recipients developed symptoms and signs of de novo amyloidosis within 10 years after transplantation. A total of 30 domino graft recipients (49.18%) presented with diabetes post transplantation. In conclusion, an advanced follow-up program is crucial to evaluate the risk of transmitting familial amyloidosis by DLT and to establish more strict selection criteria for domino recipients.