RESUMEN
Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.
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COVID-19/inmunología , Interferón-alfa/inmunología , Células Asesinas Naturales/inmunología , SARS-CoV-2/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Secuencia de Bases , Humanos , Inmunidad Innata/inmunología , Inflamación/inmunología , Interferón-alfa/sangre , Fibrosis Pulmonar/patología , RNA-Seq , Índice de Severidad de la Enfermedad , Transcriptoma/genética , Reino Unido , Estados UnidosRESUMEN
BACKGROUND: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. METHODS: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. RESULTS: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. CONCLUSIONS: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).
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Narcolepsia , Receptores de Orexina , Orexinas , Humanos , Cataplejía/complicaciones , Cataplejía/tratamiento farmacológico , Cataplejía/epidemiología , Método Doble Ciego , Narcolepsia/tratamiento farmacológico , Narcolepsia/complicaciones , Narcolepsia/epidemiología , Receptores de Orexina/agonistas , Receptores de Orexina/uso terapéutico , Somnolencia/efectos de los fármacos , Resultado del Tratamiento , Orexinas/análisis , Orexinas/deficiencia , Orexinas/farmacología , Química Encefálica/efectos de los fármacos , Administración Oral , Enfermedad Hepática Inducida por Sustancias y Drogas/etiologíaRESUMEN
BACKGROUND: Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs. METHODS: DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. RESULTS: Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. CONCLUSIONS: In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Leucaféresis , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Fenotipo , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Análisis de la Célula Individual/métodos , Transcriptoma , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Línea Celular TumoralRESUMEN
INTRODUCTION: Aducanumab selectively targets aggregated forms of amyloid beta (Aß), a neuropathological hallmark of Alzheimer's disease (AD). METHODS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. RESULTS: Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab decreased brain amyloid levels in a dose- and time-dependent manner. Exploratory endpoints suggested a continued benefit in the reduction of clinical decline over 48 months. DISCUSSION: The safety profile of aducanumab remained unchanged in the LTE of PRIME. Amyloid plaque levels continued to decrease in participants treated with aducanumab. HIGHLIGHTS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. We report cumulative safety and 48-month efficacy results from PRIME. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event (AE); 61% of participants with ARIA-E were asymptomatic. Dose titration was associated with a decrease in the incidence of ARIA-E. Aducanumab decreased levels of amyloid beta (Aß) in a dose- and time-dependent manner.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Anticuerpos Monoclonales Humanizados , Humanos , Método Doble Ciego , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Masculino , Femenino , Anciano , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Resultado del Tratamiento , Placa Amiloide/tratamiento farmacológico , Relación Dosis-Respuesta a DrogaRESUMEN
OBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon ß-1a (IFNß-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNß-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNß-1a to fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834.
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Clorhidrato de Fingolimod/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Evaluación de la Discapacidad , Método Doble Ciego , Femenino , Humanos , Inmunosupresores/uso terapéutico , Interferón beta-1a/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple Recurrente-Remitente/patología , Neuroimagen , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht-Lundborg disease (EPM1). METHODS: Two prospective, multicenter, double-blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, showing moderate-severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice-daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2-week up-titration period, 12-week stable-dose maintenance period, and down-titration or entry into long-term follow-up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale (UMRS). Primary efficacy end point was percent reduction from baseline in action myoclonus score (UMRS section 4) at last treatment visit. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min-max) percent reduction from baseline in action myoclonus score is the following-N01187: placebo 5.6 (-81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (-50.0 to 73.6), BRV 50 mg/day 26.3 (-35.8 to 69.2), BRV 150 mg/day 16.9 (-50.0 to 73.6); N01236: placebo 17.5 (-170 to 61.5), BRV 5 mg/day -4.6 (-430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (-58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAEs were reported by 72-75% placebo-treated and 56-83% BRV-treated patients. SIGNIFICANCE: Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long-term follow-up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.
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Anticonvulsivantes/uso terapéutico , Pirrolidinonas/uso terapéutico , Síndrome de Unverricht-Lundborg/tratamiento farmacológico , Adolescente , Adulto , Clonazepam/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Humanos , Isoxazoles/uso terapéutico , Levetiracetam , Masculino , Persona de Mediana Edad , Fenobarbital/uso terapéutico , Piracetam/análogos & derivados , Piracetam/uso terapéutico , Topiramato , Resultado del Tratamiento , Ácido Valproico/uso terapéutico , Adulto Joven , ZonisamidaRESUMEN
BACKGROUND: A 6-month phase 2 study of fingolimod demonstrated efficacy and safety in Japanese patients with relapsing-remitting multiple sclerosis (MS). Here we report a 6-month observational extension that evaluated efficacy and safety in patients who received fingolimod continuously for 12 months or who switched from placebo to fingolimod. METHODS: Of 147 patients who completed the 6-month core study, 143 entered the extension. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg or 0.5 mg. During the extension, all patients were switched to open-label fingolimod 0.5 mg. RESULTS: Magnetic resonance imaging (MRI) and relapse outcomes were maintained or improved in patients treated with fingolimod for 12 months versus those treated for 6 months. No new safety events were reported over 12 months of treatment. Infections occurred in similar proportions of continuously treated and switched patients, while cardiac and liver adverse events occurred in fewer continuously treated than switched patients. Four patients were aquaporin-4 (AQP4) antibody-positive, three of whom showed rapid disease exacerbations within 10 days of fingolimod initiation. CONCLUSION: Continuous fingolimod treatment for up to 12 months was associated with maintained or improved efficacy and a manageable safety profile, consistent with that previously seen. Results in a small number of patients suggest lack of benefit in AQP4 antibody-positive patients. Meaningful statistical interpretation was limited by the small sample size in each treatment group, owing to the number of patients who completed the core study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00670449.
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Pueblo Asiatico/etnología , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/etnología , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Adolescente , Adulto , Método Doble Ciego , Femenino , Clorhidrato de Fingolimod , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esfingosina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV), a novel high-affinity synaptic vesicle protein 2A ligand that also displays inhibitory activity at neuronal voltage-dependent sodium channels, in adult epilepsy patients with uncontrolled partial-onset seizures. METHODS: A phase IIb, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study (N01114; NCT00175929) was conducted in patients aged 16-65 years. To be included in the study, patients were required to have experienced four or more partial-onset seizures during a 4-week prospective baseline, despite treatment with 1-2 concomitant antiepileptic drugs. Patients were randomized in a ratio of 1:1:1 to receive BRV 50 mg/day (BRV50), 150 mg/day (BRV150), or placebo. A 3-week up-titration period was followed by a 7-week maintenance period (total treatment period of 10 weeks). KEY FINDINGS: A total of 157 patients were randomized (intent-to-treat [ITT] population; BRV50 n = 53, BRV150 n = 52, placebo n = 52) and overall 148 (94.3%) completed the study. The percent reduction in baseline-adjusted partial-onset seizure frequency/week over placebo during the 7-week maintenance period (primary efficacy outcome) did not reach statistical significance (14.7% for BRV50 [p = 0.093] and 13.6% for BRV150 [p = 0.124]). However, during the entire 10-week treatment period a statistically significant difference was observed for both BRV groups (17.7% for BRV50 [p = 0.026] and 16.3% for BRV150 [p = 0.043]). The median percent reduction from baseline in partial-onset seizure frequency/week during the maintenance period was 38.2% for BRV50 (p = 0.017) and 30.0% for BRV150 (p = 0.113) versus 18.9% in the placebo group. During the treatment period, this was 34.9% for BRV50 (p = 0.004) and 28.3% for BRV150 (p = 0.070) compared with 16.3% for placebo. Fifty percent responder rates during the maintenance period were 23.1% for placebo compared with 39.6% for BRV50 (odds ratio [OR] 2.17, p = 0.077) and 33.3% for BRV150 (OR 1.66, p = 0.261). During the treatment period, 50% responder rates were 17.3% for placebo compared with 35.8% for BRV50 (OR 2.69, p = 0.038) and 30.8% for BRV150 (OR 2.15, p = 0.114). Nine patients were free from partial-onset seizures during the 10-week treatment period (five patients [9.4%] in the BRV50 group and three [5.8%] in the BRV150 group compared with one patient [1.9%] in the placebo group). Treatment-emergent adverse events (TEAEs) reported during the treatment period were mostly mild-to-moderate with similar incidence across treatment groups (BRV50 36/53, 67.9%; BRV150 35/52, 67.3%; placebo 37/52, 71.2%). The most frequently reported TEAEs in BRV groups were headache, fatigue, nasopharyngitis, nausea, somnolence, and dizziness, although nausea had a higher incidence in the placebo group. SIGNIFICANCE: In this double-blind, placebo-controlled, phase IIb study of adjunctive BRV (50 and 150 mg/day) in adults with uncontrolled partial-onset seizures, the primary efficacy analysis did not reach statistical significance; however, statistically significant differences compared with placebo were observed on several secondary efficacy outcomes. BRV was well tolerated.
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Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Pirrolidinonas/uso terapéutico , Adolescente , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Proteínas de Arabidopsis , Proteínas Portadoras , Proteínas de Unión al ADN , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinonas/administración & dosificación , Pirrolidinonas/efectos adversos , Factores de Transcripción , Resultado del Tratamiento , Adulto JovenRESUMEN
Development, progression, and therapy of periimplantitis are nonresolved emerging problems. The aim of this pilot study was to establish a model for periimplantitis in mice to have a base for tests with immune-deficient knockout organisms to improve the knowledge about development and progression of periimplantitis and to develop further therapeutic options.In 8 mice, titanium implants were inserted in the median of the palate. Four of these implants had ligatures (periimplantitis group). After 2 weeks, the animals received a special diet enriched with sugar and flavor. After 9 weeks, micro-computed tomography (micro-CT) examinations to evaluate the periimplant tissue and histologies were performed.Dental implant insertions within the oral cavity are possible in living mice. Implants with ligatures showed significantly larger periimplant bone defects than controls. The radiologic findings were confirmed by histology. At the end of the observation period, the portion of implants lost was higher in the ligature group.This is the first publication to describe the insertion of dental implants in living mice. In addition, it is the first time that periimplant infection could be induced in that species. This model will pave the way to study knockout mice with reduced or even enhanced resistance to periimplantitis.
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Implantación Dental Endoósea/métodos , Implantes Dentales , Periimplantitis/diagnóstico por imagen , Animales , Modelos Animales de Enfermedad , Ligadura , Masculino , Ratones , Ratones Endogámicos C57BL , Proyectos Piloto , Titanio , Microtomografía por Rayos XRESUMEN
Small non-coding RNAs, in particular microRNAs(miRNAs), regulate fine-tuning of gene expression and can act as oncogenes or tumor suppressor genes. Differential miRNA expression has been reported to be of functional relevance for tumor biology. Using next-generation sequencing, the unbiased and absolute quantification of the small RNA transcriptome is now feasible. Neuroblastoma(NB) is an embryonal tumor with highly variable clinical course. We analyzed the small RNA transcriptomes of five favorable and five unfavorable NBs using SOLiD next-generation sequencing, generating a total of >188 000 000 reads. MiRNA expression profiles obtained by deep sequencing correlated well with real-time PCR data. Cluster analysis differentiated between favorable and unfavorable NBs, and the miRNA transcriptomes of these two groups were significantly different. Oncogenic miRNAs of the miR17-92 cluster and the miR-181 family were overexpressed in unfavorable NBs. In contrast, the putative tumor suppressive microRNAs, miR-542-5p and miR-628, were expressed in favorable NBs and virtually absent in unfavorable NBs. In-depth sequence analysis revealed extensive post-transcriptional miRNA editing. Of 13 identified novel miRNAs, three were further analyzed, and expression could be confirmed in a cohort of 70 NBs.
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MicroARNs/metabolismo , Neuroblastoma/genética , Secuencia de Bases , Mapeo Cromosómico , Perfilación de la Expresión Génica , Biblioteca de Genes , Humanos , MicroARNs/química , Datos de Secuencia Molecular , Neuroblastoma/metabolismo , Edición de ARN , Precursores del ARN/química , Precursores del ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARNRESUMEN
The study of Alzheimer's disease (AD) has led to an increased understanding of the multiple pathologies and pathways of the disease. As such, it has been proposed that AD and its various stages might be most effectively treated with a combination approach rather than a single therapy; however, combination approaches present many challenges that include limitations of non-clinical models, complexity of clinical trial design, and unclear regulatory requirements. The Alzheimer's Association Research Roundtable meeting on May 7-8, 2018, discussed the approaches and challenges of combination therapy for AD. Experts in the field (academia, industry, and government) provided perspectives that may help establish a path forward for the development of new combination therapies.
RESUMEN
Chronic obstructive pulmonary disease (COPD) is among the most important causes of death. Signaling systems that are relevant for tissue repair and detoxification of reactive oxygen species or xenobiotics are thought to be impaired in lungs of patients suffering from this disease. Here, we developed a simple cigarette smoke induced Drosophila model of COPD based on chronic cigarette smoke exposure that recapitulates major pathological hallmarks of the disease and thus can be used to investigate new therapeutic strategies. Chronic cigarette smoke exposure led to premature death of the animals and induced a set of phenotypes reminiscent of those seen in COPD patients, including reduced physical activity, reduced body fat, increased metabolic rate and a substantial reduction of the respiratory surface. A detailed transcriptomic analysis revealed that especially the TGF-ß, Nrf2 and the JAK/STAT signaling pathways are altered by chronic cigarette smoke exposure. Based on these results, we focused on Nrf2 signaling. A pharmacological intervention study performed with oltipraz, an activator of Nrf2 signaling, increased survival of cigarette smoke exposed animals significantly. Thus, the Drosophila COPD model recapitulates many major hallmarks of COPD and it is highly useful to evaluate the potential of alternative therapeutic strategies.
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Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Humo/efectos adversos , Productos de Tabaco , Animales , Drosophila melanogaster , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Larva/efectos de los fármacos , Actividad Motora , Factor 2 Relacionado con NF-E2/genética , ARN , Transducción de Señal/efectos de los fármacosRESUMEN
Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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Microbioma Gastrointestinal , Receptores de Calcitriol/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Bacterias/clasificación , Bacterias/genética , Estudios de Cohortes , Dieta , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS. METHODS: Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years. RESULTS: Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL. CONCLUSIONS: Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.
Asunto(s)
Encéfalo/patología , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Método Doble Ciego , Femenino , Clorhidrato de Fingolimod , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/tendencias , Masculino , Tamaño de los Órganos , Esfingosina/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate immune responses in fingolimod-treated patients with multiple sclerosis (MS) against influenza vaccine (to test for responses against anticipated novel antigens in seronegative patients) and recall (tetanus toxoid [TT] booster dose) antigens. METHODS: This was a blinded, randomized, multicenter, placebo-controlled study. Patients aged 18 to 55 years with relapsing MS were randomized (2:1) to fingolimod 0.5 mg or placebo for 12 weeks. At week 6, patients received seasonal influenza vaccine (containing antigens of California, Perth, and Brisbane virus strains) and TT booster dose. Antibody titers against influenza and TT were estimated at baseline (prevaccination) and 3 and 6 weeks postvaccination. The primary efficacy variable was responder rate (proportion of patients showing seroconversion or significant increase [≥4-fold] in antibody titers against at least one influenza virus strain) at 3 weeks postvaccination and vs placebo. RESULTS: Of 138 randomized patients (fingolimod 95, placebo 43), 136 completed the study (2 discontinued in fingolimod group). The responder rates (odds ratio; 95% confidence interval) for influenza vaccine (fingolimod vs placebo) were 54% vs 85% (0.21; 0.08-0.54) at 3 weeks and 43% vs 75% (0.25; 0.11-0.57) at 6 weeks postvaccination. For TT, responder rates were 40% vs 61% (0.43; 0.20-0.92) at 3 weeks and 38% vs 49% (0.62; 0.29-1.33) at 6 weeks postvaccination. Adverse events were reported in 86.3% and 79.1% of patients receiving fingolimod and placebo, respectively. CONCLUSION: Most fingolimod-treated patients with MS were able to mount immune responses against novel and recall antigens and the majority met regulatory criteria indicating seroprotection. However, response rates were reduced compared with placebo-treated patients. This should be kept in mind when vaccinating patients on fingolimod. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in some patients with MS receiving immunizations, concurrent fingolimod treatment in comparison to placebo decreases vaccination-induced immune responses.
Asunto(s)
Inmunosupresores/uso terapéutico , Vacunas contra la Influenza/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Vacunación , Adolescente , Adulto , Método Doble Ciego , Femenino , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/inmunología , Vacunas contra la Influenza/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Glicoles de Propileno/inmunología , Esfingosina/inmunología , Esfingosina/uso terapéutico , Resultado del Tratamiento , Vacunación/métodos , Adulto JovenRESUMEN
OBJECTIVE: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population. RESULTS: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. CONCLUSION: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.
Asunto(s)
Encéfalo/patología , Progresión de la Enfermedad , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Glicoles de Propileno/administración & dosificación , Glicoles de Propileno/farmacología , Esfingosina/análogos & derivados , Adolescente , Adulto , Evaluación de la Discapacidad , Femenino , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/efectos adversos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Glicoles de Propileno/efectos adversos , Recurrencia , Método Simple Ciego , Esfingosina/administración & dosificación , Esfingosina/efectos adversos , Esfingosina/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
Fingolimod safety and efficacy data in relapsing-remitting multiple sclerosis (RRMS) are available up to 5 years, from an extension of a randomized, placebo-controlled, double-blind, phase 2 study, at a dose higher (5.0/1.25 mg) than the approved dose of 0.5 mg. The objective of the study is to present the end-of-study data (>7 years) from the open-label extension of the phase 2 study. In the core phase (6 months), patients (N = 281) were randomized to placebo or fingolimod 1.25/5 mg. In the extension, placebo patients were randomized to fingolimod 1.25/5 mg. All patients received open-label 1.25 mg fingolimod after month 24 and 0.5 mg after month 60. Clinical visits were performed every 3 months, expanded disability status scale (EDSS) every 6 months and magnetic resonance imaging (MRI) annually. 122 (48.8%) patients completed the extension study; overall fingolimod exposure was 1230.7 patient-years. The most common (>10%) reasons for study discontinuation were adverse events (19.6%) and consent withdrawal (16.4%). Fingolimod treatment for >7 years was associated with sustained low clinical and MRI disease activity. Over 60% of patients remained relapse free and about 80% were free from any MRI activity. Overall annualized relapse rate was 0.18. Long-term fingolimod treatment was not associated with new safety concerns. Long-term fingolimod was well tolerated and associated with a sustained low level of disease activity.
Asunto(s)
Clorhidrato de Fingolimod/farmacología , Inmunosupresores/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Método Doble Ciego , Clorhidrato de Fingolimod/administración & dosificación , Clorhidrato de Fingolimod/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/patologíaRESUMEN
OBJECTIVE: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod. METHODS: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24. RESULTS: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6-2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred. CONCLUSIONS: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Sustitución de Medicamentos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Glicoles de Propileno/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Esfingosina/análogos & derivados , Sustitución de Medicamentos/métodos , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Natalizumab , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Esfingosina/administración & dosificaciónRESUMEN
Glucocorticoid receptor activation inhibits granule cell proliferation in the hippocampus, but little is known about the role of mineralocorticoid receptors in this process. Here we administered aldosterone to adrenalectomized (ADX) rats, and monitored neurogenesis by BrdU immunohistochemistry. ADX significantly increased the number of BrdU-positive cells and aldosterone replacement further augmented BrdU-positivity. Our results indicate that aldosterone, most probably acting through mineralocorticoid receptors, may positively influence the proliferation and survival of newly-generated granule cells.
Asunto(s)
Aldosterona/metabolismo , Giro Dentado/metabolismo , Neuronas/metabolismo , Adrenalectomía , Aldosterona/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Inmunohistoquímica , Masculino , Neuronas/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismoRESUMEN
The aim of this study was to evaluate short-term safety and tolerability of fingolimod in a real-world population with relapsing multiple sclerosis, focusing on cardiac safety during treatment initiation. Patients received fingolimod 0.5 mg once daily for four months. Patients excluded from the pivotal studies with certain pre-existing cardiac conditions or baseline cardiac findings (PCCs), and those receiving beta blockers (BBs) and/or calcium channel blockers (CCBs), were eligible. Heart rate (HR) and electrical conduction events were monitored using ambulatory electrocardiography for at least 6 h after the first dose. Of 2,417 enrolled patients, 2,282 (94.4 %) completed the study. Fingolimod initiation was associated with a transient, mostly asymptomatic decrease in HR. Bradycardia adverse events occurred in 0.6 % of patients and were more frequent in individuals receiving BBs/CCBs (3.3 %) than in other patient subgroups (0.5-1.4 %); most events were asymptomatic, and all patients recovered without pharmacological intervention. In the 6 h post-dose, the incidences of Mobitz type I second-degree atrioventricular block (AVB) and 2:1 AVB were higher in patients with PCCs (4.1 and 2.0 %, respectively) than in those without (0.9 and 0.3 %, respectively); at pre-dose screening, patients with PCCs had the same incidence of Mobitz type I second-degree AVB (4.1 %) and a slightly lower incidence of 2:1 AVB (0.7 %) than 6 h post-dose. All recorded conduction abnormalities were asymptomatic. This study adds to the evidence showing that cardiac effects during fingolimod initiation remain consistent with those known from previous, controlled studies, even if patients with PCCs are included.