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Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, proinflammatory and anti-inflammatory cytokines interplay to orchestrate fine-tuned and dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response. Molecular pathways underlying the interplay are complex, and time-resolved monitoring of mediators and cytokines is necessary as a basis to study them in detail. Our understanding can be advanced by mathematical models that enable to analyze the system of interactions and their dynamical interplay in detail. We, therefore, used a mathematical modeling approach to study the interplay between prominent proinflammatory and anti-inflammatory cytokines with a focus on tumor necrosis factor and interleukin 10 (IL-10) in lipopolysaccharide-primed primary human monocytes. Relevant time-resolved data were generated by experimentally adding or blocking IL-10 at different time points. The model was successfully trained and could predict independent validation data and was further used to perform simulations to disentangle the role of IL-10 feedbacks during an acute inflammatory event. We used the insight to obtain a reduced predictive model including only the necessary IL-10-mediated feedbacks. Finally, the validated reduced model was used to predict early IL-10-tumor necrosis factor switches in the inflammatory response. Overall, we gained detailed insights into fine-tuning of inflammatory responses in human monocytes and present a model for further use in studying the complex and dynamic process of cytokine-regulated acute inflammation.
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BACKGROUND & AIMS: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. METHODS: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1ß, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. CONCLUSIONS: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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Proteínas Sanguíneas/análisis , Colitis Ulcerosa/sangre , Mediadores de Inflamación/sangre , Proteoma , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Quimiocina CCL11/sangre , Quimiocina CCL2/sangre , Quimiocina CXCL11/sangre , Quimiocina CXCL9/sangre , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/inmunología , Femenino , Humanos , Masculino , Metaloproteinasa 10 de la Matriz/sangre , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteómica , Reproducibilidad de los Resultados , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/sangre , Regulación hacia Arriba , Adulto JovenRESUMEN
The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.
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Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , ARN Mensajero/metabolismo , Receptores OX40/metabolismo , Proteínas Represoras/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Antígenos CD4/metabolismo , Diferenciación Celular/genética , Células HEK293 , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Unión Proteica , Receptores OX40/genética , Proteínas Represoras/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
[Figure: see text].
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Mediadores de Inflamación/sangre , Interleucina-6/sangre , Infarto del Miocardio/sangre , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Receptor gp130 de Citocinas/sangre , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Pronóstico , Receptores de Interleucina-6/sangre , Sistema de Registros , Medición de Riesgo , Fumar/efectos adversos , Suecia/epidemiología , Factores de TiempoRESUMEN
Hepatotoxicity is a major reason for the withdrawal or discontinuation of drugs from clinical trials. Thus, better tools are needed to filter potential hepatotoxic drugs early in drug discovery. Our study demonstrates utilization of HCI phenotypes, chemical descriptors, and both combined (hybrid) descriptors to construct random forest classifiers (RFCs) for the prediction of hepatotoxicity. HCI data published by Broad Institute provided HCI phenotypes for about 30â¯000 samples in multiple replicates. Phenotypes belonging to 346 chemicals, which were tested in up to eight replicates, were chosen as a basis for our analysis. We then constructed individual RFC models for HCI phenotypes, chemical descriptors, and hybrid (chemical and HCI) descriptors. The model that was constructed using selective hybrid descriptors showed high predictive performance with 5-fold cross validation (CV) balanced accuracy (BA) at 0.71, whereas within the given applicability domain (AD), independent test set and external test set prediction BAs were equal to 0.61 and 0.60, respectively. The model constructed using chemical descriptors showed a similar predictive performance with a 5-fold CV BA equal to 0.66, a test set prediction BA within the AD equal to 0.56, and an external test set prediction BA within the AD equal to 0.50. In conclusion, the hybrid and chemical descriptor-based models presented here should be considered as a new tool for filtering hepatotoxic molecules during compound prioritization in drug discovery.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado/efectos de los fármacos , Animales , Humanos , FenotipoRESUMEN
BACKGROUND: Interleukin 6 (IL6) is a multifunctional cytokine produced by various cells, including vascular endothelial cells. IL6 has both pro- and non-/anti-inflammatory functions, and the response to IL6 is dependent on whether it acts via the membrane-bound IL6 receptor α (IL6Rα) (classic signaling) or the soluble form of the receptor (transsignaling). As human endothelial cells produce IL6 and at the same time express IL6Rα, we hypothesized that IL6 may have autocrine functions. METHODS: Knockdown of IL6 in cultured human endothelial cells was performed using siRNA. Knockdown efficiency was evaluated using ELISA. RNA sequencing was employed to characterize the transcriptional consequence of IL6 knockdown, and Ingenuity Pathway Analysis was used to further explore the functional roles of IL6. RESULTS: Knockdown of IL6 in cultured endothelial cells resulted in a 84-92% reduction in the release of IL6. Knockdown of IL6 resulted in dramatic changes in transcriptional pattern; knockdown of IL6 in the absence of soluble IL6Rα (sIL6Rα) led to differential regulation of 1915 genes, and knockdown of IL6 in the presence of sIL6Rα led to differential regulation of 1967 genes (fold change 1.5, false discovery rate < 0.05). Pathway analysis revealed that the autocrine functions of IL6 in human endothelial cells are mainly related to basal cellular functions such as regulation of cell cycle, signaling, and cellular movement. Furthermore, we found that knockdown of IL6 activates functions related to adhesion, binding, and interaction of endothelial cells, which seem to be mediated mainly via STAT3. CONCLUSION: In this study, a large number of novel genes that are under autocrine regulation by IL6 in human endothelial cells were identified. Overall, our data indicate that IL6 acts in an autocrine manner to regulate basal cellular functions, such as cell cycle regulation, signaling, and cellular movement, and suggests that the autocrine functions of IL6 in human endothelial cells are mediated via IL6 classic signaling.
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Endotelio Vascular/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Interleucina-6/metabolismo , Transcripción Genética , Citocinas/metabolismo , Células Endoteliales/citología , Células Endoteliales de la Vena Umbilical Humana , Humanos , ARN Interferente Pequeño/metabolismo , Receptores de Interleucina-6 , Factor de Transcripción STAT3 , Análisis de Secuencia de ARN , Transducción de SeñalRESUMEN
Objectives: Crohn's disease is characterized by a gut dysbiosis with decreased abundance of butyrate producers such as Faecalibacterium prausnitzii. Although F. prausnitzii secretes anti-inflammatory molecules, few studies have addressed the importance of F. prausnitzii in a longitudinal setting. We aimed to examine the relationship between temporal profiles of F. prausnitzii, the C. leptum group, overall butyrate production, and inflammatory activity. Material and methods: Fecal samples (n = 59) were collected every third month from nine patients with ileal Crohn's disease. The abundance of F. prausnitzii and C. leptum was quantified relative to the total amount of bacteria using quantitative-PCR. To assess butyrate production of gut microbiota, gene copy numbers of the butyryl-CoA:acetate-CoA transferase (BCoAT) gene were quantified by qPCR. The inflammatory activity was defined by fecal (f)-calprotectin. Results: No correlation between the relative abundance of F. prausnitzii, the C. leptum group, or copy numbers of the BCoAT gene, and f-calprotectin was observed in the total sample set. By analyzing alterations between consecutive samples, a negative correlation between changes in the relative abundance of F. prausnitzii and f-calprotectin was observed (R = -0.39; p = .009). Changes in C. leptum (R = -0.18, p = .23) and number of copies of the BCoAT gene (R = -0.12; p = .42) did not correlate with f-calprotectin. Conclusions: There was an inverse correlation between temporal changes in the relative abundance of F. prausnitzii, but not overall butyrate producing capacity, and changes in inflammatory activity in ileal Crohn's disease. These findings indicate that F. prausnitzii may play a role in gut homeostasis, even though causality is still to be demonstrated.
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Enfermedad de Crohn/microbiología , Faecalibacterium prausnitzii/aislamiento & purificación , Íleon/microbiología , Complejo de Antígeno L1 de Leucocito/análisis , Adolescente , Adulto , Estudios de Casos y Controles , Enfermedad de Crohn/metabolismo , Disbiosis/etiología , Heces/química , Heces/microbiología , Femenino , Humanos , Estudios Longitudinales , Masculino , ARN Ribosómico 16S/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Suecia , Adulto JovenRESUMEN
Estimating distances between people and robots plays a crucial role in understanding social Human-Robot Interaction (HRI) from an egocentric view. It is a key step if robots should engage in social interactions, and to collaborate with people as part of human-robot teams. For distance estimation between a person and a robot, different sensors can be employed, and the number of challenges to be addressed by the distance estimation methods rise with the simplicity of the technology of a sensor. In the case of estimating distances using individual images from a single camera in a egocentric position, it is often required that individuals in the scene are facing the camera, do not occlude each other, and are fairly visible so specific facial or body features can be identified. In this paper, we propose a novel method for estimating distances between a robot and people using single images from a single egocentric camera. The method is based on previously proven 2D pose estimation, which allows partial occlusions, cluttered background, and relatively low resolution. The method estimates distance with respect to the camera based on the Euclidean distance between ear and torso of people in the image plane. Ear and torso characteristic points has been selected based on their relatively high visibility regardless of a person orientation and a certain degree of uniformity with regard to the age and gender. Experimental validation demonstrates effectiveness of the proposed method.
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Técnicas Biosensibles , Robótica , Grabación en Video , Algoritmos , Cuerpo Humano , HumanosRESUMEN
BACKGROUND: Molecular profiles change in response to perturbations. These changes are coordinated into functional modules via regulatory interactions. The genes and their products within a functional module are expected to be differentially expressed in a manner coherent with their regulatory network. This perspective presents a promising approach to increase precision in detecting differential signals as well as for describing differential regulatory signals within the framework of a priori knowledge about the underlying network, and so from a mechanistic point of view. RESULTS: We present Coherent Network Expression (CoNE), an effective procedure for identifying differentially activated functional modules in molecular interaction networks. Differential gene expression is chosen as example, and differential signals coherent with the regulatory nature of the network are identified. We apply our procedure to systematically simulated data, comparing its performance to alternative methods. We then take the example case of a transcription regulatory network in the context of particle-induced pulmonary inflammation, recapitulating and proposing additional candidates to previously obtained results. CoNE is conveniently implemented in an R-package along with simulation utilities. CONCLUSION: Combining coherent interactions with error control on differential gene expression results in uniformly greater specificity in inference than error control alone, ensuring that captured functional modules constitute real findings.
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Contaminantes Atmosféricos/efectos adversos , Algoritmos , Biología Computacional/métodos , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Neumonía/genética , Programas Informáticos , Humanos , Neumonía/etiología , Neumonía/patologíaRESUMEN
BACKGROUND: Despite the substantial number of older adults suffering from gastrointestinal (GI) symptoms little is known regarding the character of these complaints and whether they are associated with an altered intestinal barrier function and psychological distress. Our aim was to explore the relationship between self-reported gut health, intestinal permeability and psychological distress among older adults. METHODS: Three study populations were included: 1) older adults with GI symptoms (n = 24), 2) a group of older adults representing the general elderly population in Sweden (n = 22) and 3) senior orienteering athletes as a potential model of healthy ageing (n = 27). Questionnaire data on gut-health, psychological distress and level of physical activity were collected. Intestinal permeability was measured by quantifying zonulin in plasma. The level of systemic and local inflammation was monitored by measuring C-reactive protein (CRP), hydrogen peroxide in plasma and calprotectin in stool samples. The relationship between biomarkers and questionnaire data in the different study populations was illustrated using a Principal Component Analysis (PCA). RESULTS: Older adults with GI symptoms displayed significantly higher levels of both zonulin and psychological distress than both general older adults and senior orienteering athletes. The PCA analysis revealed a separation between senior orienteering athletes and older adults with GI symptoms and showed an association between GI symptoms, psychological distress and zonulin. CONCLUSIONS: Older adults with GI symptoms express increased plasma levels of zonulin, which might reflect an augmented intestinal permeability. In addition, this group suffer from higher psychological distress compared to general older adults and senior orienteering athletes. This relationship was further confirmed by a PCA plot, which illustrated an association between GI symptoms, psychological distress and intestinal permeability.
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Permeabilidad de la Membrana Celular/fisiología , Enfermedades Intestinales/metabolismo , Mucosa Intestinal/metabolismo , Estrés Psicológico/metabolismo , Anciano , Biomarcadores/sangre , Toxina del Cólera/sangre , Comorbilidad , Femenino , Haptoglobinas , Humanos , Inflamación/sangre , Inflamación/metabolismo , Enfermedades Intestinales/sangre , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Precursores de Proteínas , Autoinforme , Estrés Psicológico/sangre , Encuestas y CuestionariosRESUMEN
Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-ß (TGF-ß) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-ß-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-ß regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-ß in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-ß and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-ß and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-ß on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-ß regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. J. Cell. Biochem. 117: 1622-1632, 2016. © 2015 Wiley Periodicals, Inc.
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Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-1alfa/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Adulto , Células Cultivadas , Femenino , Fibroblastos/citología , Perfilación de la Expresión Génica , Humanos , Interleucina-1alfa/antagonistas & inhibidores , Análisis de Secuencia por Matrices de Oligonucleótidos , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
BACKGROUND: Diseases of the digestive system have been found to contribute to a higher symptom burden in older adults. Thus, therapeutic strategies able to treat gastrointestinal discomfort might impact the overall health status and help older adults to increase their overall health status and optimal functionality. OBJECTIVE: The aim of this double-blinded, randomized, placebo-controlled clinical trial was to evaluate the effect of the probiotic strain Lactobacillus reuteri on digestive health and wellbeing in older adults. METHODS: The study enrolled general older adults (>65 years). After eligibility screening qualified subjects (n = 290) participated in a 2-arm study design, with each arm consisting of 12 weeks of intervention of either active or placebo product. Primary outcome measure was set to changes in gastrointestinal symptoms and secondary outcome measures were changes in level of wellbeing, anxiety and stress. Follow up was performed at 8 and 12 weeks. RESULTS: No persistent significant effects were observed on the primary or secondary outcome parameters of the study. A modest effect was observed in the probiotic arm, were levels of stress decreased at week 8 and 12. Similarly, we found that subjects suffering from indigestion and abdominal pain, respectively, showed a significant decrease of anxiety at week 8 after probiotic treatment, but not at week 12. CONCLUSION: The RCT failed to show any improvement in digestive health after daily intake of a probiotic supplement containing L. reuteri. Neither was any significant improvement in wellbeing, stress or anxiety observed. Even though the RCT had a negative outcome, the study highlights issues important to take into consideration when designing trials among older adults. TRIAL REGISTRATION: Clinicaltrials.gov/ NCT01837940 .
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Dolor Abdominal/prevención & control , Dispepsia/prevención & control , Limosilactobacillus reuteri , Probióticos/administración & dosificación , Anciano , Ansiedad , Depresión , Método Doble Ciego , Femenino , Humanos , Masculino , Cooperación del Paciente , Factores Socioeconómicos , Estrés Psicológico , Resultado del TratamientoRESUMEN
The present study combined a supervised machine learning framework with an unsupervised method, finite mixture modeling, to identify prognostically meaningful subgroups of diverse chronic pain patients undergoing interdisciplinary treatment. Questionnaire data collected at pre-treatment and 1-year follow up from 11,995 patients from the Swedish Quality Registry for Pain Rehabilitation were used. Indicators measuring pain characteristics, psychological aspects, and social functioning and general health status were used to form subgroups, and pain interference at follow-up was used for the selection and the performance evaluation of models. A nested cross-validation procedure was used for determining the number of classes (inner cross-validation) and the prediction accuracy of the selected model among unseen cases (outer cross-validation). A four-class solution was identified as the optimal model. Identified subgroups were separable on indicators, predictive of long-term outcomes, and related to background characteristics. Results are discussed in relation to previous clustering attempts of patients with diverse chronic pain conditions. Our analytical approach, as the first to combine mixture modeling with supervised, targeted learning, provides a promising framework that can be further extended and optimized for improving accurate prognosis in pain treatment and identifying clinically meaningful subgroups among chronic pain patients.
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Dolor Crónico , Aprendizaje Automático Supervisado , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Adulto , Anciano , Suecia , Encuestas y CuestionariosRESUMEN
INTRODUCTION: The absence of reliable prognostic markers poses a challenge to the management of inflammatory bowel disease (IBD). Patients with aggressive disease may not receive sufficient treatment with conventional 'step-up' therapy, whereas a top-down approach may expose patients with indolent disease to unnecessary treatment-related toxicity. The objective of the Nordic IBD treatment strategy trial (NORDTREAT) is to assess the feasibility of personalised therapy by stratifying patients according to a prognostic serum protein signature at diagnosis. METHODS AND ANALYSIS: NORDTREAT is a multicentre, biomarker-strategy design, open-label controlled trial. After screening consent, eligible patients are randomised (1:1) into one of two groups: a group with access to the protein signature and a group without access. In the access to protein signature group, patients displaying a protein signature suggestive of an increased risk of an aggressive disease course will be treated in line with a top-down treatment algorithm (anti-tumour necrosis factor agent with/without an immunomodulator). In contrast, those with a protein signature indicative of indolent disease will be excluded from the trial. Patients not in the access group receive treatment based on clinical management. This traditional management involves a stepwise escalation of treatment as determined by the investigator after failure of first-line treatment. After 52 weeks, outcomes are assessed in the subgroup of patients with a protein profile indicating a potentially severe disease trajectory. The primary endpoint is a composite of the proportion of patients with corticosteroid-free clinical and endoscopic remission at week 52. Surgical intervention due to IBD during follow-up will be defined as treatment failure. ETHICS AND DISSEMINATION: Ethical approval has been obtained, and recruitment is underway at sites in four participating Nordic countries (Denmark, Iceland, Norway and Sweden). Following trial completion and data analysis, the trial results will be submitted for publication in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT05180175; Pre-results. EudraCT number: 2019-002942-19.
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Biomarcadores , Enfermedades Inflamatorias del Intestino , Humanos , Biomarcadores/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Pronóstico , Medicina de Precisión/métodos , Países Escandinavos y Nórdicos , Factores Inmunológicos/uso terapéuticoRESUMEN
Strenuous exercise can result in disruption of intestinal barrier function and occurrence of gastrointestinal symptoms. The aim of this exploratory study was to elucidate systemic effects of increased intestinal permeability after high-intensity exercise. Forty-one endurance-trained subjects performed a 60-min treadmill run at 80% VO2max. Small intestinal permeability was measured as urinary excretion ratio of lactulose/rhamnose (L/R). Blood, saliva and feces were analyzed for gut barrier and immune-related biomarkers. The exercise challenge increased several markers of intestinal barrier disruption, immune function and oxidative stress. We found a negative correlation between L/R ratio and uric acid (r = -0.480), as well as a positive correlation between the L/R ratio and fecal chromogranin A in male participants (r = 0.555). No significant correlations were found between any of the markers and gastrointestinal symptoms, however, perceived exertion correlated with the combination of IL-6, IL-10 and salivary cortisol (r = 0.492). The lack of correlation between intestinal permeability and gastrointestinal symptoms could be due to minor symptoms experienced in lab settings compared to real-life competitions. The correlation between L/R ratio and uric acid might imply a barrier-protective effect of uric acid, and inflammatory processes due to strenuous exercise seem to play an important role regarding physical exhaustion.
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Biomarcadores , Ejercicio Físico , Humanos , Masculino , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Ejercicio Físico/fisiología , Femenino , Mucosa Intestinal/metabolismo , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Permeabilidad , Lactulosa/orina , Lactulosa/metabolismo , Ramnosa/metabolismo , Adulto Joven , Estrés Oxidativo , Cromogranina A/metabolismo , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Saliva/metabolismoRESUMEN
INTRODUCTION: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, can be challenging to diagnose, and treatment outcomes are difficult to predict. In the NORDTREAT cohort study, a Nordic prospective multicentre study, we aim to identify novel molecular biomarkers of diagnostic value by assessing the diagnostic test accuracy (cross-sectionally), as well as the prognostic utility when used as prognostic markers in the long-term (cohort study). In the diagnostic test accuracy study, the primary outcome is a successful diagnosis using one or more novel index tests at baseline compared with the ECCO criteria as the reference standard. The composite outcome of the prognostic utility study is 'severe IBD' within 52 weeks from inclusion, defined as one or more of the following three events: IBD-related surgery, IBD-related hospitalisation or IBD-related death. METHODS AND ANALYSIS: We aim to recruit 800 patients referred on suspicion of IBD to this longitudinal observational study, a collaboration between 11 inclusion sites in Denmark, Iceland, Norway and Sweden. Inclusion will occur from February 2022 until December 2023 with screening and baseline visits for all participants and three outcome visits at weeks 12, 26 and 52 after baseline for IBD-diagnosed patients. Biological material (blood, faeces, biopsies, urine and hair), clinical data and lifestyle information will be collected during these scheduled visits. ETHICS AND DISSEMINATION: This study will explore novel biomarkers to improve diagnostic accuracy and prediction of disease progression, thereby improving medical therapy and the quality of life for patients with IBD.The study is approved by the Ethics Committee (DK: S-20200051, v1.4, 16.10.2021; IS: VSNb2021070006/03.01, NO: 193064; SE: DNR 2021-05090) and the Danish Data Protecting Agency (20/54594). Results will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. CLINICAL TRIAL REGISTRATION NUMBER: NCT05414578; Pre-results.
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Biomarcadores , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/terapia , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/terapia , Estudios Longitudinales , Estudios Multicéntricos como Asunto , Pronóstico , Estudios Prospectivos , Proyectos de Investigación , Países Escandinavos y NórdicosRESUMEN
BACKGROUND: Faecal biomarkers can be used to assess inflammatory bowel disease (IBD). AIM: To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD. METHODS: We included 65 patients with treatment-naïve, new-onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil-derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression. RESULTS: All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79-0.89) and MPO (AUC 0.85, 95% CI: 0.80-0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006). CONCLUSIONS: This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers.
Asunto(s)
Biomarcadores , Colitis Ulcerosa , Neurotoxina Derivada del Eosinófilo , Heces , Complejo de Antígeno L1 de Leucocito , Peroxidasa , Humanos , Biomarcadores/análisis , Biomarcadores/metabolismo , Femenino , Masculino , Heces/química , Adulto , Estudios Prospectivos , Complejo de Antígeno L1 de Leucocito/análisis , Persona de Mediana Edad , Peroxidasa/metabolismo , Colitis Ulcerosa/diagnóstico , Neurotoxina Derivada del Eosinófilo/análisis , Neurotoxina Derivada del Eosinófilo/metabolismo , Enfermedad de Crohn/diagnóstico , Proteína Catiónica del Eosinófilo/análisis , Proteína Catiónica del Eosinófilo/metabolismo , Adulto Joven , Enfermedades Inflamatorias del Intestino/diagnóstico , Estudios de Casos y Controles , Curva ROC , Progresión de la Enfermedad , Valor Predictivo de las PruebasRESUMEN
The rapidly evolving landscape of biomarkers for colorectal cancer (CRC) necessitates an integrative, updated repository. In response, we constructed the Colorectal Cancer Biomarker Database (CBD), which collected and displayed the curated biomedicine information for 870 CRC biomarkers in the previous study. Building on CBD, we have now developed CBD2, which includes information on 1569 newly reported biomarkers derived from different biological sources (DNA, RNA, protein, and others) and clinical applications (diagnosis, treatment, and prognosis). CBD2 also incorporates information on nonbiomarkers that have been identified as unsuitable for use as biomarkers in CRC. A key new feature of CBD2 is its network analysis function, by which users can investigate the visible and topological network between biomarkers and identify their relevant pathways. CBD2 also allows users to query a series of chemicals, drug combinations, or multiple targets, to enable multidrug, multitarget, multipathway analyses, toward facilitating the design of polypharmacological treatments for CRC. CBD2 is freely available at http://www.eyeseeworld.com/cbd.
RESUMEN
Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.
Asunto(s)
Biomarcadores , Enfermedades Inflamatorias del Intestino , Lipidómica , Humanos , Niño , Lipidómica/métodos , Masculino , Femenino , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/metabolismo , Biomarcadores/sangre , Adolescente , Heces/química , Fosfatidilcolinas/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Preescolar , Complejo de Antígeno L1 de Leucocito/sangre , Complejo de Antígeno L1 de Leucocito/análisis , Estudios de CohortesRESUMEN
Heterosis-associated cellular and molecular processes were analyzed in seeds and seedlings of Arabidopsis thaliana accessions Col-0 and C24 and their heterotic hybrids. Microscopic examination revealed no advantages in terms of hybrid mature embryo organ sizes or cell numbers. Increased cotyledon sizes were detectable 4 days after sowing. Growth heterosis results from elevated cell sizes and numbers, and is well established at 10 days after sowing. The relative growth rates of hybrid seedlings were most enhanced between 3 and 4 days after sowing. Global metabolite profiling and targeted fatty acid analysis revealed maternal inheritance patterns for a large proportion of metabolites in the very early stages. During developmental progression, the distribution shifts to dominant, intermediate and heterotic patterns, with most changes occurring between 4 and 6 days after sowing. The highest incidence of heterotic patterns coincides with establishment of size differences at 4 days after sowing. In contrast, overall transcript patterns at 4, 6 and 10 days after sowing are characterized by intermediate to dominant patterns, with parental transcript levels showing the largest differences. Overall, the results suggest that, during early developmental stages, intermediate gene expression and higher metabolic activity in the hybrids compared to the parents lead to better resource efficiency, and therefore enhanced performance in the hybrids.