RESUMEN
OBJECTIVE: Despite the growing interest in psychological variables and mental health in young people with rheumatic diseases (RMDs), the impact of these conditions on self-concept, self-esteem, or body image is unclear. The purpose of this study was to synthesize existing research related to these domains in young people with RMDs. METHODS: Review registered on PROSPERO as CRD42023444009. The search strategy includes all articles up to September 2023, to collect qualitative and quantitate studies assessing self-concept, self-esteem, or body image in young people with RMDs. All identified articles were described, rated and Risk of bias was assessed. RESULTS: We identified 350 studies, of which 11 were analysed in this study. Our results indicated that self-concept, body image and self-esteem were a common challenge in young people with RMDs and might negatively impact physical and psychosocial health-related quality of life (QoL). The social domain of self-concept was impaired, mainly in female patients. Although studies that evaluated self-esteem show varied results, it seems that self-esteem was worse in females and was associated mainly with depression, but also with poorer QoL. Glucocorticoids consistently were associate with poor body image in all conditions due to visible side-effects of medication. Visible signs of the disease also might lead to poor body image. CONCLUSION: This review identifies important gaps and areas of improvement for future research in these issues in young patients with RMDs. This review highlights the need to actively engage patients and ensure that their psychological concerns are addressed to improve their healthcare and long-term quality of life outcomes.
RESUMEN
INTRODUCTION: In patients with rheumatoid arthritis (RA), nurses are considered as essential, not only to ensure pharmacological safety, but also in the promotion in self-care and decision-making, favouring the empowerment of patients. This systematic review aimed to summarize the available literature on the health education by the nurse in patients with RA. MATERIAL AND METHODS: Following Cochrane Collaboration procedures, the PRISMA statement and PRISMA checklist, relevant quantitative studies published were retrieved from the CINAHL, Scopus, PubMed and Medic databases and then systematically reviewed. The search ended in August 2021. Nineteen studies were retained for inclusion and evaluated with the Scottish Intercollegiate Guidelines Network for Systematic Reviews. RESULTS: We found statistically significant improvement in self-care (five studies), disease activity (three studies), quality of life (two studies), satisfaction (five studies) and adherence (one study) with the nursing-led management of patients with established rheumatoid arthritis. DISCUSSION: Although there is solid evidence of improvement in satisfaction and self-care, there seems to be a trend also to improve other outcomes, such as DAS28, from the EULAR recommendations, the expansion of the therapeutic arsenal for rheumatoid arthritis and shared decision-making. In addition, recently and due to the implementation of new technologies, the role of the nurse has been evaluated through virtual consultations. The results of recent studies have shown that this an effective and well-accepted novel approach for the management of patients with stable rheumatoid arthritis. CONCLUSION: Our study suggests that nurse-led health education, in addition of improvement in satisfaction and self-care, improve activity disease scores in RA patients.
Asunto(s)
Artritis Reumatoide , Rol de la Enfermera , Humanos , Calidad de Vida , Artritis Reumatoide/tratamiento farmacológico , Derivación y ConsultaRESUMEN
Introduction: In patients with rheumatoid arthritis (RA), nurses are considered as essential, not only to ensure pharmacological safety, but also in the promotion in self-care and decision-making, favouring the empowerment of patients. This systematic review aimed to summarize the available literature on the health education by the nurse in patients with RA. Material and methods: Following Cochrane Collaboration procedures, the PRISMA statement and PRISMA checklist, relevant quantitative studies published were retrieved from the CINAHL, Scopus, PubMed and Medic databases and then systematically reviewed. The search ended in August 2021. Nineteen studies were retained for inclusion and evaluated with the Scottish Intercollegiate Guidelines Network for Systematic Reviews. Results: We found statistically significant improvement in self-care (five studies), disease activity (three studies), quality of life (two studies), satisfaction (five studies) and adherence (one study) with the nursing-led management of patients with established rheumatoid arthritis. Discussion: Although there is solid evidence of improvement in satisfaction and self-care, there seems to be a trend also to improve other outcomes, such as DAS28, from the EULAR recommendations, the expansion of the therapeutic arsenal for rheumatoid arthritis and shared decision-making. In addition, recently and due to the implementation of new technologies, the role of the nurse has been evaluated through virtual consultations. The results of recent studies have shown that this an effective and well-accepted novel approach for the management of patients with stable rheumatoid arthritis. Conclusion: Our study suggests that nurse-led health education, in addition of improvement in satisfaction and self-care, improve activity disease scores in RA patients.(AU)
Introducción: En los pacientes con artritis reumatoide, las enfermeras se consideran esenciales, no solo para garantizar la seguridad farmacológica, sino también en la prestación de promoción en el autocuidado y la toma de decisiones, favoreciendo el empoderamiento de los pacientes. Esta revisión sistemática tuvo como objetivo resumir la literatura disponible sobre la educación sanitaria por parte de la enfermera en pacientes con artritis reumatoide. Material y métodos: Siguiendo los procedimientos de la Colaboración Cochrane, la declaración PRISMA y la lista de comprobación PRISMA, se recuperaron los estudios cuantitativos relevantes publicados en las bases de datos CINAHL, Scopus, PubMed y Medic y, a continuación, se revisaron sistemáticamente. La búsqueda finalizó en agosto de 2021. Diecinueve estudios fueron retenidos para su inclusión y evaluados con la Scottish Intercollegiate Guidelines Network for Systematic Reviews. ResultadosSe encontró una mejoría estadísticamente significativa en el autocuidado (cinco estudios), la actividad de la enfermedad (tres estudios), la calidad de vida (dos estudios), la satisfacción (cinco estudios) y la adherencia (un estudio) con el manejo dirigido por enfermería de pacientes con artritis reumatoide establecida. Discusión: Aunque siempre ha habido evidencias de mejora en la satisfacción y el autocuidado, parece haber una tendencia a mejorar también otros resultados, como el de Disease Activity Score in 28 Joints (DAS28), a partir de las recomendaciones de la European League Against Rheumatism (EULAR), la ampliación del arsenal terapéutico para la artritis reumatoide y la toma de decisiones compartida. Además, recientemente y debido a la implantación de las nuevas tecnologías, se ha evaluado el papel de la enfermera a través de las consultas virtuales. Los resultados de estudios recientes han demostrado que se trata de un nuevo enfoque...(AU)
Asunto(s)
Humanos , Masculino , Femenino , Artritis Reumatoide/enfermería , Enfermeras y Enfermeros , Calidad de Vida , Autocuidado , Relaciones Enfermero-Paciente , Rol de la Enfermera , Reumatología , Enfermedades Reumáticas , Atención de Enfermería , Atención Dirigida al PacienteRESUMEN
Current morphologic features defining advanced adenomas (size ≥10 mm, high-grade dysplasia or ≥25% villous component) cannot optimally distinguish individuals at high risk or low risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy-number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphologic advanced adenoma features.In this nested case-control study, 529 individuals with a single adenoma at first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy-number profiles were determined, by low-coverage whole-genome sequencing. Prevalence of CNAs in advanced and non-advanced adenomas and its association (OR) with me-CRC was assessed. For the latter, cases (with me-CRC) were matched to controls (without me-CRC) on follow-up, age and sex.CNAs associated with adenoma-to-carcinoma progression were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. me-CRC was statistically significantly associated, also after adjustment for other variables, with age at baseline [OR, 1.14; 95% confidence interval CI), 1.03-1.26; P = 0.012], advanced adenomas (OR, 2.46; 95% CI, 1.50-4.01; P < 0.001) and with the presence of ≥3 DNA copy-number losses (OR, 1.90; 95% CI. 1.02-3.54; P = 0.043).Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. SIGNIFICANCE: Identifying new biomarkers may improve prediction of me-CRC for individuals with adenomas and optimize surveillance intervals to reduce risk of colorectal cancer and reduce oversurveillance of patients with low risk of colorectal cancer. Use of DNA CNAs alone does not improve prediction of me-CRC. Further research to improve risk classification is required.
Asunto(s)
Adenoma , Carcinoma , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/diagnóstico , Estudios de Casos y Controles , Adenoma/diagnóstico , ADNRESUMEN
OBJECTIVES: Most studies on difficult-to-treat rheumatoid arthritis (D2T RA) have focused on established RA. Here, we analyse whether disease activity in the early stages of RA could influence progression to a D2T RA under real-life conditions. Other clinical and treatment-related factors were also analysed. METHODS: A longitudinal multicentre study of patients with RA was conducted from 2009 to 2018. Patients were followed up until January 2021. D2T RA was defined based on EULAR criteria (treatment failure, signs suggestive of currently active/progressive disease and management being perceived as problematic by the rheumatologist and/or patient). The main variable was disease activity in the early stages. The covariates were sociodemographic, clinical and treatment-related factors. We ran a multivariable logistic regression analysis to investigate risk factors associated with progression to D2T RA. RESULTS: The study population comprised 631 patients and 35 (5.87%) developed D2T RA. At the time of diagnosis, the D2T RA group were younger, with a higher disability, 28-joint Disease Activity Score (DAS28) score, tender joint count and pain scores. In our final model, DAS28 was not statistically significantly associated with D2T RA. No differences were found between groups for therapy. Disability was independently associated with D2T RA (OR: 1.89; p=0.01). CONCLUSIONS: In this cohort of patients newly diagnosed with RA, our results do not allow us to prove the influence of active disease according to DAS28. However, we did find that younger patients and those with elevated initial disability scores are more likely to develop D2T RA regardless of other factors.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Humanos , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: The objective of the present study is to describe the characteristics of interstitial pneumonia with autoimmune features (IPAF) patients, to assess the incidence rate of functional respiratory impairment over time and to evaluate the influence of therapeutic alternatives on the prognosis of these patients. METHODS: A longitudinal observational multicenter study was performed (NEREA registry). It was carried out by a multidisciplinary team in seven Hospitals of Madrid. Patients were included from IPAF diagnosis. MAIN OUTCOME: poor prognosis as functional respiratory impairment (relative decline in FVC % defined as ≥ 5% every 6 months). Covariates: therapy, sociodemographic, clinical, radiological patterns, laboratory and functional tests. STATISTICS: Survival techniques were used to estimate IR per 100 patients-semester with their 95% confidence interval [CI]. The influence of covariates in prognosis were analyzed through cox multivariate regression models (hazard ratio (HR) and [CI]). RESULTS: 79 IPAF were included, with a mean and a maximum follow-up of 3.17 and 12 years respectively. Along the study, 77.2% received treatment (52 glucocorticoids, 25 mycophenolate, 21 azathioprine, 15 rituximab and 11 antifibrotics). IR was 23.9 [19.9-28.8], and 50% of IPAF developed functional respiratory impairment after 16 months from its diagnosis. Multivariate analysis: usual interstitial pneumonia (UIP) had poorer prognosis compared to non-specific interstitial pneumonia (NSIP) (p = 0.001). In NSIP, positive ANA, increased the risk of poor prognosis. In UIP, glucocorticoids (HR: 0.53 [0.34-0.83]), age (HR: 1.04 [1.01-1.07]), and Ro-antibodies (HR: 0.36 [0.19-0.65]) influenced the prognosis. CONCLUSIONS: IPAF have functional impairment during the first years of disease. Factors predicting deterioration differ between radiographic patterns. Our real-life study suggests the potential benefit of particular therapies in IPAF.
Asunto(s)
Enfermedades Autoinmunes , Neumonías Intersticiales Idiopáticas , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Insuficiencia Respiratoria , Humanos , Estudios Retrospectivos , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/epidemiología , Neumonías Intersticiales Idiopáticas/diagnósticoRESUMEN
INTRODUCTION: The use of public bathrooms is a challenge for everyone, but especially for those who are affected by a bathroom-dependent condition. Being dependent on bathrooms is linked with different negative emotions. One of them is a clinically relevant emotion: shame associated with the chronic condition. MATERIALS AND METHODS: In a cross-sectional survey study (n = 193) of people who suffer a bathroom-dependent condition we asked about health conditions, well-being, and shame related to chronic condition outcomes. RESULTS: We show a link between negative public bathroom experiences, and diminished well-being and feelings of shame related to chronic illness. We found that this relationship between negative experiences with public bathrooms and shame is not specific to the different conditions. CONCLUSION: We conclude that the negative experiences which people with different gastrointestinal illnesses face is an environmental stressor associated with more embarrassment as a result of the condition suffered.
Asunto(s)
Vergüenza , Cuartos de Baño , Humanos , Estudios Transversales , Emociones , Enfermedad CrónicaAsunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , COVID-19 , Enfermedades Reumáticas , Humanos , Factores de Riesgo , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Hospitales , Enfermedades Reumáticas/complicaciones , Enfermedades Autoinmunes/epidemiologíaRESUMEN
OBJECTIVES: To evaluate risk factors for severe Coronavirus Disease 2019 (COVID-19) in patients with immune-mediated rheumatic diseases, stratified by systemic autoimmune conditions and chronic inflammatory arthritis. METHODS: An observational, cross-sectional multicenter study was performed. Patients from 10 Rheumatology departments in Madrid who presented with SARS-CoV-2 infection between Feb 2020 and May 2021 were included. The main outcome was COVID-19 severity (hospital admission or mortality). Risk factors for severity were estimated, adjusting for covariates (sociodemographic, clinical and treatments), using logistic regression analyses. RESULTS: 523 patients with COVID-19 were included, among whom 192 (35.6%) patients required hospital admission and 38 (7.3%) died. Male gender, older age and comorbidities such as diabetes mellitus, hypertension and obesity were associated with severe COVID-19. Corticosteroid doses over 10 mg/day, rituximab, sulfasalazine and mycophenolate use, were independently associated with worse outcomes. COVID-19 severity decreased over the different pandemic waves. Mortality was higher in the systemic autoimmune conditions (univariate analysis, p<0.001), although there were no differences in overall severity in the multivariate analysis. CONCLUSIONS: This study confirms and provides new insights regarding the harmful effects of corticosteroids, rituximab and other therapies (mycophenolate and sulfasalazine) in COVID-19. Methotrexate and anti-TNF therapy were not associated with worse outcomes.
RESUMEN
Objectives: The aim of this study was to assess the cause-specific mortality rate related to COVID-19 (CMR) in patients with rheumatic and musculoskeletal diseases (RMDs) and COVID-19 and to analyze the role of the different RMDs in their mortality risk. Methods: An observational longitudinal study was conducted during the first pandemic wave in our center. Patients with the diagnosis of RMDs and COVID-19 were included. Main outcome is the death related to COVID-19. Independent variable - type of RMDs: autoimmune rheumatic diseases (ARD), such as chronic inflammatory arthritis (CIA) and connective tissue diseases (CTD) and non-autoimmune Rheumatic Diseases (non-ARD). Survival techniques were used to estimate the CMR per 1000 patients-month with a 95% confidence interval (CI), and Cox multivariate regression analysis was run to examine the effect of ARD compared to non-ARD on mortality risk adjusted by confounders. Results were expressed by Hazard Ratio (HR) and CI. Results: Overall, 405 patients were included (642.5 patients-month). During the study period, 44 (10.86%) deaths were recorded. CMR was 68.48 (50.96-92.01). After adjusting for confounders, HR of mortality in ARD compared to non-ARD did not achieve statistical significance [HR: 1.15 (0.64-2.07)], neither CTD versus CIA nor CTD versus non-ARD. Age and certain comorbidities which are being diagnosed in March compared to April or May [HR: 2.43 (1.1-5.55)] increased the mortality risk. Glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) dropped from the final model. Conclusion: In patients with RMDs and COVID-19, CMR was 6.8% patients-month. This study shows that mortality risk is higher in males, older patients, and similar between CTD, CIA, and non-ARD. COVID-19 management improved after the first month of pandemic. Plain Language Summaries: Mortality related to the outbreak of COVID-19 in patients with rheumatic and musculoskeletal diseases Why was this study done? - To report the COVID-19-specific mortality rate in patients with a variety of RMDs during the first pandemic peak in a tertiary hospital in Madrid and to analyze the role of specific types of ARD and other possible factors in the risk of death related to COVID-19. What did the researchers do? - We performed a retrospective observational study during the first wave of the COVID-19 pandemic in Madrid, Spain. What did the researchers find? - In this study, neither the different diagnoses of RMDs, including CIA, CTD, or non-ARD disease or its treatment were not implicated as a potential risk of death related to COVID-19- In consonance with other studies, RMDs patients and COVID-19, older age, male sex, and certain comorbidities implied more mortality risk- Our data reflect COVID-19 severity in a particular context, time, and population. In times of the absence of COVID-19 vaccine, healthcare, social, and political measures taken to contain the coronavirus outbreak have worked properly. What do the findings mean? - The presence of comorbidities in RMDs patients represents a greater risk than the different types of RMDs themselves, in the development of COVID-19 fatal outcome. It is important to integrate the control of comorbidities in the daily management.
RESUMEN
OBJECTIVES: We aimed to describe persistent symptoms and sequelae in patients with rheumatic and musculoskeletal diseases (RMD) after admission owing to coronavirus disease 2019 (COVID-19), assessing the role of autoimmune rheumatic diseases (ARDs) compared with non-autoimmune rheumatic and musculoskeletal diseases (NARDs) on persistent symptoms and sequelae. METHODS: We performed an observational study including RMD patients who attended a rheumatology clinic in Madrid and required admission owing to COVID-19 (between March and May 2020) and survived. The study began at discharge and ran until October 2020. Main outcomes were persistence of symptoms and sequelae related to COVID-19. The independent variable was the RMD group (ARD and NARD). Covariates included sociodemographics, clinical and treatment data. We ran a multivariate logistic regression model to assess the risk of the main outcomes by RMD group. RESULTS: We included 105 patients, of whom 51.5% had ARD and 68.57% reported at least one persistent symptom. The most frequent symptoms were dyspnoea, fatigue and chest pain. Sequelae were recorded in 31 patients. These included lung damage in 10.4% of patients, lymphopenia in 10%, a central retinal vein occlusion and an optic neuritis. Two patients died. Eleven patients required re-admission owing to COVID-19 problems (16.7% ARD vs 3.9% NARD; P = 0.053). No statistically significant differences were found between RMD groups in the final models. CONCLUSION: Many RMD patients have persistent symptoms, as in other populations. Lung damage is the most frequent sequela. Compared with NARD, ARD does not seem to differ in terms of persistent symptoms or consequences, although ARD might have more re-admissions owing to COVID-19.
RESUMEN
OBJECTIVE: To develop and assess the feasibility in daily practice of four comorbidity checklists, for common use in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: A multidisciplinary panel of experts on comorbidity was established. Data from the GECOAR, GECOAX and GECOAP projects were analysed and a narrative literature review in Medline on RA, axSpA and PsA comorbidity was performed in order to select the most relevant and common comorbidities across the three diseases. With these results and those obtained from a focus group of patients, in a nominal group meeting, the experts generated preliminary checklists. These were afterwards modified by an external evaluation by two associations, a patients' association and an association of health professionals related to rheumatology. As a result, the final checklists were generated. A cross-sectional study was conducted to test the feasibility of three of the checklists in daily practice, in which eight health professionals evaluated the checklists in five patients with RA, five with axSpA and five with SpA. RESULTS: Four comorbidity checklists were designed, three for health professionals (one to assess current comorbidity, one on prevention/health promotion and one with the referral criteria to other health professionals), and another for patients. The feasibility study showed them to be simple, clear, and useful for use in routine clinical practice. CONCLUSIONS: The use of specific and common checklists for patients with RA, axSpA and PsA is feasible and might contribute favorably to their prognosis as well as in daily practice.
Asunto(s)
Artritis Psoriásica , Artritis Reumatoide , Espondiloartritis Axial , Espondiloartritis , Artritis Psoriásica/epidemiología , Artritis Reumatoide/epidemiología , Lista de Verificación , Comorbilidad , Estudios Transversales , Estudios de Factibilidad , Humanos , Espondiloartritis/epidemiologíaRESUMEN
Patients with rheumatoid arthritis (RA) have a significantly increased risk of sexual dysfunction. However, it is not properly included in commonly used questionnaires to assess health-related quality of life in RA. Qualisex is a questionnaire developed in France to assess the impact of RA on patients´ sexual function. Our aim was to adapt and validate this questionnaire for use with Spanish RA patients. Two independent translations and a backward translation were obtained. The final version was tested in a pilot study with 10 RA patients to detect any aspects that could hinder interpretation. The validity and reliability of the linguistically validated questionnaire were studied in a multicenter cross-sectional study, with a longitudinal component for reliability estimation. 125 RA patients were included. The response process, discrimination, internal consistency, internal structure, convergent validity (correlation with MGH-SFQ questionnaire, DAS-28, physician global assessment, patient global health assessment, RAID, HAQ, HADS and SF-12©) and reliability were analyzed. The inclusion of two extra items was proposed in the pilot study. The validity analysis detected responses for item 10 that were not coherent with responses for the rest of items. The Cronbach alpha coefficient was 0.971. The highest correlation (0.665) was obtained with MGH-SFQ (questionnaire measuring sexual functioning), followed by RAID (0.516). The intra-class correlation was 0.880 (95% CI 0.815; 0.923), higher than 0.85, which indicates excellent reliability. All parameters used to assess this questionnaire show highly acceptable values. Qualisex allows for a global score of RA patients' sexual functioning and can be self-administered.
Asunto(s)
Artritis Reumatoide , Calidad de Vida , Artritis Reumatoide/diagnóstico , Estudios Transversales , Humanos , Proyectos Piloto , Psicometría , Reproducibilidad de los Resultados , Sexualidad , España , Encuestas y CuestionariosRESUMEN
T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
Asunto(s)
Leucemia Linfocítica Granular Grande , MicroARNs , Factor de Transcripción STAT3 , Linfocitos T CD8-positivos , Humanos , Leucemia Linfocítica Granular Grande/genética , MicroARNs/genética , Receptores de Antígenos de Linfocitos T alfa-beta , Factor de Transcripción STAT3/genéticaRESUMEN
MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.
Asunto(s)
Leucemia Mieloide Aguda/genética , MicroARNs/genética , ARN Polimerasa II/genética , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Epigénesis Genética , Regulación Leucémica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genéticaRESUMEN
T-cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small- to medium-sized prolymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide range of clinical, morphological, and molecular features, which occasionally impedes the diagnosis. We hypothesized that T-PLL consists of phenotypic and/or genotypic subgroups that may explain the heterogeneity of the disease. Multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups, and no clear T-cell receptor a or ß CDR3 skewing was observed between different T-PLL cases. We revealed that the expression of microRNA (miRNA) is aberrant and often heterogeneous in T-PLL. We identified 35 miRNA that were aberrantly expressed in T-PLL with miR-200c/141 as the most differentially expressed cluster. High miR- 200c/141 and miR-181a/181b expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 correlated with downregulation of their targets ZEB2 and TGFßR3 and aberrant TGFß1- induced phosphorylated SMAD2 (p-SMAD2) and p-SMAD3, indicating that the TGFß pathway is affected in T-PLL. Our results thus highlight the potential role for aberrantly expressed oncogenic miRNA in T-PLL and pave the way for new therapeutic targets in this disease.
Asunto(s)
Leucemia Prolinfocítica de Células T , MicroARNs , Perfilación de la Expresión Génica , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/terapia , Linfocitos , MicroARNs/genética , Factor de Crecimiento Transformador beta , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genéticaRESUMEN
Extracellular vesicles (EV) derived from mesenchymal stromal cells (MSC) are a potential therapy for immunological and degenerative diseases. However, large-scale production of EV free from contamination by soluble proteins is a major challenge. The generation of particles from isolated membranes of MSC, membrane particles (MP), may be an alternative to EV. In the present study we generated MP from the membranes of lysed MSC after removal of the nuclei. The yield of MP per MSC was 1 × 105 times higher than EV derived from the same number of MSC. To compare the proteome of MP and EV, proteomic analysis of MP and EV was performed. MP contained over 20 times more proteins than EV. The proteins present in MP evidenced a multi-organelle origin of MP. The projected function of the proteins in EV and MP was very different. Whilst proteins in EV mainly play a role in extracellular matrix organization, proteins in MP were interconnected in diverse molecular pathways, including protein synthesis and degradation pathways and demonstrated enzymatic activity. Treatment of MSC with IFNγ led to a profound effect on the protein make up of EV and MP, demonstrating the possibility to modify the phenotype of EV and MP through modification of parent MSC. These results demonstrate that MP are an attractive alternative to EV for the development of potential therapies. Functional studies will have to demonstrate therapeutic efficacy of MP in preclinical disease models.
Asunto(s)
Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteoma , Membrana Celular/metabolismo , Humanos , Interferón gamma , ProteómicaRESUMEN
BACKGROUND: This study aimed to assess the baseline characteristics and clinical outcomes of coronavirus disease 2019 (COVID-19) in pediatric patients with rheumatic and musculoskeletal diseases (RMD) and identify the risk factors associated with symptomatic or severe disease defined as hospital admission, intensive care admission or death. METHODS: An observational longitudinal study was conducted during the first year of the SARS-CoV-2 pandemic (March 2020-March 2021). All pediatric patients attended at the rheumatology outpatient clinics of six tertiary referral hospitals in Madrid, Spain, with a diagnosis of RMD and COVID-19 were included. Main outcomes were symptomatic disease and hospital admission. The covariates were sociodemographic and clinical characteristics and treatment regimens. We ran a multivariable logistic regression model to assess associated factors for outcomes. RESULTS: The study population included 77 pediatric patients. Mean age was 11.88 (4.04) years Of these, 30 patients (38.96%) were asymptomatic, 41 (53.25%) had a mild-moderate COVID-19 and 6 patients (7.79%) required hospital admission. The median length of hospital admission was 5 (2-20) days, one patient required intensive care and there were no deaths. Previous comorbidities increased the risk for symptomatic disease and hospital admission. Compared with outpatients, the factor independently associated with hospital admission was previous use of glucocorticoids (OR 3.51; p = 0.00). No statistically significant risk factors for symptomatic COVID-19 were found in the final model. CONCLUSION: No differences in COVID-19 outcomes according to childhood-onset rheumatic disease types were found. Results suggest that associated comorbidities and treatment with glucocorticoids increase the risk of hospital admission.
Asunto(s)
Antirreumáticos/uso terapéutico , COVID-19/fisiopatología , Glucocorticoides/uso terapéutico , Hospitalización/estadística & datos numéricos , Enfermedades Reumáticas/tratamiento farmacológico , Adolescente , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/epidemiología , Asma/epidemiología , COVID-19/epidemiología , Portador Sano/epidemiología , Niño , Estudios de Cohortes , Comorbilidad , Femenino , Cardiopatías/epidemiología , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/epidemiología , Humanos , Unidades de Cuidado Intensivo Pediátrico , Tiempo de Internación , Modelos Logísticos , Estudios Longitudinales , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Masculino , Análisis Multivariante , Obesidad/epidemiología , Insuficiencia Renal Crónica/epidemiología , Enfermedades Reumáticas/epidemiología , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , España/epidemiologíaRESUMEN
OBJECTIVE: Clinical guidelines recommend psychological screening in cancer patients. However, most scales cover many items and hamper detection. In addition, patients are generally referred from routine consultations. The specific objective of the present study was to develop and validate a tool, Anxiety, Depression, Coping (ADAF), to screen for anxiety and depression and assess coping in cancer patients. METHODS: Cross-sectional, multicenter study performed in the medical and radiotherapy-oncology services of five hospitals in Madrid and coordinated by the Medical Oncology Service of Hospital Clínico San Carlos (CEIC nº19/265-E). To determine psychometric properties, the ADAF screening questionnaire ADAF was administered. ADAF includes five items (1 related to anxiety symptoms, 2 related to depressive symptoms, 1 for helplessness coping, and 1 for avoidance coping). Hospital Anxiety and Depression Scale and Mini-Mental Adjustment to Cancer scale were used as the gold standards. Intraclass correlation coefficients were calculated and receiver operating characteristic (ROC) curves constructed. A p value of <0.05 was considered significant. RESULTS: A total of 186 patients completed the evaluation. The correlation coefficients were significant for all dimensions (anxiety, depression, helplessness coping, and avoidance coping) (p < 0.001). The statistical analysis of the ROC curves suggested that the cut-off point for screening was >2 points (3 in the case of depression), with a sensitivity and specificity between 62% and 90%, and an area under the curve above 0.8 for the first 4 items. CONCLUSIONS: ADAF screening has adequate reliability and good sensitivity and specificity. This instrument is useful and can be easily applied to identify emotional and coping problems in cancer patients.