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AIM: Recently, the development of the oral glucagon-like peptide-1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6-month period. METHODS: Fifty-nine participants were included, and we compared various clinical parameters between before and after switching from DPP-4 inhibitors to oral semaglutide in 'study 1' (pre-post comparison) and set the control group using the propensity score matching method in 'study 2'. RESULTS: In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m2 to 28.8 kg/m2. Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP-4 inhibitor continuation group over the 6-month observation period. CONCLUSION: In this study, including obese participants with poor glycaemic control, switching DPP-4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP-4 inhibitors.
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The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.
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Condrocitos , Modelos Animales de Enfermedad , Osteocondroma , Receptores de Ácido Retinoico , Receptor de Ácido Retinoico gamma , Animales , Ratones , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Osteocondroma/tratamiento farmacológico , Osteocondroma/patología , Osteocondroma/metabolismo , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/patología , Factor de Transcripción STAT3/metabolismo , Proliferación Celular/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , MasculinoRESUMEN
OBJECTIVES: To define groups and characterize differences in the prognosis of patients with adult-onset Still's disease (AOSD). METHODS: We performed a retrospective cohort study. Patients with AOSD were grouped using hierarchical unsupervised cluster analysis according to age, sex, clinical features, and laboratory data. The primary endpoints were overall survival and drug-free remission rate. RESULTS: A total of 153 patients with AOSD were placed into four clusters. Those in Cluster 1 had a young onset, tended to be female, and had fewer complications and moderate ferritin concentrations. Those in Cluster 2 had a young onset and had more complications and higher ferritin concentrations. Those in Cluster 3 had a young onset, tended to be male, and had no lymphadenopathy and fewer complications. Those in Cluster 4 had an older onset, tended to be female, and had more complications and higher ferritin concentrations. Overall survival tended to be lower (P = .0539) in Cluster 4, and drug-free remission was higher in Clusters 1, 2, and 3 [hazard ratios (HRs) 2.19, 3.37, and 3.62 vs. Cluster 4, respectively]. CONCLUSIONS: Four groups of AOSD that have distinct clinical manifestations, ferritin concentrations, severity, and drug-free remission rate were identified, which were lowest in Cluster 4. Graphical Abstract.
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The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in >10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYC-high B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC-driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.
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Linfocitos B/patología , Carcinogénesis/genética , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción/genética , Animales , Linfocitos B/metabolismo , Carcinogénesis/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Leucemia Linfoide/genética , Leucemia Linfoide/patología , Linfoma de Células B/genética , Linfoma de Células B/patología , Ratones Endogámicos C57BL , Mutación , Células Tumorales CultivadasRESUMEN
Osteochondromas are cartilage-capped tumors that arise near growing physes and are the most common benign bone tumor in children. Osteochondromas can lead to skeletal deformity, pain, loss of motion, and neurovascular compression. Currently, surgery is the only available treatment for symptomatic osteochondromas. Osteochondroma mouse models have been developed to understand the pathology and the origin of osteochondromas and develop therapeutic drugs. Several cartilage regulatory pathways have been implicated in the development of osteochondromas, such as bone morphogenetic protein, hedgehog, and WNT/ß-catenin signaling. Retinoic acid receptor-γ is an important regulator of endochondral bone formation. Selective agonists for retinoic acid receptor-γ, such as palovarotene, have been investigated as drugs for inhibition of ectopic endochondral ossification, including osteochondromas. This review discusses the signaling pathways involved in osteochondroma pathogenesis and their possible interactions with the retinoid pathway.
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Neoplasias Óseas/etiología , Osteocondroma/etiología , Retinoides/metabolismo , Animales , Neoplasias Óseas/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Osteocondroma/patología , Transducción de Señal/fisiologíaRESUMEN
This study aimed to retrospectively compare the clinical efficacy of different types of long-acting insulin therapies-glargine U100, glargine U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes after insulin use was initiated in an outpatient setting. The study consisted of 822 insulin-naïve patients in Japan who started using long-acting insulin for treatment of type 2 diabetes and continued for over 12 months. In addition, the impact of insulin type on insulin withdrawal was investigated by dividing the participants into two groups: those who achieved insulin withdrawal and those who did not, during the 12-month observation period based on a Cox proportional hazards model. As a result, HbA1c was decreased, and BMI was increased in all participants regardless of the insulin type used. A total of 185 participants succeeded in insulin withdrawal. After adjustment was made for several confounders, the positive determinant factors for withdrawal were short duration of diabetes and the choice of IDegAsp when compared with Gla100; the negative determinant factor was use of insulin secretagogues at the start of the study. In conclusion, all long-acting insulins were a powerful tool for treatment of type 2 diabetes, and patients with short duration of diabetes and/or no usage of insulin secretagogues resulted in favorable outcomes in terms of insulin withdrawal within a year in an outpatient setting. In addition, insulin degludec/insulin aspart was found to possibly be a better choice for treatment when it was compared with glargine U100 among the four types of insulin.
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Diabetes Mellitus Tipo 2 , Hipoglucemia , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Insulina Aspart/uso terapéutico , Insulina Glargina/uso terapéutico , Insulina de Acción Prolongada/uso terapéutico , Japón , Estudios Retrospectivos , Secretagogos/uso terapéuticoRESUMEN
Interstitial lung disease (ILD) carries a risk for severe pneumonia in patients with rheumatoid arthritis (RA). Bronchiectasis, another risk of severe pneumonia, has not been well elucidated in RA. We investigated the types of respiratory diseases in RA and correlated them to severe pneumonia during the course of treatment using biologic DMARDs (bDMARDs), with special attention to bronchiectasis and ILD. RA patients were examined by computed tomography before starting bDMARDs and divided into three groups: normal, bronchiectasis and ILD. The log-rank test and Dunnett's multiple comparisons test were employed for the statistical analysis. Among 424 patients, 350 were categorized as normal, 32 as having bronchiectasis, and 42 as having ILD. Two in the normal group, three in the bronchiectasis group and four in the ILD group developed severe pneumonia. The log-rank test showed a significant difference among the three groups (p < 0.0001). The pneumonia-free rates in the bronchiectasis and ILD groups were significantly lower than the normal group, respectively, with Dunnett's multiple comparison test (p < 0.0001). This study suggests that the bronchiectasis that occurs in RA carries a risk of severe pneumonia during treatment with bDMARDs that is comparable to ILD.
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Antirreumáticos , Artritis Reumatoide , Productos Biológicos , Bronquiectasia , Enfermedades Pulmonares Intersticiales , Neumonía , Antirreumáticos/efectos adversos , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/efectos adversos , Bronquiectasia/tratamiento farmacológico , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Neumonía/inducido químicamente , Estudios RetrospectivosRESUMEN
Extracellular vesicles (EVs) released by bone marrow stromal cells (BMSCs) have been shown to act as a transporter of bioactive molecules such as RNAs and proteins in the therapeutic actions of BMSCs in various diseases. Although EV therapy holds great promise to be a safer cell-free therapy overcoming issues related to cell therapy, manufacturing processes that offer scalable and reproducible EV production have not been established. Robust and scalable BMSC manufacturing methods have been shown to enhance EV production; however, the effects on EV quality remain less studied. Here, using human BMSCs isolated from nine healthy donors, we examined the effects of high-performance culture media that can rapidly expand BMSCs on EV production and quality in comparison with the conventional culture medium. We found significantly increased EV production from BMSCs cultured in the high-performance media without altering their multipotency and immunophenotypes. RNA sequencing revealed that RNA contents in EVs from high-performance media were significantly reduced with altered profiles of microRNA enriched in those related to cellular growth and proliferation in the pathway analysis. Given that pre-clinical studies at the laboratory scale often use the conventional medium, these findings could account for the discrepancy in outcomes between pre-clinical and clinical studies. Therefore, this study highlights the importance of selecting proper culture conditions for scalable and reproducible EV manufacturing.
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Medios de Cultivo/química , Vesículas Extracelulares/genética , Células Madre Mesenquimatosas/citología , MicroARNs/análisis , Técnicas de Cultivo de Célula , Proliferación Celular , Células Cultivadas , Voluntarios Sanos , Humanos , Células Madre Mesenquimatosas/metabolismo , Análisis de Secuencia de ARN , Transducción de SeñalRESUMEN
OBJECTIVES: To investigate the usefulness of severity classification for predicting outcomes in patients with adult-onset Still's disease (AOSD). METHODS: This was a multi-centre retrospective cohort study. AOSD patients were classified into mild, moderate, and severe groups based on severity classification (Japanese Ministry of Health, Labour and Welfare) during the initial treatment, and clinical features were compared among these groups. The primary endpoints were the AOSD-related mortality and drug-free remission rate. For comparison, the same analysis was performed in parallel for patient groups stratified by the modified Pouchot systemic score. RESULTS: According to severity classification, 49 (35%), 37 (26%), and 56 patients (39%) were classified into mild, moderate, and severe groups, respectively. Patients in the severe group showed higher frequency of severe complications and the use of biological agents. Although AOSD-related survival was not significantly different (p = .0776), four of the five fatal cases were classified into the severe group. The severe group showed a reduced rate of drug-free remission (p = .0125). Patient groups classified by systemic score did not correlate with survival or drug-free remission. CONCLUSIONS: Severity classification is useful for predicting outcomes in patients with AOSD.
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Enfermedad de Still del Adulto , Adulto , Humanos , Japón , Estudios Retrospectivos , Enfermedad de Still del Adulto/diagnóstico , Enfermedad de Still del Adulto/tratamiento farmacológicoRESUMEN
OBJECTIVES: To clarify the characteristics of patients with elderly-onset Adult-onset Still's disease (AOSD). METHODS: Patients were classified into elderly-onset (>60 years: 47 patients) and younger-onset (≤60 years: 95 patients) groups according to their age at diagnosis of AOSD. Clinical features, treatments, and prognosis were compared between the elderly-onset and younger-onset groups. RESULTS: In the elderly-onset group, compared with the younger-onset group, typical skin rashes were less frequent (21.3% vs 58.9%, respectively; p < .0001), whereas pleuritis (27.7% vs 7.4%, respectively; p = .0011) and disseminated intravascular coagulation (19.1% vs 2.1%, respectively; p = .0004) were more frequent, and serum ferritin levels were higher (median 12,700 ng/ml vs 2526 ng/ml, respectively; p < .0001). Overall survival and AOSD-related survival were reduced (p = .0006 and p = .0023, respectively) and drug-free remission was less frequent (p = .0035) in the elderly-onset group compared with the younger-onset group. CONCLUSIONS: Our results demonstrated that elderly-onset AOSD patients had several characteristics that differed from younger-onset AOSD patients, including less typical skin lesions, more AOSD-related complications, higher ferritin levels, and poorer prognoses.
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Enfermedad de Still del Adulto/diagnóstico , Enfermedad de Still del Adulto/patología , Adulto , Factores de Edad , Edad de Inicio , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
PURPOSE: To examine the impact of adding droperidol to fentanyl-based intravenous patient- controlled analgesia (IVPCA) on the discontinuation of IVPCA use due to postoperative nausea and vomiting (PONV). METHODS: Patients who underwent surgeries other than abdominal surgeries and used IVPCA between April 2014 and March 2018 were selected. Patients using IVPCA with fentanyl alone were compared to patients using droperidol added to IVPCA. Patients were allocated to one of two groups depending on the drug used for IVPCA: 1) control group, fentanyl alone; 2) droperidol group, droperidol with fentanyl. The primary endpoint was the discontinuation of IVPCA due to PONV. Secondary endpoints included PONV within 48 hours after surgery, the number of antiemetics used, pain score, and adverse effects. Propensity score matching was used to control the differences in clinical features among patients. RESULTS: Among the 793 patients initially enrolled in this study, 145 were excluded via propensity score matching; 364 of the remaining patients received IVPCA supplemented with droperidol. Propensity score matching showed that discontinuation of IVPCA due to PONV was significantly decreased in the droperidol group compared to the control group (P = 0.01). Further, compared with the control group, the droperidol group had reduced nausea up to 24 hours after surgery (P < 0.01), and the number of vomiting episodes and use of antiemetics decreased within 12 hours after surgery (P < 0.01). CONCLUSIONS: The addition of droperidol to IVPCA is associated with a decrease in PONV, as well as the improved continuation of pain treatment with fentanyl-based IVPCA, similar to IVPCA with morphine. However, it is necessary to monitor the side effects of this treatment.
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Adyuvantes Anestésicos/uso terapéutico , Analgesia Controlada por el Paciente , Droperidol/uso terapéutico , Fentanilo/uso terapéutico , Náusea y Vómito Posoperatorios/tratamiento farmacológico , Adyuvantes Anestésicos/efectos adversos , Estudios de Cohortes , Droperidol/efectos adversos , Femenino , Fentanilo/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Náusea y Vómito Posoperatorios/cirugía , Estudios RetrospectivosRESUMEN
Osteochondromas are cartilage-capped growths located proximate to the physis that can cause skeletal deformities, pain, limited motion, and neurovascular impingement. Previous studies have demonstrated retinoic acid receptor gamma (RARγ) agonists to inhibit ectopic endochondral ossification, therefore we hypothesize that RARγ agonists can target on established osteochondromas. The purpose of this study was to examine the action of RARγ agonist in human osteochondromas. Osteochondroma specimens were obtained during surgery, subjected to explant culture and were treated with RARγ agonists or vehicles. Gene expression analysis confirmed the up-regulation of RARγ target genes in the explants treated with NRX 204647 and Palovarotene and revealed strong inhibition of cartilage matrix and increased extracellular matrix proteases gene expression. In addition, immunohistochemical staining for the neoepitope of protease-cleaved aggrecan indicated that RARγ agonist treatment stimulated cartilage matrix degradation. Interestingly, cell survival studies demonstrated that RARγ agonist treatment stimulated cell death. Moreover, RNA sequencing analysis indicates changes in multiple molecular pathways due to RARγ agonists treatment, showing similarly to human growth plate chondrocytes. Together, these findings suggest that RARγ agonist may exert anti-tumor function on osteochondromas by inhibiting matrix synthesis, promoting cartilage matrix degradation and stimulating cell death.
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Neoplasias Óseas/metabolismo , Osteocondroma/metabolismo , Receptores de Ácido Retinoico/agonistas , Animales , Biomarcadores , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/etiología , Neoplasias Óseas/patología , Condrocitos/metabolismo , Condrocitos/patología , Biología Computacional/métodos , Perfilación de la Expresión Génica , Ontología de Genes , Placa de Crecimiento/metabolismo , Placa de Crecimiento/patología , Humanos , Anotación de Secuencia Molecular , Osteocondroma/tratamiento farmacológico , Osteocondroma/etiología , Osteocondroma/patología , Transducción de Señal , Técnicas de Cultivo de Tejidos , Transcriptoma , Receptor de Ácido Retinoico gammaRESUMEN
The process of fracture healing consists of an inflammatory reaction and cartilage and bone tissue reconstruction. The inflammatory cytokine interleukin-1ß (IL-1ß) signal is an important major factor in fracture healing, whereas its relevance to retinoid receptor (an RAR inverse agonist, which promotes endochondral bone formation) remains unclear. Herein, we investigated the expressions of IL-1ß and retinoic acid receptor gamma (RARγ) in a rat fracture model and the effects of IL-1ß in the presence of one of several RAR inverse agonists on chondrocytes. An immunohistochemical analysis revealed that IL-1ß and RARγ were expressed in chondrocytes at the fracture site in the rat ribs on day 7 post-fracture. In chondrogenic ATDC5 cells, IL-1ß decreases the levels of aggrecan and type II collagen but significantly increased the metalloproteinase-13 (Mmp13) mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. An RAR inverse agonist (AGN194310) inhibited IL-1ß-stimulated Mmp13 and Ccn2 mRNA in a dose-dependent manner. Phosphorylated extracellular signal regulated-kinases (pERK1/2) and p-p38 mitogen-activated protein kinase (MAPK) were increased time-dependently by IL-1ß treatment, and the IL-1ß-induced p-p38 MAPK was inhibited by AGN194310. Experimental p38 inhibition led to a drop in the IL-1ß-stimulated expressions of Mmp13 and Ccn2 mRNA. MMP13, CCN2, and p-p38 MAPK were expressed in hypertrophic chondrocytes near the invaded vascular endothelial cells. As a whole, these results point to role of the IL-1ß via p38 MAPK as important signaling in the regulation of the endochondral bone formation in fracture healing, and to the actions of RAR inverse agonists as potentially relevant modulators of this process.
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Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Curación de Fractura/efectos de los fármacos , Interleucina-1beta/metabolismo , Retinoides/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Biomarcadores , Curación de Fractura/genética , Expresión Génica , Inmunohistoquímica , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Biológicos , Transporte de Proteínas , Ratas , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismoRESUMEN
Osteogenesis imperfecta (OI) is a hereditary bone disorder most commonly caused by autosomal dominant mutations in genes encoding type I collagen. In addition to bone fragility, patients suffer from impaired longitudinal bone growth. It has been demonstrated that in OI, an accumulation of mutated type I collagen in the endoplasmic reticulum (ER) induces ER stress in osteoblasts, causing osteoblast dysfunction leading to bone fragility. We hypothesize that ER stress is also induced in the growth plate where bone growth is initiated, and examined a mouse model of dominant OI that carries a G610C mutation in the procollagen α2 chain. The results demonstrated that G610C OI mice had significantly shorter long bones with growth plate abnormalities including elongated total height and hypertrophic zone. Moreover, we found that mature hypertrophic chondrocytes expressed type I collagen and ER dilation was more pronounced compared to wild type littermates. The results from in vitro chondrocyte cultures demonstrated that the maturation of G610C OI hypertrophic chondrocytes was significantly suppressed and ER stress related genes were upregulated. Given that the alteration of hypertrophic chondrocyte activity often causes dwarfism, our findings suggest that hypertrophic chondrocyte dysfunction induced by ER stress may be an underlying cause of growth deficiency in G610C OI mice.
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Condrocitos/patología , Colágeno Tipo I/genética , Estrés del Retículo Endoplásmico , Placa de Crecimiento/anomalías , Osteogénesis Imperfecta/genética , Mutación Puntual , Animales , Condrocitos/metabolismo , Modelos Animales de Enfermedad , Placa de Crecimiento/metabolismo , Placa de Crecimiento/patología , Masculino , Ratones Endogámicos C57BL , Osteogénesis Imperfecta/patologíaRESUMEN
The objective was to investigate the clinical and histological features of liver dysfunction in patients with polymyositis (PM) or dermatomyositis (DM).A total of 115 patients (38 with PM and 77 with DM), who were admitted to our hospital between 2001 and 2012, were retrospectively reviewed. Liver dysfunction was defined as an alanine transaminase (ALT) level ≥ 60 U/l and a disproportionate ALT elevation relative to the creatine kinase level. The histological findings from liver biopsies were also assessed.The frequencies of liver dysfunction were 3% and 17% in the patients with PM and DM, respectively. Liver dysfunction was not observed in the patients who had malignancies. Among the patients with DM with no malignancies (n = 50), 20% had liver dysfunction, and all of the patients with liver dysfunction were positive for the anti-melanoma differentiation-associated gene 5 (MDA5) antibody. Compared with those in the patients who did not have liver dysfunction, the ALT, alkaline phosphatase, γ-glutamyl transferase, and KL-6 levels were significantly elevated in the patients who had liver dysfunction. Six patients, comprising four with DM and two with PM, underwent liver biopsies, and the common histological findings associated with DM were steatosis, hepatocyte ballooning, increases in the pigmented macrophage numbers, and glycogenated nuclei. Hemophagocytosis was detected in two of three patients with DM who underwent liver biopsies and bone marrow aspirations. In conclusion, Liver dysfunction might be an extramuscular manifestation in patients with DM who are anti-MDA5 antibody-positive. Steatosis and hepatocyte ballooning could be common histological features.
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Dermatomiositis/epidemiología , Hepatopatías/epidemiología , Adulto , Anciano , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Autoanticuerpos/inmunología , Creatina Quinasa , Dermatomiositis/inmunología , Hígado Graso/patología , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1/genética , Hígado/patología , Hepatopatías/sangre , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Mucina-1/sangre , Polimiositis/epidemiología , Polimiositis/inmunología , gamma-Glutamiltransferasa/sangreRESUMEN
BACKGROUND: Systemic infusion of mesenchymal stromal cells (MSCs) has been shown to induce acute acceleration of growth velocity in children with osteogenesis imperfecta (OI) despite minimal engraftment of infused MSCs in bones. Using an animal model of OI we have previously shown that MSC infusion stimulates chondrocyte proliferation in the growth plate and that this enhanced proliferation is also observed with infusion of MSC conditioned medium in lieu of MSCs, suggesting that bone growth is due to trophic effects of MSCs. Here we sought to identify the trophic factor secreted by MSCs that mediates this therapeutic activity. METHODS: To examine whether extracellular vesicles (EVs) released from MSCs have therapeutic activity, EVs were isolated from MSC conditioned medium by ultracentrifugation. To further characterize the trophic factor, RNA or microRNA (miRNA) within EVs was depleted by either ribonuclease (RNase) treatment or suppressing miRNA biogenesis in MSCs. The functional activity of these modified EVs was evaluated using an in vitro chondrocyte proliferation assay. Finally, bone growth was evaluated in an animal model of OI treated with EVs. RESULTS: We found that infusion of MSC-derived EVs stimulated chondrocyte proliferation in the growth plate, resulting in improved bone growth in a mouse model of OI. However, infusion of neither RNase-treated EVs nor miRNA-depleted EVs enhanced chondrocyte proliferation. CONCLUSION: MSCs exert therapeutic effects in OI by secreting EVs containing miRNA, and EV therapy has the potential to become a novel cell-free therapy for OI that will overcome some of the current limitations in MSC therapy.
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Desarrollo Óseo , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteogénesis Imperfecta/patología , Animales , Proliferación Celular , Niño , Condrocitos/citología , Modelos Animales de Enfermedad , Endopeptidasa K/metabolismo , Humanos , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Ribonucleasas/metabolismo , SolubilidadRESUMEN
OBJECTIVES: Using an expert- and data-driven methodology, we have constructed the first clinical practice guidelines (CPGs) for adult Still's disease (ASD) after complete systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. METHODS: The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process includes (1) clarification of the purpose of CPG, (2) organization of the steering committee, (3) organization of the CPG committee and secretariat, (4) defining the scope (setting of clinical questions (CQs)), (5) SR, (6) development of recommendations, (7) drafting the CPG, (8) external evaluation and public comments, and (9) release. Because we wanted to construct CPG for ASD to encompass both adult-onset Still's disease (AOSD) and adult patients with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study. RESULTS: Twenty-six CQs were selected and roughly divided into the following items: (1) clinical findings (CQs 1-4), (2) laboratory findings (CQs 5-8), (3) complications (CQs 9-13), (4) treatment with oral medicine (CQs 14-19), (5) treatment with biological reagents (CQs 20-23), and (6) treatments for sJIA (CQs 25-26). Recommendations and the strength of the recommendations for these CQs were decided by a modified Delphi method. CONCLUSION: We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26 CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other healthcare providers, medical and health-related students, and patients and their family members to understand and treat ASD.
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Medicina Basada en la Evidencia/métodos , Guías de Práctica Clínica como Asunto , Enfermedad de Still del Adulto/tratamiento farmacológico , Medicina Basada en la Evidencia/normas , Humanos , Enfermedad de Still del Adulto/diagnósticoRESUMEN
BACKGROUND: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.
Asunto(s)
Ferritinas/sangre , Hemo-Oxigenasa 1/sangre , Enfermedad de Still del Adulto/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Endothelial cell (EC) activation underlies many vascular diseases, including pulmonary arterial hypertension (PAH). Several members of the E-twenty six (ETS) family of transcription factors are important regulators of the gene network governing endothelial homeostasis, and their aberrant expression is associated with pathological angiogenesis. The goal of this study was to determine whether deficiencies of the ETS family member, Friend leukemia integration 1 transcription factor (FLI1), and its closest homolog, ETS-related gene (ERG), are associated with PAH. We found that endothelial ERG was significantly reduced in the lung samples from patients with PAH, as well as in chronically hypoxic mice. Functional studies revealed that depletion of ERG or FLI1 in human pulmonary ECs led to increased expression of inflammatory genes, including IFN genes, whereas genes regulating endothelial homeostasis and cell-cell adhesion were down-regulated. Simultaneous knockdown of both ERG and FLI1 had synergistic or additive effects on the expression of these genes, suggesting that ERG and FLI1 coregulate at least a subset of their target genes. Functionally, knockdown of ERG and FLI1 induced cell monolayer permeability with a potency similar to that of vascular endothelial growth factor. Notably, stimulation of ECs with Toll-like receptor 3 ligand poly(I:C) suppressed ERG expression and induced ERG dissociation from the IFNB1 promoter, while promoting signal transducers and activators of transcription 1 (STAT1) recruitment. Consistent with the up-regulation of inflammatory genes seen in vitro, Erg and Fli1 double-heterozygote mice showed increased immune cell infiltration and expression of cytokines in the lung. In conclusion, loss of ERG and FLI1 might contribute to the pathogenesis of vascular lung complications through the induction of inflammation.
Asunto(s)
Endotelio Vascular/metabolismo , Homeostasis , Pulmón/irrigación sanguínea , Proteínas Oncogénicas/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Regulador Transcripcional ERG/metabolismo , Animales , Enfermedad Crónica , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Femenino , Heterocigoto , Homeostasis/efectos de los fármacos , Homeostasis/genética , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/patología , Hipoxia/complicaciones , Hipoxia/genética , Hipoxia/patología , Interferón beta/genética , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Proteínas Oncogénicas/genética , Neumonía/complicaciones , Neumonía/genética , Neumonía/patología , Poli I-C/farmacología , Regiones Promotoras Genéticas/genética , Proteína Proto-Oncogénica c-fli-1/genética , Arteria Pulmonar/patología , Factor de Transcripción STAT1/metabolismo , Regulador Transcripcional ERG/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVES: To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone. METHODS: MTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTXâMTX; n=108, PBO+MTXâMTX; n=71). Patients who flared could receive rescue treatment with open-label CZP. RESULTS: 34 CZP+MTXâMTX patients and 14 PBO+MTXâMTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTXâMTX versus PBO+MTXâMTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups. CONCLUSIONS: In MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2â years, even after stopping CZP. TRIAL REGISTRATION NUMBER: NCT01451203.