Evidence for a mitochondrial localization of the retinoblastoma protein

<p>Abstract</p> <p>Background</p> <p>The retinoblastoma protein (Rb) plays a central role in the regulation of cell cycle, differentiation and apoptosis. In cancer cells, ablation of Rb function or its pathway is a consequence of genetic inactivation, viral oncoprotein binding or deregulated hyperphosphorylation. Some recent data suggest that Rb relocation could also account for the regulation of its tumor suppressor activity, as is the case for other tumor suppressor proteins, such as p53.</p> <p>Results</p> <p>In this reported study, we present evidence that a fraction of the total amount of Rb protein can localize to the mitochondria in proliferative cells taken from both rodent and human cells. This result is also supported by the use of Rb siRNAs, which substantially reduced the amount of mitochondrial Rb, and by acellular assays, in which [³⁵S]-Methionine-labeled Rb proteins bind strongly to mitochondria isolated from rat liver. Moreover, endogenous Rb is found in an internal compartment of the mitochondria, within the inner-membrane. This is consistent with the protection of Rb from alkaline treatment, which destroys any interaction of proteins that are weakly bound to mitochondria.</p> <p>Conclusion</p> <p>Although a few data regarding an unspecific cytosolic localization of Rb protein have been reported for some tumor cells, our results are the first evidence of a mitochondrial localization of Rb. The mitochondrial localization of Rb is observed in parallel with its classic nuclear location and paves the way for the study of potential as-yet-unknown roles of Rb at this site.</p

TAFIRA [Material gráfico]

ADQUIRIDA POR EL COLECCIONISTA EN LAS PALMAS DE G.C.FOTO POSTAL DE "TAFIRA. VISTA PARCIAL"Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis

Objectives: To identify groups of people with rheumatoid arthritis (RA) with different disability trajectories over ten years, despite comparable levels of inflammation.Methods: Data for this analysis came from three European prospective cohort studies of people with RA (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN], Étude et Suivi des Polyarthrites Indifférenciées Récentes [ESPOIR]). Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1/1/2000, <24 months baseline symptom duration, and disability (Health Assessment Questionnaire [HAQ]) and inflammation (two-component disease activity score [DAS28-2C]) recorded at baseline and one other follow-up. People in each cohort also completed patient reported outcome measures at each assessment (pain, fatigue, depression). Group-based trajectory models (GBTM) were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up.Results: This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). People in ESPOIR were younger and included more women (mean [standard deviation] age: NOAR: 57.1 [14.6], ESPOIR: 47.6 [12.5], ERAN: 56.8 [13.8]; women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories that followed the hypothesised pattern (comparable DAS28-2C but different HAQ) were identified. Higher pain, fatigue and depression were associated with increased odds of being in the high HAQ trajectories. Conclusion: Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function

Personal non-commercial use only

ABSTRACT. Objective. To report the 5-year outcome of a large prospective cohort of patients with very early rheumatoid arthritis (RA), and to identify factors predictive of outcome. Methods. Patients were recruited if they had early arthritis of &lt; 6 months&apos; duration, had a high probability of developing RA, and had never been prescribed disease-modifying antirheumatic drugs (DMARD) or steroids. Logistic regression analysis was used to determine factors that predict outcome. Results. We included 813 patients from December 2002 to April 2005. Age was 48.1 ± 12.6 years, delay before referral 103.1 ± 52.4 days, 28-joint Disease Activity Score (DAS28) 5.1 ± 1.3, Health Assessment Questionnaire (HAQ) 1.0 ± 0.7; 45.8% and 38.7% had rheumatoid factor or antibodies to cyclic citrullinated peptide (anti-CCP), respectively; 22% had hand or foot erosions; 78.5% fulfilled the American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and 93.8% during followup. At 5 years, 573 patients were evaluated. The outcome was mild for most patients: disease activity (median DAS28 = 2.5) and HAQ disability (median 0.3) were well controlled over time; 50.6% achieved DAS28 remission and 64.7% low disease activity. Radiographic progression was low (2.9 Sharp unit/year) and only a few patients required joint surgery. Nevertheless, some patients developed new comorbidities. During the 5 years, 82.7% of patients had received at least 1 DMARD (methotrexate, 65.9%), 18.3% a biological DMARD, and about 60% prednisone at least once. Anti-CCP was the best predictor of remaining in the cohort for 5 years, of prescription of synthetic or biologic DMARD, and of radiographic progression. Conclusion. The 5-year outcome of an early RA cohort in the 2000s was described. Anti-CCP was a robust predictor of outcome. The generally good 5-year outcome could be related to early referral and early effective treatment, key processes in the management of early RA in daily practice

5-year RA outcomes Personal non-commercial use only

ABSTRACT. Objective. To report the 5-year outcome of a large prospective cohort of patients with very early rheumatoid arthritis (RA), and to identify factors predictive of outcome. Methods. Patients were recruited if they had early arthritis of &lt; 6 months&apos; duration, had a high probability of developing RA, and had never been prescribed disease-modifying antirheumatic drugs (DMARD) or steroids. Logistic regression analysis was used to determine factors that predict outcome. Results. We included 813 patients from December 2002 to April 2005. Age was 48.1 ± 12.6 years, delay before referral 103.1 ± 52.4 days, 28-joint Disease Activity Score (DAS28) 5.1 ± 1.3, Health Assessment Questionnaire (HAQ) 1.0 ± 0.7; 45.8% and 38.7% had rheumatoid factor or antibodies to cyclic citrullinated peptide (anti-CCP), respectively; 22% had hand or foot erosions; 78.5% fulfilled the American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and 93.8% during followup. At 5 years, 573 patients were evaluated. The outcome was mild for most patients: disease activity (median DAS28 = 2.5) and HAQ disability (median 0.3) were well controlled over time; 50.6% achieved DAS28 remission and 64.7% low disease activity. Radiographic progression was low (2.9 Sharp unit/year) and only a few patients required joint surgery. Nevertheless, some patients developed new comorbidities. During the 5 years, 82.7% of patients had received at least 1 DMARD (methotrexate, 65.9%), 18.3% a biological DMARD, and about 60% prednisone at least once. Anti-CCP was the best predictor of remaining in the cohort for 5 years, of prescription of synthetic or biologic DMARD, and of radiographic progression. Conclusion. The 5-year outcome of an early RA cohort in the 2000s was described. Anti-CCP was a robust predictor of outcome. The generally good 5-year outcome could be related to early referral and early effective treatment, key processes in the management of early RA in daily practice

Early lessons from the recent-onset rheumatoid arthritis cohort ESPOIR.

International audienceESPOIR is a French multicenter cohort of patients with undifferentiated arthritis enrolled within six months of symptom onset, naive to disease-modifying antirheumatic drugs and corticosteroid therapy, and either having rheumatoid arthritis (RA) or being at risk for progression to RA. The cohort is sponsored by the French Society for Rheumatology (Société française de rhumatologie [SFR]). Between December 2002 and March 2005, 813 patients were enrolled at 14 regional university hospitals, with the participation of a network of community-based rheumatologists. The objective was to establish a database on recent-onset inflammatory joint disease and, more specifically, on RA to serve for scientific research in the clinical, epidemiological, pathophysiological, and healthcare-cost fields. Ten years after enrolment were started, the cohort still has about 500 patients. The scientific committee has approved 104 clinical research projects, of which many are ongoing, and 54 original articles written by numerous French and international groups have been published. These projects cover a vast spectrum of topics including environmental factors, diagnosis, outcomes, prognosis, disease evaluation, imaging, genetics, biomarkers, costs, and RA management strategies

Level of agreement of the 1987 ACR and 2010 ACR/EULAR rheumatoid arthritis classification criteria: an analysis based on ESPOIR cohort data.

International audienceBACKGROUND: In 2010, new classification criteria for rheumatoid arthritis (RA) were developed. OBJECTIVE: To assess agreement between 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria and the potential source of discordance, based on ESPOIR cohort data. METHODS: 813 early arthritis patients were included in ESPOIR between 2002 and 2005. Between-criteria agreement was based on the κ coefficient. Discordance was explored by logistic regression. RESULTS: Data for 811 patients were available, with their main characteristics as follows: women 77%, swollen joint count 7.2, tender joint count 8.4, disease activity score in 28 joints 5.2, rheumatoid factor 46%, anticitrullinated protein antibody (ACPA) 39%, structural damage 22%. At baseline, 579 (71.4%) patients met the 1987 ACR criteria and 641 (79.0%) the 2010 criteria. Agreement at baseline was discordant for 168 patients: 115 satisfied the 2010 criteria and 53 the 1987 criteria. Concordance between the two sets was fair, with a κ coefficient of 0.45 and 0.42 at baseline and year 2, respectively. The main sources of discordance were the number and symmetry of joint involvement, as well as ACPA status. CONCLUSION: 2010 ACR/EULAR criteria identified more patients with RA than did 1987 criteria. The 2010 criteria failed to identify RA patients with symmetrical seronegative arthritis and limited joint involvement

Prevalence and concordance of early and sustained remission assessed by various validated indices in the early arthritis "ESPOIR" cohort.

International audienceOBJECTIVES: To assess the prevalence of remission in early arthritis, to evaluate the concordance across different criteria sets in defining this state, and to look for predictive factors for early and sustained remission. METHODS: Patients from the ESPOIR cohort were followed-up every 6months. We analysed early remission and sustained remission in 3 groups of patients: patients having rheumatoid arthritis (RA) according to 2010 ACR/EULAR criteria, undifferentiated arthritis (UA), and the whole cohort. Remission was defined according to ACR/EULAR criteria, 28 Joint Disease Activity Score (DAS28<2.6), and Simplified Disease Activity Index (SDAI≤3.3). Agreement was evaluated by k-coefficient. Predictive factors for sustained remission at 1, 3 and 5year in RA patients were analyzed. RESULTS: Eight hundred and nineteen patients were included. Early remission rates in the RA/UA/ESPOIR groups were observed in respectively 29.2% (181/682), 51.4% (55/123) and 32.7% (239/813) of patients by DAS28; 15.7%, 29.1% and 18% by SDAI; and 11.2%, 29.1% and 12.8% by ACR/EULAR criteria. Agreement between classifications of remission was low for DAS28 vs. ACR/EULAR (k=0.44), high for SDAI vs. ACR/EULAR (k=0.78), and moderate for SDAI vs. DAS28 (k=0.54). Lower baseline disease activity scores, non-menopausal status and younger age were the best predictive factors for sustained remission, with consistent results across the 3 definitions of remission. CONCLUSION: Our study showed that the rate of early and sustained remission in early arthritis is dependent on the definition used, with a variable degree of agreement across criteria sets, but with consistent predictive factors of favourable outcome in patients finally diagnosed with RA