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Abstract Background A strong consensus exists for a systematic approach to linguistic validation of patient reported outcome measures (PROMs) and discrete methods for assessing their psychometric properties. Despite the need for robust evidence of the appropriateness of measures, transition from linguistic to psychometric validation is poorly documented or evidenced. This paper demonstrates the importance of linking linguistic and psychometric testing through a purposeful stage which bridges the gap between translation and large-scale validation. Findings Evidence is drawn from a study to develop a Welsh language version of the Beck Depression Inventory-II (BDI-II) and investigate its psychometric properties. The BDI-II was translated into Welsh then administered to Welsh-speaking university students (n = 115) and patients with depression (n = 37) concurrent with the English BDI-II, and alongside other established depression and quality of life measures. A Welsh version of the BDI-II was produced that, on administration, showed conceptual equivalence with the original measure; high internal consistency reliability (Cronbach’s alpha = 0.90; 0.96); item homogeneity; adequate correlation with the English BDI-II (r = 0.96; 0.94) and additional measures; and a two-factor structure with one overriding dimension. Nevertheless, in the student sample, the Welsh version showed a significantly lower overall mean than the English (p = 0.002); and significant differences in six mean item scores. This prompted a review and refinement of the translated measure. Conclusions Exploring potential sources of bias in translated measures represents a critical step in the translation-validation process, which until now has been largely underutilised. This paper offers important findings that inform advanced methods of cross-cultural validation of PROMs.

Objective: Systemic sclerosis (SSc) is disabling. However, the different factors contributing to this disability and how these change over time have been little studied. Our aim was to examine the trajectories over time of the six visual analogue scales (VAS) of the scleroderma HAQ (SHAQ), associations of disease-related factors with these trajectories, and relationships with overall functional ability., Methods: This was a retrospective study of data collected prospectively from patients attending a single tertiary centre between 2005 and 2022. VAS (pain, intestinal, breathing, Raynaud's [RP], digital ulcers, 'overall') were analysed using linear mixed-effects models, and relationships between the six VAS and functional ability (HAQ-DI) and scleroderma functional index [FI] by correlating the average gradients obtained from individual linear regressions., Results: 537 patients with at least two time-points were included, followed for a mean (SD) of 6.8 (4.2) years. VAS intestinal scores increased (ie worsened) by 0.085 points (95% CI = 0.041-0.130,p<0.001) per year, VAS breathing by 0.056 points (95% CI = 0.016-0.096,p=0.006) and VAS overall scores by 0.073 points (95% CI = 0.032-0.114,p=0.001). The longer the duration between RP onset and SSc diagnosis, the lower the VAS pain and VAS intestinal scores. The odds of having at least one digital ulcer reduced with disease duration, with diffuse cutaneous subtype and with anti-Scl70 positivity. Average gradients for all six VAS scales correlated (albeit variably/weakly) with HAQ-DI and scleroderma FI gradients., Conclusion: Longitudinal assessment of the six SHAQ VAS, and associations of baseline characteristics with the individual VAS time courses, provide insights into disease trajectory and overall disability., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: There appear to be several variants of naevoid melanoma suspected as having different outcomes, but follow-up studies have been few. We aimed to assess the prognosis of naevoid melanomas in a multi-centre study., Material and Methods: From histopathology records we ascertained patients in the UK, Australia and Italy diagnosed with maturing naevoid melanoma (n = 65; 14; 7 respectively) and nodular/papillomatous naevoid melanoma (12; 6; 0), and patients with superficial spreading melanoma (SSM) from UK (73) and Australia (26). Melanoma deaths in UK patients were obtained from NHS Digital; in Australia, via the National Death Index and cancer registry; and in Italy, through clinical records. For maturing naevoid vs. SSM, we used Cox-proportional hazard regression models to compare survival adjusted for age, sex, tumour thickness, and ulceration, and additionally Fine-Gray regression analysis, to calculate sub-hazard ratios (SHR) in the UK cohort, accounting for competing causes of death., Results: Among UK patients, there was a non-significantly lower risk of melanoma death in maturing naevoid vs SSM, including after accounting for competing causes of death (SHR 0.40, 95% confidence interval (CI) 0.12-1.31), while among nodular/papillomatous naevoid melanoma patients, there were no melanoma deaths on follow-up. Two melanoma deaths occurred in Australian SSM patients, and none in maturing or nodular/papillomatous naevoid melanoma patients, after 5 years' minimum follow-up. None of the 7 Italian patients with maturing naevoid melanoma died of melanoma after nearly 12 years' average follow-up., Conclusions: There was no significant difference in risk of death from melanomas with naevoid features, and SSM. Nodular/ papillomatous naevoid melanoma patients did not carry higher risk of death than SSM patients though the very few cases of the papillomatous naevoid variant limited our assessment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier GmbH.)

Background: Communication difficulties can cause frustration, low mood, and stress for people living with dementia and their carer. Carers should be offered training on adapting their communication skills. However, it is not common for skills-based education to examine emotional aspects of care and the effect of dementia on relationships. The Empowered Conversations (EC) training course was developed in response to a gap in service provision and has been adapted to a virtual format (Zoom). It addresses the specific psychological, relationship, and communication needs of informal and family dementia carers. The primary aim of the study is to investigate the feasibility of conducting a multi-centre randomised controlled evaluation trial of EC. Secondary aims include exploring the acceptability of delivering the intervention online and examining the optimum way of establishing cost-effectiveness., Methods: The feasibility trial uses a pragmatic data-collector blind parallel two-group RCT design with two arms (EC intervention plus treatment as usual, and treatment as usual waitlist control). There will be a 2:1 allocation in favour of the EC-training intervention arm. 75 participants will complete baseline outcome measures exploring their role as a carer, including their physical and mental health, attitudes to caring, quality of life, and use of health and social care services. These will be repeated after six-months. Participants allocated to the treatment group who complete the course will be invited to participate in a qualitative interview discussing their experience of EC., Conclusions: The study will investigate recruitment pathways (including facilitators and barriers to recruitment), estimate retention levels and response rates to questionnaires, obtain additional evidence regarding proof of concept, and consider the most appropriate primary outcome measures and methods for evaluating cost-effectiveness. The results of the feasibility study will be used to inform the development of a multicentre randomised controlled trial in the United Kingdom., Registration: ISRCTN15261686 (02/03/2022)., Competing Interests: No competing interests were disclosed.The authors and trial team report no conflict of interest., (Copyright: © 2023 Eastham C et al.)

Objective: To estimate the effectiveness of standardised self-management kits for children with type 1 diabetes., Design: Pragmatic trial with randomisation ratio of two intervention: one control. Qualitative process evaluation., Setting: 11 diabetes clinics in England and Wales., Participants: Between February 2010 and August 2011, we validly randomised 308 children aged 6-18 years; 201 received the intervention., Intervention: We designed kits to empower children to achieve glycaemic control, notably by recording blood glucose and titrating insulin. The comparator was usual treatment. OUTCOME MEASURES AT 3 AND 6 MONTHS: Primary: Diabetes Pediatric Quality of Life Inventory (PedsQL). Secondary: HbA1c; General PedsQL; EQ-5D; healthcare resource use., Results: Of the five Diabetes PedsQL dimensions, Worry showed adjusted scores significantly favouring self-management kits at 3 months (mean child-reported difference =+5.87; Standard error[SE]=2.19; 95% confidence interval [CI]) from +1.57 to +10.18; p=0.008); but Treatment Adherence significantly favoured controls at 6 months (mean child-reported difference=-4.68; SE=1.74; 95%CI from -8.10 to -1.25; p=0.008). Intervention children reported significantly worse changes between 3 and 6 months on four of the five Diabetes PedsQL dimensions and on the total score (mean difference=-3.20; SE=1.33; 95% CI from -5.73 to -0.67; p=0.020). There was no evidence of change in HbA1c; only 18% of participants in each group achieved recommended levels at 6 months. No serious adverse reactions attributable to the intervention or its absence were reported.Use of kits was poor. Few children or parents associated blood glucose readings with better glycaemic control. The kits, costing £185, alienated many children and parents., Conclusions: Standardised kits showed no evidence of benefit, inhibited diabetes self-management and increased worry. Future research should study relationships between children and professionals, and seek new methods of helping children and parents to manage diabetes., Trial Registration Number: ISRCTN17551624., Competing Interests: Competing interests: Professor JWG has received payments from Pfizer, Bayer and Ipsen for lectures, development of educational presentations and travel/accommodation to attend scientific meetings and advisory board meetings. His employer (Cardiff University) has also received funding from Novo Nordisk to support the development of patient-support materials used in the Development and Evaluation of a Psychosocial Intervention for Children and Teenagers Experiencing Diabetes (DEPICTED) research study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background and Purpose: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH., Experimental Approach: Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14-day safety and efficacy evaluation. The primary endpoint in both steps was the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Δ max ), with secondary outcomes including pulmonary and systemic haemodynamics plus mechanistic biomarkers., Key Results: Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP or any serious adverse effects., Conclusions and Implications: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger scale prospective trial., (© 2019 The British Pharmacological Society.)

Background & Aims: Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E 2 (PGE 2 ) and other lipids., Methods: We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE 2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients' samples, we investigated the effects of PGE 2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration., Results: At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P = .0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE 2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE 2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE 2 , lipopolysaccharide, and inflammatory or anti-inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group., Conclusions: Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE 2 . We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial., Methods: We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels., Results: The patients' mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded., Conclusions: In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain., Methods: This randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5. Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801., Findings: Of 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957-1233 vs 548, 484-621, treatment effect 2·0, 95% CI 1·7-2·4, p<0·0001). Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47-66 vs 86 nmol/L, 72-102, treatment effect 0·6, 95% CI 0·5-0·8, p=0·0006). No thrombosis or major bleeding were seen. Serious adverse events occurred in four patients in each group., Interpretation: ETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism., Funding: Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cataract is one of the leading causes of low vision in the westernised world, and cataract surgery is one of the most commonly performed operations. Laser platforms for cataract surgery are now available, the anticipated advantages of which are broad and may include better visual outcomes through greater precision and reproducibility, and improved safety. FACT is a randomised single masked non-inferiority trial to establish whether laser-assisted cataract surgery is as good as or better than standard manual phacoemulsification., Methods and Analysis: 808 patients aged 18 years and over with visually significant cataract will be randomised to manual phacoemulsification cataract surgery (standard care) or laser-assisted cataract surgery (intervention arm). Outcomes will be measured at 3 and 12 months after surgery. The primary clinical outcome is uncorrected distance visual acuity (UDVA, logMAR) at 3 months in the study eye recorded by an observer masked to the trial group. Secondary outcomes include UDVA at 12 months, corrected distance visual acuity at 3 and 12 months, complications, endothelial cell loss, patient-reported outcome measures and a health economic analysis conforming to National Institute for Health and Care Excellence standards., Ethics and Dissemination: Research Ethics Committee Approval was obtained on 6 February 2015, ref: 14/LO/1937. Current protocol: v2.0 (08/04/2015). Study findings will be published in peer-reviewed journals., Isrctn: 77602616., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak., Objectives: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism., Design: FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453., Settings: Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool., Participants: Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research., Interventions: Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners., Main Outcome Measures: Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use., Results: Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%)., Conclusions: The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM., Trial Registration: Current Controlled Trials ISRCTN37558856., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.

Objective: To establish a baseline of national practice for follow-up after treatment for gynaecological cancer., Design: Questionnaire survey., Setting: Gynaecological cancer centres and units., Geographical Location Uk Participants: Members of the British Gynaecological Cancer Society and the National Forum of Gynaecological Oncology Nurses., Interventions: A questionnaire survey., Outcome Measures: To determine schedules of follow-up, who provides it and what routine testing is used for patients who have had previous gynaecological cancer., Results: A total of 117 responses were obtained; 115 (98%) reported hospital scheduled regular follow-up appointments. Two involved general practitioners. Follow-up was augmented or replaced by telephone follow-up in 29 responses (25%) and patient-initiated appointments in 38 responses (32%). A total of 80 (68%) cancer specialists also offered combined follow-up clinics with other specialties. Clinical examinations for hospital-based follow-up were mainly performed by doctors (67% for scheduled regular appointments and 63% for patient-initiated appointments) while telephone follow-up was provided in the majority by nurses (76%). Most respondents (76/117 (65%)) provided routine tests, of which 66/76 (87%) reported carrying out surveillance tests for ovarian cancer, 35/76 (46%) for cervical cancer, 8/76 (11%) for vulval cancer and 7/76 (9%) for endometrial cancer. Patients were usually discharged after 5 years (82/117 (70%)), whereas three (3%) were discharged after 4 years, nine (8%) after three years and one (1%) after 2 years., Conclusions: Practice varied but most used a standard hospital-based protocol of appointments for 5 years and routine tests were performed usually for women with ovarian cancer. A minority utilised nurse-led or telephone follow-up. General practitioners were rarely involved in routine care. A randomised study comparing various models of follow-up could be considered.

The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1-3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17-92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17-92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3'-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17-92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17-92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17-92 cluster. Altogether, these results suggest that the autoregulation between E2F1-3 and miR-20a is important for preventing an abnormal accumulation of E2F1-3 and may play a role in the regulation of cellular proliferation and apoptosis.

Intermediate filaments are composed of a family of proteins that evolved from a common ancestor. The proteins consist of three domains: a central, alpha-helical domain similar in all intermediate filaments, bracketed by two domains that are variable in length and structure. Within the intermediate-filament family, several subfamilies have been recognized by immunologic and nucleic acid hybridization techniques. In this paper we present the sequence of the genomic DNA coding for a 65-kilodalton human keratin and compare it with the sequences of other intermediate-filament proteins. While the central, alpha-helical domains of these proteins show homologies that indicate a common ancestor, the sequences of the variable terminal domains indicate that the variable domains evolved through a series of tandem duplications and possibly by gene-conversion mechanisms.