An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism.

Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear R-loops. Ddx19 depletion induces R-loop accumulation, proliferation-dependent DNA damage and defects in replication fork progression. Further, we show that Ddx19 resolves R-loops in vitro via its helicase activity. Furthermore, mutation of a residue phosphorylated by Chk1 in Ddx19 disrupts its interaction with Nup214 and allows its nuclear relocalization. Finally, we show that Ddx19 operates in resolving R-loops independently of the RNA helicase senataxin. Altogether these observations put forward a novel, ATR-dependent function for Ddx19 in R-loop metabolism to preserve genome integrity in mammalian cells.

Burden of Disease in Psoriatic Arthritis in Latin America: a Systematic Literature Review.

INTRODUCTION: Psoriatic arthritis is a chronic inflammatory pathology that generates a substantial and progressive deterioration of functionality and quality of life. It is associated with comorbidities (cardiovascular and metabolic) and involvement of mental health. In Latin America, information regarding the disease is limited. This study reviews the burden of disease (disease activity, functional involvement, clinical manifestations, comorbidities, patient-reported outcomes, quality of life, and use of health resources) in PsA patients in Latin America. METHODS: Systematic literature review of publications in PUBMED, EMBASE, Cochrane Database of Systematic Reviews-CDSR/Database of Abstracts of Reviews of Effects, LILACS, Scielo, Redalyc, conference abstracts, and grey literature. Two independent assessors selected studies and extracted information. Quality was assessed according to the type of study. RESULTS: We identified 692 references, selecting 50 studies: 41 cross-sectional, four economic-studies, four cohort studies and one systematic review. The information comes mainly from Brazil, Argentina, and Mexico. The estimated disease prevalence for Latin America ranges from 0.004 to 0.08% (95% CI 0.02-0.20). Measurements with validated instruments suggest suboptimal assessment of disease domains, significant functional compromise, loss of productivity, and high frequency of comorbidities, including mental health. Methodological and population considerations limit the generalizability of the findings. CONCLUSIONS: The available information reports a considerable burden of disease in patients with PsA in Latin America, with involvement of quality of life associated with disability in relation to disease activity and its various manifestations. Future research and funding efforts should be aimed at generating more standardized information about the impact of PsA in the region. Key Points •The functional involvement related to disease activity, the impact on the quality of life, and the frequency of cardiometabolic and psychological comorbidities are remarkable in Latin American patients with PsA. •The current synthesis offers an overview of the burden of disease (disease activity, functional involvement, clinical manifestations, comorbidities, patient-reported outcomes, quality of life, and use of health resources) in PsA patients in Latin America. •Future research efforts and clinical strategies are required in order to generate standardized data on the patients and better estimate the burden of disease in the region.

Usefulness of Lung Ultrasound as a Method for Early Diagnosis of Interstitial Lung Disease in Patients with Rheumatoid Arthritis.

Purpose: To determine the value of lung ultrasound (LUS) compared to high-resolution computed tomography (HRCT) in the early diagnosis of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Patients and Methods: An observational prospective study was performed. Were included patients with respiratory symptoms or/and, patients with crackles in auscultation during medical consultation. All patients underwent to chest X-rays, LUS, HRCT,and respiratory function tests. Results: A total of 192 patients with RA were included. Mean disease duration was 16.8 ± 11.1 years. 72% were positive for rheumatoid factor or anti-citrullinated antibodies. Of the total number of subjects, 54.7% had respiratory symptoms. The other patients did not have respiratory symptoms, but they did have had crackles on pulmonary auscultation. B lines > 11.5 on the ROC curve predicted ILD (AUC 0.63; CI 95%: 0.55-0.71; p < 0.003). A DLCO value of <7.13 significantly predicted the presence of ILD (AUC 0.61; 95% CI: 0.52-0.70; p < 0.028). Conclusion: The findings of this study suggest that LUS is a valuable tool for the early diagnosis of ILD in patients with RA, and together with DLCO, can adequately predict the presence of ILD in this population. LUS also helps to determine which patients with respiratory symptoms and signs suggestive for ILD are undergo to HRCT.

Polyautoimmunity in systemic lupus erythematosus patients: New insights from a cross-sectional study.

Objective: To assess the frequency of polyautoimmunity (PolyA) in a cohort of Colombian patients with systemic lupus erythematosus (SLE) and to identify associated factors. Methods: This is an analytical cross-sectional study in a specialized center., a comprehensive review of the medical records of SLE patients was performed from 2015 to 2020 in order to obtain demographic, clinical data, laboratory, and treatment information. Associations between PolyA, demographic, and characteristics of the disease were explored. Results: A total of 463 patients were included in the analysis. The average age was 47.3 ± 15 years. Most of this population were female (87.4%), whom were diagnosed with SLE in a long-term SLE (10.6 ± 10.1 years). Out of the total patients, 34.7% were diagnosed with PolyA. Among the most frequent clinical criteria for SLICC, arthritis (65%), kidney impairment (39.5%), and alopecia (34.8%) were found. The most frequent SLE-associated PolyA were antiphospholipid syndrome (APS) and Sjögren's syndrome (SS) (16.63% and 10.58%, respectively). PolyA-associated factors were age, xerophthalmia, central nervous system occlusion, and deep vein thrombosis (DVT). In contrast, renal impairment was significantly less frequent in PolyA patients after multivariate analysis. Conclusion: The results have showed associated factors with PolyA like age, xerophthalmia, central nervous system occlusion, and deep vein thrombosis in this cohort. On the other hand, lupus nephritis was less frequent in patients with PolyA. This study provides a spotlight of a specific SLE population as real-life evidence for a better characterization of PolyA in the future.

Immune Checkpoint Inhibitor Combination Therapy versus Sunitinib as First-Line Treatment for Favorable-IMDC-Risk Advanced Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Novel combination therapies have been shown to improve the outcomes of treatment-naive patients with locally advanced or metastatic renal cell carcinoma (aRCC). However, the optimal systemic therapy for aRCC of favorable risk has yet to be clarified. We aimed to evaluate the efficacy and safety of different immunotherapy (IO) combinations, either with another IO (IO-IO) or with an antiangiogenic (IO-TKI), versus sunitinib in the first-line setting in aRCC patients with favorable IMDC risk. METHODS: We conducted a systematic search for evidence in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials published up to February 2021. The GRADE approach was used to assess the quality of evidence. Survival hazard ratios were extracted for analysis in the favorable-risk aRCC subgroup (IMDC). A sensitivity analysis was performed excluding trials of combination therapy without TKI. RESULTS: Five randomized controlled phase III trials with a total of 1088 patients were included in the analysis. The studies compared different combinations versus sunitinib monotherapy. All clinical trials reported overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) data. Four out of five trials reported complete response (CR). There was no difference in OS nor PFS between treatment arms in the IMDC favorable-risk subgroup analysis (OS: HR = 1.07, 95% CI = 0.81-1.41; PFS: HR = 0.74, 95% CI = 0.46-1.19). A benefit in ORR and CR was found for combination therapy vs. sunitinib (ORR: HR = 1.89, 95% CI = 1.29-2.76; CR: HR = 3.58, 95% CI = 2.04-6.28). In the sensitivity analysis, including only IO-TKI vs. sunitinib, no difference in OS was found; however, an advantage in PFS was observed (OS: HR = 0.99, 95% CI 0.69-1.43; PFS: HR = 0.60 (0.45-0.81). The safety profile reported is consistent with previous reports. We did not find differences in the incidence of any adverse event (AE) or of grade ≥3 AEs. CONCLUSION: This meta-analysis shows that combinations of IO-KI as first-line treatment in favorable-IMDC-risk aRCC improve PFS, ORR, and CR, but not OS, versus sunitinib.

Metabolic Abnormalities, Cardiovascular Disease, and Metabolic Syndrome in Adult Rheumatoid Arthritis Patients: Current Perspectives and Clinical Implications.

Aim: Rheumatoid arthritis is a prevalent worldwide disease, associated with an increased risk of multiple metabolic abnormalities that generate a higher disease burden. Objective: To gather the available evidence on the epidemiology, pathophysiology, current perspectives, clinical implications and prognosis of metabolic abnormalities in patients with rheumatoid arthritis. Methods: This is a narrative literature review. Search was conducted in PubMed, OVID, and Taylor & Francis databases, using the following MeSH terms: "Arthritis Rheumatoid", "Metabolic Diseases", and "Metabolic Syndrome". Results: This study describes the main metabolic manifestations of rheumatoid arthritis. Research has recognized that rheumatoid arthritis and metabolic abnormalities share pathophysiological mechanisms with an additive effect that increases cardiovascular risk. In that context, appropriate antirheumatic treatment can also impact on cardiovascular risk. Conclusion: There are metabolic abnormalities in rheumatoid arthritis patients that increase cardiovascular risk. Therefore, it is crucial to evaluate cardiovascular risk to provide appropriate comprehensive management to reduce morbidity and mortality in patients with this disease.

Is Tofacitinib Effectiveness in Patients with Rheumatoid Arthritis Better After Conventional Than After Biological Therapy? - A Cohort Study in a Colombian Population.

Purpose: Tofacitinib is recommended for treatment of rheumatoid arthritis (RA) in patients with moderate to severe disease activity, but there is not enough evidence on its effectiveness after conventional DMARDs vs its use after biologics. The aim was evaluating the effectiveness of tofacitinib in RA as first-line treatment (after conventional DMARDs) in a real-life setting in Colombian (Latin-American) patients. Patients and Methods: Retrospective cohort study conducted at a specialized center for RA management. A complete statistical analysis was performed to compare the values of the change in the DAS28 at months 3, 6, and 12 in both treatment groups. Results: A total of 152 RA patients who received tofacitinib: first-line 85 patients (55.9%) after failure on conventional DMARDs or second-line 67 patients (44.1%) after failure on biologic DMARDs. Comparative analysis of response to treatment showed a reduction in DAS28 at 3, 6, and 12 months in both study groups without statistical differences, but a higher proportion of first-line patients achieved remission (45% vs 23%). Nonresponse at three months were associated with no response at six months of follow-up. Baseline DAS28 was significantly associated with response at 12 months (OR: 1.87, 95%CI: 1.06-3.30, p-value 0.028). In second-line patients, response to tofacitinib was not related to number of biologic DMARDs previously used. Conclusion: Tofacitinib is an effective treatment option for patients with RA, maybe better after conventional DMARDs than after biologic therapy failure. Further studies are required to determine the role of tofacitinib in different lines of RA treatment and in other groups of patients.

Better Clinical Results in Rheumatoid Arthritis Patients Treated Under a Multidisciplinary Care Model When Compared with a National Rheumatoid Arthritis Registry.

Purpose: To describe clinical characteristics and effectiveness of health care in patients with rheumatoid arthritis (RA) as part of a multidisciplinary care model (MCM) in a specialized rheumatology center, compared with the results of a national registry of RA (NARRA) as evidence of real-world management. Patients and Methods: We conducted a real-world study (July 1, 2018 to June 30, 2019) based on an analysis of electronic health records of a cohort of RA patients managed with the "Treat-to-Target" strategy in a specialized rheumatology center in Colombia with an MCM, compared with the NARRA that includes different models of usual care. Results: We have analyzed 7053 subjects with RA treated at a specialized rheumatology center and 81,492 patients from the NARRA. Cohorts were similar in their baseline characteristics, with women in predominance and diagnosis age close to 50 years. At the time of diagnosis, a higher proportion of clinical diagnostic test use and rheumatology consultation access was observed in the specialized rheumatology center than in the national registry (4-6 per year versus three or less). In addition, higher proportions of patients in remission and low disease activity were reported for the specialized rheumatology center, with a >40% amount of data lost in the national registry. Pharmacological management was similar regarding the analgesic use. In the specialized center, Certolizumab was more frequently used than in the NARRA registry; also, there were significant differences in methotrexate, leflunomide, and sulfasalazine use, being higher in the specialized rheumatology center. Conclusion: The MCM of a specialized center in RA can guarantee comprehensive care, with better access to all the services required to manage the disease. It ensures specialist management and evidence-based care that facilitates the achievement of therapeutic objectives. In addition, better patient records and follow-ups are available to evaluate health outcomes.

Certolizumab Can Also Be Effective in Monotherapy for the Treatment of Rheumatoid Arthritis Patients.

OBJECTIVE: Although it is known that methotrexate (MTX) increases the effectiveness of biological drugs (mainly anti-TNFs) in patients with rheumatoid arthritis (RA), in real life, it is known that many patients using anti-TNFs are on monotherapy due to many causes. This article compares the effectiveness of certolizumab as monotherapy as combined with MTX or leflunomide (LFN) in RA patients with failure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in a real-world setting. METHODS: A retrospective observational cohort study was conducted at a specialized centre for RA management in Colombia. Patients treated with certolizumab as monotherapy or in combination with MTX, LFN, or MTX+LFN, between 2011 and 2020 with a minimum 3-month follow-up were included. Demographics and RA clinical characteristics were recorded; effectiveness was assessed as the improvement in Disease Activity Score (DAS28) getting remission or low disease activity at 3, 6, and 12 months of treatment. RESULTS: A total of 181 patients were included, 24 received certolizumab as monotherapy, 62 certolizumab plus MTX, 47 certolizumab plus LFN and 48 certolizumab plus MTX+LFN. At 3 months of follow-up, 80% of the patients showed decreased disease activity, with no significant differences between groups; at 12 months of treatment, response in certolizumab monotherapy group was 94.4% compared to 81.8% in combination with MTX, 80.5% in combination with LFN and 51.4% in combination with MTX+LFN. Response at 3 months (OR 4.04; 95% CI 1.28-12.69) and positive anti-CCP (OR 3.83; 95% CI 1.11-13.21) were associated with 12-month response. CONCLUSION: Certolizumab seems to be effective as monotherapy in the treatment of RA patients with failure to csDMARDs.

Inhibition of filament formation of human Rad51 protein by a small peptide derived from the BRC-motif of the BRCA2 protein.

Human Rad51 is a key element of recombinational DNA repair and is related to the resistance of cancer cells to chemo- and radiotherapies. The protein is thus a potential target of anti-cancer treatment. The crystallographic analysis shows that the BRC-motif of the BRCA2 tumor suppressor is in contact with the subunit-subunit interface of Rad51 and could thus prevent filament formation of Rad51. However, biochemical analysis indicates that a BRC-motif peptide of 69 amino acids preferentially binds to the N-terminal part of Rad51. We show experimentally that a short peptide of 28 amino acids derived from the BRC4 motif binds to the subunit-subunit interface and dissociates its filament, both in the presence and absence of DNA, certainly by binding to dissociated monomers. The inhibition is efficient and specific for Rad51: the peptide does not even interact with Rad51 homologs or prevent their interaction with DNA. Neither the N-terminal nor the C-terminal half of the peptide interacts with human Rad51, indicating that both parts are involved in the interaction, as expected from the crystal structure. These results suggest the possibility of developing inhibitors of human Rad51 based on this peptide.

Targeting human Rad51 by specific DNA aptamers induces inhibition of homologous recombination.

Human Rad51 (HsRad51), a key element of the homologous recombination repair pathway, is related to the resistance of cancer cells to chemo- and radio-therapies. This protein is thus a good target for the development of anti-cancer treatments. We have searched for new inhibitors directed against HsRad51 using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach. We have selected three aptamers displaying strong effects on strand exchange activity. Analysis by circular dichroism shows that they are highly structured DNA molecules. Our results also show that they affect the first step of the strand exchange reaction by promoting the dissociation of DNA from the ATP/HsRad51/DNA complex. Moreover, these inhibitors bind only weakly to RecA, a prokaryotic ortholog of HsRad51. Both the specificity and the efficiency of their inhibition of recombinase activity offer an analytical tool based on molecular recognition and the prospect of developing new therapeutic agents.