PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases

Prevalence and characteristics of diffuse idiopathic skeletal hyperostosis (DISH) in Italy

Purpose Diffuse idiopathic skeletal hyperostosis (DISH) is a benign condition characterized by ossification of the spine and prominent enthesopathies. Highly heterogeneous epidemiological figures have been reported in the literature, while in Italy the largest study has been conducted in 1992. The aim of our research is to contribute updated information about prevalence of DISH in Italy and to describe the clinical and radiographic characteristics associated with the disorder. Material and methods A retrospective review of lumbosacral spine, thoracic spine and pelvis radiographs was performed. Consecutive patients visiting the emergency department of our Institution over 3 years were enrolled. Presence of DISH was evaluated applying the Resnick and Niwayama criteria. Clinical and radiological features were also assessed. Results We included 1012 individuals (60.6% women), and DISH was present in 130 cases. The overall prevalence of DISH was 12.8% (95% CI 10.8-15.1), with higher figures in the male sample (16.8%) than in females (10.3%). In binary logistic regression adjusted for age, BMI (OR 1.50, p < 0.001) diabetes (OR 1.85, p = 0.003), hypertension (OR 2.04, p = 0.007) ischiopubic enthesopathy (OR 7.08, p < 0.001), iliac crest enthesopathy (OR 4.63, p < 0.001) and greater trochanter enthesopathy (OR 3.51, p < 0.001), were significantly associated with the condition. Conclusion The prevalence of DISH observed in our study is consistent with previous literature, and we confirm that the disorder is more frequently retrieved in men and that it is associated with the presence of metabolic disorders and pelvic enthesopathy. Knowledge about the epidemiology and characteristics of DISH is needed to properly identify the condition

Association Between Minor Salivary Gland Biopsy During Sjӧgren’s Syndrome and Serologic Biomarkers: A Systematic Review and Meta-Analysis

ObjectivePatients with primary Sjögren’s syndrome (pSS) may develop a potentially severe disease with extra-glandular involvement and lymphoma insurgence. Minor salivary gland biopsy is routinely used in the disease diagnosis, but its potential role as a biomarker for clinical disease presentation and prognosis is still poorly understood.MethodsWe performed a systematic review and meta-analysis on clinical presentation and prognosis in pSS patients who underwent minor salivary gland biopsy at diagnosis according to the PRISMA guidelines.ResultsWe included five retrospective studies and 589 pSS patients. Ectopic GCs presence was not associated with a significant increase in the odds ratio for the clinical variables explored such as salivary gland swelling, arthritis, and Raynaud’s phenomenon. As far as serological features are concerned, ectopic GCs presence accounted for an increased ratio of antibodies anti-SSA (OR = 3.13, 95% CI: 1.25–7.85, p = 0.02, I2 = 79%), anti-SSB (OR = 3.94, 95% CI: 1.50–10.37, p = 0.0005, I2 = 80%), and RFs presence (OR = 3.12, 95% CI: 1.94–5.00, p < 0.00001, I2 = 0%).ConclusionsThis study showed that the association between ectopic GC in salivary glands identifies a clinical subset characterized by autoantibodies presence, and probably pSS patients affected from a more severe disease

The Addition of Venetoclax to Induction Chemotherapy in No Low-Risk AML Patients: A Propensity Score-Matched Analysis of the Gimema AML1718 and AML1310 Trials

Venetoclax combined with intensive chemotherapy proved to be safe with promising activity in fit patients with no-low-risk newly diagnosed acute myeloid leukemia (AML), as demonstrated also by an intermediate analysis of the GIMEMA AML1718 trial (NCT03455504). The latter trial, still ongoing, is based on the administration of venetoclax-FLAI to intermediate/high-risk ELN2017 AML and produced a complete remission (CR) rate of 84%, a minimal residual disease (MRD)-negativity rate of 74% and a 12-month Overall Survival (OS) and disease-free survival (DFS) of 75.7% (95%CI: 64.1%, 89.5%) and 80.7% (95%CI: 67.9%, 95.9%), respectively. In order to evaluate the actual advantage of the addition of venetoclax to chemotherapy, the GIMEMA AML1718 was matched to AML1310, which entailed a "3+7"-like induction and a risk-adapted, MRD-directed post-remission transplant allocation (NCT01452646, Venditti et al - Blood 2019). To generate a reliable comparison, AML1718 and AML1310 were matched by using a propensity score and then compared in terms of CR achievement, MRD-negativity and survival outcomes. Patient-level data from GIMEMA AML1718 (n=57) and AML1310 (N=445) with ELN2017 risk classification available were used to conduct a propensity score matching analysis, widely used for reducing the effects of confounding when estimating the effects of treatment on outcomes. Conditional on the propensity score, the distribution of measured variables is expected to be the same in treated (i.e. AML1718) and control (i.e. AML1310) subjects. In the present propensity score model, we included the following variables: age at diagnosis, gender, ELN2017 risk classification and transplant. Different methods for matching were attempted, including 1:1 nearest neighbor, full-matching, optimal matching (1:2, 1:3 and 1:4) and 1:2 genetic matching. The methods employed for assessing balancing were: i) Standardized Mean Difference - Love plot, ii) Empirical cumulative density function, iii) Variance ratio, iv) Empirical QQ-plot. Weights were calculated with probit or logit regression models according to the propensity score method used. Weights obtained from full-matching were used to adjust outcomes (CR, MRD negativity and survival outcomes). No patients were dropped in the full-matching process. A standardized bias score less than 0.25 was used as a criterion for adequate balancing. We used balance tables and Love plots to assess for covariate balance before and after matching. Survival curves were compared by Log-rank test and Restricted Mean Survival Time (RMST) at 12 months. AML1718 and AML1310 cohorts differed in terms of age (median: 54 vs 49 years, p=0.003) and risk category (p< .0001) - since the low risk was not represented in AML1718 trial - and female sex (35% vs 48%, p=0.069), though to a lesser extent. Contrariwise, the percentage of transplanted patients was comparable before matching (49% vs 49%, p=0.96). Being more recent, AML1718 median follow-up was shorter than AML1310 (10.5 vs 75.8 months). Full-matching, 1:2 optimal matching and 1:2 genetic matching produced the best balancing. Table 1 shows the results of the analysis for the unmatched and matched data. After balancing, according to all matching methods, the CR rate observed in the AML1718 was significantly higher than AML1310, as well as MRD-negativity rate. Comparing survival outcomes at 12 months, emerged that, upon matching, OS and DFS estimates of the AML1718 were higher than those of AML1310, though a slight statistical significance was reached only with the optimal matching on DFS (p=0.042). This result was confirmed by a statistically significant difference between the two RMST at 12 months (p=0.036). Despite this, a longer AML1718 follow-up is needed to provide a robust comparison between the two protocols. Our propensity-score analysis showed that combining venetoclax with chemotherapy in newly diagnosed AML patients resulted in improved outcomes in terms of CR rate and MRD-negativity: these achievements are crucial to allow transition to allogenic transplantation in first remission. With regards to survival outcomes, a solid conclusion will be drawn when a longer AML1718 follow-up is available. These preliminary results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy and paves the way to novel combination regimens based on venetoclax

Downregulation of miRNA17-92 cluster marks Vγ9Vδ2 T cells from patients with rheumatoid arthritis

Background: We aimed to evaluate the phenotype, function, and microRNA (miRNA)17-92 cluster expression in Vγ9Vδ2 T-cell subsets and the correlation with immune response in rheumatoid arthritis (RA) patients. Methods: Peripheral blood from 10 early RA untreated patients and 10 healthy donors (HD) was obtained. Polyclonal Vγ9Vδ2 T-cell lines were generated and analysed by flow cytometry. Analysis of miRNA17-92 cluster expression was performed by real-time polymerase chain reaction (RT-PCR), and expression of mRNA target genes was also studied. Results: A remarkable change in the distribution of Vγ9Vδ2 T-cell functional subsets was observed in the peripheral blood of RA patients compared with HD, with an expansion of effector subsets and reduction of naive cells which was accompanied by modifications in proinflammatory cytokine expression. Vγ9Vδ2 T cells with a TEM (effector memory) phenotype and producing proinflammatory cytokines were correlated with disease activity score (DAS28). The comparison of miRNA expression among Vγ9Vδ2 T-cell subsets from RA patients and HD showed a lower level of miR-106a-5p and miR-20a-5p, and a higher level of miR-21a-5p, among Vγ9Vδ2 TEM cells, and a lower level of miR-19b-3p among Vγ9Vδ2 TCM (central memory) cells was also found. These differentially expressed miRNAs correlated with higher levels of expression of interleukin (IL)-8, IL-6, and PDCD4 genes. Conclusions: Our results provide evidence for a role of miR-106a, miR-19-3p, miR-20a, and miR-21a in the regulation of Vγ9Vδ2 T-cell function in RA patients and suggest the possibility that the miRNA17-92 family and Vγ9Vδ2 T cells contribute to the pathogenesis of RA

Cardiac injury and mortality in patients with Coronavirus disease 2019 (COVID-19): insights from a mediation analysis

Patients at greatest risk of severe clinical conditions from coronavirus disease 2019 (COVID-19) and death are elderly and comorbid patients. Increased levels of cardiac troponins identify patients with poor outcome. The present study aimed to describe the clinical characteristics and outcomes of a cohort of Italian inpatients, admitted to a medical COVID-19 Unit, and to investigate the relative role of cardiac injury on in-hospital mortality