Leukemia-associated transcription factor mllt3 is important for primitive erythroid development in zebrafish embryogenesis.

BACKGROUND: MLLT3 (AF9) is a nuclear transcription factor crucial for hematopoietic stem cell and progenitor cell maintenance, but its role during embryonic hematopoiesis remains uncertain. Here, we examine the role of mllt3 in developmental hematopoiesis during embryogenesis using zebrafish. RESULTS: Cloning, sequencing, phylogenetic, and synteny analyses showed high evolutionary conservation between important functional domains of the zebrafish orthologue of mllt3 and MLLT3 in humans. Quantitative reverse transcription-PCR and in situ hybridization analyses revealed that mllt3 is maternally supplied and zygotically expressed throughout embryonic development, and that expression is highest between 10 and 24 hours post-fertilization (hpf) coincident with enrichment in the intermediate cell mass (ICM) and posterior blood island, which are the sites of the primitive and transient definitive hematopoiesis in zebrafish, respectively. Further, we found co-expression of mllt3 with the early hematopoietic progenitor markers tal1, gata2, and gata1a in the posterior ICM. By investigating zebrafish hematopoietic mutants, we discovered that mllt3 is involved in erythroid precursor formation. By 48-72 hpf, mllt3 expression proved to be restricted to non-hematopoietic tissues including head structures, pronephric tubules, and liver primordium. CONCLUSIONS: These findings establish a link between mllt3 and primitive erythropoiesis and provide the basis for future functional investigations.

Next-generation sequencing of PTEN mutations for monitoring minimal residual disease in T-cell acute lymphoblastic leukemia.

Minimal residual disease (MRD) analysis has become a powerful indicator to refine therapy in acute lymphoblastic leukemia (ALL). Here, we present an MRD detection based on the next-generation sequencing of PTEN exon 7 mutations (NGS-PTEN) in 30 pediatric T-cell ALL patients. By comparing the NGS-PTEN results with current quantitative PCR of antigen receptor gene rearrangements (qPCR-Ig/TR), an overall concordance of 80% was found between the two methods. However, the NGS-PTEN qualified a lower number of high-risk patients than qPCR-Ig/TR. These findings suggest that NGS-PTEN is a promising tool that could potentially be used to support current MRD methodologies for T-ALL patients.

The role of ultrasound in the diagnosis and follow-up of large-vessel vasculitis: an update.

Large-vessel vasculitides comprise giant cell arteritis and Takayasu's arteritis. In both conditions, early changes consist of transmural inflammation of the arterial wall, while later complications include lumen changes, such as stenoses or aneurysms. Colour Doppler sonography has the ability to depict the arterial wall as well as the lumen, and is therefore ideally suited both to diagnose early vasculitis and to monitor patients over time. In this review article, we addressed the following issues: 1) the role of colour Doppler sonography in the diagnosis of large-vessel vasculitis and its common pitfalls; 2) whether colour Doppler sonography can increase the yield of temporal artery biopsy in giant cell arteritis; 3) the role of colour Doppler sonography in monitoring patients with LVV over time; and 4) how colour Doppler sonography performs compared to other imaging techniques.

A Case of T-cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia.

A 4-year-old male with the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T-cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array-CGH) and whole-exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T-ALL.

Is colour duplex sonography-guided temporal artery biopsy useful in the diagnosis of giant cell arteritis? A randomized study.

OBJECTIVE: The aim of this study was to assess the usefulness of colour duplex sonography (CDS)-guided temporal artery biopsy (TAB) for the diagnosis of GCA in patients with suspected GCA. METHODS: From September 2009 through December 2012, 112 consecutive patients with suspected GCA were randomized to undergo CDS-guided TAB or standard TAB. All patients underwent temporal artery physical examination and temporal artery CDS prior to TAB. CDS of the temporal artery was performed by the same ultrasonographer, who was unaware of the patient's clinical data, and all TABs were evaluated by the same pathologist. Seven patients in whom biopsy failed to sample temporal artery tissue were excluded from the analysis. RESULTS: Fifty patients were randomized to undergo CDS-guided TAB and 55 patients to standard TAB. Except for a younger age in patients who underwent standard TAB (P = 0.026), no significant differences were observed between the two groups. There were no significant differences in the frequencies of positive TAB for classic transmural inflammation (28% vs 18.2%) or for periadventitial small vessel vasculitis and/or vasa vasorum vasculitis (6% vs 14.5%) between the two groups. No significant differences in the frequency of positive TAB in the two groups were observed when we excluded the patients treated with glucocorticoids and when we stratified the patients of the two groups for the presence or absence of the halo sign. CONCLUSION: Our study showed that CDS-guided TAB did not improve the sensitivity of TAB for diagnosing GCA.

Ultrasound Examination of Common Carotid Adventitial Thickness Can Differentiate Takayasu Arteritis and Large Vessel Giant Cell Arteritis.

Pathological studies have demonstrated that the adventitial layer is markedly thickened in Takayasu (TAK) as compared to large vessel giant cell arteritis (LV-GCA). An ultrasound (US) examination of the arterial vessels allows the determination of intima media thickness (IMT) and of adventitial layer thickness (extra media thickness (EMT)). No previous study has evaluated if there are differences in EMT thickness between TAK and LV-GCA. In this cross-sectional retrospective study of stored ultrasound (US) imaging, we have compared common carotid artery (CCA) EMT and IMT in a series of consecutive TAK and LV-GCA patients. US examination CCA IMT and EMT were significantly higher in TAK as compared to LV-GCA. With ROC curve analysis, we have found that an EMT > 0.76 mm has high sensitivity and specificity for TAK CCA examination. The percentage of CCA at EMT > 0.76 mm and the total arterial wall thickening were significantly higher in TAK group examinations. EMT thickness correlated with disease duration and IMT in the TAK group, as well as with the IMT and ESR values in the LV-GCA group. Upon multivariate logistic regression analysis, factors independently associated with TAK CCA were EMT > 0.76 mm and age. No significant variation in IMT and EMT could be demonstrated in subsequent US CCA examinations.

Comparison between colour duplex sonography findings and different histological patterns of temporal artery.

OBJECTIVE: To assess the findings of temporal artery colour duplex sonography (CDS) in GCA characterized by a histological pattern of periadventitial small vessel vasculitis (SVV) and/or vasa vasorum vasculitis (VVV) and compare it with those observed in classic GCA with transmural vasculitis. METHODS: We studied 30 patients with SVV and/or VVV, 63 patients with classic GCA and 67 biopsy-negative patients identified over a 9-year period. CDS of the temporal arteries was performed in all patients by one ultrasonographer. Temporal artery biopsy was used as the reference standard. Sensitivities, specificities and likelihood ratios (LRs) were calculated. RESULTS: The frequency of the halo sign on CDS was significantly lower in the patients with SVV and/or VVV compared with those with classic GCA (20% vs 82.5%, P = 0.0001). The halo sign had a sensitivity of only 20% (95% CI 8.4, 39.1%) and a specificity of 80.6% (95% CI 68.7, 88.9%) for the diagnosis of SVV and/or VVV. The negative LR was 0.992 (CI 0.824, 1.195), and the positive LR was 1.030 (CI 0.433, 2.451). The halo sign for the diagnosis of biopsy-proven classic GCA had a higher sensitivity of 82.5% (CI 70.5, 90.5%), the same specificity of 80.6% (CI 68.7, 88.9%) and a higher positive LR (4.253; CI 2.577, 7.021). CONCLUSION: The halo sign is infrequently found in GCA characterized by a histological pattern of SVV and/or VVV. This limits the sensitivity of CDS in correctly identifying patients with GCA.

miR-210-3p enriched extracellular vesicles from hypoxic neuroblastoma cells stimulate migration and invasion of target cells.

BACKGROUND: Tumor hypoxia stimulates release of extracellular vesicles (EVs) that facilitate short- and long-range intercellular communication and metastatization. Albeit hypoxia and EVs release are known features of Neuroblastoma (NB), a metastasis-prone childhood malignancy of the sympathetic nervous system, whether hypoxic EVs can facilitate NB dissemination is unclear. METHODS: Here we isolated and characterized EVs from normoxic and hypoxic NB cell culture supernatants and performed microRNA (miRNA) cargo analysis to identify key mediators of EVs biological effects. We then validated if EVs promote pro-metastatic features both in vitro and in an in vivo zebrafish model. RESULTS: EVs from NB cells cultured at different oxygen tensions did not differ for type and abundance of surface markers nor for biophysical properties. However, EVs derived from hypoxic NB cells (hEVs) were more potent than their normoxic counterpart in inducing NB cells migration and colony formation. miR-210-3p was the most abundant miRNA in the cargo of hEVs; mechanistically, overexpression of miR-210-3p in normoxic EVs conferred them pro-metastatic features, whereas miR-210-3p silencing suppressed the metastatic ability of hypoxic EVs both in vitro and in vivo. CONCLUSION: Our data identify a role for hypoxic EVs and their miR-210-3p cargo enrichment in the cellular and microenvironmental changes favoring NB dissemination.

Large-vessel involvement in recent-onset giant cell arteritis: a case-control colour-Doppler sonography study.

OBJECTIVES: The prevalence of large-vessel vasculitis (LVV) in newly diagnosed GCA is still debated. The aim of this study was to investigate the prevalence of LVV in newly diagnosed GCA using colour-Doppler sonography (CDS) and to compare the clinical and laboratory findings of GCA patients with and without LVV. METHODS: Sixty-two consecutive patients with new-onset GCA underwent CDS of the epiaortic vessels and of the aorta. The identified patients with LVV were randomly matched (1 : 2 ratio) to GCA patients without LVV. RESULTS: In 18 (29%) out of 62 patients, CDS showed the characteristic halo sign indicative of vasculitis in at least one vessel examined. Three patients had insufficient documentation and were excluded from the comparative analysis. Compared with patients without LVV, those with LVV were more frequently female (100 vs 73%), less likely to have cranial manifestations (73 vs 97%) and borderline less likely to have jaw claudication (13 vs 43%, P = 0.05). The two groups had similar ages at diagnosis, prevalence of constitutional manifestations and rates of positive temporal artery biopsies. CONCLUSIONS: LVV evidenced by CDS was found in 29% of patients with newly diagnosed GCA. This prevalence is similar to that found in previous studies with a similar design. GCA patients with LVV had less frequent cranial manifestations. Early diagnosis of LVV in GCA can help tailor treatment accordingly and may prevent vascular complications.

Ultrasound response to tofacitinib in patients with rheumatoid arthritis: Data from a multicenter 24 weeks prospective study.

Background: Treatment of rheumatoid arthritis (RA) should aim at full remission. Ultrasonography (US) might have an added value to clinical examination in assessing disease activity of RA. In this study we evaluated the ultrasound response, next to clinical and laboratory response, in RA patients treated with tofacitinib (TOF). Methods: In this observational multicenter study, patients received TOF 5 mg twice daily, with or without the contemporary use of methotrexate or other conventional DMARD, for 24 weeks. All patients underwent clinical, laboratory and US examinations of 40 sites among joints and tendons. Sonographers were blinded to clinical and laboratory parameters. Data were assessed at baseline, week 2, 4, 8, 12 and 24. For each patient we used two US joint scores (Gray Scale -GS-and power Doppler -PD- score), a 0-3 semi-quantitative scale for each joint and the EULAR-OMERACT US scoring system (combined GS and PD graded from 0 to 3). Besides, we calculated a tenosynovitis scores (GS and PD) according to the OMERACT score. Results: Fifty-two RA patients completed the 6 months period study: mean disease duration 9.97 ± 8.75 years, baseline DAS28-CRP 4.9 ± 1.2, HAQ 1.4 ± 0.7, C-reactive protein (CRP 2.25 ± 3.11 mg/dl). Baseline joint (GS, PD and combined-US) and tendon US scores (GS and PD) were 23.5 ± 18.4, 22.7 ± 19.3, 25.7 ± 20.6, 10.5 ± 11.4 and 11.0 ± 12.0, respectively. US joint and tendon scores significantly reduced as early as T1 (week 2) examination as well as at week 4, 12 and 24, as compared to baseline values (p < 0.001 for all comparisons). Improvement of joint US scores (GS, PD and US-combined) correlated at T4 examination, with the reduction of serum CRP levels (rho 0.418, p = 0.036, rho 0.495, p = 0.004 and rho 0.454, p = 0.009, respectively). We did not find any correlation between the variations of DAS28-CRP and any US scores at any visits. Conclusion: These results provide evidence that TOF treatment leads to early (2 weeks) and persistent reduction of US signs of inflammation both at tendon and joint level comparable to clinical improvement.

mll ortholog containing functional domains of human MLL is expressed throughout the zebrafish lifespan and in haematopoietic tissues.

Infant leukaemia is an embryonal disease in which the underlying MLL translocations initiate in utero. Zebrafish offer unique potential to understand how MLL impacts haematopoiesis from the earliest embryonic timepoints and how translocations cause leukaemia as an embryonal process. In this study, a zebrafish mll cDNA syntenic to human MLL spanning the 5' to 3' UTRs, was cloned from embryos, and mll expression was characterized over the zebrafish lifespan. The protein encoded by the 35-exon ORF exhibited 46·4% overall identity to human MLL and 68-100% conservation in functional domains (AT-hooks, SNL, CXXC, PHD, bromodomain, FYRN, taspase1 sites, FYRC, SET). Maternally supplied transcripts were detected at 0-2 hpf. Strong ubiquitous early zygotic expression progressed to a cephalo-caudal gradient during later embryogenesis. mll was expressed in the intermediate cell mass (ICM) where primitive erythrocytes are produced and in the kidney where definitive haematopoiesis occurs in adults. mll exhibits high cross species conservation, is developmentally regulated in haematopoietic and other tissues and is expressed from the earliest embryonic timepoints throughout the zebrafish lifespan. Haematopoietic tissue expression validates using zebrafish for MLL haematopoiesis and leukaemia models.

Aquaporins Are Differentially Regulated in Canine Cryptorchid Efferent Ductules and Epididymis.

The efferent ductules and the epididymis are parts of the male reproductive system where spermatozoa mature. Specialized epithelial cells in these ducts contribute to the transport of fluids produced by spermatozoa's metabolic activity. Aquaporins (AQPs) have been demonstrated to be expressed in the spermatozoan membrane and testis epithelial cells, where they contribute to regulating spermatozoan volume and transit through environments of differing osmolality. Due to the lack of detailed literature regarding AQP expression in the canine male genital tract, the aim of this study was to investigate both the distribution and expression of AQP7, AQP8, and AQP9 in the efferent ductules and epididymal regions (caput, corpus, and cauda) from normal and cryptorchid dogs by using immunohistochemistry, Western blotting, and real-time reverse transcription polymerase chain reaction (RT-PCR). Our results show different patterns for the distribution and expression of the examined AQPs, with particular evidence of their upregulation in the caput and downregulation in the cauda region of the canine cryptorchid epididymis. These findings are associated with a modulation of Hsp70 and caspase-3 expression, suggesting the participation of AQPs in the luminal microenvironment modifications that are peculiar characteristics of this pathophysiological condition.

The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics.

Patients with acute myeloid leukemia (AML) carrying high-risk genetic lesions or high residual disease levels after therapy are particularly exposed to the risk of relapse. Here, we identified the long non-coding RNA CDK6-AS1 able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics. CDK6-AS1 silencing triggered hematopoietic commitment in healthy CD34+ cells, whereas in AML cells the pathological undifferentiated state was rescued. This latter phenomenon derived from RUNX1 transcriptional control, responsible for the stemness of hematopoietic precursors and for the block of differentiation in AML. By CDK6-AS1 silencing in vitro, AML mitochondrial mass decreased with augmented pharmacological sensitivity to mitochondria-targeting drugs. In vivo, the combination of tigecycline and cytarabine reduced leukemia progression in the AML-PDX model with high CDK6-AS1 levels, supporting the concept of a mitochondrial vulnerability. Together, these findings uncover CDK6-AS1 as crucial in myeloid differentiation and mitochondrial mass regulation.

Muscle functional recovery is driven by extracellular vesicles combined with muscle extracellular matrix in a volumetric muscle loss murine model.

Biological scaffolds derived from decellularized tissues are being investigated as a promising approach to repair volumetric muscle losses (VML). Indeed, extracellular matrix (ECM) from decellularized tissues is highly biocompatible and mimics the original tissue. However, the development of fibrosis and the muscle stiffness still represents a major problem. Intercellular signals mediating tissue repair are conveyed via extracellular vesicles (EVs), biologically active nanoparticles secreted by the cells. This work aimed at using muscle ECM and human EVs derived from Wharton Jelly mesenchymal stromal cells (MSC EVs) to boost tissue regeneration in a VML murine model. Mice transplanted with muscle ECM and treated with PBS or MSC EVs were analyzed after 7 and 30 days. Flow cytometry, tissue analysis, qRT-PCR and physiology test were performed. We demonstrated that angiogenesis and myogenesis were enhanced while fibrosis was reduced after EV treatment. Moreover, the inflammation was directed toward tissue repair. M2-like, pro-regenerative macrophages were significantly increased in the MSC EVs treated group compared to control. Strikingly, the histological improvements were associated with enhanced functional recovery. These results suggest that human MSC EVs can be a naturally-derived boost able to ameliorate the efficacy of tissue-specific ECM in muscle regeneration up to the restored tissue function.

The Night Side of Blood Pressure: Nocturnal Blood Pressure Dipping and Emotional (dys)Regulation.

Introduction: The dipping phenomenon is a physiological drop in blood pressure (around 10-20%) during sleep and represents an event related to the circadian blood pressure trend. This phenomenon, in some cases, is characterized by some alterations that can be expressed by an increase (extreme dipping), a decrease (non-dipping), or a reverse (i.e., higher blood pressure during sleep compared to awake state; reverse-dipping) physiological decline of blood pressure. Few studies focused on the association between the circadian variation of blood pressure and psychological variables, although this information could help understanding how psychological characteristics (e.g., emotional regulation or dysregulation) interact with individuals' physiological processes. Given the association between emotional dysregulation and essential hypertension, this study aimed to investigate the relationship between alexithymia and dipping status in a sample of healthy and hypertensive adults in the absence of other medical conditions. Methods: Two hundred and ten adults took part in the study and were classified, according to ambulatorial blood pressure measure (ABPM), into three groups: dippers (n = 70), non-dippers (n = 70), and extreme dippers (n = 70). The participants completed a socio-demographic and anamnestic interview and the Toronto Alexithymia Scale-20 (TAS-20). Results: The ANOVAs on the TAS-20 subscales showed that the groups differed in the difficulty identifying feelings and difficulty describing feelings. In both the subscales, dippers showed lower scores than non-dippers and extreme dippers. The ANOVA on the global score of TAS-20 confirmed that dippers were less alexithymic than both extreme dippers and non-dippers. Conclusions: This study confirms that some psychological factors, like alexithymia, could represent a characteristic of patients who fail to exhibit an adaptive dipping phenomenon. Moreover, an association between an excessive reduction of BP (extreme dipping) or a lack of the decrease of BP during sleep (non-dipping) and a worse emotional regulation, considering alexithymia construct, was highlighted for the first time, confirming the relevant role of the emotional process in the modulation of an essential psychophysiological process such as the circadian variation of BP.

The Night Effect of Anger: Relationship with Nocturnal Blood Pressure Dipping.

INTRODUCTION: The circadian pattern of blood pressure is characterized by a physiological drop occurring after sleep onset. The alteration of this phenomenon (non-dipping, extreme dipping, or reverse dipping) is associated with an increased cardiovascular risk. Besides altered autonomic and endocrine circadian rhythms, psychological aspects seem to play a role in this modification. However, the few studies that have analyzed the influence of psychological dimensions on the dipping phenomenon have reported inconsistent results. This study aimed to examine the relationship between anger expression and blood pressure (BP) dipping. METHODS: We obtained 24 h ambulatory BP measurements from 151 participants and used them to define three groups according to their dipping status: Dippers (N = 65), Non-Dippers (N = 42), and Extreme Dippers (N = 44). Sociodemographic and anamnestic information was collected, and the State-Trait Anger Expression Inventory was used to assess anger. RESULTS: Analysis of variance evidenced significant higher scores for Trait Anger Temperament and Anger Expression in Extreme Dippers than in both Dippers and Non-Dippers. However, after controlling for confounding variables, there was no significant relationship with trait anger, and only the result concerning the suppression of anger was confirmed. CONCLUSIONS: These findings suggest that the analysis of some psychological factors, such as anger, could be necessary to better understand differences in nocturnal BP alterations. Trait anger and suppression of anger may contribute to the description and classification of patients who exhibit a maladaptive dipping phenomenon. However, modifiable (i.e., cigarette consumption) and unmodifiable (i.e., age) risk factors appear to mediate this relationship. Although further studies are necessary to explore this association, these results highlight that some aspects of anger can represent risk factors or markers of maladaptive modulation of the dipping phenomenon.

A double-blind, placebo-controlled clinical trial to assess the effects of a combined nutraceutical on endothelial function in patients with mild-to-moderate hypercholesterolaemia.

INTRODUCTION: There is growing interest in lipid-lowering nutraceuticals; however, there are a relative scarcity of data on combined compounds. This study was aimed to assess the efficacy and tolerability of a combined nutraceutical (CARDIOL® Forte - CF) containing polyunsaturated fatty acids, hydroxytyrosol, Coenzyme Q10, folic acid, B12 and E vitamins, piperine, and red yeast rice in patients with mild-to-moderate hypercholesterolaemia. MATERIAL AND METHODS: In this single-centre, double-blinded, placebo-controlled study enrolled subjects who were randomised to receive the tested combined nutraceutical for 16 weeks (CF group) or placebo (control group), in association with a low-fat diet. After 8 weeks of treatment, all patients underwent a 15-day washout period; then, a further 8 weeks of treatment was planned. RESULTS: Of 80 enrolled subjects, 37 completed the study in the CF group and 38 in the control group. After 8 weeks of treatment, low-density lipoprotein cholesterol levels were reduced by 17% in the CF group and by 6.4% in the control group, compared to baseline (p = 0.0001); these changes were improved at the end of study. Total cholesterol and triglyceride levels significantly decreased during treatment; high-density lipoprotein cholesterol did not change. In the CF group, flow-mediated dilation increased by 18.8% after 8 weeks and by 39.3% at the end of treatment. No adverse events or musculoskeletal disorders were reported in either group. CONCLUSIONS: The tested combined nutraceutical, in association with a controlled diet, can reduce cholesterol levels and improve endothelial function, thus reducing the cardiovascular risk in patients with mild-to-moderate hypercholesterolaemia.

Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes.

Circular RNAs (circRNAs) are stable RNA molecules that can drive cancer through interactions with microRNAs and proteins and by the expression of circRNA encoded peptides. The aim of the study was to define the circRNA landscape and potential impact in T-cell acute lymphoblastic leukemia (T-ALL). Analysis by CirComPara of RNA-sequencing data from 25 T-ALL patients, immature, HOXA overexpressing, TLX1, TLX3, TAL1, or LMO2 rearranged, and from thymocyte populations of human healthy donors disclosed 68 554 circRNAs. Study of the top 3447 highly expressed circRNAs identified 944 circRNAs with significant differential expression between malignant T cells and normal counterparts, with most circRNAs displaying increased expression in T-ALL. Next, we defined subtype-specific circRNA signatures in molecular genetic subgroups of human T-ALL. In particular, circZNF609, circPSEN1, circKPNA5, and circCEP70 were upregulated in immature, circTASP1, circZBTB44, and circBACH1 in TLX3, circHACD1, and circSTAM in HOXA, circCAMSAP1 in TLX1, and circCASC15 in TAL-LMO. Backsplice sequences of 14 circRNAs ectopically expressed in T-ALL were confirmed, and overexpression of circRNAs in T-ALL with specific oncogenic lesions was substantiated by quantification in a panel of 13 human cell lines. An oncogenic role of circZNF609 in T-ALL was indicated by decreased cell viability upon silencing in vitro. Furthermore, functional predictions identified circRNA-microRNA gene axes informing modes of circRNA impact in molecular subtypes of human T-ALL.

Salivary Gland Ultrasonography in Sjögren's Syndrome: A European Multicenter Reliability Exercise for the HarmonicSS Project.

Objectives: Salivary gland ultrasonography (SGUS) is increasingly applied for the management of primary Sjögren's syndrome (pSS). This study aims to: (i) compare the reliability between two SGUS scores; (ii) test the reliability among sonographers with different levels of experience. Methods: In the reliability exercise, two four-grade semi-quantitative SGUS scoring systems, namely De Vita et al. and OMERACT, were tested. The sonographers involved in work-package 7 of the HarmonicSS project from nine countries in Europe were invited to participate. Different levels of sonographers were identified on the basis of their SGUS experience and of the knowledge of the tested scores. A dedicated atlas was used as support for SGUS scoring. Results: Twenty sonographers participated in the two rounds of the reliability exercise. The intra-rater reliability for both scores was almost perfect, with a Light's kappa of 0.86 for the De Vita et al. score and 0.87 for the OMERACT score. The inter-rater reliability for the De Vita et al. and the OMERACT score was substantial with Light's Kappa of 0.75 and 0.77, respectively. Furthermore, no significant difference was noticed among sonographers with different levels of experience. Conclusion: The two tested SGUS scores are reliable for the evaluation of major salivary glands in pSS, and even less-expert sonographers could be reliable if adequately instructed.