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Thoracentesis is one of the most important invasive procedures in the clinical setting. Particularly, thoracentesis can be relevant in the evaluation of a new diagnosed pleural effusion, thus allowing for the collection of pleural fluid so that laboratory tests essential to establish a diagnosis can be performed. Furthermore, thoracentesis is a maneuver that can have therapeutic and palliative purposes. Historically, the procedure was performed based on a physical examination. In recent years, the role of ultrasound has been established as a valuable tool for assistance and guidance in the thoracentesis procedure. The use of ultrasound increases success rates and significantly reduces complications. The aim of this educational review is to provide a detailed and sequential examination of the procedure, focusing on the two main modalities, the ultrasound-assisted and ultrasound-guided form.

In this article, we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs), and cardiovascular diseases (CADs). CHIP is characterized by the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasms, or abnormalities in blood cell count. The prevalence may reach 20% of elderly healthy individuals and is considered a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is often associated with mutations such as JAK2V617F or DNMT3A, TET2, or ASXL1, which exhibit a 12.1- and 1.7–2-fold increase in CADs. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species, leading to proinflammatory modifications in the bone marrow microenvironment. Consequently, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation, which also appears to be correlated with anti-endothelial cell antibodies that sustain thrombosis. However, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factor upregulation. As a result, in patients with TET2 and DNMT3A-related CHIP, the inflammasome hyperactivation represents a potential cause of CADs. CHIP also occurs in patients with large and small vessel vasculitis, while ADs are more frequently associated with MPNs. In these diseases, monocytes and neutrophils play a key role in the formation of neutrophil extracellular trap (NET) as well as anti-endothelial cell antibodies, resulting in a final procoagulant effect. ADs, such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterized by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyperactivate the JAK-STAT pathway. Interestingly, hyperactivation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells. In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it is necessary to consider a “disease-modifying therapy” that may either reduce the clonal burden or inhibit the clonally activated JAK pathway.

Objective Assessment of circulating autoantibodies represents one of the earliest diagnostic procedures in patients with suspected connective tissue disease (CTD), providing important information for disease diagnosis, identification and prediction of potential clinical manifestations. The purpose of this study was to evaluate the ability of multiparametric assay to correctly classify patients with multiple CTDs and healthy controls (HC), independent of clinical features, and to evaluate whether serological status could identify clusters of patients with similar clinical features.Methods Patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren’s syndrome (SjS), undifferentiated connective tissue disease (UCTD), idiopathic inflammatory myopathies (IIM) and HC were enrolled. Serum was tested for 29 autoantibodies. An XGBoost model, exclusively based on autoantibody titres was built and classification accuracy was evaluated. A hierarchical clustering model was subsequently developed and clinical/laboratory features compared among clusters.Results 908 subjects were enrolled. The classification model showed a mean accuracy of 60.84±4.05% and a mean area under the receiver operator characteristic curve of 88.99±2.50%, with significant discrepancies among groups. Cluster analysis identified four clusters (CL). CL1 included patients with typical features of SLE. CL2 included most patients with SjS, along with some SLE and UCTD patients with SjS-like features. CL4 included anti-Jo1 patients only. CL3 was the largest and most heterogeneous, including all the remaining subjects, overall characterised by low titre or lower-prevalence autoantibodies.Conclusion Extended multiparametric autoantibody assay allowed an accurate classification of CTD patients, independently of clinical features. Clustering according to autoantibody titres is able to identify clusters of CTD subjects with similar clinical features, independently of their final diagnosis.

In recent decades, several pieces of evidence have drawn greater attention to the topic of innate immunity, in particular, interferon (IFN) and Interleukin 6 in the pathogenesis of idiopathic inflammatory myopathies (IIM). Both of these molecules transduce their signal through a receptor coupled with Janus kinases (JAK)/signal transducer and activator of transcription proteins (STAT). In this review, we discuss the role of the JAK/STAT pathway in IIM, evaluate a possible therapeutic role for JAK inhibitors in this group of diseases, focusing on those with the strongest IFN signature (dermatomyositis and antisynthetase syndrome).

For many decades, the clinical unmet needs of primary Sjögren’s Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs.

BACKGROUND Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects.METHODS This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab.RESULTS Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo.CONCLUSION The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes.TRIAL REGISTRATION ClinicalTrials.gov NCT02631538.FUNDING Funding was provided by GSK.

Sjögren’s Disease (SjD) is a chronic autoimmune disorder that affects the salivary and lacrimal glands, leading to xerostomia and xerophthalmia. Ultrasonography of Major Salivary Glands (SGUS) is a well-established tool for the identification of the salivary glands’ abnormalities in SjD. Recently, a growing interest has arisen in the assessment of the other exocrine glands with ultrasonography: lacrimal glands (LGUS) and labial salivary glands (LSGUS). The objective of this study is to explore the practical applications of ultra-high frequency ultrasound (UHFUS) in the assessment of lacrimal glands and labial salivary glands. Indeed, UHFUS, with its improved spatial resolution compared to conventional ultrasonography, allows for the evaluation of microscopic structures and has been successfully applied in various medical fields. In lacrimal glands, conventional high-frequency ultrasound (HFUS) can detect characteristic inflammatory changes, atrophic alterations, blood flow patterns, and neoplastic lesions associated with SjD. However, sometimes it is challenging to identify lacrimal glands characteristics, thus making UHFUS a promising tool. Regarding labial salivary glands, limited research is available with conventional HFUS, but UHFUS proves to be a good tool to evaluate glandular inhomogeneity and to guide labial salivary glands biopsy. The comprehensive understanding of organ involvement facilitated by UHFUS may significantly improve the management of SjD patients.

Sjögren’s disease (SD) is a chronic autoimmune disease primarily affecting lacrimal and salivary glands. The diagnosis of pediatric SD mostly relies on clinical suspect, resulting in a significant diagnostic delay. Recently, ultrahigh-frequency ultrasound (UHFUS) of labial glands has been proposed as a diagnostic method in adults with suspected SD. Until now, there have been no studies about UHFUS in pediatric diagnostic work-up. The aim of the study was to evaluate the potential role of UHFUS of minor salivary glands in pediatric SD. Consecutive pediatric patients with a diagnosis of pediatric SD seen at AOU Meyer IRCSS were evaluated. Intraoral UHFUS scan of the lip mucosa was performed with Vevo MD equipment, using a 70 MHz probe with a standardized protocol and the images were independently reviewed by two operators. Lip salivary glands were assessed by using a four-grade semiquantitative scoring system for parenchymal alteration and vascularization. Twelve patients were included. When applying UHFUS to this cohort of patients, all patients showed a UHFUS grade of ≥1 with 8/12 showing a mild glandular alteration (i.e., grade 1), 2/12 a moderate glandular alteration (i.e., grade 2) and finally 2/12 a severe glandular alteration (i.e., grade 3). Moderate intraglandular vascularization was seen in 9/12, with only 3/12 showing mild intraglandular vascularization. Due to limited size of the sample, the relationship between histological findings, autoantibodies status and UHFUS grade could not be performed. This preliminary study seems to report UHFUS as feasibility technique to identify salivary gland alterations in children with a clinical suspect of SD.

Goal: To present a framework for data sharing, curation, harmonization and federated data analytics to solve open issues in healthcare, such as, the development of robust disease prediction models. Methods: Data curation is applied to remove data inconsistencies. Lexical and semantic matching methods are used to align the structure of the heterogeneous, curated cohort data along with incremental learning algorithms including class imbalance handling and hyperparameter optimization to enable the development of disease prediction models. Results: The applicability of the framework is demonstrated in a case study of primary Sjögren's Syndrome, yielding harmonized data with increased quality and more than 85% agreement, along with lymphoma prediction models with more than 80% sensitivity and specificity. Conclusions: The framework provides data quality, harmonization and analytics workflows that can enhance the statistical power of heterogeneous clinical data and enables the development of robust models for disease prediction.

Connexins (Cxs) are transmembrane proteins involved in the formation of hemichannels and gap junctions (GJs). GJs are involved in various physiological functions, including secretion in glandular tissue. It has been demonstrated that Cx26, Cx32, and Cx43 are mainly expressed in glands, but no data are available in human salivary glands to date. The aim of our study was to investigate the presence and the localization of Cxs in human minor labial salivary glands. Immunofluorescence and immunoelectron microscopy were employed to evaluate the Cx26, Cx32, and Cx43 protein in human labial salivary gland biopsies (hLSGBs). RT-PCR was also used to detect their mRNA expression. Cx expression was found at both the mRNA and protein levels in all hLSGBs analysed. Cxs were observed at the level of the duct and acinar cells, as well as in myoepithelial cells. The localization of the three Cx types was very similar, suggesting colocalization of these Cxs in the same connexons. These results demonstrated the presence of Cxs in human salivary glands for the first time. Moreover, the few samples with primary Sjögren’s Syndrome analysed only by immunofluorescence showed an alteration of the Cx expression, indicating that these proteins could be involved in salivary gland dysfunctions.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).

PurposeThe prevalence of peripheral nervous system (PNS) involvement in primary Sjögren’s syndrome (pSS) has been reported to range from 2% to over 50%. Bias in study designs, including low number of patients and unclearly defined rheumatological and neurological diagnosis could explain such variability. Consequently, the exact depiction of PNS involvement in pSS is still lacking. This study aimed at analyzing the prevalence and the clinical and laboratory factors associated with PNS involvement in a very large cohort of well-characterized pSS patients with a clearly defined neurological diagnosis.MethodsClinical and serological data of 1,695 pSS patients with specific and accurate information on PNS involvement were analyzed. Comparisons between patients with and without PNS involvement and between patients with distinct subsets of PNS manifestations were performed.ResultsPrevalence of PNS involvement was 3.7%. The most frequent types observed were pure sensory neuropathies and axonal sensorimotor polyneuropathies (SMP). Patients with PNS involvement exhibited a more active disease profile and were more frequently treated with immunosuppressants. Intriguingly, clinical and serological negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinemia, principally characterized patients with SMP, while subjects with pure sensory neuropathy displayed a milder phenotype.ConclusionOur results highlight that PNS involvement is rather rare, but prognostically relevant in pSS. Main adverse prognostic features characterize patients with SMP, while pure sensory neuropathies are usually associated with a mild clinical picture. These findings, useful for patient stratification, may suggest protean pathogenic pathways underlying different types of PNS manifestations in pSS.

Primary Sjögren’s syndrome (pSS) is a complex autoimmune disorder that particularly affects the salivary and lachrymal glands, generally causing a typical dryness of the eyes and of the mouth. The disease encompasses diverse clinical representations and is characterized by B-cell polyclonal activation and autoantibodies production, including anti-Ro/SSA. Recently, it has been suggested that autoantibody profiling may enable researchers to identify susceptible asymptomatic individuals in a pre-disease state. In this pilot study, we used mass spectrometry to analyze and compare the salivary proteomics of patients with established pSS and patients with pre-clinical SS, identifying a common protein signature in their salivary fluid. We found that several inflammatory, immunity-related, and typical acinar proteins (such as MUC5B, PIP, CST4, and lipocalin 1) were differently expressed in pSS and in pre-clinical SSA+ carriers, compared to healthy controls. This suggests that saliva may closely reflect exocrine gland inflammation from the early phases of the disease. This study confirms the value of salivary proteomics for the identification of reliable biomarkers for SS that could be identified, even in a preclinical phase of the disease.

In this study, it was found that myositis-specific and myositis-associated antibodies (MSAs and MAAs) improved the recognition of idiopathic inflammatory myopathies (IIMs) in interstitial lung disease (ILD) patients. The objective of this study is to propose a clinical method to evaluate myalgia in respiratory settings as a possible tool for the recognition of MSA/MAA positivity in ILD patients. We prospectively enrolled 167 ILD patients with suspected myositis, of which 63 had myalgia evoked at specific points (M+ILD+). We also enrolled in a 174 patients with only myalgia (M+ILD-) in a rheumatological setting. The patients were assessed jointly by rheumatologists and pulmonologists and were tested for autoantibodies. M+ILD+ patients were positive for at least one MAA/MSA in 68.3% of cases, as were M-ILD+ patients in 48.1% of cases and M+ILD- patients in 17.2% of cases (p = 0.01 and p = 0.02). Myalgia was significantly associated with positivity for MSA/MAAs in ILD patients (p = 0.01, X2: 6.47). In conclusion, myalgia in ILD patients with suspected myositis is associated with MSA/MAA positivity, and could support a diagnosis of IIM. A significant proportion of M+ILD- patients also had MSA/MAA positivity, a phenomenon warranting further study to evaluate its clinical meaning.

Abstract Background This study is part of the EU‐funded project HarmonicSS, aimed at improving the treatment and diagnosis of primary Sjögren's syndrome (pSS). pSS is an underdiagnosed, long‐term autoimmune disease that affects particularly salivary and lachrymal glands. Objectives We assessed the usability of routinely recorded primary care and hospital claims data for the identification and validation of patients with complex diseases such as pSS. Methods pSS patients were identified in primary care by translating the formal inclusion and exclusion criteria for pSS into a patient selection algorithm using data from Nivel Primary Care Database (PCD), covering 10% of the Dutch population between 2006 and 2017. As part of a validation exercise, the pSS patients found by the algorithm were compared to Diagnosis Related Groups (DRG) recorded in the national hospital insurance claims database (DIS) between 2013 and 2017. Results International Classification of Primary Care (ICPC) coded general practitioner (GP) contacts combined with the mention of “Sjögren” in the disease episode titles, were found to best translate the formal classification criteria to a selection algorithm for pSS. A total of 1462 possible pSS patients were identified in primary care (mean prevalence 0.7‰, against 0.61‰ reported globally). The DIS contained 208 545 patients with a Sjögren related DRG or ICD10 code (prevalence 2017: 2.73‰). A total of 2 577 577 patients from Nivel PCD were linked to the DIS database. A total of 716 of the linked pSS patients (55.3%) were confirmed based on the DIS. Conclusion Our study finds that GP electronic health records (EHRs) lack the granular information needed to apply the formal diagnostic criteria for pSS. The developed algorithm resulted in a patient selection that approximates the expected prevalence and characteristics, although only slightly over half of the patients were confirmed using the DIS. Without more detailed diagnostic information, the fitness for purpose of routine EHR data for patient identification and validation could not be determined.

ObjectivesTo study the clinical, serological and histologic features of primary Sjögren’s syndrome (pSS) patients with early (young ≤35 years) or late (old ≥65 years) onset and to explore the differential effect on lymphoma development.MethodsFrom a multicentre study population of 1997 consecutive pSS patients, those with early or late disease onset, were matched and compared with pSS control patients of middle age onset. Data driven analysis was applied to identify the independent variables associated with lymphoma in both age groups.ResultsYoung pSS patients (19%, n = 379) had higher frequency of salivary gland enlargement (SGE, lymphadenopathy, Raynaud’s phenomenon, autoantibodies, C4 hypocomplementemia, hypergammaglobulinemia, leukopenia, and lymphoma (10.3% vs. 5.7%, p = 0.030, OR = 1.91, 95% CI: 1.11–3.27), while old pSS patients (15%, n = 293) had more frequently dry mouth, interstitial lung disease, and lymphoma (6.8% vs. 2.1%, p = 0.011, OR = 3.40, 95% CI: 1.34–8.17) compared to their middle-aged pSS controls, respectively. In young pSS patients, cryoglobulinemia, C4 hypocomplementemia, lymphadenopathy, and SGE were identified as independent lymphoma associated factors, as opposed to old pSS patients in whom SGE, C4 hypocomplementemia and male gender were the independent lymphoma associated factors. Early onset pSS patients displayed two incidence peaks of lymphoma within 3 years of onset and after 10 years, while in late onset pSS patients, lymphoma occurred within the first 6 years.ConclusionPatients with early and late disease onset constitute a significant proportion of pSS population with distinct clinical phenotypes. They possess a higher prevalence of lymphoma, with different predisposing factors and lymphoma distribution across time.

SARS-CoV-2 is the viral agent responsible for the pandemic that in the first months of 2020 caused about 400,000 deaths. Among compounds proposed to fight the SARS-CoV-2-related disease (COVID-19), tyrosine kinase inhibitors (TKIs), already effective in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML), have been proposed on the basis of their antiviral action already demonstrated against SARS-CoV-1. Very few cases of COVID-19 have been reported in Ph+ ALL and in CML Italian cohorts; authors suggested that this low rate of infections might depend on the use of TKIs, but the biological causes of this phenomenon remain unknown. In this study, the CML model was used to test if TKIs would sustain or not the viral replication and if they could damage patient immunity. Firstly, the infection and replication rate of torquetenovirus (TTV), whose load is inversely proportional to the host immunological control, have been measured in CML patients receiving nilotinib. A very low percentage of subjects were infected at baseline, and TTV did not replicate or at least showed a low replication rate during the follow-up, with a mean load comparable to the measured one in healthy subjects. Then, after gene expression profiling experiments, we found that several “antiviral” genes, such as CD28 and IFN gamma, were upregulated, while genes with “proviral” action, such as ARG-1, CEACAM1, and FUT4, were less expressed during treatment with imatinib, thus demonstrating that TKIs are not detrimental from the immunological point of view. To sum up, our data could offer some biological explanations to the low COVID-19 occurrence in Ph+ ALL and CML patients and sustain the use of TKIs in COVID-19, as already proposed by several international ongoing studies.

Saliva secretion requires effective translocation of aquaporin 5 (AQP5) water channel to the salivary glands (SGs) acinar apical membrane. Patients with Sjögren’s syndrome (SS) display abnormal AQP5 localization within acinar cells from SGs that correlate with sicca manifestation and glands hypofunction. Several proteins such as Prolactin-inducible protein (PIP) may regulate AQP5 trafficking as observed in lacrimal glands from mice. However, the role of the AQP5-PIP complex remains poorly understood. In the present study, we show that PIP interacts with AQP5 in vitro and in mice as well as in human SGs and that PIP misexpression correlates with an altered AQP5 distribution at the acinar apical membrane in PIP knockout mice and SS hMSG. Furthermore, our data show that the protein-protein interaction involves the AQP5 C-terminus and the N-terminal of PIP (one molecule of PIP per AQP5 tetramer). In conclusion, our findings highlight for the first time the role of PIP as a protein controlling AQP5 localization in human salivary glands but extend beyond due to the PIP-AQP5 interaction described in lung and breast cancers.

Abstract Background A more severe disease phenotype has been reported in men compared to women in several rheumatic diseases. However, studies have not conclusively established sex-related clinical features in primary Sjögren’s syndrome (pSS). In this study, we therefore investigated the clinical presentation of pSS in women and men at diagnosis. Methods Incident, treatment naïve patients (n = 199) during a 5-year period in a specified area were prospectively included and examined for items of classification criteria for pSS as well as extraglandular manifestations (EGM). Serum was sampled at the time of diagnosis and anti-Ro52/SSA levels were measured by ELISA. Replication of significant findings was confirmed in an independent cohort of pSS patients (n = 377), and meta-analysis was performed. Results An increased frequency of extraglandular manifestations in men was observed and replicated (p = 0.05, p = 0.0003, and p meta = 0.002). This related to pulmonary involvement, vasculitis, and lymphadenopathy being more common in men, for whom a lower age at diagnosis was observed in the exploratory cohort. Additionally, SSA-positive male patients had significantly higher levels of anti-Ro52 levels than their female counterparts in sera available for analysis (p = 0.02). Conclusions Our analysis of two independent cohorts of incident pSS demonstrates that the presence and number of EGM are significantly more frequent among men with pSS than women at diagnosis. Importantly, around half of the male patients presented with more than one EGM at diagnosis, supporting the conclusion that pSS in men represents a more severe form of disease, regardless of the lower risk for men to develop pSS.

Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a “real-life” setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were “resistant;” after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a “low” up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a “high” gene over-expression (p = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a “low” up-regulation were event-free vs. 33% of those who presented a “high” gene expression (p = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.

Cancer is fast becoming the most important cause of death worldwide, its mortality being mostly caused by late or wrong diagnosis. Novel strategies have been developed to identify early signs of cancer in a minimally obtrusive way, including the Electronic Nose (E-Nose) technology, user-friendly, cost- and time-saving alternative to classical approaches. This systematic review, conducted under the PRISMA guidelines, identified 60 articles directly dealing with the E-Nose application in cancer research published up to 31 January 2020. Among these works, the vast majority reported successful E-Nose use for diagnosing Lung Cancer, showing promising results especially when employing the Aeonose tool, discriminating subjects with Lung Cancer from controls in more than 80% of individuals, in most studies. In order to tailor the main limitations of the proposed approach, including the application of the protocol to advanced stage of cancer, sample heterogeneity and massive confounders, future studies should be conducted on early stage patients, and on larger cohorts, as to better characterize the specific breathprint associated with the various subtypes of cancer. This would ultimately lead to a better and faster diagnosis and to earlier treatment, possibly reducing the burden associated to such conditions.

Sjögren’s syndrome (SS) and autoimmune thyroid diseases (AITD) may frequently coexist in clinical practice, resulting in a complex overlapping disorder that represents a particular example of the expression of heterogeneity in patients with autoimmune disorders. Objective of this review was to describe the prevalence of the SS–AITD association in the most recent literature, exploring in particular to what extent the presence of AITD might influence the clinical expression of SS and vice versa. Moreover, we summarized some of the proposed genetic, biologic, and molecular mechanisms implied in the pathogenesis of AITD–SS association. Finally, we explored risk factors for lymphoma development in both AITD and SS. We performed a Medline search of English language articles published in the PubMed database in order to provide a critical overview of the recent literature on pathogenesis and clinical features of AITD–SS overlapping disease. All the articles were critically analyzed to select the most relevant contributions.