Mantle cell lymphoma (MCL) is an incurable B-cell malignancy characterized by a high clinical variability. Therefore, there is a critical need to define parameters that identify high-risk patients ...for aggressive disease and therapy resistance. B-cell receptor (BCR) signaling is crucial for MCL initiation and progression and is a target for therapeutic intervention. We interrogated BCR signaling proteins (SYK, LCK, BTK, PLCγ2, p38, AKT, NF-κB p65, and STAT5) in 30 primary MCL samples using phospho-specific flow cytometry. Anti-IgM modulation induced heterogeneous BCR signaling responses among samples allowing the identification of two clusters with differential responses. The cluster with higher response was associated with shorter progression free survival (PFS) and overall survival (OS). Moreover, higher constitutive AKT activity was predictive of inferior response to the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib. Time-to-event analyses showed that MCL international prognostic index (MIPI) high-risk category and higher STAT5 response were predictors of shorter PFS and OS whilst MIPI high-risk category and high SYK response predicted shorter OS. In conclusion, we identified BCR signaling properties associated with poor clinical outcome and resistance to ibrutinib, thus highlighting the prognostic and predictive significance of BCR activity and advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL.
Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The ...anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.
Cytometry comprises powerful techniques for analyzing the cell heterogeneity of a biological sample by examining the expression of protein markers. These technologies impact especially the field of ...oncoimmunology, where cell identification is essential to analyze the tumor microenvironment. Several classification tools have been developed for the annotation of cytometry datasets, which include supervised tools that require a training set as a reference (i.e. reference-based) and semisupervised tools based on the manual definition of a marker table. The latter is closer to the traditional annotation of cytometry data based on manual gating. However, they require the manual definition of a marker table that cannot be extracted automatically in a reference-based fashion. Therefore, we are lacking methods that allow both classification approaches while maintaining the high biological interpretability given by the marker table.
We present a new tool called GateMeClass (Gate Mining and Classification) which overcomes the limitation of the current methods of classification of cytometry data allowing both semisupervised and supervised annotation based on a marker table that can be defined manually or extracted from an external annotated dataset. We measured the accuracy of GateMeClass for annotating three well-established benchmark mass cytometry datasets and one flow cytometry dataset. The performance of GateMeClass is comparable to reference-based methods and marker table-based techniques, offering greater flexibility and rapid execution times.
GateMeClass is implemented in R language and is publicly available at https://github.com/simo1c/GateMeClass.
Il Sito di bonifica di Interesse Nazionale di Balangero e Corio ha prodotto crisotilo a partire dal 1918 e negli anni ‘70 si è affermato come la miniera d’amianto più grande d’Europa, causando una ...notevole contaminazione dell’area. La miniera venne chiusa nel 1990 poiché il D.L. 257/92 vietò l’estrazione, l’importazione, l’esportazione, il commercio e la produzione dell’amianto. L’obiettivo del concorso non era solamente bonificare un’area contaminata, ma anche valorizzare la cultura e il paesaggio, preservare la memoria storica e promuovere iniziative che coinvolgano la popolazione locale riaffermando la forza sociale ed economica della regione. Il progetto propone la conversione degli edifici industriali in spazi di documentazione dedicati alla storia del sito, luoghi per la produzione e promozione dell’arte e una serie di strutture ricettive volte a stimolare differenti forme di turismo.
The Italian version of the South Oaks Gambling Screen questionnaire (SOGS) and a socio-demographic questionnaire were administered to a sample of 275 healthcare professions students aged 19 to 58 ...years (mean age = 22.17; females = 81.1%) to address the research objectives: to examine the prevalence and correlates of problem gambling in a population of university healthcare professions students in Italy. Among the sample, 8.7% (
= 24) of participants showed problem gambling and 1.5% (
= 4) pathologic gambling. Lottery and scratch cards were the most frequent type of gambling in the sample, followed by cards and bingo. Compared to females, males tend to be more involved in problem gambling and pathological gambling. Males tend to be more involved than females in different types of gambling (such as cards, sports bets, gambling at the casino). Pathological gambling is positively associated with gender, being students lagging behind the regular schedule of exams and parents' level of education. These findings have important implications in terms of prevention and intervention on gambling and pathological gambling. Universities should make available educational programs and counselling services to address this issue.
Central nervous system vasculitis (CNSV) is an uncommon and poorly understood form of vasculitis. Early recognition is important because medical treatment might improve the outcome. However, ...randomized clinical trials on CNSV treatment do not exist. Endovascular treatment has been reported in few cases, but no data exist for intracranial stenting. We report two cases of patients with suspected CNSV and recurrent clinical episodes, treated with intracranial stenting. A 48-year-old man had relapsing episodes of right hemiparesis. Neuroradiological exams showed severe left carotid terminus stenosis. Despite immunosuppressive therapy, neuroradiological follow-up exams showed a worsening of the aforementioned stenosis with many transient episodes of weakness in the right limbs and aphasia. A 64-year-old woman had a sudden onset of dysarthria and transient aphasia. Neuroradiological exams showed a severe arterial stenosis involving the origin of left ACA and MCA. Despite dual antiplatel therapy she presented an acute onset of severe aphasia, due to an occlusion of the left carotid terminus and proximal MCA. In both cases endovascular procedure and intracranial stenting was performed, with marked improvement of cerebral blood flow. No more clinical episodes were reported. Intracranial stenting may be a valid therapeutic option in selected patients with CNSV and involvement of medium or large size vessels with clinical worsening despite best medical treatment.
Central nervous system vasculitis (CNSV) is an uncommon and poorly understood form of vasculitis. Early recognition is important because medical treatment might improve the outcome. However, ...randomized clinical trials on CNSV treatment do not exist. Endovascular treatment has been reported in few cases, but no data exist for intracranial stenting. We report 2 cases of patients with suspected CNSV and recurrent clinical episodes, treated with intracranial stenting. A 48-year-old man had relapsing episodes of right hemiparesis. Neuroradiological exams showed severe left carotid terminus stenosis. Despite immunosuppressive therapy, neuroradiological follow-up exams showed a worsening of the aforementioned stenosis with many transient episodes of weakness in the right limbs and aphasia. A 64-year-old woman had a sudden onset of dysarthria and transient aphasia. Neuroradiological exams showed a severe arterial stenosis involving the origin of left anterior cerebral artery and middle cerebral artery (MCA). Despite dual antiplatelet therapy, she presented an acute onset of severe aphasia, due to an occlusion of the left carotid terminus and proximal MCA. In both cases, endovascular procedure and intracranial stenting was performed, with marked improvement of cerebral blood flow. No more clinical episodes were reported. Intracranial stenting may be a valid therapeutic option in selected patients with CNSV and involvement of medium or large size vessels with clinical worsening despite best medical treatment.
The aim of this article is to describe the design and development of an online gymnasium that proposes personalized exercise videos to users affected by fibromyalgia. Fibromyalgia syndrome is a ...chronic condition characterized by widespread pain in muscles, ligaments and tendons, usually associated with sleep disorders and fatigue. Physical exercise is considered as an important component of non-pharmacological treatments of this pathology, and the internet is praised as a powerful resource to promote and improve physical exercise. Yet, while online personalization of health interventions to consumers must be grounded on empirically based guidelines, guidelines for fibromyalgia-targeted exercises are scant. The achievements presented in this paper are twofold. Firstly, we illustrate how we reached definition of the relevant factors for tailoring exercise videos in relation to fibromyalgia. Secondly, we explain the general framework of the application that is composed of an interview module (that investigates the determinant values of a specific user), an adaptation module (presenting the tailored set of exercises) and a logging component (used to monitor users’ interactions with the website). The paper concludes with a discussion on the strengths and weaknesses of the proposed approach.
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