The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia

Mesenchymal stromal cells (MSCs) have, for a long time, been recognized as pivotal contributors in the set up and maintenance of the hematopoietic stem cell (HSC) niche, as well as in the development and differentiation of the lympho-hematopoietic system. MSCs also have a unique immunomodulatory capacity, which makes them able to affect, both in vitro and in vivo, the function of immune cells. These features, namely the facilitation of stem cell engraftment and the inhibition of lymphocyte responses, have both proven essential for successful allogeneic stem cell transplantation (allo-SCT), which remains the only curative option for several hematologic malignancies. For example, in steroid-refractory acute graft-vs. host disease developing after allo-SCT, MSCs have produced significant results and are now considered a treatment option. However, more recently, the other side of the MSC coin has been unveiled, because of their emerging role in creating a protective and immune-tolerant microenvironment able to support the survival of leukemic cells and affect the response to therapies. In this light, it has been proposed that the failure of current treatments to efficiently override the stroma-mediated protection of leukemic cells accounts for the high rate of relapse in acute myeloid leukemia, at least in part. In this review, we will focus on emerging microenvironment-driven mechanisms conferring a survival advantage to leukemic cells overt physiological HSCs. This body of evidence increasingly highlights the opportunity to consider tumor-microenvironment interactions when designing new therapeutic strategies

Single-Walled Carbon Nanotubes as Enhancing Substrates for PNA-Based Amperometric Genosensors

A new amperometric sandwich-format genosensor has been implemented on single-walled carbon nanotubes screen printed electrodes (SWCNT-SPEs) and compared in terms of performance with analogous genoassays developed using the same methodology on non-nanostructured glassy carbon platforms (GC-SPE). The working principle of the genosensors is based on the covalent immobilization of Peptide Nucleic Acid (PNA) capture probes (CP) on the electrode surface, carried out through the carboxylic functions present on SWCNT-SPEs (carboxylated SWCNT) or electrochemically induced on GC-SPEs. The sequence of the CP was complementary to a 20-mer portion of the target DNA; a second biotin-tagged PNA signalling probe (SP), with sequence complementary to a different contiguous portion of the target DNA, was used to obtain a sandwich hybrid with an Alkaline Phosphatase-streptavidin conjugate (ALP-Strp). Comparison of the responses obtained from the SWCNT-SPEs with those produced from the non-nanostructured substrates evidenced the remarkable enhancement effect given by the nanostructured electrode platforms, achieved both in terms of loading capability of PNA probes and amplification of the electron transfer phenomena exploited for the signal transduction, giving rise to more than four-fold higher sensitivity when using SWCNT-SPEs. The nanostructured substrate allowed to reach limit of detection (LOD) of 71 pM and limit of quantitation (LOQ) of 256 pM, while the corresponding values obtained with GC-SPEs were 430 pM and 1.43 nM, respectively

A Folding-Based Electrochemical Aptasensor for the Single-Step Detection of the SARS-CoV-2 Spike Protein

Efficient and timely testing has taken center stage in the management, control, and monitoring of the current COVID-19 pandemic. Simple, rapid, cost-effective diagnostics are needed that can complement current polymerase chain reaction-based methods and lateral flow immunoassays. Here, we report the development of an electrochemical sensing platform based on single-walled carbon nanotube screen-printed electrodes (SWCNT-SPEs) functionalized with a redox-tagged DNA aptamer that specifically binds to the receptor binding domain of the SARS-CoV-2 spike protein S1 subunit. Single-step, reagentless detection of the S1 protein is achieved through a binding-induced, concentration-dependent folding of the DNA aptamer that reduces the efficiency of the electron transfer process between the redox tag and the electrode surface and causes a suppression of the resulting amperometric signal. This aptasensor is specific for the target S1 protein with a dissociation constant (K-D) value of 43 +/- 4 nM and a limit of detection of 7 nM. We demonstrate that the target S1 protein can be detected both in a buffer solution and in an artificial viral transport medium widely used for the collection of nasopharyngeal swabs, and that no cross-reactivity is observed in the presence of different, non-target viral proteins. We expect that this SWCNT-SPE-based format of electrochemical aptasensor will prove useful for the detection of other protein targets for which nucleic acid aptamer ligands are made available

Chemotherapy-Induced Tumor Cell Death at the Crossroads Between Immunogenicity and Immunotolerance: Focus on Acute Myeloid Leukemia

In solid tumors and hematological malignancies, including acute myeloid leukemia, some chemotherapeutic agents, such as anthracyclines, have proven to activate an immune response via dendritic cell-based cross-priming of anti-tumor T lymphocytes. This process, known as immunogenic cell death, is characterized by a variety of tumor cell modifications, i.e., cell surface translocation of calreticulin, extracellular release of adenosine triphosphate and pro-inflammatory factors, such as high mobility group box 1 proteins. However, in addition to with immunogenic cell death, chemotherapy is known to induce inflammatory modifications within the tumor microenvironment, which may also elicit immunosuppressive pathways. In particular, DCs may be driven to acquire tolerogenic features, such as the overexpression of indoleamine 2,3-dioxygensase 1, which may ultimately hamper anti-tumor T-cells via the induction of T regulatory cells. The aim of this review is to summarize the current knowledge about the mechanisms and effects by which chemotherapy results in both activation and suppression of anti-tumor immune response. Indeed, a better understanding of the whole process underlying chemotherapy-induced alterations of the immunological tumor microenvironment has important clinical implications to fully exploit the immunogenic potential of anti-leukemia agents and tune their application

O8D.8 Severity of carpal tunnel syndrome and manual work: findings from a case-control study

ObjectiveCarpal tunnel syndrome (CTS) is a socially relevant condition. This case-control study aims to investigate the association between CTS severity and manual work considering personal anthropometric risk factors as well.MethodsWe consecutively enrolled one CTS case for two controls (subjects without clinical and electrophysiological CTS signs) regardless of age and gender who were admitted to the same three outpatient electromyography labs.CTS cases were grouped in three classes of progressive clinical and electrophysiological severity according to two validated five-stage scales. Anthropometric measures and occupational history were collected. Job titles were coded according to the International Standard Classification of Occupations (ISCO 88) by two occupational physicians who were blind to case/control status. Job titles were grouped in two main occupational categories: manual workers and non-manual workers.To assess the association between CTS severity and manual work, ordered logistic regression models (adjusted for age, sex, wrist-palm ratio and waist-stature ratio) were performed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.ResultsThis case-control study enrolled 370 cases and 747 controls. After the exclusion of retired subjects, subjects older than 65 years and subjects with no information about occupational history, we included 183 cases and 445 controls in the main analysis.For manual workers with respect to non-manual workers, the OR for the electrophysiological severity scale was 2.4 (95%CI 1.5–3.7). Regarding the clinical severity scale, the OR for manual workers compared to non-manual workers were 2.3 (95%CI 1.5–3.7).ConclusionThis study confirms that manual work is an important risk factor for CTS. The association between manual work and CTS severity tends to increase from mild to severe stage of both electrophysiological and clinical scale

A Process Calculus for Molecular Interaction Maps

We present the MIM calculus, a modeling formalism with a strong biological basis, which provides biologically-meaningful operators for representing the interaction capabilities of molecular species. The operators of the calculus are inspired by the reaction symbols used in Molecular Interaction Maps (MIMs), a diagrammatic notation used by biologists. Models of the calculus can be easily derived from MIM diagrams, for which an unambiguous and executable interpretation is thus obtained. We give a formal definition of the syntax and semantics of the MIM calculus, and we study properties of the formalism. A case study is also presented to show the use of the calculus for modeling biomolecular networks.Comment: 15 pages; 8 figures; To be published on EPTCS, proceedings of MeCBIC 200

Outcome Prediction for SARS-CoV-2 Patients Using Machine Learning Modeling of Clinical, Radiological, and Radiomic Features Derived from Chest CT Images

Featured Application The present study demonstrates that semi-automatic segmentation enables the identification of regions of interest affected by SARS-CoV-2 infection for the extraction of prognostic features from chest CT scans without suffering from the inter-operator variability typical of segmentation, hence offering a valuable and informative second opinion. Machine Learning methods allow identification of the prognostic features potentially reusable for the early detection and management of other similar diseases. (1) Background: Chest Computed Tomography (CT) has been proposed as a non-invasive method for confirming the diagnosis of SARS-CoV-2 patients using radiomic features (RFs) and baseline clinical data. The performance of Machine Learning (ML) methods using RFs derived from semi-automatically segmented lungs in chest CT images was investigated regarding the ability to predict the mortality of SARS-CoV-2 patients. (2) Methods: A total of 179 RFs extracted from 436 chest CT images of SARS-CoV-2 patients, and 8 clinical and 6 radiological variables, were used to train and evaluate three ML methods (Least Absolute Shrinkage and Selection Operator [LASSO] regularized regression, Random Forest Classifier [RFC], and the Fully connected Neural Network [FcNN]) for their ability to predict mortality using the Area Under the Curve (AUC) of Receiver Operator characteristic (ROC) Curves. These three groups of variables were used separately and together as input for constructing and comparing the final performance of ML models. (3) Results: All the ML models using only RFs achieved an informative level regarding predictive ability, outperforming radiological assessment, without however reaching the performance obtained with ML based on clinical variables. The LASSO regularized regression and the FcNN performed equally, both being superior to the RFC. (4) Conclusions: Radiomic features based on semi-automatically segmented CT images and ML approaches can aid in identifying patients with a high risk of mortality, allowing a fast, objective, and generalizable method for improving prognostic assessment by providing a second expert opinion that outperforms human evaluation

Capitolo 2. La radiazione solare e il bilancio energetico di un edificio Capitolo 4. La valutazione delle prestazioni energetiche degli schermi solari in relazione all'edificio Appendice A. Determinazione delle componenti dell'irradiazione solare (CD) Appendice D. Quadro legislativo e normativo (CD)

Negli ultimi decenni i paesi industrializzati hanno maturato la consapevolezza che il modello di sviluppo attuale non è più sostenibile e che occorre controllare gli effetti dell’azione antropica sul pianeta. Dal Protocollo di Kyoto nel 1997 a oggi, si sono susseguite iniziative per ridurre le emissioni inquinanti, per mezzo di politiche rivolte alla promozione dell’efficienza energetica, allo sviluppo di fonti di energia rinnovabili, allo sviluppo di agricoltura sostenibile, nella ricerca di un maggiore equilibrio con l’ambiente. Tra tutte le azioni avviate, l’efficienza energetica delle costruzioni è sicuramente tra quelle più realizzabili: le tecnologie disponibili consentono ai progettisti di raggiungere risultati di risparmio energetico con investimenti contenuti, a condizione che la progettazione consideri tali aspetti fin dalle prime fasi, per le nuove costruzioni, o provveda all’adeguamento di quelle esistenti. Un gruppo di docenti e professionisti ha raccolto e riportato le proprie esperienze per dare strumenti di analisi e valutazione nella progettazione di nuovi elementi costruttivi. In un panorama di prodotti sempre più specializzati, le scelte richiedono motivazioni. Soluzioni comprovate che sembravano superate, dallo stimolo modernista e non considerate da quello postmoderno, ritornano attuali con la responsabilità rispetto ai nuovi obiettivi della contemporaneità. Si presenta un insieme di contributi che invitano a riprendere la progettazione degli schermi per il ruolo che possono avere nell’involucro dell’edificio (chiusura) rispetto alle nuove necessità ambientali. Una pratica poco seguita a giudicare dalla propensione per la preferenza delle grandi superfici a tutto vetro, per la chiusura, indipendentemente dal contesto climatico delle costruzioni. Dall’analisi, del primo capitolo, di alcune esperienze storiche sugli schermi e delle loro trasformazioni per raggiungere un punto di vista dell’insieme e inquadrare l’ambito di studio si passa, con il secondo e il terzo, a contributi specifici che forniscono strumenti conoscitivi e applicativi per controllare i principali fenomeni fisici che devono essere considerati nella progettazione. Con il quarto capitolo sono dati strumenti per la valutazione delle prestazioni degli schermi e quindi criteri per la scelta di prodotti. Segue un’ampia rassegna di schede, strutturate secondo un’impostazione linguistica prestazionale, che riporta il panorama delle soluzioni più diffuse. Le schede evidenziano requisiti ed esperienze progettuali implicite alle diverse articolazioni e possono essere per il progettista una memoria di argomenti da non dimenticare. Il panorama delle soluzioni è completato con un contributo specifico relativo alle schermature vegetali di cui si evidenzia il possibile contributo prestazionale oltre l’implicita visibilità paesaggistica. A conclusione due utili appendici di carattere applicativo ed esemplificativo con i programmi più diffusi e utilizzati. L’insieme dei contributi nelle intenzioni degli autori intende supportare la progettazione sia delle costruzioni edilizie sia dei prodotti per le costruzioni: conseguente l’intenzione di evidenziare le possibilità di motivate innovazioni che il settore può offrire. Un invito a riprendere in considerazione la progettazione in senso ampio, olistico, per la novità delle condizioni nelle quali ci si ritrova a operare: per affrontare progetti di nuovi elementi e non solo l’utilizzo di quelli esistenti. Il lavoro è stato impostato con la raccolta e successiva analisi di molti casi per interpretare le esperienze del passato e non trascurare esperienze rispetto ai nuovi obiettivi. Il controllo della radiazione solare attraverso l’utilizzo delle schermature rientra tra le azioni di risparmio energetico che consente di migliorare le condizioni degli spazi interni senza impiego di energia. A interpretazione della proposta di questo libro emergono due motivazioni nuove: 1. la consapevolezza della necessità del contenimento dei consumi, supportata da leggi, richiede una progettazione più responsabile e controllata. Non ci sono soluzioni disponibili e comprovate, si apre un periodo di studio e di sperimentazione; 2. si viene da lunghi periodi di costruzioni con spreco del territorio. Le costruzioni non utilizzate non sono poche, dovrebbe avviarsi un’inversione di tendenza: le attività edilizie dovrebbero essere indirizzate all’adeguamento dell’esistente, che rappresenta un patrimonio anche culturale da valorizzare, piuttosto che su nuove costruzioni. La proposta di un libro sugli schermi porta, in modo implicito, una proposta di contenimento dei costi per la climatizzazione estiva e il controllo delle dispersioni per quella invernale. Gli schermi dovrebbero avere il ruolo, oltre a quello più consueto del controllo della luce, anche della riduzione del carico solare che incide direttamente sull’involucro dell’edificio e, di conseguenza, un miglioramento delle condizioni microclimatiche degli ambienti interni senza impiego di energia. Il raggiungimento delle condizioni di comfort negli ambienti interni con un’ottimizzazione delle prestazioni dell’involucro dell’edificio può ridurre in modo significativo il contributo impiantistico, ed in alcuni casi addirittura escluderne la climatizzazione, contenendo le emissioni di inquinanti e i costi di gestione. La progettazione dell’adeguamento dell’esistente può rappresentare l’opportunità di nuove prospettive professionali, impegnative: sia per la dimensione del grande patrimonio edilizio del paese, sia per le difficoltà oggettive degli interventi. L’approccio non può essere solo di adeguamento normativo: l’esistente è espressione di tante situazioni ambientali e culturali e l’adeguamento deve avvenire all’interno di un programma di valorizzazione complessiva

Bio-PEPA for Epidemiological Models

AbstractMany models have been defined in order to describe the evolution of a disease in a population. The modelling of diseases is helpful to understand the mechanisms for their spread and to predict their future evolution. Most of the models in the literature are defined in terms of systems of differential equations and only a few of them propose stochastic simulation for the analysis.The main aim of this work is to apply the process algebra Bio-PEPA for the modelling and analysis of epidemiological models. As Bio-PEPA has been originally defined for biochemical networks, we define a variant of it suitable for representing epidemiological models. Some features of Bio-PEPA are useful in the context of epidemiology as well: location can abstract spatial structure and event can describe the introduction of prophylaxis in a population infected by a disease at a given day. Concerning the analysis, we can take advantage of the various kinds of analysis supported by Bio-PEPA, such as, for instance, stochastic simulation, model checking and ODE-based analyses. In particular, the modeller can select the most appropriate approach for the study of the model and analysis techniques can be used together for a better understanding of the behaviour of the system.In this paper we apply Bio-PEPA to the study of epidemiological models of avian influenza, based on different assumptions about the spatial structure and the possible kind of treatment. These models demonstrate that Bio-PEPA has several features that facilitate epidemiological modelling

The effect of autistic traits on disembedding and mental rotation in neurotypical women and men

Funder: Autism Research TrustFunder: Templeton World Charitable FundFunder: NIHR Cambridge Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100018956Funder: National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health ResearchFunder: Care East of England at Cambridgeshire and Peterborough NHS Foundation TrustAbstractRecent data has revealed dissociations between social and non-social skills in both autistic and neurotypical populations. In the present study, we investigated whether specific visuospatial abilities, such as figure disembedding and mental rotation, are differently related to social and non-social autistic traits, in neurotypical women and men. University students (N = 426) completed the Autism Spectrum Quotient (AQ), figure disembedding and mental rotation of two-dimensional figures tasks. AQ social skills (AQ-social) and attention-to-details (AQ-attention) subscales were used as measures of social and non-social autistic traits, respectively. Mental rotation was affected by a significant interaction between sex, social and non-social traits. When non-social traits were above the mean (+ 1 SD), no sex differences in mental rotation were found. Instead, below this value, sex differences depended on the social traits, with men on average outperforming women at middle-to-high social traits, and with a comparable performance, and with women on average outperforming men, at lower social traits. A small positive correlation between figure disembedding and social traits was observed in the overall sample. These results are interpreted in terms of the hyper-systemizing theory of autism and contribute to the evidence of individual differences in the cognitive style of autistic people and neurotypical people with autistic traits.</jats:p