1,721,148 research outputs found
IFN-gamma MODULATES TUMOR-SPECIFIC IMMUNE RESPONSE INDUCED EITHER BY GENETICALLY MODIFIED TUMOR CELLS OR DENDRITIC CELLS LOADED WITH POST-APOPTOTIC TUMORS IN A MOUSE MODEL OF PROSTATE CANCER
No full textLa linea murina di cancro della prostata TRAMP-C2 rappresenta un modello animale adatto per lo studio del ruolo dell’espressione delle molecole del complesso maggiore di istocompatibilità (MHC-I) nella protezione in vivo contro lo sviluppo e la progressione del tumore. In questa linea cellulare, l’espressione dell’MHC-I diminuisce nel tempo durante la coltura in vitro, ma può essere ripristinata mediante trattamento con IFN-γ. Abbiamo transfettato le cellule TRAMP-C2 con il cDNA della molecola costimolatoria B7-1. I transfettanti ottenuti TRAMP-C2/B7 non sviluppavano tumore in vivo, ma non riuscivano ad indurre una risposta protettiva contro il tumore parentale TRAMP-C2, se non in seguito a trattamento con IFN-γ prima dell’iniezione. L’IFN-γ induce alcune componenti del complesso di processamento e presentazione dell’MHC-I (antigen processing and presentation machinery = APM). Inoltre, è un antagonista dell’attività immunosoppressiva del TGF-β, una citochina prodotta dalle cellule TRAMP-C2. Infatti, l’immunizzazione con TRAMP-C2/B7 conferiva protezione mediata da linfociti T citotossici (CTL) contro il tumore parentale TRAMP-C2 in funzione della modulazione IFN-γ-dipendente dell’espressione dei componenti dell’APM e dell’inibizione del segnale indotto dal TGF-β. Il trattamento di TRAMP-C2 con IFN-g ha incrementato il numero di animali in cui il tumore non si è sviluppato e il livello generale di sopravvivenza, se paragoniamo gli animali trattati con IFN-γ con gli animali immunizzati o richiamati con cellule non trattate con IFN-γ. Abbiamo poi tentato di veicolare l’IFN-γ direttamente nel sito di crescita tumorale di TRAMP-C2 utilizzando cellule mesenchimali stromali (MSC) secernenti IFN-γ. Abbiamo dimostrato che le MSC/IFN-γ potevano raggiungere la massa tumorale e, in combinazione con l’immunizzazione con TRAMP-C2/B7 trattato con IFN-γ, abbiamo ottenuto risultati comparabili con il trattamento delle cellule TRAMP-C2 con IFN-γ, con un aumento dell’immunoprotezione dipendente dall’IFN-g secreto dalle MSCs infiltranti il tumore.
Per rendere questi risultati più traslabili alla clinica, abbiamo studiato anche metodi di immunizzazione che utilizzassero non più cellule transfettate, bensì cellule parentali TRAMP-C2 necrotiche dopo trattamento con ipertermia, rese così “appetibili” alle cellule dendritiche (DC) per la fagocitosi. Abbiamo testato gli effetti del trattamento ipertermico a 56°C delle cellule tumorali, stimando la percentuale di cellule necrotiche ed apoptotiche dopo il trattamento, e abbiamo visto che il trattamento a questa temperatura induceva necrosi e il conseguente rilascio di molecole associate al pericolo (danger associated molecular pattern = DAMP), dotate di grande capacità di attivare le DC, in accordo con la letteratura corrente. Abbiamo poi studiato la capacità delle DC singeniche di fagocitare queste cellule necrotiche: il trattamento con ipertermia a 56°C induceva una elevata percentuale di fagocitosi delle cellule necrotiche da parte delle DC, suggerendo anche l’induzione della maturazione di queste ultime e la capacità di attivare una risposta CTL tumore-specifica. Per validare questa ipotesi, abbiamo portato avanti una serie di esperimenti in vivo nei quali abbiamo inoculato sottocute cellule TRAMP-C2 necrotiche contando sull’attivazione delle DC residenti nel sito di inoculo oppure DC precedentemente caricate in vitro con cellule tumorali necrotiche. I risultati di questi esperimenti hanno dimostrato che l’immunizzazione con cellule tumorali necrotiche lavate e risospese in PBS dopo il trattamento ipertermico non proteggeva contro un successivo inoculo di cellule TRAMP-C2 vive. Al contrario, sia l’immunizzazione con cellule tumorali necrotiche non lavate dopo trattamento ipertermico che quella con DC caricate in vitro con cellule necrotiche erano entrambe protettive, ma a livelli diversi: le cellule necrotiche non lavate proteggevano solo contro TRAMP-C2 trattate con IFN-g, mentre le DC caricate con cellule TRAMP-C2 necrotiche proteggevano parzialmente (al 50%) anche contro cellule TRAMP-C2 non trattate con IFN-g. L’attivazione delle DC residenti nel sito di inoculo è probabilmente più complicata e delicata di quanto lo sia in vitro. Inoltre, è probabile che quando si inietta la sospensione di cellule necrotiche contenenti le molecole DAMP rilasciate, non tutto il materiale venga captato dalle DC residenti. Sono sicuramente necessari più esperimenti per migliorare l’attivazione delle DC residenti da parte dell’inoculo di sospensioni di cellule necrotiche e DAMP.The mouse prostatic adenocarcinoma tumorigenic cell line TRAMP-C2 represents a suitable animal model to study the role of Major Histocompatibility Class-I (MHC-I) molecules expression in protection against tumor development and progression in vivo. In this cell line, MHC-I expression decreases after time of in vitro cell culture, but it can be restored by treatment with IFN-g. We have transfected TRAMP-C2 cells with the cDNA of the co-stimulatory molecule B7-1. TRAMP-C2/B7 transfectants showed impaired growth in vivo, but they did not elicit a protective response against TRAMP-C2 parental tumor, unless after treatment with IFN-g prior to injection. IFN-g is an inducer of some components of the MHC-I antigen processing and presentation machinery (APM). IFN-g is also an antagonist of the immunosuppressant activity of TGF-b, largely produced by TRAMP-C2. Thus, immunization with TRAMP-C2/B7 conferred a cytotoxic T cell (CTL)-dependent protection against TRAMP-C2-derived tumors in function of the IFN-g-mediated fine-tuned modulation of either APM expression or TGF-b signaling. IFN-g-treatment of TRAMP-C2 cells resulted in an increased number of tumor-free animals and improvement of the overall survival, if compared with mice immunized or challenged with cells not treated with IFN-γ. We then attempted to deliver IFN-g to TRAMP-C2-tumor growth site by means of genetically engineered mesenchymal stromal cells (MSCs) secreting IFN-g. We demonstrated that MSCs/IFN-γ reached the tumor mass and, in combination with the immunization with TRAMP-C2/B7 treated with IFN-γ, the results matched those obtained with IFN-g-treated TRAMP-C2 cells, with an increase of tumor protection by the IFN-g secreted by tumor-infiltrating MSCs.
In order to make these results better translatable to clinics, we explored methods of immunization using wild type (w.t.) TRAMP-C2 necrotic cells, instead of alive transfected cells, made “palatable” for phagocytosis by dendritic cells (DCs), by means of hyperthermia treatment. We tested the effects of hyperthermic treatment at 56°C, estimating the percentage of necrotic and apoptotic cells after the treatment, and we have observed that the treatment at this temperature could induce necrosis and consequent release of danger associated molecular pattern (DAMP), with high capacity to activate DCs, according to current literature. We then investigated the capacity of syngeneic DCs to phagocyte the necrotic cells: the hyperthermia treatment at 56°C induced a high percentage of phagocytosed cells by DCs, suggesting their maturation and capacity to activate a tumor-specific CTL immune response. To validate this hypothesis, we moved on with in vivo experiments: we delivered subcutaneously (s.c.) either necrotic tumor cells to mice relying on activation of resident DCs, or activated DCs loaded with necrotic tumor cells in vitro. The results obtained demonstrated that immunization with necrotic tumor cells washed after heat treatment did not protect against challenge with viable TRAMP-C2 tumor cells. On the contrary, immunizations with necrotic tumor cells unwashed after heat treatment and with activated DCs loaded with necrotic cells were both protective, but at different levels: unwashed necrotic cells protected only against TRAMP-C2 treated with IFN-g, whilst DCs loaded with necrotic cells showed partial protection (50%) also against untreated TRAMP-C2 . Activation of resident DCs at inoculation site is probably more complicated and delicate than in vitro. In addition, when injecting the suspension of necrotic tumor cells containing the released DAMPs, it is conceivable that not all the material is addressed to resident DCs. More experiments are needed to improve activation of resident DCs with injection of necrotic cells in suspension with DAMPs
Exploring the Impact of Biologic Therapies on Small Airway Function in Severe Asthma
No full textL'asma è una condizione infiammatoria cronica delle vie aeree caratterizzata da sintomi respiratori e dalla limitazione variabile e reversibile del flusso espiratorio, che può essere spesso controllata con trattamenti appropriati. Nonostante i progressi nelle strategie di gestione, tra cui le nuove terapie biologiche implementate, la piccola disfunzione delle vie aeree (SAD) rimane un aspetto critico dell'asma che è spesso sottodiagnosticato e mal compreso. Le tecniche emergenti, come l'oscilometria, offrono una via promettente per valutare la SAD.
Questo studio longitudinale ha esplorato il ruolo dell'oscillometria nella gestione dell'asma, in un contesto reale, concentrandosi sulla sua integrazione nella pratica clinica di routine. L'obiettivo primario era di valutare l'impatto del dupilumab sulle piccole vie respiratorie in pazienti con asma, con o senza polipi nasali comorbi. Gli obiettivi secondari includevano la valutazione degli effetti di dupilumab su esiti asmatici più ampi, come la funzione polmonare (spirometria), biomarcatori (eosinofilo del sangue, ossido nitrico esalato frazionato), controllo dei sintomi, frequenza delle esacerbazioni e uso orale di corticosteroidi. Inoltre, lo studio ha esaminato le correlazioni tra variabili oscillometriche e gli altri risultati clinici, funzionali e di laboratorio.
I risultati hanno mostrato cambiamenti nella Resistenza e Reattanza, dopo l'inizio del dupilumab, specialmente nella fase espiratoria, che potrebbero riflettere l'impatto di questo trattamento sulle piccole vie aeree. Questi risultati hanno il potenziale per migliorare la nostra comprensione di SAD e del suo ruolo nella patofisiologia dell'asma, sostenendo l'uso dell'oscilometria come strumento prezioso per la caratterizzazione precisa della malattia e gli interventi terapeutici mirati.Asthma is a chronic inflammatory condition of the airways characterized by respiratory symptoms and variable and reversible expiratory flow limitation, which can be often controlled with appropriate treatments. Despite advancements in management strategies, including the new deployed biologic therapies, small airway dysfunction (SAD) remains a critical aspect of asthma that is often underdiagnosed and poorly understood. Emerging techniques, such as oscillometry, offer a promising avenue for assessing SAD.
This longitudinal study explored the role of oscillometry in asthma management, in a real-world setting, focusing on its integration into routine clinical practice. The primary objective was to evaluate the impact of dupilumab on small airways in patients with asthma, with or without comorbid nasal polyps. Secondary objectives included assessing dupilumab's effects on broader asthma outcomes, such as lung function (spirometry), biomarkers (blood eosinophil, fractional exhaled nitric oxide), symptom control, exacerbation frequency, and oral corticosteroid use. Additionally, the study investigated correlations between oscillometric variables and the other clinical, functional, and laboratory outcomes.
The results showed changes in Resistance and Reactance, after the start of dupilumab, especially in the expiratory phase, that might reflect the impact of this treatment on the small airways. These findings have the potential to enhance our understanding of SAD and its role in asthma pathophysiology, supporting the use of oscillometry as a valuable tool for precise disease characterization and targeted therapeutic interventions
Neural response associated with the modulation of temporal summation of second pain by affective touch
No full textTemporal summation of second pain (TSSP) is a phenomenon that has clinical relevance but insights into its functioning are limited. Lately, ‘affective touch’ (AT) has been shown to have pain relieving properties but only one study has investigated its effects on TSSP and the neural underpinnings of such interaction are unknown. In the present EEG study, thirty-six healthy participants went through three conditions where a TSSP protocol was applied in concomitance with no touch (NoT), discriminative touch (DT) and AT. A fourth no-pain no-touch condition acted as a baseline. Measures of attention during the four conditions and of pleasantness during the touch conditions were also recorded. Pain ratings were significantly lower only during the AT condition. The neural response during NoT, compared to the baseline, brought about a temporal decrease in power at delta and theta frequencies and a fronto-central increase mainly in the alpha rhythm. Adding AT to TSSP yielded, compared to NoT, a decrease in delta, theta and beta bands in midline regions at both central (Cz) and parietal (Pz) and also of gamma at Pz. Notably, DT was not associated with significant changes compared to pain alone (NoT), but a specific marked difference was found between AT and DT with the former showing a significant decrease in beta frequencies localized at Pz. While TSSP seems to be characterized by a modulation mostly of the lower frequencies, adding AT to TSSP brings a clear depression of all the major frequency bands. Additionally, the parietal beta reduction may be a biomarker of AT. Future studies can examine if such brain response can help finding a suitable intervention for TSSP-related chronic pain conditions. Perspective: This study consolidates the idea that AT can lower pain in a TSSP paradigm and shows what are the brain (EEG) responses associated with both TSSP and TSSP modulation by AT. Given that TSSP is linked to central sensitization and that it can be used as an experimental model for chronic pain, our results pave the way for further studies into the neural mechanisms of AT-led analgesia, which can lead to future effective treatments
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Day-On, Day-Off emtricitabine, tenofovir disoproxil fumarate and efavirenz single tablet regimen (DODO) as maintenance therapy in HIV-infected patients
No full textReduced dose schedules may be feasible options to simplify antiretroviral therapy (ART) in selected HIV-1-infected individuals. Efficacy and safety of a Day-on, Day-off (DODO) schedule of tenofovir disoproxil fumarate, emtricitabine and efavirenz (FTC/TDF/EFV) single tablet regimen (STR) was assessed. Twenty-seven patients were prescribed the DODO schedule and were monitored for 48 weeks. Switching criteria were: no previous ART failure, no AIDS-defining illnesses, T CD4 cell nadir >200/mmc, and HIV-RNA below detection limit (40 copies/mL) for at least six months. Clinical and laboratory data, including plasma HIV-RNA levels, T CD4 and CD8 counts, liver and kidney function, lipid levels and ultrasensitive C-reactive protein (us-CRP) were assessed at baseline, week 4, 12, 24, and 48. Statistical analysis was performed by paired Student's T-test for comparison between baseline and each time point and Chi square test for CD4/CD8 ratio comparison. In all, 26 out of 27 patients maintained plasma HIV-RNA levels below the detection limit through the entire follow-up. One patient experienced low level plasma HIV-RNA rebound at week 36 (47 copies/ml) and immediately reverted to the conventional dose schedule of FTC/TDF/EFV; plasma HIV-RNA was undetectable after four weeks. No major changes on liver and kidney function tests, lipid levels and us-CRP were observed. Although no profound modifications of T CD4 count were observed during follow-up, the CD4/CD8 ratio increased significantly at week 48 compared to the baseline (p<0.05). In conclusion, 48-week DODO administration of the fixed dose FTC/TDF/EFV STR combination was safe and effective in maintaining HIV viral replication below the detection limit in a selected group of HIV-1-infected individuals
Hymenoptera Venom Allergy and Anaphylaxis
No full textHymenoptera stings can induce allergic and occasionally fatal reactions, and are responsible for significant morbidity and deterioration in health-related quality of life. The diagnostic work-up must consider the medical history of patients, in the context of venom allergy epidemiology and Hymenoptera taxonomy, and the clinical manifestations of the reactions, to channel the available in vivo and in vitro tests towards the most accurate diagnosis and the consequent appropriate management, also considering the risk profile of the patients on a precision-medicine approach. All these aspects are covered by this work that aims at providing an up-to-date review to increase the awareness of this topic among interested stakeholders, like healthcare professionals and political decision makers, who can contribute to the proper immediate and long-term management of venom allergy and anaphylaxis
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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