471 research outputs found
The role of transforming growth factor (TGF)-β in modulating the immune response and fibrogenesis in the gut
No full textTransforming growth factor (TGF)-b, a pleiotropic cytokine released by both immune and non-immune cells in the gut, exerts an important tolerogenic action by promoting regulatory T cell differentiation. TGF-balso enhances enterocyte migration and regulates extracellular matrix turnover, thereby playing a crucial role in tissue remodeling in the gut. In this review we describe the mechanisms by which abnormal TGF-b signaling impairs intestinal immune tolerance and tissue repair, thus predisposing to the onset of immune-mediated bowel disorders, such as inflammatory bowel disease and celiac disease. Additionally, we will discuss potential therapeutic strategies aiming at restoring physiologic TGF-b signaling in chronic intestinal diseases.Fil: Biancheri, Paolo. University of Pavia; Italia. Barts and The London School of Medicine and Dentistry; Reino UnidoFil: Giuffrida, Paolo. University of Pavia; ItaliaFil: Docena, Guillermo H.. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Centro de Investigaciones en Criotecnología de Alimentos (i); ArgentinaFil: Macdonald, Thomas T.. Barts and The London School of Medicine and Dentistry; Reino UnidoFil: Corazza, Gino Roberto. University of Pavia; ItaliaFil: Di Sabatino, Antonio. University of Pavia; Itali
Identifying pathogenic, prognostic and theragnostic factors in cancer-associated gastrointestinal inflammation
No full textIntroduzione ed obiettivi
Gli adenocarcinoma del piccolo intestino (SBA) sono frequentement associati ad una
severa prognosi e hanno limitate opzioni terapeutiche. Il blocco della via proteina di
morte cellulare programmata-1/ligando della proteina di morte cellulare programmata
1 (PD-L1) è un trattamento efficace in molti tumori solidi con alta instabilità
microsatellitare (MSI-H). In aggiunta, una minoranza di SBA associate a malattia di Crohn
(CrD-SBA) mostra un comportamento relativamente favorevole, pertanto evidenziando
la necessità di migliorare la previsione istopatologica della prognosi di CrD-SBA.
L’obiettivo di questo studio è stato investigare l’espressione di PD-L1 e PD-1 negli SBA
non ereditari non ampollari, associate a malattia celiaca (CoeD), malattia di Crohn (CrD)
o sporadici, arruolati attraverso il Consorzio Italiano del Cancro del Piccolo Intestino.
L’obiettivo secondario è stato valuatare i marcatori del fronte invasivo tumore in erba
(Tb) ed i cluster scarsamente differenziati (PDC) nei CrD-SBA investigate anche per
l’obiettivo primario.
Metodi
Abbiamo valutato PD-L1 e PD-1 mediante immunoistochimica in una coorte di 121 SBA
resecati chirurgicamente, 34 CoeD-SBAs, 49 CrD-SBAs, e 38 SBA sporadici. L’espressione
di PD-L1 e PD-1 era correlata con alcune caratteristiche clinic-patologiche, comprensive
di eziologia, status dell’instabilità microsatellitare e densità dei linfociti infiltranti il
tumore (TIL). Abbiamo poi analizzato sistematicamente Tb e PDC nel fronte invasivo di
47 CrD-SBA.
Risultati
La prevalenza della positività per PD-L1 secondo lo score positive combinato (CPS) era
25.6% nell’intera coorte di SBA, con una percentuale significativamente (p=0.001)
aumentata (35%) sia in CoeD-SBAs sia in CrD-SBAs rispetto ai SBA sporadici (5%). SBA
con CPS≥1 erano significativamente (p=0.013) più frequenti nei casi con MSI-H (41%)
che nei casi non-MSI-H (18%); comunque, 15 SBA CPS≥1 con stabilità microsatellitare
sono stati anche identificati. SBA con CPS≥1 mostravano una maggiore densità di TIL e
cellule immuni PD-1+, più frequentemente un istotipo midollare, così come una migliore
sopravvivenza rispetto ai casi con CPS<1. Le analisi sia di Tb sia di PDC erano altamente
efficaci nella valutazione prognostica di CrD-SBA. In aggiunta, Tb e PDC conservavano il
loro potere prognostico quando combinati con altri due parametri, istologia ghiandolare
e stadio I/II, entrambi noti nel predire un comportamento relativamente favorevole per
SBA. In particolare, l’associazione di Tb e PDC in uno score combinato del fronte invasivo
permetteva di trovare una minoranza di tumori (12/47, 25%), caratterizzati dal fronte
invasivo combinato di basso grado associato ad una istologia ghiandolare e ad un basso
stadio (I o II), e mostranti nessuna morte relativa al cancro in un follow-up mediano di
37,5 mesi.
Conclusioni
Questo studio dimostra una aumentata proporzione di casi PD-L1+ sia in CoeD-SBA sia in
CrD-SBA rispetto a SBA sporadici. In aggiunta, l’identificazione di una minoranza di SBA
PD-L1+ con stabilità microsatellitare supporta la necessità di accertare aggiuntivi
biomarcatori di risposta agli inibitori dei checkpoint immunitari insieme a MSI-H. La
migliore separazione di CrD-SBA di grado basso da quelli di grado alto fornita dall’analisi
del fronte invasive dovrebbe rappresentare un aiuto aggiuntivo nello scegliere
l’appropriate terapia per questi tumori rari e frequentemente infausti.Background and aims
Small bowel adenocarcinomas (SBAs) are frequently associated with severe prognosis
and have restricted therapeutic options. Programmed cell death protein-1 (PD
1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment
in many microsatellite instability-high (MSI-H) solid tumours. Additionally, a minority of
Crohn’s disease-associated SBAs (CrD-SBAs) show a relatively favourable behaviour, thus
highlighting the need to improve the histopathologic prediction of CrD-SBA prognosis.
We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary
SBAs, associated with coeliac disease (CoeD), Crohn’s disease (CrD) or sporadic, recruited
through the Small Bowel Cancer Italian Consortium. Secondary aim was to assess the
invasive front markers tumor budding (Tb) and poorly differentiated clusters (PDCs) on
CrD-SBAs investigated also for the primary aim.
Methods
We evaluated PD-L1 and PD-1 by immunohistochemistry in a cohort of 121 surgically
resected SBAs, i.e. 34 CoeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1
expression was correlated with several clinico-pathological features, including the
aetiology, microsatellite instability status and tumour-infiltrating lymphocyte (TIL)
density. We then systematically analysed the Tb and PDCs in the invasive front of 47 CrD
SBAs.
Results
The prevalence of PD-L1 positivity according to combined positive score (CPS) was
25.6% in the entire cohort of SBAs, with significantly (p=0.001) increased percentage
(35%) in both CoeD-SBAs and CrD-SBAs compared to sporadic SBAs (5%). CPS≥1 SBAs
were significantly (p=0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones
(18%); however, 15 CPS≥1 microsatellite stable SBAs were also found. CPS≥1 SBAs
displayed higher TIL and PD-1+ immune cell density, more often medullary histotype, as
well as a better outcome compared to CPS<1 cases. Both Tb and PDC analyses proved
highly effective in prognostic assessment of CrD-SBA. In addition, they retained
prognostic power when combined with two other parameters, i.e. glandular histology and
stage I/II, both known to predict a relatively favourable SBA behaviour. In particular,
association of Tb and PDCs in a combined invasive front score allowed to find a minor
subset of cancers (12/47, 25%), characterised by combined invasive front-low grade
associated with a glandular histology and a low stage (I or II) and displaying no cancer
related death over a median follow-up of 73.5 months.
Conclusions
This study demonstrates an increased proportion of PD-L1+ cases in both CoeD-SBAs and
CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of
PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers
of response to immune checkpoint inhibitors along with MSI-H. The improved separation
of lower from higher grade CrD-SBAs provided by invasive front analysis should
represent an additional help in choosing appropriate therapy for these rare and
frequently ominous cancers
Issues and Prospects of Valuation Science
No full textThis introductory contribution indicates some of the main prospects of the SIEV 2019 Conference held at the Syracuse campus of the University of Catania (Italy), addressed to the relationship between the fundamentals of the science of evaluations that inspire the main issues with respect to which scholars and experts delimit and characterise their civil commitment in research, education, and field activity. The paper is divided into four sections. The first provides some reference points on the importance of value judgement in terms of the (linguistic and ethical) categories it coordinates, and thus the constitutive capacity it assumes in the reform of the home-city-landscape system, starting from a reconsideration of the foundations of the science of evaluation. The second proposes a comparison, and possible convergence, between two different ways—one “conservative”, the other “progressive”—of conceiving the interdisciplinary nature of valuation science in the prospect of its enrichment and progressive adaptation to the challenges of contemporaneity. The third section proposes the philosophical arguments underlying one of the main issues of the science of value and valuations, the search for a unique value substance, in this case beauty, capable of subsuming the entire spectrum of the authentic values that specify it and constitute the primary reference of valuations. The fourth section concludes this contribution by indicating—starting from some assumptions of project epistemology—not only the role of evaluation, but also the potentialities and responsibilities that in the synthesis of evaluators’ and designers’ expertise characterise the commitment to the formation of orderly and flourishing communities
Proteases and small intestinal barrier function in health and disease
No full textPURPOSE OF REVIEW: To summarize the recent knowledge regarding intestinal proteases and the gut barrier. RECENT FINDINGS: It is now well established that intestinal proteases, such as matrix metalloproteinase (MMP)-1, MMP-3, MMP-10 and MMP-12, are key players in the development of ulcers in inflammatory bowel disease, have direct effects on epithelial barrier function and are involved in epithelial restitution. However, more recent work has suggested that the membrane-anchored epithelial cell serine protease matriptase is critical in maintaining the gut barrier, and roles have also been described for elastase, MMP-13, gelatinases, mast cell proteases and proteases derived from parasites and gut bacteria. Interestingly, epithelial proteases often co-localize with epithelial adherens junctions, and nonepithelial-derived proteases have junctional proteins as targets. SUMMARY: The role of proteases in controlling normal barrier function in the gut is now becoming very clear, to go alongside their role in intestinal inflammation
Appraisal: Some Considerations from the Past and a Challenge for the Future
No full textThis short note has the objective of stimulating a debate on the nature of the Appraisal in the light of the recent evolution of the evaluation procedures and of the application areas. After a brief reference to the founding principles codified in the last century, the capacity of statistical-quantitative procedures to replace the role of "expertise" in evaluations is discussed. Finally, the note highlights how the discipline defined by the classic texts of the middle of the last century is still current and effective and that, more or less consciously, even the most recent scientific literature is placed in the wake of the classical economic-estimative tradition
A heuristic approach to author name disambiguation in bibliometrics databases for large-scale research assessments
No full textNational exercises for the evaluation of research activity by universities are becoming regular practice in ever more countries. These exercises have mainly been conducted through the application of peer-review methods. Bibliometrics has not been able to offer a valid large-scale alternative because of almost overwhelming difficulties in identifying the true author of each publication.We will address this problem by presenting a heuristic approach to author name disambiguation in bibliometric datasets for large-scale research assessments. The application proposed concerns the Italian university system, comprising 80 universities and a research staff of over 60,000 scientists. The key advantage of the proposed approach is the ease of implementation. The algorithms are of practical application and have considerably better scalability and expandability properties than state-of-the-art unsupervised approaches. Moreover, the performance in terms of precision and recall, which can be further improved, seems thoroughly adequate for the typical needs of large-scale bibliometric research assessments
Nota sopra talune modificazioni fatte al chiodo dello scarpa per la pronta guarigione della fistula del sacco lagrimale : letta nella tornata ordinaria del primo dicembre 1859
No full textper Paolo Berretta GiuffridaSeparatdruck aus: Atti della Accademia Gioenia di Scienze Naturali in Catania, vol. XV
Blue Energy: Salinity Gradient for Energy Conversion
No full textSimilar to a difference in elevation, potential energy is also associated with a difference in salt concentration so that electric power can eventually be produced by exploiting the salinity gradient between freshwater of rivers and seawater. Unfortunately, exploiting the salinity gradient for power production is not so easy as waterfalls. The potential energy implied in this salinity difference is of the same order of a hundred meter high water drop. The present technology advancement is still far from any commercial application. This chapter presents the different technologies, such as, The Pressure Retarded Osmosis (PRO) technology and The Reverse Electrodialysis (RED) Technology, for power generation from salinity gradient, which have been so far proposed in the technical literature pointing out the theoretical operating principles, the possible plant configurations and identifying the development gap to bridge so as to achieve technical and economical maturity
Biomarkers of intestinal fibrosis - one step towards clinical trials for stricturing inflammatory bowel disease
No full textIntestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-19, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors (i.e. basic fibroblast growth factor, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease
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