1,721,111 research outputs found
Inflammation and Notch signaling: a crosstalk with opposite effects on tumorigenesis
Full text linkThe Notch cascade is a fundamental and highly conserved pathway able to control cell-fate. The Notch pathway arises from the interaction of one of the Notch receptors (Notch1-4) with different types of ligands; in particular, the Notch pathway can be activated canonically (through the ligands Jagged1, Jagged2, DLL1, DLL3 or DLL4) or non-canonically (through various molecules shared by other pathways). In the context of tumor biology, the deregulation of Notch signaling is found to be crucial, but it is still not clear if the activation of this pathway exerts a tumor-promoting or a tumor suppressing function in different cancer settings. Untill now, it is well known that the inflammatory compartment is critically involved in tumor progression; however, inflammation, which occurs as a physiological response to damage, can also drive protective processes toward carcinogenesis. Therefore, the role of inflammation in cancer is still controversial and needs to be further clarified. Interestingly, recent literature reports that some of the signaling molecules modulated by the cells of the immune system also belong to or interact with the canonical and non-canonical Notch pathways, delineating a possible link between Notch activation and inflammatory environment. In this review we analyze the hypothesis that specific inflammatory conditions can control the activation of the Notch pathway in terms of biological effect, partially explaining the dichotomy of both phenomena. For this purpose, we detail the molecular links reported in the literature connecting inflammation and Notch signaling in different types of tumor, with a particular focus on colorectal carcinogenesis, which represents a perfect example of context-dependent interaction between malignant transformation and immune response
Neoplasia del colon-retto
No full textLe neoplasie colorettali comprendono le forme
benigne, rappresentate nella maggior parte
dei casi dagli adenomi, e quelle maligne, in particolare
dal cancro colorettale (CRC). Il cancro
colorettale rappresenta una delle maggiori cause
di cancro al mondo e, malgrado la riduzione
dei tassi di incidenza nei Paesi industrializzati
dovuta all’implemento degli screening, il rapido
cambiamento degli stili di vita in Paesi in via di
sviluppo sta determinando un aumento del CRC
in popolazioni che storicamente erano meno suscettibili
a questa patologia. Il cancro è di solito
preceduto da lesioni premaligne la cui asportazione
di fatto riduce il rischio di progressione
maligna. I fattori di rischio per lo sviluppo del
cancro colorettale sono l’età, l’obesità, la familiarità
per cancro colorettale e le sindromi ereditarie
con alta suscettibilità al cancro
Lesindromi ereditarie colorettali: Identificazione, screening, sorveglianza
No full textIl cancro colorettale è rappresentato per circa l’80% da
forme sporadiche che non presentano aggregazioni familiari.
Tuttavia, si ritiente che circa il 5% dei casi colorettali
abbia una genesi ereditaria.
Le forme ereditarie sono dovute a mutazioni costituzionali
che determinano quindi un rischio di manifestazioni
associate, e, proprio perché costituzionali, rappresentano
un rischio per i familiari: la loro identificazione ne
rende possibile una gestione clinica mirata. I tumori ereditari
hanno delle caratteristiche peculiari: sono presenti
casi multipli nella famiglia con più generazioni colpite; ci
sono associazioni di tipi specifici di cancro non solo nella
stessa famiglia ma anche nello stesso individuo; nello
stesso individuo ci può essere lo sviluppo di più tumori
dello stesso tipo non dovuti a diffusione metastatica; l’età
in cui la malattia neoplastica si sviluppa è più precoce
rispetto alle forme sporadiche; i tumori sono associati
a manifestazioni non neoplastiche tipiche di specifiche
condizioni. Per questo, l’identificazione di casi ereditari
è fondamentale per una gestione specifica dovuta
al rischio genetico. Nelle forme ereditarie, le mutazioni
possono quindi essere ereditate in modo dominante o
recessivo e, in particolare per le forme dominanti, la ricostruzione
dell’albero genealogico identifica patterns di
distribuzione della malattia che sono alquanto indicativi di
un’alta incidenza di tumori
Chemoprevention of Colorectal Cancer in High-Risk Patients: from Molecular Targets to Clinical Trials
No full textAbstract An increased understanding of the molecular pathways
involved in colorectal carcinogenesis has helped researchers
to develop possible chemopreventive strategies.
This has been of particular relevance for high-risk subjects,
for whom chemopreventive strategies may be helpful in
slowing cancer development. In order to obtain more definitive
data on chemopreventive agents, there has been a great
effort to develop preclinical models that resemble the clinical
scenarios encountered in high-risk patients. Importantly, many
compounds, in particular non-steroidal anti-inflammatory
drugs, have shown significant effects in models of highrisk
clinical settings. However, results from clinical trials
have been somewhat disappointing and no definitive
chemopreventative agent is currently given for any of the
high-risk conditions. In this review, we examine the available
data on the effects of chemopreventive drugs on molecular
targets relevant for high-risk conditions predisposing to colorectal
cancer, including data from preclinical studies that have
led to clinical trials
Chemoprevention of hereditary colon cancers: Time for new strategies
No full textColorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial
Retention Rate, Persistence and Safety of Adalimumab in Inflammatory Bowel Disease: A Real-Life, 9-Year, Single-Center Experience in Italy
No full textBackground: "Real-life" data of retention rate and persistence of adalimumab in inflammatory bowel disease are still limited.
AIMS:
To analyze retention rate, persistence, and safety of adalimumab in a 9-year real-life cohort of inflammatory bowel disease patients.
METHODS:
In this observational, retrospective single-center study, all adult patients treated with adalimumab as the first- and second-line biological treatment for steroid-dependent or refractory inflammatory bowel disease between March 2008 and March 2017 were included. Primary outcomes were persistence, retention rate, and adverse events; the secondary outcome was the identification of predictors of withdrawal.
RESULTS:
Ninety-six out of 181 patients (53%) withdrew their first course of adalimumab. The retention rate was 47% and 46.9% in Crohn's disease and ulcerative colitis patients, respectively; median persistence was 26 and 24 months in CD and UC patients, respectively. The cumulative probability of treatment persistence was 80.2%, 54.5%, and 29.6% and 69.6%, 40.4%, and 21.5% in CD and UC patients, respectively. The incidence rate of any adverse event was 12.5/100 patients-year; severe adverse events were 1.7/100 patients-year. The Cox regression revealed that CD patients with baseline disease duration > 72 months have a higher likelihood for withdrawal due to failure and/or adverse events (HR 1.62, 95% CI 1-2.62, p = 0.04); no predictors of discontinuation were found in UC.
CONCLUSIONS:
Adalimumab showed a great persistence in the first 12 months of therapy and excellent safety profile. Early treatment of CD patients could increase efficacy and reduce the adverse event rate
Clinical characteristics and patterns and predictors of response to therapy in collagenous and lymphocytic colitis.
Full text linkBACKGROUND:
Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory disorders of the colon. There is a paucity of data on differences in etiology, natural history, and treatment response between CC and LC.
METHODS:
Between 2002 and 2013, we identified new diagnoses of CC and LC using the Research Patient Data Registry in a tertiary referral center. We used chi square or Fischer's exact test and Wilcoxon rank-sum tests to compare the differences in clinical characteristics, treatment types, and response rates between LC and CC.
RESULTS:
Through 2013, we confirmed 131 patients with a new diagnosis of microscopic colitis (MC) (55 LC, 76 CC). Compared to cases of LC, patients with a diagnosis of CC were more likely to be women (86% vs. 69%, p = 0.03), have elevated erythrocyte sedimentation rate (mean 28 vs. 13 mm/h, p = 0.04), and less likely to be diabetic (5% vs. 18%, p = 0.02). Budesonide was the most effective treatment for both CC and LC (94% and 80%, respectively). However, there were no statistically significant differences in response to various treatments according to the type of MC (all p > 0.10). Older age at the time of diagnosis was associated with better response to bismuth subsalicylate (odds ratio: 1.76; 95% confidence interval: 1.21-2.56 for every 5-year increase) for both CC and LC.
CONCLUSION:
Despite differences in the clinical characteristics, response rates to available treatments appeared to be similar in both LC and CC. Older patients may have a better response to bismuth subsalicylate therapy
Polifenoli ed efficacia antinfiammatoria: lo strano caso del melograno e le malattie croniche intestinali
No full textPremesse. Il Progetto NIKE “New Insight and Knowledge on anti-inflammatory Effectiveness of dietary phenolics” è un progetto finanziato Ministero dell’Istruzione, dell’Università e della Ricerca nell’ambito del Programma SIR (Scientific Independence of young Researchers).
Obiettivi. Focus generale del progetto è studiare l’efficacia protettiva anti-infiammatoria di un alimento naturalmente ricco in ellagitannini (ET) - una sottoclasse di polifenoli - verso l’infiammazione, al fine garantire una remissione clinica più prolungata nelle malattie infiammatorie croniche intestinali (inflammatory bowel disease, IBD), quali morbo di Crohn e rettocolite ulcerosa. Inoltre, NIKE si propone di chiarire il meccanismo di azione che sottende tali effetti anti-infiammatori a livello cellulare e dell’intero organismo.
Metodi. Uno studio randomizzato controllato con placebo sarà condotto all’inizio del progetto presso l’Ospedale Sant’Orsola-Malpighi di Bologna al fine di valutare gli effetti della somministrazione di un succo di melagrana, naturalmente ricco in ET, su di un gruppo di soggetti con IBD in remissione ad alto rischio di recidiva. Il livello di calprotectina fecale sarà utilizzato come indice di attività dei processi flogistici intestinali. I metaboliti degli ET saranno identificati e misurati in plasma, urine e feci come marker dell’assunzione dietetica. Successivamente, i metaboliti identificati nel sangue saranno utilizzati per la supplementazione in due tipi di colture cellulari (cellule intestinali e immunitarie), a concentrazioni paragonabili a quelle misurate in vivo, per indagarne il/i meccanismo/i di azione dell’ipotizzato effetto anti-infiammatorio. I dati ottenuti in vitro saranno infine verificati ex-vivo in campioni di tessuti (biopsie intestinali e plasma) ottenuti durante lo studio di intervento.
Risultati attesi. Fino ad oggi, un solo studio ha esaminato gli effetti anti-infiammatori degli ET relativi alle IBD nell’animale da esperimento [1]. Quindi NIKE sarà il primo progetto a indagare gli effetti protettivi putativi di questi composti verso l’infiammazione e conseguente ricaduta di IBD nell’uomo. Inoltre, l’analisi integrata di tutti i risultati ottenuti nell’ambito del progetto consentirà ad aumentare le conoscenze su biodisponibilità, bioattività e meccanismo di azione degli ET.
Questo studio è finanziato dal Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) nell’ambito del Programma SIR 2014 (Progetto RBSI14LHMB, responsabile F.D.).
[1] Rosillo et al, Pharmacol Res 2012; 66:235-42
Pomegranate: from the Promised Land to calm the fire in Inflammatory Bowel Disease
No full textInflammatory bowel disease (IBD) has a multifactorial aetiology and it is thought to be related to a combination of individual genetic susceptibility and environmental triggers that stimulate an inflammatory response. Although evidence indicates that dietary intake plays an important role, few studies have focused on the effect of (poly)phenol-rich food consumption on early markers of mucosal inflammation. At present only one study has investigated the anti-inflammatory effects of ellagitannins (ETs), a (poly)phenolic subclass mainly found in some fruits and nuts, related to IBD in rats [1]. Therefore, we hypothesised that treatment with a fruit juice containing ETs can significantly modulate biomarkers of mucosal inflammation compared with a control group receiving placebo.
The double-blind, randomised controlled trial will include patients with IBD, ulcerative colitis and Crohn's disease, in stable clinical remission (≥3 months). Participants will be randomly allocated to one of two groups: active treatment (125 mL pomegranate juice, naturally rich in ETs) or placebo taken twice daily for 12 weeks.
The primary outcome is to measure changes to the faecal neutrophil-derived protein calprotectin, surrogate marker of mucosal improvement, between the two groups from baseline to 12 weeks later. The secondary outcomes include systemic and mucosal changes of biochemical and molecular inflammatory response markers. The compliance of trial participants will be tested by uHPLC system coupled to mass spectrometer to quantify ET-metabolites in plasma and urine. In addition to the primary and secondary objectives, this trial will include plasma level of trimethylamine-N-oxide (TMAO) that may have potential as a biomarker to assess disease activity in IBD [2].
References. 1. Rosillo et al. 2012 Pharmacol Res. 2012; 66:235-42. 2. Wilson et al. 2015 Dig Dis Sci. 60:3620-30.
Acknowledgments. This study was funded by the Italian Ministry of Education, University and Research MIUR - SIR Programme no. RBSI14LHMB funded to F.D. All beverages will be provided by Conserve Italia (Bologna, Italy)
New Insight and Knowledge on anti-inflammatory Effectiveness of dietary phenolics: the NIKE Project
No full textThe NIKE project is targeted to evaluate the impact of dietary phenolics’ intake on the maintenance of remission in patients with inflammatory bowel disease (IBD). The project is particularly focused on a (poly)phenolic subclass, namely ellagitannins (ETs), mainly found in some fruits and nuts, like berries, pomegranate, and walnuts.
Differently from common approach, the dietary intervention will be conducted at the beginning of the project. As first step, the in vivo metabolites and their concentration in the bloodstream - after consumption of the ET-rich food - will be assessed. A commercially available pomegranate juice will be used because its great richness in ETs. Volunteers suffering of asymptomatic IBD with high risk of clinical flare will be recruited at the St. Orsola-Malpighi Hospital (Bologna, Italy). The level of faecal calprotectin will be used as surrogate marker of the intestinal inflammation [1]. As second step, ET metabolites found in blood will be used for supplementation in two cell model systems (intestinal and immune cells), at concentration comparable to the in vivo ones, to unravel the mechanism/s of anti-inflammatory action. Signalling pathways potentially affected by ET metabolites in inflammatory conditions will be studied. In the third step, data obtained in cell cultures will be verified ex-vivo in tissue samples (intestinal biopsies and plasma) obtained during the intervention study.
To our knowledge, NIKE will be the first project investigating the putative protective effects of these compounds toward inflammation and consequent IBD relapse in humans. At present only one study has investigated the anti-inflammatory effects of ETs related to IBD in rats [2]. The integral analysis of all results obtained in the project will elucidate the role of ET-rich foods in the secondary prevention of IBD, deepening the existing knowledge on their mechanism/s of action at the molecular, metabolic, and genomic levels.
Acknowledgments. This study was funded by the Italian Ministry of Education, University and Research MIUR - SIR Programme no. RBSI14LHMB funded to F.D.
References. 1) Konikoff & Denson, Inflamm Bowel Dis 2006; 12:524-34. 2) Rosillo et al, Pharmacol Res 2012; 66:235-42
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