Francesco Pallone

University of Rome Tor Vergata, Roma, Latium, Italy

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Publications (574)3854.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Spondyloarthritis (SpA) and inflammatory bowel disease (IBD) are chronic autoinflammatory diseases that partially share the genetic predisposition and the unchecked inflammatory response linking the gut to the joints. The coexistence of both conditions in patients and the increased cross-risk ratios between SpA and IBD strongly suggest a shared pathophysiology. The prevalence of Enteropathic-related Spondyloarthritis (ESpA) in IBD patients shows a wide variation and may be underestimated. It is well accepted that the management of joint pain requires rheumatological expertise in conjunction with gastroenterologist assessment. In this view, we aimed at assessing, in a prospective study performed in a combined Gastro-Intestinal and Rheumatologic "GI-Rhe" clinic: (1) the prevalence of ESpA and other rheumatologic diseases in IBD patients with joint pain; (2) the features of the ESpA population; (3) the diagnostic delay and the potential impact of the combined assessment. From November 2012 to December 2014, IBD patients with joint pain referring to a dedicated rheumatologist by the IBD-dedicated gastroenterologist were enrolled. Clinical and biochemical evaluations, joint involvement and disease activity assessment, diagnostic delay, and treatment were recorded. IBD patients (n=269) with joint pain were jointly assessed in the "GI-Rhe" Unit. A diagnosis of ESpA was made in 50.5% of IBD patients with joint pain. ESpA patients showed a peripheral involvement in 53% of cases, axial in 20.6% and peripheral and axial in 26.4% of cases. ESpA patients had a higher prevalence of other autoimmune extra-intestinal manifestations and received more anti-TNF treatment compared with IBD patients. A mean diagnostic delay of 5.2 years was revealed in ESpA patients. Patients with joint disease onset in the 2002-2012 decade had reduced diagnostic delay compared with those with onset in the 1980-1990 and 1991-2001. Diagnostic delay was further reduced for patients with joint onset in the last two years in conjunction with the establishment of the GI-Rhe clinic. Multidisciplinary approach improved management of rheumatic disorders in IBD patients allowing a more comprehensive care.
    Autoimmunity reviews 11/2015; DOI:10.1016/j.autrev.2015.11.002 · 7.93 Impact Factor
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    ABSTRACT: Background and aim: Production of chemokines by intestinal epithelial cells is a key step in the amplification of the destructive immune-inflammatory response in patients with inflammatory bowel diseases (IBD). In this study, we examined whether intestinal epithelial cells express macrophage colony-stimulating factor receptor 1 (M-CSFR-1), the functional receptor of interleukin-34 (IL-34), a cytokine that is over-produced in IBD and supposed to sustain inflammatory pathways. Methods: M-CSFR-1 expression was evaluated in intestinal samples of IBD patients, controls and in colon epithelial cell lines by real-time PCR, immunohistochemistry and Western blotting. DLD-1 cells were stimulated with IL-34 in the presence or absence of MAP kinase inhibitors, and chemokine induction was assessed by real-time PCR and enzyme-linked immunosorbent assay (ELISA) and MAP kinase activation was monitored by Western blotting. The effect of a neutralizing IL-34 antibody on CCL20 synthesis was tested in ex vivo organ cultures of IBD mucosal explants. Results: Enhanced expression of M-CSFR-1 RNA transcripts was seen in inflamed mucosa of IBD patients as compared to controls. Immunohistochemical analysis confirmed up-regulation of M-CSFR-1 in IBD and showed that both epithelial and lamina propria mononuclear cells expressed this receptor. Stimulation of DLD-1 with IL-34 increased CCL20 production through an ERK1/2-dependent mechanism. Consistently, treatment of IBD explants with anti-IL-34 reduced CCL20 production. Conclusions: These data show that intestinal epithelial cells are a target of IL-34 and suggest that this cytokine contributes to mediate the cross talk between epithelial cells and immune cells in IBD.
    Journal of Crohn s and Colitis 10/2015; DOI:10.1093/ecco-jcc/jjv181 · 6.23 Impact Factor
  • Irene Marafini · Erika Angelucci · Francesco Pallone · Giovanni Monteleone ·
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    ABSTRACT: Background: In inflamed tissues of patients with inflammatory bowel disease (IBD), many immune and non-immune cells produce a vast array of cytokines, which contribute to expand and maintain the pathologic process. Key Message: Interleukin (IL)-12 and IL-23, 2 heterodimeric cytokines sharing the common p40 subunit, are over-produced in IBD and supposed to play a major role in promoting and/or sustaining the pro-inflammatory cytokine response in these disorders. IL-12 targets mostly T cells and innate lymphoid cells and through activation of Stat4 promotes T helper (Th)1 cell polarization, interferon-x03B3; and IL-21 production, while IL-23 activates Stat3 thus amplifying Th17 cell programs. These observations together with the demonstration that IL-12 and IL-23 drive pathogenic responses in animal models of colitis have paved the way for the development of IL-12p40 blockers. Two monoclonal antibodies (ustekinumab and briakinumab) targeting p40 have been tested in Crohn's disease (CD) patients. Blockade of IL-12p40 is beneficial in CD patients resistant to tumor necrosis factor (TNF) antagonists and promotes resolution of psoriatic lesions that develop in IBD patients following anti-TNF therapy. Conclusions: The available human data support the pathogenic role of IL-12/IL-23 in IBD and suggest that IL-12p40 blockers could help manage some subsets of IBD patients.
    Digestive Diseases 09/2015; 33 Suppl 1(1):113-119. DOI:10.1159/000437106 · 2.18 Impact Factor
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    ABSTRACT: To estimate the frequency and cause of nonresponsive celiac disease (CD). Treatment of CD is based on life-long adherence to a gluten-free diet (GFD). Some celiac patients experience persistence of symptoms despite a GFD. This condition is defined as nonresponsive CD. Celiac patients on a GFD for at least 12 months underwent diet compliance assessment, laboratory tests, breath tests, endoscopic, and histologic evaluations according to the symptoms/signs reported. Seventy of 321 (21.8%) patients had persistent or recurrent symptoms/signs. The cause of symptom persistence was evaluated in 56 of 70 patients. Thirteen of 56 (23%) patients were antiendomysial antibody positive. Among the patients with negative serology, 1 had fibromyalgia, and 3 had evidence that disproved the diagnosis of CD. The remaining 39 patients with negative serology underwent duodenal biopsy sampling, which evidenced histologic alterations in 24 patients. Among the 15 patients with normal histology 3 were lactose intolerant, 9 had irritable bowel syndrome, 2 had gastroesophageal reflux disease, and in 1 patient a cause for the persistent symptom was not identified. In patients with confirmed diagnosis of CD, exposure to dietary gluten was the main cause of persistence of symptoms/signs, and consistently after dietary modification, symptoms resolved in 63% of the patients at later time points during follow-up. Nonresponsive CD occurs in nearly one fifth of celiac patients on GFD and its occurrence suggests further investigations to optimize the management of celiac patients.
    Journal of clinical gastroenterology 08/2015; 46. DOI:10.1097/MCG.0000000000000392 · 3.50 Impact Factor
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    ABSTRACT: Colorectal cancer (CRC) is the third leading cause of death worldwide and represents a clinical challenge. Family members of patients affected by CRC have an increased risk of CRC development. In these individuals, screening is strongly recommended and should be started earlier than in the population with average risk, in order to detect neoplastic precursors, such as adenoma, advanced adenoma, and nonpolypoid adenomatous lesions of the colon. Fecal occult blood test (FOBT) is a non invasive, widespread screening method that can reduce CRC-related mortality. Sigmoidoscopy, alone or in addition to FOBT, represents another screening strategy that reduces CRC mortality. Colonoscopy is the best choice for screening high-risk populations, as it allows simultaneous detection and removal of preneoplastic lesions. The choice of test depends on local health policy and varies among countries.
    07/2015; 21(26):7944-7953. DOI:10.3748/wjg.v21.i26.7944
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    Giovanni Monteleone · Francesco Pallone ·

    New England Journal of Medicine 06/2015; 372(25):2461. DOI:10.1056/NEJMc1504845 · 55.87 Impact Factor
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    ABSTRACT: To evaluate a levofloxacin-doxycycline-based triple therapy with or without a susceptibility culture test in non-responders to Helicobacter pylori (H. pylori) eradication. A total of 142 (99 women, 43 men; mean 53.0 ± 12.7 years) non-responders to more than two H. pylori eradication therapies underwent susceptibility culture tests or were treated with a seven-day triple therapy consisting of esomeprazole, 20 mg b.i.d., levofloxacin, 500 mg b.i.d., and doxycycline, 100 mg b.i.d., randomly associated with (n = 71) or without (n = 71) Lactobacillus casei DG. H. pylori status was checked in all patients at enrollment and at least 8 wk after the end of therapy. Compliance and tolerability of regimens were also assessed. H. pylori eradication was achieved in < 50% of patients [per prototol (PP) = 49%; intention to treat (ITT) = 46%]. Eradication rate was higher in patients administered probiotics than in those without (PP = 55% vs 43%; ITT = 54% vs 40%). Estimated primary resistance to levofloxacin was 18% and multiple resistance was 31%. Therapy was well tolerated, and side effects were generally mild, with only one patient experiencing severe effects. Third-line levofloxacin-doxycycline triple therapy had a low H. pylori eradication efficacy, though the success and tolerability of this treatment may be enhanced with probiotics.
    06/2015; 21(21):6698-705. DOI:10.3748/wjg.v21.i21.6698
  • E. Calabrese · F. Zorzi · E. Lolli · F. Pallone ·
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    ABSTRACT: Over the past few years, the technical evolution of ultrasound equipment, the use of oral and intravenous contrast agents, and an increase in the expertise of operators have enhanced the role that ultrasonography plays in the assessment of the gastrointestinal tract. For patients with chronic inflammatory conditions, particularly Crohn's disease, it has been suggested that ultrasonography can be used not only for diagnostic purposes but also in disease management. These developments are reviewed in this article.
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    ABSTRACT: Background The association between Spondyloarthropathy (SpA) and Inflammatory Bowel Disease (IBD) is largely established. The coexistence of both conditions in patients (enteropathic SpA, SpAe) and the increased cross-risk ratios between SpA and IBD strongly suggest a shared pathophysiology. In SpAe patients, axial (ax) and peripheral (per) joint involvements are recognized. Both the innate and the adaptive immune responses are likely to contribute to the establishment of chronic inflammation. Peripheral blood CD45+ cells analyses have not been previously reported in patients with SpAe. Objectives The objective of this study was to evaluate the frequencies of Tbet+/RORγ+/Foxp3+ expressing cells in peripheral blood CD45+CD3+ and CD45+CD3- cells from SpAe patients. Intracellular expression of IL4/IFNγ/IL17 was analyzed in both CD45+CD3+ and CD45+CD3- cells. Moreover we aim at evaluating the association between cell assessment and disease activity. Methods 16 patients affected by SpAe (n=10 per, n=1 ax, n=5 both; n=9 Crhon's disease, n=6 ulcerative colitis, n=1 indeterminate colitis) were enrolled. All of them were naïve for treatment with biologic agents and none was on steroids. Patients' disease activity was recorded by DAS44-CRP, ASDAS-CRP and BASDAI whereas functional status was assessed by BASFI. Freshly isolated peripheral blood mononuclear cells were stained with fluorescent antibodies against cell-surface and intracellular markers to characterize cell subsets by flow cytometry. The frequencies of cells expressing transcriptional factors Tbet/RORγ/Foxp3 were evaluated in CD45+CD3- and CD45+CD3+ cells. The expression of IL4/IL17/IFNγ were recorded in CD45+CD3- and CD45+CD3+ cells after 4-hours in vitro stimulation with PMA and ionomicin. Ten sex- and age-matched healthy controls (HC) were also evaluated. Differences between mean values were determined by Student's t-test. The significance of correlations was determined by Pearson's correlation coefficient (r). Statistical analysis was considered significant when P values were less than 0.05 Results The frequencies of CD45+CD3+ expressing Tbet/RORγ/Foxp3 were similar in SpAe patients and in HC. The same was registered analyzing IL4/IL17/IFNγ expressing cells. The proportion of CD45+CD3- cells expressing RORγ resulted significantly higher in the SpAe group than in the HC (P<0.05, Figure 1A); the same was found in the proportion of CD45+CD3- cells expressing IL17 (P<0.05) (Figure 1B). The frequency of CD45+CD3-IL17+ cells resulted positively related to DAS44-CRP levels (r=0.7, P=0.04, Figure 1C) and BASFI (r=0.6, P<0.05, Figure 1D) while no correlations resulted between cell assessment and ASDAS-CRP or BASDAI. Conclusions The present study represents the first report regarding the assessment of the peripheral blood CD45+ cells in patients affected by SpAe. Our preliminary results may support the potential role of IL17 producing non-T cells dependent on RORγ in the pathogenesis of SpAe. References Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):493.3-494. DOI:10.1136/annrheumdis-2015-eular.5577 · 10.38 Impact Factor
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    ABSTRACT: Background Prevalence of Enteropathic-related Spondyloarthritis (SpAe) in inflammatory bowel disease (IBD) shows marked variations (18-45%) and may be underestimated by gastroenterologists. Objectives In a prospective study, in a combined GastroIntestinal and RHeumAtologic “GiRha” clinic of the University of Rome “Tor Vergata”, prevalence and characteristics of joint manifestations in inflammatory bowel disease (IBD) patients were evaluated. diagnostic delay and therapeutic modifications were also assessed. Methods The study prospectively enrolled patients affected by IBD who presented muscolo-skeletal pain between November 2012 and July 2014. Disease activity in SpA patients was assessed using the ASDAS-CRP, BASDAI, BASFI, DAS44-CRP and HAQ-S. Results SpAe was detected in 101 patients. In 65 cases this was a new diagnosis. Other rheumatologic diagnosis were: Osteoarthritis (30.3%), Fybromialgia (6.9%), Psoriatic Arthritis (4.3%), Rheumatoid Arthritis (3.2%) and Gout (1.6%). Prevalence of other extraintestinal manifestations (psoriasis, uveitis, primary sclerosing cholangitis and erythema nodosum) resulted higher in SpAe patients than that in IBD non-SpAe patients (p=0.04). 56.4% SpAe patients showed a high disease activity (ASDAS ≥2.1). 22.8% had axial involvement, peripheral involvement in 57.4% and a combination of peripheral and axial involvement in 19.8% of cases. Axial SpAe patients were preferentially male and showed increased ESR and CRP levels compared with peripheral SpAe patients. Peripheral SpAe patients showed higher DAS levels compared with that in both axial and axial+peripheral SpAe patients. The diagnostic delay (time between the onset of joint symptoms and first rheumatological encounter) was calculated for all SpAe patients. Patients with disease onset between 2000-2009 had a reduced diagnostic delay compared with those with joint onset in 1980-1989 and 1990-1999. The diagnostic delay was further reduced for those patients with joint onset after 2010 (Figure 1). A higher percentage of IBD patients were treated with disease-modifying anti-rheumatic drugs (p=0.04), anti-COX2 (p<0.0001) and anti-TNF drugs (p=0.001) after the rheumatological assessment. Clinical outcome demonstrate improuvement of disease activity after 6 months of combined aproach: ASDAS and DAS changed from 2.8±0.9 at baseline to 1.4±0.5 and 2.5±0.8 at baseline to 1.8±0.8 respectively. Conclusions Multidisciplinary care facilitates the diagnosis and the management of rheumatic disorders in IBD offering a comprehensive treatment approach. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):504.2-505. DOI:10.1136/annrheumdis-2015-eular.4947 · 10.38 Impact Factor
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    ABSTRACT: Crohn's disease and ulcerative colitis are inflammatory bowel diseases involving a genetically determined inappropriate mucosal immune response towards luminal antigens, including resident bacterial flora. Recent studies identified susceptibility genes involved in autophagy. We analyzed known autophagic loci (IRGM, ULK1 and AMBRA1) previously described as associated with inflammatory bowel diseases or with other autoimmune and/or inflammatory disorders in a sample of Italian inflammatory bowel diseases patients in order to confirm their possible involvement and relative contribution in the disease. We performed a case-control association study, a sub-phenotype correlation and a haplotype analysis. The analysis included 263 Crohn's disease, 206 ulcerative colitis patients and 245 matched healthy controls. Five polymorphisms were genotyped by allelic discrimination assays. IRGM was the most strongly associated with Crohn's disease susceptibility [rs13361189: P=0.011, OR=1.66 [95% CI: (1.12-2.45)]; rs4958847: P=0.05, OR=1.43 [95% CI: (1-2.03)]. The SNP rs13361189 was also found to increase the risk of Crohn's disease clinical sub-phenotype (fibrostricturing behaviour, ileal disease, perianal disease, intestinal resection). These findings suggest that IRGM variants may modulate clinical characteristics of Crohn's disease. Our study confirms IRGM rs13361189 and rs4958847 polymorphisms to be important for Crohn's disease susceptibility and phenotype modulation, in accordance with previous findings. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
    Digestive and Liver Disease 05/2015; 47(9). DOI:10.1016/j.dld.2015.05.012 · 2.96 Impact Factor
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    ABSTRACT: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a useful tool for the diagnosis of suspected abdominal or mediastinal neoplastic lesions. To evaluate the impact of EUS-FNA and multidisciplinary approach on the diagnostic work-up and therapeutic management of patients with abdominal or mediastinal neoplastic lesions. One hundred and twenty patients (69 men, median age 65 years) with a suspected abdominal or mediastinal neoplastic mass at computed tomography or MRI underwent EUS-FNA. All EUS-FNA findings and clinical data were evaluated by a multidisciplinary team (oncologists, surgeons, and gastroenterologists). EUS-FNA findings were compared with the final diagnosis made by histological evaluation of the surgical specimen or clinical outcome at follow-up. A correct diagnosis was obtained by EUS-FNA in 96/120 patients (80%), indicating benignancy of the lesion in 21 (18%) cases and confirming malignancy in 75 (62%). On the basis of EUS-FNA findings, chemotherapy was tailored in 57/75 (76%) patients with malignancy whereas the surgical strategy was changed in 21/120 (18%) of patients. Overall, the diagnostic accuracy of EUS-FNA was 85%. A multidisciplinary team approach enabled a correct diagnosis in patients in whom EUS-FNA was nondiagnostic and to identify five cases with false-negative EUS-FNA findings. EUS-FNA has a relevant impact on the management of suspected abdominal or mediastinal neoplastic lesions. A multidisciplinary team approach enables to overcome the EUS-FNA methodological limitations. The combination of EUS-FNA and multidisciplinary team approach could help to diagnose and tailor therapeutic options in such patients.
    European journal of gastroenterology & hepatology 05/2015; 27(9). DOI:10.1097/MEG.0000000000000390 · 2.25 Impact Factor
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    ABSTRACT: Innate lymphoid cells (ILCs) are an emerging family of innate hematopoietic cells producing inflammatory cytokines and involved in the pathogenesis of several immune-mediated diseases. The aim of this study was to characterize the tissue distribution of ILCs in celiac disease (CD), a gluten-driven enteropathy, and analyze their role in gut tissue damage. ILC subpopulations were analyzed in lamina propria mononuclear cells (LPMCs) isolated from duodenal biopsies of CD patients and healthy controls (CTR) and jejunal specimens of patients undergoing gastro-intestinal bypass by flow cytometry. Cytokines and Toll-like receptors (TLR) were assessed in ILCs either freshly isolated or following incubation of control LPMC with peptidoglycan, poly I:C, or CpG, the agonists of TLR2, TLR3, or TLR9 respectively, by flow cytometry. The role of ILCs in gut tissue damage was evaluated in a mouse model of poly I:C-driven small intestine atrophy. Although the percentage of total ILCs did not differ between CD patients and CTR, ILCs producing TNF-α and IFN-γ were more abundant in CD mucosa compared to controls. ILCs expressed TLR2, TLR3 and TLR9 but neither TLR7 nor TLR4. Stimulation of LPMC with poly I:C but not PGN or CpG increased TNF-α and IFN-γ in ILCs. RAG1-deficient mice given poly I:C exhibited increased frequency of TNF-α but not IFN-γ/IL17A-producing ILCs in the gut and depletion of ILCs prevented the poly I:C-driven intestinal damage. Our data indicate that CD-related inflammation is marked by accumulation of ILCs producing TNF-α and IFN-γ in the mucosa. Moreover, ILCs express TLR3 and are functionally able to respond to poly I:C with increased synthesis of TNF-α thus contributing to small intestinal atrophy.
    PLoS ONE 05/2015; 10(5):e0126291. DOI:10.1371/journal.pone.0126291 · 3.23 Impact Factor
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    ABSTRACT: Despite the great success of anti-tumour necrosis factor-based therapies, the treatment of Crohn's disease (CD) and ulcerative colitis (UC) still remains a challenge for clinicians, as these drugs are not effective in all patients, their efficacy may wane with time, and their use can increase the risk of adverse events and be associated with the development of new immune-mediated diseases. Therefore, new therapeutic targets are currently being investigated both in pre-clinical studies and in clinical trials. Among the technologies used to build new therapeutic compounds, the antisense oligonucleotide (ASO) approach is slowly gaining space in the field of inflammatory bowel diseases (IBDs), and three ASOs have been investigated in clinical trials. Systemic administration of alicaforsen targeting intercellular adhesion molecule-1, a protein involved in the recruitment of leukocytes to inflamed intestine, was not effective in CD, even though the same compound was of benefit when given as an enema to UC patients. DIMS0150, targeting nuclear factor (NF) κB-p65, a transcription factor that promotes pro-inflammatory responses, was very promising in pre-clinical studies and is currently being tested in clinical trials. Oral mongersen, targeting Smad7, an intracellular protein that inhibits transforming growth factor (TGF)-β1 activity, was safe and well tolerated by CD patients, and the results of a phase II clinical trial showed the efficacy of the drug in inducing clinical remission in patients with active disease. In this leading article, we review the rationale and the clinical data available regarding these three agents, and we discuss the challenge of using ASOs in IBD.
    Drugs 04/2015; 75(7). DOI:10.1007/s40265-015-0391-0 · 4.34 Impact Factor
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    ABSTRACT: Copy number variations (CNVs) can contribute to genetic variation among individuals and/or have a significant influence in causing diseases. Many studies consider new CNVs' effects on protein family evolution giving rise to gene duplicates or losses. "Unsuccessful" duplicates that remain in the genome as pseudogenes often exhibit functional roles. So, changes in gene and pseudogene number may contribute to development or act as susceptibility alleles of diseases. We report a de novo heterozygous 271 Kb microdeletion at 8q21.2 region which includes the family of REXO1L genes and pseudogenes in a young man affected by global development delay, progeroid signs, and gastrointestinal anomalies. Molecular and cellular analysis showed that the REXO1L1 gene hemizygosity in a patient's fibroblasts induces genetic instability and increased apoptosis after treatment with different DNA damage-induced agents. The present results support the hypothesis that low copy gene number within REXO1L1 cluster could play a significant role in this complex clinical and cellular phenotype.
    BMC Medical Genetics 04/2015; 16(1):20. DOI:10.1186/s12881-015-0164-3 · 2.08 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-274. DOI:10.1016/S0016-5085(15)30902-1 · 16.72 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-162. DOI:10.1016/S0016-5085(15)30543-6 · 16.72 Impact Factor
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    ABSTRACT: Inflammatory bowel disease (IBD)-related tissue damage occurs in areas, which are massively infiltrated with monocytes/macrophages. These cells respond to inflammatory stimuli with enhanced production of cytokines/chemokines. In this study, we analyzed the expression and role of interleukin-34 (IL-34), a regulator of monocyte/macrophage differentiation, survival and function, in IBD. A significant increase in IL-34 mRNA and protein expression was seen in inflamed mucosa of patients with Crohn's disease (CD) and patients with ulcerative colitis (UC) as compared to the uninvolved areas of the same patients and normal controls. IL-34 was up-regulated in lamina propria mononuclear cells (LPMC) isolated from normal colon by TNF-a and toll-like receptor ligands and wasdown-regulated in intestinal biopsies and LPMC of IBD patients upon treatment with Infliximab. Treatment of normal LPMC with IL-34 increased TNF-αexpression in an ERK1/2-dependent fashion and neutralization of IL-34 in IBD mucosal explants reduced TNF-α and IL-6 synthesis. In conclusion, data indicate that IL-34 is up-regulated in IBD and suggest a role for this cytokine in sustaining the inflammatory responses in this disease.
    Clinical Science 03/2015; 129(3). DOI:10.1042/CS20150132 · 5.60 Impact Factor
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    ABSTRACT: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).
    New England Journal of Medicine 03/2015; 372(12):1104-13. DOI:10.1056/NEJMoa1407250 · 55.87 Impact Factor
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    ABSTRACT: Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.
    Oncotarget 03/2015; 6(12). DOI:10.18632/oncotarget.3532 · 6.36 Impact Factor

Publication Stats

11k Citations
3,854.57 Total Impact Points


  • 1999-2015
    • University of Rome Tor Vergata
      • Dipartimento di Medicina dei Sistemi
      Roma, Latium, Italy
  • 1981-2013
    • The American University of Rome
      Roma, Latium, Italy
  • 2009
    • Università Degli Studi Roma Tre
      Roma, Latium, Italy
  • 2007
    • Policlinico Tor Vergata
      • Medicina Interna
      Roma, Latium, Italy
  • 1991-2007
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      • Department of Health Sciences
      Catanzaro, Calabria, Italy
  • 2004
    • Yamaguchi University
      Yamaguti, Yamaguchi, Japan
  • 2001
    • LIUCBM Libera Università Campus Bio-Medico di Roma
      Roma, Latium, Italy
  • 1985-2000
    • Umberto I Policlinico di Roma
      Roma, Latium, Italy
  • 1984-2000
    • Sapienza University of Rome
      • • Department of Surgical Sciences
      • • Department of Experimental Medicine
      Roma, Latium, Italy
  • 1995-1997
    • Mediterranean University of Reggio Calabria
      Reggio di Calabria, Calabria, Italy
    • Università della Calabria
      Rende, Calabria, Italy
  • 1994
    • Università degli Studi dell'Aquila
      Aquila, Abruzzo, Italy
  • 1990
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 1988
    • Ospedale Nuovo Regina Margherita
      Roma, Latium, Italy