Publications by authors named "Giovanni Monteleone"

271 Publications

Reply to Dr Ng's letter.

Clin Gastroenterol Hepatol 2021 May 6. Epub 2021 May 6.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2021.05.007DOI Listing
May 2021

Precision Medicine in Inflammatory Bowel Diseases.

Front Pharmacol 2021 13;12:653924. Epub 2021 Apr 13.

Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

During the last decades, a better understanding of the mechanisms sustaining the pathogenic process in inflammatory bowel diseases (IBD) has contributed to expand the therapeutic armamentarium for patients with these disorders. Alongside with traditional therapies, monoclonal antibodies against tumor necrosis factor-α, the interleukin (IL)-12/IL-23 p40 subunit and the α4β7 integrin, and tofacitinib, a small molecule inhibiting intracellular pathways downstream to cytokine receptors, have entered into the clinic. However, these drugs are not effective in all patients and some responders can lose response over time. Such a therapeutic failure is, at least in part, dependent on the fact that, in IBD, the tissue damage is driven by simultaneous activation of multiple and distinct immune-inflammatory signals and the detrimental mucosal immune response changes over time even in the same patient. Therefore, personalized approaches aimed at identifying which patient should be treated with a specific drug at a precise time point are worth pursuing. A such approach has the advantage to improve efficacy of the drug and limit adverse reactions, thereby improving quality of the life of the patients and reducing costs. In this review, we summarize all the available evidence about the possible role of precision medicine in IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.653924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076955PMC
April 2021

Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer.

Int J Mol Sci 2021 Apr 10;22(8). Epub 2021 Apr 10.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune-inflammatory responses. In patients with Crohn's disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22083922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069188PMC
April 2021

Paradoxical hidradenitis suppurativa in Crohn's disease patients receiving infliximab: a case report and review of literature.

Eur J Gastroenterol Hepatol 2021 Apr 19. Epub 2021 Apr 19.

Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

The introduction of TNF blockers in the therapeutic armamentarium of inflammatory bowel diseases (IBD) has largely advanced the way by which clinicians manage these disorders. However, some patients develop de novo immune-mediated diseases during the treatment. We here present the case of paradoxical hidradenitis suppurativa, a chronic inflammatory skin disease characterized by the development of recurrent nodules and abscesses in intertriginous areas, in a 20-year-old, nonsmoker, normal-weight women, with no family history of hidradenitis suppurativa or IBD, diagnosed with nonstricturing nonpenetrating ileocolonic Crohn's disease in 2013, during treatment with infliximab. Infliximab discontinuation was followed by a significant improvement of skin lesions. We also discuss 22 additional cases of paradoxical hidradenitis suppurativa in IBD patients on TNF antagonists reported in the literature with the aim to identify potential risk factors for the development of such a complication. All the patients had Crohn's disease, and the majority of them were women (19/23; 82.6%). All cases occurred during therapy with anti-TNF agents [14/23 (61%) patients were treated with adalimumab and 9/23 (39%) patients were treated with infliximab]. The therapeutic approach directed at maintaining/holding the undergoing biologic therapy is still uncertain. Further studies are needed to determine the most appropriate treatment choice toward ongoing biologic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEG.0000000000002170DOI Listing
April 2021

A Pharmacological Batch of Mongersen that Downregulates Smad7 is Effective as Induction Therapy in Active Crohn's Disease: A Phase II, Open-Label Study.

BioDrugs 2021 May 19;35(3):325-336. Epub 2021 Apr 19.

Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy.

Background: A recent phase III trial did not confirm the previous clinical and endoscopic improvements seen in patients with Crohn's disease (CD) receiving Mongersen, an oral Smad7 antisense oligonucleotide. Factors accounting for such a discrepancy are unknown.

Objective: Our objective was to further assess whether Mongersen was effective as induction therapy in active CD and evaluate the in vitro inhibitory effect of various batches of Mongersen used in the previous and present trials on Smad7 expression.

Methods: In a phase II, open-label study, 18 patients with active CD (Crohn's Disease Activity Index [CDAI] score > 220 and evidence of endoscopic lesions) received Mongersen 160 mg/day for 12 weeks. The rates of clinical remission, defined as CDAI < 150, and clinical response, defined as a CDAI score decrease ≥ 100, were evaluated at week 4, 8, and 12. The fraction of circulating CCR9-expressing leukocytes was assessed by flow cytometry. Smad7 expression was evaluated in the human colorectal cancer cell line HCT-116 transfected with different batches of Mongersen using real-time polymerase chain reaction (PCR) and Western blotting, RESULTS: The proportions of patients experiencing clinical remission were 38.9%, 55.6%, and 50.0% at week 4, 8, and 12, respectively. At the same time points, the rates of clinical response were 72.2%, 77.8%, and 77.8%, respectively. Mongersen reduced the percentages of CCR9-expressing CD45+ cells. The batch of Mongersen used in this study, but not two batches used in the phase III study, inhibited Smad7 expression in HCT-116 cells.

Conclusions: The present findings support the clinical benefit of Mongersen in active CD and show that various batches manufactured during the GED0301 program differ in their ability to inhibit in vitro Smad7.

Trial Registration Number: NCT02685683; EudraCT 2015-001693-18.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40259-021-00482-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084825PMC
May 2021

Low Frequency of Acute Pancreatitis in Hospitalized COVID-19 Patients.

Pancreas 2021 03;50(3):393-398

From the Department of Systems Medicine, University of Rome "Tor Vergata".

Objective: The clinical significance of increased serum pancreatic enzymes (PEs) in coronavirus disease 2019 (COVID-19) patients has not yet been fully understood. We aimed to investigate the frequency and the impact on clinical outcome of PE elevation and acute pancreatitis in such patients.

Methods: Clinical data, laboratory tests, and cross-sectional images were analyzed from COVID-19 patients admitted to the Tor Vergata Hospital in Rome. Variables associated with PE abnormalities, intensive care unit (ICU) admission, or death were investigated through univariate and multivariate analyses and Cox proportional hazard model.

Results: Pancreatic enzymes were available in 254 of 282 COVID-19 patients. Among these, 66 patients (26%) showed mild elevation of PE, and 11 patients (4.3%) had severe elevation (>3 times of the upper limit of normal). Overall, 2 patients met the diagnostic criteria for acute pancreatitis. Hepatic and renal involvements were associated with PE elevation. Multivariate analysis showed that mild and severe PE elevations were significantly associated with ICU admission (odds ratios, 5.51 [95% confidence interval, 2.36-12.89; P < 0.0001] and 26.2 [95% confidence interval, 4.82-142.39; P < 0.0001]).

Conclusions: Increase in serum PE, but not acute pancreatitis, is frequent in hospitalized COVID-19 patients and associates with ICU admission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPA.0000000000001770DOI Listing
March 2021

Natural History of Ulcerative Colitis with Coexistent Colonic Diverticulosis.

J Clin Med 2021 Mar 12;10(6). Epub 2021 Mar 12.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.

Ulcerative colitis (UC) and colonic diverticulosis can co-exist in some patients. However, the natural history of UC associated with colonic diverticulosis is not well known. We here compared the disease characteristics and outcome of UC patients with and without concomitant colonic diverticulosis. Medical records of 347 UC patients were included in an observational, retrospective, nested-matched case-control study. Cases were 92 patients with UC and concomitant colonic diverticulosis, while controls were 255 UC patients without concomitant colonic diverticulosis. A propensity score matching (PSM) was used to homogenate cases (n = 92) and controls (n = 153) for age. UC patients with concomitant colonic diverticulosis were less likely to have an extensive disease (25/92, 27.1%) and to experience steroid dependence (8/92, 8.6%) compared to patients without concomitant colonic diverticulosis (70/153, 45.7% and 48/153, 31.3%, respectively; < 0.001). The use of immunosuppressants (9/92, 9.7% vs. 37/153, 24.1%; = 0.007) or biologics (3/92, 3.2% vs. 26/153, 16.9%, < 0.001) was significantly lower in UC patients with concomitant diverticulosis compared to the control group. On multivariate analysis, steroid dependence and extensive colitis were significantly less frequent in UC patients with concomitant colonic diverticulosis compared to UC patients without diverticula. UC patients with coexisting colonic diverticulosis are less likely to have an extensive disease and to be steroid-dependent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10061192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001479PMC
March 2021

Metalloproteinases in Inflammatory Bowel Diseases.

J Inflamm Res 2021 23;14:1029-1041. Epub 2021 Mar 23.

Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy.

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract, encompassing two main disorders: Crohn's disease (CD) and ulcerative colitis (UC). In both these pathologies, excessive and local immune response against luminal antigens promotes a pathological process leading to various degrees of gut damage. Matrix metalloproteinases (MMPs) are a family of neutral proteases with the ability to degrade all components of extracellular matrix. In physiological conditions, MMPs are produced at very low level and generally in the latent form and are involved in the normal tissue turnover. Their function is inhibited by tissue inhibitors of metalloproteinases (TIMPs). However, in inflamed tissue of IBD patients, MMPs are produced in excess and/or the activity of TIMPs is not sufficient to block MMPs, thereby making a major contribution to the IBD-related mucosal degradation. In this review, we summarize the available evidence on the expression and role of MMPs in IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/JIR.S288280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001665PMC
March 2021

Ultrasonography Tight Control and Monitoring in Crohn's Disease During Different Biological Therapies: A Multicenter Study.

Clin Gastroenterol Hepatol 2021 Mar 26. Epub 2021 Mar 26.

Gastroenterology, Department of Clinical Medicine and Surgery, Federico II, School of Medicine, Naples.

Background & Aims: Bowel ultrasonography (BUS) is a noninvasive tool for evaluating bowel activity in Crohn's disease (CD) patients. Aim of our multicenter study was to assess whether BUS helps to monitor intestinal activity improvement/resolution following different biological therapies.

Methods: Adult CD patients were prospectively enrolled at 16 sites in Italy. Changes in BUS parameters [i.e. bowel wall thickening (BWT), lesion length, echo pattern, blood flow changes and transmural healing (TH: normalization of all BUS parameters)] were analyzed at baseline and after 3, 6 and 12 months of different biological therapies.

Results: One hundred eighty-eight out of 201 CD patients were enrolled and analyzed (116 males [62%]; median age 36 years). Fifty-five percent of patients were treated with adalimumab, 16% with infliximab, 13% with vedolizumab and 16% with ustekinumab. TH rates at 12 months were 27.5% with an NNT of 3.6. TH at 12 months after adalimumab was 26.8%, 37% after infliximab, 27.2% after vedolizumab and 20% after ustekinumab. Mean BWT improvement from baseline was statistically significant at 3 and 12 months (P < .0001). Median Harvey-Bradshaw index, C-reactive protein and fecal calprotectin decreased after 12 months from baseline (P < .0001). Logistic regression analysis showed colonic lesion was associated with a higher risk of TH at 3 months and a greater BWT at baseline was associated with a lower risk of TH at 3 months [P = .03 (OR 0.70, 95% CI 0.50-0.97)] and 12 months [P = .01 (OR 0.58, 95% CI 0.38-0.89)]. At 3 months therapy optimization during the study was the only independent factor associated with a higher risk of no ultrasonographic response [P = .02 (OR 3.34, 95% CI 1.18-9.47)] and at 12 months disease duration [P = .02 (OR 3.03, 95% CI 1.15-7.94)].

Conclusions: Data indicate that BUS is useful to monitor biologics-induced bowel activity improvement/resolution in CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2021.03.030DOI Listing
March 2021

Clinical care pathway program versus open-access system: a study on appropriateness, quality, and efficiency in the delivery of colonoscopy in the colorectal cancer.

Intern Emerg Med 2021 Feb 8. Epub 2021 Feb 8.

Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Rome, Italy.

Open-access colonoscopy (OAC), whereby the colonoscopy is performed without a prior office visit with a gastroenterologist, is affected by inappropriateness which leads to overprescription and reduced availability of the procedure in case of alarming symptoms. The clinical care pathway (CCP) is a healthcare management tool promoted by national health systems to organize work-up of various morbidities. Recently, we started a CCP dedicated to colorectal cancer (CRC), including a colonoscopy session for CRC diagnosis and prevention. We aimed to evaluate the appropriateness, the quality, and the efficiency in the delivery of colonoscopy with the open-access system and a CCP program in the CRC. Quality indicators for colonoscopy in subjects in the CCP were compared to referrals by general practitioners (OAC) or by non-gastroenterologist physicians (non-gastroenterologist physician colonoscopy, NGPC). Attendance rate to colonoscopy was greater in the CCP group and NGPC group than in the OAC group (99%, 99%, and 86%, respectively). Waiting time in the CCP group was shorter than in the OAC group (3.88 ± 2.27 vs. 32 ± 22.31 weeks, respectively). Appropriateness of colonoscopy prescription was better in the CCP group than in the OAC group (92 vs. 50%, respectively). OAC is affected by the lack of timeliness and low appropriateness of prescription. A CCP reduces the number of inappropriate colonoscopies, especially for post-polypectomy surveillance, and improves the delivery of colonoscopy in patients requiring a fast-track examination. The high rate of inappropriate OAC suggests that this modality of healthcare should be widely reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11739-020-02565-zDOI Listing
February 2021

Respiratory Tract Infections in Inflammatory Bowel Disease Patients Taking Vedolizumab: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Front Pharmacol 2020 22;11:585732. Epub 2021 Jan 22.

Chair of Gastroenterology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

The ongoing COVID-19 pandemic has raised concerns about the risk of SARS-CoV-2 infection in patients with Crohn's disease (CD) and patients with ulcerative colitis (UC) taking immunosuppressants or biologics. We conducted a systematic review and meta-analysis to assess the risk of respiratory infections in patients with inflammatory bowel disease (IBD) treated with vedolizumab. We searched PubMed, EMBASE and Scopus to identify randomized controlled trials (RCT) comparing vedolizumab to placebo in patients with IBD. Outcomes were the rate of respiratory tract infections (RTI), upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI) among patients receiving vedolizumab as compared with placebo. Pooled rates were reported as Odds Ratios (OR) with 95% Confidence Interval (CI). Eight RCT involving 3,287 patients (1873 CD and 1415 UC) were analyzed; 2,493 patients received vedolizumab and 794 received placebo. The rates of RTI and URTI were statistically higher in vedolizumab-treated patients compared to placebo [OR = 1.63; 95% CI (1.07-2.49); OR = 1.64 95% CI (1.07-2.53) respectively]. UC patients, but not CD patients, receiving vedolizumab had a higher risk to develop RTI and URTI [OR = 1.98; 95% CI (1.41-2.77); OR = 2.02; 95% CI (1.42-2.87)] compared to placebo-treated patients. The number of LRTI was small in both treatment groups. Data confirm the good safety profile of vedolizumab even though RTI were more frequent in patients receiving vedolizumab and the risk of URTIs was significantly higher in patients with UC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.585732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862105PMC
January 2021

Factors influencing diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in pancreatic and biliary tumors.

Scand J Gastroenterol 2021 Apr 4;56(4):498-504. Epub 2021 Feb 4.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background And Aim: Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is influenced by several factors, primarily operator expertise. Formal training in EUS-FNA, as suggested by the European Society of Gastrointestinal Endoscopy and the American Society for Gastrointestinal Endoscopy guidelines, is not always available and is often expensive and time-consuming. In this study we evaluate factors influencing the diagnostic accuracy of pancreatic EUS-FNA.

Methods: In a retrospective study, 557 consecutive EUS-FNAs were evaluated. Several variables relating to the procedures were considered to calculate the EUS-FNA performance over eight years.

Results: A total of 308 out of 557 EUS-FNAs were selected. Overall sensitivity of EUS-FNA was 66% (95% CI: 60.8-71.8), specificity 100%, and diagnostic accuracy 69% (95% CI: 64.0-74.4). An increase in diagnostic accuracy was observed to >90% using a new fine-needle biopsy (FNB) needle and in the case of simultaneous sampling of primary and metastatic lesions. Diagnostic accuracy >80% was observed after 250 procedures, in the absence of rapid on-site cytopathological examination (ROSE). Multivariate logistic regression analysis confirmed that the FNB needle, operator skill, and double EUS-FNA sampling are associated with high diagnostic accuracy.

Conclusions: The learning curve for EUS-FNA may be longer and a considerable number of procedures are needed to achieve high diagnostic accuracy in the absence of ROSE. However, the use of FNB needles and the simultaneous sampling of primary and metastatic lesions can rapidly improve the diagnostic accuracy of the procedure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00365521.2021.1880628DOI Listing
April 2021

Super selective arterial embolization to treat radiation-induced hemorrhagic gastritis: a case report and review of the literature.

Scand J Gastroenterol 2021 Jan 2;56(1):118-121. Epub 2020 Dec 2.

Department of Systems Medicine, GI Unit, University "Tor Vergata" of Rome, Rome, Italy.

Radiation-induced hemorrhagic gastritis (RIHG) is a rare but potentially fatal event following radiotherapy for locally advanced gastric cancer; the treatment of this condition is not standardized. Only few cases of RIHG have been reported, treated with different therapeutic approaches. Here we report the case of a 79-year-old patient who underwent subtotal gastrectomy for gastric cancer, followed by adjuvant chemo-radiotherapy. Approximately 3 months after the end of the treatment, she developed recurrent diffuse bleeding originating from the entire mucosa of the gastric pouch and from a marginal ulcer. As the bleeding was refractory to several endoscopic treatments and surgery was not indicated, the patient underwent two sessions of transcatheter selective arterial embolization, with resolution of bleeding. Arterial embolization has already been reported for the treatment of hemorrhagic cystitis, developing after irradiation of the pelvis for prostate, bladder, rectum, and cervix cancer. However, to our knowledge, it has never been reported as a treatment for hemorrhagic gastritis. Based on this case, we suggest arterial embolization as an option in the management of RIHG, when standard endoscopic treatment fails.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00365521.2020.1853219DOI Listing
January 2021

Role of TGF-Beta and Smad7 in Gut Inflammation, Fibrosis and Cancer.

Biomolecules 2020 12 27;11(1). Epub 2020 Dec 27.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

The human gastrointestinal tract contains the largest population of immune cells in the body and this is a reflection of the fact that it is continuously exposed to a myriad of dietary and bacterial antigens. Although these cells produce a variety of inflammatory cytokines that could potentially promote tissue damage, in normal conditions the mucosal immune response is tightly controlled by counter-regulatory factors, which help induce and maintain gut homeostasis and tolerance. One such factor is transforming growth factor (TGF)-β1, a cytokine produced by multiple lineages of leukocytes, stromal cells and epithelial cells, and virtually targets all the gut mucosal cell types. Indeed, studies in animals and humans have shown that defects in TGF-β1 production and/or signaling can lead to the development of immune-inflammatory pathologies, fibrosis and cancer in the gut. Here, we review and discuss the available evidence about the role of TGF-β1 and Smad7, an inhibitor of TGF-β1 activity, in gut inflammation, fibrosis and cancer with particular regard to the contribution of these two molecules in the pathogenesis of inflammatory bowel diseases and colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom11010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823508PMC
December 2020

Macrophages produce and functionally respond to interleukin-34 in colon cancer.

Cell Death Discov 2020 Nov 5;6(1):117. Epub 2020 Nov 5.

Department of Systems Medicine, University of Rome "TOR VERGATA", Rome, Italy.

In colorectal cancer (CRC), macrophages represent a major component of the tumor mass and exert mostly functions promoting tumor cell survival, proliferation, and dissemination. Interleukin-34 (IL-34) is a cytokine overproduced by colon cancer (CRC) cells and supposed to make a valid contribution to the growth and diffusion of CRC cells. The biological functions of IL-34 are mediated by the macrophage colony-stimulating factor receptor (M-CSFR-1), which controls monocyte/macrophage differentiation, growth, and survival. We here investigated whether, in CRC, tumor-associated macrophages (TAMs) express M-CSFR-1 and functionally respond to IL-34. By flow-cytometry analysis of tumor-infiltrating cells (TICs) and lamina propria mononuclear cells (LPMCs) isolated from normal, adjacent mucosa of CRC patients, we showed that CD68/HLA-DRII-expressing TICs and LPMCs expressed M-CSFR-1. Both these cell types produced IL-34 even though the expression of the cytokine was more pronounced in TICs as compared to normal LPMCs. Moreover, in CRC samples, there was a positive correlation between IL-34-producing cells and CD68-positive cells. Stimulation of LPMCs and TICs with IL-34 resulted in enhanced expression of CD163 and CD206, two markers of type II-polarized macrophages, and this was evident at both RNA and protein level. In the same cell cultures, IL-34 stimulated expression and production of IL-6, a cytokine known to promote CRC cell growth and diffusion. Finally, knockdown of IL-34 in TICs with specific antisense oligonucleotides with: a specific antisesne oligonucleotide decreased IL-6 production and the number of TAMs producing this cytokine. This is the first to show a positive role of IL-34 in the control of TAMs in CRC, further supporting the notion that IL-34 sustains colon tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41420-020-00350-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644720PMC
November 2020

Interleukin-34 Enhances the Tumor Promoting Function of Colorectal Cancer-Associated Fibroblasts.

Cancers (Basel) 2020 Nov 27;12(12). Epub 2020 Nov 27.

Department of Systems Medicine, University of Rome "TOR VERGATA", 00133 Rome, Italy.

The stromal compartment of colorectal cancer (CRC) is marked by the presence of large numbers of fibroblasts, termed cancer-associated fibroblasts (CAFs), which promote CRC growth and progression through the synthesis of various molecules targeting the neoplastic cells. Interleukin (IL)-34, a cytokine over-produced by CRC cells, stimulates CRC cell growth. Since IL-34 also regulates the function of inflammatory fibroblasts, we hypothesized that it could regulate the tumor promoting function of colorectal CAFs. By immunostaining and real-time PCR, we initially showed that IL-34 was highly produced by CAFs and to lesser extent by normal fibroblasts isolated from non-tumoral colonic mucosa of CRC patients. CAFs and normal fibroblasts expressed the functional receptors of IL-34. IL-34 induced normal fibroblasts to express α-SMA, vimentin and fibroblast activation protein and enhanced fibroblast growth, thus generating a cellular phenotype resembling that of CAFs. Consistently, knockdown of IL-34 in CAFs with an antisense oligonucleotide (AS) decreased expression of such markers and inhibited cell proliferation. Co-culture of CRC cells with IL-34 AS-treated CAFs supernatants resulted in less cancer cell proliferation and migration. Among CAF-derived molecules known to promote CRC cell growth/migration, only netrin-1 and basic-fibroblast growth factor were induced by IL-34. Data suggest a role for IL-34 in the control of colorectal CAF function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761053PMC
November 2020

Viruses in Cancers of the Digestive System: Active Contributors or Idle Bystanders?

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)-composing the gastrointestinal (or digestive) system-contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21218133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663754PMC
October 2020

The Fragile X Mental Retardation Protein Regulates RIPK1 and Colorectal Cancer Resistance to Necroptosis.

Cell Mol Gastroenterol Hepatol 2021 19;11(2):639-658. Epub 2020 Oct 19.

Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy. Electronic address:

Background & Aims: The fragile X mental retardation protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated.

Methods: FMR1 mRNA transcript and FMRP protein expression were analyzed in human colon samples derived from patients with sporadic colorectal cancer (CRC) and healthy subjects. We used a well-established mouse model of sporadic CRC induced by azoxymethane to determine the possible role of FMRP in CRC. To address whether FMRP controls cancer cell survival, we analyzed cell death pathway in CRC human epithelial cell lines and in patient-derived colon cancer organoids in presence or absence of a specific FMR1 antisense oligonucleotide or siRNA.

Results: We document a significant increase of FMRP in human CRC relative to non-tumor tissues. Next, using an inducible mouse model of CRC, we observed a reduction of colonic tumor incidence and size in the Fmr1 knockout mice. The abrogation of FMRP induced spontaneous cell death in human CRC cell lines activating the necroptotic pathway. Indeed, specific immunoprecipitation experiments on human cell lines and CRC samples indicated that FMRP binds receptor-interacting protein kinase 1 (RIPK1) mRNA, suggesting that FMRP acts as a regulator of necroptosis pathway through the surveillance of RIPK1 mRNA metabolism. Treatment of human CRC cell lines and patient-derived colon cancer organoids with the FMR1 antisense resulted in up-regulation of RIPK1.

Conclusions: Altogether, these data support a role for FMRP  in controlling RIPK1 expression and necroptotic activation in CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806864PMC
October 2020

High Smad7 in the early post-operative recurrence of Crohn's disease.

J Transl Med 2020 10 19;18(1):395. Epub 2020 Oct 19.

Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Roma, Italy.

Background: In Crohn's disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD.

Methods: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry.

Results: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-γ-secreting cells.

Conclusions: Smad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-020-02558-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574182PMC
October 2020

Extra-intestinal manifestations of inflammatory bowel diseases.

Pharmacol Res 2020 11 28;161:105206. Epub 2020 Sep 28.

Rheumatology Unit, Internal Medicine Department, ASST Fatebenefratelli-Sacco, Milan University School of Medicine, Milan, Italy.

Inflammatory bowel disease (IBDs), including the two main subtypes of Crohn's disease and ulcerative colitis, not only affects the gastrointestinal system, but also has a wide range of extra-intestinal manifestations (EIMs) that are major sources of morbidity and disability, and therefore represent what can be considered a real syndrome. The pathogenetic mechanisms underlying these EIMs are unknown, but some may share a common pathogenesis with IBD and others may be due to IBD treatment. The aim of this review is to examine our current knowledge of IBD EIMs and their treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2020.105206DOI Listing
November 2020

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

Ann Surg Oncol 2021 Feb 5;28(2):1167-1177. Epub 2020 Aug 5.

Unit of Pathology, Cervello Hospital, Palermo, Italy.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients And Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801310PMC
February 2021

A healthy gut for a healthy brain: preclinical, clinical and regulatory aspects.

Curr Neuropharmacol 2020 Jul 30. Epub 2020 Jul 30.

Laboratory of Pharmacology of Synaptic Plasticity, Fondazione EBRI Rita Levi Montalcini, Rome, Italy; School of Pharmacy, University of Tor Vergata, Rome. Italy.

A large body of research has shown the presence of a complex pathway of communications between the gut and the brain. It is now recognized that, through this pathway, the microbiota can influence brain homeostasis and plasticity under normal and pathological conditions. This review aims at providing an overview of preclinical and clinical pieces of evidence supporting the possible role of gutbrain axis modulation in physiological aging, in a neurodevelopmental disorder, the autism spectrum disorders and in a substance abuse disorder, the alcohol addiction. Since the normalization of gut flora can prevent changes in the behavior, we postulate that the gut-brain axis might represent a possible target for pharmacological and dietary strategies aimed at improving not only intestinal but also mental health. The present review also reports some regulatory considerations regarding the use of probiotics, illustrating the most debated issues about the possibility of considering probiotics not only as a food supplement but also as a "full" medicinal product.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1570159X18666200730111528DOI Listing
July 2020

A Novel Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn's Disease.

Biomedicines 2020 Jul 22;8(8). Epub 2020 Jul 22.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn's disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the drug, but factors contributing to the failure of this study remain unknown. Here, we analysed the frequency in CD of rs144204026 C/T single nucleotide polymorphism (SNP), which maps on the corresponding region targeted by the Smad7 AS contained in the Mongersen formulation and examined whether such a variant allele affects the ability of Smad7 AS to knockdown Smad7.

Methods: rs144204026 SNP frequency was evaluated in two independent Italian cohorts of Crohn's disease patients and normal controls. Genotyping was performed by allelic discrimination assay. expression was evaluated in or heterozygous PBMCs treated with Smad7 AS.

Results: No TT genotype was seen in CD patients and controls. Heterozygous genotype was more frequent in CD patients of both cohort 1 (11/235, 4.68%) and cohort 2 (8/122, 6.56%) as compared to controls (6/363, 1.65%; = 0.029 and = 0.01 respectively). Overall, a statistically significant association was observed between the T variant allele and CD patients' susceptibility ( = 0.008; OR = 3.28, 95%CI: 1.3-8.3). Smad7 AS down-regulated RNA independently of the presence of the variant allele.

Conclusions: This is the first study to show an association between rs144204026 SNP and CD patients. Data indicate that such a variant does not negatively influence the in vitro inhibitory effect of Smad7 AS on Smad7.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8080234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460430PMC
July 2020

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System.

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Department of Systems Medicine, University of "Tor Vergata", 00133 Rome, Italy.

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics-a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine-have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21144957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404055PMC
July 2020

Effect of Vedolizumab on Anemia of Chronic Disease in Patients with Inflammatory Bowel Diseases.

J Clin Med 2020 Jul 6;9(7). Epub 2020 Jul 6.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Background: Anemia of Chronic Disease (ACD) can negatively influence the clinical course of Inflammatory Bowel Disease (IBD) patients. The aim of this study was to evaluate the effect of Vedolizumab on ACD in IBD.

Methods: Clinical data of 75 IBD patients (25 Crohn's disease (CD) and 50 Ulcerative Colitis (UC)) receiving Vedolizumab in a tertiary referral IBD center were retrospectively evaluated and the effect of the drug on ACD was ascertained at weeks 14 and 24.

Results: ACD was diagnosed in 35 (11 CD and 24 UC) out of 75 (47%) IBD patients. At both week 14 and week 24, improvements and resolutions of ACD were achieved by 13/35 (37%) and 11/35 (31%) patients, respectively. Baseline demographic/clinical characteristics did not differ between patients with ACD improvements/resolutions and those with persistent ACD. Clinical response occurred more frequently in patients who achieved ACD resolution (10/11, 91%) than in those without ACD improvement (5/11, 45%, = 0.022). When analysis was restricted to anemic patients, ACD resolution was documented in 10/22 patients (45%) achieving clinical response and 1/13 of non-responders (8%; = 0.02).

Conclusions: ACD occurs in half of the IBD patients and, in nearly two thirds of them, Vedolizumab treatment associates with ACD resolution/improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9072126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408734PMC
July 2020

Therapeutic Oligonucleotides for Patients with Inflammatory Bowel Diseases.

Biologics 2020 15;14:47-51. Epub 2020 Jun 15.

Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

Introduction: The better understanding of the molecular mechanisms, which drive the pathological process in the gut of patients with Crohn's disease (CD) and patients with ulcerative colitis (UC), the major forms of inflammatory bowel diseases (IBD) in humans, has facilitated the development of novel therapeutic compounds. Among these, antisense oligonucleotides (ASOs) have been used to inhibit the expression of molecules, which sustain the IBD-associated mucosal inflammation.

Areas Covered: In this short review, we summarize experimental and clinical data on the use of ASOs in IBD.

Expert Opinion: Preclinical work indicates that the modulation of specific inflammatory pathways through the use of ASOs is highly effective and associates with low risk of adverse events. Initial clinical studies have confirmed the benefit of some ASOs even though no compound has yet reached the market. Further experimentation is warranted to establish the optimal route of administration for each ASO, ascertain whether and how long ASOs maintain their activity following administration, and identify which patient can benefit from specific ASO treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/BTT.S257638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305016PMC
June 2020

Low frequency of COVID-19 in inflammatory bowel diseases.

Dig Liver Dis 2020 11 13;52(11):1234-1235. Epub 2020 Jun 13.

Department of Systems Medicine, University of Rome "TOR VERGATA", Rome, Italy; IBD group of Tor Vergata University Hospital, Rome, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293454PMC
November 2020

Onset of ulcerative colitis during SARS-CoV-2 infection.

Dig Liver Dis 2020 11 11;52(11):1228-1229. Epub 2020 Jun 11.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287422PMC
November 2020

Association Between Celiac Disease and Cancer.

Int J Mol Sci 2020 Jun 10;21(11). Epub 2020 Jun 10.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Celiac disease (CD) is a chronic enteropathy that develops in genetically susceptible individuals after the ingestion of gluten. There has been a substantial increase in CD prevalence in the last 50 years, and it is now estimated that this disease affects approximately 1% of the population in the Western world. In the large majority of cases, CD is a benign disease, characterized by the complete resolution of symptoms and a normal life expectancy after the onset of a gluten-free diet (GFD). However, failure to adhere to a strict GFD bears the risk of adverse events and increases mortality. A considerable number of studies have considered the possible association between CD and neoplasms. In particular, an increased risk of malignancies, such as cancers of the gastrointestinal tract and intestinal lymphomas, has been reported. In this review, we summarize and discuss the current evidence on the possible association between CD and cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21114155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312081PMC
June 2020

No effect of a liquid diet in the management of patients with stricturing Crohn's disease.

Int J Colorectal Dis 2020 Oct 6;35(10):1881-1885. Epub 2020 Jun 6.

Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy.

Purpose: Patients with stricturing Crohn's disease (CD) may experience episodes of intestinal sub-occlusions, which in many cases lead to surgery. The aim of this study was to examine whether adding a liquid diet to medical therapy could improve the management of patients with stricturing CD.

Methods: Medical records of CD outpatients with a small bowel stricture, either receiving (group 1) or not (group 2) a 24-h liquid diet every 10-14 days, were retrospectively analyzed. Number of sub-occlusive episodes, frequency, and timing of intestinal resections for strictures were analyzed.

Results: During the 12-month follow-up, there was no significant difference in the occurrence of new sub-occlusive episodes between the 2 groups (10/37 patients (27%) in group 1 vs 9/45 patients (20%) in group 2). Similarly, the number of patients undergoing bowel resections for sub-occlusive episodes non-responsive to medical therapy did not statistically differ between the two groups (9 patients (24.3%) in group 1 vs 7 patients (15.5%) in group 2). In group 1, surgeries were equally distributed along the 12-months of follow-up, while 85.7% of patients in group 2 underwent intestinal resection within the first 3 months of follow-up.

Conclusion: Adding a liquid diet to medical therapy does not help management of patients with stricturing CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00384-020-03650-7DOI Listing
October 2020