Precision Medicine in Inflammatory Bowel Diseases

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-alpha, the interleukin (IL)-12/IL-23 p40 subunit and the alpha 4 beta 7 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

The rare case of positive FDG-positron emission tomography for giant cavernous hemangioma of the liver

Hemangioma is the most common benign liver tumor and the second most common liver tumor after metastases. Large hemangiomas are often heterogeneous. When they exceed 4 cm in diameter, they are termed giant hemangiomas. These giant hemangiomas often present heterogeneous patterns. These heterogeneous appearances are shown because of intratumoral changes due to several degenerative phenomena. PET/CT is reported to be useful for the differentiation of benign from malignant liver lesions. We report the case of a large hepatic hemangioma characterized by high FDG uptake

FUNCTIONAL ROLE OF ESTROGEN RECEPTORS DURING AGING AND THEIR INVOLVEMENT IN INFLAMMATORY PROCESSESS

Estrogens are female sex hormones, belonging to a group of steroids, and they are responsible for the sexual characteristics of the female. They also have effects on bone, cardiovascular system, brain, and skin. The effects of estrogens are mediated by binding to their cognate receptors, the estrogen receptors (ER\u3b1 and ER\u3b2). ERs are transcription factors that regulate transcription by associating with estrogen-responsive-elements (EREs) located within the promoter of target genes. The aim of my studies was to evaluate the effect of aging and blockade of ovarian functions on estrogen receptor transcriptional activity and ER anti-inflammatory action . In specific aim #1 we proposed to study genes driven by ERE-containing promoters: endogenous as well as surrogate reporters; within specific aim #2 we proposed to provide support to the theory that lack of estrogen anti-inflammatory activity is a major component for the onset of pathologies associated with menopause (osteoporosis, atherosclerosis, metabolic and neurological dysfunctions). In our study we evaluated ER activity during aging in ERE-Luc mice. The analysis showed that ER\u3b1 is still synthesized during while with age, ovariectomy further increases ER\u3b1 content in uterus, aorta and hippocampus, but not in the brain. To evaluate ER transcriptional activity in aging and after ovx we first studied the expression of the reporter luciferase (by measuring luciferase mRNA); next we evaluated the expression of ER endogenous genes such as Prothymosin alpha (PTMA) and Progesteron Receptor (PgR) known to be a direct target of ER. This study showed that the ER present in aged tissues is fully functional from the transcriptional point of view. In ovx animals the trend of ER activity is unclear. We were intrigued by the observation that, in aged female mice, a reduction of circulating levels of estrogens induced by ovariectomy was associated with an increased ER activity in several organs. To further study this phenomenon we gonadectomised male and female mice at the age of 5 months and we measured luciferase activity by in vivo imaging at 6 or 20 months of age. Luciferase activity is higher in females than in males in both groups of age, however gonadectomy does not affect luciferase activity in young males (with the exception of the chest), but clearly decreases photon emission in aged mice. In our study we also tested the hypothesis that with aging the loss of the anti-inflammatory activity of estrogens may explain the increased susceptibility to inflammatory disorders (i.e., osteoporosis, atherosclerosis, diabetes, certain neurodegenerative disorders), reported by epidemiological studies in women. Our analysis focused primarily on TNF\u3b1, IL1\u3b2, MCP1 and MIP2. The mRNA of all these inflammatory mediators was shown to increase progressively with aging. To evaluate the influence of estrogens on the expression of inflammatory genes, we measured the content of mRNA encoding for inflammatory mediators in different tissues of ovariectomized females. Due to the relevance of inflammatory processes in the CNS, we next focused on the effect of ovariectomy in the different brain areas by IHC studies the state of reactivity of microglia and astrocytes, cells known to play a relevant role in neuroinflammation. Our data show morphological differences between astrocytes in ovariectomized compared to sham operated mice in all the brain areas at all months of age. Also microglia presents a morphological activation in all the brain areas, as observed in astrocytes. Finally we investigated the extent to which the susceptibility to an inflammatory stimulus changed during aging and if the ovariectomy was playing a role in this phenomenon. In the hippocampus TNF\u3b1 production increases with aging, MIP2 and MCP1 espression changes at 12 months and is similar at 18 months, whereas mRNA levels of IL1 beta are not affected by aging. Ovariectomy does not seem to influence the inflammatory process

Effect of the Alterations in Contractility and Morphology Produced by Atrial Fibrillation on the Thrombosis Potential of the Left Atrial Appendage.

Atrial fibrillation (AF) is a common arrhythmia mainly affecting the elderly population, which can lead to serious complications such as stroke, ischaemic attack and vascular dementia. These problems are caused by thrombi which mostly originate in the left atrial appendage (LAA), a small muscular sac protruding from left atrium. The abnormal heart rhythm associated with AF results in alterations in the heart muscle contractions and in some reshaping of the cardiac chambers. This study aims to verify if and how these physiological changes can establish hemodynamic conditions in the LAA promoting thrombus formation, by means of computational fluid dynamic (CFD) analyses. In particular, sinus and fibrillation contractility was replicated by applying wall velocity/motion to models based on healthy and dilated idealized shapes of the left atrium with a common LAA morphology. The models were analyzed and compared in terms of shear strain rate (SSR) and vorticity, which are hemodynamic parameters directly associated with thrombogenicity. The study clearly indicates that the alterations in contractility and morphology associated with AF pathologies play a primary role in establishing hemodynamic conditions which promote higher incidence of ischaemic events, consistently with the clinical evidence. In particular, in the analyzed models, the impairment in contractility determined a decrease in SSR of about 50%, whilst the chamber pathological dilatation contributed to a 30% reduction, indicating increased risk of clot formation. The equivalent rigid wall model was characterized by SSR values about one order of magnitude smaller than in the contractile models, and substantially different vortical behavior, suggesting that analyses based on rigid chambers, although common in the literature, are inadequate to provide realistic results on the LAA hemodynamics

Involvement of smad7 in inflammatory diseases of the gut and colon cancer

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-beta 1 (TGF-beta 1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-beta 1 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-beta 1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-beta 1 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

IL-21 comes of age as a regulator of effector T cells in the gut

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Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases

The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance

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

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