Advances in COVID-19 and Cancer Research.

The global health crisis caused by COVID-19 has radically changed the management of several diseases [...].

Pollutants, microbiota and immune system: frenemies within the gut.

Pollution is a critical concern of modern society for its heterogeneous effects on human health, despite a widespread lack of awareness. Environmental pollutants promote several pathologies through different molecular mechanisms. Pollutants can affect the immune system and related pathways, perturbing its regulation and triggering pro-inflammatory responses. The exposure to several pollutants also leads to alterations in gut microbiota with a decreasing abundance of beneficial microbes, such as short-chain fatty acid-producing bacteria, and an overgrowth of pro-inflammatory species. The subsequent intestinal barrier dysfunction, together with oxidative stress and increased inflammatory responses, plays a role in the pathogenesis of gastrointestinal inflammatory diseases. Moreover, pollutants encourage the inflammation-dysplasia-carcinoma sequence through various mechanisms, such as oxidative stress, dysregulation of cellular signalling pathways, cell cycle impairment and genomic instability. In this narrative review, we will describe the interplay between pollutants, gut microbiota, and the immune system, focusing on their relationship with inflammatory bowel diseases and colorectal cancer. Understanding the biological mechanisms underlying the health-to-disease transition may allow the design of public health policies aimed at reducing the burden of disease related to pollutants.

Gut-Brain Axis: Focus on Sex Differences in Neuroinflammation.

In recent years, there has been a growing interest in the concept of the "gut-brain axis". In addition to well-studied diseases associated with an imbalance in gut microbiota, such as cancer, chronic inflammation, and cardiovascular diseases, research is now exploring the potential role of gut microbial dysbiosis in the onset and development of brain-related diseases. When the function of the intestinal barrier is altered by dysbiosis, the aberrant immune system response interacts with the nervous system, leading to a state of "neuroinflammation". The gut microbiota-brain axis is mediated by inflammatory and immunological mechanisms, neurotransmitters, and neuroendocrine pathways. This narrative review aims to illustrate the molecular basis of neuroinflammation and elaborate on the concept of the gut-brain axis by virtue of analyzing the various metabolites produced by the gut microbiome and how they might impact the nervous system. Additionally, the current review will highlight how sex influences these molecular mechanisms. In fact, sex hormones impact the brain-gut microbiota axis at different levels, such as the central nervous system, the enteric nervous one, and enteroendocrine cells. A deeper understanding of the gut-brain axis in human health and disease is crucial to guide diagnoses, treatments, and preventive interventions.

Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity.

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors are implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, and xenobiotics. At the gut mucosa level, a complex interplay between the immune system and gut microbiota occurs; a disequilibrium between these two factors leads to an alteration in the gut permeability, called 'leaky gut'. Subsequently, an activation of several inflammatory pathways and an alteration of gut microbiota composition with a proliferation of pro-inflammatory bacteria, known as 'pathobionts', take place, leading to a further increase in inflammation. This narrative review provides an overview on the principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), focusing on their recognition mechanisms, signaling pathways, and contributions to immune responses. We also report the genetic polymorphisms of TLRs and dysregulation of NLR signaling pathways that can influence immune regulation and contribute to the development and progression of inflammatory disease and cancer.

Pancreatic Ductal Adenocarcinoma and Nutrition: Exploring the Role of Diet and Gut Health.

The incidence of pancreatic cancer is increasing worldwide. The most common form is represented by pancreatic ductal adenocarcinoma (PDAC) which has been shown to be linked to chronic inflammation. Notably, the gut microbiota has emerged as a critical player in regulating immune responses and inflammation. Indeed, intestinal dysbiosis, characterized by an imbalance in the gut microbiota composition, can contribute to the initiation of chronic inflammation. Sterile chronic inflammation can occur, probably activated by the translocation of bacterial components, such as lipopolysaccharide (LPS), the major component of Gram-negative microbiota, with the consequent induction of innate mucosal immunity, through the activation of Toll-like receptors (TLRs). Furthermore, the interaction between LPS and TLRs could enhance cancer progression. Recent research has shed light on the pivotal role of nutrition, as a modifiable risk factor, in PDAC immunological processes, particularly focusing on the immuno-modulatory effects of the gut microbiota. Different dietary regimens, fiber intake, immunonutrients, and antioxidants have the potential to either exacerbate or mitigate chronic inflammation, thereby influencing the pathogenesis and natural history of PDAC. These dietary components may affect the gut microbiota composition and, consequently, the level of inflammation, either promoting or protecting against PDAC. In this review of reviews, we discuss the modulatory role of nutrition and the gut microbiota in PDAC's immunological processes to explore a translational therapeutic approach that could improve the survival and quality of life of these patients.

Antioxidant-Enriched Diet on Oxidative Stress and Inflammation Gene Expression: A Randomized Controlled Trial.

The Mediterranean Diet (MedDiet) is associated with beneficial effects against chronic non-communicable diseases (CNCDs). In particular, the content of micronutrients leads to an improvement of the oxidative and inflammatory profiles. A randomized, parallel, controlled study, on 24 subjects, was conducted to evaluate if 2-week supplementation with a mixed apple and bergamot juice (MAB juice), had a positive impact on the body composition, the biochemical profile, and oxidative and inflammatory gene expression (Superoxide dismutase (SOD1), Peroxisome Proliferator-Activated Receptor γ (PPARγ), catalase (CAT), chemokine C-C motif ligand 5 (CCL5), Nuclear Factor Kappa B Subunit 1 (NFKB1), Vitamin D Receptor (VDR), and Macrophage Migration Inhibitory Factor (MIF)), respect to a MedDiet. Body composition evaluation analysis showed a gain in lean mass (p < 0.01). Moreover, a significant reduction in total cholesterol/HDL index (p < 0.01) was pointed out between the two groups. Gene expression analysis highlighted an increase in MIF (p ≤ 0.05), PPARγ (p < 0.001), SOD1 (p ≤ 0.05), and VDR (p ≤ 0.05) expressions when comparing MedDiet and MedDiet + MAB juice groups. These data based on the nutrigenomics approach demonstrated that supplementing 2 weeks of MAB juice to the MedDiet could contribute to a reduction in the risk of CNCDs.

Delirium in Head Trauma: Looking for a Culprit.

Head trauma and delirium are two common conditions in the elderly population. They both carry a heavy burden in terms of mortality and morbidity and are associated with one another through several environmental and clinical factors, such as comorbidities, age, and sex. One factor that may play a role in both these conditions is inflammation, which might also represent a link between them. In particular, head trauma can cause both systemic and neuroinflammation, while delirium appears to be precipitated by inflammatory conditions, while also involving a number of inflammatory pathways in its pathogenesis. Interleukin 6 and tumor necrosis factor α are only two of the main actors in this crosstalk, which also involves microglia and immune cells. An indirect proof is that anti-inflammatory drugs have proven effective in reducing post-traumatic delirium, thus demonstrating the importance of inflammation in the pathophysiology of this disease. In this paper, we have revised the available literature exploring the links between inflammation, head trauma and delirium and we will discuss the mechanisms of this relationship, paying particular attention to the possible future implications.

Functional associations between polymorphic regions of the human 3'IgH locus and COVID-19 disease.

PURPOSE: The pandemic diffusion of Coronavirus Disease 2019 (COVID-19) has highlighted significant gender-related differences in disease severity. Despite several hypotheses being proposed, how the genetic background of COVID-19 patients might impact clinical outcomes remains largely unknown. METHODS: We collected blood samples from 192 COVID-19 patients (115 men, 77 women, mean age 67 ± 19 years) admitted between March and June 2020 at two different hospital centers in Italy, and determined the allelic distribution of nine Single Nucleotide Polymorphisms (SNPs), located at the 3'Regulatory Region (3'RR)-1 in the immunoglobulin (Ig) heavy chain locus, including *1 and *2 alleles of polymorphic hs1.2 enhancer region. RESULTS: In COVID-19 patients, the genotyped SNPs exhibited strong Linkage Disequilibrium and produced 7 specific haplotypes, associated to different degrees of disease severity, including the occurrence of pneumonia. Additionally, the allele *2, which comprises a DNA binding site for the Estrogen receptor alpha (ERα) in the polymorphic enhancer hs1.2 of 3'RR-1, was significantly enriched in women with a less severe disease. CONCLUSIONS: These findings document genetic variants associated to individual clinical severity of COVID-19 disease. Most specifically, a novel genetic protective factor was identified that might explain the sex-related differences in immune response to Sars-COV-2 infection in humans.

Pollution, Inflammation, and Vaccines: A Complex Crosstalk.

The importance of pollution in determining human health is becoming increasingly clear, also given the dramatic consequences it has had on recent geopolitical events. Yet, the consequences of contamination are not always straightforward. In this paper, we will discuss the effects of different pollutants on different aspects of human health, in particular on the immune system and inflammation. Different environmental pollutants can have different effects on the immune system, which can then promote complex pathologies, such as autoimmune disorders and cancer. The interaction with the microbiota also further helps to determine the consequences of contamination on wellbeing. The pollution can affect vaccination efficacy, given the widespread effects of vaccination on immunity. At the same time, some vaccinations also can exert protective effects against some forms of pollution.

The Challenge of Autoimmune Pancreatitis: A Portrayal From the Pediatric Perspective.

Autoimmune pancreatitis (AIP) is a rare disorder characterized by prompt clinical response to corticosteroids. Lost tolerance to a variety of pancreatic antigens and subsequent development of autoantibodies are presumably involved in the initiation of AIP. Even pediatric patients have been reported with features of AIP, and awareness of this disorder is increasing among different clinicians. The terms lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric pancreatitis refer to the different histologic patterns of AIP, named type 1 and type 2, respectively. A combination of serologic, radiologic, and histologic investigations is needed to assess diagnosis of AIP and rule out neoplastic disorders. In addition, type 1 AIP can be distinguished by raised levels of serum immunoglobulin G4 and should be considered as part of systemic immunoglobulin G4-related disease. Conversely, type 2 AIP is frequently reported in younger patients and has less clear immune-mediated pathogenetic mechanisms. The natural history of pediatric AIP is obscure, and the diagnostic usefulness of different autoimmune abnormalities found in adults with AIP is limited for children. Tips to manage pediatric patients with AIP have been recently drafted through a set of recommendation statements. This review describes the current data about AIP and the pathogenic contribution of specific autoantibodies expressly in the pediatric population.

The Interplay between Immunity and Microbiota at Intestinal Immunological Niche: The Case of Cancer.

The gut microbiota is central to the pathogenesis of several inflammatory and autoimmune diseases. While multiple mechanisms are involved, the immune system clearly plays a special role. Indeed, the breakdown of the physiological balance in gut microbial composition leads to dysbiosis, which is then able to enhance inflammation and to influence gene expression. At the same time, there is an intense cross-talk between the microbiota and the immunological niche in the intestinal mucosa. These interactions may pave the way to the development, growth and spreading of cancer, especially in the gastro-intestinal system. Here, we review the changes in microbiota composition, how they relate to the immunological imbalance, influencing the onset of different types of cancer and the impact of these mechanisms on the efficacy of traditional and upcoming cancer treatments.

Association between IgH enhancer hs1.2 and type 1 diabetes.

AIM: To investigate the association of alleles of the 3' immunoglobulin heavy-chain regulatory region 1 (3'RR-1) enhancer hs1.2 in patients with type 1 diabetes (T1D). METHODS: Eighty-one patients with T1D [among which 12 had concomitant coeliac disease (CD) and 25 an autoimmune thyroid disease (AITD)] were compared to 248 healthy individuals. All subjects were recruited from the same geographical area. Blood samples were collected from all patients and a nested PCR was performed to amplify the core of the 3'RR-1 and detect the alleles of the hs1.2 enhancer. RESULTS: Allele distribution in healthy individuals was significantly different when compared to that of patients with T1D (p < 0.01). Even greater differences were detected comparing allele distribution of patients with T1D alone versus those with concomitant CD, but not versus those with concomitant AITD. The frequency of *2 allele is increased by 23% in patients with T1D and CD. CONCLUSIONS: The present study establishes that the multiallelic hs1.2 enhancer of the 3'RR-1 is associated with T1D, with higher frequency when there is co-occurrence of CD. This evidence has been previously observed in other immune diseases.

Integrins: Integrating the Biology and Therapy of Cell-cell Interactions.

PURPOSE: Although the role of integrins has been described in a variety of diseases, these roles seem to be distinct. To date, no study has attempted to provide links to the various pathways by which such integrins can be involved in these diverse disease settings. The purpose of this review was to address this gap in our knowledge with the hypothesis that there is, in fact, a common pathway by which integrins may function. METHODS: This article provides an in-depth perspective on the discovery, development, and design of therapeutics that modulate cellular function by targeting integrin:ligand interactions by reviewing the literature on this subject; the review included the most recent results of clinical and subclinical studies. A MEDLINE search was conducted for articles pertaining to the various issues related to integrins, and the most relevant articles are discussed (ie, not only those published in journals with a higher impact factor). FINDINGS: It seems that the ligation of the integrins with their cognate ligands plays a major role in translating membrane dialogue into biological function. In addition, they also seem to play a major regulatory role that can enhance or inhibit biological function depending on the context within which such receptor:ligand interactions occur and the organ and tissues at which interactions occurs and is manipulated. Those studies that used statistical analyses have been included where appropriate. IMPLICATIONS: Our findings show that anti-integrin treatment has the potential to become a valid coadjuvant in the treatment of several diseases including cancer, inflammatory diseases, HIv infection and cardiovascular diseases.

How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology.

The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.

Obscure recurrent gastrointestinal bleeding: a revealed mystery?

OBJECTIVE: Nowadays, capsule endoscopy (CE) is the first-line procedure after negative upper and lower gastrointestinal (GI) endoscopy for obscure gastrointestinal bleeding (OGIB). Approximately, two-thirds of patients undergoing CE for OGIB will have a small-bowel abnormality. However, several patients who underwent CE for OGIB had the source of their blood loss in the stomach or in the colon. The aim of the present study is to determine the incidence of bleeding lesions missed by the previous gastroscopy/colonoscopy with CE and to evaluate the indication to repeat a new complete endoscopic workup in subjects related to a tertiary center for obscure bleeding before CE. METHODS AND METHODS: We prospectively reviewed data from 637/1008 patients underwent to CE for obscure bleeding in our tertiary center after performing negative gastroscopy and colonoscopy. RESULTS: CE revealed a definite or likely cause of bleeding in stomach in 138/637 patients (yield 21.7%) and in the colon in 41 patients (yield 6.4%) with a previous negative gastroscopy and colonoscopy, respectively. The lesions found were outside the small bowel in only 54/637 (8.5%) patients. In 111/138 patients, CE found lesions both in stomach and small bowel (small-bowel erosions in 54, AVMs in 45, active small-bowel bleeding in 4, neoplastic lesions in 3 and distal ileum AVMs in 5 patients). In 24/41 (58.5%) patients, CE found lesions both in small bowel and colon (multiple small-bowel erosions in 15; AVMs in 8 and neoplastic lesion in 1 patients. All patients underwent endoscopic therapy or surgery for their nonsmall-bowel lesions. CONCLUSIONS: Lesions in upper or lower GI tract have been missed in about 28% of patients submitted to CE for obscure bleeding. CE may play an important role in identifying lesions missed at conventional endoscopy.

The role of IL-15 in gastrointestinal diseases: a bridge between innate and adaptive immune response.

IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells. IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an 'immunological niche', in which immune response, inflammation and local homeostasis are modulated. Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases.

Increased diagnostic yield of small bowel tumors with PillCam: the role of capsule endoscopy in the diagnosis and treatment of gastrointestinal stromal tumors (GISTs). Italian single-center experience.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare tumors, accounting for 1-3% of all gastrointestinal malignancies; they are, however, the most common gastric and small bowel mesenchymal tumors. The length and relative inaccessibility of the small bowel have long constrained the diagnosis of GISTs mainly presenting with chronic or intermittent bleeding as the sole clinical manifestation. AIM: To report on the prevalence of small bowel GISTs in a prospectively recorded series of patients undergoing capsule endoscopy (CE). PATIENTS AND METHODS: Between 2001 and 2007 five hundred patients were referred to our endoscopy unit for small bowel evaluation with capsule endoscopy. We retrospectively evaluated all charts. The main indications for CE were obscure-occult or obscure-overt bleeding. Two hundred eighty-nine patients underwent CE for either obscure-occult or obscure-overt bleeding and 211 for other indications. Patient outcome and care processes were measured by follow-up telephone interviews and chart review. Statistical computations were performed using Fisher's exact test and Student's t-test. RESULTS: CE identified a small bowel tumor in 20 patients (4.0%) and 9 tumors turned out to be GISTs (45.0%). Traditional endoscopic and radiological imaging failed to detect the GIST in all these cases. In one case a small bowel GIST was diagnosed by angiography and CE proved false negative. Overall, CE was able to diagnose a small bowel GIST in 9 out of 10 cases. All patients underwent surgical treatment and showed normalized hemoglobin levels at follow-up. The main limitation of this study is the small number of cases. CONCLUSIONS: CE is an effective and sensitive diagnostic device compared with conventional radiology and plays an important role in the algorithm for the diagnostic work-up of suspected small bowel tumors.