Human retinoic acid-regulated CD161+ regulatory T cells support wound repair in intestinal mucosa.

Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.

Prostate and gut: Any relationship? A narrative review on the available evidence and putative mechanisms.

BACKGROUND: Gut microbiome is a community of microorganisms that lives in the human intestine and exerts various functions on the host, including metabolic, immunoregulatory, and control over cell proliferation. Gut microbiome alterations have been associated with various pathological conditions, such as diabetes mellitus, obesity, and cardiovascular diseases. Gut-prostate axis is explained by the association between gut microbiome quantitative and functional alterations along with increased intestinal epithelial permeability with prostatediseases. However, the pathophysiological mechanisms and clinical importance of this association are not completely clarified yet. METHODS: We conducted a narrative review of the most relevant articles in the Medline (US National Library of Medicine, Bethesda, MD, USA), Scopus (Elsevier, Amsterdam, The Netherlands) and Web of Science Core Collection (Thomson Reuters, Toronto, ON, Canada) databases. No chronological restrictions were applied, and the most related papers published until December 2023 were included. RESULTS: Gut microbiota (GM) and its metabolites are capable of modifying host androgen level, as well as prostate cancer (PCa) therapy response. Moreover, patients with inflammatory bowel disease have higher rates of prostatitis-like symptoms and a potential risk of developing PCa. CONCLUSIONS: There is evidence that interventions on the GM and its metabolites have a high potential to serve as diagnostic and therapeutic tools for prostate diseases, including PCa.

PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype.

Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA-CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity.

Indications of Helicobacter pylori Eradication Treatment and Its Influence on Prescriptions and Effectiveness (Hp-EuReg).

BACKGROUND: The influence of indications for Helicobacter pylori investigation on prescriptions and effectiveness is unknown. The aim of the study was to assess the impact of indications for H. pylori investigation on prescriptions, effectiveness, compliance, and tolerance. METHODS: International, prospective, non-interventional registry of the management of H. pylori infection by European gastroenterologists (Hp-EuReg). Treatment-näive patients registered from 2013 to 2023 at e-CRF AEG-REDCap were analyzed. The effectiveness was assessed by modified intention-to-treat analysis. RESULTS: Overall, 53,636 treatment-naïve cases from 34 countries were included. Most frequent indications were: dyspepsia with normal endoscopy (49%), non-investigated dyspepsia (20%), duodenal ulcer (11%), gastric ulcer (7.7%), and gastroesophageal reflux disease (GERD) (2.6%). Therapy effectiveness varied by indication: duodenal ulcer (91%), gastric ulcer (90%), preneoplastic lesions (90%), dyspepsia with normal endoscopy (89%), GERD (88%), and non-investigated dyspepsia (87%). Bismuth-metronidazole-tetracycline and clarithromycin-amoxicillin-bismuth quadruple therapies achieved 90% effectiveness in all indications except GERD. Concomitant clarithromycin-amoxicillin-tinidazole/metronidazole reached 90% cure rates except in patients with non-investigated dyspepsia; whereas sequential clarithromycin-amoxicillin-tinidazole/metronidazole proved optimal (≥90%) in patients with gastric ulcer only. Adverse events were higher in patients treated for dyspepsia with normal endoscopy and duodenal ulcer compared with the remaining indications (23% and 28%, p < 0.001). Therapeutic compliance was higher in patients with duodenal ulcer and preneoplastic lesions (98% and 99%, p < 0.001). CONCLUSION: In Europe, patients with gastric or duodenal ulcers and preneoplastic lesions showed higher H. pylori treatment effectiveness. Bismuth and non-bismuth quadruple therapies achieved optimal results in almost all indications. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02328131.

Prostaglandin E2/EP4 axis is upregulated in Spondyloarthritis and contributes to radiographic progression.

Ankylosing spondylitis (AS) is an inflammatory disease leading to spine ankylosis; however, the mechanisms behind new bone formation are still not fully understood. Single Nucleotide Polymorphisms (SNPs) in PTGER4, encoding for the receptor EP4 of prostaglandin E2 (PGE2), are associated with AS. Since the PGE2-EP4 axis participates in inflammation and bone metabolism, this work aims at investigating the influence of the prostaglandin-E2 axis on radiographic progression in AS. In 185 AS (97 progressors), baseline serum PGE2 predicted progression, and PTGER4 SNP rs6896969 was more frequent in progressors. Increased EP4/PTGER4 expression was observed in AS circulating immune cells, synovial tissue, and bone marrow. CD14highEP4 + cells frequency correlated with disease activity, and when monocytes were cocultured with mesenchymal stem cells, the PGE2/EP4 axis induced bone formation. In conclusion, the Prostaglandin E2 axis is involved in bone remodelling and may contribute to the radiographic progression in AS due to genetic and environmental upregulation.

The urotensin-II receptor: A marker for staging and steroid outcome prediction in ulcerative colitis.

BACKGROUND: Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome. METHODS: One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled. UTR expression was assessed by qPCR, Western Blot (WB) and immunohistochemistry (IHC). Clinical, endoscopic and histological activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), and Truelove and Richards Index (TRI). The partial and full Mayo scores (PMS and FMS) were assessed to stage the disease. RESULTS: The UTR expression, resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p < .0001 all). Direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, PMS, MES and TRI) was highlighted (p < .0001 all). UTR expression resulted also higher in the 72 patients requiring iv steroids administration compared to those who underwent alternative medications, (p < .0001). The 32 steroid-non-responders showed an increased UTR expression (WB, IHC and qPCR from lesioned mucosa), compared to 40 steroid-responders (p: .0002, .0001, p < .0001 respectively). The predictive role of UTR expression (p < .05) on the negative iv steroids administration therapeutic outcome was highlighted and ROC curves identified the thresholds expressing the better predictive performance. CONCLUSIONS: UTR represents a promising inflammatory marker related to clinical, endoscopic, and histological disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.

Prepubertal to adulthood exposure to low doses of glyphosate-based herbicide increases the expression of the Havcr1 (Kim1) biomarker and causes mild kidney alterations.

Glyphosate is a nonselective and postemergent herbicide used to combat weeds in several crops, which raises concerns about risks to human health since residues are detected in urine, human milk, surface water and several types of food. Feces and urine are the major routes of elimination of glyphosate, making the kidney a sensitive target for the development of toxicity. In fact, farmers are at high risk of developing chronic kidney disease. In this sense, this study aims to investigate kidney function by measuring the serum levels of urea and creatinine, examining the histological morphology, and analyzing the mRNA expression of genes related to tubular transport of ions, urea and urates and the biomarker of kidney disease Kim1, and the levels of lead in the kidney in male Wistar rats orally exposed to low levels of glyphosate-based herbicide (GBH: 0, 0.5 or 5 mg/kg) from weaning to adult life by gavage. GBH0.5 showed reduced serum urea concentration, presence of tubulointerstitial swelling and mononuclear cell infiltration into the interstitium, increased gene expression of Kim1 and reduced gene expression of Slc14a1. GBH5 showed reduced serum urea and increased serum creatinine concentrations, tubulointerstitial swelling, interstitial fibrosis, and reduced expression of Trpm6 and Trpv5. Exposure to GBH did not affect the levels of Pb in the kidneys of animals. In conclusion, glyphosate at low doses may cause mild kidney damage. It is necessary to evaluate whether the long-term effects of this constant injury may contribute to the development of chronic kidney disease of uncertain etiology.

Gut microbiota correlates with antitumor activity in patients with mCRC and NSCLC treated with cetuximab plus avelumab.

Gut microbiota is involved in immune modulation and immune checkpoint inhibitors (ICIs) efficacy. Single-arm phase II CAVE-mCRC and CAVE-LUNG clinical trials investigated cetuximab + avelumab combination in RAS wild-type (WT) metastatic colorectal cancer (mCRC) and chemo-refractory nonsmall cell lung cancer (NSCLC) patients, respectively. A comprehensive gut microbiota genetic analysis was done in basal fecal samples of 14 patients from CAVE-mCRC trial with circulating tumor DNA (ctDNA) RAS/BRAF WT and microsatellite stable (MSS) disease. Results were validated in a cohort of 10 patients from CAVE-Lung trial. 16S rRNA sequencing revealed 23 027 bacteria species in basal fecal samples of 14 patients from CAVE-mCRC trial. In five long-term responding patients (progression-free survival [PFS], 9-24 months) significant increases in two butyrate-producing bacteria, Agathobacter M104/1 (P = .018) and Blautia SR1/5 (P = .023) were found compared to nine patients with shorter PFS (2-6 months). A significantly better PFS was also observed according to the presence or absence of these species in basal fecal samples. For Agathobacter M104/1, median PFS (mPFS) was 13.5 months (95% confidence interval [CI], 6.5-20.5 months) vs 4.6 months (95% CI, 1.8-7.4 months); P = .006. For Blautia SR1/5, mPFS was 5.9 months (95% CI, 2.2-9.7 months) vs 3.6 months (95% CI, 3.3-4.0 months); P = .021. Similarly, in CAVE-Lung validation cohort, Agathobacter M104/1 and Blautia SR1/5 expression were associated with PFS according to their presence or absence in basal fecal samples. Agathobacter and Blautia species could be potential biomarkers of outcome in mCRC, and NSCLC patients treated with cetuximab + avelumab. These findings deserve further investigation.

Isolation and expansion of thymus-derived regulatory T cells for use in pediatric heart transplant patients.

Regulatory T-cells (Tregs) are a subset of T cells generated in the thymus with intrinsic immunosuppressive properties. Phase I clinical trials have shown safety and feasibility of Treg infusion to promote immune tolerance and new studies are ongoing to evaluate their efficacy. During heart transplantation, thymic tissue is routinely discarded providing an attractive source of Tregs. In this study, we developed a GMP-compatible protocol for expanding sorted thymus-derived CD3+ CD4+ CD25+ CD127- (Tregs) as well as CD3+ CD4+ CD25+ CD127- CD45RA+ (RA+ Tregs) cells. We aimed to understand whether thymic RA+ Tregs can be isolated and expanded offering an advantage in terms of stability as it has been previously shown for circulating adult CD45RA+ Tregs. We show that both Tregs and RA+ Tregs could be expanded in large numbers and the presence of rapamycin is essential to inhibit the growth of IFN-γ producing cells. High levels of FOXP3, CTLA4, and CD25 expression, demethylation of the FOXP3 promoter, and high suppressive ability were found with no differences between Tregs and RA+ Tregs. After freezing and thawing, all Treg preparations maintained their suppressive ability, stability, as well as CD25 and FOXP3 expression. The number of thymic Tregs that could be isolated with our protocol, their fold expansion, and functional characteristics allow the clinical application of this cell population to promote tolerance in pediatric heart transplant patients.

Adherence to international guidelines for the management of Helicobacter pylori infection among gastroenterologists and gastroenterology fellows in Italy: A Survey of the Italian Federation of Digestive Diseases - FISMAD.

BACKGROUND: Information on the management of Helicobacter (H.) pylori infection by gastroenterologists and gastroenterology fellows are scarce. We aimed to assess practice of gastroenterologists and gastroenterology fellows and their adherence to guidelines for diagnosis and treatment of H. pylori infection in Italy. MATERIALS AND METHODS: All gastroenterologists and gastroenterology fellows attending the National Congress of Digestive Diseases - FISMAD were invited to fill-in an on-line questionnaire. The questionnaire included questions on the diagnosis and treatment of H. pylori infection. RESULTS: A total of 279 gastroenterologists and 61 gastroenterology fellows participated to the study. The 13 C-urea breath test was the most preferred method among gastroenterologists and fellows for the diagnosis of H. pylori infection (40.4% and 57.6%, respectively) and the confirmation of eradication (61.3% and 70%, respectively). Sequential therapy was the most preferred first-line treatment of H. pylori for both gastroenterologists and gastroenterology fellows (31.8% and 44%, respectively), followed by bismuth quadruple therapy (31% and 27.6%, respectively) and clarithromycin triple therapy (26.8% and 22.4%, respectively). Only 30% of gastroenterologists and 38.5% of fellows used the clarithromycin triple therapy for the recommended duration of 14 days. Bismuth quadruple therapy was the most preferred second-line therapy for both gastroenterologists and fellows. The majority of gastroenterologists and fellows would prefer an empirical therapy at third line (72.6% and 62.5%, respectively) and a susceptibility-guided therapy at fourth line (46.7% and 71.4%, respectively). CONCLUSIONS: Practices of gastroenterologists and gastroenterology fellows are in line with guidelines' recommendations, apart for the first-line treatment of H. pylori infection. Targeted educational interventions to improve adherence to guidelines are needed.

TactCube: An Intelligent Device to 'converse' with Smart Environments.

Ambient Intelligence is a vision of daily life in which intelligent devices interact with humans to make their lives easier, and the technology is invisible. Artificial Intelligence (AI) governs this smart environment and must interact with humans to best meet their needs and demands. Although voice assistants are very popular and efficient as conversational AI, under some conditions they cannot be used. Therefore, this work proposed a complementary tactile and tangible interface to converse with AI, creating new Tactile Signs. A prototype of TactCube, a wireless cube-shaped device that can interact with AI using only the tactile sense, is presented. The hypothesis is that TactCube can be manipulated with one hand and generate a sequence of numbers that can be interpreted as a new tactile language by a neural network solution. The paper describes the initial research made to define how these sequences can be generated and demonstrates how TactCube is able to do it.

Interaction Design Patterns for Augmented Reality Fitting Rooms.

In this work, we explore the role of augmented reality as a meta-user interface, with particular reference to its applications for interactive fitting room systems and the impact on the related shopping experience. Starting from literature and existing systems, we synthesized a set of nine interaction design patterns to develop AR fitting rooms and to support the shopping experience. The patterns were evaluated through a focus group with possible stakeholders with the aim of evaluating and envisioning the effects on the shopping experience. The focus group analysis shows as a result that the shopping experience related to an AR fitting room based on the proposed patterns is influenced by three main factors, namely: the perception of the utility, the ability to generate interest and curiosity, and the perceived comfort of the interaction and environment in which the system is installed. As a further result, the study shows that the patterns can successfully support these factors, but some elements that emerged from the focus group should be more investigated and taken into consideration by the designers.

B lymphocytes contribute to indirect pathway T cell sensitization via acquisition of extracellular vesicles.

B cells have been implicated in transplant rejection via antibody-mediated mechanisms and more recently by presenting donor antigens to T cells. We have shown in patients with chronic antibody-mediated rejection that B cells control the indirect T cell alloresponses. To understand more about the role of B cells as antigen-presenting cells for CD4+ T cell with indirect allospecificity, B cells were depleted in C57BL/6 mice, using an anti-CD20 antibody, prior to receiving MHC class I-mismatched (Kd ) skin. The absence of B cells at the time of transplantation prolonged skin graft survival. To study the mechanisms behind this observation, T cells with indirect allospecificity were transferred in mice receiving a Kd skin transplant. T cell proliferation was markedly inhibited in the absence of recipient B cells, suggesting that B cells contribute to indirect pathway sensitization. Furthermore, we have shown that a possible way in which B cells present alloantigens is via acquisition of MHC-peptide complexes. Finally, we demonstrate that the addition of B cell depletion to the transfer of regulatory T cells (Tregs) with indirect alloresponse further prolonged skin graft survival. This study supports an important role for B cells in indirect T cell priming and further emphasizes the advantage of combination therapies in prolonging transplant survival.

Intergenerational thyroid hormone homeostasis imbalance in cerebellum of rats perinatally exposed to glyphosate-based herbicide.

Agrochemicals became a public health concern due to increased human exposure and possible endocrine disruption effects in several organs, including the brain. Thyroid hormones controls neurodevelopment, which turn them sensitive to endocrine disruptors (EDs). In this work, we evaluated the effect of glyphosate-based herbicides (GBH) as an intergenerational endocrine disrupter on thyroid homeostasis in cerebellar cells. Female pregnant Wistar rats were exposed to Roundup Transorb® solution at 5 and 50 mg/kg/day, from gestation day 18 to post-natal day 5 (P5). Cerebellum of male offspring was used to evaluate gene expression. The mRNA levels of thyroid hormone receptors, hormonal conversion enzymes, hormone transporters, as well as, de novo epigenetic regulators were altered, with some of these genes presenting a non-monotonic dose response. Furthermore, metabolomic profile correlation with tested dose demonstrated altered metabolic profile, in agreement with cerebellar gene alterations. Moreover, cerebellar primary cultures exposed to non-toxic GBH concentration presented a decrease level in glial fibrillary acidic protein, a protein regulated by endocrine signals. In conclusion, our results indicate that animals exposed to non-toxic GBH doses during perinatal phase carry intergenerational alterations in key regulators of cellular thyroid hormone homeostasis and epigenetic controllers in adulthood, indicating the possible ED effect of GBH based on epigenetic alterations.

Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy.

Three cardinal manifestations of neoplasia, namely inflammation, immune dysfunction, and coagulopathy are also seen in patients with severe SARS-CoV-2 infection, providing a biological rationale for testing selected anticancer drugs for their ability to control the symptoms and/or modify the course of COVID-19.

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation.

Regulatory T cells (Tregs) are a lymphocyte subset with intrinsic immunosuppressive properties that can be expanded in large numbers ex vivo and have been shown to prevent allograft rejection and promote tolerance in animal models. To investigate the safety, applicability, and biological activity of autologous Treg adoptive transfer in humans, we conducted an open-label, dose-escalation, Phase I clinical trial in liver transplantation. Patients were enrolled while awaiting liver transplantation or 6-12 months posttransplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under good manufacturing practices (GMP) conditions, and administered intravenously at either 0.5-1 million Tregs/kg or 3-4.5 million Tregs/kg. The primary endpoint was the rate of dose- limiting toxicities occurring within 4 weeks of infusion. The applicability of the clinical protocol was poor unless patient recruitment was deferred until 6-12 months posttransplant. Thus, only 3 of the 17 patients who consented while awaiting liver transplantation were dosed. In contrast, all six patients who consented 6-12 months posttransplant received the cell infusion. Treg transfer was safe, transiently increased the pool of circulating Tregs and reduced anti-donor T cell responses. Our study opens the door to employing Treg immunotherapy to facilitate the reduction or complete discontinuation of immunosuppression following liver transplantation.

Proteomic Profiles of Thyroid Gland and Gene Expression of the Hypothalamic-Pituitary-Thyroid Axis Are Modulated by Exposure to AgNPs during Prepubertal Rat Stages.

Silver nanoparticles (AgNPs) have potent antimicrobial activity and, for this reason, are incorporated into a variety of products, raising concern about their potential risks and impacts on human health and the environment. The developmental period is highly dependent on thyroid hormones (THs), and puberty is a sensitive period, where changes in the hormonal environment may have permanent effects. We evaluated the hypothalamic-pituitary (HP)-thyroid axis after exposure to low doses of AgNPs using a validated protocol to assess pubertal development and thyroid function in immature male rats. For stimulatory events of the HP-thyroid axis, we observed an increase in the expression of Trh mRNA and serum triiodothyronine. Negative feedback reduced the hypothalamic expression of Dio2 mRNA and increased the expression of Thra1, Thra2, and Thrb2 mRNAs. In the pituitary, there was a reduced expression of Mct-8 mRNA and Dio2 mRNA. For peripheral T3-target tissues, a reduced expression of Mct-8 mRNA was observed in the heart and liver. An increased expression of Dio3 mRNA was observed in the heart and liver, and an increased expression of Thrb2 mRNA was observed in the liver. The quantitative proteomic profile of the thyroid gland indicated a reduction in cytoskeletal proteins (Cap1, Cav1, Lasp1, Marcks, and Tpm4; 1.875 µg AgNP/kg) and a reduction in the profile of chaperones (Hsp90aa1, Hsp90ab1, Hspa8, Hspa9, P4hb) and proteins that participate in the N-glycosylation process (Ddost, Rpn1 and Rpn2) (15 µg AgNP/kg). Exposure to low doses of AgNPs during the window of puberty development affects the regulation of the HP-thyroid axis with further consequences in thyroid gland physiology.

Non-bismuth and bismuth quadruple therapies based on previous clarithromycin exposure are as effective and safe in an area of high clarithromycin resistance: A real-life study.

BACKGROUND: Bismuth quadruple (BQT) and non-bismuth quadruple (N-BQT) therapies are the recommended first-line treatments for Helicobacter (H.) pylori infection. OBJECTIVE: To compare the efficacy of BQT and N-BQT in clinical practice in an area with high clarithromycin resistance, choosing the regimen on the basis of previous exposure to clarithromycin. METHODS: A total of 404 consecutive H pylori-positive, naïve patients were enrolled. A total of 203 patients without previous exposure to clarithromycin received N-BQT, 100 patients for 10 days and 103 for 14 days, whereas 201 with previous exposure to clarithromycin received 10-day BQT. Efficacy and treatment-related adverse events were assessed. RESULTS AND CONCLUSIONS: Eradication rates by intention-to-treat analysis were 88.2% for N-BQT and 91.5% for BQT (P = .26); per-protocol analysis eradication rates were 91.2% and 95.8% for N-BQT and BQT, respectively (P = .07). Eradication rates were significantly higher with 14-day than 10-day CT (P < .003). Almost all patients had a good compliance with both N-BQT (95.6%) and BQT (95%). Adverse events occurred in 24.1% and 26.9% (P = .53) of patients in the N-BQT and BQT group, respectively. In conclusion, clarithromycin-containing non-bismuth or bismuth quadruple therapy, based on the knowledge of previous clarithromycin exposure, is effective and safe even in an area of high prevalence of clarithromycin-resistant H pylori strains.