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Supplemental material, sj-pdf-18-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-17-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-14-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-23-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-25-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-26-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-15-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-16-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-15-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-21-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-24-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-20-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-25-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-20-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-18-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-19-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-21-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-23-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-22-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-14-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-17-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-19-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-22-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-16-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-26-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

Supplemental material, sj-pdf-24-tmj-10.1177_03008916221077144 for Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis by Fabio Turco, Marcello Tucci, Tiziana Angusti, Antonella Parente, Rosario Francesco Di Stefano, Susanna Urban, Chiara Pisano, Alessandro Samuelly, Alessandro Audisio, Marco Audisio, Elena Parlagreco, Antonio Ungaro, Giorgio Vittorio Scagliotti, Massimo Di Maio and Consuelo Buttigliero in Tumori Journal

BACKGROUND: Clinical observations or animal studies implicate enteric glial cells in motility disorders, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal (GI) infections, postoperative ileus, and slow transit constipation. Mechanisms underlying glial responses to inflammation in human GI tract are not understood. Our goal was to identify the "reactive human enteric glial cell (rhEGC) phenotype" induced by inflammation, and probe its functional relevance. METHODS: Human enteric glial cells in culture from 15 GI-surgical specimens were used to study gene expression, Ca, and purinergic signaling by Ca/fluo-4 imaging and mechanosensitivity. A nanostring panel of 107 genes was designed as a read out of inflammation, transcription, purinergic signaling, vesicular transport protein, channel, antioxidant, and other pathways. A 24-hour treatment with lipopolysaccharide (200 μg/mL) and interferon-γ (10 μg/mL) was used to induce inflammation and study molecular signaling, flow-dependent Ca responses from 3 mL/min to 10 mL/min, adenosine triphosphate (ATP) release, and ATP responses. RESULTS: Treatment induced a "rhEGC phenotype" and caused up-regulation in messenger RNA transcripts of 58% of 107 genes analyzed. Regulated genes included inflammatory genes (54%/IP10; IFN-γ; CxCl2; CCL3; CCL2; C3; s100B; IL-1β; IL-2R; TNF-α; IL-4; IL-6; IL-8; IL-10; IL-12A; IL-17A; IL-22; and IL-33), purine-genes (52%/AdoR2A; AdoR2B; P2RY1; P2RY2; P2RY6; P2RX3; P2RX7; AMPD3; ENTPD2; ENTPD3; and NADSYN1), channels (40%/Panx1; CHRNA7; TRPV1; and TRPA1), vesicular transporters (SYT1, SYT2, SNAP25, and SYP), transcription factors (relA/relB, SOCS3, STAT3, GATA_3, and FOXP3), growth factors (IGFBP5 and GMCSF), antioxidant genes (SOD2 and HMOX1), and enzymes (NOS2; TPH2; and CASP3) (P < 0.0001). Treatment disrupted Ca signaling, ATP, and mechanical/flow-dependent Ca responses in human enteric glial cells. ATP release increased 5-fold and s100B decreased 33%. CONCLUSIONS: The "rhEGC phenotype" is identified by a complex cascade of pro-inflammatory pathways leading to alterations of important molecular and functional signaling pathways (Ca, purinergic, and mechanosensory) that could disrupt GI motility. Inflammation induced a "purinergic switch" from ATP to adenosine diphosphate/adenosine/uridine triphosphate signaling. Findings have implications for GI infection, inflammatory bowel disease, postoperative ileus, motility, and GI disorders.

Article first Published online 18 December 2015, The word “glia” is derived from the Greek word “γλοια,” glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the “reactive glial phenotype” is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor–α), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential.

Background: Micro-inflammation and changes in gut microbiota may play a role in the pathogenesis of diverticular disease (DD). Objective: The objective of this article is to evaluate the expression of nitric oxide (NO)-related mediators and S100B in colonic mucosa of patients with DD in an ex vivo model of bacterial infection. Methods: Intestinal biopsies obtained from patients with diverticulosis, symptomatic uncomplicated diverticular disease (SUDD) and SUDD with previous acute diverticulitis (SUDD+AD) were stimulated with the probiotic L. casei DG® (LCDG) and/or the pathogen enteroinvasive Escherichia coli (EIEC). S100B, NO release and iNOS expression were then evaluated. Results: Basal iNOS expression was significantly increased in SUDD and SUDD+AD patients. Basal NO expression was significantly increased in SUDD+AD. No differences in S100B release were found. In all groups, iNOS expression was significantly increased by EIEC and reduced by LCDG. In all groups, except for SUDD+AD, EIEC significantly increased NO release, whereas no increase was observed when LCDG was added to biopsies. EIEC did not induce significant changes in S100B release. Conclusions: Colonic mucosa of patients with DD is characterized by a different reactivity toward pathogenic stimuli. LCDG plays a role in counteracting the pro-inflammatory effects exerted by EIEC, suggesting a beneficial role of this probiotic in DD.

Objective Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice. Design Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs. Results PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans. Conclusions Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.

Background/Aims Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food intake and gut hormone release in healthy subjects. Methods Twenty healthy volunteers were enrolled in a double-blind cross-over study. On 2 different days, each subject randomly received an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were allowed to eat an ad libitum meal until satiated. Plasma samples were obtained during the experiment in order to evaluate cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status. Results Calorie intake was significantly lower when subjects received HCl quinine than placebo (514 ± 248 vs 596 ± 286 kcal; P = 0.007). Significantly higher CCK ΔT90 vs T0 and ΔT90 vs T60 were found when subjects received HCl quinine than placebo (0.70 ± 0.69 vs 0.10 ± 0.86 ng/mL, P = 0.026; 0.92 ± 0.75 vs 0.50 ± 0.55 ng/mL, P = 0.033, respectively). PTC tasters ingested a significantly lower amount of calories when they received HCl quinine compared to placebo (526 ± 275 vs 659 ± 320 kcal; P = 0.005), whereas no significant differences were found for PTC non-tasters (499 ± 227 vs 519 ± 231 kcal; P = 0.525). Conclusions This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food intake.

Glial cells in the gut represent the morphological and functional equivalent of astrocytes and microglia in the central nervous system (CNS). In recent years, the role of enteric glial cells (EGCs) has extended from that of simple nutritive support for enteric neurons to that of being pivotal participants in the regulation of inflammatory events in the gut. Similar to the CNS astrocytes, the EGCs physiologically express the S100B protein that exerts either trophic or toxic effects depending on its concentration in the extracellular milieu. In the CNS, S100B overexpression is responsible for the initiation of a gliotic reaction by the release of pro-inflammatory mediators, which may have a deleterious effect on neighboring cells. S100B-mediated pro-inflammatory effects are not limited to the brain: S100B overexpression is associated with the onset and maintenance of inflammation in the human gut too. In this review we describe the major features of EGCs and S100B protein occurring in intestinal inflammation deriving from such.