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Background and Purpose Adenosine A2B receptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2B receptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS). Colonic A2B receptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A2B receptors and adenosine deaminase was assayed by immunoprecipitation. The role of A2B receptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results A2B receptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A2B receptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A2B receptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A2B receptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A2B receptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications Under normal conditions, endogenous adenosine modulates colonic motility via A2B receptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2B receptors and adenosine deaminase, which catabolizes adenosine, thus preventing A2B receptor activation. [ABSTRACT FROM AUTHOR]

Background: The frequency and clinical features of drug-related taste and/or smell impairments are currently unclear.Objective: The aim of this study was to identify major drug classes associated with taste and smell alterations reported to the Italian spontaneous adverse drug reaction (ADR) reporting database.Methods: The association between drug and altered taste or smell was investigated by case/non-case methodology. The reporting odds ratio (ROR) was used as a measure of disproportionality. Cases were defined as patients with at least one ADR related to taste or smell impairments. The non-cases included all patients without any ADRs related to taste or smell alterations.Results: According to the selection criteria, 52 166 reports were included in the analysis. Overall, 182 cases of drug-related taste and/or smell dysfunctions were identified. Statistically significant unadjusted RORs were reported for macrolides (n = 31; 7.1; 95% CI 4.8, 10.5), terbinafine (the only drug reported within the group of antimycotics belonging to the Anatomical Therapeutic Chemical class D01AE) [n = 17; 76.4; 95% CI 44.0, 132.6], fluoroquinolones (n = 15; 1.7; 95% CI 1.0, 2.8) and protein kinase inhibitors (n = 10; 4.0; 95% CI 2.1, 7.7). When RORs were adjusted for sex and age category, the disproportion remained statistically significant for all of the previously mentioned drug classes.Conclusions: Taste and/or smell abnormalities are common, sometimes unexpected and often persistent complaints of patients during pharmacological treatments. Physicians should be aware of the impact of these ADRs on patients' quality of life. [ABSTRACT FROM AUTHOR]

The limited recapitulation of critical cancer features in 2D cultures causes poor translatability of preclinical results from in vitro assays to in vivo tumor models. This contributes to slow drug development with a low success rate. 3D cultures better recapitulate the tumor microenvironment, enabling more accurate predictions when screening drug candidates and improving the development of chemotherapeutics. Platinum (Pt) (IV) compounds are promising prodrugs designed to reduce the severe systemic toxicity of widely used Food and Drug Administration (FDA)-approved Pt(II) drugs such as cisplatin. Here, this work presents spatiotemporal evaluations in 3D colorectal cancer (CRC) spheroids of mitochondria-targeting Pt(IV) complexes. CRC spheroids provide a greater pathophysiological recapitulation of in vivo tumors than 2D cultures by a marked upregulation of the ABCG2 chemoresistance marker expression. Furthermore, new 3D-staining protocols are introduced to evaluate the real-time decrease in mitochondria membrane potential (ΔΨ) in CRC spheroids, and a Pt-sensing dye to quantify the Pt mitochondrial accumulation. Finally, this work demonstrates a correlation between in vitro results and the efficacy of the compounds in vivo. Overall, the CRC spheroids represent a fast and cost-effective model to assess the behavior of Pt compounds in vitro and predict their translational potential in CRC treatment., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies nowadays. The available chemo- and immunotherapies are often ineffective in treating PDAC due to its immunosuppressive and highly desmoplastic tumor immune microenvironment (TIME), which is hardly reproduced in the existing preclinical models. The PDAC TIME results from a peculiar spatial organization between different cell types. For this reason, developing new human models recapitulating the tissue organization and cell heterogeneity of PDAC is highly desirable. We developed human 3D heterocellular tumor spheroids of PDAC formed by cancer cells, endothelial cells, pancreatic stellate cells (PSC), and monocytes. As a control, we formed spheroids using immortalized epithelial pancreatic ductal cells (non-cancerous spheroids) with cellular heterogeneity similar to the tumor spheroids. Normal spheroids containing endothelial cells formed a complex 3D endothelial network significantly compromised in tumor spheroids. Monocyte/macrophages within the 4-culture tumor spheroids were characterized by a higher expression of CD163, CD206, PD-L1, and CD40 than those in the non-cancerous spheroids suggesting their differentiation towards an immunosuppressive phenotype. The heterocellular tumor spheroids presented a hypoxic core populated with PSC and monocytes/macrophages. The 4-culture tumor spheroids were characterized by spatial proximity of PSC and monocytes to the endothelial cells and a cytokine signature with increased concentrations of CXCL10, CCL2, and IL-6, which have been observed in PDAC patients and associated with poor survival. Further, 4-culture tumor spheroids decreased the concentrations of T-cell chemoattracting cytokines, i.e., CCL4, CCL5, and CXCL9, when compared with the non-cancerous spheroids, revealing a critical immunosuppressive feature of the different types of cells forming the tumor spheroids. Our results showed that the 4-culture tumor spheroids better resembled some critical features of patients' PDAC TIME than monoculture tumor spheroids. Using the proposed human 3D spheroid model for therapy testing at the preclinical stage may reveal pitfalls of chemo- and immuno-therapies to help the development of better anti-tumor therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Giustarini, Teng, Pavesi and Adriani.)

Nanotechnologies are rapidly increasing their role in immuno-oncology in line with the need for novel therapeutic strategies to treat patients unresponsive to chemotherapies and immunotherapies. The tumor immune microenvironment (TIME) has emerged as critical for tumor classification and patient stratification to design better treatments. Notably, the tumor infiltration of effector T cells plays a crucial role in antitumor responses and has been identified as the primary parameter to define hot, immunosuppressed, excluded, and cold tumors. Organic and inorganic nanoparticles (NPs) have been applied as carriers of new targeted therapies to turn cold or altered (i.e., immunosuppressed or excluded) tumors into more therapeutically responsive hot tumors. This mini-review discusses the significant advances in NP-based approaches to turn immunologically cold tumors into hot ones., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Giustarini, Pavesi and Adriani.)

A malfunction of the innate immune response in COVID-19 is associated with eosinopenia, particularly in more severe cases. This study tested the hypothesis that this eosinopenia is COVID-19 specific and is associated with systemic activation of eosinophils. Blood of 15 healthy controls and 75 adult patients with suspected COVID-19 at the ER were included before PCR testing and analyzed by point-of-care automated flow cytometry (CD10, CD11b, CD16, and CD62L) in the absence or presence of a formyl peptide (fNLF). Forty-five SARS-CoV-2 PCR positive patients were grouped based on disease severity. PCR negative patients with proven bacterial ( n = 20) or other viral ( n = 10) infections were used as disease controls. Eosinophils were identified with the use of the FlowSOM algorithm. Low blood eosinophil numbers (<100 cells/μL; p < 0.005) were found both in patients with COVID-19 and with other infectious diseases, albeit less pronounced. Two discrete eosinophil populations were identified in healthy controls both before and after activation with fNLF based on the expression of CD11b. Before activation, the CD11b bright population consisted of 5.4% (CI 95% = 3.8, 13.4) of total eosinophils. After activation, this population of CD11b bright cells comprised nearly half the population (42.21%, CI 95% = 35.9, 54.1). Eosinophils in COVID-19 had a similar percentage of CD11b bright cells before activation (7.6%, CI 95% = 4.5, 13.6), but were clearly refractory to activation with fNLF as a much lower percentage of cells end up in the CD11b bright fraction after activation (23.7%, CI 95% = 18.5, 27.6; p < 0.001). Low eosinophil numbers in COVID-19 are associated with refractoriness in responsiveness to fNLF. This might be caused by migration of fully functional cells to the tissue.

Coronavirus disease 2019 (COVID-19) is a rapidly emerging pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Critical COVID-19 is thought to be associated with a hyper-inflammatory process that can develop into acute respiratory distress syndrome, a critical disease normally mediated by dysfunctional neutrophils. This study tested the hypothesis whether the neutrophil compartment displays characteristics of hyperinflammation in COVID-19 patients. Therefore, a prospective study was performed on all patients with suspected COVID-19 presenting at the emergency room of a large academic hospital. Blood drawn within 2 d after hospital presentation was analyzed by point-of-care automated flow cytometry and compared with blood samples collected at later time points. COVID-19 patients did not exhibit neutrophilia or eosinopenia. Unexpectedly neutrophil activation markers (CD11b, CD16, CD10, and CD62L) did not differ between COVID-19-positive patients and COVID-19-negative patients diagnosed with other bacterial/viral infections, or between COVID-19 severity groups. In all patients, a decrease was found in the neutrophil maturation markers indicating an inflammation-induced left shift of the neutrophil compartment. In COVID-19 this was associated with disease severity., (©2020 Society for Leukocyte Biology.)

Idiosyncratic drug-induced liver injury (IDILI) is a severe disease that cannot be detected during drug development. It has been shown that hepatotoxicity of some compounds associated with IDILI becomes apparent when these are combined in vivo and in vitro with LPS or TNF. Among these compounds trovafloxacin (TVX) induced apoptosis in the liver and increased pro-inflammatory cytokines in mice exposed to LPS/TNF. The hepatocyte survival and the cytokine release after TNF/LPS stimulation relies on a pulsatile activation of NF-κB. We set out to evaluate the dynamic activation of NF-κB in response to TVX + TNF or LPS models, both in mouse and human cells. Remarkably, TVX prolonged the first translocation of NF-κB induced by TNF both in vivo and in vitro. The prolonged p65 translocation caused by TVX was associated with an increased phosphorylation of IKK and MAPKs and accumulation of inhibitors of NF-κB such as IκBα and A20 in HepG2. Coherently, TVX suppressed further TNF-induced NF-κB translocations in HepG2 leading to decreased transcription of ICAM-1 and inhibitors of apoptosis. TVX prolonged LPS-induced NF-κB translocation in RAW264.7 macrophages increasing the secretion of TNF. In summary, this study presents new, relevant insights into the mechanism of TVX-induced liver injury underlining the resemblance between mouse and human models. In this study we convincingly show that regularly used toxicity models provide a coherent view of relevant pathways for IDILI. We propose that assessment of the kinetics of activation of NF-κB and MAPKs is an appropriate tool for the identification of hepatotoxic compounds during drug development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To identify cytokines that can activate and expand NK cells in the presence of prostate cancer cells in order to determine whether these agents may be useful in future intra-tumoural administration in pre-clinical and clinical prostate cancer trials., Materials and Methods: Lymphocytes isolated from normal donor blood were set up in co-cultures with either cancer or non-cancerous prostate cell lines, together with each of the cytokines interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-γ or IL-21 for a period of 7 days. Then, expansion of NK cells, NKT cells and CD8 T cells was measured by flow cytometry and compared with the expansion of the same cells in the absence of prostate cells. The cytotoxic activity of NK cells, as measured by perforin and tumour cell killing, was also assessed. NK cell receptors and their corresponding ligands on prostate tumour cells were analysed to determine whether any of these were modulated by co-culture. The role of the tumour-secreted heat shock proteins HSP90 and HSP70 in the expansion of NK cells in the co-cultures was also investigated because of their effects on NK and CD8 T-cell activation., Results: We showed that, among a panel of cytokines known to cause NK cell activation and expansion, only IL-15 could actively induce expansion of NK, NKT and CD8 T cells in the presence of prostate cancer cell lines. Furthermore, the expansion of NK cells was far greater (up to 50% greater) in the presence of the cancer cells (LNCaP, PC3) than when lymphocytes were incubated alone. In contrast, non-cancerous cell lines (PNT2 and WPMY-1) did not exert any expansion of NK cells. The cytolytic activity of the NK cells, as measured by perforin, CD107a and killing of tumour cells, was also greatest in co-cultures with IL-15. Examination of NK cell receptors shows that NKG2D is upregulated to a greater degree in the presence of prostate cancer cells, compared with the upregulation with IL-15 in lymphocytes alone. However, blocking of NKG2D does not inhibit the enhanced expansion of NK cells in the presence of tumour cells., Conclusions: Among a panel of NK cell-activating cytokines, IL-15 was the only cytokine that could stimulate expansion of NK cells in the presence of prostate cancer cells; therefore IL-15 may be a good candidate for novel future intra-tumoural therapy of the disease., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Background: Promising therapies for food allergy are emerging, mostly based on animal experimentation. However, different mouse strains are used, which may make it hard to compare experiments. The current study investigated whether the immunological differences between C3H/HeOuJ (C3H) and BALB/c mice lead to differences in efficacy of peanut-specific immunotherapy., Methods: After sensitization using peanut extract (PE), C3H and BALB/c mice received oral immunotherapy (OIT) by intragastric dosing for three weeks. Hereafter, mice were exposed to PE via the intradermal, intragastric and intraperitoneal route, to determine allergic outcomes. Furthermore, PE-specific antibody and cytokine production were determined and the number of various immune cells at different time points during the study were measured., Results: OIT protected C3H mice against anaphylaxis, whereas no anaphylaxis was seen in BALB/c mice. In contrast, OIT induced an increase in MMCP-1 levels in BALB/c mice but not in C3H mice. No effect of OIT on the acute allergic skin response was observed in either strain. Specific antibody responses showed similar patterns in both strains for IgA and IgG1. IgE levels were a tenfold higher in BALB/c mice and after the intragastric challenge (day 70) OIT-treated BALB/c mice showed induced IgE levels. Moreover, in C3H mice IgG2a levels were higher and increased in response to OIT and challenges. After the final challenge, but not at other timepoints MLN-derived lymphocytes from OIT-treated BALB/c mice produced less IL-13 and IL-5 compared to control-treated mice, whereas no differences were seen in case of C3H mice., Conclusions: Taken together, these results show that the C3H strain is more suitable to study clinical outcomes of OIT, whereas the BALB/c strain is more optimal to study T cell responses., (© 2019 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.)

The fluoroquinolone trovafloxacin (TVX) is associated with a high risk of drug-induced liver injury (DILI). Although part of the liver damage by TVX+TNF relies on neutrophils, we have recently demonstrated that liver recruitment of monocytes and neutrophils is delayed by TVX. Here we show that the delayed leukocyte recruitment is caused by a combination of effects which are linked to the capacity of TVX to block the hemichannel pannexin 1. TVX inhibited find-me signal release in apoptotic HepG2 hepatocytes, decelerated freshly isolated human neutrophils toward IL-8 and f-MLF, and decreased the liver expression of ICAM-1. In blood of TVX+TNF-treated mice, we observed an accumulation of activated neutrophils despite an increased MIP-2 release by the liver. Depletion of monocytes and neutrophils caused increased serum concentrations of TNF, IL-6, and MIP-2 in TVX-treated mice as well as in mice treated with the fluoroquinolone levofloxacin, known to have a lower DILI-inducing profile. This supports the idea that early leukocyte recruitment regulates inflammation. In conclusion, disrupted regulation by leukocytes appears to constitute a fundamental step in the onset of TVX-induced liver injury, acting in concert with the capability of TVX to induce hepatocyte cell death. Interference of leukocyte-mediated regulation of inflammation represents a novel mechanism to explain the onset of DILI.

Scope: A major downside of oral immunotherapy (OIT) for food allergy is the risk of severe side effects. Non-digestible short- and long-chain fructo-oligosaccharides (scFOS/lcFOS) reduce allergy development in murine models. Therefore, it is hypothesized that scFOS/lcFOS can also support the efficacy of OIT in a peanut allergy model., Methods and Results: After sensitization to peanut extract (PE) using cholera toxin, C3H/HeOuJ mice are fed a 1% scFOS/lcFOS or control diet and receive OIT (1.5 or 15 mg PE). Hereafter, mice are exposed to PE via different routes to determine the safety and efficacy of treatment in clinical outcomes, PE-specific antibody production, and numbers of various immune cells. scFOS/lcFOS increases short-chain fatty acid levels in the caecum and reduce the acute allergic skin response and drop in body temperature after PE exposure. Interestingly, 15 mg and 1.5 mg OIT with scFOS/lcFOS induce protection against anaphylaxis, whereas 1.5 mg OIT alone does not. OIT, with or without scFOS/lcFOS, induces PE-specific immunoglobulin (Ig) IgG and IgA levels and increases CD103+ dendritic cells in the mesenteric lymph nodes., Conclusions: scFOS/lcFOS and scFOS/lcFOS combined with low dose OIT are able to protect against a peanut-allergic anaphylactic response., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This article addresses an apparent paradox found in Pali Buddhist literature: while the "uncompounded" (asaṅkhata) is valued over and above what is "compounded" (saṅkhata), the texts also encourage careful attention to relative (or, physical) health. The mind is the laboratory and the object of a thorough work meant to lead to final liberation from mental affliction and from the cycle of existence, whereas the body is perceived as impure, limited, and intrinsically unsatisfactory. Nonetheless, a disciple of the Buddha is supposed to take care of his/her own and others' physical wellbeing, and monastic equipment includes a set of medicines. "Ultimate health" is the final goal, but conventional healthcare supports the path to nibbāna and represents a value per se. The present article will explore the intricate connection between these two dimensions.

Idiosyncratic drug-induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)-induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX-induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX-treated mice, but even more so in control mice treated with the non-DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2 hours after TNF administration, but at 4 hours, the relative neutrophil amounts were reduced again in Veh- and LVX-treated mice whereas the amounts in TVX-treated mice remained at the same increased level as at 2 hours. The influx of monocytes/macrophages, which was unaffected in Veh- and LVX-treated mice was markedly reduced or even absent in TVX-treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti-inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development., (Copyright © 2018 John Wiley & Sons, Ltd.)

Adenosine represents a powerful modulating factor, which has been shown to orchestrate the scope, duration, and remission of the inflammatory response through the activation of four specific receptors, classified as A 1 , A 2A , A 2B , and A 3 , all being widely expressed in a variety of immune cells. Several selective A 2A receptor agonists have displayed anti-inflammatory effects, through the suppression of IL-12, TNF, and IFN-γ production by monocytes and lymphocytes, in the setting of chronic intestinal inflammation. However, the therapeutic application of A 2A receptor agonists remains hindered by the risk of serious cardiovascular adverse effects arising from the wide systemic distribution of A 2A receptors. The present study focused on evaluating the anti-inflammatory effects of the novel poorly absorbed A 2A receptor agonist PSB-0777 in a rat model of oxazolone-induced colitis as well as to evaluate its cardiovascular adverse effects, paying particular attention to the onset of hypotension, one of the main adverse effects associated with the systemic pharmacological activation of A 2A receptors. Colitis was associated with decreased body weight, an enhanced microscopic damage score and increased levels of colonic myeloperoxidase (MPO). PSB-0777, but not dexamethasone, improved body weight. PSB-0777 and dexamethasone ameliorated microscopic indexes of inflammation and reduced MPO levels. The beneficial effects of PSB-0777 on inflammatory parameters were prevented by the pharmacological blockade of A 2A receptors. No adverse cardiovascular events were observed upon PSB-0777 administration. The novel A 2A receptor agonist PSB-0777 could represent the base for the development of innovative pharmacological entities able to act in an event-specific and site-specific manner.

Introduction: Adenosine monophosphate-activated protein kinase (AMPK), known as an enzymatic complex that regulates the energetic metabolism, is emerging as a pivotal enzyme and enzymatic pathway involved in the regulation of immune homeostatic networks. It is also involved in the molecular mechanisms underlying the pathophysiology of chronic inflammatory diseases., Areas Covered: AMPK is expressed in several immune cell types including macrophages, lymphocytes, neutrophils and dendritic cells, and governs a broad array of cell functions, which include cytokine production, chemotaxis, cytotoxicity, apoptosis and proliferation. Based on its wide variety of immunoregulatory actions, the AMPK system has been targeted to reveal its impact on the course of immune-related diseases, such as atherosclerosis, psoriasis, joint inflammation and inflammatory bowel diseases., Expert Opinion: The identification of AMPK subunits responsible for specific anti-inflammatory actions and the understanding of the underlying molecular mechanisms will promote the generation of novel AMPK activators, endowed with improved pharmacodynamic and pharmacokinetic profiles. These new tools will aid us to utilize AMPK pathway activation in the management of acute and chronic inflammatory diseases, while minimizing potential adverse reactions related to the effects of AMPK on metabolic energy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E2 (PGE2) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.

Gut homeostasis results from complex neuro-immune interactions aimed at triggering stereotypical and specific programs of coordinated mucosal secretion and powerful motor propulsion. A prominent role in the regulation of this highly integrated network, comprising a variety of immune/inflammatory cells and the enteric nervous system, is played by purinergic mediators. The cells of the digestive tract are literally plunged into a "biological sea" of functionally active nucleotides and nucleosides, which carry out the critical task of driving regulatory interventions on cellular functions through the activation of P1 and P2 receptors. Intensive research efforts are being made to achieve an integrated view of the purinergic system, since it is emerging that the various components of purinergic pathways (i.e., enzymes, transporters, mediators and receptors) are mutually linked entities, deputed to finely modulating the magnitude and the duration of purinergic signaling, and that alterations occurring in this balanced network could be intimately involved in the pathophysiology of several gut disorders. This review article intends to provide a critical appraisal of current knowledge on the purinergic system role in the regulation of gastrointestinal functions, considering these pathways as a whole integrated network, which is capable of finely controlling the levels of bioactive nucleotides and nucleosides in the biophase of their respective receptors. Special attention is paid to the mechanisms through which alterations in the various compartments of the purinergic system could contribute to the pathophysiology of gut disorders, and to the possibility of counteracting such dysfunctions by means of pharmacological interventions on purinergic molecular targets., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Thalidomide is a potent anti-myeloma drug which can produce up to a 30-50% overall response rate (ORR) in pre-treated, chemorefractory multiple myeloma. Most authors agree with using 200 mg/daily with associated high dose dexamethasone (40 mg/daily x 4 days, 3 times monthly) considering lower doses investigational. We report our experience using thalidomide 100 mg/daily plus dexamethasone 40 mg/daily once a month, in 27 pre-treated patients. Thalidomide dose excalation and/or association with other drugs were established on the basis of the patient's response. Median age was 69 years (range 50-83 years) and 16 male and 11 female patients were treated. All patients had received more than 1 treatment line (range 1-5). Thalidomide was increased up to 300 mg/daily in 10 patients and 1 patient received up to 400 mg/daily. Two patients were not evaluable because of early death, 1 did not tolerate thalidomide because of pulmonary and neurological side-effects. Sixteen patients responded to this treatment, with an ORR of 66%. The combination of low-dose thalidomide plus monthly high-dose dexamethasone in chemorefractory myeloma showed interesting palliative results. According to our data, increasing thalidomide dosage and/or adding further drugs does not generally produce significant improvement.

Background: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC) followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST), due to the typically hypervascular pattern of the tumor., Aims: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST., Materials and Methods: Three patients (pts) with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate., Results: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks., Conclusion: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

Thalidomide is active both as single agent and in combination-therapy against refractory or relapsing multiple myeloma. Eigth patients previously treated were given Thalidomide 100mg/daily plus Dexametasone 40mg/daily for four days each month (Thali-Dexa) and followed for response, prognostic factors and side effects. Two patients had early death (one from massive cerebral ischemic stroke, the other from dementia and progressive renal failure), one patient progressed during Thali-Dexa (thalidomide 200mg) and was rescued with chemotherapy, two patients required increasing thalidomide dosage (to 200 and 400mg, respectively) because of progressive disease, three patients had stable disease remission lasting from 4m+ to 16m+. Thali-Dexa is a useful agent but age and vascular/metabolic diseases may increase the risk of severe side effects. Early decrease in erythrocyte sedimentation rate seems to correlate with better disease control.

Colon cancer usually has an hematogenous spread to liver and lung: rarely, or in the case of most advanced disease, also brain and bone can be involved. Thyroid metastasis is generally thought to be infrequent, breast and kidney cancer being the most frequent causes. Herein we present the case of a man affected by liver metastasis from colon cancer, who developed unusual metastasis to thyroid.

The treatment of cancerous polyps of the colon has not been definitely established. In the present study the authors have brought forth their contribution on the role played by endoscopic polypectomy alone or following a surgical resection. At our endoscopic service during the period from 1985 to 1992, there were 42 polyps diagnosed which after histologic examination showed an infiltrating carcinoma. 22 patients underwent surgery and 16 only an endoscopic polypectomy. The median follow-up was 43.3 months with a minimum period of 18 months. Four patients were lost during follow-up. We have analyzed for prognostic reasons, the type of polyps, the radicality of the polypectomy, the degree of differentiation and the infiltration of lymphatic and/or venous vessels of the polyp. The presence of carcinomal residue and lymphonodal metastases were taken into consideration in patients who underwent surgical resection. The results obtained were not evaluated statistically because of the limited number of patients with an adequately long follow-up. Nevertheless they are in line with those results from the majority of the cases quoted in other literature. In particular these cases which seem to have a favorable prognosis are those in which complete endoscopic polypectomy has coupled with a good degree of differentiation and the absence of infiltration of the lymphatic and venous vessels. In these cases surgery does not seem to have bettered the survival rate.

A study evaluating the risk of a commercial factor VIII (FVIII) concentrate's transmitting the human immunodeficiency virus (HIV) was carried out on hemophiliacs, by using multiple serological markers and the polymerase chain reaction (PCR). Twenty-nine hemophiliacs, negative for HIV antibodies, were treated for 18 months with a concentrate that had been inactivated by solvent-detergent. HIV-1 antibodies and antigen were assayed during the follow-up period. At the end of the study, all patients were also tested by the HIV 1 + 2 combined antibody assay; Western blot (WB) antibody analysis; and in eight cases, by an HIV-1 PCR technique. Patients received a yearly median FVIII dose of 35,330 IU (range 3,300-306,000); the median number of lots given to each patient was 6 (1-45). During the follow-up period and at the end of the study, HIV-1 antibodies and antigen were not detected in any of the subjects. The HIV 1 + 2 combined assay and WB analysis carried out only at the end of the study were negative. HIV-1 PCR was negative in all the tested patients. This study has shown that this solvent-detergent-treated FVIII concentrate did not transmit HIV.