Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This work received support from the “Fondazione Umberto di Mario ONLUS”, Rome, and AIRC (MFAG-12108 to CS and IG-13049 to GM)

Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC

Successful management of an aortoesophageal fistula caused by a fish bone – case report and review of literature

We report a case of aortoesophageal fistula (AEF) caused by a fish bone that had a successful outcome. Aortoesophageal fistula is a rare complication of foreign body ingestion from which few patients survive. Over one hundred cases of AEF secondary to foreign body ingestion have been documented but only seven, including our case, have survived over 12 months. Treatment involved stabilising the patient with a Sengstaken-Blakemore tube and insertion of a thoracic aortic endovascular stent-graft. Unfortunately the stent became infected and definitive open surgical repair involved removing the stent, replacing the aorta with a homograft and coverage with a left trapezius flap while under deep hypothermic arrest

Novel prokaryotic expression of thioredoxin-fused insulinoma associated protein tyrosine phosphatase 2 (IA-2), its characterization and immunodiagnostic application

Background The insulinoma associated protein tyrosine phosphatase 2 (IA-2) is one of the immunodominant autoantigens involved in the autoimmune attack to the beta-cell in Type 1 Diabetes Mellitus. In this work we have developed a complete and original process for the production and recovery of the properly folded intracellular domain of IA-2 fused to thioredoxin (TrxIA-2ic) in Escherichia coli GI698 and GI724 strains. We have also carried out the biochemical and immunochemical characterization of TrxIA-2icand design variants of non-radiometric immunoassays for the efficient detection of IA-2 autoantibodies (IA-2A). Results The main findings can be summarized in the following statements: i) TrxIA-2ic expression after 3 h of induction on GI724 strain yielded ≈ 10 mg of highly pure TrxIA-2ic/L of culture medium by a single step purification by affinity chromatography, ii) the molecular weight of TrxIA-2ic (55,358 Da) could be estimated by SDS-PAGE, size exclusion chromatography and mass spectrometry, iii) TrxIA-2ic was properly identified by western blot and mass spectrometric analysis of proteolytic digestions (63.25 % total coverage), iv) excellent immunochemical behavior of properly folded full TrxIA-2ic was legitimized by inhibition or displacement of [35S]IA-2 binding from IA-2A present in Argentinian Type 1 Diabetic patients, v) great stability over time was found under proper storage conditions and vi) low cost and environmentally harmless ELISA methods for IA-2A assessment were developed, with colorimetric or chemiluminescent detection. Conclusions E. coli GI724 strain emerged as a handy source of recombinant IA-2ic, achieving high levels of expression as a thioredoxin fusion protein, adequately validated and applicable to the development of innovative and cost-effective immunoassays for IA-2A detection in most laboratories.Fil: Guerra, Luciano Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Faccinetti, Natalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Trabucchi, Aldana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Rovitto, Bruno David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Sabljic, Adriana Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Poskus, Edgardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Iacono, Ruben Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Valdez, Silvina Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentin

Severe inflammatory reaction induced by peritoneal trauma is the key driving mechanism of postoperative adhesion formation

<p>Abstract</p> <p>Background</p> <p>Many factors have been put forward as a driving mechanism of surgery-triggered adhesion formation (AF). In this study, we underline the key role of specific surgical trauma related with open surgery (OS) and laparoscopic (LS) conditions in postoperative AF and we aimed to study peritoneal tissue inflammatory reaction (TIR), remodelling specific complications of open surgery (OS) versus LS and subsequently evaluating AF induced by these conditions.</p> <p>Methods</p> <p>A prospective randomized study was done in 80 anaesthetised female Wistar rats divided equally into 2 groups. Specific traumatic OS conditions were induced by midline incision line (MIL) extension and tissue drying and specific LS conditions were remodelled by intraperitoneal CO₂insufflation at the 10 cm of water. TIR was evaluated at the 24^th, 72^nd, 120^thand 168^thhour by scoring scale. Statistical analysis was performed by the non-parametric t test and two-way ANOVA using Bonferroni post-tests.</p> <p>Results</p> <p>More pronounced residual TIR was registered after OS than after LS. There were no significant TIR interactions though highly significant differences were observed between the OS and LS groups (p < 0.0001) with regard to surgical and time factors. The TIR change differences between the OS and LS groups were pronounced with postoperative time p < 0.05 at the 24^thand 72^nd; p < 0.01 - 120^thand p < 0.001 - 168^thhrs. Adhesion free wounds were observed in 20.0 and 31.0% of cases after creation of OS and LS conditions respectively; with no significant differences between these values (p > 0.05). However larger adhesion size (41.67 ± 33.63) was observed after OS in comparison with LS (20.31 ± 16.38). The upper-lower 95% confidential limits ranged from 60.29 to 23.04 and from 29.04 to 11.59 respectively after OS and LS groups with significant differences (p = 0.03). Analogous changes were observed in adhesion severity values. Subsequently, severe TIR parameters were followed by larger sizes of severe postoperative adhesions in the OS group than those observed in the LS group.</p> <p>Conclusions</p> <p>MIL extension and tissue drying seem to be the key factors in the pathogenesis of adhesion formation, triggering severe inflammatory reactions of the peritoneal tissue surrounding the MIL resulting in local and systemic consequences. CO₂insufflation however, led to moderate inflammation and less adhesion formation.</p

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma

Background: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. Methods: We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. Results: In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. Conclusions and interpretations: We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment

An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models

<p>Abstract</p> <p>Background</p> <p>The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A_2Aadenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.</p> <p>Methods</p> <p>Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (<it>Escherichia coli </it>or <it>Staphylococcus aureus</it>) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A_2AAR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.</p> <p>Results</p> <p>There was a significant survival benefit in mice infected with live <it>E. coli </it>(100% vs. 20%, <it>p </it>= 0.013) or <it>S. aureus </it>(60% vs. 20%, <it>p </it>= 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, <it>p </it>= 0.005). The serum concentrations of TNF-α, MIP-1α, MCP-1, IFN-γ, and IL-17 were decreased by ATL313 after LPS injection (<it>p </it>< 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (<it>p </it>< 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (<it>p </it>< 0.01).</p> <p>Conclusion</p> <p>Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.</p

Chronic kidney disease after liver, cardiac, lung, heart–lung, and hematopoietic stem cell transplant

Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease