Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients

X-linked cataract and Nance-Horan syndrome are allelic disorders

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved

Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage

IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans

The role of IL-1beta in intestinal inflammation

Although very high levels of IL 1β are present in the intestines of patients suffering from Inflammatory Bowel Diseases (IBD), little is known about the contribution of IL 1β to intestinal pathology. In the work presented in this thesis, I used several mouse models of chronic intestinal inflammation to address the role of IL 1β in driving innate and adaptive immune pathology in the intestine. My results showed that IL 1β promotes innate immune pathology in Helicobacter hepaticus triggered innate intestinal inflammation, by augmenting the recruitment of granulocytes and the accumulation and activation of a population of IFN γ and IL 17A producing innate lymphoid cells (ILC). To specifically investigate the role of IL 1R signaling on pathogenic T cell responses in the intestine, I used a T cell transfer colitis model. My results demonstrated a key role for IL 1R signals in promoting the accumulation and survival of pathogenic CD4+ T cells in the colon, particularly CD4+ IL 17A+ Th17 cells. Finally, because mutations in the NOD2 gene have been strongly associated with susceptibility to IBD, I investigated the contribution of NOD2 in the H.hepaticusinduced innate immune IBD model. I found that NOD2 expression was significantly increased in the inflamed colon. Furthermore, my preliminary studies suggested that NOD2 played a pro inflammatory role in innate immune colitis, but that NOD2 had little impact on H.hepaticus colonization of the mouse intestine. In summary, my results identify multiple mechanisms through which IL 1β promotes intestinal pathology and suggesting that targeting IL 1β, or innate immune receptors, may represent a useful therapeutic approach in IBD.</p

a community based waste management system for the historic centre of naples

The municipal area of Naples produces 1600 tons of garbage every day, only 9% of which is recycled. While many cities in Europe have made remarkable progress in managing urban waste meaningfully, it remains a major concern for Naples. As the centralized system appears incompetent, on-site waste management seems a solution. The Infra-Free (IF) system is the inspiration behind an alternative model. It reduces burden on the urban infrastructure for both; waste management and energy as the later is produced in the process of the first. Every house does not have adequate space and this leads to a solution based on the community. The proposed system will manage waste and generate energy not only for the community but also for the urban spaces around. It is economically beneficial and helps to accumulate social capital, which is a vital asset for any city. The authors worked on a block located in the historical center of Naples and found that the network of courtyards provided an ideal setup for a community based waste management system. Thus, urban waste no longer remains a problem but becomes an economically rewarding opportunity for generating social energy and revitalizing the community