Prostate cancer detection through unbiased capture of methylated cell-free DNA

Funding: Cancer Research UK, CRUK Career Development Fellowship, University of Cambridge W.D. Armstrong Trust Fund, John Black Prostate Cancer Foundation Young Investigator Award. This research was also supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).Prostate cancer screening using prostate-specific antigen (PSA) has been shown to reduce mortality but with substantial overdiagnosis, leading to unnecessary biopsies. The identification of a highly specific biomarker using liquid biopsies, represents an unmet need in the diagnostic pathway for prostate cancer. In this study, we employed a method that enriches for methylated cell-free DNA fragments coupled with a machine learning algorithm which enabled the detection of metastatic and localized cancers with AUCs of 0.96 and 0.74, respectively. The model also detected 51.8% (14/27) of localized and 88.7% (79/89) of patients with metastatic cancer in an external dataset. Furthermore, we show that the differentially methylated regions reflect epigenetic and transcriptomic changes at the tissue level. Notably, these regions are significantly enriched for biologically relevant pathways associated with the regulation of cellular proliferation and TGF-beta signaling. This demonstrates the potential of circulating tumor DNA methylation for prostate cancer detection and prognostication.Peer reviewe

Features and outcome of autoimmune hepatitis type 2 presenting with isolated positivity for anti-liver cytosol antibody

Autoimmune hepatitis (AIH) type 2 is identified by the presence in the serum of anti-liver/kidney microsome type 1 autoantibody. Anti-liver cytosol autoantibody has been reported in children with autoimmune liver disorders mostly in association with anti-liver/kidney microsome reactivity. However, its role as a sole marker of AIH type 2 is debated. We describe here a series of 18 children and adolescents (15 girls, 3 boys) with AIH with serum anti-liver cytosol type 1 (aLC1) as the only autoimmune marker. A retrospective review was conducted from 3 pediatric hepatology units of all children with an autoimmune liver disease associated with aLC1 as found by immunofluorescence and/or immunodiffusion or immunoblotting. Age at first symptoms ranged from 11 months to 14 years; 12 children presented with acute hepatitis, 1 with progressive jaundice, and 5 were asymptomatic. Anti-liver/kidney microsome, antimitochondria, and anti-actin autoantibodies were not detected. Signs of cirrhosis were present in 11 children. Immunosuppressive treatment was effective in all except 2 children who had subfulminant hepatic failure and who required liver transplantation. Sixteen patients (14 with their native liver) currently are alive; 14 patients still are on immunosuppressive therapy after 1 to 22 years. According to the international scoring system for the diagnosis of AIH, 16 patients corresponded to a definite diagnosis and 2 corresponded to a probable diagnosis. In conclusion, the presence of aLC1 in children with acute or chronic liver disease of unknown origin strongly supports a diagnosis of AIH and is an indication for early immunosuppressive therapy

Leiomyosarcoma of the inferior vena cava

International audienceBackground: Leiomyosarcoma (LMS) of the inferior vena cava (IVC) is a rare tumor with poor prognosis. Optimal treatment includes complete resection of the malignant lesion. Methods: From 1997 to 2013, eight patients underwent surgery in our department for IVC LMS. LMS was considered to arise from the IVC if the tumor presented intraluminal development or if complete resection (R0) required removal of part of the IVC with an extraluminal mass. Results: There were two grade 1 tumors (25%), four grade 2 (50%) and two grade 3 (25%). The median length of stay was 16 days and there were no peri-operative deaths. Median of follow-up was 56 months and mean overall survival was 120 months. Mean 3-year survival rate was 87.5%. Six patients (75%) developed a local recurrence. Four patients died from disease progression. Two patients underwent to surgery for recurrence. Conclusion: IVC LMS have a poor prognosis if surgical resection cannot be achieved. Long-term survival is related to an extensive surgery, in the event of recurrence, surgery should again be proposed and may be effective for controlling disease progression, possibly improving survival. (C) 2016 Published by Elsevier Masson SAS

Differential regulation of porcine beta-defensins 1 and 2 upon Salmonella infection in the intestinal epithelial cell line IPI-2I

Intestinal epithelial cells represent the first line of defence against pathogenic bacteria in the lumen of the gut. Besides acting as a physical barrier, epithelial cells orchestrate the immune response through the production of several innate immune mediator molecules including beta-defensins. Here, we establish the porcine intestinal cell line IPI-2I as a new model system to test the regulation of porcine beta-defensins 1 and 2. Gene expression of both defensins was highly upregulated by foetal calf serum components in normal growth medium. In serum-free medium, baseline expression remained low, but pBD-2 gene expression was increased 10-fold upon infection with Salmonella Typhimurium. Arcobacter cryaerophilus and Salmonella Enteritidis, pathogenic bacteria with comparable adhesion and invasion characteristics, failed to increase pBD-2 mRNA levels. Heat killed or colistin-treated Salmonella Typhimurium had no effect, showing that the upregulation of pBD-2 was dependent on the viability of the Salmonella Typhimurium. Gene expression of pBD-1 was regulated differently since an increase in pBD-1 mRNA was observed by Salmonella Enteritidis infection. We conclude that the IPI-2I cells can serve as a new model to study porcine beta-defensin regulation and that pBD-1 and pBD-2 are differentially regulated in this cell line

Understanding and measuring circular polarization

[Abstract]: The complexity and uncertainty that is inherent in the E-Commerce environment poses a number of challenges to the development of E-commerce applications. Key stakeholders consistently use heuristics to make sense of the challenges they face. The most pervasive of these heuristics is framing, whereby people rely on a conceptual set to organise their perceptions. This process has some benefits but it can also lead to a narrow approach, ignorance concerning important elements of the decision environment and an absolute reliance on a specialist area of knowledge. This has significant implications for coherence of effort and vision, elements crucial to the success of e-Commerce projects. This paper uses a case study, qualitative approach in order to establish whether there is evidence for the operation of the framing heuristic, particularly within the context of risk perception, within a variety of E-Commerce system development environments