Tumour necrosis factor gene polymorphism: a predictive factor for the development of post-transplant lymphoproliferative disease

Epstein–Barr virus-positive post-transplant lymphoproliferative disease (PTLD) is a potentially lethal complication of iatrogenic immunosupression after transplantation. Predicting the development of PTLD allowing early and effective intervention is therefore of importance. Polymorphisms within cytokine genes are implicated in susceptibility to, and progression of, disease however the published data are often conflicting. We undertook investigation of polymorphic alleles within cytokine genes in PTLD and non-PTLD transplant cohorts to determine risk factors for disease. <br/> Methods: SSP-PCR was used to analyse single nucleotide polymorphism within tumour necrosis factor (TNF)-α, interleukin- 1, -6, -10 and lymphotoxin-α genes. The TNF-α levels were measured by standard enzyme-linked immuno-absorbant assay. <br/> Results: We show an association between variant alleles within the TNF-α promoter (−1031C (<i>P</i>=0.005)); −863A (<i>P</i>=0.0001) and TNF receptor I promoter regions (−201T (<i>P</i>=0.02)); −1135C (<i>P</i>=0.03) with the development of PTLD. We also show an association with TNF-α promoter haplotypes with haplotype-3 significantly increased (<i>P</i>=0.0001) and haplotype-1 decreased (P=0.02) in PTLD patients compared to transplant controls. Furthermore, we show a significant increase (<i>P</i>=0.02) in the level of TNF-α in PTLD patient plasma (range 0–97.97 pg ml<sup>−1</sup>) compared to transplant controls (0–8.147 pg ml<sup>−1</sup>), with the highest levels found in individuals carrying the variant alleles. <br/> Conclusion: We suggest that genetic variation within TNF-α loci and the level of plasma cytokine could be used as a predictive risk factor for the development of PTLD

Molecular Signatures of Prostate Stem Cells Reveal Novel Signaling Pathways and Provide Insights into Prostate Cancer

BACKGROUND:The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS:A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-beta has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. CONCLUSIONS/SIGNIFICANCE:Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors

Stapes surgery in osteogenesis imperfecta: retrospective analysis of 34 operated ears.

Item does not contain fulltextIntraoperative findings of stapes surgery in 34 ears from 22 patients with genetically confirmed osteogenesis imperfecta (OI) are reported, as well as the audiometric results after the longest postoperative follow-up published to date. Twenty-nine out of 34 ears underwent primary stapes surgery and 5 ears revision surgery. Postoperative audiometric follow-up ranged from 6 months to 37 years. Stapes footplates were fixed in all ears. Additionally, footplates were thickened or fragile, stapes crura atrophic or fractured, and middle ear mucosae thickened or hypervascularized. Short-term postoperative audiometry revealed improved hearing and reduced air-bone gaps in 28/29 primary operated ears and in all revision cases. In the 22 ears with long-term postoperative follow-up (mean duration: 16 years), hearing gain was still significant at the latest audiometric evaluation. Independently of the patients being diagnosed with OI type I or IV and independently of the underlying OI genotype, beneficial results are obtained in the majority of OI patients undergoing primary or revision stapes surgery for reduction of conductive hearing loss components caused by stapes footplate fixation. Despite the progressive course of the concomitant sensorineural component, hearing gain remains beneficial over several decades

Osteogenesis imperfecta

Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation