The molecular pathophysiology of chronic non-bacterial osteomyelitis (CNO)-a systematic review.

Chronic non-bacterial osteomyelitis (CNO) belongs to the growing spectrum of autoinflammatory diseases and primarily affects the skeletal system. Peak onset ranges between 7 and 12 years of age. The clinical spectrum of CNO covers sometimes asymptomatic inflammation of single bones at the one end and chronically active or recurrent multifocal osteitis at the other.Despite the intense scientific efforts, the exact molecular mechanisms of CNO remain unknown. Recent data suggest CNO as a genetically complex disorder with dysregulated TLR4/MAPK/inflammasome signaling cascades resulting in an imbalance between pro- and anti-inflammatory cytokine expression, leading to osteoclast activation and osteolytic lesions.In this manuscript, the current understanding of molecular patho-mechanisms in CNO will be discussed

An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells

Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations

Biomarkers to identify and isolate senescent cells

This paper was accepted for publication in the journal Ageing Research Reviews and the definitive published version is available at http://dx.doi.org/10.1016/j.arr.2016.05.003.Aging is the main risk factor for many degenerative diseases and declining health. Senescent cells are part of the underlying mechanism for time-dependent tissue dysfunction. These cells can negatively affect neighbouring cells through an altered secretory phenotype: the senescence-associated secretory phenotype (SASP). The SASP induces senescence in healthy cells, promotes tumour formation and progression, and contributes to other age-related diseases such as atherosclerosis, immune-senescence and neurodegeneration. Removal of senescent cells was recently demonstrated to delay age-related degeneration and extend lifespan. To better understand cell aging and to reap the benefits of senescent cell removal, it is necessary to have a reliable biomarker to identify these cells. Following an introduction to cellular senescence, we discuss several classes of biomarkers in the context of their utility in identifying and/or removing senescent cells from tissues. Although senescence can be induced by a variety of stimuli, senescent cells share some characteristics that enable their identification both in vitro and in vivo. Nevertheless, it may prove difficult to identify a single biomarker capable of distinguishing senescence in all cell types. Therefore, this will not be a comprehensive review of all senescence biomarkers but rather an outlook on technologies and markers that are most suitable to identify and isolate senescent cells

Exome sequencing circumvents missing clinical data and identifies a BSCL2 mutation in congenital lipodystrophy

BACKGROUND: Exome sequencing has become more and more affordable and the technique has emerged as an important diagnostic tool for monogenic disorders at early stages of investigations, in particular when clinical information is limited or unspecific as well as in cases of genetic heterogeneity. METHODS: We identified a consanguineous Pakistani family segregating an autosomal recessive phenotype characterized by muscular hypertrophy, mild mental retardation and skeletal abnormalities. The available clinical information was incomplete and we applied whole exome sequencing in an affected family member for the identification of candidate gene variants. RESULTS: Exome sequencing identified a previously unreported homozygous mutation in the acceptor splice site of intron 5 in the BSCL2 gene (c.574-2A > G). Expression analysis revealed that the mutation was associated with skipping of exon 6. BSCL2 mutations are associated with Berardinelli-Seip congenital lipodystrophy and a clinical re-evaluation of affected individuals confirmed the diagnosis. CONCLUSIONS: Exome sequencing is a powerful technique for the identification of candidate gene variants in Mendelian traits. We applied this technique on a single individual affected by a likely autosomal recessive disorder without access to complete clinical details. A homozygous and truncating mutation was identified in the BSCL2 gene suggesting congenital generalized lipodystrophy. Incomplete phenotypic delineations are frequent limiting factors in search for a diagnosis and may lead to inappropriate care and follow-up. Our study exemplifies exome sequencing as a powerful diagnostic tool in Mendelian disorders that may complement missing clinical information and accelerate clinical diagnosis

Exome sequencing circumvents missing clinical data and identifies a BSCL2 mutation in congenital lipodystrophy

BACKGROUND: Exome sequencing has become more and more affordable and the technique has emerged as an important diagnostic tool for monogenic disorders at early stages of investigations, in particular when clinical information is limited or unspecific as well as in cases of genetic heterogeneity. METHODS: We identified a consanguineous Pakistani family segregating an autosomal recessive phenotype characterized by muscular hypertrophy, mild mental retardation and skeletal abnormalities. The available clinical information was incomplete and we applied whole exome sequencing in an affected family member for the identification of candidate gene variants. RESULTS: Exome sequencing identified a previously unreported homozygous mutation in the acceptor splice site of intron 5 in the BSCL2 gene (c.574-2A > G). Expression analysis revealed that the mutation was associated with skipping of exon 6. BSCL2 mutations are associated with Berardinelli-Seip congenital lipodystrophy and a clinical re-evaluation of affected individuals confirmed the diagnosis. CONCLUSIONS: Exome sequencing is a powerful technique for the identification of candidate gene variants in Mendelian traits. We applied this technique on a single individual affected by a likely autosomal recessive disorder without access to complete clinical details. A homozygous and truncating mutation was identified in the BSCL2 gene suggesting congenital generalized lipodystrophy. Incomplete phenotypic delineations are frequent limiting factors in search for a diagnosis and may lead to inappropriate care and follow-up. Our study exemplifies exome sequencing as a powerful diagnostic tool in Mendelian disorders that may complement missing clinical information and accelerate clinical diagnosis