The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation

<p>Abstract</p> <p>Background</p> <p>Aberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT).</p> <p>Methods</p> <p><it>TP53 </it>(a tumor suppressor gene assigned to chromosome 17), <it>AML1 </it>(a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation) and the pericentomeric satellite sequence of chromosome 17 (<it>CEN17</it>) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence <it>in situ </it>hybridization (FISH) technology applied to phytohemagglutinin (PHA)-stimulated lymphocytes.</p> <p>Results</p> <p>We show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations) displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state). A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged.</p> <p>Conclusions</p> <p>The reversible nature of the replication aberrations may serve as potential epigenetic blood markers for evaluating the success of transplant or other treatments and for long-term follow up of the patients who have overcome a hematological malignancy.</p

Replication profile of PCDH11X and PCDH11Y, a gene pair located in the non-pseudoautosomal homologous region Xq21.3/Yp11.2

In order to investigate the replication timing properties of PCDH11X and PCDH11Y, a pair of protocadherin genes located in the hominid-specific non-pseudoautosomal homologous region Xq21.3/Yp11.2, we conducted a FISH-based comparative study in different human and non-human primate (Gorilla gorilla) cell types. The replication profiles of three genes from different regions of chromosome X (ZFX, XIST and ATRX) were used as terms of reference. Particular emphasis was given to the evaluation of allelic replication asynchrony in relation to the inactivation status of each gene. The human cell types analysed include neuronal cells and ICF syndrome cells, considered to be a model system for the study of X inactivation. PCDH11 appeared to be generally characterized by replication asynchrony in both male and female cells, and no significant differences were observed between human and gorilla, in which this gene lacks X-Y homologous status. However, in differentiated human neuroblastoma and cerebral cortical cells PCDH11X replication profile showed a significant shift towards allelic synchrony. Our data are relevant to the complex relationship between X-inactivation, as a chromosome-wide phenomenon, and asynchrony of replication and expression status of single genes on chromosome X

Long-term results of cemented total hip arthroplasty in patients younger than 30 years and the outcome of subsequent revisions

Contains fulltext : 118748.pdf (publisher's version ) (Open Access)BACKGROUND: The number of total hip arthroplasties in patients under 30 years is increasing over the years. Almost all of them will face at least one or more future revisions in their life. Therefore, the implant used should have a high survival rate, and needs to be easily revisable resulting in a low re-revision rate. Several studies have evaluated the outcome of total hip arthroplasties in patients under 30 years. However, only a few reported on the follow-up outcome of 10 years or more. In addition, none of these reports published data of the subsequent revisions of these implants within their original report. METHODS: We studied historically prospective collected data of 48 consecutive patients (69 hips) younger than 30 years, treated with a cemented primary total hip prosthesis between 1988 and 2004. Since the last evaluation of this cohort, two patients were lost to follow-up. For all hip revisions in this cohort, again cemented implants were used, mostly in combination with bone impaction grafting. Kaplan-Meier survival curves at 10- and 15 years for the primary total hip arthroplasties and revisions were determined. RESULTS: The mean age at time of primary surgery was 25 years (range, 16 to 29 years). Mean follow-up of the primary hips was 11.5 years (range, 7 to 23 years). During follow-up 13 revisions were performed; in 3 cases a two-stage total revision was performed for septic loosening and 9 cups were revised for aseptic loosening. There were no aseptic stem revisions. The 10 and 15-year survival rates with endpoint revision for aseptic loosening of the primary total hip were 90% (95% CI: 79 to 96) and 82% (95% CI: 65 to 92) respectively. None of our 13 subsequent revisions needed a re-revision within 10 years after re-implantation. CONCLUSIONS: Cemented total hip implants in patients under 30 years have an encouraging outcome at 10 and 15 years after surgery in these young patients. The 13 revised hips, treated with bone grafting and the third generation cement technique, were performing well with no re-revisions within ten years after surgery