HLA-matched sibling transplantation with G-CSF mobilized PBSCs and BM decreases GVHD in adult patients with severe aplastic anemia

<p>Abstract</p> <p>Background</p> <p>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for severe aplastic anemia (SAA). However, graft failure and graft-versus-host disease (GVHD) are major causes of the early morbidity in Allo-HSCT.</p> <p>Methods</p> <p>To reduce graft failure and GVHD, we treated fifteen patients with SAA using high- dose of HSCT with both G-CSF mobilized PB and BMSCs from HLA-identical siblings to treat patients with SAA.</p> <p>Results</p> <p>All patients had successful bone marrow engraftment. Only one patient had late rejection. Median time to ANC greater than 0.5 × 10⁹/L and platelet counts greater than 20 × 10⁹/L was 12 and 16.5 days, respectively. No acute GVHD was observed. The incidence of chronic GVHD was 6.67%. The total three-year probability of disease-free survival was 79.8%.</p> <p>Conclusion</p> <p>HSCT with both G-CSF mobilized PB and BMSCs is a promising approach for heavily transfused and/or allo-immunized patients with SAA.</p

Repeatability of Foveal Measurements Using Spectralis Optical Coherence Tomography Segmentation Software

PURPOSE: To investigate repeatability and reproducibility of thickness of eight individual retinal layers at axial and lateral foveal locations, as well as foveal width, measured from Spectralis spectral domain optical coherence tomography (SD-OCT) scans using newly available retinal layer segmentation software. METHODS: High-resolution SD-OCT scans were acquired for 40 eyes of 40 young healthy volunteers. Two scans were obtained in a single visit for each participant. Using new Spectralis segmentation software, two investigators independently obtained thickness of each of eight individual retinal layers at 0°, 2° and 5° eccentricities nasal and temporal to foveal centre, as well as foveal width measurements. Bland-Altman Coefficient of Repeatability (CoR) was calculated for inter-investigator and inter-scan agreement of all retinal measurements. Spearman's ρ indicated correlation of manually located central retinal thickness (RT0) with automated minimum foveal thickness (MFT) measurements. In addition, we investigated nasal-temporal symmetry of individual retinal layer thickness within the foveal pit. RESULTS: Inter-scan CoR values ranged from 3.1μm for axial retinal nerve fibre layer thickness to 15.0μm for the ganglion cell layer at 5° eccentricity. Mean foveal width was 2550μm ± 322μm with a CoR of 13μm for inter-investigator and 40μm for inter-scan agreement. Correlation of RT0 and MFT was very good (ρ = 0.97, P 0.05); however this symmetry could not be found at 5° eccentricity. CONCLUSIONS: We demonstrate excellent repeatability and reproducibility of each of eight individual retinal layer thickness measurements within the fovea as well as foveal width using Spectralis SD-OCT segmentation software in a young, healthy cohort. Thickness of all individual retinal layers were symmetrical at 2°, but not at 5° eccentricity away from the fovea

Ubiquitous Expression of CUG or CAG Trinucleotide Repeat RNA Causes Common Morphological Defects in a Drosophila Model of RNA-Mediated Pathology

Expanded DNA repeat sequences are known to cause over 20 diseases, including Huntington’s disease, several types of spinocerebellar ataxia and myotonic dystrophy type 1 and 2. A shared genetic basis, and overlapping clinical features for some of these diseases, indicate that common pathways may contribute to pathology. Multiple mechanisms, mediated by both expanded homopolymeric proteins and expanded repeat RNA, have been identified by the use of model systems, that may account for shared pathology. The use of such animal models enables identification of distinct pathways and their ‘molecular hallmarks’ that can be used to determine the contribution of each pathway in human pathology. Here we characterise a tergite disruption phenotype in adult flies, caused by ubiquitous expression of either untranslated CUG or CAG expanded repeat RNA. Using the tergite phenotype as a quantitative trait we define a new genetic system in which to examine ‘hairpin’ repeat RNA-mediated cellular perturbation. Further experiments use this system to examine whether pathways involving Muscleblind sequestration or Dicer processing, which have been shown to mediate repeat RNA-mediated pathology in other model systems, contribute to cellular perturbation in this model

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)

Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP’s function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI

Use of Biomarkers in the Evaluation and Treatment of Hypertensive Patients

The current definition of hypertension is based on blood pressure values, and blood pressure also drives treatment decisions, is the most important treatment monitoring tool and helps estimating risk of hypertension related organ damage. In an era of precision medicine additional biomarkers are needed in the diagnosis and management of patients with hypertension. In this review we outline the areas in which functional, imaging and circulating biomarkers could help in a more individualised definition of hypertension and associated risk. We will cover biomarkers for diagnosis; of pathophysiology and prediction of hypertension; response to treatment, organ damage; and to monitor treatment. A clear focus is on the vasculature, the heart and the kidneys, whereas we see a need to further develop biomarkers of cerebral function in order to diagnose cognition deficits and monitor changes in cognition in the future to support addressing the growing burden of hypertension associated vascular dementia