332 research outputs found
Argument Structure of Classifier Predicates: Canonical and Non-canonical Mappings in Four Sign Languages
Invasive fungal infections in patients with acute myeloid leucemia and in those submitted to allogeneic hemopoieticstem cell transplant: who is at highest risk ?
Invasive fungal infections (IFIs) are a growing cause
of morbidity and mortality in patients with acute
myeloid leukemia (AMLs) and in recipients of allogeneic
hemopoietic stem cell transplantation (allo-HSCTs) (1–6).
It is widely debated if either allo-HSCTs or AMLs are to
be considered at higher risk, but no data comparing the
two categories of patients have been reported in
literature so far.
This cohort study has been conducted from January
1999 to December 2003 in hematology wards located
throughout Italy. The study was aimed at evaluating the
incidence and mortality for IFIs in adult AMLs and in
patients submitted to all types of allo-HSCT procedures;
a comparison between the two categories of patients was
carried out
Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss
Inactivating variants as well as a missense variant in the centrosomal CEP78 gene
have been identified in autosomal recessive cone-rod dystrophy with hearing loss
(CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome.
Apart from this, a complex structural variant (SV) implicating CEP78 has been reported
in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL
by the identification of complex SVs of the CEP78 region and characterization of
their underlying mechanisms. Approaches used for the identification of the SVs are
shallow whole-genome sequencing (sWGS) combined with quantitative polymerase
chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome
sequencing (WES) data. Targeted or whole-genome nanopore long-read sequencing
(LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs
cases, the effect of the SVs on CEP78 expression was assessed using quantitative
PCR on patient-derived RNA. Apart from two novel canonical CEP78 splice variants
and a frameshifting single-nucleotide variant (SNV), two SVs affecting CEP78 were
identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion
of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous
state, respectively. Assessment of the molecular consequences of the SVs on patient’s
materials displayed a loss-of-function effect. Delineation and characterization of the 15-kb deletion using targeted LRS revealed the previously described complex CEP78
SV, suggestive of a recurrent genomic rearrangement. A founder haplotype was
demonstrated for the latter SV in cases of Belgian and British origin, respectively. The
novel 235-kb deletion was delineated using whole-genome LRS. Breakpoint analysis
showed microhomology and pointed to a replication-based underlying mechanism.
Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets,
together with CEP78 immunostaining on human retina, linked the CEP78 expression
domain with its phenotypic manifestations. Overall, this study supports that the CEP78
locus is prone to distinct SVs and that SV analysis should be considered in a genetic
workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted
and whole-genome LRS in identifying and characterizing complex SVs in patients with
ocular diseases
CRISPR screens in sister chromatid cohesion defective cells reveal PAXIP1-PAGR1 as regulator of chromatin association of cohesin
The cohesin complex regulates higher order chromosome architecture through maintaining sister chromatid cohesion and folding chromatin by DNA loop extrusion. Impaired cohesin function underlies a heterogeneous group of genetic syndromes and is associated with cancer. Here, we mapped the genetic dependencies of human cell lines defective of cohesion regulators DDX11 and ESCO2. The obtained synthetic lethality networks are strongly enriched for genes involved in DNA replication and mitosis and support the existence of parallel sister chromatid cohesion establishment pathways. Among the hits, we identify the chromatin binding, BRCT-domain containing protein PAXIP1 as a novel cohesin regulator. Depletion of PAXIP1 severely aggravates cohesion defects in ESCO2 mutant cells, leading to mitotic cell death. PAXIP1 promotes global chromatin association of cohesin, independent of DNA replication, a function that cannot be explained by indirect effects of PAXIP1 on transcription or DNA repair. Cohesin regulation by PAXIP1 requires its binding partner PAGR1 and a conserved FDF motif in PAGR1. PAXIP1 co-localizes with cohesin on multiple genomic loci, including active gene promoters and enhancers. Possibly, this newly identified role of PAXIP1-PAGR1 in regulating cohesin occupancy on chromatin is also relevant for previously described functions of PAXIP1 in transcription, immune cell maturation and DNA repair.</p
Impact of T‐cell depletion strategies on outcomes following hematopoietic stem cell transplantation for idiopathic aplastic anemia: A study on behalf of the European blood and marrow transplant severe aplastic anemia working party
We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) hemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either anti‐thymocyte globulin (ATG) (n = 1283), alemtuzumab (n = 261), or no serotherapy (NS) (n = 293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared with NS (P = .021 and .003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared with ATG (P = .012) and NS (P < .001). By multivariate analysis, when compared with ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14‐0.47; P < .001) and chronic GVHD (HR 0.58; 95% CI 0.35‐0.94; P = .027). OS was significantly better in ATG and alemtuzumab patients compared with NS (P = .010 and .025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared with ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA
Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction
AIMS: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. METHODS AND RESULTS: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27–55]. During a median follow-up of 4.3 years (IQR 1.7–7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78–0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61–0.75). CONCLUSION: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach
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