103 research outputs found
Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy
X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD
Quantifying fixed individual heterogeneity in demographic parameters: Performance of correlated random effects for Bernoulli variables
Circulating endothelial cell count: a reliable marker of endothelial damage in patients undergoing hematopoietic stem cell transplantation
The physio-pathologic interrelationships between endothelium and GvHD have been better elucidated and have led to definition of the entity 'endothelial GvHD' as an essential early phase prior to the clinical presentation of acute GvHD. Using the CellSearch system, we analyzed circulating endothelial cells (CEC) in 90 allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients at the following time-points: T1 (pre-conditioning), T2 (pre-transplant), T3 (engraftment), T4 (onset of GvHD) and T5 (1 week after steroid treatment). Although CEC changes in allo-HSCT represent a dynamic phenomenon influenced by many variables (that is, conditioning, immunosuppressive treatments, engraftment syndrome and infections), we showed that CEC peaks were constantly seen at onset of acute GvHD and invariably returned to pre-transplant values after treatment response. Since we showed that CEC changes during allo-HSCT has rapid kinetics that may be easily missed if blood samples are drawn at pre-fixed time-points, we rather suggest an 'on demand' evaluation of CEC counts right at onset of GvHD clinical symptoms to possibly help differentiate GvHD from other non-endothelial complications. We confirm that CEC changes are a suitable biomarker to monitor endothelial damage in patients undergoing allo-transplantation and hold the potential to become a useful tool to support GvHD diagnosis (ClinicalTrials.gov NCT02064972).Bone Marrow Transplantation advance online publication, 11 September 2017; doi:10.1038/bmt.2017.194
The caudo-ventral pallium is a novel pallial domain expressing Gdf10 and generating Ebf3-positive neurons of the medial amygdala
In rodents, the medial nucleus of the amygdala receives direct inputs from the accessory olfactory bulbs and is mainly implicated in pheromone-mediated reproductive and defensive behaviors. The principal neurons of the medial amygdala are GABAergic neurons generated principally in the caudo-ventral medial ganglionic eminence and preoptic area. Beside GABAergic neurons, the medial amygdala also contains glutamatergic Otp-expressing neurons cells generated in the lateral hypothalamic neuroepithelium and a non-well characterized Pax6-positive population. In the present work, we describe a novel glutamatergic Ebf3-expressing neuronal subpopulation distributed within the periphery of the postero-ventral medial amygdala. These neurons are generated in a pallial domain characterized by high expression of Gdf10. This territory is topologically the most caudal tier of the ventral pallium and accordingly, we named it Caudo-Ventral Pallium (CVP). In the absence of Pax6, the CVP is disrupted and Ebf3-expressing neurons fail to be generated. Overall, this work proposes a novel model of the neuronal composition of the medial amygdala and unravels for the first time a new novel pallial subpopulation originating from the CVP and expressing the transcription factor Ebf3.This work was supported by Grants of the French National Research Agency (Agence Nationale de la Recherche; ANR) [ANR-13-BSV4-0011] and by the French Government through the ‘Investments for the Future’ LABEX SIGNALIFE [ANR-11-LABX-0028-01] to M.S., by the Spanish Government (BFU2007-60263 and BFU2010-17305) to A.F, and by the Medical Research Council (MR/K013750/1) to T.T. N.R.-R. is funded by a postdoctoral fellowship from the Ville de Nice, France (“Aide Individuelle aux Jeunes Chercheurs 2016”).Peer reviewe
Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms
Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients
Phosphatase and tensin homolog (PTEN) in antigen-presenting cells controls Th17-mediated autoimmune arthritis
Long-term renal function after allogenic haematopoietic stem cell transplantation in adult patients: a single-centre study
BACKGROUND: Reported data regarding chronic kidney disease (CKD) in haematopoietic stem cells transplantation (HSCT) recipients are highly discrepant. Materials and methods. We undertook a retrospective single-centre study in order to assess the rate, risk factors and outcome of HSCT-associated CKD in 123 allogeneic HSCT patients. RESULTS: Twenty-four months after HSCT, CKD [e.g. glomerular filtration rate (GFR) estimated using the MDRD formula <60 ml/min/1.73 m(2)] was noted in 49 patients (40%). Age >or= 45 years, early acute kidney injury and a baseline GFR < 90 ml/min/1.73 m(2) predicted the occurrence of CKD at 24 months after HSCT. One hundred and six patients (45 with and 61 without CKD at 24 months) were followed up for more than 36 months (range 36-142). Among the 45 patients with CKD at 24 months after HSCT, CKD persisted in 30 (67%), 10 patients (22%) showed a transient improvement in GFR but retained CKD and 10 patients (22%) had a sustained improvement of GFR. Among 61 patients without CKD at 24 months after HSCT, 3 (5%) developed CKD during the follow-up. Our data indicate that HSCT-related CKD probably includes two subsets: a frequent early-onset CKD, a consequence of ARF in older patients with pre-existent renal impairment, and a rare late-onset CKD occurring more than 2 years following HSCT. CONCLUSIONS: Careful monitoring of renal function is mandatory in patients undergoing HSCT, especially old patients with pre-existent renal impairment
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