PECULIARITIES OF MESENCHYMAL STEM CELLS AND THE LEVEL OF GDF 15 IN THE BONE MARROW OF PATIENTS WITH HIGH THALASSEMIA

Mesenchymal stem cell (MSC) are the important component of the microenvironment of the bone marrow and. Playing an active role in case of ineffective erythropoiesis they take part in regulation of erythropoiesis through the synthesis of cytokines. In the present study proliferative characteristics, morphology, phenotype and differentiation capacity of MSCs were examined. In addition, culture supernatants and bone marrow plasmas were analyzed for GDF 15

Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature

Diamond Blackfan Anemia (DBA) is an inherited bone marrow (BM) failure syndrome, characterized by a paucity of erythroid differentiation. DBA is mainly caused by the mutations in ribosomal protein genes, hence classified as ribosomopathy. However, in approximately 30% of patients, the molecular etiology cannot be discovered. RPS19 germline mutations caused 25% of the cases. On the other hand, CECR1 mutations also cause phenotypes similar to DBA but not being a ribosomopathy. Due to the blockade of erythropoiesis in the BM, we investigated the transcriptomic profile of three different cell types of BM resident cells of DBA patients and compared them with healthy donors. From BM aspirates BM mononuclear cells (MNCs) were isolated and hematopoietic stem cells (HSC) [CD71–CD34+ CD38mo/lo], megakaryocyte–erythroid progenitor cells (MEP) [CD71–CD34+ CD38hi] and Proerythroblasts [CD71+ CD117+ CD38+] were sorted and analyzed with a transcriptomic approach. Among all these cells, proerythroblasts had the most different transcriptomic profile. The genes associated with cellular stress/immune responses were increased and some of the transcription factors that play a role in erythroid differentiation had altered expression in DBA proerythroblasts. We also showed that gene expression levels of ribosomal proteins were decreased in DBA proerythroblasts. In addition to these, colony formation assay (CFU-E) provided functional evidence of the failure of erythroid differentiation in DBA patients. According to our findings that all patients resembling both RPS19 and CECR1 mutations have common transcriptomic signatures, it may be possible that inflammatory BM niche may have a role in DBA pathogenesis

The Effect of Granulocyte Colony–Stimulating Factor on Immune-Modulatory Cytokines in the Bone Marrow Microenvironment and Mesenchymal Stem Cells of Healthy Donors

AbstractGranulocyte colony stimulating factor (G-CSF) is sometimes administered to donors before bone marrow (BM) harvest. G-CSF–primed (G-BM) and unprimed BM (U-BM)–derived mesenchymal stem cells (MSC) were obtained from 16 healthy donors and were expanded in vitro. Their proliferative characteristics, morphology, and differentiation capacity were examined. Supernatants of the second passage of MSCs were evaluated for transforming growth factor β1, hepatocyte growth factor, and prostaglandin E2 (PGE2) levels and compared with controls. The analyses of cytokines in the G-BM– and U-BM–derived MSCs supernatants revealed that PGE2 levels were significantly lower in the G-CSF–primed samples. These cytokines were also measured in BM plasma. The level of hepatocyte growth factor in G-BM plasma was significantly increased. The current study is the first to show the effects of G-CSF on the BM microenvironment of healthy human donors. The preliminary data suggest that G-BM– and U-BM–derived MSCs have similar morphologic/phenotypic properties and differentiation capacity but differ in their secretory capacity. Significant changes in cytokine levels of BM plasma in G-CSF–primed donors were also demonstrated. These findings suggest that BM MSCs and changes in the BM microenvironment may contribute to the effects of G-CSF on inflammation and immunomodulation

Stem cell transplantation for congenital dyserythropoietic anemia : an analysis from the European Society for Blood and Marrow Transplantation

Non peer reviewe

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

peer reviewedAllogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT

Coexisting or underlying risk factors of hepatic veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients receiving prophylaxis.

Wo

Bone Marrow Transplantation with Favorable Outcome in Three Patients with LPS-Responsive Beige-like Anchor (LRBA) Deficiency

Wo

Pediatric Bone Marrow Transplantation: Psychopathologic Features in Recipients a Long with Siblings

Wo

Evaluation of Drug-Related Problems in a Pediatric Bone Marrow Transplantation Unit Identified by a Clinical Pharmacist in-training in a 7-Month Period

Objective: This cross sectional study was performed to demonstrate the importance of clinical pharmacists’ participation in pediatric hematopoietic stem cell transplantation patient management with regards to the detection, prevention, and management of drug-related problems.Methods: The study was carried out from 1st October 2015 to 1st May 2016 in a pediatric bone marrow transplantation unit of a tertiary care hospital. The inpatients and outpatients between 0 to 18 years of age were included and the patients were monitored and evaluated for drug-related problems (interactions, side effects, preparation, and administration). A clinical pharmacist-in-training made recommendations to the physicians and the nurses on the problems that were identified.Results: Twenty inpatients and twenty-two outpatients were monitored during the study. In total, 245 problems were identified in the inpatients, 37.14 % of which were drug-related; 33 % of the drug-related problems were the side effects of cyclosporine. Eleven recommendations on drug-related problems were made to the physicians and six of them were for the problems identified in the inpatient services with regards to drug dosing and administration. Five recommendations regarding total parenteral nutrition, drug incompatibility, drug administration from the feeding tube, and drug side effects were made to the nurses. Twenty-nine information on the dosing, side effects, incompatibilities, administration, and preparation of the drugs, were given by the pharmacist to the physicians and the nurses.Conclusion: Clinical pharmacists’ participation will improve the detection and the management of drug-related problems in pediatric hematopoietic stem cell transplantation units in TurkeyDiğe

Successful Hematopoietic Stem Cell Transplantation in a Patient with a Novel DNA Ligase IV Mutation

Abstract DNA Ligase IV deficiency syndrome (LIG4 syndrome) is a rare autosomal recessive disorder caused by mutations in the DNA ligase IV gene (LIG4), which is essential for the repair of DNA double-strand breaks in mamalian cells by non-homologous end joining (O’Driscoll et al, 2001; Critchlow et al, 1998). LIG4-deficient patients are characterized by microcephaly, growth retardation, developmental delay, low birth weight, dysmorphic facial findings called bird-like face, immunodeficiency, pancytopenia, and pronounced clinical and cellular radiosensitivity (O’Driscoll et al, 2001). Herein, we report two siblings with a novel DNA ligase IV mutation, one of whom underwent hematopoietic stem cell transplantation (HSCT). Case 1, was a 10 year-old girl, whose pancytopenia started at 4 years of age. History revealed a birth weight of 2400 g. There was a first-degree consanguinity between parents. Body weight, height, and head circumference were below the third percentile. Low anterior hairline, prominent nasal bridge and bilateral epicanthus were present. Recurrent upper respiratory infection (URI) history was striking. Serum IgM was low for age. Pancytopenia deepened progressively and HSCT was performed from 6/6 HLA matched father after non-myeloablative conditioning; however autologous reconstruction developed and a 2nd HSCT was performed after busulfan, cyclophosphamide and ATG conditioning. Engraftment was achieved by +12 day. Case 2 was a 6 year-old boy, presented with widespread echymoses at three years of age. Microcephaly, body weight and height below the third percentile, inguinal hernia, prominent nasal bridge and bilateral epicanthi were positive findings. History revealed recurrent URI. Serum IgG and IgM were low for age. DEB and mitomycin-C induced chromosomal analyses were within normal limits, whereas spontaneous breakage was found to be increased. Bone marrow examination revealed hypercellularity in both siblings. Alpha-fetoprotein levels were within normal limits. Mutation analysis for Nijmegen breakage syndrome was negative, however sequencing revealed a novel mutation in the LIG4 gene. A homozygous sequence variant, 1762delAAG, which results in the amino acid deletion 588delK, was identified in case 2. Both parents were heterozygous for the alteration. This novel mutation is located in a highly conserved peptide in the ligase IV protein, adjacent to the ligase domain, with previously unknown function (Wei et al, 1995). Our results demonstrate that non-myeloablative conditioning may not be adequate for LIG4 syndrome patients with hypercellular bone marrow. However, successful treatment of LIG4 syndrome can be achieved by HSCT after more potent conditioning