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1.
J Cell Physiol ; 235(4): 3508-3518, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31549411

RESUMO

Muscle loss is a major problem for many in lifetime. Muscle and bone degeneration has also been observed in individuals exposed to microgravity and in unloading conditions. C2C12 myoblst cells are able to form myotubes, and myofibers and these cells have been employed for muscle regeneration purposes and in myogenic regeneration and transplantation studies. We exposed C2C12 cells in an random position machine to simulate microgravity and study the energy and the biochemical challenges associated with this treatment. Simulated microgravity exposed C2C12 cells maintain positive proliferation indices and delay the differentiation process for several days. On the other hand this treatment significantly alters many of the biochemical and the metabolic characteristics of the cell cultures including calcium homeostasis. Recent data have shown that these perturbations are due to the inhibition of the ryanodine receptors on the membranes of intracellular calcium stores. We were able to reverse this perturbations treating cells with thapsigargin which prevents the segregation of intracellular calcium ions in the mitochondria and in the sarco/endoplasmic reticula. Calcium homeostasis appear a key target of microgravity exposure. In conclusion, in this study we reported some of the effects induced by the exposure of C2C12 cell cultures to simulated microgravity. The promising information obtained is of fundamental importance in the hope to employ this protocol in the field of regenerative medicine.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31876783

RESUMO

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

3.
Br J Haematol ; 187(4): 502-508, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31309545

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to  other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

4.
Mol Genet Genomic Med ; 7(5): e639, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924321

RESUMO

BACKGROUND: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms. METHODS: Mutational screening and functional analyses (protein expression and 3D-modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients. RESULTS: We report the clinical history of two sisters affected by WABS with a pathological mytomicin C test carrying compound heterozygous mutations (c.2507T > C / c.907_920del) of the DDX11 gene. The pathogenicity of this variant was confirmed in the light of a bioinformatic study and protein three-dimensional modeling, as well as expression analysis. CONCLUSION: These findings further extend the clinical and molecular knowledge about the WABS showing a possible mild phenotype without major malformations or intellectual disability.


Assuntos
Anormalidades Múltiplas/genética , Manchas Café com Leite/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Perda Auditiva Neurossensorial/genética , Fenótipo , Anormalidades Múltiplas/patologia , Manchas Café com Leite/patologia , Linhagem Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Mutação , Síndrome
5.
Metab Syndr Relat Disord ; 17(1): 53-59, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30376422

RESUMO

PURPOSE: Fanconi anemia (FA) is a complex tumor-prone disease defined by an entangled genotype and phenotype. Despite enormous efforts in the last 20 years, a comprehensive and integrated view of the disease is still missing. The aim of this pilot study was to establish whether a global microRNA (miRNA) analysis approach could be helpful in defining aspects in FA phenotype, which might deserve future attention with the perspective to develop miRNA-based therapies. METHODS: miRNA array were employed to characterize the global miRNA (miRNoma) profile of FA RNA samples with respect to normal samples. RESULTS: We report and compare miRNA profile from two FA established cell lines and three FA patients. This analysis reveals that 36 and 64 miRNAs, respectively, are found differentially expressed (>2-fold variation and P < 0.05) in the samples from FA cell lines and FA patients. Overlap of these data results in 24 miRNAs as shared in the two sample populations. Available bioinformatics methods were used to predict target genes for the differentially expressed miRNAs and to perform pathway enrichment analysis. CONCLUSIONS: Seven pathway results associated with the FA phenotype. It is interesting to note that some of these pathways were previously unrelated to FA phenotype. It might be important to focus on these pathways not previously emerged as dysfunctional in FA to better define the pathophysiological context of this disease. This is the first report of a global miRNA analysis in FA.


Assuntos
Anemia de Fanconi/genética , MicroRNAs/genética , Transcriptoma , Estudos de Casos e Controles , Linhagem Celular , Criança , Anemia de Fanconi/epidemiologia , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Masculino , Análise em Microsséries , Fenótipo , Projetos Piloto
10.
Haematologica ; 103(3): 417-426, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269525

RESUMO

Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mitocôndrias , Mutação de Sentido Incorreto , Trifosfato de Adenosina/biossíntese , Adolescente , Núcleo Celular/metabolismo , Criança , Pré-Escolar , Reparo do DNA/genética , Transporte de Elétrons , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Feminino , Humanos , Mutação com Perda de Função , Masculino , Fenótipo
11.
J Cell Physiol ; 233(2): 1736-1751, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28681917

RESUMO

Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild-type cells to MET is concentration dependent. Low concentrations (15 and 150 µM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5 mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150 µM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Anemia de Fanconi/tratamento farmacológico , Leucemia/tratamento farmacológico , Linfócitos/efeitos dos fármacos , Metformina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Estudos de Casos e Controles , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Ativação Enzimática , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Células HL-60 , Humanos , Leucemia/metabolismo , Leucemia/patologia , Linfócitos/metabolismo , Linfócitos/patologia , Metformina/toxicidade , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo
13.
Biochim Biophys Acta Mol Basis Dis ; 1863(6): 1214-1221, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28315453

RESUMO

Energetic metabolism plays an essential role in the differentiation of haematopoietic stem cells (HSC). In Fanconi Anaemia (FA), DNA damage is accumulated during HSC differentiation, an event that is likely associated with bone marrow failure (BMF). One of the sources of the DNA damage is altered mitochondrial metabolism and an associated increment of oxidative stress. Recently, altered mitochondrial morphology and a deficit in the energetic activity in FA cells have been reported. Considering that mitochondria are the principal site of aerobic ATP production, we investigated FA metabolism in order to understand what pathways are able to compensate for this energy deficiency. In this work, we report that the impairment in mitochondrial oxidative phosphorylation (OXPHOS) in FA cells is countered by an increase in glycolytic flux. By contrast, glutaminolysis appears lower with respect to controls. Therefore, it is possible to conclude that in FA cells glycolysis represents the main pathway for producing energy, balancing the NADH/NAD+ ratio by the conversion of pyruvate to lactate. Finally, we show that a forced switch from glycolytic to OXPHOS metabolism increases FA cell oxidative stress. This could be the cause of the impoverishment in bone marrow HSC during exit from the homeostatic quiescent state. This is the first work that systematically explores FA energy metabolism, highlighting its flaws, and discusses the possible relationships between these defects and BMF.


Assuntos
Anemia de Fanconi/metabolismo , Glicólise , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Linhagem Celular , Anemia de Fanconi/patologia , Humanos , Mitocôndrias/patologia
14.
Cell Cycle ; 15(19): 2571-2575, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27579499

RESUMO

Inherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases.


Assuntos
Anemia Aplástica/metabolismo , Doenças da Medula Óssea/metabolismo , Metabolismo Energético , Hemoglobinúria Paroxística/metabolismo , Dano ao DNA , Células-Tronco Hematopoéticas/metabolismo , Humanos , Modelos Biológicos , Nicho de Células-Tronco
15.
Sci Rep ; 6: 25441, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27146429

RESUMO

Isomorphic mutation of the SBDS gene causes Shwachman-Diamond syndrome (SDS). SDS is a rare genetic bone marrow failure and cancer predisposition syndrome. SDS cells have ribosome biogenesis and their protein synthesis altered, which are two high-energy consuming cellular processes. The reported changes in reactive oxygen species production, endoplasmic reticulum stress response and reduced mitochondrial functionality suggest an energy production defect in SDS cells. In our work, we have demonstrated that SDS cells display a Complex IV activity impairment, which causes an oxidative phosphorylation metabolism defect, with a consequent decrease in ATP production. These data were confirmed by an increased glycolytic rate, which compensated for the energetic stress. Moreover, the signalling pathways involved in glycolysis activation also appeared more activated; i.e. we reported AMP-activated protein kinase hyper-phosphorylation. Notably, we also observed an increase in a mammalian target of rapamycin phosphorylation and high intracellular calcium concentration levels ([Ca(2+)]i), which probably represent new biochemical equilibrium modulation in SDS cells. Finally, the SDS cell response to leucine (Leu) was investigated, suggesting its possible use as a therapeutic adjuvant to be tested in clinical trials.


Assuntos
Células da Medula Óssea/metabolismo , Doenças da Medula Óssea/metabolismo , Cálcio/metabolismo , Deficiência de Citocromo-c Oxidase/metabolismo , Insuficiência Pancreática Exócrina/metabolismo , Lipomatose/metabolismo , Mitocôndrias/metabolismo , Proteínas/genética , Ribossomos/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/deficiência , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Deficiência de Citocromo-c Oxidase/genética , Deficiência de Citocromo-c Oxidase/patologia , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/patologia , Regulação da Expressão Gênica , Glicólise/genética , Humanos , Leucina/farmacologia , Lipomatose/genética , Lipomatose/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mutação , Fosforilação , Cultura Primária de Células , Biossíntese de Proteínas , Proteínas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
16.
Am J Hematol ; 91(7): 666-71, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27013026

RESUMO

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Tomada de Decisões , Anemia de Fanconi/mortalidade , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Pancitopenia/induzido quimicamente , Fenótipo , Irmãos , Doadores de Tecidos , Resultado do Tratamento , Adulto Jovem
17.
Birth Defects Res A Clin Mol Teratol ; 103(12): 1003-10, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26033879

RESUMO

BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups. METHODS: The FA genes were analyzed using a next generation sequencing approach in two unrelated families. RESULTS: The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of-function mutation with a severe phenotype characterized by multiple malformations. CONCLUSION: The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling.


Assuntos
Anemia de Fanconi/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem
18.
Cytokine ; 73(1): 203-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25769809

RESUMO

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. Several studies show alterations of the immunological status of FA patients including defects in peripheral blood lymphocyte subsets, serum immunoglobulin levels, and inflammatory cytokines. However scanty information is available on the response of FA cells to specific infectious antigens. In this work we examined the response of FA cells to different immunological stimuli and found a defective response of IL-1ß, TNF-α and IL-17 to Candida albicans stimulation thus pointing to a potentially impaired response to fungal infections of FA patients.


Assuntos
Candida albicans/imunologia , Anemia de Fanconi/imunologia , Anemia de Fanconi/microbiologia , Imunidade , Adolescente , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Citocinas/biossíntese , Anemia de Fanconi/patologia , Humanos , Lactente , Adulto Jovem
19.
Sci Rep ; 5: 8088, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25627108

RESUMO

Fanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.


Assuntos
Cálcio/metabolismo , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Fibroblastos/metabolismo , Homeostase , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , ATPases Transportadoras de Cálcio/metabolismo , Carbocianinas/metabolismo , Linhagem Celular , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Compostos Heterocíclicos com 3 Anéis/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Cinética , Microscopia Confocal , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Resveratrol , Estilbenos/farmacologia , Tapsigargina/farmacologia
20.
Exp Hematol ; 43(4): 295-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25534205

RESUMO

Bone marrow failure in Fanconi anemia (FA) has been linked in part to overproduction of inflammatory cytokines, to which FA stem and progenitor cells are hypersensitive. In cell lines and murine models p38 mitogen-activated protein kinase (MAPK)-dependent tumor necrosis factor α (TNF-α) overexpression can be induced by the Toll-like receptors (TLRs) 4 and 7/8 ligands Lipopolysaccharide (LPS) and R848. Ex vivo exposure of FA stem cells to TNF-α suppresses their replication and selects preleukemic clones. Here we show that inhibition of p38 MAPK also reduces TLR4 and 7/8-mediated TNF-α production in primary human FA complementation group A (FANCA)-deficient monocytes from nine patients and demonstrate that, while p38 MAPK inhibition also enhances clonal growth of FANCA-deficient erythroid progenitors, the effect was mediated indirectly by the influence of the inhibitor on auxiliary cells, not erythroid colony-forming units themselves. Taken together, these results support the view that inhibition of the p38 MAPK pathway in monocytes may improve hematopoiesis in FANCA patients.


Assuntos
Células da Medula Óssea/metabolismo , Eritropoese , Anemia de Fanconi/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Adolescente , Western Blotting , Células da Medula Óssea/patologia , Criança , Anemia de Fanconi/metabolismo , Feminino , Imunofluorescência , Humanos , Técnicas In Vitro , Masculino
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