Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first case of haemoglobin H (HbH) disease in combination with haemoglobin C (HbC) is reported in a man of Surinamese origin. Only haemoglobin A (HbA) and HbC were detected by electrophoresis. The amount of HbC was much less than expected in HbC heterozygotes. The synthesis ratio (beta A+ beta C/alpha) indicated an alpha-thalassaemia defect with two non-functional alpha genes, which did not correlate with the degree of haemolysis and anaemia displayed by the patient. The DNA analysis of the alpha-genes clusters revealed a defect combination -SEA/-alpha 3.7. The haematological data and the physiopathology of this atypical case are compared with the typical HbH disease found in a first cousin of the propositus. Data on the globin chains expression and on the formation of beta A and beta C homotetramers in HbH/HbC disease are presented.
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PMID:Atypical HbH disease in a Surinamese patient resulting from a combination of the -SEA and -alpha 3.7 deletions with HbC heterozygosity. 907 24

In the myelodysplastic syndromes (MDS), P-glycoprotein (P-gp) expression is clinically associated with drug resistance, whereas the clinical significance of multidrug resistance-associated protein (MRP1) is uncertain. Bone marrow from 56 patients with MDS, including six with refractory anaemia (RA)/RA with ringed sideroblasts (RARS), 23 cases of RA with excess blasts/in transformation (RAEB/T), four patients with chronic myelomonocytic leukaemia (CMML) and 23 cases of MDS having progressed to acute myeloid leukaemia (MDS-AML), were studied. MRP1 expression was investigated by immunocytochemistry (ICC) and by flow cytometry using MRPm6 monoclonal antibody. The efflux test using calcein-AM (CAM) +/- probenecid to evaluate MRP1 activity was performed in ten of the 56 patients. Twenty-eight of the 56 cases (50%) expressed MRP1. MRP1 expression was more frequent in MDS-AML than in MDS (70% vs. 36%). The efflux test using CAM was positive in three out of the ten patients tested. The results were in agreement with expression of MRP1 in six cases, and were discordant in four cases (1 MRP-/CAM+, 3 MRP+/CAM-). No correlation was observed between MRP1 expression and P-gp, lung resistance-associated protein (LRP) or CD34 expression, although there was a trend for more frequent MRP1 expression in P-gp-positive cases in MDS-AML (P = 0.08). Ten of the 26 patients treated with intensive chemotherapy achieved complete remission including six out of 16 MRP1+ and four out of ten MRP1- cases (P = NS). In conclusion, MRP1 expression was correlated with disease stage in MDS in our study. As for P-gp, discordant expression/function of MRP1 could be found in some cases, suggesting the existence of non-functional transport proteins in MDS. MRP1 expression did not seem to be a prognostic factor in MDS in our experience.
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PMID:Expression of the multidrug resistance-associated protein in myelodysplastic syndromes. 1099 69

We describe the molecular and the hematological characteristics of a Korean family with a dominantly inherited beta-thalassemia. Carriers were characterized by moderate anemia, hypochromia, microcytosis, elevated Hb A2 and Hb F levels, and splenomegaly. DNA analysis revealed a CTG (Leu) to CCG (Pro) substitution at codon 114 of the beta-globin gene, that leads to a highly unstable hemoglobin variant, Hb Durham-N.C./Brescia, and this was linked to the beta haplotype V, [+----+-], and framework 2. RNA analysis showed that the proband had comparable levels of mutant and normal beta-mRNA. Translation of the mutant mRNA would give rise to non-functional hyperunstable beta-globin chains, and their degradation would, by placing an additional burden on the proteolytic process of the red blood cell precursors, result in a more severe phenotype.
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PMID:A Korean family with a dominantly inherited beta-thalassemia due to Hb Durham-N.C./Brescia. 1130 Mar 52

Fanconi anemia (FA) is a fatal genetic disorder associated with pancytopenia and cancer. Cells lacking functional FA genes are hypersensitive to bifunctional alkylating agents, and are deficient in DNA double-strand break repair. Multiple genes with FA-causing mutations have been cloned, however, the molecular basis for FA remains obscure. The results presented herein indicate that a Rad50-dependent end-joining process is non-functional in diploid fibroblasts from FA patients. Introduction of anti-Rad50 antibody into normal fibroblasts sensitized them to DNA damaging agents, whereas this treatment had no effect on fibroblasts from FA patients. The DNA end-joining process deficient in FA cells also requires the Mre11, Nbs1 and DNA ligase IV proteins. These data reveal the existence of a previously uncharacterized Rad50-dependent DNA double-strand break repair pathway in mammalian somatic cells, and suggest that failure to activate this pathway is responsible, at least in part, for the defective DNA end-joining observed in FA cells.
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PMID:A Rad50-dependent pathway of DNA repair is deficient in Fanconi anemia fibroblasts. 1519 73

The intimate relationship between Fe and Cu in human nutrition has been recognised for many years. The best-characterised link is provided by caeruloplasmin, a multiCu-binding protein that acts as a serum ferrioxidase and is essential for the mobilisation of Fe from storage tissues. Decreased Cu status has been shown to reduce holo-caeruloplasmin production and impair ferrioxidase activity, leading, in a number of cases, to decreased tissue Fe release and the generation of anaemia that is responsive to dietary supplementation with Cu but not Fe. Dietary Fe absorption also requires the presence of a multiCu ferrioxidase. Hephaestin, a caeruloplasmin homologue, works in concert with the IREG1 transporter to permit Fe efflux from enterocytes for loading onto transferrin. The essential role of hephaestin in this process has been recognised from studies in the sex-linked anaemic (sla) mouse, in which Fe efflux is markedly impaired as a result of a mutation in the hephaestin gene that results in a truncated and non-functional version of the protein. There is emerging evidence that a number of other components of the intestinal Fe transport pathway are also Cu sensitive. Divalent metal transporter 1 (DMT1), the Fe transporter located at the apical membrane of enterocytes, is also a physiologically-relevant Cu transporter, suggesting that these two metals may compete with each other for uptake into the duodenal enterocytes. Furthermore, expression of both DMT1 and the basolateral Fe-efflux transporter IREG1 can be regulated by Cu, suggesting that the Fe-Cu relationship may be more complex than first thought.
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PMID:The molecular basis of copper and iron interactions. 1583 Nov 28

Apoptosis or programmed cell death plays a pivotal role in regulating tissue homeostasis in the adult and in tissue remodeling during embryogenesis. As in other tissues, apoptosis plays an important role within the hematopoietic system in removing aged and non-functional cells. It plays a particularly important role in regulating the cells of the immune system. The signals and molecules regulating apoptosis in these immune cells have been intensely investigated over the years, providing great insight into the mechanisms involved. In contrast, much less is known about the regulation and role of apoptosis in the cells that produce differentiated hematopoietic cells, namely the hematopoietic stem cells (HSCs). It is appreciated that HSCs are under tight regulatory control, as either excessive proliferation or apoptosis will result in too many or too few hematopoietic cells (for example, leukemia or anemia). Apoptosis thus plays an essential role in maintaining the appropriate balance of HSC and mature blood cells and in protecting the HSC pool for life-long hematopoiesis. This review summarizes the current knowledge concerning apoptosis and its role in the physiology of the hematopoietic system, especially within the HSC compartment.
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PMID:Bcl-2 expression and apoptosis in the regulation of hematopoietic stem cells. 1732 44

All human cells have a genetic program that upon activation will cause cell death, named apoptosis. Cancer cells can grow due to unbalances in proliferation, cell cycle regulation and their apoptosis machinery: genomic mutations resulting in non-functional pro-apoptosis proteins or over-expression of anti-apoptosis proteins form the basis of tumor formation. Surprisingly, lessons learned from viruses show that cancer cannot be regarded simply as the opposite of apoptosis. For instance, adenovirus can only transform cells when both its anti- and pro-apoptotic proteins are produced. Oncolytic viruses are known to replicate selectively in tumor cells resulting in cell death. Proteins derived from viruses, i.e. chicken anemia virus (CAV)-derived apoptosis-inducing protein (apoptin), adenovirus early region 4 open reading frame (E4orf4) and parvovirus-H1 derived non-structural protein 1 (NS1), the human alpha-lactalbumin made lethal to tumor cells (HAMLET), which is present in human milk or the human cytokines melanoma differentiation-associated gene-7 (mda-7) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have all the ability to induce tumor-selective apoptosis. The tumor-selective apoptosis-inducing proteins seem to interact with transforming survival processes, which can become redirected by these proteins into cell death. Transformation-related processes have been identified, which seem to be crucial for the tumor-selectively killing activity of these proteins. For instance, the transformation-related protein phosphatase 2A (PP2A) plays a role in the induction of tumor-selective apoptosis. The proteins mda-7, TRAIL and HAMLET are already successfully tested in first clinical trials. Proteins harboring tumor-selective apoptosis characteristics represent, therefore, a therapeutic potential and a tool for unraveling tumor-related processes. Fundamental molecular and (pre)clinical therapeutic studies of the various tumor-selective apoptosis-inducing proteins apoptin, E4orf4, HAMLET, mda-7, NS1, TRAIL and related proteins will be discussed.
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PMID:Proteins selectively killing tumor cells. 1983 76

Gaucher disease (GD) is an inherited disorder characterized by excessive accumulation of glucocerebroside in cells due to a non-functional glucocerebrosidase that is linked to programmed cell death pathways. Although clinical manifestations vary, type II GD is the most severe phenotype characterized by endoplasmic reticulum (ER) stress, neurological dysfunction, and anemia. Recombinant human erythropoietin (EPO) has been very popular for treating renal anemia and recently was shown to have extra-hematopoietic effects including neuroprotective properties. EPO's hematopoietic and neuroprotective effects prompted us to test EPO's beneficial action on type II GD patient cells. Initially, to examine the responsiveness of type II GD cells to EPO, the expression of the EPO receptor was determined at mRNA and protein levels. EPO effects on signaling pathways and ER stress in GD cells were also investigated. Finally, the proliferative effect of EPO on GD cells was verified. We found that EPO stimulated signaling pathways, enhanced the expression of glucocerebrosidase, reduced ER stress marker protein levels, and enhanced the proliferation rate of type II GD patient cells. This novel approach involving a beneficial role of EPO in GD should provide insights into new concepts for treating GD.
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PMID:Protective effect of recombinant human erythropoietin in type II Gaucher disease patient cells by scavenging endoplasmic reticulum stress. 2177 95

Fanconi anemia (FA) is a genetic disorder characterized by progressive bone marrow failure and a predisposition to cancers like acute myeloid leukemia, lung and squamous cell carcinomas. DNA damage in a healthy cell activates the FA pathway where 15 individual FA proteins interact and function together to maintain genomic stability. The disruption of this pathway results in the characteristic cellular phenotype and clinical outcome of the disease. The diverse clinical symptoms of FA such as impaired immunity and predisposition to cancers may not be explained exclusively by a non-functional FA pathway. These symptoms could then be attributed to defects in other functions of the individual FA proteins. To identify the effects of a mutant FA protein, FANCC, a transcriptome analysis was carried out on a FANCC mutant cell line (EUFA 450) and its revertant isogenic control cell line (EUFA 450Rev). Microarray data revealed dysregulation of genes involved in regulation of cell death and immune response. This study reports for the first time, the lowered expression of a tumor suppressor gene - caveolin-1, in FANCC mutant cells. The downregulation of caveolin-1 can be significant as Fanconi anemia patients have an elevated predisposition to develop cancer.
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PMID:Lowered expression levels of a tumor suppressor gene - caveolin-1 within dysregulated gene networks of Fanconi anemia. 2384 78

Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
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PMID:Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. 2570 6


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