Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A clonal origin of hematopoiesis was studied by investigation of X-chromosome inactivation patterns (XCIP) in isolated granulocyte, CD14(+) and CD3(+) subpopulations obtained from bone marrow and peripheral blood of 36 female patients with primary myelodysplastic syndrome (MDS). Clonality was assessed by PCR amplification of polymorphic short tandem repeats of the human androgen receptor (HUMARA) gene and by investigation of silent polymorphism of iduronate sulphatase (IDS) or p55 genes. On the basis of results in a control group of 20 healthy age related females, a ratio of at least 9:1 between the two alleles was considered a significant marker of monoclonal hematopoiesis. Ten of the 11 patients with advanced forms of MDS (RAEB, RAEB-T, CMML) had clonal granulocytes and CD14(+) cells in peripheral blood. In patients with early disease, only 2 out of 11 patients (18%) with RA or RARS, according to WHO classification, had clonal granulocytes and CD14(+) cells in peripheral blood and bone marrow and 2 other patients with 5q-syndrome exhibited extremely oligoclonal granulocyte subpopulation in bone marrow. In contrast, we found clonal granulocytes in 12 out of 14 patients (86%) with refractory cytopenia with multilineage dysplasia (RCMD) and 8 of them simultanously exhibited clonal CD14(+) cells. Estimated 3 years survival of patients with early disease and clonal cell subpopulations was 61% as compared with 88% in patients without clonal hematopoiesis. Karyotype abnormalities were detected in 11 of the 25 females with early disease. Clonal patterns were present in 7 out of 8 patients with abberations diagnosed by routine cytogenetics, nevertheless, FISH revealed 5q deletion in 3 patients without signs of clonality in XCIP assay. No correlation was found between the presence of clonal subpopulations and the degree of telomere shortening in early MDS. Despite some limitations, the measurement of XCIP remains a sensitive tool for diagnosis of the first transforming mutation in the clonal development of MDS especially when combined with FISH and when an age related group is used to establish an appropriate allele ratio to exclude constitutional or acquired skewing. The occurrence of clonal cell subpopulations in most of the RCMD patients in contrast to RA may reflect a proposed multistep pathogenesis of MDS with dysplastic changes limited to erythropoiesis in early step and with subsequent development of multilineage dysplasia. The results also support the usefulness of separation of RCMD from 'pure' RA; however, a more complex insight combining different molecular techniques performed in a large number of patients is needed for refined classification of MDS on the basis of new molecular prognostic factors and for indication of more effective targeted therapy.
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PMID:The presence of clonal cell subpopulations in peripheral blood and bone marrow of patients with refractory cytopenia with multilineage dysplasia but not in patients with refractory anemia may reflect a multistep pathogenesis of myelodysplasia. 1572 70

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and leukemia progression. Racial differences may exist on clinical pictures and the molecular events leading to MDS, which are heterogeneous. To better define the clinical and cytogenetic features in Chinese patients, a retrospective multicentric study was performed in 508 MDS cases. Compared with Western countries, Chinese patients showed younger age (median: 49 vs 65-73 years), lower percentages of RARS (2.8 vs 6.6-15.3%), and CMML (5.2 vs 11.7-30.6%). Cytogenetically, among 367 cases with evaluable data, abnormal karyotypes were found in 136 cases, including 56 numerical and 80 structural changes. Incidences of single chromosome 5 and 7 abnormalities were lower than those in Western countries (2.2 vs 17.8-42.5%). However, complex cytogenetic aberrations and chromosome translocations were frequently observed and related to poor prognosis. Both multiple chromosome deletions and translocations were detected in advanced subtypes (RAEB and RAEB-T). Analysis of 200 cases revealed a higher incidence of hepatitis-B-virus infection than that in non-MDS population (21.00 vs 9.75%). This study further confirmed: (1) different genetic/environmental backgrounds between Asian and Western MDS populations; (2) a strong predictive value of cytogenetic abnormalities on disease outcome and involvement of genomic instability in leukemia clone development.
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PMID:Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries. 1575 35

Several prognostic factors for patients with myelodysplastic syndromes (MDS) have been identified in previous years. In order to determine prognostic factors characterizing haematopoietic cell kinetics, bone marrow proliferative activity and serum TNF-a levels were measured in 51 cases of MDS. Cell proliferation was evaluated by employing a monoclonal antibody directed against the proliferating cell nuclear antigen (PCNA). The PCNA proliferating index (PCNA PI) and serum TNF-a levels showed significant differences between patients with MDS and normal controls (p<0.0001). PCNA PI and serum TNF-a were significantly higher in the high risk for leukemic transformation FAB subgroups (RAEB, RAEB-t and CMML) in comparison to the low risk group (RA and RARS) (p<0.001). PCNA PI and TNF-a also increased with increasing IPSS score (p<0.05). A positive correlation was noted between TNF-a concentrations and PCNA PI (r:0.36, p<0.008). Univariate analysis using the log-rank test showed that a higher PCNA PI was associated with a significantly shorter survival (p<0.001). We conclude that elevated PCNA PI and TNF-a serum levels are increased in high risk myelodysplastic disease and that a high PCNA PI is predictive of a shorter survival in this group of patients.
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PMID:The assessment of proliferating cell nuclear antigen immunostaining in myelodysplastic syndromes and its prognostic significance. 1582 91

Recent studies concerning the pathophysiology of myelodysplastic syndromes (MDS) have shown evidences for the existence of complex interactions between hematopoietic stem cells and the bone marrow (BM) microenvironment. We analyzed the B-lymphocyte maturation in BM of patients with MDS. For this purpose, 41 newly-diagnosed patients were analyzed. Enumeration and characterization of CD34+ and CD34- B-cell precursors and mature B-lymphocytes was performed using multiparameter flow cytometry. BM from eight transplant donors and six orthopedic surgery patients were used as controls. CD34+/CD45(lo) B-cells were found in 17/22 patients with RA/RARS and in 5/13 with RAEB. In patients with RAEB-t and CMML no CD34+ B-cell precursors could be detected. A positive correlation was found between CD34+ and CD34- B-cell precursors (r=0.52). CD34+ B-cell precursors presented an inverse correlation with BM percentage of blasts and peripheral leukocytes and a positive one with hemoglobin. Asynchronous antigen expression (CD19+/CD79a- cells) was found in 7/11 cases of RA/RARS and 6/18 cases of RAEB in which this phenotype was examined. Abnormal patterns of expression for at least one antigen was found in 91% of RA/RARS cases and in 74% of RAEB. Underexpression of TdT and CD79a were the most frequent abnormalities. Our results present evidences of an abnormal B-cell maturation in MDS. This may be an evidence that B-lymphocytes are derived of the abnormal clone. But it may also be the consequence of influences of abnormalities of BM microenvironment leading to an impaired commitment and maturation of the B-cell line in MDS. Studies performed with purified well-characterized B-cells may further elucidate these abnormalities.
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PMID:Maturation-associated immunophenotypic abnormalities in bone marrow B-lymphocytes in myelodysplastic syndromes. 1600 14

In 1999, WHO proposed a revised classification for myelodysplastic syndromes (MDS). According to this system, FAB low risk MDS (RA and RARS) were defined as such when the presence of dysplastic features was only restricted to the erythroid lineage, and new categories, refractory cytopenia with multilineage dysplasia (RCMD) and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS), were added. In a retrospective analysis of 240 consecutive patients diagnosed at our institution as having FAB RA and RARS, we reclassified the disease following the WHO criteria and we found that 179/214 patients (84%) still remained in the RA category, while 35/214 (16%) moved to RCMD. Moreover, 17/26 patients (65%) maintained the RARS diagnosis, whereas 9/26 (35%) were re-classified as RCMD-RS. We detected differences among the WHO subgroups as to age and sex distribution as well as to median survival observed by stratifying patients according to different prognostic scoring systems. Furthermore we confirmed the usefulness of WHO segregation with regard to its predictive value for evolution into acute leukaemia. Our study provides evidence that WHO classification may have prognostic impact on MDS subgroups which are usually categorized by FAB as having a favourable outcome.
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PMID:Usefulness and prognostic impact on survival of WHO reclassification in FAB low risk myelodyplastic syndromes. 1610 25

From 1987 an abrupt increase of the number of patients presented with MDS has been registered. We present our experiences in the treatment of 42 patients. The number of the male patients was two times larger than of the females. They were most frequently diagnosed as having RAB (43%) and RAEBt (28.5%). RA was found in 14%, RARS in 9.5% and CMML. in only 5% of the cases. The treatment was accomplished with ultralow (3 mg/m2/12h s.c.) and low doses (10 mg/m2/12h s.c.) of ARA-C in 75% of the patients with RAEBt and 44.4% with RAEB, while the CMML group received hydroxyurea. The treatment improved hematologic results but the complete remission lacked. In 23.8% of the cases the disease developed into acute nonlymphoblastic leukemia. Patients excepted from cytostatic therapy were observed by the use of androgens, anabolics, vitamin A+D3 and transfusion of separated erythrocytes. In 38% of the patients with MDS a lethal outcome followed. Life of those in whom the disease developed into acute leukemia in statistically significatly shorter (p < 0.05). There was no statistically significant difference in the survival rate between the treated and nontreated patients (p > 0.05). Further treatment of these patients includes, apart from ultralow doses of ARA-C, the use of retinoic acid, a growth factor (GM-CSF) and bone marrow transplantation.
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PMID:[Our experiences in the treatment of myelodysplastic syndromes]. 1610 83

Tumor necrosis factor (TNF)-alpha, a potent stimulus of nuclear factor-kappaB (NF-kappaB), is up-regulated in myelodysplastic syndrome (MDS). Here, we show that bone marrow mononuclear cells (BMMCs) and purified CD34+ cells from patients with low-grade/early-stage MDS (refractory anemia/refractory anemia with ring sideroblasts [RA/RARS]) have low levels of NF-kappaB activity in nuclear extracts comparable with normal marrow, while patients with RA with excess blasts (RAEB) show significantly increased levels of activity (P = .008). Exogenous TNF-alpha enhanced NF-kappaB nuclear translocation in MDS BMMCs above baseline levels. Treatment with arsenic trioxide (ATO; 2-200 microM) inhibited NF-kappaB activity in normal marrow, primary MDS, and ML1 cells, even in the presence of exogenous TNF-alpha (20 ng/mL), and down-regulated NF-kappaB-dependent antiapoptotic proteins, B-cell leukemia XL (Bcl-XL), Bcl-2, X-linked inhibitor of apoptosis (XIAP), and Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme (FLICE) inhibitory protein (FLIP), leading to apoptosis. However, overexpression of FLIP resulted in increased NF-kappaB activity and rendered ML1 cells resistant to ATO-induced apoptosis. These data are consistent with the observed up-regulation of FLIP and resistance to apoptosis with advanced MDS, where ATO as a single agent may show only limited efficacy. However, the data also suggest that combinations of ATO with agents that interfere with other pathways, such as FLIP autoamplification via NF-kappaB, may have considerable therapeutic activity.
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PMID:NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs). 1610 82

Reports on spontaneous remissions in patients with primary myelodysplastic syndromes (MDS) occasionally appear in the literature. We report five adult patients with spontaneous remission of MDS, achieved without cytotoxic or any other treatment. These five patients represent 1.6% of 307 MDS patients, diagnosed in our Institute since 1987. According to FAB criteria, three patients had RA, and one patient had RARS and RAEB, each. All patients were women, median age of 63 yr (range 32-68 yr). Patients were without significant complaints and peripheral cytopenia was mild. Bone marrow dyshematopoiesis was also mild, mostly affecting erythroid and megakaryocytic series. At diagnosis, three patients had cytogenetic abnormalities [+8,+12; +15 and del(16)(q22)]. Median time to complete hematological and cytogenetical remission was 51 mo, while median duration of spontaneous remission was 45 mo (range 44-60 mo). As for the follow-up, none of the patients relapsed. In conclusion, although spontaneous remissions (i.e., "regression") of MDS are uncommon, better understanding of their basis may lead to crucial advances in the study of leukemogenesis.
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PMID:Spontaneous remission in adults with primary myelodysplastic syndromes: incidence and characteristics of patients. 1626 Aug 59

TNF-alpha mediated apoptosis of the hematopoietic cells has been thought to contribute to the ineffective hematopoiesis observed in myelodysplastic syndrome (MDS). The combination of pentoxifylline (P) and ciprofloxacin (C) has been shown to reduce the serum levels of TNF-alpha, and an earlier trial of P and C with dexamethasone (D) provided good palliation for patients with MDS. The purpose of this study is to assess the hematologic response to PCD therapy for patients suffering with MDS. 21 of 25 patients who completed at least of 12 weeks of treatment were evaluable for the treatment efficacy. At baseline, the patient's median age was 60 yr (range: 18-75 yr). The diagnoses according to WHO classification included: RA (n=5), RCMD (n=10), RARS (n=1), RCMD/RS (n=1), RAEB (3), and CMML (n=1). 11 patients (52%) had at least single lineage response. 3 patients (11%) showed improvement of triple lineage cytopenia. There were no differences in the response rates between the FAB subtypes. The median time to response was 4 weeks (range: 2-12 weeks), and it is interesting that 9 of 11 patients who had a response remained without relapse for a median of 177 days (range: 78-634 days). These preliminary results indicate that anti-cytokine therapy with PCD is an effective and well tolerated palliative treatment for patients with MDS.
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PMID:The hematologic response to anti-apoptotic cytokine therapy: results of pentoxifylline, ciprofloxacin, and dexamethasone treatment for patients with myelodysplastic syndrome. 1647 63

Hypermethylation of CpG islands within the promoter region is one of the mechanisms by which genes are inactivated and may be one of the reason for silencing of cell cycle control or DNA-mismatch repair genes in myelodysplastic syndrome (MDS). Since the function of cell cycle control genes including the cyclin-dependent kinase inhibitors known as p15(INK4b) and p16(INK4a), as well as p14(ARF) which blocks MDM-2 (an inhibitor of p53), the retinoblastoma (RB1) protein and the mismatch repair gene MGMT is critical for hematopoietic proliferation and differentiation, we performed methylation specific polymerase chain reaction (MSP) in low-density, non-adherent bone marrow cells from 49 patients with MDS. In addition, expression of p15(INK4b) and RB1 was analysed by quantitative real-time PCR. From selected patients, we analyzed the methylation pattern of cell cycle control genes in CD34+ bone marrow cells. Thirty-nine of 49 cases (80%) had at least one of five genes methylated in our MDS samples by analysing low-density non-adherent bone marrow cells. The frequency of p15(INK4b) methylation was 34 of 49 samples (69%). The incidence of methylation of both p14(ARF) and p16(INK4a) was four of 49 (8%). RB1 gene was methylated in seven samples (14%) and each patient had RA. Interestingly, none of these genes were methylated in the purified CD34+ hematopoietic stem cells from the MDS patients. Furthermore, all our RARS patients had a methylated p15(INK4b) promoter correlating with non-detectable expression of this gene in bone marrow cells from those patients. These results indicate that hypermethylation of cell cycle control genes in MDS may occur late during the differentiation of myelodysplastic stem cells.
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PMID:Comparative analysis of hypermethylation of cell cycle control and DNA-mismatch repair genes in low-density and CD34+ bone marrow cells from patients with myelodysplastic syndrome. 1668 76


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