Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Bone mineral density (BMD) and biochemical markers of bone metabolism were analyzed in 67 adults with ALL (n = 27), AML (n = 14), MDS (n = 6) and CML (n = 20) before and after allogeneic stem cell transplantation (SCT). Median age was 36 years (17-56). Twenty-six out of 53 patients (49%) had osteopenia and osteoporosis before SCT, 21/26 had acute leukemias and 5/26 had chronic myeloid leukemia (CML). T-score before SCTwas -1.23 in patients with acute leukemias and 0.62 in CML patients (P = 0.001). After SCT, a significant loss of BMD was observed in all patients. After 6 months, 24 of 36 evaluable patients (67%) had pathologic BMD, 11 of them (30%) had developed osteoporosis. After 12 months, 20 of 32 evaluable patients (62%) had BMD values below normal and nine of them (28%) had osteoporosis. Increased pyridinium excretion was observed in 12/20 patients (60%) with acute leukemias, but only in 3/13 (23%) with CML (P = 0.014). A prolonged vitamin D deficiency for more than 6 months developed early after SCT in all patients. Patients with acute leukemias frequently have osteopenia and osteoporosis before SCT. After SCT, a further loss of BMD occurs independent from the underlying disease. Standard prophylactic measures are not sufficient to prevent loss of bone mass. Studies on prophylactic interventions are needed to prevent severe osteoporosis in long-term survivors of SCT.
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PMID:Loss of bone mass and vitamin D deficiency after hematopoietic stem cell transplantation: standard prophylactic measures fail to prevent osteoporosis. 1168 10

We analysed by immunocytochemistry the expression of p53, bcl-2 and ras proteins in bone marrow blasts from 59 patients with acute leukaemia (AL), 36 myeloid (AML) and 23 lymphoid (ALL), and from 22 patients with myelodysplastic syndrome (MDS); our aim was to examine if abnormalities in their expression were associated with peculiar biological and clinical findings, or with an altered apoptosis rate, as measured by TUNEL technique. The oncoproteins were expressed with extreme variability, without significant differences among the various morphological or immunological AL subtypes. The mean percentages of bcl-2+ blasts were significantly higher in AML than in MDS (p = 0.01), and in MDS with bone marrow blastosis than in the forms without excess of blasts (p = 0.007). The lowest percentages of apoptotic cells were observed in ALL (mean 1%, p = 0.006), whereas in MDS the apoptotic index was higher (16.7%) than in AML (8.6%) and than in the normal controls (10.8%). but the difference tended to be statistically significant only for cases of refractory anaemia. Whereas in AML and MDS the apoptotic rate was independent of the oncoprotein expression, in ALL there was a significant linear relationship between TUNEL and ras positivity (p = 0.01). Among AML patients treated with intensive polychemotherapy, no differences were observed in oncoprotein expression and apoptotic rate between responders and resistant cases. In conclusion, our data are in agreement with the hypothesis that decreased apoptosis and enhanced cell survival are associated with AL, whereas a high level of apoptosis may be responsible for the ineffective hematopoiesis in MDS; abnormal expression of oncoproteins, even if not strictly related to apoptosis level, may influence disease behaviour.
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PMID:Expression of p53, bcl-2 and ras oncoproteins and apoptosis levels in acute leukaemias and myelodysplastic syndromes. 1169 13

Using red cell phenotyping (RCP) and/or cytogenetics (CYT) we identified 19 patients with persisting mixed chimerism (MC) among 231 patients transplanted with partially T cell-depleted stem cell grafts from HLA-identical siblings. Persisting MC is defined as MC for more than 2 years in patients without any evidence of relapse. Median leukemia-free survival in these patients was 150 (range, 50-218) months. Diagnoses were ALL (n= 10); AML (n = 2); CML (n = 2); NHL (n = 2); MDS (n= 1); MM (n = 1) and SAA (n = 1). Purpose of this study was the long-term follow-up of MC and definition of patterns of chimerism in the various subsets of PBMCs and granulocytes. Using a PCR-STR technique CD3(+)/CD4(+) (T4 lymphocytes), CD3(+)/CD8(+) (T8 lymphocytes), CD45(+)/CD19(+) (B lymphocytes), CD45(+)/CD14(+) (monocytes), CD45(+)/CD15(+) (granulocytes) and CD3(-)/CD56(+) (NK-cells) were analyzed. The majority of patients with persisting MC were conditioned with a less intensive conditioning regimen and had little GVHD. Sequential monitoring of the chimerism resulted in a group of patients (n = 7) with very slow transient mixed chimerism that resulted in complete DC after median 7 years. Another nine patients had a relatively high percentage of persisting autologous cells for a median of 12 years and in three patients we observed a stable low percentage of autologous cells. Only two out of 19 patients (AML-CR1, CML-CP1) relapsed during follow-up. Both patients had a relatively high percentage of autologous cells. Chimerism in granulocytes and PBMC subsets was analyzed at a median of 8 years after SCT in nine patients. In five patients mixed chimerism simultaneously detected by RCP and CYT was associated with MC in all subsets. Within each individual patient the percentages of donor and recipient cells were very different between the different subsets. Two CML-CP1 patients were mixed chimera in only two subsets and in one patient these subsets represented pending relapse. In another two patients mixed chimerism with a very low number of autologous red cells was not found in the PBMCs because of the different sensitivity level of the RCP and the PCR-STR technique. We conclude that in patients with persisting mixed chimerism after partially T cell-depleted SCT a remarkable number of patients had lymphoid malignancies, the majority of the patients were conditioned with less intensive conditioning regimens and the mixed chimerism was not correlated with relapse. Chimerism in granulocytes and PBMC subsets did show great intra-individual differences in the subsets and these data correlated well with RCP and CYT data with the exception of the NK cells.
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PMID:Long-term follow-up of persisting mixed chimerism after partially T cell-depleted allogeneic stem cell transplantation. 1184 Feb 58

Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities.
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PMID:Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 74

Wilms tumor gene WT1 is expressed at high levels in hematopoietic malignancies, such as leukemias and myelodysplastic syndromes (MDS), and in various kinds of solid tumors, including lung cancer, and it exerts an oncogenic function in these malignancies. IgM and IgG WT1 antibodies were measured by means of dot blot assay in 73 patients with hematopoietic malignancies (16 acute myeloid leukemia [AML], 11 acute lymphoid leukemia [ALL], 13 chronic myeloid leukemia [CML], and 33 MDS) and 43 healthy volunteers. Immunoglobulin IgM, IgG, and IgM+IgG WT1 antibodies were detected in 40 (54.8%), 40 (54.8%), and 24 (32.8%), respectively, of the 73 patients with hematopoietic malignancies, whereas 7 (16.2%), 2 (4.7%), and none of the 43 healthy volunteers had IgM, IgG, or IgM+IgG WT1 antibodies, respectively. Furthermore, immunoglobulin isotype class switching of WT1 antibodies from IgM to IgG occurred in conjunction with disease progression from refractory anemia (RA) to RA with excess of blasts (RAEB), and further to RAEB in transformation (RAEB-t) in MDS patients. These results showed that humoral immune responses against the WT1 protein could be elicited in patients with WT1-expressing hematopoietic malignancies, and they suggested that the helper T-cell responses needed to induce humoral immune responses and immunoglobulin isotype class switching from IgM to IgG were also generated in these patients. Our findings may provide new insight into the rationale for elicitation of cytotoxic T-cell responses against the WT1 protein in cancer immunotherapy using the WT1 vaccine.
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PMID:Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. 1196 93

Chromosome bands 1p36 and 3p21 are known to be recurring breakpoints in therapy-related (t-) leukemia. We identified a recurring translocation, t(1;3)(p36;p21), in eight patients with various hematologic malignancies: three patients with ALL, one with chronic myelogenous leukemia (CML) in accelerated phase (AP), two with MDS, and two with AML(M3). Five of the eight patients had a history of chemotherapy, including alkylating agents in three, before the translocation was detected. In two of these five patients, the t(1;3)(p36;p21) emerged only at relapse or in the accelerated phase of CML. The karyotypes of the patients were complex, including -7 and structural abnormalities of 5q, 6q, 7q, 9p, and 11q23. Survival time varied among patients (25 days to more than 16 years). Using FISH with 13 1p35-36 cosmid probes (tel-FB12-CA5-G7-FD2-CB1-ED8-FD9-G32-AE3-G50-AD8-GG4-G43-cen), we delineated the 1p36 breakpoint in two patients with MDS and ALL as lying between FB12 and FD2 (between BAC47P3 and PAC963K15), with a small deletion near the breakpoint in both cases. In the patient with MDS, there was also a deletion at 3p21.3, as detected with the cosmid probe cosNRL9. The results of the present study suggest that t(1;3)(p36;p21) in hematologic diseases is associated with prior exposure to mutagens, including alkylating agents.
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PMID:t(1;3)(p36;p21) is a recurring therapy-related translocation. 1197 52

To compare the hematopoietic and immune recoveries after allogeneic transplantation with different cell sources, we analyzed the recovery patterns of blood components after allogeneic peripheral blood stem cell transplantation (PBSCT) in comparison with that after allogeneic bone marrow transplantation (BMT) in a pediatric population. Sixteen patients received PBSCT, and 24 received BMT between January, 1995 and March, 2000. The patients had acute lymphoblastic leukemia (ALL; n = 22), acute myelogenous leukemia (AML; n = 8), myelodysplastic syndrome (MDS; n = 3), or other diseases (n = 7). The median ages of patients in the PBSCT and BMT groups were 9 yr and 6 yr, respectively. Cyclosporin A (CsA) plus methotrexate or methylprednisolone was used as a graft-vs.-host disease (GvHD) prophylaxis regimen in the PBSCT group, whereas CsA alone or methotrexate alone was used in the BMT group. Circulating lymphocyte numbers and subpopulations determined by flow cytometric analysis were used as markers of immune recovery. In the PBSCT group, the median number of harvested CD34+ cells was 7.25 (range: 1.3-27.6) x 106/kg of the recipient's body weight, while the median number of harvested nucleated cells was 4.7 (range: 3.7-10.5) x 108/kg. All of the patients were engrafted. Myeloid engraftment occurred sooner after PBSCT than after BMT (median number of days to achieve absolute neutrophil counts (ANC) > 0.5 x 109/L; 11 and 15, respectively; p < 0.0001) and similar results were found for platelet engraftment (median number of days to achieve a platelet count of > 20 x 109/L; 12 and 21, respectively; p = 0.004). On the other hand, after PBSCT the absolute numbers of total circulating lymphocytes and lymphocyte subpopulations were not significantly different from those after BMT. The incidence of acute GvHD after PBSCT was the same as that after BMT, while chronic GvHD developed more frequently after PBSCT than after BMT (p = 0.005). In a pediatric population, the indications for PBSCT and BMT should be based on these findings in addition to regard for the donor's safety.
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PMID:Hematopoietic and immune recovery after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation in a pediatric population. 1223 73

FLT3 is a receptor tyrosine kinase that may play a role in a significant proportion of leukemias. In addition to being aberrantly expressed in acute leukemias, activating mutations of the FLT3 gene have been found in patients with AML, myelodysplastic syndrome (MDS) and more rarely, ALL. Internal tandem duplications (ITDs) of the FLT3 gene have been detected in 17-34% of patients with AML and portend a poor prognosis for these patients. FLT3 receptors containing ITD mutations (FLT3/ITDs) are constitutively activated in the absence of FLT3 ligand (FL) stimulation leading to the activation of downstream signaling proteins, including ERK and STAT 5. FLT3 activity, therefore, is a logical target for therapeutic intervention. AG1296 is a tyrosine kinase inhibitor of the tyrphostin class that shows inhibitory activity for wild-type FLT3, in addition to the PDGF and c-KIT receptors. We examined the inhibitory effects of AG1296 on FLT3/ITDs isolated from AML patients in the IL-3-dependent cell line, Ba/F3, as well as in primary leukemia samples from AML patients. Immunoprecipitation and immunoblotting analyses demonstrated that FLT3/ITDs were constitutively phosphorylated in the absence of FL. The auto-phosphorylation of FLT3/ITDs was inhibited by AG1296 with an IC(50) of approximately 1 microM. FLT3/ITDs were associated with constitutive phosphorylation of ERK, STAT 5A, STAT 5B, CBL, VAV and SHP2 in Ba/F3 cells. The phosphorylation of these downstream signaling molecules was suppressed in a dose-responsive fashion by AG1296. AG1296 inhibited IL-3 independent growth and induced apoptosis in Ba/F3 cells transformed by FLT3/ITDs. AG1296 also inhibited FLT3 auto-phosphorylation, and induced a cytotoxic effect, in primary AML cells. These findings suggest that inhibiting the activity of FLT3 may have a therapeutic value in some leukemias expressing FLT3/ITDs.
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PMID:Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. 1235 54

According to recent reports, fast engraftment with minimal transplant-related toxicity and mortality (TRT, TRM) can be achieved by using reduced-intensity preparative regimens in allogeneic hematopoietic stem cell transplantation (HSCT). We report our experience with related (39%) and unrelated (61%) HSCT in 44 high risk patients (AML, ALL, CML, CLL) receiving either busulfan/fludarabine or busulfane/fludarabine/ATG or TBI/fludarabine as reduced-intensity preparative regimens. Organ toxicity was minimal with mild mucositis and no major bleeding. Acute GVHD was recorded in 64% of the patients. Twenty-three patients achieved complete remission after transplantation, and complete chimerism was obtained in all patients with stable engraftment (35 patients). Twenty-nine patients died: 15 due to relapse/progression, 14 due to TRM. Survival with median follow-up of 18.5 months was significantly better in patients with matched related transplants compared to patients with other transplants. However, there was no difference between related and unrelated transplants with regard to engraftment, TRM and GVHD. In conclusion, our results in high-risk patients transplanted in CR or with smoldering leukemia from a related donor are encouraging, although a longer follow-up and a larger group of patients is needed in order to evaluate the role of different reduced-intensity preparative regimens in unrelated and related HSCT.
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PMID:Reduced intensity preparative regimens for allogeneic hematopoietic stem cell transplantation: a single center experience. 1242 Feb 3

Somatic mutation of the FLT3 gene as an internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence causes constitutive tyrosine phosphorylation and activation. Tumor-specific DNA has been documented in the sera of patients with solid tumors even when it is in an early stage. We compared the detection of FLT3 ITD in DNA extracted from cells of bone marrow (BM) aspirations with DNA extracted from peripheral blood (PB) plasma in patients newly diagnosed with acute myeloid leukemia (AML; 85 patients), myelodysplastic syndrome (MDS; 16 patients), and acute lymphocytic leukemia (ALL; 16 patients). FLT3 ITD was detected in 18 (21%) AML samples and in one (6%) MDS sample in both cellular and plasma DNA but in none of the ALL samples. Hemizygous/homozygous FLT3 ITD was detected in five (28%) of the FLT3 ITD-positive AML using plasma DNA, whereas only four of these cases showed hemizygous/homozygous FLT3 ITD using cellular DNA. The presence of FLT3 ITD was associated with significantly shorter survival (P = 0.02) when only patients younger than 50 years of age (48 AML+MDS patients) were considered. This finding was independent of cytogenetics in this age group. However, patients with the FLT3 ITD hemizygous/homozygous phenotype had even shorter survival (P = <0.001). As expected, the presence of FLT3 ITD correlated with higher white blood cell (WBC) counts. These data demonstrate that plasma DNA is a reliable alternative resource for detecting FLT3ITD, especially the hemizygous/homozygous genotype. Furthermore, the data derived from this study support the notion that the presence of FLT3 ITD in conjunction with the absence of the wild-type FLT3 allele predicts an especially poor prognosis for patients with AML.
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PMID:Better detection of FLT3 internal tandem duplication using peripheral blood plasma DNA. 1252 67


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