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1.
Braz J Med Biol Res ; 50(5): e6019, 2017 Apr 13.
Article in English | MEDLINE | ID: mdl-28423121

ABSTRACT

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL). MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.


Subject(s)
B-Lymphocytes/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphocytosis/genetics , Lymphocytosis/pathology , Telomere Shortening/genetics , Age Factors , Aged , Aged, 80 and over , Case-Control Studies , Disease Progression , Female , Flow Cytometry , Genetic Markers , Humans , Lymphocyte Count , Male , Middle Aged , Reference Standards , Statistics, Nonparametric , Telomere/pathology
2.
Vox Sang ; 103(4): 309-21, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22624696

ABSTRACT

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is characterized by leukocyte transmigration and alveolar capillary leakage shortly after transfusion. TRALI pathogenesis has not been fully elucidated. In some cases, the infusion of alloantibodies (immune model), whereas in others the combination of neutrophil priming by proinflammatory molecules with the subsequent infusion of biological response modifiers (BRMs) in the hemocomponent (non-immune model) have been implicated. Our aim was to compare the pathological events involved in TRALI induced by antibodies or BRMs using murine models. MATERIALS AND METHODS: In the immune model, human HNA-2(+) neutrophils were incubated in vitro with a monoclonal antibody (anti-CD177, clone 7D8) directed against the HNA-2 antigen and injected i.v. in NOD/SCID mice. In the non-immune model, BALB/c mice were treated with low doses of lipopolysaccharide (LPS) followed by platelet-activating factor (PAF) infusion 2 h later. Forty minutes after PAF administration, or 6 h after neutrophil injection, lungs were isolated and histological analysis, determination of a variety of cytokines and chemokines including keratinocyte-derived chemokine (KC), MIP-2, the interleukins IL-1ß, IL-6, IL-8 as well as TNFα, cell influx and alveolar capillary leakage were performed. RESULTS: In both models, characteristic histological findings of TRALI and an increase in KC and MIP-2 levels were detected. In contrast to the immune model, in the non-immune model, there was a dramatic increase in IL-1ß and TNFα. However, capillary leakage was only detected if PAF was administrated. CONCLUSIONS: Regardless of the triggering event(s), KC, MIP-2 and integrins participate in TRALI pathogenesis, whereas PAF is essential for capillary leakage when two events are involved.


Subject(s)
Acute Lung Injury/immunology , Acute Lung Injury/pathology , Transfusion Reaction , Acute Lung Injury/etiology , Animals , Chemokines/immunology , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, SCID , Neutrophils/immunology , Neutrophils/pathology
3.
Leukemia ; 26(3): 451-60, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21869839

ABSTRACT

The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.


Subject(s)
Arsenicals/therapeutic use , Electron Transport Complex I/antagonists & inhibitors , Leukemia, Promyelocytic, Acute/drug therapy , Mitochondria/drug effects , Oxides/therapeutic use , Tretinoin/therapeutic use , alpha-Tocopherol/pharmacology , alpha-Tocopherol/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Apoptosis/drug effects , Arsenic Trioxide , Caspases/metabolism , Cell Line, Tumor , Cytochromes c/metabolism , Disease Models, Animal , Electron Transport Complex II/antagonists & inhibitors , Humans , Leukemia, Promyelocytic, Acute/mortality , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Transgenic , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Oncogene Proteins, Fusion/metabolism , Protein Stability/drug effects , Rats , Reactive Oxygen Species/metabolism , Transplantation, Isogeneic
4.
Biochim Biophys Acta ; 1798(9): 1714-23, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20488162

ABSTRACT

10-(Octyloxy) decyl-2-(trimethylammonium) ethyl phosphate (ODPC) is an alkylphospholipid that can interact with cell membranes because of its amphiphilic character. We describe here the interaction of ODPC with liposomes and its toxicity to leukemic cells with an ED-50 of 5.4, 5.6 and 2.9 microM for 72 h of treatment for inhibition of proliferation of NB4, U937 and K562 cell lines, respectively, and lack of toxicity to normal hematopoietic progenitor cells at concentrations up to 25 microM. The ED-50 for the non-malignant HEK-293 and primary human umbilical vein endothelial cells (HUVEC) was 63.4 and 60.7 microM, respectively. The critical micellar concentration (CMC) of ODPC was 200 microM. Dynamic light scattering indicated that dipalmitoylphosphatidylcholine (DPPC) liposome size was affected only above the CMC of ODPC. Differential calorimetric scanning (DCS) of liposomes indicated a critical transition temperature (T(c)) of 41.5 degrees C and an enthalpy (H) variation of 7.3 kcal mol(-1). The presence of 25 microM ODPC decreased T(c) and H to 39.3 degrees C and 4.7 kcal mol(-1), respectively. ODPC at 250 microM destabilized the liposomes (36.3 degrees C, 0.46 kcal mol(-1)). Kinetics of 5(6)-carboxyfluorescein (CF) leakage from different liposome systems indicated that the rate and extent of CF release depended on liposome composition and ODPC concentration and that above the CMC it was instantaneous. Overall, the data indicate that ODPC acts on in vitro membrane systems and leukemia cell lines at concentrations below its CMC, suggesting that it does not act as a detergent and that this effect is dependent on membrane composition.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Membrane/drug effects , Leukemia/drug therapy , Phospholipids/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Membrane Permeability/drug effects , Cell Survival/drug effects , Hematopoietic Stem Cells/drug effects , Humans , Leukemia/pathology , Liposomes , Micelles , Thermodynamics
5.
Int J Lab Hematol ; 31(4): 453-6, 2009 Aug.
Article in English | MEDLINE | ID: mdl-18294235

ABSTRACT

We report a case of T-cell prolymphocytic leukemia (T-PLL) in a 41-year-old male. Classical cytogenetic, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) studies of a blood sample obtained at diagnosis revealed the co-existence of t(X;14)(q28;q11), t(Y;14)(q12;q11) and a ring chromosome derived from i(8)(q10). Immunophenotypic studies revealed involvement of T-cell lineage, with proliferation of CD4(-) CD8+. The co-existence of two translocations involving both sex chromosomes in a case of T-PLL is rare. Chromosomal instability associated with the disease progression may have allowed the emergence of cell clones with translocations involving the sex chromosomes and the ring chromosome observed.


Subject(s)
Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, X/genetics , Chromosomes, Human, Y/genetics , Leukemia, Prolymphocytic, T-Cell/genetics , Ring Chromosomes , Translocation, Genetic , Adult , Chromosomal Instability/genetics , Humans , Male , Spectral Karyotyping
6.
Hum Exp Toxicol ; 27(12): 919-29, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19273547

ABSTRACT

Glioblastoma multiforme (GBM) is a highly invasive and radioresistant brain tumor. Aiming to study how glioma cells respond to gamma-rays in terms of biological processes involved in cellular responses, we performed experiments at cellular context and gene expression analysis in U343-MG-a GBM cells irradiated with 1 Gy and collected at 6 h post-irradiation. The survival rate was approximately 61% for 1 Gy and was completely reduced at 16 Gy. By performing the microarray technique, 859 cDNA clones were analyzed. The Significance Analysis of Microarray algorithm indicated 196 significant expressed genes (false discovery rate (FDR) = 0.42%): 67 down-regulated and 97 up-regulated genes, which belong to several classes: metabolism, adhesion/cytoskeleton, signal transduction, cell cycle/apoptosis, membrane transport, DNA repair/DNA damage signaling, transcription factor, intracellular signaling, and RNA processing. Differential expression patterns of five selected genes (HSPA9B, INPP5A, PIP5K1A, FANCG, and TPP2) observed by the microarray analysis were further confirmed by the quantitative real time RT-PCR method, which demonstrated an up-regulation status of those genes. These results indicate a broad spectrum of biological processes (which may reflect the radio-resistance of U343 cells) that were altered in irradiated glioma cells, so as to guarantee cell survival.


Subject(s)
Brain Neoplasms/genetics , Gamma Rays , Gene Expression Regulation, Neoplastic/radiation effects , Glioblastoma/genetics , Transcription, Genetic/radiation effects , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Cell Line, Tumor , Cell Survival , Dose-Response Relationship, Radiation , Gene Expression Profiling/methods , Glioblastoma/pathology , Glioblastoma/radiotherapy , Humans , Oligonucleotide Array Sequence Analysis , Radiation Tolerance/genetics , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction , Time Factors
7.
Braz. j. med. biol. res ; 40(11): 1435-1440, Nov. 2007. graf, tab
Article in English | LILACS | ID: lil-464315

ABSTRACT

MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL) using the TaqMan® MicroRNA Assays Human Panel (Applied Biosystems). Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator) by the 2-DD Ct method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.


Subject(s)
Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , MicroRNAs/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies
8.
Braz J Med Biol Res ; 40(11): 1435-40, 2007 11.
Article in English | MEDLINE | ID: mdl-17934639

ABSTRACT

MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL) using the TaqMan MicroRNA Assays Human Panel (Applied Biosystems). Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator) by the 2-DD Ct method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/genetics , MicroRNAs/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies , Humans
9.
Braz J Med Biol Res ; 39(10): 1349-55, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17053842

ABSTRACT

We evaluated the expression of 10 adhesion molecules on peripheral blood tumor cells of 17 patients with chronic lymphocytic leukemia, 17 with mantle-cell lymphoma, and 13 with nodal or splenic marginal B-cell lymphoma, all in the leukemic phase and before the beginning of any therapy. The diagnosis of B-cell non-Hodgkin's lymphomas was based on cytological, histological, immunophenotypic, and molecular biology methods. The mean fluorescence intensity of the adhesion molecules in tumor cells was measured by flow cytometry of CD19-positive cells and differed amongst the types of lymphomas. Comparison of chronic lymphocytic leukemia and mantle-cell lymphoma showed that the former presented a higher expression of CD11c and CD49c, and a lower expression of CD11b and CD49d adhesion molecules. Comparison of chronic lymphocytic leukemia and marginal B-cell lymphoma showed that the former presented a higher expression of CD49c and a lower expression of CD11a, CD11b, CD18, CD49d, CD29, and CD54. Finally, comparison of mantle-cell lymphoma and marginal B-cell lymphoma showed that marginal B-cell lymphoma had a higher expression of CD11a, CD11c, CD18, CD29, and CD54. Thus, the CD49c/CD49d pair consistently demonstrated a distinct pattern of expression in chronic lymphocytic leukemia compared with mantle-cell lymphoma and marginal B-cell lymphoma, which could be helpful for the differential diagnosis. Moreover, the distinct profiles of adhesion molecules in these diseases may be responsible for their different capacities to invade the blood stream.


Subject(s)
Cell Adhesion Molecules/biosynthesis , Leukocytes, Mononuclear/metabolism , Lymphoma, B-Cell/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , Diagnosis, Differential , Female , Flow Cytometry , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lymphoma, B-Cell, Marginal Zone/metabolism , Lymphoma, Mantle-Cell/metabolism , Male , Middle Aged
10.
Braz. j. med. biol. res ; 39(10): 1349-1355, Oct. 2006. ilus, tab
Article in English | LILACS | ID: lil-437817

ABSTRACT

We evaluated the expression of 10 adhesion molecules on peripheral blood tumor cells of 17 patients with chronic lymphocytic leukemia, 17 with mantle-cell lymphoma, and 13 with nodal or splenic marginal B-cell lymphoma, all in the leukemic phase and before the beginning of any therapy. The diagnosis of B-cell non-Hodgkin's lymphomas was based on cytological, histological, immunophenotypic, and molecular biology methods. The mean fluorescence intensity of the adhesion molecules in tumor cells was measured by flow cytometry of CD19-positive cells and differed amongst the types of lymphomas. Comparison of chronic lymphocytic leukemia and mantle-cell lymphoma showed that the former presented a higher expression of CD11c and CD49c, and a lower expression of CD11b and CD49d adhesion molecules. Comparison of chronic lymphocytic leukemia and marginal B-cell lymphoma showed that the former presented a higher expression of CD49c and a lower expression of CD11a, CD11b, CD18, CD49d, CD29, and CD54. Finally, comparison of mantle-cell lymphoma and marginal B-cell lymphoma showed that marginal B-cell lymphoma had a higher expression of CD11a, CD11c, CD18, CD29, and CD54. Thus, the CD49c/CD49d pair consistently demonstrated a distinct pattern of expression in chronic lymphocytic leukemia compared with mantle-cell lymphoma and marginal B-cell lymphoma, which could be helpful for the differential diagnosis. Moreover, the distinct profiles of adhesion molecules in these diseases may be responsible for their different capacities to invade the blood stream.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged, 80 and over , Cell Adhesion Molecules/biosynthesis , Leukocytes, Mononuclear/metabolism , Lymphoma, B-Cell/metabolism , Diagnosis, Differential , Flow Cytometry , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lymphoma, Mantle-Cell/metabolism , Lymphoma, B-Cell, Marginal Zone/metabolism , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism
11.
Braz J Med Biol Res ; 39(5): 615-20, 2006 May.
Article in English | MEDLINE | ID: mdl-16648899

ABSTRACT

Acute promyelocytic leukemia (APL) is characterized by the expansion of blasts that resemble morphologically promyelocytes and harbor a chromosomal translocation involving the retinoic acid receptor alpha (RARalpha) and the promyelocytic leukemia (PML) genes on chromosomes 17 and 15, respectively. The expression of the PML/RARalpha fusion gene is essential for APL genesis. In fact, transgenic mice (TM) expressing PML/RARalpha develop a form of leukemia that mimics the hematological findings of human APL. Leukemia is diagnosed after a long latency (approximately 12 months) during which no hematological abnormality is detected in peripheral blood (pre-leukemic phase). In humans, immunophenotypic analysis of APL blasts revealed distinct features; however, the precise immunophenotype of leukemic cells in the TM model has not been established. Our aim was to characterize the expression of myeloid antigens by leukemic cells from hCG-PML/RARalpha TM. In this study, TM (N = 12) developed leukemia at the mean age of 13.1 months. Morphological analysis of bone marrow revealed an increase of the percentage of immature myeloid cells in leukemic TM compared to pre-leukemic TM and wild-type controls (48.63 +/- 16.68, 10.83 +/- 8.11, 7.4 +/- 5.46%, respectively; P < 0.05). Flow cytometry analysis of bone marrow and spleen from leukemic TM identified the asynchronous co-expression of CD34, CD117, and CD11b. This abnormal phenotype was rarely detected prior to the diagnosis of leukemia and was present at similar frequencies in hematologically normal TM and wild-type controls of different ages. The present results demonstrate that, similarly to human APL, leukemic cells from hCG-PML/RARalpha TM present a specific immunophenotype.


Subject(s)
Antigens, CD/immunology , Leukemia, Myeloid, Acute/immunology , Leukemia, Promyelocytic, Acute/immunology , Oncogene Proteins, Fusion/immunology , Animals , Antigens, CD/genetics , Bone Marrow/immunology , Bone Marrow/pathology , Cathepsin G , Cathepsins , Flow Cytometry , Genotype , Immunophenotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Promyelocytic, Acute/genetics , Mice , Mice, Transgenic , Oncogene Proteins, Fusion/genetics , Serine Endopeptidases , Spleen/immunology , Spleen/pathology
12.
Braz. j. med. biol. res ; 39(5): 615-620, May 2006. tab
Article in English | LILACS | ID: lil-425793

ABSTRACT

Acute promyelocytic leukemia (APL) is characterized by the expansion of blasts that resemble morphologically promyelocytes and harbor a chromosomal translocation involving the retinoic acid receptor a (RARa) and the promyelocytic leukemia (PML) genes on chromosomes 17 and 15, respectively. The expression of the PML/RARa fusion gene is essential for APL genesis. In fact, transgenic mice (TM) expressing PML/RARa develop a form of leukemia that mimics the hematological findings of human APL. Leukemia is diagnosed after a long latency (approximately 12 months) during which no hematological abnormality is detected in peripheral blood (pre-leukemic phase). In humans, immunophenotypic analysis of APL blasts revealed distinct features; however, the precise immunophenotype of leukemic cells in the TM model has not been established. Our aim was to characterize the expression of myeloid antigens by leukemic cells from hCG-PML/RARa TM. In this study, TM (N = 12) developed leukemia at the mean age of 13.1 months. Morphological analysis of bone marrow revealed an increase of the percentage of immature myeloid cells in leukemic TM compared to pre-leukemic TM and wild-type controls (48.63 ± 16.68, 10.83 ± 8.11, 7.4 ± 5.46 percent, respectively; P < 0.05). Flow cytometry analysis of bone marrow and spleen from leukemic TM identified the asynchronous co-expression of CD34, CD117, and CD11b. This abnormal phenotype was rarely detected prior to the diagnosis of leukemia and was present at similar frequencies in hematologically normal TM and wild-type controls of different ages. The present results demonstrate that, similarly to human APL, leukemic cells from hCG-PML/RARa TM present a specific immunophenotype.


Subject(s)
Animals , Mice , Antigens, CD/immunology , Leukemia, Myeloid, Acute/immunology , Leukemia, Promyelocytic, Acute/immunology , Oncogene Proteins, Fusion/immunology , Antigens, CD/genetics , Bone Marrow/immunology , Bone Marrow/pathology , Cathepsins , Flow Cytometry , Genotype , Immunophenotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Promyelocytic, Acute/genetics , Mice, Transgenic , Oncogene Proteins, Fusion/genetics , Serine Endopeptidases , Spleen/immunology , Spleen/pathology
15.
Braz J Med Biol Res ; 36(12): 1653-7, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14666249

ABSTRACT

The multidrug resistance P-glycoprotein is a transmembrane efflux pump expressed by lymphocytes and is involved in their cytolytic activity. In the present study, we investigated the age-related changes of P-glycoprotein function in normal peripheral blood lymphocytes. Blood samples from 90 normal volunteers (age range, 0 to 86 years) were analyzed. P-glycoprotein function was assessed by the flow cytometric rhodamine 123 assay. P-glycoprotein function was highest in cord blood and progressively declined with age in peripheral blood T CD4+ and CD8+ cells. In contrast, P-glycoprotein function did not vary with age in CD19+ B or CD16+CD56+ natural killer cells. These data suggest that the decline in P-glycoprotein function in T CD4+ and CD8+ lymphocytes as a function of age may contribute to the decrease in T cell cytolytic activity with aging.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Drug Resistance, Multiple/physiology , T-Lymphocytes/physiology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Aging/physiology , Child , Child, Preschool , Flow Cytometry , Fluorescent Dyes , Humans , Infant , Infant, Newborn , Killer Cells, Natural/physiology , Middle Aged , Rhodamine 123 , Stem Cells/physiology
16.
Braz. j. med. biol. res ; 36(12): 1653-1657, Dec. 2003. ilus
Article in English | LILACS | ID: lil-350469

ABSTRACT

The multidrug resistance P-glycoprotein is a transmembrane efflux pump expressed by lymphocytes and is involved in their cytolytic activity. In the present study, we investigated the age-related changes of P-glycoprotein function in normal peripheral blood lymphocytes. Blood samples from 90 normal volunteers (age range, 0 to 86 years) were analyzed. P-glycoprotein function was assessed by the flow cytometric rhodamine 123 assay. P-glycoprotein function was highest in cord blood and progressively declined with age in peripheral blood T CD4+ and CD8+ cells. In contrast, P-glycoprotein function did not vary with age in CD19+ B or CD16+CD56+ natural killer cells. These data suggest that the decline in P-glycoprotein function in T CD4+ and CD8+ lymphocytes as a function of age may contribute to the decrease in T cell cytolytic activity with aging.


Subject(s)
Adolescent , Infant, Newborn , Infant , Child, Preschool , Child , Adult , Middle Aged , Humans , Drug Resistance, Multiple , ATP Binding Cassette Transporter, Subfamily B, Member 1 , T-Lymphocytes , Age Factors , Aged, 80 and over , Flow Cytometry , Fluorescent Dyes , Rhodamine 123
17.
Pharmacogenomics J ; 3(3): 178-82, 2003.
Article in English | MEDLINE | ID: mdl-12815366

ABSTRACT

Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Low-activity phenotypes are correlated with several mutations in the TPMT gene. Polymorphisms of TPMT have been reported for Caucasians, African-Americans and Asians. Since ethnic differences have been demonstrated worldwide, it remains to be elucidated in Brazil. The Brazilian population is the result of five centuries of interethnic crosses between peoples from almost all continents as well as autochthonous Amerindians, all forming the fifth largest and one of the most heterogeneous populations in the world. The frequency of six allelic variants of the TPMT gene, *2 (G238C) (2.2%), *3A (G460A and A719G) (1.5%), *3B (G460A) (0.2%), *3C (A719G) (1.0%), *5 (0%) and *6 (0%) were determined in Brazilian subjects using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. This study provides the first analysis of TPMT mutant allele frequency in a sample of the Brazilian population.


Subject(s)
Methyltransferases/genetics , Polymorphism, Genetic/genetics , Asian People/ethnology , Asian People/genetics , Black People/ethnology , Black People/genetics , Brazil/ethnology , Gene Frequency/genetics , Humans , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , White People/ethnology , White People/genetics
19.
Br J Haematol ; 115(3): 616-8, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11736945

ABSTRACT

We have determined the prevalence of methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C in 71 children (< or = 15 years) with acute lymphoblastic leukaemia (ALL) and in 71 control subjects. Odds ratio (OR) for ALL linked to MTHFR C677T was 0.4 (95% CI 0.2-0.8); for heterozygotes it was 0.5 (95% CI 0.2-0.9) and for homozygotes it was 0.3 (95%CI 0.09-0.8). MTHFR A1298C yielded an overall OR for ALL of 1.3 (95% CI: 0.7-2.6); for heterozygotes it was 1.3 (95% CI: 0.7-7.6) and for homozygotes it was 2.8 (95% CI 0.5-15.6). In conclusion, MTHFR C677T was linked to a significant 2.4-fold decreased risk of developing childhood ALL, whereas MTHFR A1298C did not significantly affect the risk of ALL in our population.


Subject(s)
Oxidoreductases Acting on CH-NH Group Donors/genetics , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Burkitt Lymphoma/genetics , Case-Control Studies , Child , Child, Preschool , Confidence Intervals , Female , Germ-Line Mutation , Heterozygote , Homozygote , Humans , Infant , Leukemia-Lymphoma, Adult T-Cell/genetics , Male , Methylenetetrahydrofolate Reductase (NADPH2) , Odds Ratio , Prevalence , Risk
20.
Braz J Med Biol Res ; 34(2): 183-94, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11175493

ABSTRACT

The distinction between normal and leukemic bone marrow (BM) B-precursors is essential for the diagnosis and treatment monitoring of acute lymphoblastic leukemia (ALL). In order to evaluate the potential use of quantitative fluorescence cytometry (QFC) for this distinction, we studied 21 normal individuals and 40 patients with CD10+ ALL. We characterized the age-related changes of the CD10, CD19, TdT, CD34 and CD79a densities in normal and leukemic BM. Compared to normal adults, the B-precursors from normal children expressed significantly lower values of CD34-specific antibody binding capacity (SABC) (median value of 86.6 vs 160.2 arbitrary units (a.u.) in children and adults, respectively). No significant age-related difference was observed in the expression of the other markers in the normal BM, or in any of the markers in the leukemic BM. Based on the literature, we set the cut-off value for the normal CD10 expression at 45 x 10(3) a.u. for both age groups. For the remaining markers we established the cut-off values based on the minimum-maximum values in the normal BM in each age group. The expression of CD10 was higher than the cut-off in 30 ALL cases and in 18 of them there was a concomitant aberrant expression of other markers. In 9 of the 10 CD10+ ALL with normal CD10 SABC values, the expression of at least one other marker was aberrant. In conclusion, the distinction between normal and leukemic cells by QFC was possible in 38/40 CD10+ ALL cases.


Subject(s)
Antigens, CD/analysis , Bone Marrow Cells/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Adolescent , Adult , Biomarkers , Bone Marrow Cells/cytology , Bone Marrow Cells/pathology , Case-Control Studies , Child , Child, Preschool , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoelectrophoresis, Two-Dimensional , Immunophenotyping , Infant , Linear Models , Middle Aged , Neoplasm, Residual/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Statistics, Nonparametric , Sternum
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