Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
1.
Leukemia ; 31(10): 2011-2019, 2017 10.
Article in English | MEDLINE | ID: mdl-28074068

ABSTRACT

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP+=not reached, CIMP-=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+=2.34, A-CIMP-=1.00; P=0.01). Hypermethylation in A-CIMP+ favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP+ was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP+ function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP+ AML should be validated prospectively.


Subject(s)
CpG Islands , DNA Methylation , Leukemia, Myeloid, Acute/genetics , Adolescent , Adult , Aged , DNA, Neoplasm/genetics , Datasets as Topic , Female , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Phenotype , Pilot Projects , Prognosis , Retrospective Studies , Risk , Survival Analysis , Young Adult
2.
Water Sci Technol ; 70(11): 1888-96, 2014.
Article in English | MEDLINE | ID: mdl-25500478

ABSTRACT

Quantifying groundwater availability depends upon sound methods and the use of integrated models. To determine availability or sustainable yield, the influence of scientific uncertainty from key sources, such as anthropogenic recharge, must be considered. This study evaluates uncertainty in recharge interpretations on the modeled available water balance for an urban case in Texas, USA. Analyses are completed using the Groundwater Decision Support System, which is a research code-base for an integrated modeling. The case study develops spatially and temporally resolved recharge interpretations based on NEXRAD precipitation and detailed land use data. Results demonstrate the implications of scientific uncertainty as it influences recommendations for policy and urban water management decisions that are based on modeled outputs. Geospatial methods account for spatial and temporal components and can be replicated for other systems. These methods are also useful for resolving uncertainty in relation to the influence of urbanization on recharge through land use change.


Subject(s)
Decision Support Techniques , Groundwater , Models, Theoretical , Uncertainty , Water Supply , Climate , Humans , Texas , Water Movements
3.
Leukemia ; 19(11): 1912-8, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16167059

ABSTRACT

Little is known about the etiology of myelodysplastic syndromes (MDS). A hospital-based case-control study of 354 adult de novo MDS cases and 452 controls was conducted to investigate associations between lifestyle characteristics and MDS risk. The distribution by French-American-British (FAB) type was 67 (19%) refractory anemia (RA), 38 (11%) refractory anemia with ringed sideroblasts (RARS), 43 (12%) chronic myelomonocytic leukemia (CMML), 136 (38%) RA with excess blasts (RAEB), and 70 (20%) RAEB in transformation (RAEBT). Multivariate logistic regression analyses were performed among all MDS cases and among each FAB type and gender. For all MDS combined, family history of hematopoietic cancer (odds ratio (OR) = 1.92), smoking (OR = 1.65), and exposure to agricultural chemicals (OR = 4.55) or solvents (OR = 2.05) were associated with MDS risk. Among RA/RARS cases, smoking (OR = 2.23) and agricultural chemical exposure (OR = 5.68) were the only risk factors identified. For RAEB/RAEBT cases, family history of hematopoietic cancer (OR = 2.10), smoking (OR = 1.52), and exposure to agricultural chemicals (OR = 3.79) or solvents (OR = 2.71) were independent risk factors. Drinking wine reduced risk for all FAB types by almost 50% (OR = 0.54). We found a joint effect between smoking and chemical exposure with the highest risk among smokers exposed to solvents/agricultural chemicals (OR = 3.22). Results from this large study suggest that several factors play a role in MDS predisposition with possible joint effects. Risk profiles seem to differ by FAB type and gender.


Subject(s)
Environmental Exposure , Genetic Predisposition to Disease , Myelodysplastic Syndromes/etiology , Smoking/adverse effects , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Life Style , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Odds Ratio , Pesticides/poisoning , Risk Factors , Sex Factors , Solvents/poisoning
4.
Leukemia ; 19(9): 1567-72, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16049515

ABSTRACT

Determining the percentage of peripheral blood (PB) and bone marrow (BM) blasts is important for diagnosing and classifying acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Although most patients with acute leukemia or MDS have a higher percentage of BM blasts than PB blasts, the relative proportion is reversed in some patients. We explored the clinical relevance of this phenomenon in MDS (n = 446), AML (n = 1314), and acute lymphoblastic leukemia (ALL) (n = 385). Among patients with MDS or ALL, but not AML, having a higher blast percentage in PB than in BM was associated with significantly shorter survival. In multivariate analyses, these associations were independent of other relevant predictors, including cytogenetic status. Our findings suggest that MDS and ALL patients who have a higher percentage of PB blasts than BM blasts have more aggressive disease. These data also suggest that MDS classification schemes should take into account the percentage of blasts in PB differently from the percentage of blasts in BM.


Subject(s)
Blast Crisis/blood , Bone Marrow/blood supply , Leukemia, Lymphoid/blood , Leukemia, Myeloid/blood , Myelodysplastic Syndromes/blood , Acute Disease , Adolescent , Adult , Aged , Aged, 80 and over , Blast Crisis/pathology , Child , Female , Humans , Leukemia, Lymphoid/classification , Leukemia, Lymphoid/pathology , Leukemia, Myeloid/classification , Leukemia, Myeloid/pathology , Male , Middle Aged , Multivariate Analysis , Myelodysplastic Syndromes/classification , Myelodysplastic Syndromes/pathology , Retrospective Studies , Survival Analysis
5.
Blood ; 98(13): 3575-83, 2001 Dec 15.
Article in English | MEDLINE | ID: mdl-11739159

ABSTRACT

It has been unclear whether regimens containing topotecan + ara-C (TA) or fludarabine + ara-C (FA) +/- idarubicin are superior to regimens containing idarubicin + ara-C (IA) without either fludarabine or topotecan for treatment of newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or RAEB. Of 1279 patients treated here for these diagnoses between 1991 and 1999, 322 received IA regimens, 600 FA regimens, and 357 TA regimens. All regimens used ara-C doses of 1 to 2 gm/m(2)/d, given by continuous infusion in IA, and over 2 to 4 hours in FA and TA. Complete remission (CR) rates were lower with FA (55%) and TA (59%) than with IA (77%). Both event-free survival (EFS) in CR and survival were shorter: median EFS in CR (95% confidence interval) was 63 weeks (range, 55-76 weeks) for IA, 40 (range, 31-46 weeks) for FA, and 36 (range, 27-44 weeks) for TA; median survival was 77 weeks (range, 57-88 weeks) for IA, 30 (range, 27-35 weeks) for FA, and 41 (range, 35-50 weeks) for TA. These trials were not randomized, and patients with worse prognoses were disproportionately given the FA and TA regimens. Nonetheless, after accounting for prognosis the FA and TA regimens remained highly significantly associated with lower CR rates, shorter EFS in CR, and shorter survival. Accounting for possible effects of individual trials within each of the IA, FA, and TA groups did not alter these findings. It is unlikely that, as given here, either FA or TA is, in general, superior to IA, highlighting the need for new treatments.


Subject(s)
Anemia, Refractory, with Excess of Blasts/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Vidarabine/analogs & derivatives , Cytarabine/administration & dosage , Disease-Free Survival , Humans , Idarubicin/administration & dosage , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Prognosis , Recurrence , Remission Induction , Survival Rate , Time Factors , Topotecan/administration & dosage , Treatment Failure , Vidarabine/administration & dosage
6.
J Bone Miner Res ; 15(9): 1786-97, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10976998

ABSTRACT

The study objective was to analyze the three-dimensional (3D) trabecular architecture and mechanical properties in vertebral specimens of young and mature Sinclair minipigs to assess the relative contribution of architecture to bone strength. We used 3D magnetic resonance microimaging (MRmicroI) and direct image analysis to evaluate a set of standard structural measurements and new architectural descriptors of trabecular bone in biopsy specimens from L2, L3, and L4 vertebrae (n = 16 in each group) from young (mean age, 1.2 years) and mature (mean age, 4.8 years) minipigs. The measurements included bone volume/tissue volume (BV/TV), marrow star volume (Ma.St.V), connectivity density (ConnD), and two new parameters, percent platelike trabeculae (% plate) and percent bone in the load direction (% boneLD). The % plate, calculated from surface curvature, allowed the delineation of plates from rods. The % boneLD quantified the percentage of bone oriented along the long axis of the vertebral body. We showed that 3D MRmicroI can detect the subtle changes in trabecular architecture between the two age groups. ConnD, star volume, % plate, % boneLD, and BV/TV were found to be more effective than the model-based, derived indices (trabecular thickness [Tb.Th], trabecular separation [Tb.Sp], and trabecular number [Tb.N]) in differentiating the structural changes. BV/TV, % plate, and % boneLD significantly increased (p < 0.05) in all three vertebral sites of the mature minipigs. The significant decrease in ConnD and star volume in the mature vertebra was consistent with the concurrent increase of platelike trabecular bone (p < 0.05). Overall, ConnD, star volume, % plate, and % boneLD provided a coherent picture of the architectural changes between the two age groups. Apparent modulus and maximum stress were determined experimentally on biopsy specimens from L2 vertebrae (n = 16). When apparent modulus was predicted using 3D MRmicroI data sets as input for finite element modeling (FEM), the results were similar to the experimentally determined apparent modulus (p = 0.12). Both methods were then used to compare the young and the mature animals; the experimental and predicted apparent modulus were significantly higher for the mature group (p = 0.003 and 0.012, respectively). The experimental maximum stress in the vertebra of the mature animals was twice as high as that for the young animals (p = 0.006). Bone quantity (BV/TV or bone mineral content [BMC]) alone could explain approximately 74-85% of the total variability in stress and modulus. The inclusion of either ConnD or % boneLD with BV/TV in a multiple regression analysis significantly improved the predictability of maximum stress, indicating that architecture makes additional contributions to compressive strength in normal minipig vertebra.


Subject(s)
Lumbar Vertebrae/anatomy & histology , Lumbar Vertebrae/physiology , Magnetic Resonance Imaging/methods , Swine, Miniature/physiology , Aging/physiology , Animals , Compressive Strength , Computer Simulation , Female , Image Processing, Computer-Assisted , Lumbar Vertebrae/growth & development , Statistics as Topic , Stress, Mechanical , Swine
7.
J Chromatogr B Biomed Sci Appl ; 741(2): 213-20, 2000 May 12.
Article in English | MEDLINE | ID: mdl-10872591

ABSTRACT

A short reversed-phase HPLC column and a tandem mass spectrometer were used to develop a stable-isotope-dilution assay for the rapid and sensitive analysis of fluprostenol, a prostaglandin analog, in rat plasma. A Waters Symmetry ODS column (2.1x10 mm) afforded rapid isocratic elution of fluprostenol (t(R)=40 s) but still provided a relatively large k' value of 4. The use of tandem mass spectrometry allowed the interference-free detection of fluprostenol under the rapid elution conditions, with a limit of quantitation of 25 pg ml(-1) fluprostenol, using 0.2 ml plasma sample volumes. The method was linear over three orders of magnitude, yielded accurate and precise results and allowed the pharmacokinetic profile of fluprostenol to be defined following intravenous administration in rats.


Subject(s)
Chromatography, High Pressure Liquid/methods , Prostaglandins F, Synthetic/blood , Animals , Calibration , Male , Mass Spectrometry , Prostaglandins F, Synthetic/pharmacokinetics , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity
8.
Leuk Lymphoma ; 37(3-4): 319-31, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10752983

ABSTRACT

The significance of terminal deoxynucleotidyl transferase (TdT) expression in acute myelogenous leukemia (AML) remains controversial. Therefore, we studied TdT expression by flow cytometry in 120 previously untreated patients with AML or myelodysplastic syndrome (MDS) to determine the distribution of TdT-positive blasts and the intensity of TdT expression and to seek clinically significant associations. TdT expression measured by flow cytometry (flow TdT%) was heterogeneous, ranging from 0.1% to 87% (median, 8.5%), and 74 patients (62%) had at least 5% TdT-positive blasts. TdT positivity was associated with the M0 or M1 subtype and with expression of CD34 and CD7. No significant correlation was found between TdT expression and type of cytogenetic abnormality or rearrangement of immunoglobulin or T-cell receptor genes. Remission lasted longer in patients with a flow TdT% < 5 than in patients with a flow TdT% > 5 (median, 95 weeks vs 55 weeks, p = 0.02); however, complete remission rates did not differ when patients were classified by initial flow TdT%. Survival was slightly better for patients with flow TdT% less than 5%. Among patients with a flow TdT% > 5%, those with a higher TdT intensity survived longer than those with a lower intensity. These data suggest that quantitative TdT measurement may contribute to prognostic estimate in AML patients.


Subject(s)
DNA Nucleotidylexotransferase/biosynthesis , Leukemia, Myeloid, Acute/enzymology , Myelodysplastic Syndromes/enzymology , Adult , Female , Flow Cytometry/methods , Gene Rearrangement, B-Lymphocyte , Gene Rearrangement, T-Lymphocyte , Humans , Immunophenotyping , Karyotyping , Leukemia, Myeloid, Acute/genetics , Male , Myelodysplastic Syndromes/genetics , Treatment Outcome
9.
Appl Environ Microbiol ; 65(8): 3473-82, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10427037

ABSTRACT

Bioluminescent reporter organisms have been successfully exploited as analytical tools for in situ determination of bioavailable levels of contaminants in static environmental samples. Continued characterization and development of such reporter systems is needed to extend the application of these bioreporters to in situ monitoring of degradation in dynamic environmental systems. In this study, the naphthalene-degrading, lux bioreporter bacterium Pseudomonas putida RB1353 was used to evaluate the relative influences of cell growth stage, cell density, substrate concentration, oxygen tension, and background carbon substrates on both the magnitude of the light response and the rate of salicylate disappearance. The effect of these variables on the lag time required to obtain maximum luminescence and degradation was also monitored. Strong correlations were observed between the first three factors and both the magnitude and induction time of luminescence and degradation rate. The maximum luminescence response to nonspecific background carbon substrates (soil extract broth or Luria broth) was 50% lower than that generated in response to 1 mg of sodium salicylate liter(-1). Oxygen tension was evaluated over the range of 0.5 to 40 mg liter(-1), with parallel inhibition to luminescence and degradation rate (20 mg of sodium salicylate liter(-1)) observed at 1.5 mg liter(-1) and below and no effect observed above 5 mg liter(-1). Oxygen tensions from 2 to 4 mg liter(-1) influenced the magnitude of luminescence but not the salicylate degradation rate. The results suggest that factors causing parallel shifts in the magnitude of both luminescence and degradation rate were influencing regulation of the nah operon promoters. For factors that cause nonparallel shifts, other regulatory mechanisms are explored. This study demonstrates that lux reporter bacteria can be used to monitor both substrate concentration and metabolic response in dynamic systems. However, each lux reporter system and application will require characterization and calibration.


Subject(s)
Genes, Reporter , Luciferases/genetics , Pseudomonas putida/genetics , Biodegradation, Environmental , Biological Availability , Colony Count, Microbial , Environmental Pollutants/metabolism , Environmental Pollutants/pharmacokinetics , Gene Expression , Genes, Bacterial , Kinetics , Luminescence , Operon , Pseudomonas putida/growth & development , Pseudomonas putida/metabolism
10.
J Clin Oncol ; 13(11): 2827-34, 1995 Nov.
Article in English | MEDLINE | ID: mdl-7595745

ABSTRACT

PURPOSE: To estimate the incidence of idarubicin (IDA)-related cardiomyopathy in acute myeloid leukemia (AML) and myelodysplasia (MDS). PATIENTS AND METHODS: We analyzed a group of 127 AML/MDS patients who received IDA-based induction and postremission or salvage therapy and achieved a complete remission (CR) that lasted > or = 12 weeks for the development of IDA-related congestive heart failure (CHF). CHF was defined as definite if a resting left ventricular ejection fraction (LVEF) of < or = 45% measured by radionuclide ventriculogram (RV) accompanied the clinical diagnosis of CHF, which had to be made during or within 6 months of receiving IDA and for which no other cause was apparent; without RV confirmation, the diagnosis was considered probable. Patients who had RVs performed were evaluated for decreasing LVEF. Older age (> or = 70 years), prior/sequential anthracycline/mitoxantrone (anthraquinone) therapy, and cardiac disease/hypertension were evaluated as risk factors for the development of CHF. RESULTS: One hundred fifteen patients were assessable (median age, 40 years; median dose, 96 mg/m2). Sixty-five had RVs performed during therapy; 43 had risk factors. The probability of IDA-related cardiomyopathy was 5% at a cumulative IDA dose of 150 to 290 mg/m2, with 18 patients receiving doses greater than 150 mg/m2. At a cumulative IDA dose of 150 mg/m2, the probability of a mild or greater asymptomatic decrease probability of a mild or greater asymptomatic decrease in LVEF (> or = 10% to a level < or = 50%) was 18%, whereas the probability of a moderate or greater asymptomatic decrease in LVEF (> or = 15% to a level < or = 45%) was 7%. No patient with asymptomatic LVEF decreases developed CHF. CHF was more frequent in patients with prior/sequential exposure to anthracyclines/mitoxantrone (P = .01). CONCLUSION: In this patient group, IDA-related cardiomyopathy was uncommon with cumulative IDA doses of up to 290 mg/m2. Asymptomatic LVEF decreases were more frequent, but their predictive value for the development of CHF is unclear.


Subject(s)
Antibiotics, Antineoplastic/adverse effects , Heart Failure/chemically induced , Heart/drug effects , Idarubicin/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibiotics, Antineoplastic/administration & dosage , Female , Heart/physiopathology , Heart Failure/physiopathology , Humans , Idarubicin/administration & dosage , Male , Middle Aged , Remission Induction , Retrospective Studies , Risk Factors , Stroke Volume/drug effects
11.
Leukemia ; 8(5): 823-6, 1994 May.
Article in English | MEDLINE | ID: mdl-7514247

ABSTRACT

The mechanisms of extramedullary leukemic infiltration are not well characterized. The cell-surface glycoprotein CD56, which is identical to the neural cell adhesion molecule, may be involved. Using the Leu-19 antibody and flow cytometric methods, the leukemic blasts of 22% (70 of 314) of patients were CD56 positive. This was most common in acute monocytic leukemia (15 of 18, 83%) and in patients with the cytogenetic abnormalities t(8;21) (seven of 13, 54%) and trisomy 8 (nine of 22, 41%). CD56 expression was not associated with extramedullary leukemic infiltration, but was correlated with positivity for CD11b (p < 0.001), CD14 (p < 0.001) and CD19 (p = 0.018). Although associated with morphologic and cytogenetic features, CD56 expression alone cannot account for most instances of tissue infiltration in acute myeloid leukemia (AML).


Subject(s)
Antigens, CD/analysis , Antigens, Differentiation, T-Lymphocyte/analysis , Cell Adhesion Molecules, Neuronal/analysis , Chromosome Aberrations , Leukemia, Myeloid, Acute/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Antigens, CD19 , Antigens, Differentiation, B-Lymphocyte/analysis , Antigens, Differentiation, Myelomonocytic/analysis , CD56 Antigen , Cats , Chromosomes, Human, Pair 21 , Chromosomes, Human, Pair 8 , Female , Flow Cytometry , Humans , Immunophenotyping , Karyotyping , Leukemia, Monocytic, Acute/immunology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Leukemic Infiltration , Lipopolysaccharide Receptors , Macrophage-1 Antigen/analysis , Male , Translocation, Genetic , Trisomy
SELECTION OF CITATIONS
SEARCH DETAIL
...