BCR‐ABL1‐positive leukemias have historically been classified as either chronic myelogenous leukemia or Ph+ acute lymphoblastic leukemia. Recent analyses suggest there may be a wider range of ...subtypes. We report a patient with BCR‐ABL1 fusion positive T‐cell ALL with a previously undescribed cell distribution of the fusion gene. The examination of sorted cells by fluorescence in situ hybridization showed the BCR‐ABL1 fusion in the malignant T cells and a subpopulation of the nonmalignant B cells, but not nonmalignant T cells or myeloid or CD34+ progenitor cells providing evidence that the fusion may have occurred in an early lymphoid progenitor.
Aneuploidy and Ig light chain restriction were used as separate, independent tumor specific markers to study 26 patients with multiple myeloma to determine whether bone marrow B cells, as defined by ...CD19 expression, are clonally related to myeloma plasma cells. Specimens were characterized using multidimensional flow cytometry to identify the presence of clonality in both the B lymphoid and plasma cell populations using both surface and cytoplasmic staining with antibodies specific for kappa or lambda Ig light chain. In none of the patients with multiple myeloma were CD19+ cells found to be clonally restricted to kappa or lambda. The monoclonal plasma cells (MPC) were found to be uniformly negative for CD10, CD19, and CD34, while the CD19+ B lymphoid cells present within the samples expressed normal intensities and relationships of these antigens, which allowed them to serve as internal positive controls. Combined analysis of cell surface antigen expression and DNA content allowed plasma cell populations to be characterized for aneuploidy without interference from normal bone marrow cells. The MPC, detected on the basis of bright CD38 expression (CD38++), demonstrated DNA aneuploidy in 65% of cases (DNA index range of 0.9 to 1.3). These aneuploid DNA distributions had typical cell cycle profiles (including G1, S, and G2 + M) expected of a proliferating population. In all cases, DNA aneuploidy was confined almost entirely to the CD38++, CD19 malignant plasma cells, while cells expressing CD19 were diploid. These results support the concept that myeloma is a disease process mediated by self-replicating, late compartments of B-cell ontogeny.
Despite their small spatial extent, fluvial ecosystems play a significant role in processing and transporting carbon in aquatic networks, which results in substantial emission of methane (CH4) into ...the atmosphere. For this reason, considerable effort has been put into identifying patterns and drivers of CH4 concentrations in streams and rivers and estimating fluxes to the atmosphere across broad spatial scales. However, progress toward these ends has been slow because of pronounced spatial and temporal variability of lotic CH4 concentrations and fluxes and by limited data availability across diverse habitats and physicochemical conditions. To address these challenges, we present a comprehensive database of CH4 concentrations and fluxes for fluvial ecosystems along with broadly relevant and concurrent physical and chemical data. The Global River Methane Database (GriMeDB; https://doi.org/10.6073/pasta/f48cdb77282598052349e969920356ef, Stanley et al., 2023) includes 24 024 records of CH4 concentration and 8205 flux measurements from 5029 unique sites derived from publications, reports, data repositories, unpublished data sets, and other outlets that became available between 1973 and 2021. Flux observations are reported as diffusive, ebullitive, and total CH4 fluxes, and GriMeDB also includes 17 655 and 8409 concurrent measurements of concentrations and 4444 and 1521 fluxes for carbon dioxide (CO2) and nitrous oxide (N2O), respectively. Most observations are date-specific (i.e., not site averages), and many are supported by data for 1 or more of 12 physicochemical variables and 6 site variables. Site variables include codes to characterize marginal channel types (e.g., springs, ditches) and/or the presence of human disturbance (e.g., point source inputs, upstream dams). Overall, observations in GRiMeDB encompass the broad range of the climatic, biological, and physical conditions that occur among world river basins, although some geographic gaps remain (arid regions, tropical regions, high-latitude and high-altitude systems). The global median CH4 concentration (0.20 µmol L−1) and diffusive flux (0.44 mmolm-2d-1) in GRiMeDB are lower than estimates from prior site-averaged compilations, although ranges (0 to 456 µmol L−1 and −136 to 4057 mmolm-2d-1) and standard deviations (10.69 and 86.4) are greater for this larger and more temporally resolved database. Available flux data are dominated by diffusive measurements despite the recognized importance of ebullitive and plant-mediated CH4 fluxes. Nonetheless, GriMeDB provides a comprehensive and cohesive resource for examining relationships between CH4 and environmental drivers, estimating the contribution of fluvial ecosystems to CH4 emissions, and contextualizing site-based investigations.
The terrestrial planets accreted from a diverse suite of solar system materials ranging from strongly O-deficient materials similar to enstatite chondrites via ordinary chondrite materials to fully ...oxidised carbonaceous chondrite and cometary materials. Heliocentric zoning with increasingly oxidised planetesimals outwards through the protoplanetary disc is broadly reflected in core fraction and FeOmantle concentration, ranging from 68 wt% core and 0.5 wt% FeOmantle for Mercury to 18 wt% core and 24 wt% FeOmantle for Vesta. Mercury, Venus and Earth grew mostly from materials which were isotopically similar to enstatite chondrites, although Earth and Venus also received more oxidised material. The elevated (Mg + Fe)/Si ratio, compared to chondrites, in the bulk silicate fraction of the terrestrial planets, except for Mercury, may be related to a combination of nebular fractionation associated with forsterite condensation, concentration of olivine-rich chondrules near the mid-plane of the accretion disc and multi-cycle impact erosion of protocrusts. For the extremely reduced Mercury the silicate magma ocean (MO) and a core with 15 wt% Si might have equilibrated with a melt layer of FeS at the core-mantle boundary (CMB). Recent data from the MESSENGER mission combined with experimentally derived phase relations, support estimates of about 0.5 wt% FeO and 10 wt% S in the MO and the current mantle. Core segregation at very high temperatures for the largest planets, Venus and Earth, led to cores with high Si content, even at relatively high oxygen fugacities and FeOmantle contents, because increasing temperature shifts the equilibrium:SiO2MO+2Fecore=2FeOMO+Sicoretowards the products (right side). The hot protocores of Venus and Earth might have started with about 5–7 wt% Si and 2–3 wt% O. Mars and Vesta segregated S-rich cores at high oxygen fugacity and low pressure.
Strong partitioning of Fe and Mg to melt and solids, respectively, caused neutrally buoyant bridgmanite (bm) to crystallise from the MO at 1700–1860 km depth (72–80 GPa), resulting in a separate basal magma ocean (BMO) within Earth, and probably also in Venus. Slow cooling of a thermally insulated BMO and core, accompanied by protracted crystallisation of bm and ferropericlase (fp), would facilitate core-BMO chemical exchange by reversing the equilibrium SiO2MO + 2Fecore = 2FeOMO + Sicore towards the reactants. Transfer of silica crystals and a liquid SiO2 component from the core to the BMO, and liquid FeO and Fe2O3 components from the BMO to the core, would increase the Si/Mg, Mg/Fe and bm/fp ratio of the resulting cumulates. Because the solidus temperature of peridotite is <200–300 K above the present temperature of the outermost core, and the melting interval of late-stage BMO melt enriched in Al, Fe, Ca and Na would be lower than that of peridotite, the BMO might have persisted through the Hadean and possibly also the Archean. Low solid state diffusion rates, especially in bm, would have restricted the core-mantle interaction upon BMO solidification, but limited core-mantle interaction could possibly occur via partially molten ultra-low velocity zones. An outermost stagnant low-density and low-velocity core layer (E′-layer), with reduced Si and elevated O contents relative to the convecting core, appears to trace the core-BMO exchange. The E′-layer is compositionally gradational towards the convecting core at 445 km below the CMB. High thermal conductivity and minimal convective entrainment in the low-viscosity core fluid might have developed and stabilised such a gradational layer since the Hadean or early Archean.
The primordial bm-dominated cumulates with high Mg/Fe ratios and viscosities may have become convectively aggregated into large refractory domains, remaining neutrally buoyant in the middle to upper parts of the lower mantle and resistant to convective destruction. Late-stage dense BMO cumulates with elevated Fe/Mg ratios relative to the bulk mantle composition might represent a suitable material for 100–200 km thick thermochemical piles at the bottom of the large low S-wave velocity provinces (LLSVPs) under Africa and the Pacific. A degree-2 convection pattern, possibly initiated and stabilised during Earth's early rapid rotation, involving antipodally ascending columns in equatorial positions and an intermediary descending longitudinal belt, might have swept the late-stage, dense bridgmanitic cumulates with high Fe/Mg-ratios, viscosity and bulk modulus towards the root zones of the upwelling columns.
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•Core and mantle compositional estimates for the terrestrial planets are provided•Melting and silicate-metal partitioning led to magma oceans (MO) and cores•Core-mantle separation in Earth and Venus occurred at high temperature and pressure•Mineral-melt density relations led to a separate basal MO (BMO) in Earth and Venus•Cooling of Earth and Venus cores led to core-BMO chemical exchange
Hox patterning of the vertebrate rib cage McIntyre, Daniel C; Rakshit, Sabita; Yallowitz, Alisha R ...
Development (Cambridge),
08/2007, Letnik:
134, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Unlike the rest of the axial skeleton, which develops solely from somitic mesoderm, patterning of the rib cage is complicated by its derivation from two distinct tissues. The thoracic skeleton is ...derived from both somitic mesoderm, which forms the vertebral bodies and ribs, and from lateral plate mesoderm, which forms the sternum. By generating mouse mutants in Hox5, Hox6 and Hox9 paralogous group genes, along with a dissection of the Hox10 and Hox11 group mutants, several important conclusions regarding the nature of the ;Hox code' in rib cage and axial skeleton development are revealed. First, axial patterning is consistently coded by the unique and redundant functions of Hox paralogous groups throughout the axial skeleton. Loss of paralogous function leads to anterior homeotic transformations of colinear regions throughout the somite-derived axial skeleton. In the thoracic region, Hox genes pattern the lateral plate-derived sternum in a non-colinear manner, independent from the patterning of the somite-derived vertebrae and vertebral ribs. Finally, between adjacent sets of paralogous mutants, the regions of vertebral phenotypes overlap considerably; however, each paralogous group imparts unique morphologies within these regions. In all cases examined, the next-most posterior Hox paralogous group does not prevent the function of the more-anterior Hox group in axial patterning. Thus, the ;Hox code' in somitic mesoderm is the result of the distinct, graded effects of two or more Hox paralogous groups functioning in any anteroposterior location.
In this study we demonstrate the technical application of flow cytometry and cell sorting combined with gene-rearrangement clonality profiling to detect and confirm minimal disease in 2 leukemia and ...2 lymphoma cases.
Specimens with low percentages (0.05%-5%) of abnormal lymphoid populations were identified by flow cytometry. The abnormal lymphoid populations were sorted by flow cytometry, and the purified tumor populations along with unsorted fractions were subsequently analyzed for the presence of clonal gene rearrangements by PCR and fluorescence-based capillary electrophoresis fragment analysis.
In 3 cases, distinct clonality profiles could be detected in the purified tumor cell fraction, and suspicious amplicons of identical sizes were detected among the polyclonal backgrounds in the unsorted specimens. For 1 patient, a monoclonal signal was detected in the sorted tumor cell fraction but not in the unseparated bone marrow specimen containing 0.05% abnormal lymphoblasts. A subsequent bone marrow specimen containing 4.8% recurring leukemia cells tested positive with a clonality profile that matched the previous profile in the sorted cell population.
The described method integrating 2 technologies allows genotypic confirmation of an aberrant population detected by immunophenotype to increase diagnostic certainty. This strategy provides a sensitive tool for disease monitoring without the need for patient-specific primer design and assay optimization required for quantitative PCR analysis.
Abstract
Measurement of plasmalogens is useful for the biochemical diagnosis of rhizomelic chondrodysplasia punctata (RCDP) and is also informative for Zellweger spectrum disorders (ZSD). We have ...developed a test method for the simultaneous quantitation of C16:0, C18:0, and C018:1 plasmalogen (PG) species and their corresponding fatty acids (FAs) in dried blood spots (DBS) and erythrocytes (RBC) by using capillary gas chromatography–mass spectrometry. Normal reference ranges for measured markers and 10 calculated ratios were established by the analysis of 720 and 473 unaffected DBS and RBC samples, respectively. Determination of preliminary disease ranges was made by using 45 samples from 43 unique patients: RCDP type 1 (DBS: 1 mild, 17 severe; RBC: 1 mild, 6 severe), RCDP type 2 (DBS: 2 mild, 1 severe; RBC: 2 severe), RCDP type 3 (DBS: 1 severe), RCDP type 4 (RBC: 2 severe), and ZSD (DBS: 3 severe; RBC: 2 mild, 7 severe). Postanalytical interpretive tools in Collaborative Laboratory Integrated Reports (CLIR) were used to generate an integrated score and a likelihood of disease. In conjunction with a review of clinical phenotype, phytanic acid, and very long‐chain FA test results, the CLIR analysis allowed for differentiation between RCDP and ZSD. Data will continue to be gathered to improve CLIR analysis as more samples from affected patients with variable disease severity are analyzed. The addition of DBS analysis of PGs may allow for at‐home specimen collection and second‐tier testing for newborn screening programs.
Background
Detection of measurable residual disease detection (MRD) by flow cytometry after the first course of chemotherapy is a standard measure of early response in patients with acute myeloid ...leukemia (AML). Myeloid leukemia associated with Down Syndrome (ML‐DS) is a distinct form of AML. Differences in steady‐state and regenerating hematopoiesis between patients with or without DS are not well understood. This understanding is essential to accurately determine the presence of residual leukemia in patients with ML‐DS.
Methods
A standardized antibody panel defined quantitative antigen expression in 115 follow‐up bone marrow (BM) aspirates from 45 patients following chemotherapy for ML‐DS or DS precursor B‐cell acute lymphoblastic leukemia (B‐ALL‐DS) with the “difference from normal (ΔN)” technique. When possible, FISH and SNP/CGH microarray studies were performed on sorted cell fractions.
Results
93% of BM specimens submitted post chemotherapy had a clearly identifiable CD34+CD56+ population present between 0.06% and 2.6% of total non‐erythroid cells. An overlapping CD34+HLA‐DRheterogeneous population was observed among 92% of patients at a lower frequency (0.04%–0.8% of total non‐erythroid cells). In B‐ALL‐DS patients, the same CD34+CD56+ HLA‐DRheterogeneous expression was observed. FACS‐FISH/Array studies demonstrated no residual genetic clones in the DS‐specific myeloid progenitor cells.
Conclusions
Non‐malignant myeloid progenitors in the regenerating BM of patients who have undergone chemotherapy for either ML‐DS or B‐ALL‐DS express an immunophenotype that is different from normal BM of non‐DS patients. Awareness of this DS‐specific non‐malignant myeloid progenitor is essential to the interpretation of MRD by flow cytometry in patients with ML‐DS.
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