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Results for “hematopoiesis”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Association of clonal hematopoiesis mutations with clinical outcomes: A systematic review and meta-analysis

Clonal hematopoiesis (CH) mutations are common among individuals without known hematologic disease. CH mutations have been associated with numerous adverse clinical outcomes across many different studies. We systematically reviewed the available literature for clinical outcomes associated with CH mutations in patients without hematologic disease. We searched PubMed, EMBASE, and Scopus for eligible studies. Three investigators independently extracted the data, and each study was verified by a second author. Risk of bias was assessed using the Newcastle-Ottawa Scale. We identified 32 studies with 56 cohorts that examine the association between CH mutations and clinical outcomes. We conducted meta-analyses comparing outcomes among individuals with and without detectable CH mutations. We conducted meta-analyses for cardiovascular diseases (nine studies; HR = 1.61, 95% CI = 1.26–2.07, p = .0002), hematologic malignancies (seven studies; HR = 5.59, 95% CI = 3.31–9.45, p < .0001), therapy-related myeloid neoplasms (four studies; HR = 7.55, 95% CI = 4.3–13.57, p < .001), and death (nine studies; HR = 1.34, 95% CI = 1.2–1.5, p < .0001). The cardiovascular disease analysis was further stratified by variant allele fraction (VAF) and gene, which showed a statistically significant association only with a VAF of ≥ 10% (HR = 1.42, 95% CI = 1.24–1.62, p < .0001), as well as statistically significant associations for each gene examined with the largest magnitude of effect found for CH mutations in JAK2 (HR = 3.5, 95% CI = 1.84–6.68, p < .0001). Analysis of the association of CH mutations with hematologic malignancy demonstrated a numeric stepwise increase in risk with increasing VAF thresholds. This analysis strongly supports the association of CH mutations with a clinically meaningful increased risk of adverse clinical outcomes among individuals without hematologic disease, particularly with increasing VAF thresholds.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Ultra-high-dose-rate FLASH and Conventional-Dose-Rate Irradiation Differentially Affect Human Acute Lymphoblastic Leukemia and Normal Hematopoiesis

Ultra-high-dose-rate FLASH radiation therapy has been shown to minimize side effects of irradiation in various organs while keeping antitumor efficacy. This property, called the FLASH effect, has caused enthusiasm in the radiation oncology community because it opens opportunities for safe dose escalation and improved radiation therapy outcome. Here, we investigated the impact of ultra-high-dose-rate FLASH versus conventional-dose-rate (CONV) total body irradiation (TBI) on humanized models of T-cell acute lymphoblastic leukemia (T-ALL) and normal human hematopoiesis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS1984

Regulation of hematopoiesis in the suspended rat as a model for space flight

A series of studies was completed in which a variety of routine hematological and other parameters were obtained from sequential sampling of control and suspended rats. These data showed that, during suspension, the rats failed to gain weight at the same rate as the controls, ate and drank significantly less, demonstrated a transient increase in peripheral hematocrit and RBC count, a transient decrease in MCH, suppressed reticulocyte counts and a progressive decrease in MCV but no change in RBC shape. Leukocyte counts were variably decreased but no significant changes in platelet numbers were noted. Post-suspension, evidence of anemia was present from a reduced RBC count, hemoglobin, hematocrit, and MCV. A leukocytosis was also noted. Efforts directed to the collection of data aimed at understanding changes in blood volume during suspension are also discussed. As part of these studies the following parameters were investigated; RBC survival, in vitro leukocyte reactivity to PHA, bone marrow and spleen cellularity and morphology, ferrokinetics, and the hematopoietic inductive microenvironment.

Dunn, C. D. R.↗
NASA NTRS1983

Hematopoiesis in antiorthostatic, hypokinesic rats

Rats exposed to antiorthostatic, hypokinesia showed the following effects which are comparable to those seen in man during or after space flight: weight loss, reduced food and water consumption, transient increases in peripheral hematocrit and RBC count, decreasing MCV and reduced reticulocyte count. In addition, the hemoglobin P50 was shifted to the right. A significant shortening of RBC t1/2 was only seen after suspension. Changes in leukocyte and platelet numbers in suspended rats were also comparable to those in man during space flight, but leukocyte PHA sensitivity in rats showed no consistent alteration. The results demonstrate that this model reproduces many of the hematological effects of space flight and has potential as a tool in understanding the hematopoietic response to zero gravity.

Dunn, C. D. R.↗
NASA NTRS1985

Regulation of hematopoiesis in rats exposed to antiorthostatic, hypokinetic/hypodynamia. I - Model description

The effect of a 7-day suspension in a jacket and harness with 20-deg head-down tilt on body weight, food and water consumption, and hematological parameters is investigated experimentally in male Sprague-Dawley rats weighing 150-175 g. The results are presented in graphs and compared with those for unsuspended controls and with published data on rats and humans exposed to microgravity in space flight. Suspended rats are found to have reduced red-blood-cell mass, erythropoiesis, plasma volume (leading to temporarily increased hematocrit), body weight, and food and water consumption; rightward-shifted oxyhemoglobin-dissociation curves; and unchanged platelet count, leucocyte count or PHA reactivity, and red-blood-cell shape distribution. Since many of these effects are also seen in space flight, the present experimental model is considered a promising technique for simulating the hematopoietic effects of microgravity at 1 g.

Dunn, C. D. R.↗
NASA NTRS1986

Regulation of hematopoiesis in rats exposed to antiorthostatic hypokinetic/hypodynamia. II - Mechanisms of the 'anemia'

The cause of the red cell mass (RCM) deficit, which occurs in rats during suspenion, is investigated. The experimental conditions and procedures, in which male Sprague-Dawley rats are subjected to antiorthostatic hyypokinetic/hypodynamia and changes in RCM are monitored, are described. The influences of stress, reduced food and water consumption, and antiorhostatic posture on RCM are analyzed. Changes in body weight, RCM, radioiron incorporation, red blood cells (RBC), and reticulocytes, for the rats after head-down suspension are graphically presented; only the changes in RBC are related to the antiorthostatic posture. The data reveal that anemia is primarily caused by reduced food and water consumption and secondly by restricted movements.

Dunn, C. D. R.↗
NASA NTRS2001

Evolution of hematopoiesis: Three members of the PU.1 transcription factor family in a cartilaginous fish, Raja eglanteria

T lymphocytes and B lymphocytes are present in jawed vertebrates, including cartilaginous fishes, but not in jawless vertebrates or invertebrates. The origins of these lineages may be understood in terms of evolutionary changes in the structure and regulation of transcription factors that control lymphocyte development, such as PU.1. The identification and characterization of three members of the PU.1 family of transcription factors in a cartilaginous fish, Raja eglanteria, are described here. Two of these genes are orthologs of mammalian PU.1 and Spi-C, respectively, whereas the third gene, Spi-D, is a different family member. In addition, a PU.1-like gene has been identified in a jawless vertebrate, Petromyzon marinus (sea lamprey). Both DNA-binding and transactivation domains are highly conserved between mammalian and skate PU.1, in marked contrast to lamprey Spi, in which similarity is evident only in the DNA-binding domain. Phylogenetic analysis of sequence data suggests that the appearance of Spi-C may predate the divergence of the jawed and jawless vertebrates and that Spi-D arose before the divergence of the cartilaginous fish from the lineage leading to the mammals. The tissue-specific expression patterns of skate PU.1 and Spi-C suggest that these genes share regulatory as well as structural properties with their mammalian orthologs.

NASA Discipline Evolutionary Biology↗
NASA NTRS1995

The effect of space and parabolic flight on macrophage hematopoiesis and function

We used weak electric fields to monitor macrophage spreading in microgravity. Using this technique, we demonstrated that bone marrow-derived macrophages responded to microgravity within 8 s. We also showed that microgravity differentially altered two processes associated with bone marrow-derived macrophage development. Spaceflight enhanced cellular proliferation and inhibited differentiation. These data indicate that the space/microgravity environment significantly affects macrophages.

NASA Discipline Cell Biology↗
NASA NTRSDate not supplied

Utility of Terrestrial Cardiovascular Disease Data in Astronaut Radiation Risk Assessment – A Case Study Showing Increased Risk with Clonal Hematopoiesis of Indeterminate Potential

Cardiovascular disease (CVD) is associated with high doses of radiation and is are cognized health risk for astronauts on multiple or long duration exploration missions to the Moon or Mars. Currently, radiation risk assessment is based on background population disease rates and does not consider individual risk factors that may modify analysis, especially at lower radiation doses.

Zarana S Patel↗
NASA NTRSDate not supplied

Mechanical Unloading Effects Hematopoiesis and Subsequent Red Blood Cell Life Cycle Evaluated at Singe Cell Resolution

Red blood cell formation or erythropoiesis in the bone marrow and exit into circulation are known to be affected by mechanical loading. Specifically, space anemia is a condition observed during prolonged microgravity unloading in which the red blood cell (RBC) mass in circulation is reduced. However, the mechanisms causing space anemia are yet to be clearly established, but may include increased hemolysis of RBC in circulation, decreased RBC production or a combination of both factors. The presentation of space anemia is comparable to chronic anemia conditions associated with aging, disuse, and poor health. Molecular dysregulation in the RBC's life cycle is poorly defined and is a significant concern in the context of disuse anemia as mechanotransduction significantly alters of gene expression, protein synthesis and cell signaling pathways. Our study analyzes mouse single cell RNA sequencing libraries from the bone marrow, circulating blood, and spleen and integrates the RBC lineage populations from the tissues into a RBC life cycle atlas. This study also probes how age at time of spaceflight contributes to the molecular signature of space anemia. The overarching objective of the study is to develop a mechanistic understanding of space anemia and translate the findings to a better understanding of aging, disuse, and poor health-related anemia to defining the role of mechanical loading in health and devise potential therapeutic interventions. Important findings of our study are: 1) that mechanical unloading in microgravity alters the proportion of developmental RBC lineage cells, skewing toward progenitor, indicating that fewer RBCs may be present in blood; 2) that late reticulocyte number is elevated in the bone marrow of older animals, suggesting a failure to enter circulation; and 3) that the molecular signature of the circulating RBCs is not significantly altered in microgravity. However, expression markers for eryptosis and erythrophagocytosis are elevated in circulating and spleen RBCs, suggesting spaceflight may shorten the lifetime of RBCs after exit from the marrow. In conclusion our results suggest early stages of erythropoiesis proliferation and differentiation in the marrow are key factors in space anemia and mechanical loading may be a necessary step of RBC entry in circulation.

blood↗
DOE OSTI2024

The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1β–mediated AML progression

Identifying and targeting microenvironment-driven pathways that are active across acute myeloid leukemia (AML) genetic subtypes should allow the development of more broadly effective therapies. The proinflammatory cytokine interleukin-1β (IL-1β) is abundant in the AML microenvironment and promotes leukemic growth. Through RNA-sequencing analysis, we identify that IL-1β–upregulated ASF1B (antisilencing function-1B), a histone chaperone, in AML progenitors compared with healthy progenitors. ASF1B, along with its paralogous protein ASF1A, recruits H3-H4 histones onto the replication fork during S-phase, a process regulated by Tousled-like kinase 1 and 2 (TLKs). Although ASF1s and TLKs are known to be overexpressed in multiple solid tumors and associated with poor prognosis, their functional roles in hematopoiesis and inflammation-driven leukemia remain unexplored. In this study, we identify that ASF1s and TLKs are overexpressed in multiple genetic subtypes of AML. We demonstrate that depletion of ASF1s significantly reduces leukemic cell growth in both in vitro and in vivo models using human cells. Using a murine model, we show that overexpression of ASF1B accelerates leukemia progression. Moreover, Asf1b or Tlk2 deletion delayed leukemia progression, whereas these proteins are dispensable for normal hematopoiesis. Through proteomics and phosphoproteomics analyses, we uncover that the TLK-ASF1 pathway promotes leukemogenesis by affecting the cell cycle and DNA damage pathways. Collectively, our findings identify the TLK1-ASF1 pathway as a novel mediator of inflammatory signaling and a promising therapeutic target for AML treatment across diverse genetic subtypes. Finally, selective inhibition of this pathway offers potential opportunities to intervene effectively, address intratumoral heterogeneity, and ultimately improve clinical outcomes in AML.

60 APPLIED LIFE SCIENCES↗