Proper regulation of the balance between hematopoietic stem cell (HSC) proliferation, self‐renewal, and differentiation is necessary to maintain hematopoiesis throughout life. The Wnt family of ...ligands has been implicated as critical regulators of these processes through a network of signaling pathways. Previously, we have demonstrated that the Wnt5a ligand can induce HSC quiescence through a noncanonical Wnt pathway, resulting in an increased ability to reconstitute hematopoiesis. In this study, we tested the hypothesis that the Ryk protein, a Wnt ligand receptor that can bind the Wnt5a ligand, regulated the response of HSCs to Wnt5a. We observed that inhibiting Ryk blocked the ability of Wnt5a to induce HSC quiescence and enhance short‐term and long‐term hematopoietic repopulation. We found that Wnt5a suppressed production of reactive oxygen species, a known inducer of HSC proliferation. The ability of Wnt5a to inhibit ROS production was also regulated by Ryk. From these data, we propose that Wnt5a regulates HSC quiescence and hematopoietic repopulation through the Ryk receptor and that this process is mediated by suppression of reactive oxygen species. Stem Cells 2014;32:105–115
In this paper a new dynamic model for an actuator applied as a pneumatic artificial muscle (PAM) is developed. The model simulates the two-direction motion of a PAM caused by a nonlinear force which ...depends on pressure and deformation. Parameters of the acting force are obtained analytically, applying the optimal parameter identification method, and experimentally proved on the model tested on an experimental rig. In the dynamic model the stiffness and also the damping are nonlinear functions of displacement. The nonlinear displacement force causes self-excited vibrations of PAM. Influence of different loadings on the system is investigated. Using MS Excel software and MATLAB Simulink the simulation of motion of the system is given.
•New investigation on dynamics of a vibrating pendulum with PAM is discussed.•Dynamic model of the vibrating system based on the static force model is developed.•The model corresponds to a PAM of any length and diameter with any pressure.•It can also determine the nonlinear stiffness and damping properties of PAM.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical ...outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, although the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is IFN regulatory factor (IRF)-8, which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. In this study, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8
granulocyte progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8
GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8
GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.
The mechanisms that regulate hematopoietic stem cell (HSC) fate decisions between proliferation and multilineage differentiation are unclear. Members of the Wnt family of ligands that activate the ...canonical Wnt signaling pathway, which utilizes β-catenin to relay the signal, have been demonstrated to regulate HSC function. In this study, we examined the role of noncanonical Wnt signaling in regulating HSC fate. We observed that noncanonical Wnt5a inhibited Wnt3a-mediated canonical Wnt signaling in HSCs and suppressed Wnt3a-mediated alterations in gene expression associated with HSC differentiation, such as increased expression of myc. Wnt5a increased short- and long-term HSC repopulation by maintaining HSCs in a quiescent G₀ state. From these data, we propose that Wnt5a regulates hematopoiesis by the antagonism of the canonical Wnt pathway, resulting in a pool of quiescent HSCs.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Interferon-γ release assays (IGRAs) are now established for the immunodiagnosis of latent infection with Mycobacterium tuberculosis in many countries. However, the role of IGRAs for the diagnosis of ...active tuberculosis (TB) remains unclear. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and quality assessment of diagnostic accuracy studies (QUADAS) guidelines, we searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001-November 2009 that evaluated the evidence of using QuantiFERON-TB® Gold in-tube (QFT-G-IT) and T-SPOT.TB® directly on blood or extrasanguinous specimens for the diagnosis of active TB. The literature search yielded 844 studies and 27 met the inclusion criteria. In blood and extrasanguinous fluids, the pooled sensitivity for the diagnosis of active TB was 80% (95% CI 75-84%) and 48% (95% CI 39-58%) for QFT-G-IT, and 81% (95% CI 78-84%) and 88% (confirmed and unconfirmed cases) (95% CI 82-92%) for T-SPOT.TB®, respectively. In blood and extrasanguinous fluids, the pooled specificity was 79% (95% CI 75-82%) and 82% (95% CI 70-91%) for QFT-G-IT, and 59% (95% CI 56-62%) and 82% (95% CI 78-86%) for T-SPOT.TB®, respectively. Although the diagnostic sensitivities of both IGRAs were higher than that of tuberculin skin tests, it was still not high enough to use as a rule out test for TB. Positive evidence for the use of IGRAs in compartments other than blood will require more independent and carefully designed prospective studies.
While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune ...suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1-based (PD-1-based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.
Decreased diffusion (DD) consistent with acute ischemia may be detected on MRI after acute intracerebral hemorrhage (ICH), but its risk factors and impact on functional outcomes are not well-defined. ...We tested the hypotheses that DD after ICH is related to acute blood pressure (BP) reduction and lower hemoglobin and presages worse functional outcomes.
Patients who underwent MRI were prospectively evaluated for DD by certified neuroradiologists blinded to outcomes. Hemoglobin and BP data were obtained via electronic queries. Outcomes were obtained at 14 days and 3 months with the modified Rankin Scale, a functional scale scored from 0 (no symptoms) to 6 (dead). We used logistic regression for dependence or death (modified Rankin Scale score 4-6).
DD distinct from the hematoma was found on MRI in 39 of 95 patients (41%). DD was associated with greater BP reductions from baseline and a higher risk of dependence or death at 3 months (odds ratio, 4.8; 95% confidence interval, 1.7-13.9; P=0.004) after correction for ICH score (1.8 per point; 95% confidence interval, 1.2-3.1; P=0.01). Lower hemoglobin was associated with worse ICH score, larger hematoma volume, and worse outcomes, but not DD.
DD is common after ICH, associated with greater acute BP reductions, and associated with disability and death at 3 months in multivariate analysis. The potential benefits of acute BP reduction to reduce hematoma growth may be limited by DD. The prevention and treatment of cerebral ischemia manifested as DD are potential methods to improve outcomes.
High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the ...impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.
Arginine vasopressin (AVP) made by hypothalamic neurons is released into the circulation to stimulate water resorption by the kidneys and restore water balance after blood loss. Patients who lack ...this antidiuretic hormone suffer from central diabetes insipidus. We observed that many of these patients were anemic and asked whether AVP might play a role in red blood cell (RBC) production. We found that all three AVP receptors are expressed in human and mouse hematopoietic stem and progenitor cells. The AVPR1B appears to play the most important role in regulating erythropoiesis in both human and mouse cells. AVP increases phosphorylation of signal transducer and activator of transcription 5, as erythropoietin (EPO) does. After sublethal irradiation, AVP-deficient Brattleboro rats showed delayed recovery of RBC numbers compared to control rats. In mouse models of anemia (induced by bleeding, irradiation, or increased destruction of circulating RBCs), AVP increased the number of circulating RBCs independently of EPO. In these models, AVP appears to jump-start peripheral blood cell replenishment until EPO can take over. We suggest that specific AVPR1B agonists might be used to induce fast RBC production after bleeding, drug toxicity, or chemotherapy.
Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant ...primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified. Interferon regulatory factor-8 (IRF-8) is a transcription factor that is essential for myelopoiesis. Depressed IRF-8 levels are observed in a majority of CML patients and Irf-8−/− mice exhibit a CML-like disease. The underlying mechanisms of IRF-8 loss in CML are unknown. We hypothesized that BCR-ABL suppresses transcription of IRF-8 through STAT5, a proximal BCR-ABL target. Treatment of primary cells from newly diagnosed CML patients in chronic phase as well as BCR-ABL+ cell lines with imatinib increased IRF-8 transcription. Furthermore, IRF-8 expression in cell line models was necessary for imatinib-induced antitumor responses. We have demonstrated that IRF-8 is a direct target of STAT5 and that silencing of STAT5 induced IRF-8 expression. Conversely, activating STAT5 suppressed IRF-8 transcription. Finally, we showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples. These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets.
The IRF-8 tumor suppressor gene is down-regulated in chronic myeloid leukemia (CML).
The STAT5 transcription factor regulates IRF-8 expression in CML cells.
In CML, oncogene-mediated activation of STAT5 is responsible for suppressing the IRF-8 gene.
An oncogene driven STAT5-IRF-8 signaling axis regulates CML biology and may be implicated in other types of myeloid malignanices.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
