59 research outputs found
HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α
Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic
Efficient derivation of NPCs, spinal motor neurons and midbrain dopaminergic neurons from hESCs at 3% oxygen
This protocol has been designed to generate neural precursor cells (NPCs) from human embryonic stem cells (hESCs) using a physiological oxygen (O(2)) level of 3% and chemically defined conditions. The first stage involves suspension culture of hESC colonies at 3% O(2), where they acquire a neuroepithelial identity over two weeks. This timescale is comparable to that at 20% O(2), but survival is enhanced. Sequential application of retinoic acid (RA) and purmorphamine (PM), from day 14 to 28, directs differentiation towards spinal motor neurons. Alternatively, addition of FGF-8 and PM generates midbrain dopaminergic neurons. OLIG2 induction in motor neuron precursors is 2-fold greater than at 20% O(2), whereas EN1 is 5-fold enhanced. 3% NPCs can be differentiated into all three neural lineages, and such cultures can be maintained long-term in the absence of neurotrophins. The ability to generate defined cell types at 3% O(2) should represent a significant advance for in vitro disease modelling and potentially cell-based therapies
Continuing C3 breakdown after bilateral nephrectomy in patients with membrano-proliferative glomerulonephritis
Regional nodal metastasis and 5-year survival in patients with thin melanoma in Queensland: a population-based study
Background: Optimal management of regional lymph nodes for thin cutaneous melanoma is uncertain. We evaluated regional lymph node involvement and 5-year melanoma-specific survival (MSS) in patients with thin (≤1 mm) primary melanoma. Methods: Patients with a melanoma, American Joint Committee on Cancer Staging 8th Edition pT1a (60 years. The 5-year MSS was similar for observed and SLNB cohorts (99.66% versus 98.92%) but worse for T1b lesions (98.90%) and clinical nodal recurrence (66.89%). Conclusion: Overall prognosis for T1 melanoma is excellent with nodal involvement being rare. However, the American Joint Committee on Cancer 8th Edition T1b melanoma correlates with significantly worse 5-year MSS and increased regional nodal recurrence (notably for 0.8–1.0 mm lesions with ulceration). Further characterization of high-risk groups for nodal positivity that impacts patient outcome is needed for the pT1 melanoma cohort
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Trough Receiver Heat Loss Testing
This presentation describes the design, fabrication, and qualification of an experimental capability for thermal loss testing of full-size trough receiver elements; and the testing on a variety of receivers
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