ABSTRACT
SDF-1/CXCR4 axis plays a principle role in the homing and engraftment of hematopoietic stem/progenitor cells (HSPCs), a process that defines cells ability to reach and seed recipient bone marrow niche following their intravenous infusion. However, the proper functioning of CXCR4 downstream signaling depends upon consistent optimal expression of both SDF-1 ligand and its receptor CXCR4, which in turn is variable and regulated by several factors. The constitutive active mutants of CXCR4 (N119A and N119S) being able to induce autonomous downstream signaling, overcome the limitation of ligand-receptor interaction for induction of CXCR4 signaling. Therefore, we intended to explore their potential in Chemotaxis; a key cellular process which crucially regulates cells homing to bone marrow. In present study, Tet-on inducible gene expression vector system was used for doxycycline inducible regulated transgene expression of CXCR4 active mutants in hematopoietic stem progenitor cell line K-562. Both of these mutants revealed significantly enhanced Chemotaxis to SDF-1 gradient as compared to wild type. Furthermore, gene expression profiling of these genetically engineered cells as assessed by microarray analysis revealed the up-regulation of group of genes that are known to play a crucial role in CXCR4 mediated cells homing and engraftment. Hence, this study suggest the potential prospects of CXCR4 active mutants in research and development aimed to improve the efficiency of cells in the mechanism of homing and engraftment process.
ABSTRACT
BACKGROUND: A variety of neurodegenerative disorders produce significant abnormal brain function which can be detected using fluorodeoxyglucose positron emission tomography (FDG PET) scan even when structural changes are not detected on CT or MRI Scan. A study was undertaken at our institute to evaluate the FDG PET/CT findings in Indian population suffering from mild cognitive impairment (MCI), Alzheimer's disease (AD), fronto-temporal dementia (FTD), dementia with lewy body disease (DLBD) and other miscellaneous causes of dementia. MATERIALS AND METHODS: 117 subjects having neurocognitive deficits and 36 normals were included in our study. All patients underwent a detailed history and clinical examination. This was followed by a mini mental state examination. Subsequently an FDG brain PET scan and an MRI were done. RESULTS: In the patient population included in our study group 36 were normal, 39 had MCI, 40 had AD, 14 had FTD, and 13 had DLBD and 11 dementia due to other miscellaneous causes. MCI patients showed primarily reduced tracer uptake in the mesio-temporal cortex. AD patients showed reduced tracer concentration in temporo-parietal lobes, while patients with advanced diseases showed frontal lobe disease additionally. In subjects of FTD, reduced radiotracer uptake in the fronto-temporal lobes was noted. In addition, FTD patients also showed basal ganglia defects. In contrast the DLBD patients showed globally reduced FDG uptake including severely affecting the occipital cortices. CONCLUSION: In the current study the F18-FDG PET scans have been shown to be highly useful in the diagnosis of various neurocognitive disorders of the brain. AD was found to be the most common dementia in the Indian population followed by MCI. Diffuse Lewy body disease, FTD and other miscellaneous categories of dementia had a near similar incidence.
