Cell fusion likely drives tumor evolution by undermining chromosomal and DNA stability and/or by generating phenotypic diversity; however, whether a cell fusion event can initiate malignancy and direct tumor evolution is unknown. We report that a fusion event involving normal, nontransformed, cytogenetically stable epithelial cells can initiate chromosomal instability, DNA damage, cell transformation, and malignancy. Clonal analysis of fused cells reveals that the karyotypic and phenotypic potential of tumors formed by cell fusion is established immediately or within a few cell divisions after the fusion event, without further ongoing genetic and phenotypic plasticity, and that subsequent evolution of such tumors reflects selection from the initial diverse population rather than ongoing plasticity of the progeny. Thus, one cell fusion event can both initiate malignancy and fuel evolution of the tumor that ensues.
Spontaneous intracranial hemorrhage (ICH) is a common hemorrhagic stroke subtype with significant neurological sequelae. The management of ICH is usually supportive treatment in the neuro-intensive care setting, while the body humors deal with the hematoma. Treatment of the hematoma is usually expectant management unless there is neurological deterioration caused by mass effect from the hemorrhage. Some minimally invasive techniques have been explored for lysing and evacuating the hematoma, but none of them have gained a stronghold in the routine clinical management of this condition. Studies mainly in animal (rodent and porcine) ICH models have shown the role of bound and unbound iron in causing neurotoxicity following an ICH. There is currently no noninvasive method for assessing iron levels in the cerebral tissue following ICH. Our study intends to explore the role of magnetic resonance imaging (MRI) in establishing iron levels in cerebral tissue at the periphery of the hematoma following an ICH. Initially, an MRI phantom was constructed with varying concentrations of liquid iron preparation in a water bath container. Susceptibility weighted sequences were utilized to scan this phantom to generate T2* signal magnitude measurements corresponding to the iron concentration in the phantom. Encouraged by the reliability of the measurements on the phantom, patients with ICH were then recruited into this experimental study once the inclusion criteria were met. One control and two human subjects had their brains scanned in a 3 T MRI scanner utilizing the same susceptibility weighted sequence. We found that ICH perihematomal brain tissue iron susceptibility signal measurements were 4 times higher than those of the baseline control and normal contralateral brain tissue. Three different baseline measurements (one control and two contralateral normal brain) revealed a level of 0.1 mg/ml of iron concentration in the contralateral brain tissue in the identical anatomical location as the hematoma, typically in the basal ganglia region. T2 * signal measurements in the brain tissue at the periphery of the basal ganglia hematoma at day 7 following hemorrhage revealed iron concentration of 0.4 mg/ml (approximately 4 times the baseline/control) in two human subjects included in the study. These measurements mimic those obtained in published animal ICH model studies.
Purpose: Intracerebral hemorrhage (ICH) is a fatal subtype of Hemorrhagic stroke. Tissue iron at the periphery of ICH has been demonstrated to be neurotoxic in animal models. No robust method to quantify tissue iron following ICH currently exists. Our aim is to determine a robust algorithm based on MRI to quantify tissue iron in the wake of ICH. Methods: Following Institutional review board approval we constructed an MRI phantom. Eight 4 cc vials with 50 % decreasing dilutions of Ferraheme (iron for IV therapy) were prepared starting from 0.6 mg/ml ending at 0.005 mg/ml. The vials were stuck to the undersurface of the lid of a water bath container and scanned in a 3T MRI with T2* sequences. The T2* signal magnitudes were calculated for each concentration. Subsequently a human control brain and two patients with left basal ganglia ICH were scanned with identical parameters. The T2* signal magnitude was calculated at 3 ROIs at the periphery of the ICH. Results: The R2* maps demonstrated a near linear correlation with the iron concentration in the phantom. The control T2* signal magnitude corresponded to 0.01 mg/ml iron concentration. The two patients on ICH day 7 had measurements of iron concentration of 0.04 mg/ml (4 x baseline) at the periphery of the hematoma. This corresponds favorably to a threefold increase in measured tissue iron levels in animal ICH model studies. Conclusion: Our experiment demonstrates that quantitative susceptibility measurements on MRI may be a robust technique to assess iron level in brain tissue following ICH. Encouraged by the results we have applied to the NIH (#GRANT11426089) for funding to be able to evaluate the validity of the algorithm. Tissue iron quantification by MRI may assist in judging severity of ICH and act as a surrogate marker for assessing treatment with iron chelator.
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