Purpose: To present a modified pharmacokinetic model for improved parameter accuracy and to investigate the influence of an inaccurate arterial input function (AIF) on dynamic contrast-enhanced (DCE)-MRI parameter estimates of the transfer constant (K trans ), blood volume (v p ), and interstitial volume (v e ). Materials and Methods:Tissue uptake curves were simulated over a large range of physiological values and analyzed for different AIF measurement errors and temporal resolutions. The AIF measurement was assumed to be inaccurate in the bolus amplitude (rapid sampling) or susceptible to unknown temporal offsets (slow sampling with biexponential decay fit). Results:The modified model adequately reduces errors in parameter estimates arising from transit time effects. An error in the AIF bolus amplitude results in an inversely proportional error in K trans and v p ; v e remains robust. More consistent error in K trans (Ϸ20% underestimation) was obtained using a biexponential AIF, at the expense of severely underestimating v p . Conclusion:While an accurate, high temporal resolution AIF is essential for estimating v p , a biexponential AIF acquired at low temporal resolution (Ͻ20 seconds) provides robust estimates of v e and results in a K trans underestimation comparable to that from a 25% error in the initial AIF bolus amplitude. DYNAMIC CONTRAST-ENHANCED (DCE)-MRI for characterizing tissue uptake of a contrast agent is an established method for assessing microcirculation physiology. It is relevant in studying a wide range of diseases and conditions, including cancer (1), ischemia (2), and inflammation (3). Quantitative parameters directly related to underlying physiological properties, such as vessel permeability, perfusion, and blood volume, may be obtained by applying a pharmacokinetic model to the DCE-MRI data (4). This physiology-based information is beneficial in a number of ways, from improving cancer diagnostic sensitivity and specificity to elucidating microvascular changes that accompany novel anticancer therapies. However, the degree to which measured parameters represent true physiology is influenced by a number of factors, and accurate DCE-MRI quantification remains challenging (5).A problematic but necessary requirement for quantitative DCE-MRI is measurement of the arterial input function (AIF), or contrast agent concentration time course in the blood pool. The simplest approach is to use a standard AIF (6), but this may differ from the individual's input function, and large errors in pharmacokinetic parameter estimates have been reported (7). The ideal approach is to obtain individual measurements. This, however, is beset by a number of challenges. One challenge is achieving a high temporal resolution (1 second) to capture rapid changes during the initial bolus passage, which is believed to be essential for reliable DCE-MRI quantification (8). Despite the availability of faster scanners and parallel imaging, a lower temporal resolution is often used due to competing demands for high spatial res...
Background Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. Methods Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. Results Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. Conclusions Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.
Objective: Aberrations in the PI3K/AKT/mTOR survival pathway in many cancers are the most common genomic abnormalities. The phytochemical and bioactive agent sulforaphane (SFN) has nutrigenomic potential in activating the expression of several cellular protective genes via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is primarily related to mechanisms of endogenous cellular defense and survival. The efficacy of SFN in combination with acetazolamide (AZ) was investigated in reducing typical H727 and atypical H720 BC survival, migration potential, and apoptosis in vitro and in vivo preclinical xenograft tissues. Materials and Methods: Microscopic imaging, immunocytochemistry, wound healing assay, caspase-cleaved cytokeratin 18 (M30, CCK18) CytoDeath ELISA assay, immunofluorescence labeling assays for apoptosis, hypoxia, Western Blotting, Tunnel assay, measurement of 5-HT secretion by carbon fiber amperometry assay, quantitative methylation-specific PCR (qMSP), morphologic changes, cell viability, apoptosis activity and the expression levels of phospho-Akt1, Akt1, HIF-1α, PI3K, p21, CAIX, 5-HT, phospho-mTOR, and mTOR in xenografts derived from typical H727 and atypical H720 BC cell lines. Results: Combining AZ+SFN reduced tumor cell survival compared to each agent alone, both in vitro and in vivo xenograft tissues. AZ+SFN targeted multiple pathways
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.