Browsing by Author "Qi, Yi"

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    A Diffusion MRI Tractography Connectome of the Mouse Brain and Comparison with Neuronal Tracer Data.
    (Cereb Cortex, 2015-11) Calabrese, Evan; Badea, Alexandra; Cofer, Gary; Qi, Yi; Johnson, G Allan
    Interest in structural brain connectivity has grown with the understanding that abnormal neural connections may play a role in neurologic and psychiatric diseases. Small animal connectivity mapping techniques are particularly important for identifying aberrant connectivity in disease models. Diffusion magnetic resonance imaging tractography can provide nondestructive, 3D, brain-wide connectivity maps, but has historically been limited by low spatial resolution, low signal-to-noise ratio, and the difficulty in estimating multiple fiber orientations within a single image voxel. Small animal diffusion tractography can be substantially improved through the combination of ex vivo MRI with exogenous contrast agents, advanced diffusion acquisition and reconstruction techniques, and probabilistic fiber tracking. Here, we present a comprehensive, probabilistic tractography connectome of the mouse brain at microscopic resolution, and a comparison of these data with a neuronal tracer-based connectivity data from the Allen Brain Atlas. This work serves as a reference database for future tractography studies in the mouse brain, and demonstrates the fundamental differences between tractography and neuronal tracer data.
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    A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy.
    (Theranostics, 2015) Liu, Yang; Ashton, Jeffrey R; Moding, Everett J; Yuan, Hsiangkuo; Register, Janna K; Fales, Andrew M; Choi, Jaeyeon; Whitley, Melodi J; Zhao, Xiaoguang; Qi, Yi; Ma, Yan; Vaidyanathan, Ganesan; Zalutsky, Michael R; Kirsch, David G; Badea, Cristian T; Vo-Dinh, Tuan
    Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.
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    Assessing cardiac injury in mice with dual energy-microCT, 4D-microCT, and microSPECT imaging after partial heart irradiation.
    (Int J Radiat Oncol Biol Phys, 2014-03-01) Lee, Chang-Lung; Min, Hooney; Befera, Nicholas; Clark, Darin; Qi, Yi; Das, Shiva; Johnson, G Allan; Badea, Cristian T; Kirsch, David G
    PURPOSE: To develop a mouse model of cardiac injury after partial heart irradiation (PHI) and to test whether dual energy (DE)-microCT and 4-dimensional (4D)-microCT can be used to assess cardiac injury after PHI to complement myocardial perfusion imaging using micro-single photon emission computed tomography (SPECT). METHODS AND MATERIALS: To study cardiac injury from tangent field irradiation in mice, we used a small-field biological irradiator to deliver a single dose of 12 Gy x-rays to approximately one-third of the left ventricle (LV) of Tie2Cre; p53(FL/+) and Tie2Cre; p53(FL/-) mice, where 1 or both alleles of p53 are deleted in endothelial cells. Four and 8 weeks after irradiation, mice were injected with gold and iodinated nanoparticle-based contrast agents, and imaged with DE-microCT and 4D-microCT to evaluate myocardial vascular permeability and cardiac function, respectively. Additionally, the same mice were imaged with microSPECT to assess myocardial perfusion. RESULTS: After PHI with tangent fields, DE-microCT scans showed a time-dependent increase in accumulation of gold nanoparticles (AuNp) in the myocardium of Tie2Cre; p53(FL/-) mice. In Tie2Cre; p53(FL/-) mice, extravasation of AuNp was observed within the irradiated LV, whereas in the myocardium of Tie2Cre; p53(FL/+) mice, AuNp were restricted to blood vessels. In addition, data from DE-microCT and microSPECT showed a linear correlation (R(2) = 0.97) between the fraction of the LV that accumulated AuNp and the fraction of LV with a perfusion defect. Furthermore, 4D-microCT scans demonstrated that PHI caused a markedly decreased ejection fraction, and higher end-diastolic and end-systolic volumes, to develop in Tie2Cre; p53(FL/-) mice, which were associated with compensatory cardiac hypertrophy of the heart that was not irradiated. CONCLUSIONS: Our results show that DE-microCT and 4D-microCT with nanoparticle-based contrast agents are novel imaging approaches complementary to microSPECT for noninvasive assessment of the change in myocardial vascular permeability and cardiac function of mice in whom myocardial injury develops after PHI.
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    Characterization complex collagen fiber architecture in knee joint using high-resolution diffusion imaging.
    (Magnetic resonance in medicine, 2020-01-21) Wang, Nian; Mirando, Anthony J; Cofer, Gary; Qi, Yi; Hilton, Matthew J; Johnson, G Allan
    PURPOSE:To evaluate the complex fiber orientations and 3D collagen fiber network of knee joint connective tissues, including ligaments, muscle, articular cartilage, and meniscus using high spatial and angular resolution diffusion imaging. METHODS:Two rat knee joints were scanned using a modified 3D diffusion-weighted spin echo pulse sequence with the isotropic spatial resolution of 45 μm at 9.4T. The b values varied from 250 to 1250 s/mm2 with 31 diffusion encoding directions for 1 rat knee. The b value was fixed to 1000 s/mm2 with 147 diffusion encoding directions for the second knee. Both the diffusion tensor imaging (DTI) model and generalized Q-sampling imaging (GQI) method were used to investigate the fiber orientation distributions and tractography with the validation of polarized light microscopy. RESULTS:To better resolve the crossing fibers, the b value should be great than or equal to 1000 s/mm2 . The tractography results were comparable between the DTI model and GQI method in ligament and muscle. However, the tractography exhibited apparent difference between DTI and GQI in connective tissues with more complex collagen fibers network, such as cartilage and meniscus. In articular cartilage, there were numerous crossing fibers found in superficial zone and transitional zone. Tractography generated with GQI also resulted in more intact tracts in articular cartilage than DTI. CONCLUSION:High-resolution diffusion imaging with GQI method can trace the complex collagen fiber orientations and architectures of the knee joint at microscopic resolution.
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    Detection of Lung Nodules in Micro-CT Imaging Using Deep Learning
    (Tomography) Holbrook, Matthew D; Clark, Darin P; Patel, Rutulkumar; Qi, Yi; Bassil, Alex M; Mowery, Yvonne M; Badea, Cristian T
    We are developing imaging methods for a co-clinical trial investigating synergy between immunotherapy and radiotherapy. We perform longitudinal micro-computed tomography (micro-CT) of mice to detect lung metastasis after treatment. This work explores deep learning (DL) as a fast approach for automated lung nodule detection. We used data from control mice both with and without primary lung tumors. To augment the number of training sets, we have simulated data using real augmented tumors inserted into micro-CT scans. We employed a convolutional neural network (CNN), trained with four competing types of training data: (1) simulated only, (2) real only, (3) simulated and real, and (4) pretraining on simulated followed with real data. We evaluated our model performance using precision and recall curves, as well as receiver operating curves (ROC) and their area under the curve (AUC). The AUC appears to be almost identical (0.76–0.77) for all four cases. However, the combination of real and synthetic data was shown to improve precision by 8%. Smaller tumors have lower rates of detection than larger ones, with networks trained on real data showing better performance. Our work suggests that DL is a promising approach for fast and relatively accurate detection of lung tumors in mice.
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    Dual-Energy CT Imaging of Tumor Liposome Delivery After Gold Nanoparticle-Augmented Radiation Therapy
    (Theranostics, 2018-02-12) Ashton, Jeffrey; Castle, Katherine; Qi, Yi; Kirsch, David; West, J; Badea, Cristian
    Gold nanoparticles (AuNPs) are emerging as promising agents for both cancer therapy and computed tomography (CT) imaging. AuNPs absorb x-rays and subsequently release low-energy, short-range photoelectrons during external beam radiation therapy (RT), increasing the local radiation dose. When AuNPs are near tumor vasculature, the additional radiation dose can lead to increased vascular permeability. This work focuses on understanding how tumor vascular permeability is influenced by AuNP-augmented RT, and how this effect can be used to improve the delivery of nanoparticle chemotherapeutics. Methods: Dual-energy CT was used to quantify the accumulation of both liposomal iodine and AuNPs in tumors following AuNP-augmented RT in a mouse model of primary soft tissue sarcoma. Mice were injected with non-targeted AuNPs, RGD-functionalized AuNPs (vascular targeting), or no AuNPs, after which they were treated with varying doses of RT. The mice were injected with either liposomal iodine (for the imaging study) or liposomal doxorubicin (for the treatment study) 24 hours after RT. Increased tumor liposome accumulation was assessed by dual-energy CT (iodine) or by tracking tumor treatment response (doxorubicin). Results: A significant increase in vascular permeability was observed for all groups after 20 Gy RT, for the targeted and non-targeted AuNP groups after 10 Gy RT, and for the vascular-targeted AuNP group after 5 Gy RT. Combining targeted AuNPs with 5 Gy RT and liposomal doxorubicin led to a significant tumor growth delay (tumor doubling time ~ 8 days) compared to AuNP-augmented RT or chemotherapy alone (tumor doubling time ~3-4 days). Conclusions: The addition of vascular-targeted AuNPs significantly improved the treatment effect of liposomal doxorubicin after RT, consistent with the increased liposome accumulation observed in tumors in the imaging study. Using this approach with a liposomal drug delivery system can increase specific tumor delivery of chemotherapeutics, which has the potential to significantly improve tumor response and reduce the side effects of both RT and chemotherapy.
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    Ex Vivo MR Histology and Cytometric Feature Mapping Connect Three-dimensional in Vivo MR Images to Two-dimensional Histopathologic Images of Murine Sarcomas.
    (Radiology. Imaging cancer, 2021-05) Blocker, Stephanie J; Cook, James; Mowery, Yvonne M; Everitt, Jeffrey I; Qi, Yi; Hornburg, Kathryn J; Cofer, Gary P; Zapata, Fernando; Bassil, Alex M; Badea, Cristian T; Kirsch, David G; Johnson, G Allan
    Purpose To establish a platform for quantitative tissue-based interpretation of cytoarchitecture features from tumor MRI measurements. Materials and Methods In a pilot preclinical study, multicontrast in vivo MRI of murine soft-tissue sarcomas in 10 mice, followed by ex vivo MRI of fixed tissues (termed MR histology), was performed. Paraffin-embedded limb cross-sections were stained with hematoxylin-eosin, digitized, and registered with MRI. Registration was assessed by using binarized tumor maps and Dice similarity coefficients (DSCs). Quantitative cytometric feature maps from histologic slides were derived by using nuclear segmentation and compared with registered MRI, including apparent diffusion coefficients and transverse relaxation times as affected by magnetic field heterogeneity (T2* maps). Cytometric features were compared with each MR image individually by using simple linear regression analysis to identify the features of interest, and the goodness of fit was assessed on the basis of R2 values. Results Registration of MR images to histopathologic slide images resulted in mean DSCs of 0.912 for ex vivo MR histology and 0.881 for in vivo MRI. Triplicate repeats showed high registration repeatability (mean DSC, >0.9). Whole-slide nuclear segmentations were automated to detect nuclei on histopathologic slides (DSC = 0.8), and feature maps were generated for correlative analysis with MR images. Notable trends were observed between cell density and in vivo apparent diffusion coefficients (best line fit: R2 = 0.96, P < .001). Multiple cytoarchitectural features exhibited linear relationships with in vivo T2* maps, including nuclear circularity (best line fit: R2 = 0.99, P < .001) and variance in nuclear circularity (best line fit: R2 = 0.98, P < .001). Conclusion An infrastructure for registering and quantitatively comparing in vivo tumor MRI with traditional histologic analysis was successfully implemented in a preclinical pilot study of soft-tissue sarcomas. Keywords: MRI, Pathology, Animal Studies, Tissue Characterization Supplemental material is available for this article. © RSNA, 2021.
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    Micro-CT imaging of breast tumors in rodents using a liposomal, nanoparticle contrast agent.
    (Int J Nanomedicine, 2009) Samei, Ehsan; Saunders, Robert S; Badea, Cristian T; Ghaghada, Ketan B; Hedlund, Laurence W; Qi, Yi; Yuan, Hong; Bentley, Rex C; Mukundan, Srinivasan
    A long circulating liposomal, nanoscale blood pool agent encapsulating traditional iodinated contrast agent (65 mg I/mL) was used for micro-computed tomography (CT) imaging of rats implanted with R3230AC mammary carcinoma. Three-dimensional vascular architecture of tumors was imaged at 100-micron isotropic resolution. The image data showed good qualitative correlation with pathologic findings. The approach holds promise for studying tumor angiogenesis and for evaluating anti-angiogenesis therapies.
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    Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
    (Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian T
    This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
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    Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
    (Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian T
    This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
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    Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology.
    (Neurotoxicology, 2014-05) Johnson, G Allan; Calabrese, Evan; Little, Peter B; Hedlund, Laurence; Qi, Yi; Badea, Alexandra
    The growing exposure to chemicals in our environment and the increasing concern over their impact on health have elevated the need for new methods for surveying the detrimental effects of these compounds. Today's gold standard for assessing the effects of toxicants on the brain is based on hematoxylin and eosin (H&E)-stained histology, sometimes accompanied by special stains or immunohistochemistry for neural processes and myelin. This approach is time-consuming and is usually limited to a fraction of the total brain volume. We demonstrate that magnetic resonance histology (MRH) can be used for quantitatively assessing the effects of central nervous system toxicants in rat models. We show that subtle and sparse changes to brain structure can be detected using magnetic resonance histology, and correspond to some of the locations in which lesions are found by traditional pathological examination. We report for the first time diffusion tensor image-based detection of changes in white matter regions, including fimbria and corpus callosum, in the brains of rats exposed to 8 mg/kg and 12 mg/kg trimethyltin. Besides detecting brain-wide changes, magnetic resonance histology provides a quantitative assessment of dose-dependent effects. These effects can be found in different magnetic resonance contrast mechanisms, providing multivariate biomarkers for the same spatial location. In this study, deformation-based morphometry detected areas where previous studies have detected cell loss, while voxel-wise analyses of diffusion tensor parameters revealed microstructural changes due to such things as cellular swelling, apoptosis, and inflammation. Magnetic resonance histology brings a valuable addition to pathology with the ability to generate brain-wide quantitative parametric maps for markers of toxic insults in the rodent brain.