Browsing by Author "Liu, Fang"

Now showing 1 - 6 of 6
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    Associating Multi-modal Brain Imaging Phenotypes and Genetic Risk Factors via A Dirty Multi-task Learning Method
    (IEEE, 2020) Du, Lei; Liu, Fang; Liu, Kefei; Yao, Xiaohui; Risacher, Shannon L.; Han, Junwei; Saykin, Andrew J.; Shen, Li; Radiology and Imaging Sciences, School of Medicine
    Brain imaging genetics becomes more and more important in brain science, which integrates genetic variations and brain structures or functions to study the genetic basis of brain disorders. The multi-modal imaging data collected by different technologies, measuring the same brain distinctly, might carry complementary information. Unfortunately, we do not know the extent to which the phenotypic variance is shared among multiple imaging modalities, which further might trace back to the complex genetic mechanism. In this paper, we propose a novel dirty multi-task sparse canonical correlation analysis (SCCA) to study imaging genetic problems with multi-modal brain imaging quantitative traits (QTs) involved. The proposed method takes advantages of the multi-task learning and parameter decomposition. It can not only identify the shared imaging QTs and genetic loci across multiple modalities, but also identify the modality-specific imaging QTs and genetic loci, exhibiting a flexible capability of identifying complex multi-SNP-multi-QT associations. Using the state-of-the-art multi-view SCCA and multi-task SCCA, the proposed method shows better or comparable canonical correlation coefficients and canonical weights on both synthetic and real neuroimaging genetic data. In addition, the identified modality-consistent biomarkers, as well as the modality-specific biomarkers, provide meaningful and interesting information, demonstrating the dirty multi-task SCCA could be a powerful alternative method in multi-modal brain imaging genetics.
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    Development of a primate model to evaluate the effects of ketamine and surgical stress on the neonatal brain
    (Sage, 2023) Wang, Cheng; Bhutta, Adnan; Zhang, Xuan; Liu, Fang; Liu, Shuliang; Latham, Leah E.; Talpos, John C.; Patterson, Tucker A.; Slikker, William, Jr.; Pediatrics, School of Medicine
    With advances in pediatric and obstetric surgery, pediatric patients are subject to complex procedures under general anesthesia. The effects of anesthetic exposure on the developing brain may be confounded by several factors including pre-existing disorders and surgery-induced stress. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is routinely used as a pediatric general anesthetic. However, controversy remains about whether ketamine exposure may be neuroprotective or induce neuronal degeneration in the developing brain. Here, we report the effects of ketamine exposure on the neonatal nonhuman primate brain under surgical stress. Eight neonatal rhesus monkeys (postnatal days 5-7) were randomly assigned to each of two groups: Group A (n = 4) received 2 mg/kg ketamine via intravenous bolus prior to surgery and a 0.5 mg/kg/h ketamine infusion during surgery in the presence of a standardized pediatric anesthetic regimen; Group B (n = 4) received volumes of normal saline equivalent to those of ketamine given to Group A animals prior to and during surgery, also in the presence of a standardized pediatric anesthetic regimen. Under anesthesia, the surgery consisted of a thoracotomy followed by closing the pleural space and tissue in layers using standard surgical techniques. Vital signs were monitored to be within normal ranges throughout anesthesia. Elevated levels of cytokines interleukin (IL)-8, IL-15, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1β at 6 and 24 h after surgery were detected in ketamine-exposed animals. Fluoro-Jade C staining revealed significantly higher neuronal degeneration in the frontal cortex of ketamine-exposed animals, compared with control animals. Intravenous ketamine administration prior to and throughout surgery in a clinically relevant neonatal primate model appears to elevate cytokine levels and increase neuronal degeneration. Consistent with previous data on the effects of ketamine on the developing brain, the results from the current randomized controlled study in neonatal monkeys undergoing simulated surgery show that ketamine does not provide neuroprotective or anti-inflammatory effects.
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    DUSP1 Is a Novel Target for Enhancing Pancreatic Cancer Cell Sensitivity to Gemcitabine
    (Public Library of Science, 2014-01-07) Liu, Fang; Gore, A. Jesse; Wilson, Julie L.; Korc, Murray; Medicine, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1) is a key negative regulator of mitogen activated protein kinases (MAPKs). Yet, DUSP1 is overexpressed in pancreatic cancer cells (PCCs) in PDAC where it paradoxically enhances colony formation in soft agar and promotes in vivo tumorigenicity. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human PCCs, we show that gemcitabine activates c-JUN N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK), key kinases in two major stress-activated signaling pathways. Gemcitabine-induced JNK and p38 MAPK activation mediates increased apoptosis, but also transcriptionally upregulates DUSP1, as evidenced by increased DUSP1 mRNA levels and RNA polymerase II loading at DUSP1 gene body. Conversely, shRNA-mediated inhibition of DUSP1 enhances JNK and p38 MAPK activation and gemcitabine chemosensitivity. Using doxycycline-inducible knockdown of DUSP1 in established orthotopic pancreatic tumors, we found that combining gemcitabine with DUSP1 inhibition improves animal survival, attenuates angiogenesis, and enhances apoptotic cell death, as compared with gemcitabine alone. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the advantage of enhancing gemcitabine chemosensitivity while suppressing angiogenesis.
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    GRASP-Pro: imProving GRASP DCE‐MRI through self-calibrating subspace-modeling and contrast phase automation
    (Wiley, 2020-01) Feng, Li; Wen, Qiuting; Huang, Chenchan; Tong, Angela; Liu, Fang; Chandarana, Hersh; Radiology and Imaging Sciences, School of Medicine
    Purpose: To propose a highly accelerated, high-resolution dynamic contrast-enhanced MRI (DCE-MRI) technique called GRASP-Pro (golden-angle radial sparse parallel imaging with imProved performance) through a joint sparsity and self-calibrating subspace constraint with automated selection of contrast phases. Methods: GRASP-Pro reconstruction enforces a combination of an explicit low-rank subspace-constraint and a temporal sparsity constraint. The temporal basis used to construct the subspace is learned from an intermediate reconstruction step using the low-resolution portion of radial k-space, which eliminates the need for generating the basis using auxiliary data or a physical signal model. A convolutional neural network was trained to generate the contrast enhancement curve in the artery, from which clinically relevant contrast phases are automatically selected for evaluation. The performance of GRASP-Pro was demonstrated for high spatiotemporal resolution DCE-MRI of the prostate and was compared against standard GRASP in terms of overall image quality, image sharpness, and residual streaks and/or noise level. Results: Compared to GRASP, GRASP-Pro reconstructed dynamic images with enhanced sharpness, less residual streaks and/or noise, and finer delineation of the prostate without prolonging reconstruction time. The image quality improvement reached statistical significance (P < 0.05) in all the assessment categories. The neural network successfully generated contrast enhancement curves in the artery, and corresponding peak enhancement indexes correlated well with that from the manual selection. Conclusion: GRASP-Pro is a promising method for rapid and continuous DCE-MRI. It enables superior reconstruction performance over standard GRASP and allows reliable generation of artery enhancement curve to guide the selection of desired contrast phases for improving the efficiency of GRASP MRI workflow.
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    Identifying diagnosis-specific genotype–phenotype associations via joint multitask sparse canonical correlation analysis and classification
    (Oxford, 2020-07-13) Du, Lei; Liu, Fang; Liu, Kefei; Yao, Xiaohui; Risacher, Shannon L; Han, Junwei; Guo, Lei; Saykin, Andrew J; Shen, Li; Radiology and Imaging Sciences, School of Medicine
    Motivation Brain imaging genetics studies the complex associations between genotypic data such as single nucleotide polymorphisms (SNPs) and imaging quantitative traits (QTs). The neurodegenerative disorders usually exhibit the diversity and heterogeneity, originating from which different diagnostic groups might carry distinct imaging QTs, SNPs and their interactions. Sparse canonical correlation analysis (SCCA) is widely used to identify bi-multivariate genotype–phenotype associations. However, most existing SCCA methods are unsupervised, leading to an inability to identify diagnosis-specific genotype–phenotype associations. Results In this article, we propose a new joint multitask learning method, named MT–SCCALR, which absorbs the merits of both SCCA and logistic regression. MT–SCCALR learns genotype–phenotype associations of multiple tasks jointly, with each task focusing on identifying one diagnosis-specific genotype–phenotype pattern. Meanwhile, MT–SCCALR cannot only select relevant SNPs and imaging QTs for each diagnostic group alone, but also allows the selection of those shared by multiple diagnostic groups. We derive an efficient optimization algorithm whose convergence to a local optimum is guaranteed. Compared with two state-of-the-art methods, MT–SCCALR yields better or similar canonical correlation coefficients and classification performances. In addition, it owns much better discriminative canonical weight patterns of great interest than competitors. This demonstrates the power and capability of MTSCCAR in identifying diagnostically heterogeneous genotype–phenotype patterns, which would be helpful to understand the pathophysiology of brain disorders.
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    Limited Regeneration Potential with Minimal Epicardial Progenitor Conversions in the Neonatal Mouse Heart after Injury
    (Elsevier, 2019-07-02) Cai, Weibin; Tan, Jing; Yan, Jianyun; Zhang, Lu; Cai, Xiaoqiang; Wang, Haiping; Liu, Fang; Ye, Maoqing; Cai, Chen-Leng; Pediatrics, School of Medicine
    The regeneration capacity of neonatal mouse heart is controversial. In addition, whether epicardial cells provide a progenitor pool for de novo heart regeneration is incompletely defined. Following apical resection of the neonatal mouse heart, we observed limited regeneration potential. Fate-mapping of Tbx18MerCreMer mice revealed that newly formed coronary vessels and a limited number of cardiomyocytes were derived from the T-box transcription factor 18 (Tbx18) lineage. However, further lineage tracing with SM-MHCCreERT2 and Nfactc1Cre mice revealed that the new smooth muscle and endothelial cells are in fact derivatives of pre-existing coronary vessels. Our data show that neonatal mouse heart can regenerate but that its potential is limited. Moreover, although epicardial cells are multipotent during embryogenesis, their contribution to heart repair through "stem" or "progenitor" cell conversion is minimal after birth. These observations suggest that early embryonic heart development and postnatal heart regeneration are distinct biological processes. Multipotency of epicardial cells is significantly decreased after birth.