Christopher Liang
University of California, Irvine
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Featured researches published by Christopher Liang.
Molecular Cancer Therapeutics | 2006
Shem Patyna; A. Douglas Laird; Dirk B. Mendel; Anne-Marie O'farrell; Christopher Liang; Huiping Guan; Tomas Vojkovsky; Stefan Vasile; Xueyan Wang; Jeffrey H. Chen; Maren Grazzini; Cheng Y. Yang; Joshua Ö. Haznedar; Juthamas Sukbuntherng; Wei-Zhu Zhong; Julie M. Cherrington; Dana Hu-Lowe
Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-β, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies. [Mol Cancer Ther 2006;5(7):1774–82]
Nuclear Medicine and Biology | 2015
Kimberly N. Schade; Aparna Baranwal; Christopher Liang; M. Reza Mirbolooki; Jogeshwar Mukherjee
BACKGROUND We have investigated β3-adrenoceptor agonist mediated brown adipose tissue (BAT) activation using (18)F-FDG PET/CT in Zucker lean (ZL) and obese (ZF) rats. METHODS (18)F-FDG was injected into ZL and ZF rats pretreated with saline or agonist CL316,243 for scans. (18)F-FDG metabolic activity was computed as standard uptake values. RESULTS CL316,243 in ZL activated BAT up to 4-fold compared to saline, while ZF BAT was only up by 2 fold. The decreased activation was consistent with lower β3-adrenoceptor levels in ZF rats. CONCLUSIONS The genetically modified ZL and ZF rats may provide a useful rat model to evaluate the significance of β3-adrenoceptor agonist-induced BAT activation in obesity.
The Journal of Comparative Neurology | 2018
Jogeshwar Mukherjee; Patrick J. Lao; Tobey J. Betthauser; Gurleen K. Samra; Min-Liang Pan; Ishani Patel; Christopher Liang; Raju Metherate; Bradley T. Christian
Nicotinic acetylcholinergic receptors (nAChRs) have been implicated in several brain disorders, including addiction, Parkinsons disease, Alzheimers disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [18F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.34 nM), hα3β2 (0.80 nM) and hα4β2 (0.83 nM) nAChR but weaker (27–219 nM) for hβ4 nAChR subtypes and 169 nM for hα7 nAChR. In functional assays, Nifene (100 μM) exhibited 14% agonist and >50% antagonist characteristics. In 14‐day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 μg/kg/day (278 μg/m2/day). In human PET studies, [18F]Nifene (185 MBq; <0.10 μg) was well tolerated with no adverse effects. Distribution volume ratios (DVR) of [18F]Nifene in white matter thalamic radiations were ∼1.6 (anterior) and ∼1.5 (superior longitudinal fasciculus). Habenula known to contain α3β2 nAChR exhibited low levels of [18F]Nifene binding while the red nucleus with α2β2 nAChR had DVR ∼1.6–1.7. Females had higher [18F]Nifene binding in all brain regions, with thalamus showing >15% than males. No significant aging effect was observed in [18F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18F]Nifene PET may be used to study α4β2* nAChRs in various CNS disorders and for translational research.
Synapse | 2016
Min-Liang Pan; Meenakshi Mukherjee; Himika Patel; Bhavin Patel; Cristian Constantinescu; M. Reza Mirbolooki; Christopher Liang; Jogeshwar Mukherjee
Objective: Alzheimers disease (AD) is a neurodegenerative disease characterized by Aβ plaques in the brain. The aim of this study was to evaluate the effectiveness of a novel radiotracer, 4‐[11C]methylamino‐4′‐N,N‐dimethylaminoazobenzene ([11C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Methods: Radiosyntheses of [11C]TAZA, related [11C]Dalene (11C‐methylamino‐4′‐dimethylaminostyrylbenzene), and reference [11C]PIB were carried out using [11C]methyltriflate prepared from [11C]CO2 and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [3H]PIB. In vitro autoradiography studies with the three radiotracers were performed on hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. Results: The three radiotracers were produced in high radiochemical yields (>40%) and had specific activities >37 GBq/μmol. TAZA had an affinity, Ki = 0.84 nM and was five times more potent than PIB. [11C]TAZA bound specifically to Aβ plaques present in AD brains with gray matter to white matter ratios >20. [11C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [11C]TAZA and [11C]PIB. [11C]TAZA exhibited slow kinetics of uptake in the rat brain and whole body images showed uptake in interscapular brown adipose tissue (IBAT). Binding in brain and IBAT were affected by preinjection of atomoxetine, a norepinephrine transporter blocker. Conclusion: [11C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics was slow and peripheral binding to IBAT needs to be further evaluated. Synapse, 2016.
Molecular Imaging | 2017
Robert Coleman; Christopher Liang; Rima Patel; Sarah Ali; Jogeshwar Mukherjee
Objective: Imaging animal models of Alzheimer disease (AD) is useful for the development of therapeutic drugs and understanding AD. Transgenic Swedish hAPPswe Tg2576 mice are a good model of β-amyloid plaques. We report 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) imaging of brain and intrascapular brown adipose tissue (IBAT) in transgenic mice 2576 (Tg2576) and wild-type (WT) mice. Methods: Transgenic Tg2576 mice and WT mice, >18 months were injected intraperitonally with ≈ 25 to 30 MBq 18F-FDG while awake. After 60 minutes, they were anesthetized with isoflurane (2.5%) and imaged with Inveon MicroPET. Select mice were killed, imaged ex vivo, and 20 µm sections cut for autoradiography. 18F-FDG uptake in brain and IBAT PET and brain autoradiographs were analyzed. Results: Fasting blood glucose levels averaged 120 mg/dL for WT and 100 mg/dL for Tg2576. Compared to WT, Tg2576 mice exhibited a decrease in SUVglc in the various brain regions. Average reductions in the cerebrum regions were as high as −20%, while changes in cerebellum were −3%. Uptake of 18F-FDG in IBAT decreased by −60% in Tg2576 mice and was found to be significant. Intrascapular brown adipose tissue findings in Tg2576 mice are new and not previously reported. Use of blood glucose for PET data analysis and corpus callosum as reference region for autoradiographic analysis were important to detect change in Tg2576 mice. Conclusion: Our results suggest that 18F-FDG uptake in the Tg2576 mice brain show 18F-FDG deficits only when blood glucose is taken into consideration.
Bioorganic & Medicinal Chemistry Letters | 2017
Gurleen K. Samra; Irakli Intskirveli; Anitha P. Govind; Christopher Liang; Ronit Lazar; William N. Green; Raju Metherate; Jogeshwar Mukherjee
Nicotinic acetylcholine α4β2∗ receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2∗ nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [18F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2∗ nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the α4β2∗ nAChRs in [3H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in α4β2∗ nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface α4β2∗ nAChRs, labeled with antibodies specific for a β2 subunit extracellular epitope indicating that nifrofam labels α4β2∗ nAChR high-affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of α4β2∗ nAChRs in brain regions.
Bioorganic & Medicinal Chemistry Letters | 2004
Huiping Guan; A. Douglas Laird; Robert A. Blake; Cho Tang; Christopher Liang
The Journal of Nuclear Medicine | 2013
Himika Patel; Bhavin Patel; Min-Liang Pan; Christopher Liang; Meenakshi Mukherjee; Jogeshwar Mukherjee
Society of Nuclear Medicine Annual Meeting Abstracts | 2013
Joanne Thio; Christopher Liang; Alisha K. Bajwa; Dustin Wooten; Ansel T. Hillmer; Bradley Christian; Jogeshwar Mukherjee
Bioorganic & Medicinal Chemistry Letters | 2016
Christopher Liang; Xiang-Zuo Pan; Min-Liang Pan; Jogeshwar Mukherjee