A5101957764- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Cancer, Lipids, and Metabolism
- Cancer Treatment and Pharmacology
- HIV/AIDS drug development and treatment
- Colorectal Cancer Treatments and Studies
- Advanced Radiotherapy Techniques
- Prostate Cancer Treatment and Research
- Medical Imaging Techniques and Applications
- Statistical Methods in Clinical Trials
- Liver Disease Diagnosis and Treatment
- RNA Research and Splicing
- Cancer therapeutics and mechanisms
- Cancer, Hypoxia, and Metabolism
- Medical Image Segmentation Techniques
- RNA modifications and cancer
- Health Systems, Economic Evaluations, Quality of Life
- Immunodeficiency and Autoimmune Disorders
- RNA and protein synthesis mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Plant-based Medicinal Research
- Radiopharmaceutical Chemistry and Applications
- interferon and immune responses
The Ohio State University
2018-2023
Siemens Healthcare (United States)
2017
Kunming Medical University
2009-2015
First Affiliated Hospital of Kunming Medical University
2015
Siemens (United States)
2012
University of Iowa Hospitals and Clinics
2010
Second Affiliated Hospital of Kunming Medical College
2009
Paclitaxel is among the most widely used anticancer drugs and known to cause a dose-limiting peripheral neurotoxicity, initiating mechanisms of which remain unknown. Here, we identified murine solute carrier organic anion–transporting polypeptide B2 (OATP1B2) as mediator paclitaxel-induced neurotoxicity. Additionally, using established tests assess acute chronic found that genetic or pharmacologic knockout OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia,...
Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance various solute carriers toxicity anticancer drugs, contribution these proteins oxaliplatin-induced peripheral remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide for critical role organic cation transporter 2 (OCT2)...
Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing inaccurate dose level time, drug concentrations below analytical limit quantification, sample times, incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set recommendations for commonly occurring errors has published. In this tutorial, we review existing literature and results our simulation...
The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and expressed in enterocytes. Based its distribution pattern functional similarity to OATP1B-type transporters, OATP2B1 might have a role absorption disposition range xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are substrates vitro, evidence supporting vivo relevance this...
Abstract Purpose: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in liver a key mediator of xenobiotic clearance. However, regulatory mechanisms that determine activity remain uncertain, as result, unexpected drug–drug interactions involving substrates continue to be reported, including several tyrosine kinase inhibitors (TKI). Experimental Design: OATP1B1-mediated overexpressing HEK293 cells hepatocytes was assessed presence FDA-approved TKIs, while...
Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small‐molecule multikinase inhibitor sorafenib is associated large interindividual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter (OCT1; gene SLC22A1 ) has been proposed as a clinical biomarker HCC response. Because proof lacking that OCT1 transports sorafenib, we used combinatorial approach to define how contributes...
Abstract Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation improves outcome hormone-sensitive disease. We studied whether testosterone AR interferes treatment efficacy castration-resistant cancer (CRPC). found supplementation significantly impaired tumour accumulation a CRPC model, resulting decreased tubulin stabilisation antitumour activity. Furthermore, competed...
Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes dose-limiting peripheral neurotoxicity. There no clinically effective preventative vincristine-induced sensory neurotoxicity (VIPN), and mechanistic details this side effect remain poorly understood. We hypothesized VIPN dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using xenobiotic transporter screen, we identified OATP1B3 as neuronal...
Murine pharmacokinetics (PK) represents the absorption, distribution, metabolism, and elimination of drugs from body, which helps to guide clinical studies, ultimately resulting in more effective drug treatment. The purpose this protocol is describe a serial bleeding protocol, obtaining blood samples at six time points single mouse yield complete PK profile. This has proved be rapid, highly repeatable, relatively easy acquire. Comparing with conventional method not only dramatically reduces...
Purpose: To quantify diaphragm motion in megavoltage (MV) cone‐beam computed tomography (CBCT) projections. Methods: User identified ipsilateral hemidiaphragm apex (IHDA) positions two full exhale and inhale frames were used to create bounding rectangles all other of a CBCT scan. The rectangle was enlarged region interest (ROI). ROI pixels associated with cost function: product image gradients gradient direction matching function for an ideal determined from 40 training sets. A dynamic Hough...
Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG ), but contribution hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, pharmacokinetics regorafenib remains poorly understood. Using NONMEM ‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex...
Background The human organic anion‐transporting polypeptide 2B1 (OATP2B1; SLC21A9) is localized to the basolateral membrane of hepatocytes and brush‐border small‐intestinal enterocytes. Based on its distribution pattern functional similarity OATP1B‐type transporters, it has been hypothesized that OATP2B1 might influence absorption disposition properties a wide range xenobiotic agents. Although several prescription drugs, including statins such as fluvastatin, have identified substrates in...
Background The organic cation transporter OCT2 is expressed in renal tubular cells, dorsal root ganglia, and outer hair where it regulates uptake of xenobiotic substrates such as the widely used anticancer drug, cisplatin. We previously reported that various tyrosine kinase inhibitors (TKIs) with YES1‐kinase inhibitory ability, including dasatinib, can potently reduce function (Sprowl et al , Nat Commun 2016). Against this background, we here explored utility zebrafish ( Danio rerio ),...
The real time X-ray angiography based on C-arm cone beam system is the workhorse imaging modality for interventional cardiac procedures. These images are two-dimensional (2D) projections of three dimensional (3D) objects along direction. organ interest (OOI), such as left ventricle (LV) endocardium, in projection image superimposed with other anatomical structures and often has low contrast. In this study, a novel approach proposed to isolate OOI by subtracting background image, which...
Objective To explore the significance of pedigree analysis and gene screening for atrisk membership a kindred with familial adenomatous polyposis (FAP) , to report results germline mutations in APC that predispose disease susceptibility FAP from Yunnan Province. Methods Using patient as index patient, all lineal collateral relatives were interviewed, then was protracted. Genomic DNA extracted peripheral blood leukocytes individuals family screened by using PCR direct sequencing. Results...
Introduction Liver uptake of numerous pharmaceutical drugs is mediated by the hepatic transport protein OATP1B1. Altered function this protein, either genetic variation or drug‐drug interaction associated with systemic changes drug concentrations that can lead to onset severe adverse events. We previously used mass‐spectrometric data from global phospho‐proteome databases show a substantial number clinically‐relevant human transporters, including OATP1B1, have conserved...
777 Background: Surgical resection can improve survival of patients with resectable colorectal liver metastases (CLMs). Here, we investigatedthe efficacy and safety XELOX as perioperative treatment for potentially CLM. Methods: Patients liver-only from CRC were enrolled. The primary endpoint this study was progression-free (PFS); the secondary endpoints included objective response rate (ORR), R0 rate, overall (OS) profile XELOX. Eligible treated (oxaliplatin 130 mg/m 2 on day 1 plus...
<p>Assessment of lapatinib or trametinib as OATP1B1 substrates. (A) Percent uptake 3H-lapatinib (1 µM) in overexpressing HEK293 cells relative to transfected with a vector control (VC) (n=3, from single experiment). (B) Lineweaver-Burke plot for OATP1B1-dependent HEK293-OATP1B1 treated various concentrations (0 - 5 and 8FcA 40 (n=9, combination 3 independent experiments) . * denotes P < 0.001 vs VC. All values represent mean {plus minus} SEM.</p>
<p>Assessment of LYN kinase expression, and function in the presence various TKIs. (A) Detection protein expression human hepatocyte spleen lysates as determined by Western blot analysis. Prior to analysis, (1:10) liver (1:1) were diluted. Protein GAPDH was measured a loading control. The image is representative 3 independent experiments. (B) activity TKI concentrations (10-doses) using assay. (C) Regression IC50 values several TKIs percent inhibition.</p>
<p>A structural model of OATP1B1. The was generated by Phyre2 and presented as a cartoon. Y640 Y645 are highlighted in blue the image produced with PyMOL.</p>
<p>Influence of TKIs on OATP1B1-dependent uptake or substrate disposition. (A) Uptake 3H-EβG (2 µM, 2 min) in OATP1B1 overexpressing HEK293 cells the presence absence select individual FDA approved (10 μM) identified as positive negative inhibitors, following pre-treatment with for 15 minutes (n=6) (A). Data are presented a percent activity compared to treatment DMSO (Vehicle). *denotes P < 0.05 vs vehicle and all values represent mean {plus minus} SEM experiment was repeated two...
<p>Mean {plus minus} SEM change of 8FcA uptake (Mean difference) in OATP1B1 overexpressing HEK293 cells between vehicle (DMSO) and exposure to FDA approved TKIs. Statistical significance was measured by ANOVA Fisher's LSD test.</p>
<p>Cellular viability and uptake of 8FcA by OATP1B1 following reverse transfection with 25 nM siRNA for various protein kinases. Percent was determined relative to control siRNA.</p>