Wei Wang

University of Kentucky, Lexington, Kentucky, United States

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Publications (9)28.81 Total impact

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    ABSTRACT: Background & Aims Hyperactivation of the RAS–RAF signaling pathway in colorectal tumors is associated with metastasis and poor outcomes of patients. Little is known about how RAS–RAF signaling is turned off once activated. We investigated how the pH domain and leucine-rich repeat protein phosphatases (PHLPPs) control RAS–RAF signaling and colorectal cancer (CRC) development. Methods We used co-immunoprecipitation assays to identify substrates of PHLPP1 and PHLPP2.We studied phosphorylation of RAF1 in CRC cells that express transgenic PHLPP1 or PHLPP2, or lentiviral-based small hairpin (sh)RNAs against their transcripts; we measured effects on cell motility, migration, and invasion in vitro. Tumor progression and survival were analyzed in Phlpp1–/– mice, ApcMin mice, and ApcMin/Phlpp1–/– mice. Microarray data sets of colorectal tumor and non-tumor tissues were analyzed for PHLPP gene expression. Results PHLPP1 and 2 were found to dephosphorylate RAF1 at S338, inhibiting its kinase activity in vitro and in CRC cells. In cells, shRNA knockdown of PHLPP1 or PHLPP2 increased the amplitude and duration of RAF–MEK–ERK signaling downstream of EGFR and KRAS, whereas overexpression had the opposite effect. Knockdown of PHLPP1 or PHLPP2 caused CRC cells to express markers of the epithelial–mesenchymal transition (EMT), and increased migration and invasion in vitro. ApcMin/Phlpp1–/– mice had decreased survival and developed larger intestinal and colon tumors than ApcMin mice, which developed mostly low-grade adenomas; in contrast, 20% of the tumors that developed in ApcMin/Phlpp1–/– mice were invasive adenocarcinomas. Normal villi and adenomas of ApcMin/Phlpp1–/– mice had significantly fewer apoptotic cells than ApcMin mice. Human CRC patient microarray data revealed that the expression of PHLPP1 or PHLPP2 is positively correlated with CDH1. Conclusions PHLPP1 and 2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the EMT. In ApcMin mice, loss of PHLPP1 promotes tumor progression.
    Gastroenterology 01/2014; · 12.82 Impact Factor
  • International journal of radiation oncology, biology, physics 08/2013; 86(5):811-812. · 4.59 Impact Factor
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    ABSTRACT: The purpose of this study was to compare anatomical and dosimetric variations in first 15 fractions, and between fractions 16 and 25, during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). Twenty-three NPC patients who received IMRT in 33 fractions were enrolled. Each patient had two repeat computed tomography (CT) scans before the 16th and 25th fraction. Hybrid IMRT plans were generated to evaluate the dosimetric changes. There was a significant decrease of the transverse diameter of nasopharyngeal and neck as well as gross tumor volume (GTV) in the primary nasopharyngeal carcinoma (GTVnx) and involved lymph nodes (GTVnd) during the first 15 fractions, and between fraction 16 and 25 (p < 0.05). Consequently, there was a significant reduction of the percentage of the volume receiving the prescribed dose (V100) of CTV1 and GTVnd, which was more prominent after the first 15 fractions treatment compared to that between fraction 16 and 25 (p < 0.05). Additionally, there was a significant increase in the mean dose (Dmean) and percentage of volume receiving ≥ 30 Gy (V30) to the bilateral parotid in the first 15 fractions (p < 0.05), but not between fraction 16 and 25. While the maximum dose to the spinal cord was significantly increased both in the first 15 fractions, and between fraction 16 and 25 (p < 0.05), the increase of the percent of spinal cord volume receiving ≥ 40 Gy (V40) was significantly higher in the first 15 fractions compared to that between fraction 16 and 25 (p < 0.05). Based on the dose constraint criterion in the RTOG0225 protocol, a total 39.1% (9/23) of phantom plan 1 (generated by applying the beam configurations of the original IMRT treatment plan to the anatomy of the second CT scan) and 17.4% (4/23) of phantom 2 (generated by applying the beam configurations of the replan 1 to the anatomy of the third CT scan) were out of limit for the dose to the normal critical structures. In conclusion, our data indicated that anatomic changes resulted in more predominant dosimetric effects in the first 15 fractions, and between fractions 16 and 25, of IMRT.
    Journal of Applied Clinical Medical Physics 01/2013; 14(6):3918. · 0.96 Impact Factor
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    ABSTRACT: PURPOSE: Anatomic and dosimetric changes have been reported during intensity modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the effects of replanning on quality of life (QoL) and clinical outcomes during the course of IMRT for NPC patients. METHODS AND MATERIALS: Between June 2007 and August 2011, 129 patients with NPC were enrolled. Forty-three patients received IMRT without replanning, while 86 patients received IMRT replanning after computed tomography (CT) images were retaken part way through therapy. Chinese versions of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Head and Neck Quality of Life Questionnaire 35 were completed before treatment began and at the end of treatment and at 1, 3, 6, and 12 months after the completion of treatment. Overall survival (OS) data were compared using the Kaplan-Meier method. RESULTS: IMRT replanning had a profound impact on the QoL of NPC patients, as determined by statistically significant changes in global QoL and other QoL scales. Additionally, the clinical outcome comparison indicates that replanning during IMRT for NPC significantly improved 2-year local regional control (97.2% vs 92.4%, respectively, P=.040) but did not improve 2-year OS (89.8% vs 82.2%, respectively, P=.475). CONCLUSIONS: IMRT replanning improves QoL as well as local regional control in patients with NPC. Future research is needed to determine the criteria for replanning for NPC patients undergoing IMRT.
    International journal of radiation oncology, biology, physics 11/2012; · 4.59 Impact Factor
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    ABSTRACT: To quantify changes of the transverse diameter and volume and dosimetry, and to illustrate the inferiority of non-replanning during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients. Fifty-three NPC patients who received IMRT in 33 fractions were enrolled in this prospective trial. Before the 25th fraction, a new simulation computed tomography (CT) scan was acquired for all patients. The dose-volume histograms of the phantom plan were compared with the initial plan. Significant reduction of the transverse diameter of the nasopharyngeal, the neck, and 2 parotid glands volume was observed on second CT compared with the first CT (mean reduction 7.48 ± 4.45 mm, 6.80 ± 15.14 mm, 5.70 ± 6.26 mL, and 5.04 ± 5.85 mL, respectively; p < 0.01). The maximum dose and V-40 of the spinal cord, mean dose, and V30 of the left and right parotid, and V-50 of the brain stem were increased significantly in the phantom plan compared with the initial plan (mean increase 4.75 ± 5.55 Gy, 7.18 ± 10.07%, 4.51 ± 8.55 Gy, 6.59 ± 17.82%, 5.33 ± 8.55 Gy, 11.68 ± 17.11% and 1.48 ± 3.67%, respectively; p < 0.01). On the basis of dose constraint criterion in the RTOG0225 protocol, the dose of the normal critical structures for 52.83% (28/53) of the phantom plans were out of limit compared with 1.89% (1/53) of the initial plans (p < 0.0001). Because of the significant change in anatomy and dose before the 25th fraction during IMRT, replanning should be necessary during IMRT with NPC.
    Medical dosimetry: official journal of the American Association of Medical Dosimetrists 12/2011; 37(2):225-9. · 1.26 Impact Factor
  • Computer and Computing Technologies in Agriculture V - 5th IFIP TC 5/SIG 5.1 Conference, CCTA 2011, Beijing, China, October 29-31, 2011, Proceedings, Part III; 01/2011
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    ABSTRACT: To quantify the target and normal structures on dose distributing variations during intensity-modulated radiotherapy (IMRT) and to assess the value of replanning for nasopharyngeal carcinoma (NPC) patients. Twenty-eight NPC patients treated with IMRT were recruited. The IMRT was delivered in 33 fractions, to 70 to 76Gy, to the gross tumor volume (GTV). Before the 25th fraction of IMRT, a new simulation computed tomography (CT) scan was acquired for all patients. According to the dose constraint criterion in the Radiation Therapy Oncology Group (RTOG) 0225 protocol, the replanning was generated on the new simulation CT. With the Quality Assessment Center of a CORVUS 6.3 treatment planning system, a phantom plan was generated for each patient by applying the beam configurations of the initial plan to the anatomy of the new simulation CT. The dose-volume histograms of the phantom plan were compared with the replanning. The percentage of prescription dose delivered to the clinical target volume (CTV1) was significantly increased by 4.91% +/- 10.89%, whereas the maximum dose to the spinal cord, mean dose to the left parotid, and V30 to the right parotid were significantly decreased by 5.00 +/- 9.23Gy, 4.23 +/- 10.03Gy, and 11.47% +/- 18.89% respectively in the replanning, compared with the phantom plan (p < 0.05). Based on the dose constraint criterion in the RTOG0225 protocol, 50% of phantom plans (14/28) were out of limit for the dose to the normal critical structures, whereas no plan was out of limit in replanning (p < 0.001). Replanning for patients with NPC before the 25th fraction during IMRT helps to ensure adequate dose to the target volumes and safe doses to critical normal structures.
    International journal of radiation oncology, biology, physics 02/2010; 77(2):617-21. · 4.59 Impact Factor
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    ABSTRACT: This paper is aiming at designing a novel jujube transplanter with mechanic arms, which can support the sapling for a while when other operations is going on. It improves uniformity and stability. Pro-E software has been used for the design process, by which transplanting process has been analyzed and simulated.
    Computer and Computing Technologies in Agriculture IV - 4th IFIP TC 12 Conference, CCTA 2010, Nanchang, China, October 22-25, 2010, Selected Papers, Part I; 01/2010
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    ABSTRACT: In this paper an automatic bionic mechanical arm of jujube transplanter has been designed and simulated with Pro/E and ADAMS software. The device can achieve the work of clamping—sending—setting the sapling and support the sapling to guarantee it perpendicularity in setting process. Design the structure of manipulator utilizing the simulation of hand working. There is 5-DOF at the manipulator to achieve simulating. Constitute dynamics mathematical model and estimated inseminate error of bionic manipulator. The three dimensional model of the manipulator was build up and simulated by using Pro/E software. Then up build the virtual prototype and kinetics simulation in ADAMS software and chalk up the dynamics parameter curve of clamping force etc. This manipulator will establish theory and practice foundation to the cyber-identify and cyber-supervise of sapling translating.
    Computer and Computing Technologies in Agriculture IV - 4th IFIP TC 12 Conference, CCTA 2010, Nanchang, China, October 22-25, 2010, Selected Papers, Part I; 01/2010