Person: Wu, Shulin
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Wu
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Shulin
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Wu, Shulin
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Publication Combination of vinblastine and oncolytic herpes simplex virus vector expressing IL-12 therapy increases antitumor and antiangiogenic effects in prostate cancer models(2013) Passer, Brent J.; Cheema, Tooba A; Wu, Shulin; Wu, Chen-lee; Rabkin, Samuel; Martuza, RobertOncolytic herpes simplex virus-1 (oHSV)–based vectors selectively replicate in tumor cells causing direct killing, ie., oncolysis, while sparing normal cells. oHSV’sare promising anticancer agents, but their efficacy, when used as single agents, leaves room for improvement. We hypothesized that combining the direct oncolytic and antiangiogenic activities of the IL-12 secreting NV1042 oHSV with microtubule disrupting agents (MDA’s) would be an effective means to enhance antitumor efficacy. Vinblastine (VB) was identified among several MDA’s screened that displayed consistent and potent cytotoxic killing of both prostate cancer and endothelial cell lines. In matrigel tube forming assays, VB was found to be highly effective at inhibiting tube formation of HUVEC cells. The combination of VB with NV1023 (the parental virus lacking IL-12) or NV1042 showed additive or synergistic activity against prostate cancer cell lines and was not due to increased oHSV replication by VB. In athymic mice bearing CWR22 prostate tumors, VB in combination with NV1042 was superior to the combination of VB plus NV1023 in reducing tumor burden, appeared to be nontoxic and resulted in a statistically significant diminution in the number of CD31+ cells as compared to other treatment groups. In human organotypic cultures using surgical samples from radical prostatectomies, both NV1023 and NV1042 were localized specifically to the epithelial cells of prostatic glands but not to the surrounding stroma. These data highlight the therapeutic advantage of combining the dual-acting anti-tumor and anti-angiogenic activities of oHSV’s and MDA’s.Publication Peutz-Jeghers syndrome: a critical look at colonic Peutz-Jeghers polyps(Springer Nature, 2013) Tse, Julie Yi; Wu, Shulin; Shinagare, Shweta A; Lauwers, Gregory Y.; Yilmaz, Omer; Wu, Chin-Lee; Deshpande, VikramPeutz-Jeghers syndrome is an autosomal dominant condition characterized by gastrointestinal hamartomatous polyps. The pathologic identification of a Peutz-Jeghers polyp is integral to the diagnosis of this syndrome that often remains undiagnosed until after these polyps are identified. Histologically, Peutz-Jeghers polyps are characterized by a distinctive arborization of smooth muscle within the lamina propria. Colonic Peutz-Jeghers polyps, however, may mimic mucosal prolapse polyps or virtually any colonic polyp that undergoes prolapse. In this paper, we explore the morphological features of colonic Peutz-Jeghers polyps and the diagnostic challenges associated with these polyps. Colonic polyps from patients with Peutz-Jeghers syndrome were identified (n=34). The control cohort, included mucosal prolapse polyps (n=5), hyperplastic polyps (n=10) and tubular adenomas with prolapse (n=9), ganglioneuromatous polyps (n=2) and juvenile polyps (n=14). Intramucosal smooth muscle fibers were identified in all classes of polyps. Twenty-three of the 34 colonic Peutz-Jeghers polyps were characterized by lobulated clusters of colonic crypts. On immunohistochemistry, desmin-positive smooth muscle fibers were seen surrounding these lobules. This lobular organization of the crypts was not identified in mucosal prolapse polyps and hyperplastic polyps or tubular adenomas with prolapse; only one of the 14 juvenile polyps showed this pattern of reactivity on a desmin stain. Our data suggests that the histologic hallmark of colonic Peutz-Jeghers polyps is the lobular organization of the crypts, and that an arborizing pattern of smooth muscle proliferation is neither sensitive nor a specific marker of colonic Peutz-Jeghers polyps. The presence of desmin-positive smooth muscle fibers surrounding the lobules is a helpful diagnostic feature of colonic Peutz-Jeghers polyps, and facilitates the distinction of these polyps from non-Peutz-Jeghers polyps with prolapse-like changes.Publication Mitotic Figure Recognition: Agreement among Pathologists and Computerized Detector(IOS Press, 2012) Malon, Christopher; Brachtel, Elena; Cosatto, Eric; Graf, Hans Peter; Kurata, Atsushi; Kuroda, Masahiko; Meyer, John S.; Saito, Akira; Wu, Shulin; Yagi, YukakoDespite the prognostic importance of mitotic count as one of the components of the Bloom – Richardson grade [3], several studies ([2, 9, 10]) have found that pathologists’ agreement on the mitotic grade is fairly modest. Collecting a set of more than 4,200 candidate mitotic figures, we evaluate pathologists' agreement on individual figures, and train a computerized system for mitosis detection, comparing its performance to the classifications of three pathologists. The system’s and the pathologists’ classifications are based on evaluation of digital micrographs of hematoxylin and eosin stained breast tissue. On figures where the majority of pathologists agree on a classification, we compare the performance of the trained system to that of the individual pathologists. We find that the level of agreement of the pathologists ranges from slight to moderate, with strong biases, and that the system performs competitively in rating the ground truth set. This study is a step towards automatic mitosis count to accelerate a pathologist's work and improve reproducibility.Publication Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells(Impact Journals LLC, 2015) Ge, Rongbin; Wang, Zongwei; Wu, Shulin; Zhuo, Yangjia; Otsetov, Aleksandar G.; Cai, Chao; Zhong, Weide; Wu, Chin-Lee; Olumi, AriaMetformin has emerged as a potential anticancer agent. Here, we demonstrate that metformin plays an anti-tumor role via repressing N-cadherin, independent of AMPK, in wild-type N-cadherin cancer cells. Ectopic-expression of N-cadherin develops metformin-resistant cancer cells, while suppression of N-cadherin sensitizes cancer to metformin. Manipulation of AMPK expression does not alter sensitivity of cancer to metformin. We show that NF-kappaB is a downstream molecule of N-cadherin and metformin regulates NF-kappaB signaling via suppressing N-cadherin. Moreover, we also suggest that TWIST1 is an upstream molecule of N-cadherin/NF-kappaB signaling and manipulation of TWIST1 expression changes the sensitivity of cancer cells to metformin. In contrast to the cells that express N-cadherin, in N-cadherin deficient cells, metformin plays an anti-tumor role via activation of AMPK. Ectopic expression of N-cadherin makes cancer more resistant to metformin. Therefore, we suggest that metformin's anti-cancer therapeutic effect is mediated through different molecular mechanism in wild-type vs. deficient N-cadherin cancer cells. At last, we selected 49 out of 984 patients’ samples with prostatic cancer after radical prostatectomy (selection criteria: Gleason score ≥ 7 and all patients taking metformin) and showed levels of N-cadherin, p65 and AMPK could predict post-surgical recurrence in prostate cancer after treatment of metformin.Publication Preoperative Neutrophil-to-Lymphocyte Ratio and Neutrophilia Are Independent Predictors of Recurrence in Patients with Localized Papillary Renal Cell Carcinoma(Hindawi Publishing Corporation, 2015) Huang, Jiwei; Dahl, Douglas; Dong, Liang; Liu, Qiang; Cornejo, Kristine; Wang, Qi; Wu, Shulin; Feldman, Adam; Huang, Yiran; Xue, Wei; Wu, Chin-LeeObjective:. To evaluate the role of preoperative neutrophil-to-lymphocyte ratio (NLR) and absolute neutrophil count (ANC) in patients' prognosis with localized papillary renal cell carcinoma (pRCC). Methods:. Data from 218 localized pRCC patients (T1-3 N0/+ M0), operated between 1991 and 2011 at two centers, were evaluated retrospectively. Univariable and multivariable analyses using the Cox regression model were performed to determine the associations of NLR and ANC with recurrence-free survival (RFS). Prognostic accuracy was evaluated with the Harrell concordance index. Results:. The 5-year RFS rate was 87.0%. Multivariable analysis identified increased NLR (≥3.6) and ANC (≥5300/μL) as independent prognostic factors for RFS (hazard ratio (HR) = 4.01, P = 0.018) and (HR = 4.71, P = 0.045). The final model built by the addition of NLR or ANC improved predictive accuracy (c-index: 0.824, 0.842) compared with the clinicopathological base model (c-index: 0.800), which included TNM stage and tumor necrosis. Conclusions:. The NLR and ANC appear to be independent prognostic factors for RFS after surgery for localized pRCC. They significantly increase the accuracy of established prognostic factors. Therefore, we recommend adding NLR and ANC to traditional prognostic model, which may improve its predictive accuracy.Publication SOXs in Human Prostate Cancer: Implication as Progression and Prognosis Factors(BioMed Central, 2012) Zhong, Wei-de; Qin, Guo-qiang; Dai, Qi-shan; Han, Zhao-dong; Chen, Shan-ming; Ling, Xiao-hui; Fu, Xin; Chen, Jia-hong; Chen, Xi-bin; Lin, Zhuo-yuan; Deng, Ye-han; He, Hui-chan; Wu, Chin-Lee; Wu, Shulin; Cai, ChaoBackground: SOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa). Methods: The gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa. Results: The microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P < 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the up-regulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance. Conclusions: Our data offer the convince evidence that the dis-regulation of SOX7, SOX9 and SOX10 may be associated with the aggressive progression of PCa. SOX7 and SOX9 may be potential markers for prognosis in PCa patients. Interestingly, the down-regulation of SOX7 and the up-regulation of SOX9 may be important mechanisms for castration-resistant progression of PCa.Publication Estrogen Receptor β2 and β5 are Associated with Poor Prognosis in Prostate Cancer, and Promote Cancer Cell Migration and Invasion(Society for Endocrinology, 2010) Leung, Yuet-Kin; Lam, Hung-Ming; Song, Dan; Levin, Linda; Ho, Shuk-Mei; Wu, Shulin; Cheng, Liang; Wu, Chin-LeeEstrogens play a pivotal role in the development and progression of prostate cancer (PCa). Their actions are mediated by estrogen receptors (ERs), particularly ERβ in the prostate epithelium. With the discovery of ERβ isoforms, data from previous studies that focused principally on the wild-type ERβ (ERβ1) may not be adequate in explaining the still controversial role of ERβ(s) in prostate carcinogenesis. In this study, using newly generated isoform-specific antibodies, immunohistochemistry (IHC) was performed on a tumor microarray comprised of 144 specimens. IHC results were correlated with pathological and clinical follow-up data to delineate the distinct roles of ERβ1, ERβ2, and ERβ5 in PCa. ERβ2 was commonly found in the cytoplasm and was the most abundant isoform followed by ERβ1 localized predominantly in the nucleus, and ERβ5 was primarily located in the cytoplasm. Logistic regression analyses demonstrated that nuclear ERβ2 (nERβ2) is an independent prognostic marker for prostate specific antigen (PSA) failure and postoperative metastasis (POM). In a Kaplan–Meier analysis, the combined expression of both nERβ2 and cytoplasmic ERβ5 identified a group of patients with the shortest POM-free survival. Cox proportional hazard models revealed that nERβ2 predicted shorter time to POM. In concordance with IHC data, stable, ectopic expression of ERβ2 or ERβ5 enhanced PCa cell invasiveness but only PCa cells expressing ERβ5 exhibited augmented cell migration. This is the first study to uncover a metastasis-promoting role of ERβ2 and ERβ5 in PCa, and show that the two isoforms, singularly and conjointly, have prognostic values for PCa progression. These findings may aid future clinical management of PCa.