Xiaoli Zhang

The Ohio State University, Columbus, Ohio, United States

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Publications (61)370.83 Total impact

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    ABSTRACT: Na(+)/I(-) Symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. MicroRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs on NIS-mediated RAIU has not been investigated. In silico analysis was used to identify miRs that may bind to hNIS-3'UTR. The top candidate miR-339-5p directly bound to hNIS-3'UTR. MiR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, deceased NIS mRNA levels and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropin-stimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGF-β, Akti-1/2 or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38 miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to hNIS-3'UTR and its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. MiR-339-5p was modestly increased in most papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs were able to separate most PTCs from non-malignant thyroid tissues. This is the first report demonstrating that hNIS-mediated RAIU can be modulated by miRs, and the same miRs may also play roles in development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt thyroid cancer progression and to enhance efficacy of radioiodine therapy.
    Endocrine Related Cancer 11/2014; · 5.26 Impact Factor
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    ABSTRACT: Na+/I- Symporter (NIS)-mediated radioiodide uptake (RAIU) in thyroid cells allows targeted treatment of thyroid cancer. Many patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced/absent NIS expression/function. MicroRNA (miR) has emerged as a promising therapeutic target in many diseases. However, the role of miRs on NIS-mediated RAIU has not been investigated. TargetScan and microRNA.org were used to identify miRs that may bind to hNIS 3'UTR. The role of selected miRs on NIS-mediated RAIU was investigated using HEK293 cells expressing exogenous hNIS. The effect of miR-339-5p was further confirmed in MCF-7 human breast cancer cells and PCCl3 rat thyroid cells that endogenously express NIS upon treatment with transretinoic acid/hydrocortisone (tRA/H) and TSH respectively. Luciferase reporter assay was employed to examine if miR-339-5p directly binds to NIS 3'UTR. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by 17-AAG, Akti-1/2 or TGF-β known to modulate NIS-mediated RAIU in PCCl3 cells. The miR expression profiles in a cohort of thyroid tissues were determined by Next Generation Sequencing. Among the two candidate miRs identified, overexpression of miR-339-5p decreased NIS-mediated RAIU in HEK293/hNIS cells and miR-339-5p directly binds to hNIS 3'UTR. The miR-339-5p decreased NIS mRNA levels and RAIU in tRA/H-treated MCF-7 cells as well as TSH-stimulated PCCl3 cells. Among 38 miRs deregulated by 17-AAG, Akti-1/2 or TGF-β in PCCl3 rat thyroid cells, 18 miRs were conserved in human. The expression profiles of these 18 miRs were able to separate most papillary thyroid tumors from adjacent non-malignant thyroid tissues and thyroid tissues from normal individuals. The miR-339-5p was not selected in the list of 38 miRs due to its low expression level in PCCl3 cells, which did not meet the cut-off value of Nanostring analysis. However, miR-339-5p expression was increased in most papillary thyroid carcinomas. We identify miR-339-5p as the first miR that modulates NIS-mediated RAIU in various cells. Targeting miR-339-5p may have the potential to further enhance NIS-mediated therapy.
    84TH ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, Coronado, San Diego; 10/2014
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    ABSTRACT: Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the PI3K/AKT pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the Phosphoinositide 3-kinase (PI3K)/AKT pathway in a novel manner. Dose-dependent, selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful BTK and PI3K inhibitors that inhibit BCR signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40 and TLR9-mediated AKT activation in an ILK-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.
    Blood 10/2014; · 9.78 Impact Factor
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    ABSTRACT: Increased p21 activated kinase (PAK) signaling and expression has been identified in the invasive fronts of aggressive papillary thyroid cancers (PTCs), including those with RET/PTC, BRAF V600E, and mutant RAS expression. Functionally, thyroid cancer cell motility in vitro is dependent on Group 1 PAKs particularly PAK1. In the present study, we hypothesize that BRAF, a central kinase in PTC tumorigenesis and invasion, regulates thyroid cancer cell motility in part through PAK activation. Using three well-characterized human thyroid cancer cell lines, we demonstrated in all cell lines that BRAF knockdown reduced PAK phosphorylation of direct downstream targets. In contrast, inhibition of MEK activity either pharmacologically or with siRNA did not reduce PAK activity indicating MEK is dispensable for PAK activity. Inhibition of cell migration through BRAF loss is rescued by overexpression of either constitutive active (CA) MEK1 or PAK1, demonstrating that both signaling pathways are involved in BRAF-regulated cell motility. To further characterize BRAF-PAK signaling, immunofluorescence and immunoprecipitation demonstrated that both exogenously overexpressed and endogenous PAK1 and BRAF co-localize and physically interact, and that this interaction was enhanced in mitosis. Finally, we demonstrated that acute induction of BRAFV600E expression in vivo in murine thyroid glands results in increased PAK expression and activity confirming a positive signaling relationship in vivo. In conclusion, we have identified a signaling pathway in thyroid cancer cells which BRAF activates and physically interacts with PAK and regulates cell motility.
    Endocrine Related Cancer 09/2014; · 5.26 Impact Factor
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    ABSTRACT: Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia has been successful with durable remissions observed with several targeted therapeutics. Protein Kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as cMyc, cyclin D1 and CD44. Lastly, our preliminary in vivo studies indicate beneficial anti-tumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
    Blood 07/2014; · 9.78 Impact Factor
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    ABSTRACT: Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells. However, the effects of silvestrol on immune function have not been described. We utilized in vitro and in vivo models of EBV-LPD to simultaneously examine the impact of silvestrol on both tumor and normal immune function. We show that silvestrol induces direct anti-tumor activity against EBV-transformed lymphoblastoid cell lines (LCL), with growth inhibition, decreased expression of the EBV oncogene latent membrane protein-1, and inhibition of the downstream AKT, STAT1 and STAT3 signaling pathways. Silvestrol promoted potent indirect anti-tumor effects by preserving expansion of innate and EBV antigen-specific adaptive immune effector subsets capable of effective clearance of LCL tumor targets in autologous co-cultures. In an animal model of spontaneous EBV-LPD, silvestrol demonstrated significant therapeutic activity dependent on the presence of CD8-positive T-cells. These findings establish a novel immune-sparing activity of silvestrol, justifying further exploration in patients with EBV-positive malignancies.
    Oncotarget 06/2014; · 6.64 Impact Factor
  • Blood 03/2014; 123(12):1957-60. · 9.78 Impact Factor
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    ABSTRACT: Context: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC. Objective: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC. Design: We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes, and compared signaling alterations observed in the mouse FTC to the corresponding human tumors. Setting: Academic research laboratory. Human samples obtained from academic hospitals. Patients: Deidentified, formalin fixed, paraffin embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, 5 follicular variant PTC (FVPTC) cases and 10 FTC cases. Interventions: None. Main outcome measures: Mouse and patient samples were analyzed for expression of activated CREB, AKT, ERK, and mTOR. Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression. Results: Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of PKA and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement Conclusions: These data imply that the PKA and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis, and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.
    The Journal of Clinical Endocrinology and Metabolism 02/2014; · 6.31 Impact Factor
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    ABSTRACT: Glioblastoma (GBM) is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric di-methylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell cycle arrest, apoptosis and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Lastly, PRMT5 attenuation enhanced GBM cell survival in a mouse xenograft model of aggressive GBM. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in GBM, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.
    Cancer Research 01/2014; · 9.28 Impact Factor
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    ABSTRACT: Background : Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. Methods : PC Cl3 rat thyroid cells, PC Cl3 cells overexpressing BRAF<sup>V600E</sup>, or primary cultured tumor cells from thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hrs. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by western blotting against selected antibodies. Results : We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin´s action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity, but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF<sup>V600E</sup> and in primary cultured thyroid tumor cells from TRβ<sup>PV/PV</sup> mice. Conclusion : Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.
    Thyroid 01/2014; · 3.54 Impact Factor
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    ABSTRACT: Semaphorins are a class of membrane-bound and secreted proteins. They have been found to regulate basic cell functions such as axonal growth cone guidance and recent studies have focused on their effect on tumor progression. Semaphorin 3B (Sema3B) particularly is a secreted protein that has been known to modulate proliferation and apoptosis, processes that are critical for tumor progression and development. In spite of its importance, there is yet no high-throughput screening assay available to detect or quantify the expression of Sema3B for natural product cancer drug discovery purposes. Therefore, the development of a new high-throughput bioassay for the discovery of Sema3B inducing agents from natural product sources is described herein. A wide variety of pure compounds and extracts from plants and microorganisms have been found suitable for screening using this Sema3B assay to detect and quantify the effect of Sema3B inducing agents and thereby identify new selective bioactive Sema3B lead compounds for cancer drug discovery and development. Also, this new bioassay procedure is based on a high-throughput platform using an enzyme-linked immunosorbent assay that involves the optimization of sensitivity and selectivity levels as well as accuracy, reproducibility, robustness, and cost effectiveness.
    Fitoterapia 01/2014; · 2.23 Impact Factor
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    ABSTRACT: Background This study compared immediate versus delayed massage-like compressive loading on skeletal muscle viscoelastic properties following eccentric exercise. Methods Eighteen rabbits were surgically instrumented with peroneal nerve cuffs for stimulation of the tibialis anterior muscle. Rabbits were randomly assigned to a massage loading protocol applied immediately post exercise (n = 6), commencing 48 hours post exercise (n = 6), or exercised no-massage control (n = 6). Viscoelastic properties were evaluated in vivo by performing a stress-relaxation test pre- and post-exercise and daily pre- and post-massage for four consecutive days of massage loading. A quasi-linear viscoelastic approach modeled the instantaneous elastic response (AG0), fast (g1p) and slow (g2p) relaxation coefficients, and the corresponding relaxation time constants τ1 and τ2. Findings Exercise increased AG0 in all groups (P < 0.05). After adjusting for the three multiple comparisons, recovery of AG0 was not significant in the immediate (P = 0.021) or delayed (P = 0.048) groups compared to the control group following four days of massage. However, within-day (pre- to post-massage) analysis revealed a decrease in AG0 in both massage groups. Following exercise, g1p increased and g2p and τ1 decreased for all groups (P < 0.05). Exercise had no effect on τ2 (P > 0.05). After four days of massage, there was no significant recovery of the relaxation parameters for either massage loading group compared to the control group. Interpretation Our findings suggest that massage loading following eccentric exercise has a greater effect on reducing muscle stiffness, estimated by AG0, within-day rather than affecting recovery over multiple days. Massage loading also has little effect on the relaxation response.
    Clinical Biomechanics. 01/2014;
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    ABSTRACT: Calcium-sensing receptor (CaSR) is expressed by parathyroid cells and thyroid C-cells (from which medullary thyroid carcinoma [MTC] is derived). A molecular imaging agent localizing to the CaSR could improve the detection of parathyroids and MTC preoperatively or intraoperatively. We synthesized a novel compound containing a fluorine residue for potential future labeling and demonstrated that the compound inhibited CaSR function in vitro. We synthesized compound M, a derivative of a known calcilytic compound, Calhex-231. Human embryonic kidney cells transfected with green-fluorescent protein-tagged CaSR or control vector were preincubated with compound M before the addition of calcium. Immunoblotting for total mitogen-activated protein kinase (MAPK: ERK1/2), activated MAPK (phosphorylated ERK1/2), and glyceraldehyde 3-phosphate dehydrogenase was performed. Synthesis of compound M was confirmed by mass spectrometry. Inhibition of the MAPK signaling pathway by compound M was demonstrated in a dose-dependent manner by a decrease in phosphorylated ERK1/2 with no change in total ERK1/2 levels. Compound M inhibited MAPK signaling slightly better than the parent compound. We have developed a novel molecule which demonstrates functional inhibition of CaSR and has a favorable structure for labeling. This compound appears to be appropriate for further development as a molecular imaging tool to enhance the surgical treatment of parathyroid disease and MTC.
    Surgery 12/2013; 154(6):1378-84. · 3.37 Impact Factor
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    ABSTRACT: Loss of miR-122 causes chronic steatohepatitis and spontaneous hepatocellular carcinoma. However, the consequence of miR-122 deficiency on genotoxic stress-induced liver pathogenesis has not been explored. Here, we investigated the impact of miR-122 depletion on liver pathobiology by treating liver-specific miR-122 knockout (LKO) mice with the hepatocarcinogen diethylnitrosamine (DEN). At 25 weeks post-DEN injection, all LKO mice developed CK-19-positive hepatobiliary cysts, which correlated with DEN-induced transcriptional activation of Cdc25a mediated through E2f1. Additionally, LKO livers were more fibrotic and vascular, and developed larger microscopic tumors, possibly due to elevation of the Axl oncogene, a receptor tyrosine kinase as a novel target of miR-122, and several protumorigenic miR-122 targets. At 35 weeks following DEN exposure, LKO mice exhibited a higher incidence of macroscopic liver tumors (71%) and cysts (86%) compared to a 21.4% and 0% incidence of tumors and cysts, respectively, in control mice. The tumors in LKO mice were bigger (ninefold, P = 0.015) and predominantly hepatocellular carcinoma, whereas control mice mostly developed hepatocellular adenoma. DEN treatment also reduced survival of LKO mice compared to control mice (P = 0.03). Interestingly, induction of oxidative stress and proinflammatory cytokines in LKO liver shortly after DEN exposure indicates predisposition of a pro-tumorigenic microenvironment. Collectively, miR-122 depletion facilitates cystogenesis and hepatocarcinogenesis in mice on challenge with DEN by up-regulating several genes involved in proliferation, growth factor signaling, neovascularization, and metastasis.
    American Journal Of Pathology 10/2013; · 4.60 Impact Factor
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    ABSTRACT: The co-expression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at start of therapy yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Context:P21 activated kinases (PAKs) are a family of serine/threonine kinases that are downstream effectors of small GTPase Cdc42 and Rac. PAKs regulate cell motility, proliferation, and cytoskeletal rearrangement. PAK isoform expression and activity have been shown to be enhanced in cancer and to function as an oncogene in vivo. PAKs also have been implicated in cancer progression.Objective:In thyroid cancer we have previously determined that PAK overactivation is common in the invasive fronts of aggressive tumors and that it is functionally involved in thyroid cancer cell motility using molecular inhibitors. We report the development of two new PAK inhibiting compounds that were modified from the structure OSU-03012, a previously identified multi-kinase inhibitor that competitively blocks ATP binding of both phosphoinositide dependent kinase 1 (PDK1) and PAK1.Results:Seventeen compounds were created by combinatorial chemistry predicted to inhibit PAK activity with reduced anti-PDK1 effect. Two lead compounds were identified based the ability to inhibit PAK1 activity in an ATP-competitive manner without discernible in vivo PDK1 inhibitory activity in thyroid cancer cell lines. Both compounds reduced thyroid cancer cell viability. Although they are not PAK-specific on a multi-kinase screening assay, the anti-migration activity effect of the compounds in thyroid cancer cells was rescued by overexpression of a constitutively active PAK1, suggesting this activity is involved in this biological effect.Conclusions:We have developed two new multi-kinase inhibitors with anti-PAK activity that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.
    The Journal of Clinical Endocrinology and Metabolism 05/2013; · 6.31 Impact Factor
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    ABSTRACT: ABSTRACT The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavir's effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveals that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well known drugs as a combinatorial therapy with anti-cancer properties.
    Leukemia & lymphoma 03/2013; · 2.61 Impact Factor
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    ABSTRACT: Loss of miR-122 causes chronic steatohepatitis and spontaneous hepatocellular carcinoma. However, the consequence of miR-122 deficiency on genotoxic stress–induced liver pathogenesis is poorly understood. Here, we investigated the impact of miR-122 depletion on liver pathobiology by treating liver-specific miR-122 knockout (LKO) mice with the hepatocarcinogen diethylnitrosamine (DEN). At 25 weeks post-DEN injection, all LKO mice developed CK-19–positive hepatobiliary cysts, which correlated with DEN-induced transcriptional activation of Cdc25a mediated through E2f1. Additionally, LKO livers were more fibrotic and vascular, and developed larger microscopic tumors, possibly due to elevation of the Axl oncogene, a receptor tyrosine kinase as a novel target of miR-122, and several protumorigenic miR-122 targets. At 35 weeks following DEN exposure, LKO mice exhibited a higher incidence of macroscopic liver tumors (71%) and cysts (86%) compared to a 21.4% and 0% incidence of tumors and cysts, respectively, in control mice. The tumors in LKO mice were bigger (ninefold, P = 0.015) and predominantly hepatocellular carcinoma, whereas control mice mostly developed hepatocellular adenoma. DEN treatment also reduced survival of LKO mice compared to control mice (P = 0.03). Interestingly, induction of oxidative stress and proinflammatory cytokines in LKO liver shortly after DEN exposure indicates predisposition of a pro-tumorigenic microenvironment. Collectively, miR-122 depletion facilitates cystogenesis and hepatocarcinogenesis in mice on DEN challenge by up-regulating several genes involved in proliferation, growth factor signaling, neovascularization, and metastasis.
    The American Journal of Pathology. 01/2013; 183(6):1719–1730.
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    ABSTRACT: PURPOSE: This study compared the effect of immediate versus delayed massage-like compressive loading (MLL) on peak isometric torque recovery and inflammatory cell infiltration following eccentric exercise (EEX). METHODS: Eighteen skeletally mature New Zealand White rabbits were instrumented with peroneal nerve cuffs for stimulation of hindlimb tibialis anterior muscles. Following a bout of EEX, rabbits were randomly assigned to a MLL protocol (0.5Hz, 10N, 15min) started immediately post-EEX, 48 hours post-EXX, or no-MLL control and performed for four consecutive days. A torque-angle (T-Θ) relationship was obtained for 21 joint angles pre and post-EEX and post four consecutive days of MLL or no-MLL. Muscle wet weights and immunohistochemical sections were obtained following final treatments. RESULTS: EEX produced an average 51% (±13%) decrease in peak isometric torque output. Greatest peak torque recovery occurred with immediate application of MLL. There were differences in torque recovery between immediate and delayed MLL (p=0.0012), immediate MLL and control (p<0.0001), and delayed MLL and control (p=0.025). Immunohistochemical analysis showed 39.3% and 366.0% differences in the number of RPN3/57 and CD11b positive cells between immediate (p=0.71) and delayed MLL (p=0.12). Area under the T-Θ curve showed a difference for immediate (p<0.0001) and delayed (p=0.0051) MLL as compared to control. Exercise produced an average 10°± 0.2 rightward shift from pre exercise peak isometric torque angle. Control, immediate MLL and delayed MLL produced an average leftward angular shift from the post exercise angle (p=0.28, p=0.03, and p=0.47, respectively). CONCLUSIONS: Post-EEX, immediate MLL was more beneficial than delayed MLL in restoring muscle function and modulating inflammatory cell infiltration. These findings invite similar human studies in order to make definitive conclusions on optimal timing of massage-based therapies.
    Medicine and science in sports and exercise 12/2012; · 4.48 Impact Factor

Publication Stats

1k Citations
370.83 Total Impact Points

Institutions

  • 2010–2014
    • The Ohio State University
      • Center for Biostatistics
      Columbus, Ohio, United States
    • Columbus State University
      Columbus, Georgia, United States
  • 2013
    • Nationwide Children's Hospital
      Columbus, Ohio, United States