Matthew D Ringel

The Ohio State University, Columbus, Ohio, United States

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Publications (132)722.2 Total impact

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    ABSTRACT: Background: Integrin-linked kinase (ILK) is a serine-threonine kinase that regulates interactions between the cell and the extracellular matrix. In many cancers, overexpression of ILK leads to increased cell proliferation, motility, and invasion. We hypothesized that ILK functions as a regulator of viability and migration in thyroid cancer cells. Methods: Eleven human thyroid cancer cell lines were screened for ILK protein expression. The cell lines with the greatest expression were treated with either ILK small interfering RNA (siRNA) or a novel ILK inhibitor, T315, and the effects were evaluated via Western blot and migration assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays were performed to assess cell viability. Results: siRNA against ILK decreased phosphorylation of downstream effectors Akt and MLC, as well as decreased migration. Treatment with T315 showed a dose-related decrease in both Akt and MLC phosphorylation, as well as decreased migration. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays showed T315 to have an half maximal inhibitory concentration of less than 1 μM in cell lines with high ILK expression. Conclusion: ILK is expressed differentially in thyroid cancer cell lines. Both ILK siRNA and T315 inhibit motility of thyroid cancer cell lines, and T315 is shown to be cytotoxic at low concentrations. Altogether, our study suggests that ILK may represent an important kinase in aggressive thyroid cancers.
    Surgery 11/2015; DOI:10.1016/j.surg.2015.10.016 · 3.38 Impact Factor
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    ABSTRACT: Objective: Patients with progressive thyroid cancer in distant metastatic sites represent a population with a need for new therapeutic options. Aspiring to improve the treatment of such patients, the objective of this position statement from the International Thyroid Oncology Group (ITOG) is to clarify the importance of incorporating high-quality correlative studies into clinical trials. Participants: The ITOG was formed to develop and support high-quality multicenter and multidisciplinary clinical trials for patients with aggressive forms of thyroid cancer. The Correlative Sciences Committee of the ITOG focuses on the quality and types of correlative studies included in ITOG-associated clinical trials. Evidence: This document represents expert consensus from the ITOG regarding this issue based on extensive collective experience in clinical and translational trials informed by basic science. Consensus process: The Correlative Studies Committee identified an international writing group representative of diverse specialties, including basic sciences. Drafts were reviewed by all members of the writing group, the larger committee, and the ITOG board. After consideration of all comments by the writing group and modification of the document, the final document was then approved by the authors and the ITOG board. Conclusions: High-quality correlative studies, which include variety in the types of correlates, should be intrinsic to the design of thyroid cancer clinical trials to offer the best opportunity for each study to advance treatment for patients with advanced and progressive thyroid cancer.
    The Journal of Clinical Endocrinology and Metabolism 09/2015; DOI:10.1210/jc.2015-2818 · 6.21 Impact Factor
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    ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.
    Journal of the National Comprehensive Cancer Network: JNCCN 09/2015; 13(9):1140-50. · 4.18 Impact Factor
  • Matthew D. Ringel ·

    05/2015; 15(4):i-i. DOI:10.1177/1559897715584926
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    ABSTRACT: Exosome size distributions and numbers of exosomes released per cell are measured by asymmetric flow-field flow fractionation/multi-angle light scattering (A4F/MALS) for three thyroid cancer cell lines as a function of a treatment that inhibits MAPK signaling pathways in the cells. We show that these cell lines release exosomes with well-defined morphological features and size distributions that reflect a common biological process for their formation and release into the extracellular envi- ronment. We find that those cell lines with constitutive activation of the MAPK signaling pathway display MEK-dependent exosome release characterized by increased numbers of exosomes released per cell. Analysis of the measured exosome size distributions based on a generalized extreme value distribution model for exosome formation in intracellular multivesicular bodies highlights the im- portance of this experimental observable for delineating different mechanisms of vesicle formation and predicting how changes in exosome release can be modified by pathway inhibitors in a cellular context-dependent manner.
    Langmuir 04/2015; 31(19). DOI:10.1021/acs.langmuir.5b00095 · 4.46 Impact Factor
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    ABSTRACT: Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC. © 2015 The authors.
    Endocrine Related Cancer 04/2015; 22(2):121-30. DOI:10.1530/ERC-14-0537 · 4.81 Impact Factor
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    ABSTRACT: MicroRNA (miRNA) profiles obtained for extracellular vesicles (EVs) derived from MCF7 and MCF10A cells were analyzed to identify unique characteristics that distinguish their cell sources. One characteristic common to the miRNA profiles of MCF7 EVs and their parent cells is high abundances of miR-21, let-7a, miR-100, and miR-125b, and the low levels of miR-205. A second characteristic is the high abundance of "microRNA-like" transfer RNA (tRNA) fragments, which is unique to the MCF7 EVs, and is not found in comparing the cellular profiles. We also examined correlations in the MCF7 cellular expression levels of these five miRNAs and two tRNA-derived miRNAs, miR-720 and miR-1274b, and compared them to correlations in the MCF7 EV levels. We find that correlations in the cellular expression levels of miR-125b, miR-100, and let-7a are mirrored in the EVs. In contrast, correlations in tRNA-derived miRNA levels are found only in the EVs. The findings suggest that EV miRNA clusters can be defined based on functional miRNA interactions related to correlated cellular expression levels or purely physical miRNA interactions - e.g., aggregation due to comparable binding affinities to common targets. Implications: Recognizing that tRNAs are over-expressed in proliferative diseases, such as cancer, our results point to using high levels of tRNA-derived small RNA fragments in combination with known miRNA signatures of cancer tumors to distinguish tumor-derived EVs in circulation from EVs derived by other cell sources. Such biomarkers would be unique to the EVs where high abundances of tRNA fragments are amplified with respect to their cellular levels. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Research 02/2015; 13(5). DOI:10.1158/1541-7786.MCR-14-0533 · 4.38 Impact Factor
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    ABSTRACT: Context: Activated 5' adenosine monophosphate protein kinase (AMPK) is a key regulator of intracellular energy homeostasis, and may also function as a tumor suppressor by inhibiting cell growth through suppression of mTOR/p70S6K signaling. AMPK activating agents, such as metformin and AICAR, have been demonstrated to inhibit thyroid cancer cell growth in in vitro and in vivo models. OSU-53, a recently developed AMPK activator, was previously shown to exhibit both in vitro and in vivo anti-tumor activity against aggressive breast cancer cell lines and their xenografts in nude mice. Objective: To assess the in vitro effects of OSU-53 treatment in a panel of thyroid cancer cells. Design: Experiments were performed to determine the effects of OSU-53 on cell growth, oncogenic signaling, apoptosis, autophagy, and cell rescue after selective knockdown of AMPK. Results: OSU-53 inhibited in vitro cell growth of all seven thyroid cancer cells tested and induced activation of AMPK. Cell lines with activating mutations in RAS or BRAF, compared to cells with PTEN null and RET/PTC1 mutations, were more sensitive to drug treatment and demonstrated a more robust AMPK activation, inhibition of mTOR signaling, and autophagy stimulation. After selective knockdown of AMPK, cell rescue from OSU-53 treatment was not observed. We demonstrated an off target effect of direct mTOR inhibition by OSU-53. Increased autophagy was observed in cells with activation RAS or BRAF mutations. Conclusions: OSU-53, a novel dual AMPK activator/mTOR inhibitor, effectively inhibits growth in a variety of thyroid cancer cell lines, and is most potent in cells with activating mutations in RAS or BRAF.
    Journal of Clinical Endocrinology &amp Metabolism 02/2015; 100(5):jc20141777. DOI:10.1210/jc.2014-1777 · 6.21 Impact Factor
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    ABSTRACT: These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents. Copyright © 2014 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 12/2014; 12(12):1671-80. · 4.18 Impact Factor
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    ABSTRACT: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
    Cell 10/2014; 159(3):676-90. DOI:10.1016/j.cell.2014.09.050. · 32.24 Impact Factor
  • Rebecca Nagy · Matthew D Ringel ·
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    ABSTRACT: Nonmedullary thyroid cancer (NMTC) can be sporadic or can occur as a component cancer as part of several well-described hereditary cancer syndromes. NMTC, particularly papillary thyroid cancer, also can occur by itself in families and is often termed familial NMTC or familial papillary thyroid cancer. The occurrence of NMTC in families, along with extensive population-based evidence from patients with sporadic thyroid cancer, together suggest that NMTC has a strong genetic component, only a small proportion of which has been characterized to date. Advances in genetic and genomic technology have rapidly advanced our understanding of the complex nature of NMTC susceptibility, although much remains to be explained. Herein, we describe the current state of knowledge, starting with a brief review of hereditary syndromic causes and moving on to describe recent data using modern genomic approaches to identifying genes involved in the predisposition to NMTC.
    10/2014; 6(1). DOI:10.1007/s12672-014-0205-y
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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; 21(6). DOI:10.1530/ERC-14-0424 · 4.81 Impact Factor
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    ABSTRACT: Carotid body tumors represent the most common of head and neck tumors. They account for less than 0.03 percent of all human tumors. The underlying physiology and pathogenesis of this tumor type is not well understood. Several different genetic abnormalities have been associated with the development of carotid body paragangliomas. We present a case report with an unusual genetic mutation in the SDHB gene and a review of the paragangliioma syndromes.
    Annals of Vascular Surgery 07/2014; 28(5). DOI:10.1016/j.avsg.2013.12.012 · 1.17 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; 99(5):jc20133101. DOI:10.1210/jc.2013-3101 · 6.21 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: PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. 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 the 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(V600E) and in primary cultured thyroid tumor cells from TRβ(PV/PV) 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; DOI:10.1089/thy.2013.0614 · 4.49 Impact Factor
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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. DOI:10.1016/j.surg.2013.06.044 · 3.38 Impact Factor
  • John E Phay · Matthew D Ringel ·
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    ABSTRACT: Thyroid cancer incidence is rising annually largely related to enhanced detection and of early stage well-differentiated primary tumors. The prognosis for patients with early stage thyroid cancer is outstanding with most patients being cured with surgery. In selected cases, I-131 is administered to treat known or suspected residual or metastatic disease. Even patients with loco-regional metastases typically have an outstanding long-term prognosis, albeit with monitoring and occasional intervention for residual or recurrent disease. In contrast, individuals with distant metastases from thyroid cancer, particular older patients with larger metastatic burdens and those with poorly differentiated tumors, have a poor prognosis. Patients with metastatic anaplastic thyroid cancer have a particularly poor prognosis. Published clinical trials indicate that transient disease control and partial remissions can be achieved with kinase inhibitor therapy directed toward angiogenic targets, and that in some cases, I-131 uptake can be enhanced. However, the direct targets of activity in metastatic lesions are incompletely defined and clear evidence that these treatments increase the duration or quality of life of patients is lacking, underscoring the need for improved knowledge regarding the metastatic process to inform the development of new therapies. In this review, we will focus on current data and hypotheses regarding key regulators of metastatic dormancy, metastatic progression, and the role of putative cancer stem cells.
    Endocrine Related Cancer 09/2013; 20(6). DOI:10.1530/ERC-13-0187 · 4.81 Impact Factor
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    ABSTRACT: Objective: Image-based localization of medullary thyroid cancer (MTC) and parathyroid glands would improve the surgical outcomes of these diseases. MTC and parathyroid glands express high levels of calcium-sensing receptor (CaSR). The aim of this study was to prove the concept that CaSR antagonists specifically localize to CaSR-expressing tumors in vivo. Design: We synthesized two isomers of a known CaSR calcilytic, Calhex 231, and four new analogs, which have a favorable structure for labeling. Their antagonistic activity was determined using immunoblots demonstrating decreased ERK1/2 phosphorylation after calcium stimulation in human embryonic kidney cells overexpressing CaSR. Compound 9 was further radiolabeled with (125)I and evaluated in nude mice with and without heterotransplanted xenografts of MTC cell lines, TT and MZ-CRC-1, that do and do not express CaSR, respectively. Results: Two newly synthesized compounds, 9 and 11, exhibited better antagonistic activity than Calhex 231. The half-life of (125)I-compound 9 in nude mice without xenografts was 9.9 hours. A biodistribution study in nude mice bearing both tumors demonstrated that the uptake of radioactivity in TT tumors was higher than in MZ-CRC-1 tumors at 24 hours: 0.39 ± 0.24 vs 0.18 ± 0.12 percentage of injected dose per gram of tissue (%ID/g) (P = .002), with a ratio of 2.25 ± 0.62. Tumor-to-background ratios for TT tumors, but not MZ-CRC-1 tumors, increased with time. Tumor-to-blood values increased from 2.02 ± 0.52 at 1 hour to 3.29 ± 0.98 at 24 hour (P = .015) for TT tumors, and 1.7 ± 0.56 at 1 hour to 1.48 ± 0.33 at 24 hour (P = .36) for MZ-CRC-1 tumors. Conclusions: Our new CaSR antagonists specifically inhibit CaSR function in vitro, preferentially localize to CaSR-expressing tumors in vivo, and therefore have the potential to serve as scaffolds for further development as imaging pharmaceuticals.
    The Journal of Clinical Endocrinology and Metabolism 09/2013; 98(11). DOI:10.1210/jc.2013-1756 · 6.21 Impact Factor
  • Matthew D Ringel · Fadi Nabhan ·
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    ABSTRACT: Anti-thyroglobulin antibodies are commonly identified in patients with differentiated follicular cell-derived thyroid cancer. When present, they interfere with the measurement of thyroglobulin (Tg), which is the primary biochemical marker used for disease surveillance, creating challenges in monitoring patients for residual or recurrent disease. Moreover, there is variability in measuring anti-Tg antibodies according to the different assays, such that not all patients with anti-Tg antibodies are identifiable on a single assay system. The persistence of anti-Tg antibodies, especially if levels are rising, may indicate persistent, recurrent, or progressive thyroid cancer. In contrast, declining anti-Tg antibody levels may indicate reduced tumor burden or the absence of disease. In this review, we will explore in a case-based manner the data supporting monitoring and treatment paradigms for patients with anti-Tg antibodies and will stress areas where more evidence is needed to better inform clinicians regarding the management of patients with this challenging situation.
    The Journal of Clinical Endocrinology and Metabolism 08/2013; 98(8):3104-10. DOI:10.1210/jc.2013-1412 · 6.21 Impact Factor
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    ABSTRACT: Context: The 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 multikinase 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 on 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 multikinase screening assay, the antimigration 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 2 new multikinase 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; 98(8). DOI:10.1210/jc.2012-3937 · 6.21 Impact Factor

Publication Stats

6k Citations
722.20 Total Impact Points


  • 2004-2015
    • The Ohio State University
      • • Division of Endocrinology, Diabetes, and Metabolism
      • • Department of Internal Medicine
      • • The James Comprehensive Cancer Center
      • • Division of Hospital Medicine
      Columbus, Ohio, United States
  • 2014
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 2009
    • Columbus State University
      Columbus, Georgia, United States
  • 2005
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2000-2005
    • Washington Hospital Center
      Washington, Washington, D.C., United States
  • 2002
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States
  • 2001-2002
    • MedStar Health Research Institute
      Maryland, United States
    • Stanford University
      Palo Alto, California, United States
    • Uniformed Services University of the Health Sciences
      • Department of Pediatrics
      베서스다, Maryland, United States
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 1998-1999
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States