Matthew D Ringel

The Ohio State University, Columbus, Ohio, United States

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Publications (118)615.03 Total impact

  • 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.
    Hormones & cancer. 10/2014;
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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: 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; · 0.99 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: 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: 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
  • John 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; · 5.26 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 analogues 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 h. 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 h: 0.39 ± 0.24 vs 0.18 ± 0.12 percentage of injected dose per gram of tissue (%ID/g) (p = 0.002), 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 h to 3.29 ± 0.98 at 24 h (p = 0.015) for TT tumors, and 1.7 ± 0.56 at 1 h to 1.48 ± 0.33 at 24 h (p = 0.36) 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; · 6.31 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. · 6.31 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: Background: Two recent genome-wide association studies (GWAS) identified five single nucleotide polymorphisms (SNPs) (rs965513, rs944289, rs966423, rs2439302, and rs116909374) associated with papillary thyroid carcinoma (PTC). Each variant showed highly significant but moderate to low disease risk. Here we assessed the cumulative risk and predictive value of the five SNPs. Methods: We genotyped two cohorts of individuals, 747 PTC cases and 1047 controls from Ohio, and 1795 PTC and 2090 controls from Poland. Cumulative genetic risk scores were calculated using un-weighted and weighted approaches. Results: All five SNPs showed significant association with PTC. The average cumulative risk score in cases was significantly higher than in controls (p < 2.2e-16). Each additional risk allele increased the risk of having PTC by 1.51 (95% CI, 1.4 to 1.64) in Ohio and by 1.35 (95% CI, 1.27 to 1.44) in Poland. An analysis was performed weighing risk alleles by effect size and assigning individuals to 3 weighted risk score groups, Low (<=2), Medium (2-5) and High (>5). Individuals in the High group were significantly more susceptible to PTC compared to individuals in the Low group with an odds ratio of 8.7 (95% CI, 5.8 to 13.3) in Ohio and 4.24 (95% CI, 3.10 to 5.84) in Poland. Almost identical results were obtained when follicular variant PTCs and micro PTCs were omitted. These five SNPs explain about 11% of the familial risk of thyroid cancer in the Ohio cohort and 6% in the Polish cohort. Conclusion: As the genetic risk score increases, the risk of having PTC increases. However the predictive power of the cumulative effect of these five variants is only moderately high and clinical use may not be feasible until more variants are detected.
    Thyroid: official journal of the American Thyroid Association 05/2013; · 2.60 Impact Factor
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    ABSTRACT: Background:Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative.Objectives:The objective of this study was to identify susceptibility genes for PTC.Methods:A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies.Results:Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants.Conclusions:Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.
    The Journal of Clinical Endocrinology and Metabolism 03/2013; · 6.31 Impact Factor
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    ABSTRACT: Abstract Background: The TSH level or duration of thyroid hormone withdrawal (THW) to detect stimulated thyroglobulin (Tg) in differentiated thyroid cancer (DTC) monitoring is unknown. The objective of this study is to evaluate the TSH cutoff of >30 uU/ml to detect stimulated Tg >2 ng/ml after THW (THW-Tg≥2), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire sensitivity to detect hypothyroid symptoms. Methods: This was a prospective longitudinal cohort study done at a tertiary academic medical center. 47 DTC patients undergoing first Tg stimulation or after previously abnormal Tg stimulation had weekly measurements of TSH and Tg during 4 weeks THW, and repeated questionnaire assessments. Results: TSH did not reach a plateau in any patient and, in those whose Tg did not remain suppressed, Tg continued to rise. Seventy-five percent of patients had an undetectable Tg <0.2 ng/ml at baseline (95% were <0.5 mg/ml) with 16% undetectable throughout THW. The majority of patients (72.7% and 97.8%) achieved TSH >30 uU/ml by 3 and 4 weeks THW, respectively. Of the 15 patients with maximum stimulated THW-Tg≥2, 38% were detected before the minimal TSH >30 uU/ml cutoff. At 2 weeks THW, 3 had a TSH >30 uU/ml and none of them had Tg >2 ng/ml. At 3 weeks THW, 11 had a TSH >30 uU/ml and 64% of them had Tg >2 ng/ml. Only 60% were detected at 3 weeks THW regardless of their TSH level. Eighty-six percent were detected by TSH 60- <80 uU/ml. Conversely, all patients whose serum Tg was < 0.2 ng/ml when their serum TSH was >20 uU/ml did not achieve a THW-Tg≥2. Conclusion: The minimal TSH cutoff of >30 uU/ml was inadequate to detect many patients with final stimulated THW-Tg≥2 during complete THW. TSH >80-100 uU/ml was a better cutoff, achieved in only 53% after 4 weeks THW. Conversely, we propose a preliminary THW stopping rule for ending THW early in selected patients. In patients with a Tg <0.2 ng/ml when TSH >20 uU/ml all had a final stimulated Tg ≤2 ng/ml, potentially saving qualifying patients 40% of THW duration compared to 4 weeks THW. FACIT-F correlated with TSH, but was not sensitive to detect mild hypothyroidism.
    Thyroid: official journal of the American Thyroid Association 09/2012; · 2.60 Impact Factor
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    ABSTRACT: Context:Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden syndrome (CS) and Cowden-like syndrome (CSL) that predisposes to high risks of benign and malignant tumors of thyroid and breast.Objective:The objective of the study was to analyze the subcellular pattern of phosphorylated (P)-AKT expression in nonmedullary thyroid cancers from PTEN hamartoma tumor syndrome patients and to investigate whether the lack of PTEN in the nucleus and/or lack of proper PTEN function in the nucleus affect(s) nuclear AKT activity in CS patients.Design:In all, 664 patients with CS/CSL were screened for PTEN germline mutations and nonmedullary thyroid cancers. Twenty-two patients who have both pathogenic PTEN germline mutations and nonmedullary thyroid cancers were selected. Thyroid samples from these patients were stained for PTEN and P-AKT. In our in vitro study, PTEN was knocked down or overexpressed in both thyroid cancer cells and breast cancer cells, and nuclear P-AKT was compared with the control.Results:Loss of PTEN protein was found in thyroid adenomas and carcinomas from all 22 (100%) PTEN(Mut+) CS/CSL patients. AKT activation was identified in 17 of 22 (77.3%) thyroid adenoma/carcinoma specimens, and most patients (63.7%) have activated nuclear AKT. Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase-dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells. We also showed that in breast cancer but not thyroid cancer cells, PTEN suppressesnuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3/P-AKT reservoir in the cytoplasm. In thyroid cancer cells, PTEN suppresses phosphorylation of AKT already resident in the nucleus.Conclusions:PTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.
    The Journal of Clinical Endocrinology and Metabolism 09/2012; · 6.31 Impact Factor
  • Yu-Yu Liu, Xiaoli Zhang, Matthew D Ringel, Sissy M Jhiang
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    ABSTRACT: The selective increase of Na(+)/I(-) symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I(131) for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.
    Endocrine Related Cancer 02/2012; 19(3):291-304. · 5.26 Impact Factor
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    ABSTRACT: Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been recently reported in 23% of a large series of classic CS. Here, we validated our small (n = 10) pilot study in a large patient series that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% (49/608) of PTEN mutation-negative CS and CS-like (CSL) individuals (SDH(var+)). None of these SDHx variants was found in 700 population controls (P < 0.0001). We then found that SDHx variants also occur in 6% (26/444) of PTEN mutation-positive (PTEN(mut+)) CS/CSL individuals (PTEN(mut+)/SDH(var+)). Of 22 PTEN(mut+)/SDH(var+) females, 17 had breast cancers compared with 34/105 PTEN(mut+) (P < 0.001) or 27/47 SDH(var+) patients (P = 0.06). Notably, individuals with SDH(var+) alone had the highest thyroid cancer prevalence (24/47) compared with PTEN(mut+) patients (27/105, P = 0.002) or PTEN(mut+)/SDH(var+) carriers (6/22, P = 0.038). Patient-derived SDH(var+) lymphoblastoid cells had elevated cellular reactive oxygen species, highest in PTEN(mut+)/SDH(var+) cells, correlating with apoptosis resistance. SDH(var+) cells showed stabilized and hyperactivated hypoxia inducible factor (HIF)1α signaling. Most interestingly, we also observed the loss of steady-state p53 in the majority of SDH(var+) cells. This loss of p53 was regulated by MDM2-independent NADH quinone oxidoreductase 1-mediated protein degradation, likely due to the imbalance of flavin adenine dinucleotide/nicotinamide adenine dinucleotide in SDH(var+) cells. Our data suggest the potential regulation of HIF1α, p53 and PTEN signaling by mitochondrial metabolism in CS/CSL tumorigenesis. Together, our findings suggest the importance of considering SDHx as candidate predisposing and modifier genes for CS/CSL-related malignancy risks, and a mechanism which suggests ways of therapeutic reversal or prevention.
    Human Molecular Genetics 01/2012; 21(2):300-10. · 7.69 Impact Factor
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    ABSTRACT: To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 × 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 × 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 × 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
    Nature Genetics 01/2012; 44(3):319-22. · 35.21 Impact Factor
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    ABSTRACT: MicroRNA (miR) expression signatures are proposed to be able to differentiate thyroid cancer from benign thyroid lesions. We selected eight miRs (miR-146b, -221, -187, -197, -346, -30d, -138, and -302c) to examine the potential use of miRs to supplement diagnostic cytology in cases designated as "atypia of undetermined significance." miR expression was measured in thyroid fine needle aspiration (FNA) specimens by quantitative polymerase chain reaction. Gene expression analyses and linear discriminant analysis (LDA) were performed in a training sample set (n=60) to obtain a classification rule to predict FNA cases as benign or malignant. The predictions were cross-validated by comparing with the corresponding histological diagnoses. A validation sample set (n=68) was further tested with the established four-miR LDA classification rule. A set of four miRs (miR-146b, -221, -187, and -30d) was identified that could differentiate malignant from benign lesions. A four-miR LDA classification rule was obtained and used to predict FNA cases as benign or malignant. For the training sample set, we obtained a diagnostic accuracy of 93.3%, sensitivity of 93.2%, specificity of 93.8%, positive predictive value (PPV) of 0.98, and negative predictive value (NPV) of 0.83. For the validation sample set, we obtained a diagnostic accuracy of 85.3%, sensitivity of 88.9%, specificity of 78.3%, PPV of 0.89, and NPV of 0.78. For the 30 atypia cases in the validation sample set, we obtained a diagnostic accuracy of 73.3%, sensitivity of 63.6%, specificity of 78.9%, PPV of 0.64, and NPV of 0.79. Based on the miR predictions, we classified the atypia cases predicted as "malignant" into "high risk" and those predicted as "benign" into "low risk" categories. While thyroid carcinomas, particularly papillary thyroid carcinomas (PTCs), were relatively enriched in the high-risk category, this particular miR panel is subject to inaccurate results in follicular neoplasias in atypia cases. We demonstrate that miR amplification from FNA samples is feasible and that the particular four miR profile in this study can identify PTCs. However, further refinement is required for application to FNA cytology of "atypia of undetermined significance" cases due to low accuracy in classifying follicular neoplasias.
    Thyroid: official journal of the American Thyroid Association 12/2011; 22(1):9-16. · 2.60 Impact Factor
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    ABSTRACT: Clinical trials using kinase inhibitors have demonstrated transient partial responses and disease control in patients with progressive medullary thyroid cancer (MTC). The goal of this study was to identify potential combinatorial strategies to improve on these results using sorafenib, a multikinase inhibitor with activity in MTC, as a base compound to explore signaling that might predict synergystic interactions. Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to sorafenib, everolimus, and AZD6244 alone and in combination. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) and poly (ADP-ribose) polymerase (PARP) cleavage assays were performed to measure cell survival and apoptosis. Western blots were performed to confirm activity of the compounds and to determine possible mechanisms of resistance and predictors of synergy. As a solitary agent, sorafenib was the most active compound on MTT assay. Western blots confirmed that sorafenib, everolimus, and AZD6244 inhibited their anticipated targets. At concentrations below its IC(50), sorafenib-treated TT and MZ-CRC-1 cells demonstrated transient inhibition and then re-activation of Erk over 6 h. In concordance, synergistic effects were only identified using sorafenib in combination with the Mek inhibitor AZD6244 (P<0.001 for each cell line). Cells treated with everolimus demonstrated activation of Akt and Ret via TORC2 complex-dependent and TORC2 complex-independent mechanisms respectively. Everolimus was neither additive nor syngergistic in combination with sorafenib or AZD6244. In conclusion, sorafenib combined with a Mek inhibitor demonstrated synergy in MTC cells in vitro. Mechanisms of resistance to everolimus in MTC cells likely involved TORC2-dependent and TORC2-independent pathways.
    Endocrine Related Cancer 11/2011; 19(1):29-38. · 5.26 Impact Factor

Publication Stats

4k Citations
615.03 Total Impact Points

Institutions

  • 2004–2013
    • The Ohio State University
      • • Division of Hospital Medicine
      • • Division of Hematology
      Columbus, Ohio, United States
  • 2012
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 2009
    • Columbus State University
      Columbus, Georgia, United States
  • 2005
    • National Cancer Institute (USA)
      • Laboratory of Molecular Biology
      Maryland, United States
  • 2000–2005
    • Washington Hospital Center
      Washington, Washington, D.C., United States
  • 2001–2004
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
    • National Institutes of Health
      Maryland, United States
    • Uniformed Services University of the Health Sciences
      • Department of Pediatrics
      Maryland, United States
    • Walter Reed National Military Medical Center
      • Department of Surgery
      Washington, Washington, D.C., United States
  • 2003
    • The University of Warwick
      • Biological Sciences
      Warwick, ENG, United Kingdom
  • 2002
    • MedStar Health Research Institute
      Maryland, United States
  • 1996–2002
    • Johns Hopkins University
      • • Department of Pediatrics
      • • Department of Medicine
      Baltimore, MD, United States
  • 1999–2001
    • MedStar Health
      Baltimore, Maryland, United States
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
    • William Beaumont Army Medical Center
      El Paso, Texas, United States
  • 1997–2001
    • Georgetown University
      • • Department of Otolaryngology-Head and Neck Surgery
      • • Department of Medicine
      Washington, D. C., DC, United States
    • University of Texas MD Anderson Cancer Center
      • Endocrine Neoplasia and Hormonal Disorders
      Houston, TX, United States