16 results on '"Ringel MD"'
Search Results
2. Building on strength.
- Author
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Ringel MD
- Subjects
- Humans, Endocrine Gland Neoplasms
- Published
- 2021
- Full Text
- View/download PDF
3. HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The state of science in medullary thyroid carcinoma: current challenges and unmet needs.
- Author
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Dadu R, Bagheri-Yarmand R, Ringel MD, Grubbs EG, Zafereo M, Cote G, Gagel RF, Robinson BG, Shaw KR, and Hu MI
- Subjects
- Carcinoma, Neuroendocrine pathology, Humans, Thyroid Neoplasms pathology, Carcinoma, Neuroendocrine etiology, Multiple Endocrine Neoplasia complications, Thyroid Neoplasms etiology
- Abstract
The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.
- Published
- 2020
- Full Text
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4. MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition.
- Author
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Knippler CM, Saji M, Rajan N, Porter K, La Perle KMD, and Ringel MD
- Subjects
- Animals, Cell Cycle drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Survival drug effects, Drug Resistance, Neoplasm, Drug Synergism, Female, Humans, MAP Kinase Signaling System drug effects, Male, Mice, Mice, Transgenic, Mutation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Pyridines pharmacology, Pyridones, Pyrimidines pharmacology, Thyroid Neoplasms genetics, Thyroid Neoplasms metabolism, Thyroid Neoplasms pathology, Vemurafenib pharmacology, p21-Activated Kinases metabolism, Mitogen-Activated Protein Kinases metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Thyroid Neoplasms drug therapy, p21-Activated Kinases antagonists & inhibitors
- Abstract
The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P < 0.0001) and reduced carcinoma formation (P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.
- Published
- 2019
- Full Text
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5. Thyroid nodules and cancer management guidelines: comparisons and controversies.
- Author
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Nabhan F and Ringel MD
- Subjects
- Biopsy, Fine-Needle, Humans, Iodine Radioisotopes therapeutic use, Lymphatic Metastasis, Thyroid Gland pathology, Thyroid Neoplasms drug therapy, Thyroid Neoplasms pathology, Thyroid Neoplasms surgery, Thyroid Nodule diagnosis, Thyroid Nodule pathology
- Abstract
Thyroid cancer is an increasingly prevalent malignancy throughout the world. Management guidelines for both thyroid nodules and thyroid cancer have been published and updated by a number of societies internationally. All of these guidelines recognize this increasing incidence, particularly of small papillary thyroid cancers, due in part to improved technology enabling early or even 'over' diagnosis. Recent advances in molecular imaging and molecular methods have been developed to better characterize thyroid nodules, and a number of studies that have clarified risk stratification systems that can be modified over time allow for individualization of diagnosis, initial treatment, and subsequent follow-up strategies. Advances in surgical approaches and new treatments for patients with the most aggressive forms of thyroid cancer have all influenced management guidelines. Despite substantial similarities, there also are important differences between recent guidelines for some of the common clinical scenarios encountered by physicians in clinical practice. In the present manuscript, we will highlight similarities and differences between several of the most recently published guidelines focused on key areas of importance to clinical care and controversy. These are key areas for future research to strengthen the data to support future guideline recommendations., Competing Interests: Declaration of Interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review, (© 2017 Society for Endocrinology.)
- Published
- 2017
- Full Text
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6. Genetic variants in thyroid cancer distant metastases.
- Author
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Justiniano SE, McElroy JP, Yu L, Yilmaz AS, Coombes KR, Senter L, Nagy R, Wakely P Jr, Volinia S, Vinco M, Giordano TJ, Croce CM, Saji M, and Ringel MD
- Subjects
- Ataxia Telangiectasia Mutated Proteins genetics, Case-Control Studies, Cell Line, Tumor, Female, GTP Phosphohydrolases genetics, Humans, INDEL Mutation, Male, Membrane Proteins genetics, Mutation, Missense, Neoplasm Metastasis, Polymorphism, Genetic, Proto-Oncogene Proteins B-raf genetics, DNA Mutational Analysis, Mutation, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology
- Abstract
Competing Interests: Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
- Published
- 2016
- Full Text
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7. Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer.
- Author
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Ni Y, Seballos S, Ganapathi S, Gurin D, Fletcher B, Ngeow J, Nagy R, Kloos RT, Ringel MD, LaFramboise T, and Eng C
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Carcinoma, Papillary, Female, Genetic Variation, Humans, Middle Aged, Mutation, Thyroid Cancer, Papillary, Adenocarcinoma, Follicular genetics, Carcinoma genetics, Membrane Proteins genetics, Succinate Dehydrogenase genetics, Thyroid Neoplasms genetics
- 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.)
- Published
- 2015
- Full Text
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8. BRAF activates and physically interacts with PAK to regulate cell motility.
- Author
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McCarty SK, Saji M, Zhang X, Knippler CM, Kirschner LS, Fernandez S, and Ringel MD
- Subjects
- Animals, Apoptosis, Blotting, Western, Cell Proliferation, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Immunoprecipitation, Mice, Mitosis, Mutation genetics, Phosphorylation, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, RNA, Small Interfering genetics, Tumor Cells, Cultured, Cell Movement, Proto-Oncogene Proteins B-raf metabolism, Thyroid Neoplasms metabolism, Thyroid Neoplasms pathology, p21-Activated Kinases metabolism
- Abstract
Increased p21-activated kinase (PAK) signaling and expression have been identified in the invasive fronts of aggressive papillary thyroid cancers (PTCs), including those with RET/PTC, BRAFV600E, and mutant RAS expression. Functionally, thyroid cancer cell motility in vitro is dependent on group 1 PAKs, particularly PAK1. In this 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 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., (© 2014 Society for Endocrinology.)
- Published
- 2014
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9. Metastatic mechanisms in follicular cell-derived thyroid cancer.
- Author
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Phay JE and Ringel MD
- Subjects
- Animals, Humans, Neoplasm Metastasis, Adenocarcinoma, Follicular pathology
- Abstract
Thyroid cancer incidence is rising annually largely related to enhanced detection and 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. By contrast, individuals with distant metastases from thyroid cancer, particularly 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.
- Published
- 2013
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10. Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells.
- Author
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Liu YY, Zhang X, Ringel MD, and Jhiang SM
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinases antagonists & inhibitors, Cell Line, Enzyme Inhibitors pharmacology, Flavonoids pharmacology, HEK293 Cells, Humans, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Phosphoinositide-3 Kinase Inhibitors, Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, RNA, Messenger metabolism, Rats, Symporters genetics, TOR Serine-Threonine Kinases, Thyroid Gland cytology, Thyrotropin pharmacology, Benzylamines pharmacology, Chromones pharmacology, Iodine Radioisotopes metabolism, Morpholines pharmacology, Quinoxalines pharmacology, Sirolimus pharmacology, Symporters metabolism
- 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.
- Published
- 2012
- Full Text
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11. Sorafenib and Mek inhibition is synergistic in medullary thyroid carcinoma in vitro.
- Author
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Koh YW, Shah MH, Agarwal K, McCarty SK, Koo BS, Brendel VJ, Wang C, Porter K, Jarjoura D, Saji M, and Ringel MD
- Subjects
- Antineoplastic Agents administration & dosage, Benzenesulfonates administration & dosage, Benzimidazoles administration & dosage, Carcinoma metabolism, Carcinoma, Neuroendocrine, Cell Line, Tumor, Cell Survival drug effects, Drug Synergism, Everolimus, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Niacinamide analogs & derivatives, Phenylurea Compounds, Protein Kinase Inhibitors administration & dosage, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-ret antagonists & inhibitors, Proto-Oncogene Proteins c-ret metabolism, Pyridines administration & dosage, Sirolimus administration & dosage, Sirolimus analogs & derivatives, Sorafenib, TOR Serine-Threonine Kinases antagonists & inhibitors, Thyroid Neoplasms metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma drug therapy, MAP Kinase Signaling System drug effects, Thyroid Neoplasms drug therapy
- 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.
- Published
- 2012
- Full Text
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12. Group I p21-activated kinases regulate thyroid cancer cell migration and are overexpressed and activated in thyroid cancer invasion.
- Author
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McCarty SK, Saji M, Zhang X, Jarjoura D, Fusco A, Vasko VV, and Ringel MD
- Subjects
- Blotting, Western, Cell Line, Tumor, Humans, Immunohistochemistry, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Phosphorylation, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Thyroid Gland pathology, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Up-Regulation, p21-Activated Kinases genetics, Cell Movement physiology, Thyroid Gland metabolism, Thyroid Neoplasms metabolism, p21-Activated Kinases metabolism
- Abstract
p21-activated kinases (PAKs) are a family of serine/threonine kinases that regulate cytoskeletal dynamics and cell motility. PAKs are subdivided into group I (PAKs 1-3) and group II (PAKs 4-6) on the basis of structural and functional characteristics. Based on prior gene expression data that predicted enhanced PAK signaling in the invasive fronts of aggressive papillary thyroid cancers (PTCs), we hypothesized that PAKs functionally regulate thyroid cancer cell motility and are activated in PTC invasive fronts. We examined PAK isoform expression in six human thyroid cancer cell lines (BCPAP, KTC1, TPC1, FTC133, C643, and SW1746) by quantitative reverse transcription-PCR and western blot. All cell lines expressed PAKs 1-4 and PAK6 mRNA and PAKs 1-4 protein; PAK6 protein was variably expressed. Samples from normal and malignant thyroid tissues also expressed PAKs 1-4 and PAK6 mRNA; transfection with the group I (PAKs 1-3) PAK-specific p21 inhibitory domain molecular inhibitor reduced transwell filter migration by ∼50% without altering viability in all cell lines (P<0.05). BCPAP and FTC133 cells were transfected with PAK1, PAK2, or PAK3-specific small interfering RNA (siRNA); only PAK1 siRNA reduced migration significantly for both cell lines. Immunohistochemical analysis of seven invasive PTCs demonstrated an increase in PAK1 and pPAK immunoactivity in the invasive fronts versus the tumor center. In conclusion, PAK isoforms are expressed in human thyroid tissues and cell lines. PAK1 regulates thyroid cancer cell motility, and PAK1 and pPAK levels are increased in PTC invasive fronts. These data implicate PAKs as regulators of thyroid cancer invasion.
- Published
- 2010
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13. Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202.
- Author
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Mody M, Dharker N, Bloomston M, Wang PS, Chou FS, Glickman TS, McCaffrey T, Yang Z, Pumfery A, Lee D, Ringel MD, and Pinzone JJ
- Subjects
- Blotting, Western, Breast Neoplasms genetics, Cell Line, Tumor, Chalcones pharmacology, DNA Replication drug effects, Drug Resistance, Neoplasm drug effects, Drug Synergism, Humans, PPAR gamma genetics, Purines pharmacology, Response Elements drug effects, Reverse Transcriptase Polymerase Chain Reaction, Roscovitine, Rosiglitazone, Transcriptional Activation, Tumor Necrosis Factor-alpha pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms metabolism, Gene Expression drug effects, PPAR gamma agonists, Thiazolidinediones pharmacology
- Abstract
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone superfamily and has multiple endogenous and pharmacological ligands, including 15-deoxy-Delta (12,14)-prostaglandin J(2) and two thiazolidinediones (TZD), rosiglitazone and pioglitazone, which are used clinically to treat type-2 diabetes mellitus. PPARgamma agonists regulate development, cellular growth and metabolism in various tissues and have been documented to decrease cellular proliferation and to induce apoptosis of various tumour phenotypes, including breast cancer. However, the full spectrum of anti-tumour effects occurs only at suprapharmacological doses. In this study, we investigated the mechanism of rosiglitazone-induced anti-tumour effects of MDA-MB-231 human breast cancer cells, and used that information to predict rosiglitazone-induced sensitization of breast cancer cells to the effects of other compounds. We first confirmed that 100 microM rosiglitazone, but not lower doses, decreases MDA-MB-231 cell viability in vitro. We then used microarray gene expression analysis to determine early rosiglitazone-induced gene expression changes after 4-h exposure, which included 1298 genes that we grouped into functional categories. We selectively confirmed rosiglitazone-mediated effects on expression of key regulators of breast cancer proliferation and apoptosis, including p53, p21 and Bax. Finally, we used this information to predict that rosiglitazone would sensitize MDA-MB-231 cells to the anti-tumour effects of CH11, which trimerizes Fas, as well as tumour necrosis factor-alpha. Moreover, we used the confirmed array data to predict cooperative activity of rosiglitazone and R-roscovitine (CYC202), an inhibitor of multiple cyclin-dependent kinases. We conclude that microarray analysis can determine early TZD-modulated changes in gene expression that help to predict effective in vitro drug combinations.
- Published
- 2007
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14. Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones.
- Author
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Weng JR, Chen CY, Pinzone JJ, Ringel MD, and Chen CS
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Cyclin D1 metabolism, Humans, Neoplasms drug therapy, PPAR gamma agonists, Thiazolidinediones chemistry, Thiazolidinediones therapeutic use, Antineoplastic Agents pharmacology, PPAR gamma physiology, Proteasome Endopeptidase Complex drug effects, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Thiazolidinediones pharmacology
- Abstract
Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARgamma activation. To discern the role of PPARgamma in the antitumor effects of TZDs, we have synthesized PPARgamma-inactive TZD analogs which, although devoid of PPARgamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARgamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARgamma-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARgamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.
- Published
- 2006
- Full Text
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15. ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients.
- Author
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Di Cristofaro J, Vasko V, Savchenko V, Cherenko S, Larin A, Ringel MD, Saji M, Marcy M, Henry JF, Carayon P, and De Micco C
- Subjects
- Adult, Aged, Carcinoma, Papillary epidemiology, Child, France epidemiology, Gene Rearrangement, Humans, Middle Aged, Neoplasms, Radiation-Induced epidemiology, Nuclear Receptor Coactivators, Oncogene Proteins, Fusion, Protein-Tyrosine Kinases, Thyroid Neoplasms epidemiology, Ukraine epidemiology, Carcinoma, Papillary etiology, Neoplasms, Radiation-Induced etiology, Oncogene Proteins genetics, Radioactive Hazard Release, Thyroid Neoplasms etiology, Transcription Factors genetics
- Abstract
Like children exposed to Chernobyl fallout, the workers who cleaned up after the accident, also known as liquidators, have exhibited an increased incidence of thyroid cancer. A high prevalence of ret/PTC3 rearrangement has been found in pediatric post-Chernobyl thyroid tumors, but this feature has not been investigated in liquidator thyroid tumors. In this study we analyzed the prevalence of ret/PTC1 and ret/PTC3 in thyroid tumors from 21 liquidators, 31 nonirradiated adult Ukrainian patients, and 34 nonirradiated adult French patients. ret rearrangements in carcinomas were found in 83.3% of liquidators, 64.7% of Ukrainian patients, and 42.9% of French patients. The prevalence of ret/PTC1 was statistically similar in the three groups. The prevalence of ret/PTC3 was significantly higher in liquidators than in French patients (P = 0.03) but it was also high in nonirradiated Ukrainian patients who exhibited values intermediate between liquidators and French patients. In adenomas the prevalence of rearrangement was significantly higher in all Ukrainians than in French patients (P = 0.004). Like children exposed to Chernobyl fallout, liquidators showed a high prevalence of ret/PTC3. This finding suggests that irradiation had the same effect regardless of age. However, given the high rate of ret/PTC3 in nonirradiated adult Ukrainians, the possibility of genetic susceptibility or low-level exposure to radiation in that group cannot be excluded.
- Published
- 2005
- Full Text
- View/download PDF
16. Controversies in the follow-up and management of well-differentiated thyroid cancer.
- Author
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Ringel MD and Ladenson PW
- Subjects
- Follow-Up Studies, Humans, Iodine Radioisotopes therapeutic use, Neoplasm Staging, RNA, Messenger analysis, Thyroglobulin, Thyroid Neoplasms surgery, Thyrotropin therapeutic use, Thyroid Neoplasms diagnosis, Thyroid Neoplasms therapy
- Abstract
Thyroid cancer is a common malignancy with an apparent increasing incidence and a wide spectrum of clinical behavior and therapeutic responsiveness. Recent advances in diagnosis, primary treatment, and long-term monitoring have led to enhanced detection of primary and recurrent disease and improvements in therapy. Controversy still surrounds several issues: the most accurate predictive staging system and histological subclassification scheme, optimal preoperative assessment and surgical extent, appropriate use of radioiodine for remnant ablation, goal for thyrotropin-suppressive thyroid hormone therapy, best practices in immediate postoperative and long-term monitoring, and approach to the patient with thyroglobulin evidence of residual disease. In this paper, recent data related to these controversial issues are critically reviewed.
- Published
- 2004
- Full Text
- View/download PDF
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