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Thyroid cancer (TC) is the most common endocrine malignancy. Most TCs have a favorable prognosis, whereas anaplastic thyroid carcinoma (ATC) is a lethal form of cancer. Different genetic and epigenetic alterations have been identified in aggressive forms of TC such as ATC. Non-coding RNAs (ncRNAs) represent functional regulatory molecules that control chromatin reprogramming, including transcriptional and post-transcriptional mechanisms. Intriguingly, they also play an important role as coordinators of complex gene regulatory networks (GRNs) in cancer. GRN analysis can model molecular regulation in different species. Neural networks are robust computing systems for learning and modeling the dynamics or dependencies between genes, and are used for the reconstruction of large data sets. Canonical network motifs are coordinated by ncRNAs through gene production from each transcript as well as through the generation of a single transcript that gives rise to multiple functional products by post-transcriptional modifications. In non-canonical network motifs, ncRNAs interact through binding to proteins and/or protein complexes and regulate their functions. This article overviews the potential role of ncRNAs GRNs in TC. It also suggests prospective applications of deep neural network analysis to predict ncRNA molecular language for early detection and to determine the prognosis of TC. Validation of these analyses may help in the design of more effective and precise targeted therapies against aggressive TC.

Abstract Context Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-β [PDGFR-β]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also targets PDGFR-β. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression. Objectives Develop a gene signature of pericyte abundance to assess with tumor aggressiveness and determine both the response of thyroid-derived pericytes to lenvatinib and their synergies with thyroid carcinoma-derived cells. Design Using a new gene signature, we estimated the relative abundance of pericytes in papillary thyroid carcinoma (PTC) and normal thyroid (NT) TCGA samples. We also cocultured CD90+;PAX8- thyroid-derived pericytes and BRAFWT/V600E-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response. Results Pericyte abundance is significantly higher in BRAFV600E-PTC with hTERT mutations and copy number alterations compared with NT or BRAFWT-PTC samples, even when data are corrected for clinical-pathologic confounders. We have identified upregulated pathways important for tumor survival, immunomodulation, RNA transcription, cell-cycle regulation, and cholesterol metabolism. Pericyte growth is significantly increased by platelet-derived growth factor-BB, which activates phospho(p)-PDGFR-β, pERK1/2, and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT, and p-p70S6-kinase downstream PDGFR-β. Critically, lenvatinib significantly induces higher BRAFWT/V600E-PTC cell death when cocultured with pericytes, as a result of pericyte targeting via PDGFR-β. Conclusions This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib.

Abstract Background Management of patients with thyroid nodules is based on establishing an accurate diagnosis; however, differentiating benign from malignant lesions preoperatively is not always possible using current cytological techniques. Novel molecular testing on cytological material could lead to clearer treatment algorithms. B-RafV600E mutation is the most common genetic alteration in thyroid cancer, specifically found in papillary thyroid cancer (PTC), and usually reported to be associated with aggressive disease. Data source A literature search using PubMed identified all the pertinent literature on the identification and utilization of the B-RafV600E mutation in thyroid cancer. Conclusions The utility of using B-Raf mutation testing for nodules with indeterminate cytology is limited since many of those nodules (benign and malignant) do not harbor B-Raf mutations. However, when the pathologist sees cytological features suspicious for PTC, B-RafV600E mutation analysis may enhance the assessment of preoperative risks for PTC, directing a more aggressive initial surgical management when appropriate.

Context: Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-[beta] [PDGFR-[beta]]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also targets PDGFR-[beta]. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression. Objectives: Develop a gene signature of pericyte abundance to assess with tumor aggressiveness and determine both the response of thyroid-derived pericytes to lenvatinib and their synergies with thyroid carcinoma-derived cells. Design: Using a new gene signature, we estimated the relative abundance of pericytes in papillary thyroid carcinoma (PTC) and normal thyroid (NT) TCGA samples. We also cocultured CD90+;PAX8- thyroid-derived pericytes and BRA[F.sup.WT/V600E]-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response. Results: Pericyte abundance is significantly higher in BRA[F.sup.V600E]-PTC with hTERT mutations and copy number alterations compared with NT or BRA[F.sup.WT]-PTC samples, even when data are corrected for clinical-pathologic confounders. We have identified upregulated pathways important for tumor survival, immunomodulation, RNA transcription, cell-cycle regulation, and cholesterol metabolism. Pericyte growth is significantly increased by platelet-derived growth factor-BB, which activates phospho(p)-PDGFR-[beta], pERK1/2, and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT, and p-p70S6-kinase downstream PDGFR-[beta]. Critically, lenvatinib significantly induces higher BRA[F.sup.WT/V600E]-PTC cell death when cocultured with pericytes, as a result of pericyte targeting via PDGFR-[beta]. Conclusions: This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib. Key Words: thyroid cancer, pericyte, lenvatinib, PDGFR-[beta], BRA[F.sup.V600E], microenvironment

Although B-Raf V600E is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf V600E gene set signature associated with tumor progression in PTCs. An independent cohort of B-Raf V600E -positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-Raf V600E resulted in TSP-1 down-regulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-Raf V600E cells in which either B-Raf V600E or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-Raf V600E , caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-Raf V600E plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patient's thyroid cancer for B-Raf V600E will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-Raf V600E inhibitors, such as PLX4720.

Although B-Raf(V600E) is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf(V600E) gene set signature associated with tumor progression in PTCs. An independent cohort of B-Raf(V600E)-positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-Raf(V600E) resulted in TSP-1 down-regulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-Raf(V600E) cells in which either B-Raf(V600E) or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-Raf(V600E), caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-Raf(V600E) plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patient's thyroid cancer for B-Raf(V600E) will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-Raf(V600E) inhibitors, such as PLX4720.

Background Management of patients with thyroid nodules is based on establishing an accurate diagnosis; however, differentiating benign from malignant lesions preoperatively is not always possible using current cytological techniques. Novel molecular testing on cytological material could lead to clearer treatment algorithms. B-RafV600Emutation is the most common genetic alteration in thyroid cancer, specifically found in papillary thyroid cancer (PTC), and usually reported to be associated with aggressive disease. Data source A literature search using PubMed identified all the pertinent literature on the identification and utilization of the B-RafV600Emutation in thyroid cancer. Conclusions The utility of using B-Raf mutation testing for nodules with indeterminate cytology is limited since many of those nodules (benign and malignant) do not harbor B-Raf mutations. However, when the pathologist sees cytological features suspicious for PTC, B-RafV600Emutation analysis may enhance the assessment of preoperative risks for PTC, directing a more aggressive initial surgical management when appropriate.

Management of patients with thyroid nodules is based on establishing an accurate diagnosis; however, differentiating benign from malignant lesions preoperatively is not always possible using current cytological techniques. Novel molecular testing on cytological material could lead to clearer treatment algorithms. B-Raf V600E mutation is the most common genetic alteration in thyroid cancer, specifically found in papillary thyroid cancer (PTC), and usually reported to be associated with aggressive disease. A literature search using PubMed identified all the pertinent literature on the identification and utilization of the B-Raf V600E mutation in thyroid cancer. The utility of using B-Raf mutation testing for nodules with indeterminate cytology is limited since many of those nodules (benign and malignant) do not harbor B-Raf mutations. However, when the pathologist sees cytological features suspicious for PTC, B-Raf V600E mutation analysis may enhance the assessment of preoperative risks for PTC, directing a more aggressive initial surgical management when appropriate.

Even though several studies highlighted the role of maternal thyroid hormones (THs) during embryo–foetal development, direct evidence of their interaction with embryonic thyroid receptors (TRs) is still lacking. We generated a transgenic mouse model ubiquitously expressing a reporter gene tracing TH action during development. We engineered a construct (TRE2×) containing two TH‐responsive elements controlling the expression of the LacZ reporter gene, which encodes β‐galactosidase (β‐gal). The specificity of the TRE2× activation by TH was evaluated in NIH3T3 cells by cotransfecting TRE2× along with TRs, retinoic or oestrogen receptors in the presence of their specific ligands. TRE2× transgene was microinjected into the zygotes, implanted in pseudopregnant BDF1 (a first‐generation (F1) hybrid from a cross of C57BL/6 female and a DBA/2 male) mice and transgenic mouse models were developed. β‐gal expression was assayed in tissue sections of transgenic mouse embryos at different stages of development. In vitro, TRE2× transactivation was observed only following physiological T3 stimulation, mediated exclusively by TRs. In vivo, β‐gal staining, absent until embryonic day 9.5–10.5 (E9.5–E10.5), was observed as early as E11.5–E12.5 in different primordia (i.e. central nervous system, sense organs, intestine, etc.) of the TRE2× transgenic embryos, while the foetal thyroid function (FTF) was still inactive. Immunohistochemistry for TRs essentially colocalized with β‐gal staining. No β‐gal staining was detected in embryos of hypothyroid transgenic mice. Importantly, treatment with T3 in hypothyroid TRE2× transgenic mice rescued β‐gal expression. Our results provide in vivo direct evidence that during embryonic life and before the onset of FTF, maternal THs are transcriptionally active through the action of embryonic TRs. This model may have clinical relevance and may be employed to design end‐point assays for new molecules affecting THs action.

Although B-Raf... is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf... gene set signature associated with tumor progression in PTCs. An independent cohort of B-RafV600E-positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-Raf... resulted in TSP-1 down-regulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-Raf... cells in which either B-Raf... or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-Raf..., caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-Raf... plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patient's thyroid cancer for B-Raf... will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-Raf... inhibitors, such as PLX4720. (ProQuest: ... denotes formulae/symbols omitted.)