Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma
Background: Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase ( DIO3 , D3) has been shown to be reactivated in human neoplasias. Here, we evaluated DIO3 expression in...
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| Veröffentlicht in: | Thyroid (New York, N.Y.) N.Y.), 2012-09, Vol.22 (9), p.897-904 |
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| creator | Romitti, Mírian Wajner, Simone Magagnin Zennig, Nadja Goemann, Iuri Martin Bueno, Ana Laura Meyer, Erika L. Souza Maia, Ana Luiza |
| description | Background:
Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase (
DIO3
, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated
DIO3
expression in human papillary thyroid carcinoma (PTC).
Methods:
Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records.
DIO3
mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of
DIO3
gene regulation were performed in a human PTC-derived cell line (K1 cells).
BRAF
V600E
mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody.
Results:
Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTC-derived cells,
DIO3
transcripts were further upregulated by the transforming growth factor β1 (TGFβ1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased
DIO3
mRNA levels and blocked the TGFβ1-induced increase in
DIO3
transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly,
DIO3
mRNA and activity levels were significantly higher in
BRAF
V600E
-mutated samples (
p
=0.001). Increased D3 activity was correlated with tumor size (
r
=0.68,
p
=0.003), and associated with lymph node (
p
=0.03) or distant metastasis (
p
=0.006) at diagnosis. Conversely, decreased levels of the thyroid-hormone-activating type 2 deiodinase (
DIO2
) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples.
Conclusions:
These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in
DIO3
and
DIO2
expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentr |
| doi_str_mv | 10.1089/thy.2012.0031 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1036876414</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1036876414</sourcerecordid><originalsourceid>FETCH-LOGICAL-c337t-eeb57f917277960413e6fa6ba0483cf075ee6696fa2de210d1dba6fc2a38d91f3</originalsourceid><addsrcrecordid>eNqFkD1PwzAQhi0EoqUwsiKPLCn-SOx4RKVApUowlDly4otqlDjBTiXy73HUwsp0p1ePXt09CN1SsqQkVw_DflwyQtmSEE7P0JxmmUwUkfI87iQjiWSZmKGrED4JoSKX_BLNGMsZVyqbo_XGVR50AIN3Yw-Y4yewnbEuRnj93XsIwXYOW4ffdW-bRvsR7_aj76zBK-0r67pWX6OLWjcBbk5zgT6e17vVa7J9e9msHrdJxbkcEoAyk7WikkmpBEkpB1FrUWqS5ryqicwAhFAxYwYYJYaaUou6YprnRtGaL9D9sbf33dcBwlC0NlQQr3LQHUJBCY8fipSmEU2OaOW7EDzURe9tG6-PUDGZK6K5YjJXTOYif3eqPpQtmD_6V1UE-BGYYu1cY6EEP_xT-wODh3p6</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1036876414</pqid></control><display><type>article</type><title>Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Romitti, Mírian ; Wajner, Simone Magagnin ; Zennig, Nadja ; Goemann, Iuri Martin ; Bueno, Ana Laura ; Meyer, Erika L. Souza ; Maia, Ana Luiza</creator><creatorcontrib>Romitti, Mírian ; Wajner, Simone Magagnin ; Zennig, Nadja ; Goemann, Iuri Martin ; Bueno, Ana Laura ; Meyer, Erika L. Souza ; Maia, Ana Luiza</creatorcontrib><description>Background:
Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase (
DIO3
, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated
DIO3
expression in human papillary thyroid carcinoma (PTC).
Methods:
Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records.
DIO3
mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of
DIO3
gene regulation were performed in a human PTC-derived cell line (K1 cells).
BRAF
V600E
mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody.
Results:
Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTC-derived cells,
DIO3
transcripts were further upregulated by the transforming growth factor β1 (TGFβ1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased
DIO3
mRNA levels and blocked the TGFβ1-induced increase in
DIO3
transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly,
DIO3
mRNA and activity levels were significantly higher in
BRAF
V600E
-mutated samples (
p
=0.001). Increased D3 activity was correlated with tumor size (
r
=0.68,
p
=0.003), and associated with lymph node (
p
=0.03) or distant metastasis (
p
=0.006) at diagnosis. Conversely, decreased levels of the thyroid-hormone-activating type 2 deiodinase (
DIO2
) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples.
Conclusions:
These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in
DIO3
and
DIO2
expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentration on the thyroid tumor cell proliferation or/and dedifferentiation.</description><identifier>ISSN: 1050-7256</identifier><identifier>EISSN: 1557-9077</identifier><identifier>DOI: 10.1089/thy.2012.0031</identifier><identifier>PMID: 22823995</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Adult ; Butadienes - pharmacology ; Carcinoma - enzymology ; Carcinoma, Papillary ; Cell Line, Tumor ; Child ; Enzyme Inhibitors - pharmacology ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Imidazoles - pharmacology ; Immunohistochemistry ; Iodide Peroxidase - analysis ; Iodide Peroxidase - biosynthesis ; Male ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - physiology ; Middle Aged ; Mutation ; Nitriles - pharmacology ; Proto-Oncogene Proteins B-raf - genetics ; Pyridines - pharmacology ; Retrospective Studies ; Thyroid Cancer and Nodules ; Thyroid Cancer, Papillary ; Thyroid Neoplasms - enzymology ; Transforming Growth Factor beta1 - metabolism ; Young Adult</subject><ispartof>Thyroid (New York, N.Y.), 2012-09, Vol.22 (9), p.897-904</ispartof><rights>2012, Mary Ann Liebert, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c337t-eeb57f917277960413e6fa6ba0483cf075ee6696fa2de210d1dba6fc2a38d91f3</citedby><cites>FETCH-LOGICAL-c337t-eeb57f917277960413e6fa6ba0483cf075ee6696fa2de210d1dba6fc2a38d91f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22823995$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Romitti, Mírian</creatorcontrib><creatorcontrib>Wajner, Simone Magagnin</creatorcontrib><creatorcontrib>Zennig, Nadja</creatorcontrib><creatorcontrib>Goemann, Iuri Martin</creatorcontrib><creatorcontrib>Bueno, Ana Laura</creatorcontrib><creatorcontrib>Meyer, Erika L. Souza</creatorcontrib><creatorcontrib>Maia, Ana Luiza</creatorcontrib><title>Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma</title><title>Thyroid (New York, N.Y.)</title><addtitle>Thyroid</addtitle><description>Background:
Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase (
DIO3
, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated
DIO3
expression in human papillary thyroid carcinoma (PTC).
Methods:
Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records.
DIO3
mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of
DIO3
gene regulation were performed in a human PTC-derived cell line (K1 cells).
BRAF
V600E
mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody.
Results:
Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTC-derived cells,
DIO3
transcripts were further upregulated by the transforming growth factor β1 (TGFβ1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased
DIO3
mRNA levels and blocked the TGFβ1-induced increase in
DIO3
transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly,
DIO3
mRNA and activity levels were significantly higher in
BRAF
V600E
-mutated samples (
p
=0.001). Increased D3 activity was correlated with tumor size (
r
=0.68,
p
=0.003), and associated with lymph node (
p
=0.03) or distant metastasis (
p
=0.006) at diagnosis. Conversely, decreased levels of the thyroid-hormone-activating type 2 deiodinase (
DIO2
) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples.
Conclusions:
These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in
DIO3
and
DIO2
expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentration on the thyroid tumor cell proliferation or/and dedifferentiation.</description><subject>Adult</subject><subject>Butadienes - pharmacology</subject><subject>Carcinoma - enzymology</subject><subject>Carcinoma, Papillary</subject><subject>Cell Line, Tumor</subject><subject>Child</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Immunohistochemistry</subject><subject>Iodide Peroxidase - analysis</subject><subject>Iodide Peroxidase - biosynthesis</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Nitriles - pharmacology</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Pyridines - pharmacology</subject><subject>Retrospective Studies</subject><subject>Thyroid Cancer and Nodules</subject><subject>Thyroid Cancer, Papillary</subject><subject>Thyroid Neoplasms - enzymology</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Young Adult</subject><issn>1050-7256</issn><issn>1557-9077</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkD1PwzAQhi0EoqUwsiKPLCn-SOx4RKVApUowlDly4otqlDjBTiXy73HUwsp0p1ePXt09CN1SsqQkVw_DflwyQtmSEE7P0JxmmUwUkfI87iQjiWSZmKGrED4JoSKX_BLNGMsZVyqbo_XGVR50AIN3Yw-Y4yewnbEuRnj93XsIwXYOW4ffdW-bRvsR7_aj76zBK-0r67pWX6OLWjcBbk5zgT6e17vVa7J9e9msHrdJxbkcEoAyk7WikkmpBEkpB1FrUWqS5ryqicwAhFAxYwYYJYaaUou6YprnRtGaL9D9sbf33dcBwlC0NlQQr3LQHUJBCY8fipSmEU2OaOW7EDzURe9tG6-PUDGZK6K5YjJXTOYif3eqPpQtmD_6V1UE-BGYYu1cY6EEP_xT-wODh3p6</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Romitti, Mírian</creator><creator>Wajner, Simone Magagnin</creator><creator>Zennig, Nadja</creator><creator>Goemann, Iuri Martin</creator><creator>Bueno, Ana Laura</creator><creator>Meyer, Erika L. Souza</creator><creator>Maia, Ana Luiza</creator><general>Mary Ann Liebert, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120901</creationdate><title>Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma</title><author>Romitti, Mírian ; Wajner, Simone Magagnin ; Zennig, Nadja ; Goemann, Iuri Martin ; Bueno, Ana Laura ; Meyer, Erika L. Souza ; Maia, Ana Luiza</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c337t-eeb57f917277960413e6fa6ba0483cf075ee6696fa2de210d1dba6fc2a38d91f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Butadienes - pharmacology</topic><topic>Carcinoma - enzymology</topic><topic>Carcinoma, Papillary</topic><topic>Cell Line, Tumor</topic><topic>Child</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Immunohistochemistry</topic><topic>Iodide Peroxidase - analysis</topic><topic>Iodide Peroxidase - biosynthesis</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Nitriles - pharmacology</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Pyridines - pharmacology</topic><topic>Retrospective Studies</topic><topic>Thyroid Cancer and Nodules</topic><topic>Thyroid Cancer, Papillary</topic><topic>Thyroid Neoplasms - enzymology</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Romitti, Mírian</creatorcontrib><creatorcontrib>Wajner, Simone Magagnin</creatorcontrib><creatorcontrib>Zennig, Nadja</creatorcontrib><creatorcontrib>Goemann, Iuri Martin</creatorcontrib><creatorcontrib>Bueno, Ana Laura</creatorcontrib><creatorcontrib>Meyer, Erika L. Souza</creatorcontrib><creatorcontrib>Maia, Ana Luiza</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Thyroid (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Romitti, Mírian</au><au>Wajner, Simone Magagnin</au><au>Zennig, Nadja</au><au>Goemann, Iuri Martin</au><au>Bueno, Ana Laura</au><au>Meyer, Erika L. Souza</au><au>Maia, Ana Luiza</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma</atitle><jtitle>Thyroid (New York, N.Y.)</jtitle><addtitle>Thyroid</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>22</volume><issue>9</issue><spage>897</spage><epage>904</epage><pages>897-904</pages><issn>1050-7256</issn><eissn>1557-9077</eissn><abstract>Background:
Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase (
DIO3
, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated
DIO3
expression in human papillary thyroid carcinoma (PTC).
Methods:
Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records.
DIO3
mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of
DIO3
gene regulation were performed in a human PTC-derived cell line (K1 cells).
BRAF
V600E
mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody.
Results:
Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTC-derived cells,
DIO3
transcripts were further upregulated by the transforming growth factor β1 (TGFβ1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased
DIO3
mRNA levels and blocked the TGFβ1-induced increase in
DIO3
transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly,
DIO3
mRNA and activity levels were significantly higher in
BRAF
V600E
-mutated samples (
p
=0.001). Increased D3 activity was correlated with tumor size (
r
=0.68,
p
=0.003), and associated with lymph node (
p
=0.03) or distant metastasis (
p
=0.006) at diagnosis. Conversely, decreased levels of the thyroid-hormone-activating type 2 deiodinase (
DIO2
) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples.
Conclusions:
These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in
DIO3
and
DIO2
expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentration on the thyroid tumor cell proliferation or/and dedifferentiation.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>22823995</pmid><doi>10.1089/thy.2012.0031</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1050-7256 |
| ispartof | Thyroid (New York, N.Y.), 2012-09, Vol.22 (9), p.897-904 |
| issn | 1050-7256 1557-9077 |
| language | eng |
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| source | MEDLINE; Alma/SFX Local Collection |
| subjects | Adult Butadienes - pharmacology Carcinoma - enzymology Carcinoma, Papillary Cell Line, Tumor Child Enzyme Inhibitors - pharmacology Female Gene Expression Regulation, Neoplastic - drug effects Humans Imidazoles - pharmacology Immunohistochemistry Iodide Peroxidase - analysis Iodide Peroxidase - biosynthesis Male MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology Middle Aged Mutation Nitriles - pharmacology Proto-Oncogene Proteins B-raf - genetics Pyridines - pharmacology Retrospective Studies Thyroid Cancer and Nodules Thyroid Cancer, Papillary Thyroid Neoplasms - enzymology Transforming Growth Factor beta1 - metabolism Young Adult |
| title | Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma |
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