X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 2 ( 2017-01-15), p. 430-440
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 2 ( 2017-01-15), p. 430-440
    Abstract: Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. Experimental Design: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1–CDK4–Rb–E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430–40. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-0914
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer
    The Endocrine Society ; 2017
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 102, No. 7 ( 2017-07-01), p. 2268-2280
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 102, No. 7 ( 2017-07-01), p. 2268-2280
    Abstract: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated. Objective: To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models. Design: We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells. Results: JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling. Conclusions: These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2016-3771
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2017
    detail.hit.zdb_id: 2026217-6
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    Regulation of cancer stem cell activity by thyroid hormone receptor β
    Springer Science and Business Media LLC ; 2022
    In:  Oncogene Vol. 41, No. 16 ( 2022-04-15), p. 2315-2325
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 41, No. 16 ( 2022-04-15), p. 2315-2325
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-022-02242-9
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2008404-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    Distinct DNA Methylation Signatures in Neuroendocrine Tumors Specific for Primary Site and Inherited Predisposition
    The Endocrine Society ; 2020
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 105, No. 10 ( 2020-10-01), p. 3285-3294
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 105, No. 10 ( 2020-10-01), p. 3285-3294
    Abstract: To compare the deoxyribonucleic acid (DNA) methylation signature of neuroendocrine tumors (NETs) by primary tumor site and inherited predisposition syndromes von Hippel–Lindau disease (VHL) and multiple endocrine neoplasia type 1 (MEN1). Methods Genome-wide DNA methylation (835 424 CpGs) of 96 NET samples. Principal components analysis (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures. Results Hypomethylated CpGs were significantly more common in VHL-related versus sporadic and MEN1-related NETs (P & lt; .001 for both comparisons). Small-intestinal NETs (SINETs) had the most differentially methylated CpGs, either hyper- or hypomethylated, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, P & lt; .001 for all comparisons). There was complete separation of SINETs on PCA, and 3 NETs of unknown origin clustered with the SINET samples. Sporadic, VHL-related, and MEN1-related PNETs formed distinct groups on PCA, and VHL clustered separately, showing pronounced DNA hypomethylation, while sporadic and MEN1-related NETs clustered together. MEN1-related PNETs, DNETs, and gastric NETs each had a distinct DNA methylome signature, with complete separation by PCA and unsupervised clustering. Finally, we identified 12 hypermethylated CpGs in the 1A promoter of the APC (adenomatous polyposis coli) gene, with higher methylation levels in MEN1-related NETs versus VHL-related and sporadic NETs (P & lt; .001 for both comparisons). Conclusions DNA CpG methylation profiles are unique in different primary NET types even when occurring in MEN1-related NETs. This tumor DNA methylome signature may be utilized for noninvasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgaa477
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2026217-6
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 5
    Online Resource
    Online Resource
    Immunohistochemical Loss of Succinate Dehydrogenase Subunit A (SDHA) in Gastrointestinal Stromal Tumors (GISTs) Signals SDHA Germline Mutation
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  American Journal of Surgical Pathology Vol. 37, No. 2 ( 2013-02), p. 234-240
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. 2 ( 2013-02), p. 234-240
    Type of Medium: Online Resource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0b013e3182671178
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 2029143-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 6
    Online Resource
    Online Resource
    Abstract 366: A novel transcript variant of androgen receptor identified in circulating tumor cells from castration-resistant prostate cancer patients as a potentially prognostic biomarker
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 366-366
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 366-366
    Abstract: Circulating tumor cells (CTCs) are rare cancer cells in the bloodstream thought to have a key role in cancer metastasis. There are enormous interests in their analysis for castration-resistant prostate cancer (CRPC) due to their tendency to metastasize to bone. In this study, we applied a surface marker-independent microfluidic device for CTCs capture and retrieval that is based on cell size and deformability. Our device was able to capture 90% and recover 30% of tumor cells in spike experiments. We also developed and validated assays capable of detecting the transcript levels of selected molecular markers in single cells prepared with C1TM Single-Cell AutoPrep System. Blood samples drawn from 34 CRPC patients and 10 primary prostate cancer patients (PPC) were preceded for CTC isolation and molecular characterization. We found that 73% CRPC patients and 10% PPC patients were positive for EpCAM, and only about half of the EpCAM-positive CRPC cases were PSA or AR positive. It is interesting that while there is a strong association between AR and PSA expression in CTC samples, there is no correlation between AR or PSA transcripts in CTCs and serum PSA protein levels in CRPC patients. The positive detection of AR or PSA, but not EpCAM is statistically associated with poor prognosis of the CRPC patients. Very intriguingly, we identified a novel androgen receptor (AR) transcript variant -ARv from four CRPC patients’ CTCs. This ARv lacks a 554bp sequence region in the ligand binding domain (LBD), resulting in a loss of the entire LBD. Clinical data analysis revealed that the ARv is significantly associated with worse survival of CRPC patients (p & lt;0.0001). In vitro functional studies showed this novel ARv is constitutively active in the absence of testosterone. Our findings suggest that this AR variant might contribute to the late stage progression of the diseases and could be used as a potential indicator for alternative therapies. In summary, our new fluidic device is capable of isolating CTC to enable molecular marker analysis, providing value in prognosis and guidance to therapy. Citation Format: Zhigang Kang, Avani Shah, Yunkai Yu, Yuelin Zhu, Ali Asgar Bhagat, Kyra Zhao, Andrew Wu, James Gao, Ravi Madan, James Gulley, William Dahut, Paul Meltzer, Liang Cao. A novel transcript variant of androgen receptor identified in circulating tumor cells from castration-resistant prostate cancer patients as a potentially prognostic biomarker. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2015-366
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-366
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 7
    Online Resource
    Online Resource
    Author Correction: Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans
    Springer Science and Business Media LLC ; 2020
    In:  Nature Communications Vol. 11, No. 1 ( 2020-01-30)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-01-30)
    Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-020-14448-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2553671-0
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 8
    Online Resource
    Online Resource
    Negative Regulation of TSHα Target Gene by Thyroid Hormone Involves Histone Acetylation and Corepressor Complex Dissociation
    The Endocrine Society ; 2009
    In:  Molecular Endocrinology Vol. 23, No. 5 ( 2009-05-01), p. 600-609
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 23, No. 5 ( 2009-05-01), p. 600-609
    Abstract: Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T3) decreased transcription, and surprisingly increased histone acetylation, of TSHα promoter. This increase was mediated directly by thyroid hormone receptor. Histone acetylation of H3K9 and H3K18 sites, two modifications usually associated with transcriptional activation, occur in negative regulation of TSHα promoter. T3 also caused release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin β-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSHα promoter in chromatin immunoprecipitation assays. NCoR and HDAC3 overexpression selectively increased ligand-independent basal transcription. Two histone acetyltransferase inhibitors increased overall transcription but did not abrogate negative regulation or NCoR/HDAC3 complex release by T3. Chromatin immunoprecipitation analyses of an endogenous positively regulated target gene showed increased histone acetylation and corepressor complex release with T3 treatment. Finally, microarray analyses suggested there is a subset of negatively regulated genes with increased histone acetylation. These findings demonstrate the critical role of NCoR/HDAC3 complex in negative regulation of TSHα gene expression and show that similar complexes and overlapping epigenetic modifications can participate in both negative and positive transcriptional regulation.
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/me.2008-0389
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2009
    detail.hit.zdb_id: 1492112-1
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 9
    Online Resource
    Online Resource
    Abstract 1719: Down-regulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1719-1719
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1719-1719
    Abstract: Agents targeting the insulin-like growth factor-1 receptor (IGF1R) are in clinical development, but, despite some initial success of single agents in sarcoma, response rates are low with brief durations. Thus, it is important to identify markers predictive of response, to understand mechanisms of resistance, and to explore combination therapies. In this study, we found that, while associated with PAX3-FKHR translocation, increased IGF1R level is an independent prognostic marker for worse overall survival, particularly in patients with PAX3-FKHR-positive rhabdomyosarcoma (RMS). IGF1R antibody-resistant RMS cells were generated using an in vivo model. Expression analysis indicated that IGFBP2 is both the most affected gene in the IGF signaling pathway and the most significantly down-regulated gene in the resistant lines, indicating that there is a strong selection to repress IGFBP2 expression in tumor cells resistant to IGF1R antibody. IGFBP2 is inhibitory to IGF1R phosphorylation and its signaling. Similar to antibodies to IGF1/2 or IGF2, the addition of exogenous IGFBP2 potentiates the activity of IGF1R antibody against the RMS cells, and it reverses the resistance to IGF1R antibody. In contrast to IGF1R, lower expression of IGFBP2 is associated with poorer overall survival, consistent with its inhibitory activity found in this study. Finally, blocking downstream AKT activation with PI3K- or mTOR-specific inhibitors significantly sensitized the resistant cells to the IGF1R antibody. These findings show that constitutive IGFBP2 down-regulation may represent a novel mechanism for acquired resistance to IGF1R therapeutic antibody in vivo and suggest various drug combinations to enhance antibody activity and to overcome resistance. Citation Format: Zhigang Kang, Yunkai Yu, Yuelin J. Zhu, Lee Helman, Paul Meltzer, Liang Cao. Down-regulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1719. doi:10.1158/1538-7445.AM2014-1719
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1719
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 10
    Online Resource
    Online Resource
    SUN-115 Distinct DNA Methylation Signature in Neuroendocrine Tumors of Different Primary Sites and Hereditary Predisposition
    The Endocrine Society ; 2020
    In:  Journal of the Endocrine Society Vol. 4, No. Supplement_1 ( 2020-05-08)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 4, No. Supplement_1 ( 2020-05-08)
    Abstract: Objective There is scant data of the genome-wide methylome alterations in neuroendocrine tumors (NET). Thus, the goal of this study was to compare the DNA methylation signature of NETs with respect to various primary sites and inherited genetic predisposition syndromes including von Hippel-Lindau (VHL) and multiple endocrine neoplasia type 1 (MEN1). Methods Genome-wide DNA methylation analysis of 96 NETs (primary and metastatic) was performed by using the Illumina Infinium EPIC Array. Principal component analysis (PCA) and unsupervised clustering analyses were performed to identify distinct methylome signatures. The methylation status of genetic drivers such as APC were assessed by primary site. Results A total of 835,424 CpGs methylation sites were quantified. Hypermethylated CpG sites were detected more frequently in sporadic vs. MEN1-related vs. VHL-related NETs, respectively (p & lt; 0.001 for all comparisons), while hypomethylated CpGs sites were more common in VHL-related NETs vs. sporadic and MEN1-related NETs (p & lt;0.001 for both comparisons). Small-intestinal NETs (SINETs) had the most differences at CpGs with the highest number of hyper- and hypomethylated CpG sites, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, p & lt;0.001 for all comparisons). PCA showed distinct clustering of SINETs and three NETs of unknown primary. Sporadic, VHL-related and MEN1-related PNETs formed distinct groups on PCA. VHL-related NETs clustered separately showing pronounced CpG hypomethylation, while sporadic and MEN1-related NETs clustered together showing relative CpG hypermethylation. In a subgroup analysis, MEN1-related SINETs, DNETs and gastric NETs had distinct methylome signatures, respectively, with complete separation by PCA and unsupervised hierarchical clustering. Furthermore, we found CpG hypermethylation in the APC (adenomatous polyposis coli) gene, specifically in the 1A promoter, with higher methylation levels in gastric- and DNETs vs. SINETs, PNETs and NETs of unknown primary (p & lt; 0.001 for all comparisons). Conclusion Various primary NET sites and genetically predisposed MEN1-related NETs have distinct DNA CpG methylation signatures. The methylome signatures identified in this study may be useful for non-invasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or circulating tumor DNA.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvaa046.1560
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2881023-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages