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Sheueyann Cheng - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of tumorigenesis by the Thyroid hormone receptor β in xenograft models
    Thyroid, 2014
    Co-Authors: Won Gu Kim, Mark C Willingham, Li Zhao, Dong Wook Kim, Sheueyann Cheng
    Abstract:

    Background: Previous studies showed a close association between several types of human Cancers and somatic mutations of Thyroid hormone receptor β (TRβ) and reduced expression of TRβ due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TRβ could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TRβ could function to inhibit tumorigenesis are less well understood. Methods: We used the human Follicular Thyroid Cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TRβ on Cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. Results: Expression of TRβ in FTC-133 cells, as compared with control FTC cells without TRβ, reduced Cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70 S6K pat...

  • role of tsh in the spontaneous development of asymmetrical Thyroid carcinoma in mice with a targeted mutation in a single allele of the Thyroid hormone β receptor
    Endocrinology, 2012
    Co-Authors: Li Zhao, Mark C Willingham, Jeong Won Park, Laura Fozzatti, Sheueyann Cheng
    Abstract:

    Mutations of the Thyroid hormone receptor-β gene (THRB) cause resistance to Thyroid hormone (RTH). A mouse model of RTH harboring a homozygous Thyroid hormone receptor (TR)-β mutation known as PV (ThrbPV/PV mouse) spontaneously develops Follicular Thyroid Cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the ThrbPV/PV mouse exhibits elevated Thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous ThrbPV/+ mouse with mildly elevated TSH (∼2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in ThrbPV/+ mice under stimulation by high TSH. ThrbPV/+ mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. ThrbPV/+mice treated with PTU (ThrbPV/+-PTU) spontaneously developed FTC similar to human Thyroid Cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of ThrbPV/+-PTU mice developed asy...

  • inhibition of phosphatidylinositol 3 kinase delays tumor progression and blocks metastatic spread in a mouse model of Thyroid Cancer
    Carcinogenesis, 2007
    Co-Authors: Fumihiko Furuya, Mark C Willingham, Sheueyann Cheng
    Abstract:

    Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B-signaling pathway has been associated with multiple human Cancers, including Thyroid Cancer. Recently, we showed that, similar to human Thyroid Cancer, the PI3K-AKT pathway is overactivated in both the Thyroid and metastatic lesions of a mouse model of Follicular Thyroid carcinoma (TRbeta(PV/PV) mice). This TRbeta(PV/PV) mouse harbors a knockin mutant Thyroid hormone receptor beta gene (TRbetaPV mutant) that spontaneously develops Thyroid Cancer and distant metastasis similar to human Follicular Thyroid Cancer. That the activation of the PI3K-AKT signaling contributes to Thyroid carcinogenesis raised the possibility that this pathway could be a potential therapeutic target in Follicular Thyroid carcinoma. The present study tested this possibility by treating TRbeta(PV/PV) mice with LY294002 (LY), a potent and specific PI3K inhibitor, and evaluating the effect of LY on the spontaneous development of Thyroid Cancer. LY treatment inhibited the AKT-mammalian target of rapamycin (mTOR)-p70(S6K) signaling, and it decreased cyclin D1 and increased p27(Kip1) expression to inhibit Thyroid tumor growth and reduce tumor cell proliferation. LY treatment increased caspase 3 and decreased phosphorylated-BAD to induce apoptosis. In addition, LY treatment reduced the AKT-matrix metalloproteinase 2 signaling to decrease cell motility to block metastatic spread of Thyroid tumors. Thus, these altered signaling pathways converged effectively to prolong survival of TRbeta(PV/PV) mice treated with LY. No significant adverse effects were observed for wild-type mice treated similarly with LY. The present study provides the first preclinical evidence for the in vivo efficacy for LY in the treatment of Follicular Thyroid Cancer.

  • gelsolin a novel Thyroid hormone receptor β interacting protein that modulates tumor progression in a mouse model of Follicular Thyroid Cancer
    Endocrinology, 2007
    Co-Authors: Caroline S Kim, Hao Ying, Fumihiko Furuya, Yasuhito Kato, John A Hanover, Sheueyann Cheng
    Abstract:

    Follicular Thyroid Cancer (FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant Thyroid hormone receptor-beta (TRbeta(PV/PV) mouse) that spontaneously develops Thyroid Cancer with metastasis similar to humans has provided new opportunities to study contributors to FTC metastasis. This study evaluates the role of gelsolin, an actin-regulatory protein, in modulating the metastatic potential of FTC. Gelsolin was previously found by cDNA microarray analysis to be down-regulated in TRbeta(PV/PV) mice as compared with wild-type mice. This study found an age-dependent reduction of gelsolin protein abundance in TRbeta(PV/PV) mice as tumorigenesis progressed. Knockdown of gelsolin by small interfering RNA resulted in increased tumor cell motility and increased gelsolin expression by histone deacetylase inhibitor (trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that gelsolin physically interacted with TRbeta1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of gelsolin and the DNA binding domain of TR. The physical interaction of gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local tumor progression and metastatic potential of Thyroid carcinogenesis.

  • the pituitary tumor transforming gene promotes angiogenesis in a mouse model of Follicular Thyroid Cancer
    Carcinogenesis, 2006
    Co-Authors: Caroline S Kim, Hao Ying, Mark C Willingham, Sheueyann Cheng
    Abstract:

    Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops Follicular Thyroid Cancer (FTC) with distant metastasis (TRbPV mouse), PTTG is overexpressed, similar to human Thyroid Cancer. To evaluate the role of PTTG in Thyroid carcinogenesis, we studied the offspring of TRbPV mice with mice lacking PTTG (PTTG � /� mice). The Thyroids of TRb PV/PV PTTG � /� mice were significantly smaller than TRb PV/PV mice. Ki-67 staining showed a decrease in Thyroid proliferation in TRb PV/PV PTTG � /� mice. Our evaluation of the Rb‐E2F pathway, a central mediator of cell growth, found that TRb PV/PV PTTG � /� mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRb PV/PV and TRb PV/PV PTTG � /� mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRb PV/PV PTTG � /� mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease invessel density in TRb PV/PV PTTG � /� versus TRb PV/PV Thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genesinvolvedinangiogenesis.Real-time reverse transcription‐polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of Thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.

Bruno Niederle - One of the best experts on this subject based on the ideXlab platform.

  • Follicular Thyroid carcinoma in an iodine replete endemic goiter region a prospectively collected retrospectively analyzed clinical trial
    Annals of Surgery, 2009
    Co-Authors: Reza Asari, Oskar Koperek, Christian Scheuba, Philipp Riss, Klaus Kaserer, Martha Hoffmann, Bruno Niederle
    Abstract:

    Objective:To determine risk factors for presence of lymph node or distant metastases in patients with Follicular Thyroid Cancer (FTC) at the time of diagnosis and whether there is a relationship between the type of tumor invasion and metastases.Summary Background Data:FTC often presents distant meta

  • the influence of gender age and ret polymorphisms on c cell hyperplasia and medullary Thyroid carcinoma
    Thyroid, 2008
    Co-Authors: Andreas Weinhaeusel, Christian Scheuba, Klaus Kaserer, Martin Lauss, Albert Kriegner, Klemens Vierlinger, Oskar A Haas, Bruno Niederle
    Abstract:

    Background RET germline mutations predispose to the development of hereditary medullary Thyroid carcinoma (hMTC). Several single nucleotide polymorphisms (SNPs) are described associated with sporadic MTC (sMTC). However, the findings regarding their influence on the clinical course and biological behavior of this disorder are discordant. To clarify the contradictory findings, we studied the association of certain SNPs considering age, gender, and histopathology in a large Austrian cohort with C-cell hyperplasia (CCH) and MTC. Methods Genotyping of SNPs located in RET codons 691, 769, 836, and 904 from 199 patients with MTC and CCH (basal calcitonin > 10 pg/mL, pentagastrin stimulated > 100 pg/mL) was performed, and the results were analyzed considering gender, age at diagnosis, and histopathology. Results No significant difference of SNP frequencies was found in the study patients versus normal controls. In sMTC and sporadic CCH (sCCH) no significant association of SNP frequency with the age at diagnosis was found. In patients with sporadic C-cell disease (sCCH and sMTC), 3.7 times more males than females suffered synchronously from papillary or Follicular Thyroid Cancer (20/97 [20.6%] males; 3/54 [5.6%] females; p = 0.02). sCCH was revealed more frequently in males (89/97, 91.7%) than in females (27/54, 50%; p = 10(-8)). In contrast to males, the ratio of CCH to total C-cell disease was significantly higher in females with hereditary (26/32, 81%) compared to those with sporadic disease (27/54, 50%; p = 0.006). Conclusions In this study RET SNPs had no clinical impact on the development of sporadic C-cell disease when the age of diagnosis or gender is considered. C-cell disease seems to predispose males to the development of papillary and Follicular Thyroid Cancer. In addition, at least in females with CCH RET germline mutation, screening is recommended even if the family history is negative for MTC.

  • importance of tumour size in papillary and Follicular Thyroid Cancer
    British Journal of Surgery, 2005
    Co-Authors: Christian Passler, Christian Scheuba, Klaus Kaserer, R Asari, Klaus Kaczirek, Bruno Niederle
    Abstract:

    Background: The most controversial change in the new pathological tumour node metastasis (pTNM) classification of Thyroid tumours is the extension of the pT1 classification to include tumours up to 20 mm. Methods: Four hundred and three patients with pT1 or pT2 differentiated Thyroid carcinomas were divided into three groups according to tumour diameter (group 1, 10 mm or less; group 2, 11–20 mm; group 3, 21–40 mm). They were analysed retrospectively with respect to carcinoma-specific and disease-free survival. Results: No patient in group 1 died from papillary Thyroid carcinoma, compared with three patients in group 2 and six in group 3. There was a statistically significant difference in carcinoma-specific survival between groups 1 and 2 (P = 0·033). Two patients in group 1, six in group 2 and eight in group 3 developed recurrence. The difference in disease-free survival between groups 1 and 2 was significant (P = 0·025). One patient in group 1, three in group 2 and four in group 3 died from Follicular Thyroid carcinoma, but there were no significant differences in survival between the three groups. Conclusion: Extension of the pT1 classification to cover all tumours up to 20 mm does not appear to be justified for papillary Thyroid carcinoma. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

  • prognostic factors of papillary and Follicular Thyroid Cancer differences in an iodine replete endemic goiter region
    Endocrine-related Cancer, 2004
    Co-Authors: Christian Passler, Christian Scheuba, Klaus Kaserer, Klaus Kaczirek, G Prager, Georg Zettinig, Bruno Niederle
    Abstract:

    Papillary (PTC) and Follicular Thyroid carcinoma (FTC) are known as differentiated Thyroid carcinoma (DTC). Nevertheless, according to the UICC/AJCC (TNM) classification PTC and FTC are frequently analyzed as one Cancer. The aim of this study is to show differences in outcome and specific prognostic factors in an iodine-replete endemic goiter region. Six hundred and three patients with DTC treated within a 35-year-period were retrospectively analyzed with respect to carcinoma-specific survival. Prognostic factors were tested for their significance using univariate and multivariate analysis. The histological type (PTC versus FTC) was found to be a highly significant factor - carcinoma-specific survival both in univariate (P or =45 years, positive lymph nodes and increasing tumor size were confirmed as independent prognostic factors. Univariate analysis of FTC patients revealed age at presentation, gender, extraThyroidal tumor spread, lymph node and distant metastases, increasing tumor size, multifocality, widely invasive tumor growth and oxyphilic variant to be factors bearing prognostic significance. The presence of distant metastases and increasing tumor size could be identified as independent prognostic factors for FTC patients. This study shows distinctive differences in prognostic factors of PTC and FTC: independent factors predicting poor prognosis are age > or =45 years, positive lymph nodes and increasing tumor size for PTC, and distant metastases and increasing tumor size for FTC. PTC and FTC patients should be analyzed and reported separately.

Herbert Chen - One of the best experts on this subject based on the ideXlab platform.

  • characterization of somatostatin receptors sstrs expression and antiproliferative effect of somatostatin analogues in aggressive Thyroid Cancers
    Surgery, 2019
    Co-Authors: Danilea Carmona M Matos, Samuel Jang, Baraa A Hijaz, Alexander W Chang, Ricardo V Lloyd, Herbert Chen, Renata Jaskulasztul
    Abstract:

    Abstract Background Certain human carcinomas have demonstrated a distinct expression of somatostatin receptors. Data on somatostatin receptor expression in Follicular Thyroid Cancer and anaplastic Thyroid Cancer has been limited and conflicting. This study seeks to characterize somatostatin receptor expression in Follicular Thyroid Cancer and anaplastic Thyroid Cancer and to assess the effects of somatostatin analogues. Methods Anaplastic Thyroid Cancer (Hth7 and 8505C) and Follicular Thyroid Cancer (FTC-236) (Sigma-Aldrich, St. Louis, MO) cells were cultured. Capillary immunoblotting and reverse transcription polymerase chain reaction (RT-PCR) were used to determine the basal expression of protein and mRNA of SSTR1–SSTR5. Cells were treated with the somatostatin analogues octreotide, pasireotride (SOM230), and KE-108 for 48h. IC50 was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and cell proliferation was measured by viable cell count. Presence of SSTR2 was assessed by immunohistochemistry. Results Immunoblotting analysis demonstrated that most cell lines expressed SSTR1–SSTR3 and SSTR5 in varying degrees. Reverse transcription polymerase chain reaction analysis showed that mRNA expression for SSTR2 and SSTR3 correlated with protein expression. MTT assays showed that KE-108 and SOM230 were able to inhibit cell proliferation. Tissue microarray (TMA) showed that SSTR2 was highly expressed in human tissues of aggressive Thyroid carcinomas. Conclusion Follicular Thyroid Cancer and anaplastic Thyroid Cancer express SSTR1-3 and SSTR5 in distinct fashions both at a message and protein level. Our results suggest that somatostatin receptors are still a relevant and promising drug target against non-medullary Thyroid Cancers.

  • minimally invasive Follicular Thyroid Cancer treat as a benign or malignant lesion
    Journal of Surgical Research, 2017
    Co-Authors: Aaron Robinson, Rebecca S Sippel, David F Schneider, Herbert Chen
    Abstract:

    Abstract Background Follicular Thyroid Cancer is the second most common Thyroid Cancer, accounting for 10%-15% of all cases. Follicular Thyroid carcinomas (FTCs) can be classified into two subtypes: classic (C), which exhibit both vascular and capsular invasion and minimally invasive (MI), which only has limited capsular invasion. Both types, like most well-differentiated Thyroid Cancers, are traditionally treated the same: a completion Thyroidectomy usually followed by radioiodine ablation. We hypothesize that MI-FTC may behave more like a benign Follicular adenoma rather than C-FTC and may not require total Thyroidectomy and radioiodine. Methods A prospective Thyroid database was screened for patients with Follicular cell tumors. Data on recurrence rates, disease-free survival, and requirement for follow-up surgery and/or radioiodine were compared. Disease-free survival was determined by the Kaplan–Meier method. Analysis of variance and chi-square test were used to evaluate other factors. Results In total, there were 419 benign adenomas (87%), 21 MI-FTCs (4.5%), and 41 C-FTCs (8.5%). Patients with adenomas were younger ( P  = 0.035) and were more likely to be female ( P  = 0.001). Importantly, the 16-y disease-free survival was 100% in the adenoma group, 100% in the MI-FTC group, and 36.6% in the C-FTC group ( P Conclusions MI-FTCs behave similar to adenomas with 100% disease-free survival with up to 16 y of follow-up. These data suggest MI-FTCs could be potentially treated by Thyroid lobectomy alone like Follicular adenomas and perhaps should be classified as a distinct clinical entity.

  • lymph node metastases do not impact survival in Follicular variant papillary Thyroid Cancer
    Annals of Surgical Oncology, 2015
    Co-Authors: David F Schneider, Ricardo V Lloyd, Herbert Chen, Dawn M Elfenbein, Rebecca S Sippel
    Abstract:

    Follicular variant of papillary Thyroid Cancer (FVPTC) is the most common and fastest growing subtype of papillary Thyroid Cancer (PTC) with features of both PTC and Follicular Thyroid Cancer (FTC). The purpose of this study was to determine the patient and tumor features associated with lymph node metastases (LNM) in FVPTC. This was a retrospective review of adult (≥18) patients with histologically confirmed diagnoses of FVPTC within the SEER database between 1988 and 2009. LNM were defined by at least two lymph nodes with metastatic disease. To determine factors associated with LNM, we constructed a multivariate logistic regression model from significant variables (p  4 cm (hazards ratio [HR] 5.3, 95% CI 2.2–12.8, p < 0.01) and extraThyroidal extension (HR 8.2, 95% CI 3.0–22.0, p < 0.01) were the strongest predictors of DSM. LNM occur in less than 10% of patients with FVPTC but do not impact DSM. Instead, DSM in FVPTC is related to size and local invasion.

  • in patients with Thyroid Cancer of Follicular cell origin a family history of nonmedullary Thyroid Cancer in one first degree relative is associated with more aggressive disease
    Thyroid, 2012
    Co-Authors: Haggi Mazeh, Herbert Chen, Joy Benavidez, Jennifer L Poehls, Linda M Youngwirth, Rebecca S Sippel
    Abstract:

    Background: About 5% of nonmedullary Thyroid Cancers (NMTCs) are familial. Most patients with a family history of Thyroid Cancer do not meet the definition of familial NMTC (FNMTC; two or more affected family members). The aim of this study was to determine whether patients with a family history of NMTC, but who do not meet the definition of FNMTC, have more aggressive disease. Methods: A database of 1502 Thyroidectomies was reviewed and 358 patients with NMTC who did not have a family history of benign Thyroid disease and who underwent Thyroidectomy from January 1994 to December 2008 were identified. These included 324 (90%) patients with papillary Thyroid carcinoma (PTC), 24 (7%) with Follicular Thyroid Cancer, and 10 (3%) with anaplastic or Hurthle cell carcinoma. Among them, those with and without a family history of NMTC in first-degree relatives were compared. Then patients with only one affected family member were compared with FNMTC patients. Results: Thirty-seven (10%) patients had a family histo...

  • notch1 mediates growth suppression of papillary and Follicular Thyroid Cancer cells by histone deacetylase inhibitors
    Molecular Cancer Therapeutics, 2009
    Co-Authors: Xueming Xiao, Li Ning, Herbert Chen
    Abstract:

    Notch1 is a multifunctional transmembrane receptor that regulates cellular differentiation, development, proliferation, and survival in a variety of contexts. We have previously shown that Notch1 may function as a tumor suppressor and that histone deacetylase (HDAC) inhibitors can induce Notch1 expression in some endocrine Cancers. Here, we showed that although there was minimal Notch1 expression in Follicular Thyroid Cancer FTC236 and papillary Thyroid Cancer DRO cells, transfection of constitutive Notch1 plasmid into these cells led to growth inhibition, down-regulation of cyclin D1, and up-regulation of p21. Treatment of FTC236 cells with HDAC inhibitors valproic acid (1-4 mmol/L) or suberoyl bishydroxamic acid (10-30 micromol/L) induced functional Notch1 protein expression and suppressed cell growth in a dose-dependent manner. Notch1 siRNA interference blocked the antiproliferative effect of HDAC inhibitors. Western blot analysis revealed the reduction of cyclin D1 and the increase of p21 in HDAC inhibitor-treated cells. These results indicate that HDAC inhibitors activate Notch1 signaling in Thyroid Cancer cells and lead to the suppression of proliferation by cell cycle arrest. Our findings provide the first documentation of the role of Notch1 signaling as a tumor suppressor in DRO and FTC236 cells, suggesting that Notch1 activation may be a potential therapeutic target for papillary and Follicular Thyroid Cancers.

Daniela Grimm - One of the best experts on this subject based on the ideXlab platform.

  • proteome analysis of human Follicular Thyroid Cancer cells exposed to the random positioning machine
    International Journal of Molecular Sciences, 2017
    Co-Authors: Johann Bauer, Jirka Grosse, Markus Wehland, Manfred Infanger, Stefan Riwaldt, Sascha Kopp, Elisabeth Maria Schlagberger, Jayashree Sahana, Ronald Luetzenberg, Daniela Grimm
    Abstract:

    Several years ago, we detected the formation of multicellular spheroids in experiments with human Thyroid Cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular mechanisms triggering the cells to leave a monolayer and aggregate to spheroids. Our work focused on spheroid-related changes in gene expression patterns, in protein concentrations, and in factors secreted to the culture supernatant during the period when growth is altered. We detected that factors inducing angiogenesis, the composition of integrins, the density of the cell monolayer exposed to microgravity, the enhanced production of caveolin-1, and the nuclear factor kappa B p65 could play a role during spheroid formation in Thyroid Cancer cells. In this study, we performed a deep proteome analysis on FTC-133 Thyroid Cancer cells cultured under conditions designed to encourage or discourage spheroid formation. The experiments revealed more than 5900 proteins. Their evaluation confirmed and explained the observations mentioned above. In addition, we learned that FTC-133 cells growing in monolayers or in spheroids after RPM-exposure incorporate vinculin, paxillin, focal adhesion kinase 1, and adenine diphosphate (ADP)-ribosylation factor 6 in different ways into the focal adhesion complex.

  • Mechanisms of apoptosis in irradiated and sunitinib-treated Follicular Thyroid Cancer cells
    Apoptosis, 2014
    Co-Authors: Jirka Grosse, Elisabeth Warnke, Jessica Pietsch, Fabian Pohl, Petra Wise, Nils E. Magnusson, Christoph Eilles, Markus Wehland, Daniela Grimm
    Abstract:

    The multikinase inhibitor sunitinib (S) seems to have promising potential in the treatment of Thyroid Cancer. We focused on the impact of S and/or irradiation (R) on mechanisms of apoptosis in Follicular Thyroid Cancer cells. The effects of R, S and their combination were evaluated 2 and 4 days after treatment, using the human Thyroid Cancer cell line CGTH W-1. The transcription of genes involved in the regulation of apoptosis was investigated using quantitative real-time PCR. Western blot analyses of caspases and survivin were also performed. S elevated BAX (day 4), CASP9 , CASP3 , BIRC5 (day 4) and PRKACA (day 4) gene expression, whereas the mRNAs of BCL2 , CASP8 , PRKCA , ERK1 , and ERK2 were not significantly changed. S, R and R+S clearly induced caspase-9 protein and elevated caspase-3 activity. Survivin was down-regulated at day 4 in control cells and the expression was blunted by S treatment. R+S induced survivin expression at day 2 followed by a reduction at day 4 of treatment. Sunitinib and the combined application with radiation induced apoptosis in Follicular Thyroid Cancer cells via the intrinsic pathway of apoptosis. In addition, sunitinib might induce apoptosis via decreased expression of the anti-apoptotic protein survivin. These findings suggest the potential use of sunitinib for the treatment of poorly differentiated Follicular Thyroid carcinomas.

  • interleukin 6 expression under gravitational stress due to vibration and hypergravity in Follicular Thyroid Cancer cells
    PLOS ONE, 2013
    Co-Authors: Markus Wehland, Daniela Grimm, Ganna Aleshcheva, Jens Hauslage, Kai Waser, Ruth Hemmersbach, Manfred Infanger, Johann Bauer
    Abstract:

    It is known that exposing cell lines in vitro to parabolic flights changes their gene expression and protein production patterns. Parabolic flights and spaceflight in general are accompanied by transient hypergravity and vibration, which may impact the cells and therefore, have to be considered too. To estimate the possible impact of transient hypergravity and vibration, we investigated the effects of these forces separately using dedicated ground-based facilities. We placed Follicular Thyroid ML-1 and CGTH W-1 Cancer cells in a specific centrifuge (MuSIC Multi Sample Incubator Centrifuge; SAHC Short Arm Human Centrifuge) simulating the hypergravity phases that occur during one (P1) and 31 parabolas (P31) of parabolic flights, respectively. On the Vibraplex device, the same cell lines were treated with vibration waves corresponding to those that occur during a whole parabolic flight lasting for two hours. After the various treatments, cells were harvested and analyzed by quantitative real-time PCR, focusing on the genes involved in forming (ACTB, MYO9, TUBB, VIM, TLN1, and ITGB1) and modulating (EZR, RDX, and MSN) the cytoskeleton, as well as those encoding growth factors (EGF, CTGF, IL6, and IL8) or protein kinases (PRKAA1 and PRKCA). The analysis revealed alterations in several genes in both cell lines; however, fewer genes were affected in ML-1 than CGTH W-1 cells. Interestingly, IL6 was the only gene whose expression was changed in both cell lines by each treatment, while PKCA transcription remained unaffected in all experiments. We conclude that a PKCa-independent mechanism of IL6 gene activation is very sensitive to physical forces in Thyroid cells cultured in vitro as monolayers.

Janice M. Mehnert - One of the best experts on this subject based on the ideXlab platform.

  • safety and antitumor activity of the anti pd 1 antibody pembrolizumab in patients with advanced pd l1 positive papillary or Follicular Thyroid Cancer
    BMC Cancer, 2019
    Co-Authors: Janice M. Mehnert, Andrea Varga, Marcia S. Brose, Chia-chi Lin, Amy Prawira, Filippo De Braud, Kenji Tamura, Toshihiko Doi, Rahul Aggarwal, Sarina Anne Pihapaul
    Abstract:

    Treatment options for advanced Thyroid Cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated Thyroid Cancer expressing programmed death ligand 1 (PD-L1). Patients with advanced Thyroid Cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti–programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or Follicular Thyroid Cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7–34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1–29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2–14 months); median overall survival was not reached (95% CI, 22 months to not reached). Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated Thyroid Cancer in a minority of patients treated. Further analyses are necessary to confirm these findings. Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.

  • Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced, PD-L1–positive papillary or Follicular Thyroid Cancer
    BMC, 2019
    Co-Authors: Janice M. Mehnert, Andrea Varga, Marcia S. Brose, Rahul R. Aggarwal, Chia-chi Lin, Amy Prawira, Filippo De Braud, Kenji Tamura, Toshihiko Doi, Sarina A. Piha-paul
    Abstract:

    Abstract Background Treatment options for advanced Thyroid Cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated Thyroid Cancer expressing programmed death ligand 1 (PD-L1). Methods Patients with advanced Thyroid Cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti–programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or Follicular Thyroid Cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Results Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7–34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1–29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2–14 months); median overall survival was not reached (95% CI, 22 months to not reached). Conclusions Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated Thyroid Cancer in a minority of patients treated. Further analyses are necessary to confirm these findings. Trial registration Clinicaltrials.gov identifier: NCT02054806. Registered 4 February 2014

  • Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or Follicular Thyroid Cancer
    'Springer Science and Business Media LLC', 2019
    Co-Authors: Janice M. Mehnert, Andrea Varga, Rahul R. Aggarwal, Amy Prawira, Filippo De Braud, Kenji Tamura, Toshihiko Doi, C. Lin, Sarina A. Piha-paul
    Abstract:

    BackgroundTreatment options for advanced Thyroid Cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated Thyroid Cancer expressing programmed death ligand 1 (PD-L1).MethodsPatients with advanced Thyroid Cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or Follicular Thyroid Cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10mg/kg was administered every 2weeks up to 24months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsTwenty-two patients were enrolled: median age was 61years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31months (range, 7-34months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in 15% of patients were diarrhea (n=7) and fatigue (n=4). One grade3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1-29%); response duration was 8 and 20months. Median progression-free survival was 7months (95% CI, 2-14months); median overall survival was not reached (95% CI, 22months to not reached).ConclusionsResults of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated Thyroid Cancer in a minority of patients treated. Further analyses are necessary to confirm these findings.Trial registrationClinicaltrials.gov identifier: NCT02054806. Registered 4 February 2014

  • pembrolizumab for advanced papillary or Follicular Thyroid Cancer preliminary results from the phase 1b keynote 028 study
    Journal of Clinical Oncology, 2016
    Co-Authors: Janice M. Mehnert, Andrea Varga, Marcia S. Brose, Amy Prawira, Filippo De Braud, Kenji Tamura, Rahul Aggarwal, Sarina Anne Pihapaul, Jill Gilbert, Sanatan Saraf
    Abstract:

    6091Background: Treatment options are limited for patients (pts) with advanced Thyroid Cancer. PD-L1 expression in Thyroid Cancer tumors has been shown to correlate with poor prognosis. Pembrolizum...