22 results on '"Yeh AH"'
Search Results
2. Abstract 1642: Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis
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Kim, Soon-Chan, primary, Hong, Chang-Won, additional, Jang, Sang-Geun, additional, Kim, Yeh-Ah, additional, Jung, Seung-Yong, additional, Park, Jea-Gab, additional, and Ku, Ja-Lok, additional
- Published
- 2016
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3. Abstract 1642: Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis
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Jea-Gab Park, Soon-Chan Kim, Sang-Geun Jang, Chang-Won Hong, Seung-Yong Jung, Yeh-Ah Kim, and Ja-Lok Ku
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,Colorectal cancer ,Cell growth ,Calponin ,Cancer ,Vimentin ,medicine.disease ,Metastasis ,Small hairpin RNA ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Gene expression ,medicine ,biology.protein - Abstract
(a) An introductory sentence indicating the purposes of the study Distant metastasis is the major cause of cancer-related death in colorectal cancer (CRC) patients. Although the Calponin family has emerged as a distinguishing feature in epithelial-to-mesenchymal transition (EMT) in human cancer, the role of CNN3 member in the metastatic CRC has not been investigated. (b) A brief description of pertinent experimental procedures. Three pairs of primary CRC and corresponding matched metastasis cell lines were analyzed for gene expression by microarray and western blotting. CNN3 was transduced to CRC cell line with lower CNN3 expression level (SW-480), and CNN3 with higher CNN3 expression CRC cell lines (SW-620, HCT-116) was suppressed by lentiviral-induced shRNA. Functional analysis of CNN3 overexpression and suppression was investigated in these CRC cell lines for proliferation and invasion. Expression of several potential CNN3 target genes (ERK1/2) and EMT markers (E-cadherin and vimentin) in primary CRC and matching metastasis CRC cell lines was validated. (c) A summary of the new, unpublished data. Global CNN3 expression levels were significantly higher in metastasis cell lines compared with the matched primary cell lines in both mRNA (FC = 2.3, p = 0.017) and protein levels. CRC cell lines with suppressed CNN3 showed decreased cell proliferation and reduced invasive behavior in CRC cell lines. Suppression of CNN3 in CRC cell lines with higher CNN3 expression resulted in increased E-cadherin and decreased vimentin. pERK1/2 were decreased in accordance with suppression of CNN3 in both SW-620 and HCT-116. Overexpression of CNN3 in CRC cell lines caused reduced E-cadherin in SW-480 and HT-29. (d) A statement of the conclusions CNN3 is involved in mediating EMT and metastatic behavior in the colon. Its expression is accordantly related to EMT markers, and CNN3 may serve as a possible diagnostic marker and therapeutic target for patients with CRC. Citation Format: Soon-Chan Kim, Chang-Won Hong, Sang-Geun Jang, Yeh-Ah Kim, Seung-Yong Jung, Jea-Gab Park, Ja-Lok Ku. Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1642.
- Published
- 2016
4. A Study of the Theories of Yāvad-bhāvikatāand Yathāvad-bhāvikatāin the Abhidharma-samuccaya
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YEH, Ah-yueh
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- 1984
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5. On the Three Minds of Cultivation in the Pan-jo po-lo-mi-to hsin-ching yu-tsan
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Yeh, Ah yueh, primary
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- 1989
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6. The Characteristics of “vijñana” according to the Paratantra-svabhava Theory in the Madhyantavibhaga-bhasya
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Yeh, ah-yueh, primary
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- 1967
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7. The Meaning of ‘asrayaparavrtti’ in the Madhyantavibhagabhasya
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Yeh, Ah-yueh, primary
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- 1969
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8. ‘Sad asac ca tattvam’ as the Parinispanna-svabhava
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Yeh, Ah-ueh, primary
- Published
- 1971
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9. De novo design of high-affinity binders of bioactive helical peptides.
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Vázquez Torres S, Leung PJY, Venkatesh P, Lutz ID, Hink F, Huynh HH, Becker J, Yeh AH, Juergens D, Bennett NR, Hoofnagle AN, Huang E, MacCoss MJ, Expòsit M, Lee GR, Bera AK, Kang A, De La Cruz J, Levine PM, Li X, Lamb M, Gerben SR, Murray A, Heine P, Korkmaz EN, Nivala J, Stewart L, Watson JL, Rogers JM, and Baker D
- Subjects
- Biosensing Techniques, Diffusion, Glucagon chemistry, Glucagon metabolism, Luminescent Measurements, Mass Spectrometry, Parathyroid Hormone chemistry, Parathyroid Hormone metabolism, Protein Structure, Secondary, Substrate Specificity, Models, Molecular, Computer-Aided Design, Deep Learning, Peptides chemistry, Peptides metabolism, Proteins chemistry, Proteins metabolism
- Abstract
Many peptide hormones form an α-helix on binding their receptors
1-4 , and sensitive methods for their detection could contribute to better clinical management of disease5 . De novo protein design can now generate binders with high affinity and specificity to structured proteins6,7 . However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion8 to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar-affinity binders can be generated to helical peptide targets by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimize by partial diffusion both natural and designed proteins, should be broadly useful., (© 2023. The Author(s).)- Published
- 2024
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10. Small-molecule binding and sensing with a designed protein family.
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Lee GR, Pellock SJ, Norn C, Tischer D, Dauparas J, Anischenko I, Mercer JAM, Kang A, Bera A, Nguyen H, Goreshnik I, Vafeados D, Roullier N, Han HL, Coventry B, Haddox HK, Liu DR, Yeh AH, and Baker D
- Abstract
Despite transformative advances in protein design with deep learning, the design of small-molecule-binding proteins and sensors for arbitrary ligands remains a grand challenge. Here we combine deep learning and physics-based methods to generate a family of proteins with diverse and designable pocket geometries, which we employ to computationally design binders for six chemically and structurally distinct small-molecule targets. Biophysical characterization of the designed binders revealed nanomolar to low micromolar binding affinities and atomic-level design accuracy. The bound ligands are exposed at one edge of the binding pocket, enabling the de novo design of chemically induced dimerization (CID) systems; we take advantage of this to create a biosensor with nanomolar sensitivity for cortisol. Our approach provides a general method to design proteins that bind and sense small molecules for a wide range of analytical, environmental, and biomedical applications.
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- 2023
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11. HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.
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Sun N, Zhang C, Lee YT, Tran BV, Wang J, Kim H, Lee J, Zhang RY, Wang JJ, Hu J, Zhang Z, Alsudaney MS, Hou KC, Tang H, Zhang TX, Liang IY, Zhou Z, Chen M, Yeh AH, Li W, Zhou XJ, Chang HR, Han SB, Sadeghi S, Finn RS, Saab S, Busuttil RW, Noureddin M, Ayoub WS, Kuo A, Sundaram V, Al-Ghaieb B, Palomique J, Kosari K, Kim IK, Todo T, Nissen NN, Tomasi ML, You S, Posadas EM, Wu JX, Wadehra M, Sim MS, Li Y, Wang HL, French SW, Lu SC, Wu L, Pei R, Liang L, Yang JD, Agopian VG, Tseng HR, and Zhu Y
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- Humans, Biomarkers, Tumor analysis, Membrane Proteins, Electrocardiography, Glypicans, Carcinoma, Hepatocellular diagnosis, Carcinoma, Hepatocellular pathology, Liver Neoplasms diagnosis, Liver Neoplasms pathology, Extracellular Vesicles chemistry
- Abstract
Background and Aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC., Approach and Results: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n = 106) and an independent validation cohort ( n = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99)., Conclusion: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)
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- 2023
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12. De novo design of luciferases using deep learning.
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Yeh AH, Norn C, Kipnis Y, Tischer D, Pellock SJ, Evans D, Ma P, Lee GR, Zhang JZ, Anishchenko I, Coventry B, Cao L, Dauparas J, Halabiya S, DeWitt M, Carter L, Houk KN, and Baker D
- Subjects
- Biocatalysis, Catalytic Domain, Enzyme Stability, Hot Temperature, Luciferins metabolism, Luminescence, Oxidation-Reduction, Substrate Specificity, Deep Learning, Luciferases chemistry, Luciferases metabolism
- Abstract
De novo enzyme design has sought to introduce active sites and substrate-binding pockets that are predicted to catalyse a reaction of interest into geometrically compatible native scaffolds
1,2 , but has been limited by a lack of suitable protein structures and the complexity of native protein sequence-structure relationships. Here we describe a deep-learning-based 'family-wide hallucination' approach that generates large numbers of idealized protein structures containing diverse pocket shapes and designed sequences that encode them. We use these scaffolds to design artificial luciferases that selectively catalyse the oxidative chemiluminescence of the synthetic luciferin substrates diphenylterazine3 and 2-deoxycoelenterazine. The designed active sites position an arginine guanidinium group adjacent to an anion that develops during the reaction in a binding pocket with high shape complementarity. For both luciferin substrates, we obtain designed luciferases with high selectivity; the most active of these is a small (13.9 kDa) and thermostable (with a melting temperature higher than 95 °C) enzyme that has a catalytic efficiency on diphenylterazine (kcat /Km = 106 M-1 s-1 ) comparable to that of native luciferases, but a much higher substrate specificity. The creation of highly active and specific biocatalysts from scratch with broad applications in biomedicine is a key milestone for computational enzyme design, and our approach should enable generation of a wide range of luciferases and other enzymes., (© 2023. The Author(s).)- Published
- 2023
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13. Glucocorticoid Receptor Maintains Vasopressin Responses in Kidney Collecting Duct Cells.
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Yang HH, Su SH, Ho CH, Yeh AH, Lin YJ, and Yu MJ
- Abstract
Water permeability of the kidney collecting ducts is regulated in part by the amount of the molecular water channel protein aquaporin-2 (AQP2), whose expression, in turn, is regulated by the pituitary peptide hormone vasopressin. We previously showed that stable glucocorticoid receptor knockdown diminished the vasopressin-induced Aqp2 gene expression in the collecting duct cell model mpkCCD. Here, we investigated the pathways regulated by the glucocorticoid receptor by comparing transcriptomes of the mpkCCD cells with or without stable glucocorticoid receptor knockdown. Glucocorticoid receptor knockdown downregulated 5,394 transcripts associated with 55 KEGG pathways including "vasopressin-regulated water reabsorption," indicative of positive regulatory roles of these pathways in the vasopressin-induced Aqp2 gene expression. Quantitative RT-PCR confirmed the downregulation of the vasopressin V2 receptor transcript upon glucocorticoid receptor knockdown. Glucocorticoid receptor knockdown upregulated 3,785 transcripts associated with 42 KEGG pathways including the "TNF signaling pathway" and "TGFβ signaling pathway," suggesting the negative regulatory roles of these pathways in the vasopressin-induced Aqp2 gene expression. Quantitative RT-PCR confirmed the upregulation of TNF and TGFβ receptor transcripts upon glucocorticoid receptor knockdown. TNF or TGFβ inhibitor alone, in the absence of vasopressin, did not induce Aqp2 gene transcription. However, TNF or TGFβ blunted the vasopressin-induced Aqp2 gene expression. In particular, TGFβ reduced vasopressin-induced increases in Akt phosphorylation without inducing epithelial-to-mesenchymal transition or interfering with vasopressin-induced apical AQP2 trafficking. In summary, our RNA-seq transcriptomic comparison revealed positive and negative regulatory pathways maintained by the glucocorticoid receptor for the vasopressin-induced Aqp2 gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Su, Ho, Yeh, Lin and Yu.)
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- 2022
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14. α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells.
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Ho CH, Yang HH, Su SH, Yeh AH, and Yu MJ
- Abstract
Water permeability of the kidney collecting ducts is regulated by the peptide hormone vasopressin. Between minutes and hours (short-term), vasopressin induces trafficking of the water channel protein aquaporin-2 to the apical plasma membrane of the collecting duct principal cells to increase water permeability. Between hours and days (long-term), vasopressin induces aquaporin-2 gene expression. Here, we investigated the mechanisms that bridge the short-term and long-term vasopressin-mediated aquaporin-2 regulation by α-actinin 4, an F-actin crosslinking protein and a transcription co-activator of the glucocorticoid receptor. Vasopressin induced F-actin depolymerization and α-actinin 4 nuclear translocation in the mpkCCD collecting duct cell model. Co-immunoprecipitation followed by immunoblotting showed increased interaction between α-actinin 4 and glucocorticoid receptor in response to vasopressin. ChIP-PCR showed results consistent with α-actinin 4 and glucocorticoid receptor binding to the aquaporin-2 promoter. α-actinin 4 knockdown reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. α-actinin 4 knockdown did not affect vasopressin-induced glucocorticoid receptor nuclear translocation, suggesting independent mechanisms of vasopressin-induced nuclear translocation of α-actinin 4 and glucocorticoid receptor. Glucocorticoid receptor knockdown profoundly reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. In the absence of glucocorticoid analog dexamethasone, vasopressin-induced increases in glucocorticoid receptor nuclear translocation and aquaporin-2 mRNA were greatly reduced. α-actinin 4 knockdown further reduced vasopressin-induced increase in aquaporin-2 mRNA in the absence of dexamethasone. We conclude that glucocorticoid receptor plays a major role in vasopressin-induced aquaporin-2 gene expression that can be enhanced by α-actinin 4. In the absence of vasopressin, α-actinin 4 crosslinks F-actin underneath the apical plasma membrane, impeding aquaporin-2 membrane insertion. Vasopressin-induced F-actin depolymerization in one hand facilitates aquaporin-2 apical membrane insertion and in the other hand frees α-actinin 4 to enter the nucleus where it binds glucocorticoid receptor to enhance aquaporin-2 gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ho, Yang, Su, Yeh and Yu.)
- Published
- 2021
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15. Fixation of lung apex in spontaneous pneumothorax is safe and efficient in decrease recurrences.
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Yang W, Chang PY, Yeh AH, Ming YC, Chen JC, and Lai JY
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- Adolescent, Adult, Female, Humans, Male, Pleurodesis adverse effects, Pneumothorax diagnosis, Pneumothorax epidemiology, Recurrence, Retrospective Studies, Thoracic Surgery, Video-Assisted adverse effects, Pleurodesis methods, Pneumothorax therapy, Postoperative Complications epidemiology, Thoracic Surgery, Video-Assisted methods
- Abstract
Background: Video-assisted thoracoscopic bullectomy with pleurodesis is widely used to treat spontaneous pneumothorax. However, 1%-3% of patients experience postoperative complications that may require reoperation, such as bleeding or prolonged air leaks, and 3%-7% of patients require a repeat thoracoscopic bullectomy due to recurrence. Therefore, a modified procedure with improved outcomes is required., Methods: Between January 1, 2011 and December 31, 2015, 196 patients with spontaneous pneumothorax underwent thoracoscopic bullectomy and pleurodesis with or without fixation of the lung apex to the chest wall. In patients in the fixation group, the lung apex was fixed to the chest wall with two non-absorbable sutures after bullectomy and pleurodesis. The treatment of each lung was considered an independent operation in patients with bilateral spontaneous pneumothorax., Results: The patients in each group had comparable backgrounds. In the fixation group, 67 patients underwent 87 operations, four of which (in three patients) led to recurrences (recurrence rate, 4.60%). There were no readmissions or reoperations within 30 days in this group. In the non-fixation group, 128 patients underwent 161 operations, 14 of which (in nine patients) led to recurrences (recurrence rate, 8.7%). In addition, three patients in this group required reoperation and two were readmitted within 30 days., Conclusions: Modified thoracoscopic bullectomy with fixation of the lung apex is a safe procedure that provides better outcomes with lower complication rates., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2019
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16. Interface-Controlled Synthesis of Au-BINOL Hybrid Nanostructures and Mechanism Study.
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Patlolla SR, Kao CR, Yeh AH, Lin HM, Chuang YC, Wen YS, Sneed BT, Chen WC, Ong TG, and Kuo CH
- Abstract
The combined functionality of components in organic-inorganic hybrid nanomaterials render them efficient nanoreactors. However, the development in this field is limited due to a lack of synthetic avenues and systematic control of the growth kinetics of hybrid structures. In this work, we take advantage of an ionic switch for regio-control of Au-BINOL(1,1'-Bi-2-naphthol) hybrid nanostructures. Aromatic BINOL molecules assemble into nanospheres, concomitant with the growth of the Au nanocrystals. The morphological evolution of Au nanocrystals is solely controlled by the presence of halides in the synthetic system. Here we show that quaternary ammonium surfactants (CTAB or CTAC), not only bridging Au and BINOL, but also contributing to the formation of concentric or eccentric structures when their concentrations are tuned to the range of 10
-5 to 10-3 M. This facile strategy offers the potential advantage of scalable production, with diverse functional organic-inorganic hybrid nanocomposites being produced based on the specific archetype of Au-BINOL hybrid nanocomposites.- Published
- 2018
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17. Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs.
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Yeh AH, Bohula EA, and Macaulay VM
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- Antineoplastic Agents therapeutic use, Cell Survival, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Silencing, Humans, Melanocytes metabolism, Melanoma drug therapy, Melanoma genetics, Point Mutation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms metabolism, Transfection, Tumor Cells, Cultured, Melanoma metabolism, Proto-Oncogene Proteins B-raf metabolism, RNA, Small Interfering metabolism, Receptor, IGF Type 1 metabolism
- Abstract
The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by malignant melanomas compared with benign naevi, and mediates proliferation, motility and protection from apoptosis. However, the utility of IGF1R targeting as anti-cancer therapy may be limited by activating mutations in downstream signaling intermediates. We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss. The current study investigated effects of IGF1R targeting in cells harboring activating RAS-RAF mutations, found in 70-80% of human melanomas. We assembled a panel of eight human melanoma cell lines: two expressing wild-type (WT) B-RAF and N-RAS, two with activating N-RAS mutations and four harboring V600E B-RAF. We also generated isogenic cell populations overexpressing WT or V600E B-RAF. Cells expressing V600E B-RAF were relatively resistant to apoptosis. However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and approximately two-fold sensitization to cisplatin and temozolomide. These effects were independent of mutation status and were associated with reduced activation of Akt and also, unexpectedly, of ERKs. These results support development of IGF1R targeting as therapy for melanoma, regardless of the presence of activating mutations in the RAS-RAF pathway.
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- 2006
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18. Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines.
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Jeffery PL, Murray RE, Yeh AH, McNamara JF, Duncan RP, Francis GD, Herington AC, and Chopin LK
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- Amino Acid Sequence, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Breast Neoplasms diagnosis, Breast Neoplasms pathology, Carcinoma diagnosis, Carcinoma pathology, Cell Line, Tumor, Cell Proliferation drug effects, Female, Ghrelin, Humans, Immunohistochemistry, Molecular Sequence Data, Peptide Hormones analysis, Peptide Hormones genetics, Protein Isoforms analysis, Protein Isoforms genetics, RNA, Messenger analysis, RNA, Messenger metabolism, Receptors, G-Protein-Coupled analysis, Receptors, G-Protein-Coupled genetics, Receptors, Ghrelin, Sequence Deletion, Transcription, Genetic, Breast Neoplasms metabolism, Carcinoma metabolism, Peptide Hormones metabolism, Peptide Hormones pharmacology, Peptide Hormones physiology
- Abstract
While oestrogen, progesterone and growth factors, including growth hormone (GH), are clearly implicated in the pathogenesis of breast cancer, there is now evidence that the newly described ghrelin axis is also involved. The aims of this study were to investigate the expression of the ghrelin axis in breast cancer tissues and cell lines and to examine the effect of ghrelin on breast cancer cell proliferation in vitro. Ghrelin and its functional receptor, the growth hormone secretagogue receptor (GHSR) type 1a, were expressed in normal breast tissue and breast cancer specimens and cell lines. In contrast, the truncated GHSR type 1b isoform was exclusively expressed in breast carcinoma, suggesting that it has potential as a diagnostic marker. Ghrelin treatment significantly increases the proliferation of the MDA-MB-435 and MDA-MB-231 breast cancer cell lines in vitro. In addition, we have described the expression of a human preproghrelin isoform, exon 3-deleted preproghrelin, which encodes mature ghrelin plus a novel C-terminal peptide. Quantitative RT-PCR was used to demonstrate that this mRNA isoform is highly expressed in the MDA-MB-435 metastatic breast cancer cell line relative to the benign MCF-10A breast epithelial cell line. The unique C-terminal peptide of exon 3-deleted preproghrelin is expressed in the glandular epithelium of breast cancer tissues, with high-grade carcinoma exhibiting the strongest immunoreactivity. The data presented here suggest that components of the ghrelin axis may represent novel markers for breast cancer and potential therapeutic targets.
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- 2005
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19. Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer and ghrelin activates mitogen-activated protein kinase in prostate cancer.
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Yeh AH, Jeffery PL, Duncan RP, Herington AC, and Chopin LK
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- Apoptosis, Cell Proliferation, Culture Media, Conditioned, Enzyme Activation drug effects, Exons genetics, Ghrelin, Humans, Male, Peptide Fragments pharmacology, Prostatic Hyperplasia enzymology, Prostatic Hyperplasia genetics, Prostatic Hyperplasia pathology, Prostatic Neoplasms enzymology, Prostatic Neoplasms pathology, Sequence Deletion, Tumor Cells, Cultured, Mitogen-Activated Protein Kinases metabolism, Motilin genetics, Peptide Hormones genetics, Peptide Hormones pharmacology, Prostatic Neoplasms genetics
- Abstract
Purpose: There is evidence that the hormone ghrelin stimulates proliferation in the PC3 prostate cancer cell line although the underlying mechanism(s) remain to be determined. A novel, exon 3-deleted preproghrelin isoform has previously been detected in breast and prostate cancer cells; however, its characterization, expression, and potential function in prostate cancer tissues are unknown., Experimental Design: Expression of ghrelin and exon 3-deleted preproghrelin was investigated in prostate cancer cell lines and tissues by reverse transcription-PCR and immunohistochemistry. Proliferation and apoptosis assays were done in the LNCaP prostate cancer cell line to determine if ghrelin stimulates proliferation and/or cell survival. Stimulation of mitogen-activated protein kinase (MAPK) pathway activation by ghrelin was determined in PC3 and LNCaP cells by immunoblotting with antibodies specific for phosphorylated MAPKs., Results: Prostate cancer tissues display greater immunoreactivity for ghrelin and exon 3-deleted preproghrelin than normal prostate tissues, and prostate cancer cell lines secrete mature ghrelin into conditioned medium. Treatment with ghrelin (10 nmol/L), but not the unique COOH-terminal peptide derived from exon 3-deleted preproghrelin, stimulates proliferation in the LNCaP cells (45.0 +/- 1.7% above control, P < 0.01) and rapidly activates the extracellular signal-regulated kinase-1/2 MAPK pathway in both PC3 and LNCaP cell lines. Ghrelin, however, does not protect prostate cancer cells from apoptosis induced by actinomycin D (1 microg/mL). The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as proliferation, in both cell lines., Conclusions: These data suggest that these components of the ghrelin axis may have potential as novel biomarkers and/or adjunctive therapeutic targets for prostate cancer.
- Published
- 2005
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20. Expression of the ghrelin axis in the mouse: an exon 4-deleted mouse proghrelin variant encodes a novel C terminal peptide.
- Author
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Jeffery PL, Duncan RP, Yeh AH, Jaskolski RA, Hammond DS, Herington AC, and Chopin LK
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- Amino Acid Sequence, Animals, Base Sequence, Blotting, Western, Computer Systems, Gastric Mucosa metabolism, Ghrelin, Immunohistochemistry, Mice, Mice, Inbred Strains, Molecular Sequence Data, Peptide Fragments genetics, Peptide Hormones metabolism, Polymerase Chain Reaction, Protein Precursors metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Receptors, Ghrelin, Sequence Homology, Amino Acid, Tissue Distribution, Exons, Gene Deletion, Gene Expression, Genetic Variation, Peptide Hormones genetics, Protein Precursors genetics
- Abstract
Ghrelin, an n-octanoylated 28-amino-acid peptide capable of inducing GH secretion and food intake in humans and rats, is the endogenous ligand for the GH secretagogue receptor (GHS-R). Here we describe the expression and tissue distribution of the ghrelin/GHS-R axis in the mouse. We also report for the first time the identification of a novel mouse ghrelin mRNA variant in which there is a complete deletion of exon 4. Translation of this variant mRNA yields a protein containing ghrelin and an alternative C-terminal domain with a unique C-terminal peptide sequence. RT-PCR with primers specific for mouse ghrelin was used to demonstrate the mRNA expression of the full preproghrelin transcript and the exon 4-deleted variant in multiple mouse tissues. Real-time PCR was also employed to quantitate mRNA expression of ghrelin, the novel isoform and a previously reported ghrelin gene variant, ghrelin gene-derived transcript. We also demonstrated the tissue expression of the functional GHS-R in the mouse. Immunohistochemistry, employing antibodies raised against the mature human n-octanoylated ghrelin peptide and the putative C-terminal peptide encoded by the exon 4-deleted proghrelin variant, was used to demonstrate protein expression of ghrelin and the variant in multiple mouse tissues including stomach, kidney, and reproductive tissues. The coexpression of ghrelin and its receptor in a wide range of murine tissues suggests varied autocrine/paracrine roles for these peptides. Exon 4-deleted proghrelin, a novel mouse proghrelin isoform with a unique C-terminal peptide sequence, is also widely expressed in the mouse and thus may possess biological activity in these tissues.
- Published
- 2005
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21. Efficacy of telephone-administered cognitive behaviour therapy for obsessive-compulsive spectrum disorders: case studies.
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Yeh AH, Taylor S, Thordarson DS, and Corcoran KM
- Abstract
Cognitive behaviour therapy is effective for obsessive-compulsive disorder and for obsessive-compulsive spectrum disorders such as trichotillomania. Unfortunately, many people with these disorders, especially those living in rural areas, have limited access to treatment. Telephone-administered cognitive behaviour therapy may help address this problem. In a recent study of telephone treatment for obsessive-compulsive disorder, we found that such treatment was often effective (42% in remission at post-treatment, and 47% in remission at 12-week follow-up). This article presents 2 case reports of the same treatment, applied to obsessive-compulsive spectrum disorders (trichotillomania and compulsive skin picking). Treatment was associated with symptom reduction for both participants, although one subsequently relapsed. Possible reasons for relapse are discussed. The findings encourage further studies to identify the characteristics of people most likely to benefit from telephone treatment for spectrum disorders.
- Published
- 2003
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22. Telephone-administered cognitive behavior therapy for obsessive-compulsive disorder.
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Taylor S, Thordarson DS, Spring T, Yeh AH, Corcoran KM, Eugster K, and Tisshaw C
- Abstract
Exposure with response prevention and cognitive behavior therapy are widely recognized as effective treatments for obsessive-compulsive disorder. Unfortunately, many people with obsessive-compulsive disorder--particularly those living in rural areas--do not have access to therapists providing these treatments. Accordingly, we investigated the efficacy of telephone-administered cognitive behavior therapy for obsessive-compulsive disorder. Two open trials are reported, for a total of 33 people with obsessive-compulsive disorder (without major depression). The first trial consisted of 12 weeks on a waiting list followed by 12 weeks of treatment (delayed treatment). The second trial consisted of 12 weeks of immediate treatment. Obsessive-compulsive symptoms did not change during the waiting period. Symptoms declined from pre- to post-treatment, with gains maintained at 12-week follow-up. For the pooled sample our pre-to-post-treatment effect size was as large or larger than those obtained in other studies of reduced contact treatment, and similar to those of face-to-face exposure with response prevention. Our proportion of treatment dropouts tended to be lower than those of other reduced contact interventions. The results suggest that telephone-administered cognitive behavior therapy is effective and well-tolerated, at least for people with obsessive-compulsive disorder without major depression. It remains to be seen whether this treatment is safe and effective when comorbid major depression is present.
- Published
- 2003
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