44 results on '"Yip-Schneider M"'
Search Results
2. Development of a Microfluidic Cyst Fluid Assay to Identify Pancreatic Cystic Neoplasms that Require Surgical Resection
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Pollini, T., primary, Kone, L., additional, Brugge, W., additional, Fernandez-del Castillo, C., additional, Winter, J., additional, Yeo, C., additional, Hackert, T., additional, Buechler, M., additional, Roggin, K., additional, Schmidt, C.M., additional, Yip-Schneider, M., additional, Salvia, R., additional, Bassi, C., additional, Chlipala, G., additional, and Maker, A., additional
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- 2022
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3. NOVEL MODEL OF ALCOHOL-INDUCED HEPATOCELLULAR CARCINOMA (HCC): 103
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Schmidt, C. M., Klein, P. J., Wentz, S. C., Hennig, M. E., Yip-Schneider, M. T., Matos-Bramblia, J. M., and Froehlich, J. C.
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- 2007
4. Prostaglandin E2: a pancreatic fluid biomarker of IPMN dysplasia
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Yip-Schneider, M., primary, Carr, R., additional, Wu, H., additional, and Schmidt, C.M., additional
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- 2017
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5. Characterization of the Serum Proteome in Patients with Malignant Intraductal Papillary Mucinous Neoplasm
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Roch, A.M., primary, Doyle, C.J., additional, Wang, M., additional, Bemis, K., additional, Yip-Schneider, M., additional, and Schmidt, C., additional
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- 2014
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6. Regulation of the Raf-1 kinase domain by phosphorylation and 14-3-3 association
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Yip-Schneider, M T, Miao, W, Lin, A, Barnard, D S, Tzivion, G, and Marshall, M S
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Tyrosine 3-Monooxygenase ,hemic and immune systems ,Binding, Competitive ,Peptide Fragments ,Oncogene Protein pp60(v-src) ,Protein Structure, Tertiary ,Enzyme Activation ,Proto-Oncogene Proteins c-raf ,Phosphoserine ,14-3-3 Proteins ,Catalytic Domain ,COS Cells ,Mutation ,Animals ,Tetradecanoylphorbol Acetate ,Phosphorylation ,Research Article ,Protein Binding - Abstract
The Raf-1 kinase domain is kept in an inactive state by the N-terminal regulatory domain. Activation of the kinase domain occurs following release from the N-terminal repression and possible catalytic upregulation. To distinguish the regulatory mechanisms that directly influence the catalytic activity of the enzyme from those which act through the inhibitory domain, the catalytic domain of Raf-1 (CR3) was expressed in COS-7 cells. The role of phosphorylation in the direct regulation of this domain was determined by substituting non-phosphorylatable amino acids for known serine and tyrosine phosphorylation sites. The intrinsic activity of each mutant protein was determined as well as stimulation by v-Src and phorbol esters. Both v-Src and phorbol esters were potent activators of CR3, requiring the serine 338/339 (p21-activated protein kinase, Pak) and tyrosine 340/341 (Src) phosphorylation sites for full stimulation of CR3. In contrast, loss of the serine 497/499 protein kinase C phosphorylation sites had little effect on CR3 activation by either v-Src or phorbol esters. Loss of serine 621, a 14-3-3 adaptor-protein-binding site, prevented activation of CR3 by v-Src or phorbol esters and partially decreased the high basal activity of the kinase fragment. When co-expressed in COS-7 cells, 14-3-3 associated strongly with full-length Raf-1, weakly with wild-type CR3 and not at all with the A621 and D621 CR3 mutants. The role of 14-3-3 in maintaining the activity of the catalytic domain of Raf-1 was investigated further by performing peptide-competition studies with wild-type CR3, wild-type CR3 and v-Src or constitutively active CR3 (CR3[YY340/341DD]). In each case, incubation of the proteins with a phosphoserine-621 Raf-1 peptide, which we show displaced Raf-1 and CR3[YY340/341DD] from 14-3-3, was found to substantially reduce catalytic activity. Taken together, our results support a model of Raf regulation in which the activity of the Raf-1 catalytic domain is directly upregulated by phosphorylation, following relief of inhibition by the N-terminal regulatory domain upon Ras-GTP binding. Moreover, the presence of serine 621 in the free catalytic fragment is required for full CR3 activation by stimulatory factors, and the continuous presence of 14-3-3 at this site is necessary for retaining activity once the kinase is activated.
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- 2000
7. Alcohol-Preferring High Alcohol Drinking (HAD2) Rats: A Model for Ethanol-Induced Liver Neoplasia
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Doyle, C., primary, Yip-Schneider, M., additional, Matos, J., additional, Wu, H., additional, and Schmidt, C., additional
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- 2010
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8. QS314. TGF-Alpha Levels as Potential Biomarker for High Grade Intraductal Papillary Mucinous Neoplasm
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Doyle, C., primary, Schmidt, C., additional, and Yip-Schneider, M., additional
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- 2009
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9. Neoadjuvant gemcitabine, erlotinib, and hypofractionated radiation therapy for potentially resectable pancreatic cancer: A pilot study
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Cardenes, H. R., primary, Chiorean, E. G., additional, Perkins, S., additional, DeWitt, J., additional, Schmidt, C. M., additional, Crowell, P., additional, Yip-Schneider, M., additional, Zyromski, N., additional, Cramer, H., additional, and Howard, T., additional
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- 2008
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10. THE PROTEOME OF NORMAL PANCREATIC JUICE
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Yancey, K., primary, Pitt, H. A., additional, Wang, M., additional, Yip-Schneider, M., additional, Sherman, S., additional, Lillemoe, K. D., additional, Goggins, M. D., additional, and Schmidt, C. M., additional
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- 2007
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11. P88
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Vegeler, R., primary, Yip-Schneider, M., additional, and Schmidt, C.M., additional
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- 2007
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12. Inhibition of the Phosphatidylinositol 3′–Kinase Signaling Pathway Increases the Responsiveness of Pancreatic Carcinoma Cells to Sulindac,
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Yip-Schneider, M, primary
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- 2003
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13. Cyclooxygenase-2 expression in human pancreatic adenocarcinomas
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Yip-Schneider, M. T., primary
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- 2000
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14. Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression.
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Yip-Schneider, M T, primary, Lin, A, additional, Barnard, D, additional, Sweeney, C J, additional, and Marshall, M S, additional
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- 1999
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15. Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells.
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T, Yip-Schneider M, J, Sweeney C, H, Jung S, L, Crowell P, and S, Marshall M
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Increased cyclooxygenase-2 (COX-2) expression in human pancreatic adenocarcinomas, as well as the growth-inhibitory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, suggests that NSAIDs may be an effective treatment for pancreatic cancer. Gemcitabine is currently the most effective chemotherapeutic drug available for patients with pancreatic cancer, but is only minimally effective against this aggressive disease. Clearly, other treatment options must be identified. To design successful therapeutic strategies involving compounds either alone or in combination with others, it is necessary to understand their mechanism of action. In the present study, we evaluated the effects of three NSAIDs (sulindac, indomethacin, and NS-398) or gemcitabine in two human pancreatic carcinoma cell lines, BxPC-3 (COX-2-positive) and PaCa-2 (COX-2-negative), previously shown to be growth-inhibited by these NSAIDs. Effects on cell cycle and apoptosis were investigated by flow cytometry or Western blotting. Treatment with NSAIDs or gemcitabine altered the cell cycle phase distribution as well as the expression of multiple cell cycle regulatory proteins in both cell lines, but did not induce substantial levels of apoptosis. Furthermore, we demonstrated that the combination of the NSAID sulindac or NS-398 with gemcitabine inhibited cell growth to a greater degree than either compound alone. These results indicate that the antiproliferative effects of NSAIDs and gemcitabine in pancreatic tumor cells are primarily due to inhibition of cell cycle progression rather than direct induction of apoptotic cell death, regardless of COX-2 expression. In addition, NSAIDs in combination with gemcitabine may hold promise in the clinic for the treatment of pancreatic cancer.
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- 2001
16. P88: Effect of LC-1, a novel nuclear factor-kappaB (NF-KB) inhibitor, and celecoxib, a COX-2 inhibitor, in a N-nitrosobis(2-oxopropyl)amine (BOP) model of lung cancer
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Vegeler, R., Yip-Schneider, M., and Schmidt, C.M.
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- 2007
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17. Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic cancers
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Cui Ping, Liu Jianguo, Yip-Schneider Michele, Myer David, Dong Zizheng, Li Zhaomin, Schmidt C Max, and Zhang Jian-Ting
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Pancreatic cancer is the fourth leading cause of death in the US. Unlike other solid tumors such as testicular cancer which are now curable, more than 90% of pancreatic cancer patients die due to lack of response to therapy. Recently, the level of 14-3-3σ mRNA was found to be increased in pancreatic cancers and this increased expression may contribute to the failure in treatment of pancreatic cancers. In the present study, we tested this hypothesis. Methods Western blot analysis was used to determine 14-3-3σ protein level in fresh frozen tissues and was correlated to clinical outcome. A stable cell line expressing 14-3-3σ was established and the effect of 14-3-3σ over-expression on cellular response to radiation and anticancer drugs were tested using SRB assay and clonogenic assays. Cell cycle distribution and apoptosis analyses were performed using propidium iodide staining and PARP cleavage assays. Results We found that 14-3-3σ protein level was increased significantly in about 71% (17 of 24) of human pancreatic cancer tissues and that the 14-3-3σ protein level in cancers correlated with lymph node metastasis and poor prognosis. Furthermore, we demonstrated that over-expression of 14-3-3σ in a pancreatic cancer cell line caused resistance to γ-irradiation as well as anticancer drugs by causing resistance to treatment-induced apoptosis and G2/M arrest. Conclusion The increased level of 14-3-3σ protein likely contributes to the poor clinical outcome of human pancreatic cancers by causing resistance to radiation and anticancer drugs. Thus, 14-3-3σ may serve as a prognosis marker predicting survival of pancreatic cancer patients and guide the clinical treatment of these patients.
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- 2010
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18. Preoperative nomogram predicts non-home discharge in patients undergoing pancreatoduodenectomy.
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Flick, K., Sublette, C., Colgate, C., Yip-Schneider, M., Soufi, M., Maatman, T., Ceppa, E., M house, Zyromski, N., Nakeeb, A., and Schmidt, C.
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HOSPITAL admission & discharge , *NOMOGRAPHY (Mathematics) , *PREOPERATIVE risk factors - Abstract
This study aimed to develop and validate a preoperative prediction model to identify patients with a high likelihood of NHD following PD. A training cohort composed of 80% of the sampled patients was used to create the prediction model, and model validation was carried out using the remaining 20%. [Extracted from the article]
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- 2020
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19. Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project.
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Semaan A, Bernard V, Wong J, Makino Y, Swartzlander DB, Rajapakshe KI, Lee JJ, Officer A, Schmidt CM, Wu HH, Scaife CL, Affolter KE, Nachmanson D, Firpo MA, Yip-Schneider M, Lowy AM, Harismendy O, Sen S, Maitra A, Jakubek YA, and Guerrero PA
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- Humans, Pilot Projects, Pancreatic Intraductal Neoplasms genetics, Pancreatic Neoplasms genetics, Carcinoma, Pancreatic Ductal genetics, Neoplasms, Cystic, Mucinous, and Serous
- Abstract
Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification being associated with HG progression and with cases that harbored co-occurring PDAC. Furthermore, the combined assessment of single-nucleotide variants (SNV) and CNAs identified both linear and branched evolutionary trajectories, underscoring the heterogeneity in the progression of LG lesions to HG and PDAC. At the transcriptome level, upregulation of MYC-regulated targets and downregulation of transcripts associated with the MHC class I antigen presentation machinery as well as pathways related to glycosylation were a common feature of progression to HG. In addition, the established PDAC transcriptional subtypes (basal-like and classical) were readily apparent within IPMNs. Taken together, this work emphasizes the role of 1q copy-number amplification as a putative biomarker of high-risk IPMNs, underscores the importance of immune evasion even in noninvasive precursor lesions, and reinforces that evolutionary pathways in IPMNs are heterogenous, comprised of both SNV and CNA-driven events., Significance: Integrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of IPMNs, which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies., (© 2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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20. Integrated spatial transcriptomics and lipidomics of precursor lesions of pancreatic cancer identifies enrichment of long chain sulfatide biosynthesis as an early metabolic alteration.
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Sans M, Chen Y, Thege FI, Dou R, Min J, Yip-Schneider M, Zhang J, Wu R, Irajizad E, Makino Y, Rajapakshe KI, Hurd MW, León-Letelier RA, Vykoukal J, Dennison JB, Do KA, Wolff RA, Guerrero PA, Kim MP, Schmidt CM, Maitra A, Hanash S, and Fahrmann JF
- Abstract
Background: The development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted the first integrated cross-species assessment of spatial transcriptomics and spatial metabolomics alterations associated with progression of intraductal papillary mucinous neoplasms (IPMN), bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC)., Methods: Matrix Assisted Laster Desorption/Ionization (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) (10X Genomics) was performed on human resected IPMN tissues (N= 23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN. Findings were further compared with lipidomic analyses of cystic fluid from 89 patients with histologically confirmed IPMNs, as well as single-cell and bulk transcriptomic data of PDAC and normal tissues., Results: MALDI-MS analyses of IPMN tissues revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Integrated ST analyses confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1 , and FA2H , were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid identified several sulfatide species, including the C24:0(OH) and C24:1(OH) species, to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Targeting of sulfatide metabolism via the selective galactosylceramide synthase inhibitor, UGT8-IN-1, resulted in ceramide-induced lethal mitophagy and subsequent cancer cell death in vitro , and attenuated tumor growth of mutant Kras;Gnas allografts. Transcript levels of UGT8 and FA2H were also selectively enriched in PDAC transcriptomic datasets compared to non-cancerous areas, and elevated tumoral UGT8 was prognostic for poor overall survival., Conclusion: Enhanced sulfatide metabolism is an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception.
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- 2023
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21. Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential.
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Sans M, Makino Y, Min J, Rajapakshe KI, Yip-Schneider M, Schmidt CM, Hurd MW, Burks JK, Gomez JA, Thege FI, Fahrmann JF, Wolff RA, Kim MP, Guerrero PA, and Maitra A
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- Animals, Mice, Cell Differentiation genetics, Pancreas pathology, Transcriptome, Tumor Microenvironment, Carcinoma, Pancreatic Ductal pathology, Neoplasms, Cystic, Mucinous, and Serous, Pancreatic Intraductal Neoplasms genetics, Pancreatic Neoplasms pathology
- Abstract
Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbors a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross-species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while reexpression of Nkx6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis., Significance: Identification of the molecular features driving IPMN development and differentiation is critical to prevent cancer progression and enhance risk stratification. We used spatial profiling to characterize the epithelium and microenvironment of IPMN, which revealed a previously unknown link between NKX6-2 and gastric differentiation, the latter associated with indolent biological potential. See related commentary by Ben-Shmuel and Scherz-Shouval, p. 1768. This article is highlighted in the In This Issue feature, p. 1749., (©2023 American Association for Cancer Research.)
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- 2023
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22. Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception.
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Hernandez S, Parra ER, Uraoka N, Tang X, Shen Y, Qiao W, Jiang M, Zhang S, Mino B, Lu W, Pandurengan R, Haymaker C, Affolter K, Scaife CL, Yip-Schneider M, Schmidt CM, Firpo MA, Mulvihill SJ, Koay EJ, Wang H, Wistuba II, Maitra A, Solis LM, and Sen S
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- Humans, Tumor Microenvironment, Pancreatic Neoplasms, Adenocarcinoma, Mucinous pathology, Carcinoma, Pancreatic Ductal pathology, Pancreatic Intraductal Neoplasms, Pancreatic Neoplasms pathology
- Abstract
Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses., Experimental Design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set., Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression., Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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23. Comparison of skin closure techniques in patients undergoing open pancreaticoduodenectomy: A single center experience.
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Flick KF, Simpson RE, Soufi M, Fennerty ML, Yip-Schneider MT, Colgate CL, Ceppa EP, House MG, Zyromski NJ, Nakeeb A, and Schmidt CM
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- Aged, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Prognosis, Retrospective Studies, United States epidemiology, Pancreaticoduodenectomy methods, Postoperative Complications epidemiology, Wound Closure Techniques
- Abstract
Background: This study evaluated closure techniques and incisional surgical site complications (SSCs) and incisional surgical site infections (SSIs) after pancreaticoduodenectomy (PD)., Methods: Retrospective review of open PDs from 2015 to 2018 was performed. Outcomes were compared among closure techniques (subcuticular + topical skin adhesive (TSA); staples; subcuticular only). SSCs were defined as abscess, cellulitis, seroma, or fat necrosis. SSIs were defined according to the National Surgical Quality Improvement Program (NSQIP)., Results: Patients with subcuticular + TSA (n = 205) were less likely to develop an incisional SSC (9.8%) compared to staples (n = 139) (20.1%) and subcuticular (n = 74) (16.2%) on univariable analysis (P = 0.024). Multivariable analysis revealed no statistically significant difference in incisional SSC between subcuticular + TSA and subcuticular (P = 0.528); a significant difference remained between subcuticular + TSA and staples (P = 0.014). Unadjusted median length of stay (LOS) (days) was significantly longer for staples (9) vs. subcuticular (8) vs. subcuticular + TSA (7); P < 0.001. Incisional SSIs were evaluated separately according to the NSQIP definition. When comparing rates, the subcuticular + TSA group experienced lower incisional SSIs compared to the other two techniques (4.9% vs. 10.1%, 10.8%). However, this difference was not statistically significant by either univariable or multivariable analysis., Conclusions: Subcuticular suture + TSA reduces the risk of incisional SSCs when compared to staples alone after pancreaticoduodenectomy., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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24. Secretin-induced Duodenal Aspirate of Pancreatic Juice (SIDA): Utility of Commercial Genetic Analysis.
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Simpson RE, Yip-Schneider M, Flick KF, Soufi M, Ceppa EP, Al-Haddad MA, Easler JJ, Sherman S, Dewitt JM, and Schmidt CM
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- Aged, DNA genetics, Databases, Genetic, Female, Humans, Male, Middle Aged, Secretin metabolism, Duodenum metabolism, Genetic Testing methods, Pancreatic Juice metabolism, Pancreatic Neoplasms genetics, Secretin genetics
- Abstract
Background: Secretin-induced duodenal aspiration (SIDA) of pancreatic duct fluid has been proposed for pancreatic neoplasm screening in very high-risk patients. We sought to determine the clinical yield and safety of commercially-analyzed SIDA samples in patients at moderately elevated risk., Patients and Methods: A prospectively maintained institutional database of pancreatic fluid DNA profiles was retrospectively reviewed., Results: Fifty-seven patients underwent SIDA testing, most commonly for intraductal papillary mucinous neoplasms (n=43) and not otherwise specified solitary cysts (n=9). SIDA mutation yield was low compared to 37 concomitant endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples of pancreatic fluid: KRAS (2.5% vs. 40.0%), GNAS (2.6% vs. 11.1%) and allelic loss of heterozygosity (3.1% vs. 0%). Patients undergoing SIDA alone experienced no complications while 3 patients with concomitant EUS-FNA had post-procedural pancreatitis., Conclusion: The genetic yield of commercially-analyzed SIDA samples was relatively low in a moderately elevated risk cohort. SIDA testing may have a better safety profile than EUS-FNA., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
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- 2020
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25. Discussion on: Performance of candidate urinary biomarkers for pancreatic cancer - Correlation with pancreatic cyst malignant progression?
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Yip-Schneider MT, Soufi M, Carr RA, Flick KF, Wu H, and Schmidt CM
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- Biomarkers, Humans, Pancreatic Cyst, Pancreatic Neoplasms
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- 2020
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26. A multimodality test to guide the management of patients with a pancreatic cyst.
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Springer S, Masica DL, Dal Molin M, Douville C, Thoburn CJ, Afsari B, Li L, Cohen JD, Thompson E, Allen PJ, Klimstra DS, Schattner MA, Schmidt CM, Yip-Schneider M, Simpson RE, Fernandez-Del Castillo C, Mino-Kenudson M, Brugge W, Brand RE, Singhi AD, Scarpa A, Lawlor R, Salvia R, Zamboni G, Hong SM, Hwang DW, Jang JY, Kwon W, Swan N, Geoghegan J, Falconi M, Crippa S, Doglioni C, Paulino J, Schulick RD, Edil BH, Park W, Yachida S, Hijioka S, van Hooft J, He J, Weiss MJ, Burkhart R, Makary M, Canto MI, Goggins MG, Ptak J, Dobbyn L, Schaefer J, Sillman N, Popoli M, Klein AP, Tomasetti C, Karchin R, Papadopoulos N, Kinzler KW, Vogelstein B, Wolfgang CL, Hruban RH, and Lennon AM
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- Aged, Female, Humans, Machine Learning, Male, Middle Aged, Pancreatic Cyst genetics, Pancreatic Cyst pathology, Pancreatic Cyst surgery, Algorithms, Pancreatic Cyst diagnosis
- Abstract
Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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- 2019
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27. Response to Comment on Sims et al. Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes. Diabetes Care 2019;42:258-264.
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Sims EK, Bahnson HT, Nyalwidhe J, Haataja L, Davis AK, Speake C, DiMeglio LA, Blum J, Morris MA, Mirmira RG, Nadler J, Mastracci TL, Marcovina S, Qian WJ, Yi L, Swensen AC, Yip-Schneider M, Schmidt CM, Considine RV, Arvan P, Greenbaum CJ, and Evans-Molina C
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- C-Peptide, Humans, Insulin, Diabetes Mellitus, Type 1, Proinsulin
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- 2019
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28. A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer.
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Fahrmann JF, Bantis LE, Capello M, Scelo G, Dennison JB, Patel N, Murage E, Vykoukal J, Kundnani DL, Foretova L, Fabianova E, Holcatova I, Janout V, Feng Z, Yip-Schneider M, Zhang J, Brand R, Taguchi A, Maitra A, Brennan P, Max Schmidt C, and Hanash S
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- Adenocarcinoma, Mucinous genetics, Adenocarcinoma, Mucinous metabolism, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Papillary genetics, Carcinoma, Papillary metabolism, Case-Control Studies, Follow-Up Studies, Humans, Neoplasm Invasiveness, Neoplasm Staging, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Adenocarcinoma, Mucinous pathology, Biomarkers, Tumor blood, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Papillary pathology, Metabolome, Pancreatic Neoplasms pathology, Transcriptome
- Abstract
Background: We applied a training and testing approach to develop and validate a plasma metabolite panel for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC) alone and in combination with a previously validated protein panel for early-stage PDAC., Methods: A comprehensive metabolomics platform was initially applied to plasmas collected from 20 PDAC cases and 80 controls. Candidate markers were filtered based on a second independent cohort that included nine invasive intraductal papillary mucinous neoplasm cases and 51 benign pancreatic cysts. Blinded validation of the resulting metabolite panel was performed in an independent test cohort consisting of 39 resectable PDAC cases and 82 matched healthy controls. The additive value of combining the metabolite panel with a previously validated protein panel was evaluated., Results: Five metabolites (acetylspermidine, diacetylspermine, an indole-derivative, and two lysophosphatidylcholines) were selected as a panel based on filtering criteria. A combination rule was developed for distinguishing between PDAC and healthy controls using the Training Set. In the blinded validation study with early-stage PDAC samples and controls, the five metabolites yielded areas under the curve (AUCs) ranging from 0.726 to 0.842, and the combined metabolite model yielded an AUC of 0.892 (95% confidence interval [CI] = 0.828 to 0.956). Performance was further statistically significantly improved by combining the metabolite panel with a previously validated protein marker panel consisting of CA 19-9, LRG1, and TIMP1 (AUC = 0.924, 95% CI = 0.864 to 0.983, comparison DeLong test one-sided P= .02)., Conclusions: A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone., (© The Author(s) 2018. Published by Oxford University Press.)
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- 2019
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29. Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes.
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Sims EK, Bahnson HT, Nyalwidhe J, Haataja L, Davis AK, Speake C, DiMeglio LA, Blum J, Morris MA, Mirmira RG, Nadler J, Mastracci TL, Marcovina S, Qian WJ, Yi L, Swensen AC, Yip-Schneider M, Schmidt CM, Considine RV, Arvan P, Greenbaum CJ, and Evans-Molina C
- Subjects
- Adolescent, Adult, C-Peptide blood, Cohort Studies, Diabetes Mellitus, Type 1 blood, Fasting metabolism, Female, Humans, Insulin blood, Male, Meals, Middle Aged, Proinsulin blood, Time Factors, Young Adult, Diabetes Mellitus, Type 1 metabolism, Proinsulin metabolism
- Abstract
Objective: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin., Research Design and Methods: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1 ) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2 ) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3 ) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years., Results: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide., Conclusions: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide., (© 2018 by the American Diabetes Association.)
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- 2019
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30. A combination of molecular markers and clinical features improve the classification of pancreatic cysts.
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Springer S, Wang Y, Dal Molin M, Masica DL, Jiao Y, Kinde I, Blackford A, Raman SP, Wolfgang CL, Tomita T, Niknafs N, Douville C, Ptak J, Dobbyn L, Allen PJ, Klimstra DS, Schattner MA, Schmidt CM, Yip-Schneider M, Cummings OW, Brand RE, Zeh HJ, Singhi AD, Scarpa A, Salvia R, Malleo G, Zamboni G, Falconi M, Jang JY, Kim SW, Kwon W, Hong SM, Song KB, Kim SC, Swan N, Murphy J, Geoghegan J, Brugge W, Fernandez-Del Castillo C, Mino-Kenudson M, Schulick R, Edil BH, Adsay V, Paulino J, van Hooft J, Yachida S, Nara S, Hiraoka N, Yamao K, Hijioka S, van der Merwe S, Goggins M, Canto MI, Ahuja N, Hirose K, Makary M, Weiss MJ, Cameron J, Pittman M, Eshleman JR, Diaz LA Jr, Papadopoulos N, Kinzler KW, Karchin R, Hruban RH, Vogelstein B, and Lennon AM
- Subjects
- Adult, Female, Genetic Predisposition to Disease, Genetic Testing methods, Humans, Male, Middle Aged, Mutation, Pancreatic Cyst genetics, Pancreatic Cyst surgery, Phenotype, Predictive Value of Tests, Prognosis, Retrospective Studies, Algorithms, Biomarkers, Tumor genetics, Pancreas pathology, Pancreatic Cyst classification, Pancreatic Cyst pathology
- Abstract
Background & Aims: The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients., Methods: We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers., Results: We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%., Conclusions: We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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- 2015
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31. Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts.
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Waters JA, Matos J, Yip-Schneider M, Aguilar-Saavedra JR, Crean CD, Beane JD, Dumas RP, Suvannasankha A, and Schmidt CM
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- Animals, Antimetabolites, Antineoplastic pharmacology, Biomarkers, Tumor antagonists & inhibitors, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Drug Administration Schedule, Humans, I-kappa B Proteins therapeutic use, Male, Mice, Mice, Nude, NF-KappaB Inhibitor alpha, NF-kappa B antagonists & inhibitors, Pancreatic Neoplasms metabolism, Random Allocation, Xenograft Model Antitumor Assays, Gemcitabine, Antimetabolites, Antineoplastic therapeutic use, Carcinoma, Pancreatic Ductal drug therapy, Deoxycytidine analogs & derivatives, Drug Resistance, Neoplasm drug effects, I-kappa B Proteins pharmacology, Pancreatic Neoplasms drug therapy
- Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model., Methods: To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks., Results: The mean increase in tumor volume was 47 mm(3) (89%) and 196 mm(3) (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm(3) (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9)., Conclusion: Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB-targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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32. Vascular endothelial growth factor: in reply to Giorgakis and colleagues.
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Yip-Schneider M and Schmidt CM
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- Female, Humans, Male, Carcinoma, Pancreatic Ductal diagnosis, Pancreatic Cyst diagnosis, Pancreatic Neoplasms diagnosis, Precancerous Conditions diagnosis, Vascular Endothelial Growth Factor A metabolism
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- 2014
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33. Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers.
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Yang Y, Liu H, Li Z, Zhao Z, Yip-Schneider M, Fan Q, Schmidt CM, Chiorean EG, Xie J, Cheng L, Chen JH, and Zhang JT
- Abstract
Human fatty acid synthase (FASN) is a homo-dimeric protein with multi-enzymatic activity responsible for the synthesis of palmitate. FASN expression has been found to be up-regulated in multiple types of human cancers and its expression correlates with poor prognosis possibly by causing treatment resistance. In this study, we tested if FASN expression is up-regulated in human pancreatic cancers and if its higher expression level in pancreatic cancers causes intrinsic resistance to gemcitabine and radiation. We found that FASN expression is significantly up-regulated in human pancreatic cancer tissues without any correlation to age, sex, race, and tumor stage. Knocking down or over-expressing FASN significantly down- or up-regulate resistance of pancreatic cancer cell lines to both gemcitabine and radiation treatments. These findings imply that the elevated FASN expression in pancreatic cancers may contribute to unsuccessful treatments of pancreatic cancers by causing intrinsic resistance to both chemotherapy and radiation therapy.
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- 2011
34. Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic cancers.
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Li Z, Dong Z, Myer D, Yip-Schneider M, Liu J, Cui P, Schmidt CM, and Zhang JT
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- Antineoplastic Agents pharmacology, Cell Cycle, Cell Line, Tumor, DNA Damage, Exoribonucleases, Gamma Rays, Humans, Lymphatic Metastasis, Pancreas metabolism, Pancreatic Neoplasms metabolism, Prognosis, Treatment Outcome, 14-3-3 Proteins physiology, Biomarkers, Tumor physiology, Drug Resistance, Neoplasm, Exonucleases physiology, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Background: Pancreatic cancer is the fourth leading cause of death in the US. Unlike other solid tumors such as testicular cancer which are now curable, more than 90% of pancreatic cancer patients die due to lack of response to therapy. Recently, the level of 14-3-3σ mRNA was found to be increased in pancreatic cancers and this increased expression may contribute to the failure in treatment of pancreatic cancers. In the present study, we tested this hypothesis., Methods: Western blot analysis was used to determine 14-3-3σ protein level in fresh frozen tissues and was correlated to clinical outcome. A stable cell line expressing 14-3-3σ was established and the effect of 14-3-3σ over-expression on cellular response to radiation and anticancer drugs were tested using SRB assay and clonogenic assays. Cell cycle distribution and apoptosis analyses were performed using propidium iodide staining and PARP cleavage assays., Results: We found that 14-3-3σ protein level was increased significantly in about 71% (17 of 24) of human pancreatic cancer tissues and that the 14-3-3σ protein level in cancers correlated with lymph node metastasis and poor prognosis. Furthermore, we demonstrated that over-expression of 14-3-3σ in a pancreatic cancer cell line caused resistance to γ-irradiation as well as anticancer drugs by causing resistance to treatment-induced apoptosis and G2/M arrest., Conclusion: The increased level of 14-3-3σ protein likely contributes to the poor clinical outcome of human pancreatic cancers by causing resistance to radiation and anticancer drugs. Thus, 14-3-3σ may serve as a prognosis marker predicting survival of pancreatic cancer patients and guide the clinical treatment of these patients.
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- 2010
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35. Natural and synthetic α,β-unsaturated carbonyls for NF-κB inhibition.
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Ramachandran PV, Yip-Schneider M, and Schmidt CM
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- Caffeic Acids chemical synthesis, Caffeic Acids chemistry, Caffeic Acids pharmacology, Flavonoids chemical synthesis, Flavonoids chemistry, Flavonoids pharmacology, NF-kappa B metabolism, Quinones chemical synthesis, Quinones chemistry, Quinones pharmacology, Sesquiterpenes chemical synthesis, Sesquiterpenes chemistry, Sesquiterpenes pharmacology, Stilbenes chemical synthesis, Stilbenes chemistry, Stilbenes pharmacology, NF-kappa B antagonists & inhibitors
- Abstract
Background: The nuclear transcription factor NF-κB has gained considerable importance due to its major involvement in inflammation and constitutive activity in malignant cells. It is induced by a variety of stimuli and controls the expression of several proteins involved in biological processes. Numerous natural products and synthesized organic molecules have been reported to inhibit NF-κB and have played an integral role in identifying implicated pathways. Prominent among them are the sesquiterpene lactones, polyphenolic enones and other α,β-unsaturated carbonyl-containing molecules, particularly α-methylene-γ-butyrolactones., Discussion: This mini-review provides an introductory overview of some of the associated pathways involving NF-κB in cancer and discusses the structures and mode of action of natural α,β-unsaturated carbonyl-containing inhibitors and their synthetic counterparts. A review of the recent methods for the synthesis of α-alkylidene-γ-butyrolactones is also provided, with the aim of arousing the interest of synthetic chemists for the design and development of novel NF-κB inhibitors., Conclusions: Modulating damaging effects without harming the inflammatory and immune responses are crucial parameters for developing NF-κB inhibitors. Examination of novel α,β-unsaturated carbonyls and the further discovery of simple methods to prepare such molecules should lead to the identification of site-specific inhibitors.
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- 2009
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36. The effect of doxorubicin on MEK-ERK signaling predicts its efficacy in HCC.
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Choi J, Yip-Schneider M, Albertin F, Wiesenauer C, Wang Y, and Schmidt CM
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- Aniline Compounds pharmacology, Antineoplastic Combined Chemotherapy Protocols, Apoptosis drug effects, Benzamides pharmacology, Butadienes pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Enzyme Inhibitors pharmacology, Humans, Nitriles pharmacology, Phosphorylation drug effects, Antibiotics, Antineoplastic pharmacology, Carcinoma, Hepatocellular drug therapy, Doxorubicin pharmacology, Liver Neoplasms drug therapy, MAP Kinase Signaling System drug effects, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
- Abstract
Background: Hepatocellular cancer (HCC) is a leading cause of cancer-related death worldwide. Historically, doxorubicin (DOX) has been widely used against unresectable HCC with variable response rates., Materials and Methods: We hypothesized that DOX combined with mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) targeted therapy may provide enhanced anti-cancer effects. Human HCC cell lines (HepG2, Hep3B) were treated with DOX and MEK enzyme inhibitors, U0126 or PD184161, alone or in combination. Growth, apoptosis, and ERK expression/MEK activity were respectively determined by proliferation assay, DNA fragmentation enzyme-linked immunoassay or fluorochrome inhibitor of caspases, and Western blot., Results: DOX (0.01-1 microM) decreased cell proliferation in Hep3B cells (IC(50) approximately 0.12 microM) at 48 to 72 h; DOX was less effective in HepG2 cells (IC(50) approximately 0.25 microM). At early time points (30 min) after DOX treatment of Hep3B cells, MEK activity was unchanged at low doses and decreased at higher doses; after 24 h, phospho-ERK levels increased at higher doses. Contrarily, in HepG2 cells, DOX caused a sustained, dose-dependent increase in phospho-ERK levels at early and late time points. The MEK inhibitor U0126 decreased phospho-ERK in both HCC lines. In contrast to DOX, HepG2 cells were more sensitive than Hep3B cells to U0126. The combination of DOX with U0126 (or PD184161) resulted in greater inhibition of proliferation in HepG2 but not in Hep3B cells. This effect may be mediated in part by enhanced apoptosis., Conclusions: The effect of DOX on early and late induction of MEK activity predicts its chemotherapeutic response in HCC. Furthermore, this effect may also determine the utility of MEK inhibitor combination treatment.
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- 2008
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37. The role of nuclear factor kappaB in pancreatic cancer and the clinical applications of targeted therapy.
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Holcomb B, Yip-Schneider M, and Schmidt CM
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- Antineoplastic Agents therapeutic use, Apoptosis, Combined Modality Therapy, Drug Resistance, Neoplasm, Humans, Models, Biological, NF-kappa B antagonists & inhibitors, Neoplasm Invasiveness, Neovascularization, Pathologic, Pancreatic Neoplasms therapy, Signal Transduction, NF-kappa B physiology, Pancreatic Neoplasms etiology, Pancreatic Neoplasms physiopathology
- Abstract
Pancreatic cancer is one of the leading causes of cancer mortality in the United States. Current therapy for pancreatic cancer involves surgery, chemotherapy, and radiation therapy; however, the 5-year survival rate remains less than 5%. New strategies for treating pancreatic cancer include targeting intracellular signaling that provides survival advantages to cancer cells. One of these targets is the transcription factor nuclear factor (NF) kappaB, which is activated by a variety of mechanisms. Data demonstrate that increased NF-kappaB activity can promote growth and tumorigenesis, inhibit apoptosis, promote angiogenesis, promote invasion and metastasis, and promote chemoresistance in pancreatic cancer. This review explores the roles of NF-JB in these processes and examines the evidence that different NF-kappaB-inhibiting drugs can improve the treatment of pancreatic cancer.
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- 2008
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38. Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model.
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Shanmugam R, Jayaprakasan V, Gokmen-Polar Y, Kelich S, Miller KD, Yip-Schneider M, Cheng L, Bhat-Nakshatri P, Sledge GW Jr, Nakshatri H, Zheng QH, Miller MA, DeGrado T, Hutchins GD, and Sweeney CJ
- Subjects
- Androgen Antagonists pharmacology, Anilides pharmacology, Animals, Antineoplastic Agents, Phytogenic pharmacology, Bridged-Ring Compounds pharmacology, Cell Line, Tumor, Docetaxel, Drug Synergism, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Fibroblast Growth Factor 2 metabolism, Humans, JNK Mitogen-Activated Protein Kinases metabolism, Male, Mice, Mice, Nude, NF-kappa B metabolism, Neovascularization, Pathologic diagnostic imaging, Nitriles, Prostatic Neoplasms diagnostic imaging, Radionuclide Imaging, TNF Receptor-Associated Factor 1 metabolism, TNF Receptor-Associated Factor 2 metabolism, Taxoids pharmacology, Tosyl Compounds, Umbilical Veins cytology, Vascular Endothelial Growth Factor A metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Neovascularization, Pathologic drug therapy, Prostatic Neoplasms drug therapy, Sesquiterpenes pharmacology
- Abstract
Background: Nuclear Factor kappa B (NFkappaB) is a eukaryotic transcription factor that is constitutively active in human cancers and can be inhibited by the naturally occurring sesquiterpene lactone, parthenolide (P)., Methods: The in vitro effects of P were assessed using the androgen independent cell line, CWR22Rv1, and human umbilical endothelial cells (HUVECs). The in vivo activity of P as a single agent and its ability to augment the efficacy of docetaxel and the anti-androgen, bicalutamide, were determined using the CWR22Rv1 xenograft model., Results: Parthenolide at low micromolar concentration inhibited proliferation of CWR22Rv1 and HUVEC cells, promoted apoptosis and abrogated NFkappaB-DNA binding. Parthenolide downregulated anti-apoptotic genes under NFkappaB control, TRAF 1 and 2, and promoted sustained activation of c-jun-NH2 kinase (JNK). Parthenolide also augmented the in vivo efficacy of docetaxel and restored sensitivity to anti-androgen therapy., Conclusion: These studies demonstrate parthenolide's anti-tumor and anti-angiogenic activity, and its potential to augment the efficacy of chemotherapy and hormonal therapy., ((c) 2006 Wiley-Liss, Inc.)
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- 2006
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39. Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells.
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Yip-Schneider MT, Sweeney CJ, Jung SH, Crowell PL, and Marshall MS
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- Apoptosis drug effects, Blotting, Western, Cell Cycle Proteins biosynthesis, Cell Division drug effects, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors pharmacology, Deoxycytidine analogs & derivatives, Humans, Isoenzymes biosynthesis, Isoenzymes drug effects, Male, Membrane Proteins, Pancreatic Neoplasms metabolism, Prostaglandin-Endoperoxide Synthases biosynthesis, Prostaglandin-Endoperoxide Synthases drug effects, Sulindac pharmacology, Tumor Cells, Cultured, Gemcitabine, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cell Cycle drug effects, Deoxycytidine pharmacology, Enzyme Inhibitors pharmacology, Pancreatic Neoplasms pathology
- Abstract
Increased cyclooxygenase-2 (COX-2) expression in human pancreatic adenocarcinomas, as well as the growth-inhibitory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, suggests that NSAIDs may be an effective treatment for pancreatic cancer. Gemcitabine is currently the most effective chemotherapeutic drug available for patients with pancreatic cancer, but is only minimally effective against this aggressive disease. Clearly, other treatment options must be identified. To design successful therapeutic strategies involving compounds either alone or in combination with others, it is necessary to understand their mechanism of action. In the present study, we evaluated the effects of three NSAIDs (sulindac, indomethacin, and NS-398) or gemcitabine in two human pancreatic carcinoma cell lines, BxPC-3 (COX-2-positive) and PaCa-2 (COX-2-negative), previously shown to be growth-inhibited by these NSAIDs. Effects on cell cycle and apoptosis were investigated by flow cytometry or Western blotting. Treatment with NSAIDs or gemcitabine altered the cell cycle phase distribution as well as the expression of multiple cell cycle regulatory proteins in both cell lines, but did not induce substantial levels of apoptosis. Furthermore, we demonstrated that the combination of the NSAID sulindac or NS-398 with gemcitabine inhibited cell growth to a greater degree than either compound alone. These results indicate that the antiproliferative effects of NSAIDs and gemcitabine in pancreatic tumor cells are primarily due to inhibition of cell cycle progression rather than direct induction of apoptotic cell death, regardless of COX-2 expression. In addition, NSAIDs in combination with gemcitabine may hold promise in the clinic for the treatment of pancreatic cancer.
- Published
- 2001
40. Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2.
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Yip-Schneider MT, Lin A, and Marshall MS
- Subjects
- Animals, Blotting, Western, Carcinoma enzymology, Cell Line, Down-Regulation, Dual-Specificity Phosphatases, Enzyme Inhibitors pharmacology, Humans, Kinetics, Mitogen-Activated Protein Kinase Phosphatases, Pancreatic Neoplasms enzymology, Phosphorylation drug effects, Protein Phosphatase 2, Rats, Signal Transduction, Time Factors, Tumor Cells, Cultured, Up-Regulation, Vanadates pharmacology, Carcinoma genetics, Gene Expression Regulation, Enzymologic, Genes, ras genetics, Mitogen-Activated Protein Kinase Kinases metabolism, Mitogen-Activated Protein Kinases metabolism, Mutation, Pancreatic Neoplasms genetics, Protein Tyrosine Phosphatases metabolism
- Abstract
Activating mutations within the K-ras gene occur in a high percentage of human pancreatic carcinomas. We reported previously that the presence of oncogenic, activated K-ras in human pancreatic carcinoma cell lines did not result in constitutive activation of the extracellular signal-regulated kinases (ERK1 and ERK2). In the present study, we further characterized the ERK signaling pathway in pancreatic tumor cell lines in order to determine whether the ERK pathway is subject to a compensatory downregulation. We found that the attenuation of serum-induced ERK activation was not due to a delay in the kinetics of ERK phosphorylation. Treatment with the tyrosine phosphatase inhibitor orthovanadate increased the level of ERK phosphorylation, implicating a vanadate-sensitive tyrosine phosphatase in the negative regulation of ERK. Furthermore, expression of a dual specificity phosphatase capable of inactivating ERK known as mitogen-activated protein (MAP) kinase phosphatase-2 (MKP-2) was elevated in most of the pancreatic tumor cell lines and correlated with the presence of active MAP kinase kinase (MEK). Taken together, these results suggest that pancreatic tumor cells expressing oncogenic K-ras compensate, in part, by upregulating the expression of MKP-2 to repress the ERK signaling pathway., (Copyright 2001 Academic Press.)
- Published
- 2001
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41. Regulation of the Raf-1 kinase domain by phosphorylation and 14-3-3 association.
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Yip-Schneider MT, Miao W, Lin A, Barnard DS, Tzivion G, and Marshall MS
- Subjects
- 14-3-3 Proteins, Animals, Binding, Competitive, COS Cells, Catalytic Domain, Enzyme Activation drug effects, Mutation genetics, Oncogene Protein pp60(v-src) genetics, Oncogene Protein pp60(v-src) metabolism, Peptide Fragments chemistry, Peptide Fragments metabolism, Phosphorylation, Phosphoserine metabolism, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-raf genetics, Tetradecanoylphorbol Acetate pharmacology, Tyrosine 3-Monooxygenase genetics, Proto-Oncogene Proteins c-raf chemistry, Proto-Oncogene Proteins c-raf metabolism, Tyrosine 3-Monooxygenase metabolism
- Abstract
The Raf-1 kinase domain is kept in an inactive state by the N-terminal regulatory domain. Activation of the kinase domain occurs following release from the N-terminal repression and possible catalytic upregulation. To distinguish the regulatory mechanisms that directly influence the catalytic activity of the enzyme from those which act through the inhibitory domain, the catalytic domain of Raf-1 (CR3) was expressed in COS-7 cells. The role of phosphorylation in the direct regulation of this domain was determined by substituting non-phosphorylatable amino acids for known serine and tyrosine phosphorylation sites. The intrinsic activity of each mutant protein was determined as well as stimulation by v-Src and phorbol esters. Both v-Src and phorbol esters were potent activators of CR3, requiring the serine 338/339 (p21-activated protein kinase, Pak) and tyrosine 340/341 (Src) phosphorylation sites for full stimulation of CR3. In contrast, loss of the serine 497/499 protein kinase C phosphorylation sites had little effect on CR3 activation by either v-Src or phorbol esters. Loss of serine 621, a 14-3-3 adaptor-protein-binding site, prevented activation of CR3 by v-Src or phorbol esters and partially decreased the high basal activity of the kinase fragment. When co-expressed in COS-7 cells, 14-3-3 associated strongly with full-length Raf-1, weakly with wild-type CR3 and not at all with the A621 and D621 CR3 mutants. The role of 14-3-3 in maintaining the activity of the catalytic domain of Raf-1 was investigated further by performing peptide-competition studies with wild-type CR3, wild-type CR3 and v-Src or constitutively active CR3 (CR3[YY340/341DD]). In each case, incubation of the proteins with a phosphoserine-621 Raf-1 peptide, which we show displaced Raf-1 and CR3[YY340/341DD] from 14-3-3, was found to substantially reduce catalytic activity. Taken together, our results support a model of Raf regulation in which the activity of the Raf-1 catalytic domain is directly upregulated by phosphorylation, following relief of inhibition by the N-terminal regulatory domain upon Ras-GTP binding. Moreover, the presence of serine 621 in the free catalytic fragment is required for full CR3 activation by stimulatory factors, and the continuous presence of 14-3-3 at this site is necessary for retaining activity once the kinase is activated.
- Published
- 2000
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42. Transcriptional induction of pim-1 protein kinase gene expression by interferon gamma and posttranscriptional effects on costimulation with steel factor.
- Author
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Yip-Schneider MT, Horie M, and Broxmeyer HE
- Subjects
- Base Sequence, Binding Sites genetics, Drug Synergism, Gene Expression drug effects, Humans, Leukemia metabolism, Molecular Sequence Data, Promoter Regions, Genetic genetics, Protein Serine-Threonine Kinases biosynthesis, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-pim-1, RNA, Messenger biosynthesis, Recombinant Proteins, Stem Cell Factor, Transcription, Genetic drug effects, Tumor Cells, Cultured, Hematopoietic Cell Growth Factors pharmacology, Interferon-gamma pharmacology, Proto-Oncogene Proteins biosynthesis
- Abstract
Steel factor (SLF) synergizes with interferon gamma (IFN gamma) to stimulate proliferation of the human factor-dependent cell line MO7e. We examined the effects of IFN gamma and SLF treatment, alone or in combination, on the expression of a 33-kD cytoplasmic protein serine/threonine kinase designated pim-1 whose expression has been closely associated with proliferation induced by related myeloid cytokines. IFN gamma alone, but not SLF, stimulated expression of pim-1 RNA and protein in MO7e cells; compared with IFN gamma alone, costimulation with IFN gamma and SLF resulted in a twofold to threefold increase in pim-1 message and protein expression, correlating with synergistic effects on cell proliferation. Both IFN gamma and IFN gamma/SLF induced pim-1 mRNA in the absence of de novo protein synthesis. Nuclear run-on assays showed that, although IFN gamma alone increased the rate of pim-1 gene transcription, costimulation with IFN gamma and SLF did not further potentiate this effect; however, the stability of pim-1 message was significantly enhanced in the presence of both cytokines. An IFN gamma-responsive element within the 5' flanking region of the pim-1 gene that could confer IFN gamma responsiveness on a heterologous promoter was identified. This sequence, designated PMGAS, formed a specific complex with Stat (signal transducers and activators of transcription) 1 alpha (the p91 subunit of the transcription factor ISGF3 [interferon-stimulated gene factor 3]) in IFN gamma-treated cell extracts, suggesting that the transcriptional effects of IFN gamma on pim-1 expression may be mediated by Stat 1 alpha.
- Published
- 1995
43. Commentary: a rapid proliferation assay for unknown co-stimulating factors in cord blood plasma possibly involved in enhancement of in vitro expansion and replating capacity of human hematopoietic stem/progenitor cells.
- Author
-
Broxmeyer HE, Benninger L, Yip-Schneider M, and Braun SE
- Subjects
- Cell Division drug effects, Culture Techniques instrumentation, Fetal Blood chemistry, Hematopoietic Cell Growth Factors classification, Hematopoietic Cell Growth Factors pharmacology, Hematopoietic Stem Cells drug effects, Humans, Infant, Newborn, Colony-Forming Units Assay, Fetal Blood cytology, Hematopoietic Cell Growth Factors blood, Hematopoietic Stem Cells cytology, Membrane Proteins pharmacology, Plasma chemistry
- Published
- 1994
44. Characterization of interleukin-7-induced changes in tyrosine phosphorylation and c-myc gene expression in normal human T cells.
- Author
-
Yip-Schneider MT, Horie M, and Broxmeyer HE
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Blotting, Northern, Cell Division, Humans, Immunoblotting, Isoquinolines pharmacology, Molecular Weight, Phosphorylation, Phosphotyrosine, Piperazines pharmacology, Protein Kinase Inhibitors, Protein Kinases metabolism, Signal Transduction, T-Lymphocytes cytology, Tetradecanoylphorbol Acetate pharmacology, Transcription, Genetic, Tyrosine metabolism, Gene Expression drug effects, Genes, myc, Interleukin-7 pharmacology, Phosphoproteins metabolism, T-Lymphocytes metabolism, Tyrosine analogs & derivatives
- Abstract
Interleukin-7 (IL-7) is a growth factor involved in regulating lymphopoiesis. We have chosen to study the signal transduction pathway of IL-7 in normal human peripheral blood T lymphocytes. Two early events that occur as a consequence of specific ligand-receptor interaction were examined: activation of protein tyrosine kinases and induction of primary response gene expression. Following treatment of human peripheral blood T cells with IL-7, four cellular proteins with relative molecular weights of 95- (doublet), 105-, and 130-kd were rapidly tyrosine phosphorylated as detected by immunoblotting with an antiphosphotyrosine monoclonal antibody (MAB). The 105-kd tyrosine-phosphorylated protein was membrane-associated after IL-7 stimulation. Treatment of human peripheral blood T cells with IL-7 enhanced expression of the primary response gene c-myc approximately three-fold, as detected by Northern blotting, in the presence or absence of protein synthesis. The rate of c-myc gene transcription increased in the presence of IL-7 and could account for the observed elevation of c-myc RNA levels. In addition, IL-7 treatment induced a slight increase in c-myc message stability. Experiments performed with the protein tyrosine kinase inhibitor genistein and the serine-threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) demonstrated that these kinases were required for IL-7 enhancement of c-myc expression. Treatment with tetradecanoyl phorbol acetate (TPA), a potent activator of protein kinase C (PKC), in combination with IL-7 induced a level of c-myc expression greater than that elicited by either factor alone, suggesting that TPA and IL-7 utilize cooperative signaling pathways to increase c-myc gene expression.
- Published
- 1993
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