, a bio/informatics shared resource is still "open for business" - Visit the CDS website


Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 11 to 20 of 44

Publication Record

Connections

Pyruvate Kinase Muscle Isoenzyme 2 (PKM2) Expression Is Associated with Overall Survival in Pancreatic Ductal Adenocarcinoma.
Lockney NA, Zhang M, Lu Y, Sopha SC, Washington MK, Merchant N, Zhao Z, Shyr Y, Chakravarthy AB, Xia F
(2015) J Gastrointest Cancer 46: 390-8
MeSH Terms: Aged, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Carrier Proteins, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Male, Membrane Proteins, Middle Aged, Neoplasm Grading, Neoplasm Staging, Pancreatic Neoplasms, Prognosis, Survival Rate, Thyroid Hormones, Tissue Array Analysis
Show Abstract · Added February 22, 2016
PURPOSE - Pyruvate kinase muscle isoenzyme 2 (PKM2) is a key enzyme in aerobic glycolysis and is thought to contribute to cancer cell metabolic reprogramming. The aim of this study was to evaluate PKM2 immunohistochemical expression as a potential prognostic biomarker in pancreatic ductal adenocarcinoma (PDAC).
METHODS - A tissue microarray was constructed using surgical specimens for 115 patients who underwent resections for PDAC, stained with PKM2 antibody, and scored for expression level. Statistical analyses were performed to investigate the association between PKM2 and patient survival, tumor stage, tumor grade, surgical margin status, lymph node ratio, perineural invasion status, or the use of adjuvant chemotherapy.
RESULTS - Fifty-three percent of tumors had positive PKM2 expression, and 47 % of tumors had negative PKM2 expression. PKM2 expression was associated with overall survival (HR 0.56, p = 0.007) and CA 19-9 levels (p = 0.035), but was not associated with tumor stage, tumor grade, surgical margin status, lymph node ratio, perineural invasion, or adjuvant chemotherapy use.
CONCLUSIONS - PKM2 expression is associated with overall survival in PDAC. Further studies are warranted to validate the value of PKM2 as a prognostic biomarker and to examine the potential utility of PKM2 in predicting treatment response, as well as a potential therapeutic target in PDAC.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer.
Nagathihalli NS, Castellanos JA, Shi C, Beesetty Y, Reyzer ML, Caprioli R, Chen X, Walsh AJ, Skala MC, Moses HL, Merchant NB
(2015) Gastroenterology 149: 1932-1943.e9
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Collagen, Deoxycytidine, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Humans, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Molecular Targeted Therapy, Neoplasm Staging, Osteonectin, Pancreatic Neoplasms, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins p21(ras), Pyrazoles, Pyrimidines, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, STAT3 Transcription Factor, Signal Transduction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Stromal Cells, Time Factors, Transcription Factors, Transfection, Tumor Burden, Tumor Microenvironment, Xenograft Model Antitumor Assays
Show Abstract · Added October 15, 2015
BACKGROUND & AIMS - A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance.
METHODS - Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density.
RESULTS - STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase.
CONCLUSIONS - Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
3 Members
0 Resources
33 MeSH Terms
Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing.
Chiou SH, Winters IP, Wang J, Naranjo S, Dudgeon C, Tamburini FB, Brady JJ, Yang D, Grüner BM, Chuang CH, Caswell DR, Zeng H, Chu P, Kim GE, Carpizo DR, Kim SK, Winslow MM
(2015) Genes Dev 29: 1576-85
MeSH Terms: Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, Clustered Regularly Interspaced Short Palindromic Repeats, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Genetic Vectors, Genome, Humans, Lentivirus, Mice, Mice, Inbred C57BL, Mice, Transgenic
Show Abstract · Added September 7, 2016
Pancreatic ductal adenocarcinoma (PDAC) is a genomically diverse, prevalent, and almost invariably fatal malignancy. Although conventional genetically engineered mouse models of human PDAC have been instrumental in understanding pancreatic cancer development, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately understand this disease. Here we demonstrate that retrograde pancreatic ductal injection of either adenoviral-Cre or lentiviral-Cre vectors allows titratable initiation of pancreatic neoplasias that progress into invasive and metastatic PDAC. To enable in vivo CRISPR/Cas9-mediated gene inactivation in the pancreas, we generated a Cre-regulated Cas9 allele and lentiviral vectors that express Cre and a single-guide RNA. CRISPR-mediated targeting of Lkb1 in combination with oncogenic Kras expression led to selection for inactivating genomic alterations, absence of Lkb1 protein, and rapid tumor growth that phenocopied Cre-mediated genetic deletion of Lkb1. This method will transform our ability to rapidly interrogate gene function during the development of this recalcitrant cancer.
© 2015 Chiou et al.; Published by Cold Spring Harbor Laboratory Press.
0 Communities
0 Members
0 Resources
13 MeSH Terms
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.
Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC
(2015) Elife 4:
MeSH Terms: Acinar Cells, Adenocarcinoma, Animals, Carcinoma in Situ, Carcinoma, Pancreatic Ductal, Cell Transdifferentiation, Disease Models, Animal, Gene Expression Profiling, Humans, Mice, Transcription Factors
Show Abstract · Added August 4, 2015
Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R
(2014) Cancer Cell 25: 719-34
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Disease Models, Animal, Fibroblasts, Fibrosis, Humans, Immune Tolerance, Mice, Mice, Transgenic, Pancreatic Neoplasms, Survival Analysis
Show Abstract · Added May 27, 2014
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
Copyright © 2014 Elsevier Inc. All rights reserved.
2 Communities
1 Members
0 Resources
11 MeSH Terms
Loss of HNF6 expression correlates with human pancreatic cancer progression.
Pekala KR, Ma X, Kropp PA, Petersen CP, Hudgens CW, Chung CH, Shi C, Merchant NB, Maitra A, Means AL, Gannon MA
(2014) Lab Invest 94: 517-27
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Disease Progression, Hepatocyte Nuclear Factor 6, Homeostasis, Humans, Liver Neoplasms, Experimental, Mice, Mice, Inbred C57BL, Pancreatic Neoplasms
Show Abstract · Added March 26, 2014
Normal pancreatic epithelium progresses through various stages of pancreatic intraepithelial neoplasms (PanINs) in the development of pancreatic ductal adenocarcinoma (PDAC). Transcriptional regulation of this progression is poorly understood. In mouse, the hepatic nuclear factor 6 (Hnf6) transcription factor is expressed in ductal cells and at lower levels in acinar cells of the adult pancreas, but not in mature endocrine cells. Hnf6 is critical for terminal differentiation of the ductal epithelium during embryonic development and for pancreatic endocrine cell specification. We previously showed that, in mice, loss of Hnf6 from the pancreatic epithelium during organogenesis results in increased duct proliferation and altered duct architecture, increased periductal fibrosis and acinar-to-ductal metaplasia. Here we show that decreased expression of HNF6 is strongly correlated with increased severity of PanIN lesions in samples of human pancreata and is absent from >90% of PDAC. Mouse models in which cancer progression can be analyzed from the earliest stages that are seldom accessible in humans support a role for Hnf6 loss in progression from early- to late-stage PanIN and PDAC. In addition, gene expression analyses of human pancreatic cancer reveal decreased expression of HNF6 and its direct and indirect target genes compared with normal tissue and upregulation of genes that act in opposition to HNF6 and its targets. The negative correlation between HNF6 expression and pancreatic cancer progression suggests that HNF6 maintains pancreatic epithelial homeostasis in humans, and that its loss contributes to the progression from PanIN to ductal adenocarcinoma. Insight on the role of HNF6 in pancreatic cancer development could lead to its use as a biomarker for early detection and prognosis.
1 Communities
3 Members
0 Resources
11 MeSH Terms
Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction.
Shi C, Washington MK, Chaturvedi R, Drosos Y, Revetta FL, Weaver CJ, Buzhardt E, Yull FE, Blackwell TS, Sosa-Pineda B, Whitehead RH, Beauchamp RD, Wilson KT, Means AL
(2014) Lab Invest 94: 409-21
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Line, Disease Models, Animal, Disease Progression, Fibrosis, Macrophages, Metaplasia, Mice, Pancreas, Pancreatic Neoplasms, Pancreatic Stellate Cells, Receptor Cross-Talk
Show Abstract · Added March 5, 2014
Pancreatic cancer occurs in the setting of a profound fibrotic microenvironment that often dwarfs the actual tumor. Although pancreatic fibrosis has been well studied in chronic pancreatitis, its development in pancreatic cancer is much less well understood. This article describes the dynamic remodeling that occurs from pancreatic precursors (pancreatic intraepithelial neoplasias (PanINs)) to pancreatic ductal adenocarcinoma, highlighting similarities and differences between benign and malignant disease. Although collagen matrix is a commonality throughout this process, early stage PanINs are virtually free of periostin while late stage PanIN and pancreatic cancer are surrounded by an increasing abundance of this extracellular matrix protein. Myofibroblasts also become increasingly abundant during progression from PanIN to cancer. From the earliest stages of fibrogenesis, macrophages are associated with this ongoing process. In vitro co-culture indicates there is cross-regulation between macrophages and pancreatic stellate cells (PaSCs), precursors to at least some of the fibrotic cell populations. When quiescent PaSCs were co-cultured with macrophage cell lines, the stellate cells became activated and the macrophages increased cytokine production. In summary, fibrosis in pancreatic cancer involves a complex interplay of cells and matrices that regulate not only the tumor epithelium but the composition of the microenvironment itself.
1 Communities
6 Members
0 Resources
13 MeSH Terms
Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry.
Shi C, Merchant N, Newsome G, Goldenberg DM, Gold DV
(2014) Arch Pathol Lab Med 138: 220-8
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Diagnosis, Differential, Humans, Immunohistochemistry, Mucin-1, Neoplasm Grading, Neoplasm Staging, Pancreas, Pancreatectomy, Pancreatic Cyst, Pancreatic Ducts, Pancreatic Neoplasms, Pancreatitis, Chronic, Precancerous Conditions, Tissue Array Analysis
Show Abstract · Added March 10, 2014
CONTEXT - PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC.
OBJECTIVE - To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas.
DESIGN - Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9.
RESULTS - PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue.
CONCLUSIONS - PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Timing versus duration of adjuvant therapy for pancreatic cancer: all the lessons we need in life are taught to us as children.
Chan E, Berlin J
(2014) J Clin Oncol 32: 487-8
MeSH Terms: Adenocarcinoma, Carcinoma, Pancreatic Ductal, Female, Humans, Male, Pancreatic Neoplasms
Added March 20, 2014
0 Communities
2 Members
0 Resources
6 MeSH Terms
Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the society of abdominal radiology and the american pancreatic association.
Al-Hawary MM, Francis IR, Chari ST, Fishman EK, Hough DM, Lu DS, Macari M, Megibow AJ, Miller FH, Mortele KJ, Merchant NB, Minter RM, Tamm EP, Sahani DV, Simeone DM
(2014) Gastroenterology 146: 291-304.e1
MeSH Terms: Carcinoma, Pancreatic Ductal, Documentation, Humans, Pancreatic Neoplasms, Radiology, Tomography, X-Ray Computed
Show Abstract · Added March 10, 2014
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions.
Copyright © 2014 AGA Institute and RSNA. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
6 MeSH Terms