Publications by authors named "Teresa A Brentnall"

97 Publications

PolyG-DS: An ultrasensitive polyguanine tract-profiling method to detect clonal expansions and trace cell lineage.

Proc Natl Acad Sci U S A 2021 Aug;118(31)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195;

Polyguanine tracts (PolyGs) are short guanine homopolymer repeats that are prone to accumulating mutations when cells divide. This feature makes them especially suitable for cell lineage tracing, which has been exploited to detect and characterize precancerous and cancerous somatic evolution. PolyG genotyping, however, is challenging because of the inherent biochemical difficulties in amplifying and sequencing repetitive regions. To overcome this limitation, we developed PolyG-DS, a next-generation sequencing (NGS) method that combines the error-correction capabilities of duplex sequencing (DS) with enrichment of PolyG loci using CRISPR-Cas9-targeted genomic fragmentation. PolyG-DS markedly reduces technical artifacts by comparing the sequences derived from the complementary strands of each original DNA molecule. We demonstrate that PolyG-DS genotyping is accurate, reproducible, and highly sensitive, enabling the detection of low-frequency alleles (<0.01) in spike-in samples using a panel of only 19 PolyG markers. PolyG-DS replicated prior results based on PolyG fragment length analysis by capillary electrophoresis, and exhibited higher sensitivity for identifying clonal expansions in the nondysplastic colon of patients with ulcerative colitis. We illustrate the utility of this method for resolving the phylogenetic relationship among precancerous lesions in ulcerative colitis and for tracing the metastatic dissemination of ovarian cancer. PolyG-DS enables the study of tumor evolution without prior knowledge of tumor driver mutations and provides a tool to perform cost-effective and easily scalable ultra-accurate NGS-based PolyG genotyping for multiple applications in biology, genetics, and cancer research.
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http://dx.doi.org/10.1073/pnas.2023373118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346827PMC
August 2021

X-aptamers targeting Thy-1 membrane glycoprotein in pancreatic ductal adenocarcinoma.

Biochimie 2021 Feb 23;181:25-33. Epub 2020 Nov 23.

The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA; Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. Electronic address:

Modified DNA aptamers incorporated with amino-acid like side chains or drug-like ligands can offer unique advantages and enhance specificity as affinity ligands. Thy-1 membrane glycoprotein (THY1 or CD90) was previously identified as a biomarker candidate of neovasculature in pancreatic ductal adenocarcinoma (PDAC). The current study developed and evaluated modified DNA X-aptamers targeting THY1 in PDAC. The expression and glycosylation of THY1 in PDAC tumor tissues were assessed using immunohistochemistry and quantitative proteomics. Bead-based X-aptamer library that contains 10 different sequences was used to screen for high affinity THY1 X-aptamers. The sequences of the X-aptamers were analyzed with the next-generation sequencing. The affinities of the selected X-aptamers to THY1 were quantitatively evaluated with flow cytometry. Three high affinity THY1 X-aptamers, including XA-B217, XA-B216 and XA-A9, were selected after library screening and affinity binding evaluation. These three X-aptamers demonstrated a high binding affinity and specificity to THY1 protein and the THY1 expressing cell lines, using THY1 antibody as a comparison. The development of these X-aptamers provides highly specific and non-immunogenic affinity ligands for THY1 binding in the context of biomarker development and clinical applications. They could be further exploited to assist molecular imaging of PDAC targeting THY1.
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http://dx.doi.org/10.1016/j.biochi.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863625PMC
February 2021

Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients.

Cancers (Basel) 2020 Jun 11;12(6). Epub 2020 Jun 11.

Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population.

Methods: A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels.

Results: Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels.

Conclusions: Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.
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http://dx.doi.org/10.3390/cancers12061534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352938PMC
June 2020

Proteome alterations in pancreatic ductal adenocarcinoma.

Cancer Lett 2020 01 14;469:429-436. Epub 2019 Nov 14.

Division of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

Proteins are the essential functional biomolecules profoundly implicated in all aspects of pancreatic tumorigenesis and its progression. While common genomic factors, such as KRAS, TP53, SMAD4, and CDKN2A have been well recognized in association of pancreatic ductal adenocarcinoma (PDAC), our understanding of functional changes at the proteome level merits further investigation. Malignance associated proteome alterations can be attributed to the convoluted outcomes from genetic, epigenetic and environmental factors in initiating and progressing PDAC, and may reflect on changes in protein expressional level, structure, localization, as well as post-translational modifications (PTMs) status. The study of localized or systemic proteome alterations in PDAC, as well as its precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN) and mucinous pancreatic cystic neoplasm, would provide unique perspectives in elucidating functional molecular events underlying PDAC. While efforts have been made, challenges still exist to comprehensively integrate much of the proteomic discovery to the perspectives gained from genomic studies in the context of biomarker discovery. Novel approaches and data from well-defined longitudinal clinical studies and experimental models are needed to facilitate the study of PDAC and precursor lesions for early detection and intervention.
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http://dx.doi.org/10.1016/j.canlet.2019.11.020DOI Listing
January 2020

Predictive proteomic signatures for response of pancreatic cancer patients receiving chemotherapy.

Clin Proteomics 2019 17;16:31. Epub 2019 Jul 17.

1Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, TX 77030 USA.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that is characterized by its poor prognosis, rapid progression and development of drug resistance. Chemotherapy is a vital treatment option for most of PDAC patients. Stratification of PDAC patients, who would have a higher likelihood of responding to chemotherapy, could facilitate treatment selection and patient management.

Methods: A quantitative proteomic study was performed to characterize the protein profiles in the plasma of PDAC patients undergoing chemotherapy to determine if specific biomarkers could be used to predict likelihood of therapeutic response.

Results: By comparing the plasma proteome of the PDAC patients with positive therapeutic response and longer overall survival (Good-responders) to those who did not respond as well with shorter survival time (Limited-responders), we identified differential proteins and protein variants that could effectively segregate Good-responders from Limited-responders. Functional clustering and pathway analysis further suggested that many of these differential proteins were involved in pancreatic tumorigenesis. Four proteins, including vitamin-K dependent protein Z (PZ), sex hormone-binding globulin (SHBG), von Willebrand factor (VWF) and zinc-alpha-2-glycoprotein (AZGP1), were further evaluated as single or composite predictive biomarker with/without inclusion of CA 19-9. A composite biomarker panel that consists of PZ, SHBG, VWF and CA 19-9 demonstrated the best performance in distinguishing Good-responders from Limited-responders.

Conclusion: Based on the cohort investigated, our data suggested that systemic proteome alterations involved in pathways associated with inflammation, immunoresponse, coagulation and complement cascades may be reporters of chemo-treatment outcome in PDAC patients. For the majority of the patients involved, the panel consisting of PZ, SHBG, VWF and CA 19-9 was able to segregate Good-responders from Limited-responders effectively. Our data also showed that dramatic fluctuations of biomarker concentration in the circulating system of a PDAC patient, which might result from biological heterogeneity or confounding complications, could diminish the performance of a biomarker. Categorization of PDAC patients in terms of their tumor stages and histological types could potentially facilitate patient stratification for treatment.
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http://dx.doi.org/10.1186/s12014-019-9251-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636003PMC
July 2019

Mitochondrial DNA Mutations are Associated with Ulcerative Colitis Preneoplasia but Tend to be Negatively Selected in Cancer.

Mol Cancer Res 2019 02 16;17(2):488-498. Epub 2018 Nov 16.

Department of Pathology, University of Washington, Seattle, Washington.

The role of mitochondrial DNA (mtDNA) mutations in cancer remains controversial. Ulcerative colitis is an inflammatory bowel disease that increases the risk of colorectal cancer and involves mitochondrial dysfunction, making it an ideal model to study the role of mtDNA in tumorigenesis. Our goal was to comprehensively characterize mtDNA mutations in ulcerative colitis tumorigenesis using Duplex Sequencing, an ultra-accurate next-generation sequencing method. We analyzed 46 colon biopsies from non-ulcerative colitis control patients and ulcerative colitis patients with and without cancer, including biopsies at all stages of dysplastic progression. mtDNA was sequenced at a median depth of 1,364x. Mutations were classified by mutant allele frequency: clonal > 0.95, subclonal 0.01-0.95, and very low frequency (VLF) < 0.01. We identified 208 clonal and subclonal mutations and 56,764 VLF mutations. Mutations were randomly distributed across the mitochondrial genome. Clonal and subclonal mutations increased in number and pathogenicity in early dysplasia, but decreased in number and pathogenicity in cancer. Most clonal, subclonal, and VLF mutations were C>T transitions in the heavy strand of mtDNA, which likely arise from DNA replication errors. A subset of VLF mutations were C>A transversions, which are probably due to oxidative damage. VLF transitions and indels were less abundant in the non-D-loop region and decreased with progression. Our results indicate that mtDNA mutations are frequent in ulcerative colitis preneoplasia but negatively selected in cancers. IMPLICATIONS: While mtDNA mutations might contribute to early ulcerative colitis tumorigenesis, they appear to be selected against in cancer, suggesting that functional mitochondria might be required for malignant transformation in ulcerative colitis.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481604PMC
February 2019

Similarities and Differences of Blood N-Glycoproteins in Five Solid Carcinomas at Localized Clinical Stage Analyzed by SWATH-MS.

Cell Rep 2018 05;23(9):2819-2831.e5

Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland; Faculty of Science, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection.
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http://dx.doi.org/10.1016/j.celrep.2018.04.114DOI Listing
May 2018

Precancer in ulcerative colitis: the role of the field effect and its clinical implications.

Carcinogenesis 2018 01;39(1):11-20

Division of Gasteroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.

Cumulative evidence indicates that a significant proportion of cancer evolution may occur before the development of histological abnormalities. While recent improvements in DNA sequencing technology have begun to reveal the presence of these early preneoplastic clones, the concept of 'premalignant field' was already introduced by Slaughter more than half a century ago. Also referred to as 'field effect', 'field defect' or 'field cancerization', these terms describe the phenomenon by which molecular alterations develop in normal-appearing tissue and expand to form premalignant patches with the potential to progress to dysplasia and cancer. Field effects have been well-characterized in ulcerative colitis, an inflammatory bowel disease that increases the risk of colorectal cancer. The study of the molecular alterations that define these fields is informative of mechanisms of tumor initiation and progression and has provided potential targets for early cancer detection. Herein, we summarize the current knowledge about the molecular alterations that comprise the field effect in ulcerative colitis and the clinical utility of these fields for cancer screening and prevention.
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http://dx.doi.org/10.1093/carcin/bgx117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248676PMC
January 2018

Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer.

Sci Rep 2017 08 11;7(1):7950. Epub 2017 Aug 11.

Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.
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http://dx.doi.org/10.1038/s41598-017-08436-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554139PMC
August 2017

Spectral library-based glycopeptide analysis-detection of circulating galectin-3 binding protein in pancreatic cancer.

Proteomics Clin Appl 2017 09 10;11(9-10). Epub 2017 Jul 10.

Department of Medicine, University of Washington, Seattle, WA, USA.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by its late diagnosis, poor prognosis and rapid development of drug resistance. Using the data-independent acquisition (DIA) technique, the authors applied a spectral library-based proteomic approach to analyze N-glycosylated peptides in human plasma, in the context of pancreatic cancer study.

Experimental Design: The authors extended the application of DIA to the quantification of N-glycosylated peptides enriched from plasma specimens from a clinically well-defined cohort that consists of patients with early stage PDAC, chronic pancreatitis and healthy subjects.

Results: The analytical platform was evaluated in light of its robustness for quantitative analysis of large-scale clinical specimens. The authors analysis indicated that the level of N-glycosylated peptides derived from galectin-3 binding proteins (LGALS3BP) were frequently elevated in plasma from PDAC patients, concurrent with the altered N-glycosylation of LGALS3BP observed in the tumor tissue.

Conclusion And Clinical Relevance: The glycosylation form of LGALS3BP influences its function in the galectin network, which profoundly involves in cancer progression, immune response and drug resistance. As one of the major binding ligands of galectin network, discovery of site specific N-glycosylation changes of LGALS3BP in association of PDAC may provide useful clues to facilitate cancer detection or phenotype stratification.
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http://dx.doi.org/10.1002/prca.201700064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880677PMC
September 2017

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.

Gut 2017 05 14;66(5):852-862. Epub 2016 Jan 14.

Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

Objective: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD.

Design: We determined promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured mRNA levels in a tissue microarray consisting of normal colons and CAC samples. and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels.

Results: mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, was underexpressed in experimental inflammatory carcinogenesis, and mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction.

Conclusion: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. promoter methylation status may serve as a CAC biomarker.
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http://dx.doi.org/10.1136/gutjnl-2015-310255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385850PMC
May 2017

Quantitative Proteomics Based on Optimized Data-Independent Acquisition in Plasma Analysis.

J Proteome Res 2017 02 3;16(2):665-676. Epub 2017 Jan 3.

Department of Medicine, University of Washington , Seattle, Washington 98195, United States.

The advent of high-resolution and frequency mass spectrometry has ushered in an era of data-independent acquisition (DIA). This approach affords enormous multiplexing capacity and is particularly suitable for clinical biomarker studies. However, DIA-based quantification of clinical plasma samples is a daunting task due to the high complexity of clinical plasma samples, the diversity of peptides within the samples, and the high biologic dynamic range of plasma proteins. Here we applied DIA methodology, including a highly reproducible sample preparation and LC-MS/MS analysis, and assessed its utility for clinical plasma biomarker detection. A pancreatic cancer-relevant plasma spectral library was constructed consisting of over 14 000 confidently identified peptides derived from over 2300 plasma proteins. Using a nonhuman protein as the internal standard, various empirical parameters were explored to maximize the reliability and reproducibility of the DIA quantification. The DIA parameters were optimized based on the quantification cycle times and fragmentation profile complexity. Higher analytical and biological reproducibility was recorded for the tryptic peptides without labile residues and missed cleavages. Quantification reliability was developed for the peptides identified within a consistent retention time and signal intensity. Linear analytical dynamic range and the lower limit of quantification were assessed, suggesting the critical role of sample complexity in optimizing DIA settings. Technical validation of the assay using a cohort of clinical plasma indicated the robustness and unique advantage for targeted analysis of clinical plasma samples in the context of biomarker development.
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http://dx.doi.org/10.1021/acs.jproteome.6b00727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889294PMC
February 2017

Glycoproteins and glycoproteomics in pancreatic cancer.

World J Gastroenterol 2016 Nov;22(42):9288-9299

Sheng Pan, Teresa A Brentnall, Ru Chen, Department of Medicine, University of Washington, Seattle, WA 98195, United States.

Aberrations in protein glycosylation and polysaccharides play a pivotal role in pancreatic tumorigenesis, influencing cancer progression, metastasis, immuno-response and chemoresistance. Abnormal expression in sugar moieties can impact the function of various glycoproteins, including mucins, surface receptors, adhesive proteins, proteoglycans, as well as their effectors and binding ligands, resulting in an increase in pancreatic cancer invasiveness and a cancer-favored microenvironment. Recent advance in glycoproteomics, glycomics and other chemical biology techniques have been employed to better understand the complex mechanism of glycosylation events and how they orchestrate molecular activities in genomics, proteomics and metabolomics implicated in pancreatic adenocarcinoma. A variety of strategies have been demonstrated targeting protein glycosylation and polysaccharides for diagnostic and therapeutic development.
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http://dx.doi.org/10.3748/wjg.v22.i42.9288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107693PMC
November 2016

Biomarkers for colitis-associated colorectal cancer.

World J Gastroenterol 2016 Sep;22(35):7882-91

Ru Chen, Lisa A Lai, Teresa A Brentnall, Sheng Pan, Department of Medicine, University of Washington, Seattle, WA 98195, United States.

Patients with extensive ulcerative colitis (UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques - including cutting-edge OMICS technologies - recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.
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http://dx.doi.org/10.3748/wjg.v22.i35.7882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028804PMC
September 2016

Pancreatic Cancer Chemoprevention Translational Workshop: Meeting Report.

Pancreas 2016 09;45(8):1080-91

From the *Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; †Department of Surgery, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY; ‡Division of Gastroenterology, University of Washington at Seattle, Seattle, WA; §Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD; ∥Department of Epidemiology, Health Sciences Research, Mayo Clinic, Rochester, MN; ¶Department of Medicine, Center for Cancer Prevention and Drug Development Program, PC Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK; #Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA; **Department of Medicine, Mayo Clinic, Rochester, MN; ††Department of Oncology, National Familial Pancreas Tumor Registry, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD; ‡‡Department of Surgery, Pancreatic Cancer Center, University of Michigan, Ann Arbor, MI; §§Department of Internal Medicine, Pancreatic Cancer Center, University of Michigan, Ann Arbor, MI; ∥∥Department of Surgery, Translational Oncology Program, Pancreatic Cancer Center, University of Michigan, Ann Arbor, MI; and ¶¶Department of Medicine, Pancreatic Tumor Center, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, MA.

Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 10%. The Division of Cancer Prevention of the National Cancer Institute sponsored the Pancreatic Cancer Chemoprevention Translational Workshop on September 10 to 11, 2015. The goal of the workshop was to obtain information regarding the current state of the science and future scientific areas that should be prioritized for pancreatic cancer prevention research, including early detection and intervention for high-risk precancerous lesions. The workshop addressed the molecular/genetic landscape of pancreatic cancer and precursor lesions, high-risk populations and criteria to identify a high-risk population for potential chemoprevention trials, identification of chemopreventative/immunopreventative agents, and use of potential biomarkers and imaging for assessing short-term efficacy of a preventative agent. The field of chemoprevention for pancreatic cancer is emerging, and this workshop was organized to begin to address these important issues and promote multi-institutional efforts in this area. The meeting participants recommended the development of an National Cancer Institute working group to coordinate efforts, provide a framework, and identify opportunities for chemoprevention of pancreatic cancer.
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http://dx.doi.org/10.1097/MPA.0000000000000705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988336PMC
September 2016

Progress in the Earlier Detection of Pancreatic Cancer.

J Clin Oncol 2016 06 25;34(17):1973-4. Epub 2016 Apr 25.

University of Washington Medical Center, Seattle, WA

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http://dx.doi.org/10.1200/JCO.2016.66.5265DOI Listing
June 2016

Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

Radiology 2015 Dec;277(3):644-61

From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307, Stanford, CA 94305-5621 (P.F.L., R.B.J., J.K.W.); and Department of Medicine, University of Washington, Seattle, Wash (R.C., T.A.B.).

Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.
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http://dx.doi.org/10.1148/radiol.2015141020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666099PMC
December 2015

Early detection of sporadic pancreatic cancer: summative review.

Pancreas 2015 Jul;44(5):693-712

From the *Department of Medicine, Mayo Clinic, Rochester, MN; †Department of Biomedical Engineering, University of Virginia, Charlottesville, VA; Departments of ‡Biochemistry and Molecular Biology, §Pathology and Microbiology, and ∥Surgery, Fred & Pamela Buffett Cancer Center, University of Nebraska, Omaha, NE; ¶Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD; #Division of Gastroenterology, University of Washington, Seattle, WA; **Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD; ††Sawgrass Leadership Institute, Ponte Vedra Beach, FL; ‡‡Department of Surgery, University of Utah, Salt Lake City, UT; §§Department of Radiology, Stanford University School of Medicine, Stanford; ∥∥Department of Medicine, David Geffen School of Medicine, and ¶¶General Surgery, University of California Los Angeles, Los Angeles, CA; ##Kenner Family Research Fund; ***Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; †††Department of Internal Medicine, University of Greifswald, Greifswald, Germany; ‡‡‡Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; §§§Department of Health Sciences Research, Mayo Clinic, Rochester, MN; ∥∥∥Gastroenterology Division, Department of Internal Medicine and Comprehensive Cancer Center, and ¶¶¶Department of Surgery, School of Medicine, University of Michigan, Ann Arbor, MI; ###Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD; ****Departments of Surgery and Oncology, Kyushu University, Fukuoka, Japan; ††††Department of Medicine, Eastern Virginia Medical School, Norfolk, VA; and ‡‡‡‡Division of Oral Biology and Medicine, CLA School of Dentistry, Jonnson Comprehensive Cancer Center, University of California Los Angeles, L

Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.
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http://dx.doi.org/10.1097/MPA.0000000000000368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467589PMC
July 2015

Proteomics analysis of bodily fluids in pancreatic cancer.

Proteomics 2015 Aug 27;15(15):2705-15. Epub 2015 Apr 27.

Department of Medicine, University of Washington, Seattle, WA, USA.

Proteomics study of pancreatic cancer using bodily fluids emphasizes biomarker discovery and clinical application, presenting unique prospect and challenges. Depending on the physiological nature of the bodily fluid and its proximity to pancreatic cancer, the proteomes of bodily fluids, such as pancreatic juice, pancreatic cyst fluid, blood, bile, and urine, can be substantially different in terms of protein constitution and the dynamic range of protein concentration. Thus, a comprehensive discovery and specific detection of cancer-associated proteins within these varied fluids is a complex task, requiring rigorous experiment design and a concerted approach. While major challenges still remain, fluid proteomics studies in pancreatic cancer to date have provided a wealth of information in revealing proteome alterations associated with pancreatic cancer in various bodily fluids.
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http://dx.doi.org/10.1002/pmic.201400476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526406PMC
August 2015

Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer.

World J Gastroenterol 2014 Dec;20(45):17037-48

Ru Chen, Sheng Pan, Lisa A Lai, David A Crispin, Teresa A Brentnall, Department of Medicine, University of Washington, Seattle, WA 98195, United States.

Aim: To characterize tumor necrosis factor receptor-associated protein 1 (TRAP1) expression in the progression of ulcerative colitis (UC)-associated colorectal cancer.

Methods: Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer. Immunohistochemical analysis was used to evaluate TRAP1 expression on tissue microarrays containing colonic tissues from 42 UC progressors (patients with cancer or dysplasia) and 38 non-progressors (dysplasia/cancer free patients). Statistical analyses of the TRAP1 immunohistochemistry staining were performed using GraphPad Prism. Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test. Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.

Results: TRAP1 was up-regulated in the colon tissues from UC progressors, but not in the colon tissues from UC non-progressors. Moreover, up-regulation of TRAP1 preceded the neoplastic changes: it was present in both the dysplastic and non-dysplastic tissues of UC progressors. When TRAP1 staining in rectal tissue was used as a diagnostic marker, it could distinguish progressors from non-progressors with 59% sensitivity and 80% specificity. Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues, which could be related to the increased oxidation present in the colonic mucosa from UC progressors. We then investigated the cellular proteome changes underlying oxidative stress, and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.

Conclusion: These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1, which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis. TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.
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http://dx.doi.org/10.3748/wjg.v20.i45.17037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258572PMC
December 2014

Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma.

Lab Invest 2015 Jan 27;95(1):43-55. Epub 2014 Oct 27.

Department of Medicine, University of Washington, Seattle, WA, USA.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFβ-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.
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http://dx.doi.org/10.1038/labinvest.2014.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281293PMC
January 2015

Vascular endothelial growth factor receptor type 2-targeted contrast-enhanced US of pancreatic cancer neovasculature in a genetically engineered mouse model: potential for earlier detection.

Radiology 2015 Mar 14;274(3):790-9. Epub 2014 Oct 14.

From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford University, 300 Pasteur Dr, Room H1307, Stanford, CA 94305 (M.A.P., S.B.M., J.R., J.K.W.); Department of Pathology, University of California at San Francisco, San Francisco, Calif (E.S.S.); Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford School of Medicine, Stanford University, Stanford, Calif (J.J.L.); Department of Medicine, University of Washington, Seattle, Wash (T.A.B.); and Bracco Suisse SA, Geneva, Switzerland (F.T.).

Purpose: To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma (PDAC) in a transgenic mouse model of pancreatic cancer development.

Materials And Methods: Experiments involving animals were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Transgenic mice (n = 44; Pdx1-Cre, KRas(G12D), Ink4a(-/-)) that spontaneously develop PDAC starting at 4 weeks of age were imaged by using a dedicated small-animal US system after intravenous injection of 5 × 10(7) clinical-grade VEGFR2-targeted microbubble contrast material. The pancreata in wild-type (WT) mice (n = 64) were scanned as controls. Pancreatic tissue was analyzed ex vivo by means of histologic examination (with hematoxylin-eosin staining) and immunostaining of vascular endothelial cell marker CD31 and VEGFR2. The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis.

Results: VEGFR2-targeted US of PDAC showed significantly higher signal intensities (26.8-fold higher; mean intensity ± standard deviation, 6.7 linear arbitrary units [lau] ± 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT mice (mean intensity, 0.25 lau ± 0.25). The highest VEGFR2-targeted US signal intensities were observed in smaller tumors, less than 3 mm in diameter (30.8-fold higher than control tissue with mean intensity of 7.7 lau ± 9.3 [P < .001]; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau ± 5.8 [P < .024]). Ex vivo quantitative VEGFR2 immunofluorescence demonstrated that VEGFR2 expression was significantly higher in pancreatic tumors (P < .001; mean fluorescent intensity, 499.4 arbitrary units [au] ± 179.1) compared with normal pancreas (mean fluorescent intensity, 232.9 au ± 83.7).

Conclusion: US with clinical-grade VEGFR2-targeted microbubbles allows detection of small foci of PDAC in transgenic mice.
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http://dx.doi.org/10.1148/radiol.14140568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372059PMC
March 2015

Quantitative glycoproteomics analysis reveals changes in N-glycosylation level associated with pancreatic ductal adenocarcinoma.

J Proteome Res 2014 Mar 28;13(3):1293-306. Epub 2014 Jan 28.

The Division of Gastroenterology, Department of Medicine, University of Washington , 1959 North East Pacific Street, Seattle, Washington 98195, United States.

Glycosylation plays an important role in epithelial cancers, including pancreatic ductal adenocarcinoma. However, little is known about the glycoproteome of the human pancreas or its alterations associated with pancreatic tumorigenesis. Using quantitative glycoproteomics approach, we investigated protein N-glycosylation in pancreatic tumor tissue in comparison with normal pancreas and chronic pancreatitis tissue. The study lead to the discovery of a roster of glycoproteins with aberrant N-glycosylation level associated with pancreatic cancer, including mucin-5AC (MUC5AC), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), insulin-like growth factor binding protein (IGFBP3), and galectin-3-binding protein (LGALS3BP). Pathway analysis of cancer-associated aberrant glycoproteins revealed an emerging phenomenon that increased activity of N-glycosylation was implicated in several pancreatic cancer pathways, including TGF-β, TNF, NF-kappa-B, and TFEB-related lysosomal changes. In addition, the study provided evidence that specific N-glycosylation sites within certain individual proteins can have significantly altered glycosylation occupancy in pancreatic cancer, reflecting the complexity of the molecular mechanisms underlying cancer-associated glycosylation events.
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http://dx.doi.org/10.1021/pr4010184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993895PMC
March 2014

Response.

J Natl Cancer Inst 2014 Feb 8;106(2):djt437. Epub 2014 Jan 8.

Affiliations of authors: Department of Pathology (RAR, CU, JJS, PSR), Department of Medicine (JJS, TAB), and Division of Gastroenterology (TAB), University of Washington, Seattle, WA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (PSR).

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http://dx.doi.org/10.1093/jnci/djt437DOI Listing
February 2014

Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer.

Proc Natl Acad Sci U S A 2013 Nov 11;110(48):19414-9. Epub 2013 Nov 11.

Department of Biomedical Engineering, University of Virginia School of Engineering and Applied Sciences, Charlottesville, VA 22908.

We recently demonstrated that plectin is a robust biomarker for pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies. In normal physiology, plectin is an intracellular scaffolding protein, but we have demonstrated localization on the extracellular surface of PDAC cells. In this study, we confirmed cell surface localization. Interestingly, we found that plectin cell surface localization was attributable to its presence in exosomes secreted from PDAC cells, which is dependent on the expression of integrin β4, a protein known to interact with cytosolic plectin. Moreover, plectin expression was necessary for efficient exosome production and was required to sustain enhanced tumor growth in immunodeficient and in immunocompetent mice. It is now clear that this PDAC biomarker plays a role in PDAC, and further understanding of plectin's contribution to PDAC could enable improved therapies.
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http://dx.doi.org/10.1073/pnas.1309720110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845200PMC
November 2013

Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis.

Inflamm Bowel Dis 2013 Nov;19(12):2593-602

*Department of Pathology, †Department of Medicine, ‡Department of Biostatistics, and §Division of Gastroenterology, University of Washington, School of Medicine, Seattle, Washington; ‖Division of Anatomic Pathology, University of Utah, Salt Lake City, Utah; and ¶Division of Public Health Science, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Patients with ulcerative colitis (UC) are at risk of developing colorectal cancer. We have previously reported that cancer progression is associated with the presence of clonal expansions and shorter telomeres in nondysplastic mucosa. We sought to validate these findings in an independent case-control study.

Methods: This study included 33 patients with UC: 14 progressors (patients with high-grade dysplasia or cancer) and 19 nonprogressors. For each patient, a mean of 5 nondysplastic biopsies from proximal, mid, and distal colon were assessed for clonal expansions, as determined by clonal length altering mutations in polyguanine tracts, and telomere length, as measured by quantitative PCR. Both parameters were compared with individual clinicopathological characteristics.

Results: Clonal expansions and shorter telomeres were more frequent in nondysplastic biopsies from UC progressors than nonprogressors, but only for patients with early-onset of UC (diagnosis at younger than 50 years of age). Late-onset progressor patients had very few or no clonal expansions and longer telomeres. A few nonprogressors exhibited clonal expansions, which were associated with older age and shorter telomeres. In progressors, clonal expansions were associated with proximity to dysplasia. The mean percentage of clonally expanded mutations distinguished early-onset progressors from nonprogressors with 100% sensitivity and 80% specificity.

Conclusions: Early-onset progressors develop cancer in a field of clonally expanded epithelium with shorter telomeres. The detection of these clones in a few random nondysplastic colon biopsies is a promising cancer biomarker in early-onset UC. Curiously, patients with late-onset UC seem to develop cancer without the involvement of such fields.
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http://dx.doi.org/10.1097/MIB.0b013e3182a87640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885330PMC
November 2013

Family history of diabetes and pancreatic cancer as risk factors for pancreatic cancer: the PACIFIC study.

Cancer Epidemiol Biomarkers Prev 2013 Oct 21;22(10):1913-7. Epub 2013 Aug 21.

Authors' Affiliations: Departments of Epidemiology and Gastroenterology, University of Washington; Group Health Research Institute and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Research, Kaiser Permanente Northern California, Oakland, California; and Centre for Public Health Research, Massey University, Wellington, New Zealand.

Genetic association studies have identified more than a dozen genes associated with risk of pancreatic cancer. Given this genetic heterogeneity, family history can be useful for identifying individuals at high risk for this disease. The goal of this analysis was to evaluate associations of family history of diabetes and family history of pancreatic cancer with risk of pancreatic cancer. PACIFIC is a case-control study based on two large health plans. Cases were diagnosed with pancreatic ductal adenocarcinoma (PDA) and controls were selected from the health plan enrollment databases and frequency matched to cases. Family history data were collected using an interviewer-administered questionnaire and were available on 654 cases and 697 controls. Logistic regression was used for the association analyses. First-degree relative history of diabetes was statistically significantly associated with increased risk of PDA [OR, 1.37; 95% confidence interval (CI), 1.10-1.71]. The highest risk of PDA was observed for an offspring with diabetes (OR, 1.95; 95% CI, 1.23-3.09). In addition, history of pancreatic cancer increased risk for PDA with an OR of 2.79 (95% CI, 1.44-4.08) for any first-degree relative history of pancreatic cancer. This population-based analysis showed that family history of diabetes was associated with increased risk of PDA and confirmed previous studies showing that first-degree family history of pancreatic cancer is associated with PDA. These results support the need for ongoing studies of genetic influences on pancreatic cancer in large samples and investigations of possible pleiotropic genetic effects on diabetes and pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-0518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808252PMC
October 2013

Mitochondria and tumor progression in ulcerative colitis.

J Natl Cancer Inst 2013 Aug 12;105(16):1239-48. Epub 2013 Jul 12.

Department of Pathology, University of Washington, Seattle, WA, USA.

Background: The role of mitochondria in cancer is poorly understood. Ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer and is an excellent model to study tumor progression. Our goal was to characterize mitochondrial alterations in UC tumorigenesis.

Methods: Nondysplastic colon biopsies from UC patients with high-grade dysplasia or cancer (progressors; n = 9) and UC patients dysplasia free (nonprogressors; n = 9) were immunostained for cytochrome C oxidase (COX), a component of the electron transport chain, and were quantified by multispectral imaging. For six additional progressors, nondysplastic and dysplastic biopsies were stained for COX and additional mitochondrial proteins including PGC1α, the master regulator of mitochondrial biogenesis. Mitochondrial DNA (mtDNA) copy number was determined by quantitative polymerase chain reaction. Generalized estimating equations with two-sided tests were used to account for correlation of measurements within individuals.

Results: Nondysplastic biopsies of UC progressors showed statistically significant COX loss compared with UC nonprogressors by generalized estimating equation (-18.5 units, 95% confidence interval = -12.1 to -24.9; P < .001). COX intensity progressively decreased with proximity to dysplasia and was the lowest in adjacent to dysplasia and dysplastic epithelium. Surprisingly, COX intensity was statistically significantly increased in cancers. This bimodal pattern was observed for other mitochondrial proteins, including PGC1α, and was confirmed by mtDNA copy number.

Conclusions: Mitochondrial loss precedes the development of dysplasia, and it could be used to detect and potentially predict cancer. Cancer cells restore mitochondria, suggesting that mitochondria are needed for further proliferation. This bimodal pattern might be driven by transcriptional regulation of mitochondrial biogenesis by PGC1α.
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http://dx.doi.org/10.1093/jnci/djt167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748006PMC
August 2013

Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1.

Gastroenterology 2013 Oct 18;145(4):885-894.e3. Epub 2013 Jun 18.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California.

Background & Aims: Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.

Methods: Thymocyte differentiation antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Up-regulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.

Results: Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P = .007) or normal tissue samples (P < .0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.

Conclusions: We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.
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http://dx.doi.org/10.1053/j.gastro.2013.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783557PMC
October 2013
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