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1
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Peng L, Chen H. A novel nomogram and risk classification system based on inflammatory and immune indicators for predicting prognosis of pancreatic cancer patients with liver metastases. Cancer Med 2023; 12:18622-18632. [PMID: 37635391 PMCID: PMC10557906 DOI: 10.1002/cam4.6471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/18/2023] [Accepted: 08/14/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND The study determined to construct a novel predictive nomogram to access the prognosis of pancreatic cancer patients with liver metastases (PCLM). METHODS Medical records included clinical and laboratory variables were collected. The patients were randomly divided into training and validation cohort. First, in the training cohort, the optimal cutoff value of SII, PNI, NLR, PLR were obtained. Then the survival analysis evaluated the effects of above indices on OS. Next, univariate and multivariate analyses were used to identify the independent factors of OS. Moreover, a nomogram was constructed based on LASSO cox analysis. Additionally, the predictive efficacy of the nomogram was evaluated by ROC curve and calibration curve in the training and validation cohort. Finally, a risk stratification system based on the nomogram was performed. RESULTS A total of 472 PCLM patients were enrolled in the study. The optimal cutoff values of SII, PNI, PLR and NLR were 372, 43.6, 285.7143 and 1.48, respectively. By combing SII and PNI, named coSII-PNI, we divided the patients into three groups. The Kaplan-Meier curves demonstrated above indices were correlated with OS. Univariate and multivariate analyses found the independent prognostic factors of OS. Through LASSO cox analysis, coSII-PNI, PNI, NLR, CA199, CEA, chemotherapy and gender were used to construct the nomogram. Lastly, the ROC curve and calibration curve demonstrated that the nomogram can predict prognosis of PCLM patients. Significant differences were observed between high and low groups. CONCLUSIONS The nomogram based on immune, inflammation, nutritional status and other clinical factors can accurately predict OS of PCLM patients.
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Affiliation(s)
- Linjia Peng
- Department of Integrative OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Hao Chen
- Department of Integrative OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
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2
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Pan S, Brentnall TA, Chen R. Proteome alterations in pancreatic ductal adenocarcinoma. Cancer Lett 2020; 469:429-436. [PMID: 31734355 PMCID: PMC9017243 DOI: 10.1016/j.canlet.2019.11.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023]
Abstract
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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3
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Lennon KM, Wakefield DL, Maddox AL, Brehove MS, Willner AN, Garcia-Mansfield K, Meechoovet B, Reiman R, Hutchins E, Miller MM, Goel A, Pirrotte P, Van Keuren-Jensen K, Jovanovic-Talisman T. Single molecule characterization of individual extracellular vesicles from pancreatic cancer. J Extracell Vesicles 2019; 8:1685634. [PMID: 31741725 PMCID: PMC6844376 DOI: 10.1080/20013078.2019.1685634] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 08/30/2019] [Accepted: 10/21/2019] [Indexed: 12/19/2022] Open
Abstract
Biofluid-accessible extracellular vesicles (EVs) may represent a new means to improve the sensitivity and specificity of detecting disease. However, current methods to isolate EVs encounter challenges when they are used to select specific populations. Moreover, it has been difficult to comprehensively characterize heterogeneous EV populations at the single vesicle level. Here, we robustly assessed heterogeneous EV populations from cultured cell lines via nanoparticle tracking analysis, proteomics, transcriptomics, transmission electron microscopy, and quantitative single molecule localization microscopy (qSMLM). Using qSMLM, we quantified the size and biomarker content of individual EVs. We applied qSMLM to patient plasma samples and identified a pancreatic cancer-enriched EV population. Our goal is to advance single molecule characterization of EVs for early disease detection. Abbreviations: EV: Extracellular Vesicle; qSMLM: quantitative Single Molecule Localization Microscopy; PDAC: Pancreatic Ductal Adenocarcinoma; EGFR: epidermal growth factor receptor 1; CA19-9: carbohydrate antigen 19-9; SEC: size exclusion chromatography; WGA: wheat germ agglutinin; AF647: Alexa Fluor 647; Ab: antibody; HPDEC: Healthy Pancreatic Ductal Epithelial Cell; TEM: Transmission Electron Microscopy.
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Affiliation(s)
- Kathleen M Lennon
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Devin L Wakefield
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Adam L Maddox
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Matthew S Brehove
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Ari N Willner
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Krystine Garcia-Mansfield
- Collaborative Center for Translational Mass Spectrometry, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Bessie Meechoovet
- Neurogenomics Division, Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Rebecca Reiman
- Neurogenomics Division, Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Elizabeth Hutchins
- Neurogenomics Division, Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Marcia M Miller
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Patrick Pirrotte
- Collaborative Center for Translational Mass Spectrometry, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Kendall Van Keuren-Jensen
- Neurogenomics Division, Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ, USA.,Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Tijana Jovanovic-Talisman
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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4
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Jelski W, Mroczko B. Biochemical diagnostics of pancreatic cancer - Present and future. Clin Chim Acta 2019; 498:47-51. [PMID: 31430440 DOI: 10.1016/j.cca.2019.08.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 08/14/2019] [Accepted: 08/16/2019] [Indexed: 12/23/2022]
Abstract
Pancreatic cancer is one of the deadliest cancers having an exceptionally high mortality rate. Despite a relatively low incidence (10th among cancers), it is the fourth leading cause of cancer-related deaths in most developed countries. Improving early diagnosis of pancreatic cancer and strengthening the standardised comprehensive treatment remain the main focus of pancreatic cancer research. Tumor markers are usually tumor-associated proteins of clinical relevance in these patients. Although tumor markers carbohydrate antigen (CA 19-9) and carcino-embryonic antigen (CEA) are commonly used, neither demonstrate high diagnostic accuracy. Recently, hematopoietic growth factors (HGFs) and various enzymes have been reported as potential biomarkers for pancreatic cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-colony stimulating factor (G-CSF), interleukin-3 (IL-3), macrophage inhibitory cytokine (MIC-1) and various enzymes (alcohol dehydrogenase, aldehyde dehydrogenase, lysosomal exoglycosidases). With the development of molecular technology, detecting K-ras mutation in serum via polymerase chain reaction (PCR) is becoming more common and efficient. Because K-ras mutation rates are high in many cancers, some regard it as a potential tumor marker. Others have shown the value of serum miRNAs in detection of pancreatic cancer. Unfortunately, there are currently no effective methods of sufficient diagnostic accuracy to detect early-stage surgically resectable pancreatic cancer. In this article we highlight these biomarkers and summarise recent developments in the diagnosis and treatment of pancreatic cancer.
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Affiliation(s)
- Wojciech Jelski
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland.
| | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland
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5
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Permuth JB, Chen DT, Yoder SJ, Li J, Smith AT, Choi JW, Kim J, Balagurunathan Y, Jiang K, Coppola D, Centeno BA, Klapman J, Hodul P, Karreth FA, Trevino JG, Merchant N, Magliocco A, Malafa MP, Gillies R. Linc-ing Circulating Long Non-coding RNAs to the Diagnosis and Malignant Prediction of Intraductal Papillary Mucinous Neoplasms of the Pancreas. Sci Rep 2017; 7:10484. [PMID: 28874676 PMCID: PMC5585319 DOI: 10.1038/s41598-017-09754-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 07/31/2017] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective biomarkers for early detection. We hypothesized that circulating long non-coding RNAs (lncRNAs) may act as diagnostic markers of incidentally-detected cystic PDAC precursors known as intraductal papillary mucinous neoplasms (IPMNs) and predictors of their pathology/histological classification. Using NanoString nCounter® technology, we measured the abundance of 28 candidate lncRNAs in pre-operative plasma from a cohort of pathologically-confirmed IPMN cases of various grades of severity and non-diseased controls. Results showed that two lncRNAs (GAS5 and SRA) aided in differentiating IPMNs from controls. An 8-lncRNA signature (including ADARB2-AS1, ANRIL, GLIS3-AS1, LINC00472, MEG3, PANDA, PVT1, and UCA1) had greater accuracy than standard clinical and radiologic features in distinguishing 'aggressive/malignant' IPMNs that warrant surgical removal from 'indolent/benign' IPMNs that can be observed. When the 8-lncRNA signature was combined with plasma miRNA data and quantitative 'radiomic' imaging features, the accuracy of predicting IPMN pathological classification improved. Our findings provide novel information on the ability to detect lncRNAs in plasma from patients with IPMNs and suggest that an lncRNA-based blood test may have utility as a diagnostic adjunct for identifying IPMNs and their pathology, especially when incorporated with biomarkers such as miRNAs, quantitative imaging features, and clinical data.
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Affiliation(s)
- Jennifer B Permuth
- Departments of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. .,Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
| | - Dung-Tsa Chen
- Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Sean J Yoder
- Molecular Genomics Core Facility, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jiannong Li
- Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Andrew T Smith
- Molecular Genomics Core Facility, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jung W Choi
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jongphil Kim
- Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Yoganand Balagurunathan
- Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Kun Jiang
- Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Domenico Coppola
- Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Barbara A Centeno
- Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jason Klapman
- Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Pam Hodul
- Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Florian A Karreth
- Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jose G Trevino
- Department of Surgery, Division of General Surgery, University of Florida Health Sciences Center, Gainesville, Florida, USA
| | - Nipun Merchant
- Department of Surgery, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Anthony Magliocco
- Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Mokenge P Malafa
- Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Robert Gillies
- Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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Pan S, Brentnall TA, Chen R. Glycoproteins and glycoproteomics in pancreatic cancer. World J Gastroenterol 2016; 22:9288-9299. [PMID: 27895417 PMCID: PMC5107693 DOI: 10.3748/wjg.v22.i42.9288] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/23/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
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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Karandish F, Mallik S. Biomarkers and Targeted Therapy in Pancreatic Cancer. BIOMARKERS IN CANCER 2016; 8:27-35. [PMID: 27147897 PMCID: PMC4847554 DOI: 10.4137/bic.s34414] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 03/06/2016] [Accepted: 03/11/2016] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%-3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.
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Affiliation(s)
- Fataneh Karandish
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
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8
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Yang XL, Li XJ. Combined detection of serum OPN, MIC-1 and CA19-9 for diagnosis of pancreatic cancere. Shijie Huaren Xiaohua Zazhi 2014; 22:2966-2970. [DOI: 10.11569/wcjd.v22.i20.2966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the diagnostic value of combined detection of serum OPN, MIC-1 and CA19-9 in pancreatic cancer.
METHODS: Serum levels of OPN, MIC-1 and CA19-9 were detected and compared in 20 pancreatic cancer patients, 20 patients with benign pancreatic tumors, 20 patients with chronic pancreatitis, and 20 normal controls by ELISA. By plotting the ROC curve, the diagnostic performance of these tumor markers alone or in combination was compared.
RESULTS: Compared with the normal group, serum levels of CA19-9, OPN, and MIC-1 in the chronic pancreatitis, pancreatic cancer and benign groups were significantly increased. Serum levels of CA19-9, OPN, and MIC-1 were not significantly different between the pancreatic cancer, benign tumors and chronic pancreatitis groups. The ability of individual biomarkers to identify pancreatic cancer, chronic pancreatitis and benign tumors was limited, while combined detection of OPN, MIC-1 and CA19-9 was better than detection of single markers. The sensitivity and specificity of combined detection of the three tumor markers were 91.23% and 92.30% in distinguishing pancreatic cancer and benign tumor, and 90.45% and 91.89% in distinguishing pancreatic cancer and chronic pancreatitis.
CONCLUSION: Combined detection of serum OPN, MIC-1 and CA19-9 can help to improve the diagnosis of pancreatic cancer.
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9
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Sun S, Ge N, Wang S, Liu X, Wang G, Guo J. Pilot trial of endoscopic ultrasound-guided interstitial chemoradiation of UICC-T4 pancreatic cancer. Endosc Ultrasound 2014; 1:41-7. [PMID: 24949334 PMCID: PMC4062203 DOI: 10.7178/eus.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2012] [Revised: 01/26/2012] [Accepted: 02/04/2012] [Indexed: 12/29/2022] Open
Abstract
Background and aims: Both interstitial brachytherapy and interstitial chemotherapy are effective in improving local control in patients with local UICC-T4 pancreatic cancer. In this study, we report the results of endoscopic ultrasound (EUS)-guided interstitial chemoradiation (EUS-ICR) in patients with advanced pancreatic cancer, with respect to tumor response, clinical response, safety, and complications. Patients and methods: A total of 8 patients (3 men, 5 women; median age of 69) with T4 pancreatic adenocarcinoma were the subjects of this study. A mean of 18 radioactive seeds and 36 intratumoral implants for sustained delivery of 5-fluorouracil in each patient were implanted into the tumors using EUS-guided needle puncture. The mean total implanted radioactive activity was 13.68 mCi, the mean total dose of intratumoral 5-fluorouracil was 3.6 g, and the mean volume of implants was 28 cm3. The conditions of the patients were followed-up by examination and imaging tests every two months. Clinical endpoints included the Karnofsky performance status, pain response, tumor response (assessed by computed tomography and/or EUS), and survival. Results: During a median follow-up period of 8.3 months, the objective tumor response was classified as “partial” in 1 of 8 patients (with a median duration of partial response of 3 months), “minimal” in 2 patients, and indicative of “stable disease”, in 3 of 8 patients. Clinical benefit was shown in 4 of 8 patients, which was mostly due to pain reduction, and lasted for 3.5 months. No local complications or hematologic toxicity occurred. Conclusions: EUS-ICR had a moderate local anti-tumor effect, showed some clinical benefits in 4 of the 8 patients, and was well tolerated by all the patients in this study.
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Affiliation(s)
- Siyu Sun
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Nan Ge
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Sheng Wang
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiang Liu
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Guoxin Wang
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jintao Guo
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang, China
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Costanzi E, Urbanelli L, Bellezza I, Magini A, Emiliani C, Minelli A. Hypermethylation contributes to down-regulation of lysosomal β-hexosaminidase α subunit in prostate cancer cells. Biochimie 2014; 101:75-82. [PMID: 24389457 DOI: 10.1016/j.biochi.2013.12.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 12/21/2013] [Indexed: 10/25/2022]
Abstract
β-Hexosaminidase, involved in degradation of glycoproteins and glycosphingolipids, is altered in several tumours leading to enhanced migration capacity. To date, the expression of the β-hexosaminidase isoenzymes in prostate cancer cells has not been elucidated. By using PC3, LNCaP, DUCaP, MDAPCa 2b, and hyperplasic prostate (BPH-1) cell lines, we analysed the β-hexosaminidase activity in each cell line and determined β-hexosaminidase α subunit gene expression in PC3, LNCaP, and BPH-1. We then investigated the methylation status of the gene promoter and determined the cellular responses of PC3 and LNCaP after transfection with β-hexosaminidase α subunit. We found that each prostate cancer cell line had a decrease in total hexosaminidase activity and that the lack of hexosaminidase A activity, observed in PC3 and LNCaP cells, was associated with mRNA disappearance. The HEXA promoter region in LNCaP and PC3 cell lines had methylated CpG islands, as confirmed by 5'-Aza-2'-deoxycitidine treatment, in PC3 cells, used as cell cancer model. We also tested, the involvement of hexosaminidase A in the migration capacity by migration assay using Hex α subunit-transfected PC3. Finally, we found that, after Hex α subunit transfection, both PC3 and LNCaP were less susceptible to exogenous ceramide treatment. Results indicate a likely contribution of the lysosomal enzyme to the acquisition of cancerous features.
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Affiliation(s)
- Egidia Costanzi
- Dipartimento Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia, 06124 Perugia, Italy.
| | - Lorena Urbanelli
- Dipartimento Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia, 06124 Perugia, Italy
| | - Ilaria Bellezza
- Dipartimento Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia, 06124 Perugia, Italy
| | - Alessandro Magini
- Dipartimento Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia, 06124 Perugia, Italy
| | - Carla Emiliani
- Dipartimento Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia, 06124 Perugia, Italy
| | - Alba Minelli
- Dipartimento Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia, 06124 Perugia, Italy
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Bello C, Farbiarz K, Möller JF, Becker CFW, Schwientek T. A quantitative and site-specific chemoenzymatic glycosylation approach for PEGylated MUC1 peptides. Chem Sci 2014. [DOI: 10.1039/c3sc52641k] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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12
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Ballehaninna UK, Chamberlain RS. Biomarkers for pancreatic cancer: promising new markers and options beyond CA 19-9. Tumour Biol 2013; 34:3279-92. [PMID: 23949878 DOI: 10.1007/s13277-013-1033-3] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 07/18/2013] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma accounts for nearly 90-95% of exocrine malignant tumors of the pancreas. Traditionally, overexpressed proteins/epitopes such as CA 19-9, CA-50, CEA, and many others were being used as pancreatic cancer tumor markers. The main utility of these biomarkers was in the diagnosis of pancreatic cancer as well as to assess response to chemotherapy and to determine prognosis and to predict tumor recurrence. However, these markers had significant limitations such as lack of sensitivity, false-negative results in certain blood groups, as well as false-positive elevation in the presence of obstructive jaundice. To circumvent these limitations, an extraordinary amount of research is being performed to identify an accurate tumor marker or a panel of markers that could aid in the management of the pancreatic cancer. Although this research has identified a large number and different variety of biomarkers, few hold future promise as a preferred marker for pancreatic cancer. This review provides an insight into exciting new areas of pancreatic biomarker research such as salivary, pancreatic juice, and stool markers that can be used as a noninvasive test to identify pancreatic cancer. This manuscript also provides a discussion on newer biomarkers, the role of microRNAs, and pancreatic cancer proteomics, which have the potential to identify a preferred tumor marker for pancreatic adenocarcinoma. This review further elaborates on important genetic changes associated with the development and progression of pancreatic cancer that holds the key for the identification of a sensitive biomarker and which could also serve as a therapeutic target.
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Affiliation(s)
- Umashankar K Ballehaninna
- Department of Surgery, Saint Barnabas Medical Center, 94, Old Short Hills Road, Livingston, NJ, 07039, USA
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13
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Pásztói M, Sódar B, Misják P, Pálóczi K, Kittel Á, Tóth K, Wellinger K, Géher P, Nagy G, Lakatos T, Falus A, Buzás EI. The recently identified hexosaminidase D enzyme substantially contributes to the elevated hexosaminidase activity in rheumatoid arthritis. Immunol Lett 2012; 149:71-6. [PMID: 23099419 DOI: 10.1016/j.imlet.2012.10.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 09/25/2012] [Accepted: 10/15/2012] [Indexed: 01/08/2023]
Abstract
Since the 1970s, numerous reports have described elevated hexosaminidase activities in rheumatoid arthritis. However, due to the overlapping substrate specificities of different hexosaminidases, identification of the exact enzyme(s) responsible for the elevated activity remains incomplete. In this work we tested if the recently described enzyme, hexosaminidase D was expressed in human arthritic joints, and could contribute to the elevated hexosaminidase activity in rheumatoid arthritis. Thermostable β-d-N-acetyl-galactosaminidase (hexosaminidase D) activities were determined in synovial fluid samples, synovial membranes, synovial fibroblast cell strains and synovial fibroblast-derived extracellular vesicles of patients with rheumatoid arthritis and osteoarthritis using chromogenic substrates. Expression of the HEXDC gene was detected both in steady state and in TGF-β treated synovial fibroblasts by real time PCR. Strikingly, hexosaminidase D accounted for approximately 50% of the total β-N-acetyl-galactosaminidase activity in synovial membranes and synovial fibroblasts, and it was responsible for the vast majority of the β-d-N-acetyl-galactosaminidase activity in synovial fluid samples. TGF-β downregulated the expression of hexosaminidase D in synovial fibroblasts dose-dependently. Of note, significant activity of hexosaminidase D was also found in association with extracellular vesicles released by synovial fibroblasts. This first study that describes the expression and disease relevance of the HEXDC gene in humans demonstrates the expression of this novel enzyme within the joints, and suggests that its activity may significantly contribute to the overall local exoglycosidase activity.
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Affiliation(s)
- Mária Pásztói
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary.
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Sharon E, Zhang J, Hollevoet K, Steinberg SM, Pastan I, Onda M, Gaedcke J, Ghadimi BM, Ried T, Hassan R. Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers. Clin Chem Lab Med 2012; 50:721-5. [PMID: 22149739 DOI: 10.1515/cclm.2011.816] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor mesothelin overexpression is present in different malignancies, including the majority of patients with pancreatic or biliary cancers. The objective of this study was to evaluate the use of shed serum mesothelin and megakaryocyte potentiating factor (MPF) concentrations as biomarkers for these cancers. METHODS A total of 151 individuals, divided into five groups, were retrospectively analyzed: healthy donors (n=15), patients with benign non-pancreatic conditions (n=52), benign pancreatic conditions (n=33), biliary carcinoma (n=9), and pancreatic ductal adenocarcinoma (n=42). Mesothelin and MPF concentrations were measured in serum with the Mesomark™ and Human MPF ELISA, respectively. RESULTS Mesothelin and MPF concentrations did not significantly differ among the five individual participant groups (p=0.34, p=0.33, respectively), nor did any other combination and pair-wise comparison of the participant groups demonstrated a significant difference in biomarker concentrations. In patients with pancreatic cancer, mesothelin or MPF concentrations were not associated with tumor stage (p=0.87, p=0.48, respectively) or differentiation grade (p=0.73, p=0.52, respectively). CONCLUSIONS Serum mesothelin and MPF concentrations, measured with standard available ELISAs, were not specific for benign or pancreatic disease. Both biomarkers were not elevated in patients with pancreatic or biliary cancers, and consequently do not appear to be useful biomarkers for these malignancies.
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Affiliation(s)
- Elad Sharon
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA
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15
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Husi H, Fearon KC, Ross JA. Can a simple proteomics urine test assist in the early diagnosis of early-stage cancer? Expert Rev Proteomics 2012; 8:555-7. [PMID: 21999825 DOI: 10.1586/epr.11.52] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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16
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Sahraei M, Roy LD, Curry JM, Teresa TL, Nath S, Besmer D, Kidiyoor A, Dalia R, Gendler SJ, Mukherjee P. MUC1 regulates PDGFA expression during pancreatic cancer progression. Oncogene 2012; 31:4935-45. [PMID: 22266848 PMCID: PMC3337953 DOI: 10.1038/onc.2011.651] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatic Ductal Adenocarcinoma (PDA) has one of the worst prognoses of all cancers. Mucin 1 (MUC1), a transmembrane mucin glycoprotein, is a key modulator of several signaling pathways that affect oncogenesis, motility, and metastasis. Its expression is known to be associated with poor prognosis in patients. However, the precise mechanism remains elusive. We report a novel association of MUC1 with Platelet-Derived Growth Factor-A (PDGFA). PDGFA is one of the many drivers of tumor growth, angiogenesis, and metastasis in PDA. Using mouse PDA models as well as human samples, we show clear evidence that MUC1 regulates the expression and secretion of PDGFA. This, in turn, influences proliferation and invasion of pancreatic cancer cells leading to higher tumor burden in vivo. In addition, we reveal that MUC1 over expressing cells are heavily dependent on PDGFA both for proliferation and invasion while MUC1-null cells are not. Moreover, PDGFA and MUC1 are critical for translocation of βcatenin to the nucleus for oncogenesis to ensue. Finally, we elucidate the underlying mechanism by which MUC1 regulates PDGFA expression and secretion in pancreatic cancer cells. We show that MUC1 associates with Hif1-α, a known transcription factor involved in controlling PDGFA expression. Furthermore, MUC1 facilitates Hif1-α translocation to the nucleus. In summary, we have demonstrated that MUC1-induced invasion and proliferation occurs via increased exogenous production of PDGFA. Thus, impeding MUC1 regulation of PDGFA signaling may be therapeutically beneficial for patients with PDA.
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Affiliation(s)
- M Sahraei
- Department of Biology, University of North Carolina, Charlotte, NC 28223, USA
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17
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Bhat K, Wang F, Ma Q, Li Q, Mallik S, Hsieh TC, Wu E. Advances in biomarker research for pancreatic cancer. Curr Pharm Des 2012; 18:2439-51. [PMID: 22372502 PMCID: PMC3408036 DOI: 10.2174/13816128112092439] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/18/2012] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related deaths in United States. The lack of early symptoms results in latestage detection and a high mortality rate. Currently, the only potentially curative approach for PC is surgical resection, which is often unsuccessful because the invasive and metastatic nature of the tumor masses makes their complete removal difficult. Consequently, patients suffer relapses from remaining cancer stem cells or drug resistance that eventually lead to death. To improve the survival rate, the early detection of PC is critical. Current biomarker research in PC indicates that a serum carbohydrate antigen, CA 19-9, is the only available biomarker with approximately 90% specificity to PC. However, the efficacy of CA 19-9 for assessing prognosis and monitoring patients with PC remains contentious. Thus, advances in technology and the detection of new biomarkers with high specificity to PC are needed to reduce the mortality rate of pancreatic cancer.
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Affiliation(s)
- Kruttika Bhat
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Fengfei Wang
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Qinyu Li
- Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Tze-chen Hsieh
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | - Erxi Wu
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
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18
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-The advancement of biomarker-based diagnostic tools for ovarian, breast, and pancreatic cancer through the use of urine as an analytical biofluid. Int J Biol Markers 2011; 26:141-52. [PMID: 21928247 DOI: 10.5301/jbm.2011.8613] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2011] [Indexed: 02/06/2023]
Abstract
Despite considerable advancements, the development of effective cancer screening tools based on serum biomarker measurements has thus far failed to achieve a meaningful clinical impact. The incremental progress observed over the course of serum biomarker development suggests that further refinements based on novel approaches may yet result in a breakthrough. The use of urine as an analytical biofluid for biomarker development may represent such an approach. The unique characteristics of urine including a high level of stability, ease of sampling, and an inactive and low-complexity testing matrix offer several potential advantages over the use of serum. A number of recent reports have demonstrated the utility of urine in the identification of novel cancer biomarkers and also the improved performance of biomarkers previously evaluated in serum. In this review, advancements related to the use of urine biomarkers within the settings of ovarian, breast, and pancreatic cancer are presented and discussed. Findings regarding the identification of specific urine biomarkers for each disease are highlighted along with comparative analyses of urine and serum biomarkers as diagnostic tools.
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