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1. B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients

Author: Eveline E. Vietsch, Diba Latifi, Maaike Verheij, Elise W.A. van der Oost, Roeland F. de Wilde, Roel Haen, Anne Loes van den Boom, Bas Groot Koerkamp, Pascal G. Doornebosch, Victorien M.T. van Verschuer, Ariadne H.A.G. Ooms, Farzana Mohammad, Marcella Willemsen, Joachim G.J.V. Aerts, Ricki T. Krog, Noel F.C.C. de Miranda, Thierry P.P. van den Bosch, Yvonne M. Mueller, Peter D. Katsikis, and Casper H.J. van Eijck
Subjects: vermiform appendix, pancreatic cancer, colon cancer, mucosal B cells, gut associated lymphoid tissue, gut microbiome, Immunologic diseases. Allergy, RC581-607
Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.
Published: 2023
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2. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity

Author: Yuan-Na Lin, Marcel O. Schmidt, Ghada M. Sharif, Eveline E. Vietsch, Amber J. Kiliti, Megan E. Barefoot, Anna T. Riegel, and Anton Wellstein
Subjects: pancreatic cancer, t cell resistance, cytotoxicity, co-culture, chemokines, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Pancreatic cancer remains largely unresponsive to immune modulatory therapy attributable in part to an immunosuppressive, desmoplastic tumor microenvironment. Here, we analyze mechanisms of cancer cell-autonomous resistance to T cells. We used a 3D co-culture model of cancer cell spheroids from the KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/p48-Cre) pancreatic ductal adenocarcinoma (PDAC) model, to examine interactions with tumor-educated T cells isolated from draining lymph nodes of PDAC-bearing mice. Subpopulations of cancer cells resistant to these tumor-educated T cells were isolated from the in vitro co-culture and their properties compared with sensitive cancer cells. In co-culture with resistant cancer cell subpopulations, tumor-educated T cells showed reduced effector T cell functionality, reduced infiltration into tumor cell spheroids and decreased induction of apoptosis. A combination of comparative transcriptomic analyses, cytometric and immunohistochemistry techniques allowed us to dissect the role of differential gene expression and signaling pathways between sensitive and resistant cells. A decreased expression of the chemokine CXCL12 (SDF-1) was revealed as a common feature in the resistant cell subpopulations. Adding back CXCL12 reversed the resistant phenotype and was inhibited by the CXCR4 inhibitor AMD3100 (plerixafor). We conclude that reduced CXCL12 signaling contributes to PDAC subpopulation resistance to T cell-mediated attack.
Published: 2022
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3. Cardiomyocyte-Specific Circulating Cell-Free Methylated DNA in Esophageal Cancer Patients Treated with Chemoradiation

Author: Sarah Martinez Roth, Eveline E. Vietsch, Megan E. Barefoot, Marcel O. Schmidt, Matthew D. Park, Archana Ramesh, Michael R. Lindberg, Giuseppe Giaccone, Anna T. Riegel, Ana Barac, Keith Unger, and Anton Wellstein
Subjects: esophageal cancer, therapy response, circulating cell-free DNA, DNA methylation, amplicon sequencing, Medicine, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Thoracic high-dose radiation therapy (RT) for cancer has been associated with early and late cardiac toxicity. To assess altered rates of cardiomyocyte cell death due to RT we monitored changes in cardiomyocyte-specific, cell-free methylated DNA (cfDNA) shed into the circulation. Eleven patients with distal esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy (RT) and concurrent carboplatin and paclitaxel were enrolled. Subjects underwent fasting blood draws prior to the initiation and after completion of RT as well as 4–6 months following RT. An island of six unmethylated CpGs in the FAM101A locus was used to identify cardiomyocyte-specific cfDNA in serum. After bisulfite treatment this specific cfDNA was quantified by amplicon sequencing at a depth of >35,000 reads/molecule. Cardiomyocyte-specific cfDNA was detectable before RT in the majority of patient samples and showed some distinct changes during the course of treatment and recovery. We propose that patient-specific cardiac damages in response to the treatment are indicated by these changes although co-morbidities may obscure treatment-specific events.
Published: 2021
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4. Serum cytokine levels are associated with tumor progression during FOLFIRINOX chemotherapy and overall survival in pancreatic cancer patients

Author: Fleur van der Sijde, Willem A. Dik, Dana A. M. Mustafa, Eveline E. Vietsch, Marc G. Besselink, Reno Debets, Bas Groot Koerkamp, Brigitte C. M. Haberkorn, Marjolein Y. V. Homs, Quisette P. Janssen, Saskia A. C. Luelmo, Leonie J. M. Mekenkamp, Astrid A. M. Oostvogels, Marja A. W. Smits-te Nijenhuis, Johanna W. Wilmink, Casper H. J. van Eijck, and the Dutch Pancreatic Cancer Group
Subjects: pancreatic cancer, biomarker, treatment response, cytokine, IL-1RA, Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundBiomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS).MethodsSerum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (n=83) of all disease stages. Overall, 34 circulating cytokines were analyzed with a multiplex immunoassay. In addition, changes in peripheral blood immune cell counts were determined by flow cytometry to correlate with differences in cytokine levels. Chemotherapy response was determined by CT scans with the RECIST 1.1 criteria, as disease control (n=64) or progressive disease (n=19) within eight cycles of FOLFIRINOX.ResultsPatients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25, P=0.040). Increase of circulating IL-1RA concentrations correlated with increase of total, classical (CD14+CD16-), and non-classical monocytes (CD14-CD16+), and dendritic cells. In multivariable cox regression, including the variables chemotherapy response outcome and baseline CA19-9 level, serum concentrations of IL-7 (HR 2.14, P=0.010), IL-18 (HR 2.00, P=0.020), and MIP-1β (HR 0.51, P=0.025) after one cycle of FOLFIRINOX showed correlations with OS.ConclusionsCirculating IL-1RA, IL-7, IL-18, and MIP-1β concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies.
Published: 2022
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5. Circulating mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

Author: Fleur van der Sijde, Zakia Azmani, Marc G. Besselink, Bert A. Bonsing, Jan Willem B. de Groot, Bas Groot Koerkamp, Brigitte C. M. Haberkorn, Marjolein Y. V. Homs, Wilfred F. J. van IJcken, Quisette P. Janssen, Martijn P. Lolkema, Saskia A. C. Luelmo, Leonie J. M. Mekenkamp, Dana A. M. Mustafa, Ron H. N. van Schaik, Johanna W. Wilmink, Eveline E. Vietsch, and Casper H. J. van Eijck
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control ( n = 30) or progressive disease ( n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
Published: 2021
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6. Serum miR-373-3p and miR-194-5p Are Associated with Early Tumor Progression during FOLFIRINOX Treatment in Pancreatic Cancer Patients: A Prospective Multicenter Study

Author: Fleur van der Sijde, Marjolein Y. V. Homs, Marlies L. van Bekkum, Thierry P. P. van den Bosch, Koop Bosscha, Marc G. Besselink, Bert A. Bonsing, Jan Willem B. de Groot, Thomas M. Karsten, Bas Groot Koerkamp, Brigitte C. M. Haberkorn, Saskia A. C. Luelmo, Leonie J. M. Mekenkamp, Dana A. M. Mustafa, Johanna W. Wilmink, Casper H. J. van Eijck, Eveline E. Vietsch, and on behalf of the Dutch Pancreatic Cancer Group
Subjects: pancreatic cancer, FOLFIRINOX, predictive biomarker, miR-373, miR-194, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD −0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10–14.49; miR-194-5p OR 0.91, 95% CI 0.83–0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.
Published: 2021
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7. Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib

Author: Narayan Shivapurkar, Eveline E. Vietsch, Erin Carney, Claudine Isaacs, and Anton Wellstein
Subjects: MicroRNA, Liquid biopsy, Tyrosine kinase inhibitor, Breast cancer, Clinical trial, Medicine (General), R5-920
Abstract: Abstract Background Serial analysis of biomarkers in the circulation of patients undergoing treatment (“liquid biopsies”) can provide new insights into drug effects. In particular the analysis of cell-free, circulating nucleic acids such as microRNAs (miRs) can reveal altered expression patterns indicative of mechanism of drug action, cancer growth, and tumor–stroma interactions. Results Here we analyzed plasma miRs in patients with hormone receptor positive, metastatic breast cancer with prior disease progression during aromatase inhibitor therapy (n = 8) in a phase I/II trial with the multiple tyrosine kinase inhibitor dovitinib (TKI258). Plasma miR levels were measured by quantitative RT-qPCR before and after treatment with dovitinib. A candidate miR signature of drug response was established from a 379 miR screen for detectable plasma miRs as well as from the published literature. Changes in miR expression patterns and tumor sizes were compared. In this analysis we identified miR-21-5p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-375 and miR-424-5p as potential indicators of a response to dovitinib. The altered expression patterns observed for the six circulating miRs separated patients with resistant disease from those with drug responsive disease. There was no relationship between adverse effects of dovitinib treatment and identifiable changes in miR patterns. Conclusion We conclude that changes in the expression patterns of circulating miRs can be indicators of drug responses that merit prospective studies for validation.
Published: 2017
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8. Circulating biomarkers to monitor cancer progression and treatment

Author: Suthee Rapisuwon, Eveline E. Vietsch, and Anton Wellstein
Subjects: cell-free DNA, cell-free RNA, cell-free microRNA, cell-free circulating nucleic acids, circulating tumor DNA, circulating mutant DNA, Biotechnology, TP248.13-248.65
Abstract: Tumor heterogeneity is a major challenge and the root cause of resistance to treatment. Still, the standard diagnostic approach relies on the analysis of a single tumor sample from a local or metastatic site that is obtained at a given time point. Due to intratumoral heterogeneity and selection of subpopulations in diverse lesions this will provide only a limited characterization of the makeup of the disease. On the other hand, recent developments of nucleic acid sequence analysis allows to use minimally invasive serial blood samples to assess the mutational status and altered gene expression patterns for real time monitoring in individual patients. Here, we focus on cell-free circulating tumor-specific mutant DNA and RNA (including mRNA and non-coding RNA), as well as current limitations and challenges associated with circulating nucleic acids biomarkers.
Published: 2016
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9. Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

Author: Eveline E. Vietsch, Ivana Peran, Mustafa Suker, Thierry P. P. van den Bosch, Fleur van der Sijde, Johan M. Kros, Casper H. J. van Eijck, and Anton Wellstein
Subjects: pancreatic cancer, resection, circulating micrornas, biomarkers, progression free survival, immune cells, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract: Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+; Trp53R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.
Published: 2019
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10. Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma

Author: Michail Doukas, Casper H.J. van Eijck, Bharath Sampadi, Bas Groot Koerkamp, Freek Van 't Land, Jiang Chang, Fleur van der Sijde, Elham Aida Farshadi, Joris Pothof, Eveline E. Vietsch, Pulmonary Medicine, Molecular Genetics, Pathology, and Surgery
Subjects: Cancer Research, Combination therapy, FOLFIRINOX, medicine.medical_treatment, Leucovorin, Irinotecan, SDG 3 - Good Health and Well-being, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Retrospective Studies, Chemotherapy, business.industry, medicine.disease, Primary tumor, Neoadjuvant Therapy, digestive system diseases, Oxaliplatin, Organoids, Pancreatic Neoplasms, Regimen, Oncology, Cancer research, Fluorouracil, Folfirinox Regimen, business, Carcinoma, Pancreatic Ductal, medicine.drug
Abstract: Purpose: We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. Experimental Design: We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents—5-FU, irinotecan, and oxaliplatin—of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways. Results: All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples—in both organoids and corresponding matched tumor tissues—uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system. Conclusions: Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.
Published: 2021

11. Serum miR-338-3p and miR-199b-5p are associated with the absolute neutrophil count in patients with resectable pancreatic cancer

Author: Dana A M Mustafa, Fleur van der Sijde, Eveline E. Vietsch, Yunlei Li, Casper H.J. van Eijck, Surgery, and Pathology
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Neutrophils, Lymphocyte, Clinical Biochemistry, Inflammation, Systemic inflammation, Polymerase Chain Reaction, Biochemistry, Cohort Studies, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, Immune system, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Internal medicine, medicine, Humans, Peripheral blood cell, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Biochemistry (medical), Reproducibility of Results, General Medicine, Middle Aged, Survival Analysis, Blood Cell Count, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, MicroRNAs, Circulating MicroRNA, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Absolute neutrophil count, Female, medicine.symptom, business
Abstract: Background: Several peripheral blood cell counts and immune ratios, such as the systemic immune-inflammation index (SII = platelet x neutrophil count/lymphocyte count) have prognostic value in patients with resectable pancreatic cancer (PDAC). Circulating microRNAs (miRNAs) are involved in various aspects of cancer and inflammation. We aimed to identify measurable circulating miRNAs in PDAC patients correlating with systemic inflammation parameters. Methods: A total of 42 PDAC patients was included in this study: twelve in the discovery (n = 6 SII low; n = 6 SII high) and 30 patients in the validation cohort (n = 19 SII low, n = 11 SII high). MiRNAs isolated from preoperative serum samples were measured with a 352 miRNA panel in the discovery cohort and individual miRNA primers in the validation cohort, using RT-qPCR (ID3EAL assays, MiRXES). Results: Only in the discovery cohort miR-328-3p, miR-338-3p, miR-1258 and miR-199b-5p were upregulated in high compared to low SII patients (fold difference ≥ 2, P
Published: 2020

12. Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors

Author: Ivana Peran, Eveline E. Vietsch, Gai Yan, Anna T. Riegel, and Anton Wellstein
Subjects: Cancer Research, Oncology, microRNA, miR, circulating miR, pancreatic cancer, pancreatic adenocarcinoma, treatment response, biomarker, stroma
Abstract: Pancreatic adenocarcinoma is typically detected at a late stage and thus shows only limited sensitivity to treatment, making it one of the deadliest malignancies. In this study, we evaluate changes in microRNA (miR) patterns in peripheral blood as a potential readout of treatment responses of pancreatic cancer to inhibitors that target tumor–stroma interactions. Mice with pancreatic cancer cell (COLO357PL) xenografts were treated with inhibitors of either fibroblast growth factor receptor kinase (FGFR; PD173074) or anaplastic lymphoma kinase receptor (ALK; TAE684). While both treatments inhibited tumor angiogenesis, signal transduction, and mitogenesis to a similar extent, they resulted in distinct changes in circulating miR signatures. Comparison of the miR pattern in the tumor versus that in circulation showed that the inhibitors can be distinguished by their differential impact on tumor-derived miRs as well as host-derived circulating miRs. Distinct signatures that include circulating miR-1 and miR-22 are associated with the efficacy of ALK and FGFR inhibition, respectively. We propose that monitoring changes in circulating miR profiles can provide an early signature of treatment response or resistance to pathway-targeted drugs, and thus provide a non-invasive measurement to rapidly assess the efficacy of candidate therapies.
Published: 2022

13. Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

Author: Fleur van der Sijde, Leonie J. M. Mekenkamp, Quisette P. Janssen, Marjolein Y.V. Homs, Zakia Azmani, Johanna W. Wilmink, Wilfred F. J. van IJcken, Bert A. Bonsing, Saskia A C Luelmo, Bas Groot Koerkamp, Brigitte C M Haberkorn, Eveline E. Vietsch, Dana A M Mustafa, Jan Willem B. de Groot, Casper H.J. van Eijck, Marc G. Besselink, Martijn P. Lolkema, Ron H.N. van Schaik, Surgery, CCA - Cancer Treatment and Quality of Life, Amsterdam Gastroenterology Endocrinology Metabolism, Oncology, CCA - Cancer biology and immunology, Cell biology, Medical Oncology, Pathology, and Clinical Chemistry
Subjects: circulating tumor DNA, Treatment response, Pancreatic ductal adenocarcinoma, business.industry, FOLFIRINOX, pancreatic cancer, Tp53 mutation, medicine.disease, Oncology, SDG 3 - Good Health and Well-being, Tumor progression, Circulating tumor DNA, Pancreatic cancer, Cancer research, Medicine, TP53, business, predictive biomarker, Predictive biomarker, Original Research
Abstract: Background:Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS).Methods:Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control ( n = 30) or progressive disease ( n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria.Results:Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months).Conclusion:The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
Published: 2021

14. Circulating Immunological Biomarkers: Prognosis of Pancreatic Cancer Patients Reflected by the Immune System

Author: Casper H.J. van Eijck, Fleur van der Sijde, Eveline E. Vietsch, Dana A M Mustafa, Peter D. Katsikis, Surgery, Pathology, and Immunology
Subjects: Poor prognosis, Neutrophils, Endocrinology, Diabetes and Metabolism, Proinflammatory cytokine, Endocrinology, Immune system, SDG 3 - Good Health and Well-being, T-Lymphocyte Subsets, Pancreatic cancer, Biomarkers, Tumor, Internal Medicine, medicine, Animals, Humans, Predictive biomarker, B-Lymphocytes, Hepatology, business.industry, Macrophages, Myeloid-Derived Suppressor Cells, Prognosis, medicine.disease, Primary tumor, Peripheral blood, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, Innovative Therapies, Immune System, Cancer research, Immunotherapy, business, Carcinoma, Pancreatic Ductal
Abstract: To date, little advances have been made toward new and more effective therapies for pancreatic ductal adenocarcinoma (PDAC). Discovery of prognostic and predictive biomarkers is needed to stratify patients for available treatments and to elucidate how new therapies could be developed. Recent studies have made clear that the immune system is not only affected in the microenvironment of the primary tumor and it is also systemically disrupted in PDAC patients. Under normal circumstances, the immune system is in perfect balance with both proinflammatory and anti-inflammatory components present. In this review, we focus on circulating immunological characteristics including immune cells and their subtypes, cytokines, and immune checkpoints in the peripheral blood not only to understand the poor prognosis of PDAC patients but also to find new leads for new innovative therapies.
Published: 2021

15. Cardiomyocyte-Specific Circulating Cell-Free Methylated DNA in Esophageal Cancer Patients Treated with Chemoradiation

Author: Archana Ramesh, Giuseppe Giaccone, Marcel O. Schmidt, Anna T. Riegel, Ana Barac, Sarah Martinez Roth, Eveline E. Vietsch, Megan E. Barefoot, Keith Unger, Matthew D. Park, Michael R. Lindberg, and Anton Wellstein
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, RC799-869, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, esophageal cancer, DNA methylation, amplicon sequencing, business.industry, therapy response, Cancer, Diseases of the digestive system. Gastroenterology, Esophageal cancer, medicine.disease, circulating cell-free DNA, Carboplatin, Circulating Cell-Free DNA, Radiation therapy, 030104 developmental biology, chemistry, Paclitaxel, 030220 oncology & carcinogenesis, Medicine, business, Blood drawing
Abstract: Thoracic high-dose radiation therapy (RT) for cancer has been associated with early and late cardiac toxicity. To assess altered rates of cardiomyocyte cell death due to RT we monitored changes in cardiomyocyte-specific, cell-free methylated DNA (cfDNA) shed into the circulation. Eleven patients with distal esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy (RT) and concurrent carboplatin and paclitaxel were enrolled. Subjects underwent fasting blood draws prior to the initiation and after completion of RT as well as 4–6 months following RT. An island of six unmethylated CpGs in the FAM101A locus was used to identify cardiomyocyte-specific cfDNA in serum. After bisulfite treatment this specific cfDNA was quantified by amplicon sequencing at a depth of &gt, 35,000 reads/molecule. Cardiomyocyte-specific cfDNA was detectable before RT in the majority of patient samples and showed some distinct changes during the course of treatment and recovery. We propose that patient-specific cardiac damages in response to the treatment are indicated by these changes although co-morbidities may obscure treatment-specific events.
Published: 2021
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16. Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis

Author: Ashley Jermusyck, Irene Collins, Juan Wang, Narayan Shivapurkar, Sandeep Nadella, Emanuel F. Petricoin, Matthew Huber, Simina M. Boca, Hong Cao, Eveline E. Vietsch, K. Alex Hodge, Jill P. Smith, Bhaskar Kallakury, Waxing Cui, Mariaelena Pierobon, Laufey T. Amundadottir, Robin D. Tucker, and Julian Burks
Subjects: endocrine system diseases, Carcinogenesis, Endocrinology, Diabetes and Metabolism, Pancreatic Intraepithelial Neoplasia, Mice, Transgenic, Biology, medicine.disease_cause, digestive system, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cell Line, Tumor, Pancreatic cancer, Gastrins, microRNA, Internal Medicine, medicine, Animals, Humans, Autocrine signalling, Pancreas, Cell Proliferation, Laser capture microdissection, Gastrin, Mice, Knockout, Hepatology, Kinase, Gene Expression Profiling, medicine.disease, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, MicroRNAs, 030220 oncology & carcinogenesis, Mutation, Cancer research, 030211 gastroenterology & hepatology, KRAS, Carcinoma in Situ, hormones, hormone substitutes, and hormone antagonists
Abstract: Objective The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. Methods LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. Results In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. Conclusions This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.
Published: 2019

17. Circulating cytokine levels as biomarkers for response to FOLFIRINOX chemotherapy in pancreatic cancer patients

Author: F. van der Sijde, W A Dik, Dana A. M. Mustafa, Eveline E. Vietsch, and C.H.J. van Eijck
Subjects: Oncology, Chemotherapy, medicine.medical_specialty, Hepatology, business.industry, FOLFIRINOX, medicine.medical_treatment, Gastroenterology, medicine.disease, Cytokine, Internal medicine, Pancreatic cancer, Medicine, business
Published: 2021

18. Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

Author: Ivana Peran, Casper H.J. van Eijck, Fleur van der Sijde, Mustafa Suker, Johan M. Kros, Eveline E. Vietsch, Thierry P P van den Bosch, Anton Wellstein, Surgery, and Pathology
Subjects: endocrine system diseases, medicine.medical_treatment, pancreatic cancer, In situ hybridization, lcsh:Technology, Article, lcsh:Chemistry, 03 medical and health sciences, 0302 clinical medicine, Immune system, immune cells, SDG 3 - Good Health and Well-being, Pancreatic cancer, medicine, General Materials Science, Progression-free survival, resection, skin and connective tissue diseases, Instrumentation, lcsh:QH301-705.5, 030304 developmental biology, Fluid Flow and Transfer Processes, 0303 health sciences, progression free survival, business.industry, lcsh:T, Process Chemistry and Technology, General Engineering, Cancer, biomarkers, CD79A, medicine.disease, Pancreaticoduodenectomy, lcsh:QC1-999, digestive system diseases, Computer Science Applications, Circulating MicroRNA, lcsh:Biology (General), lcsh:QD1-999, lcsh:TA1-2040, 030220 oncology & carcinogenesis, Cancer research, circulating microRNAs, sense organs, business, lcsh:Engineering (General). Civil engineering (General), lcsh:Physics
Abstract: Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+, Trp53R172H/+, P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated &ge, 3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.
Published: 2019

19. Circulating DNA in Cancer Diagnosis and Prognosis

Author: Anton Wellstein and Eveline E. Vietsch
Subjects: Oncology, medicine.medical_specialty, Metastatic lesions, medicine.diagnostic_test, business.industry, Cancer, Disease, medicine.disease, Tumor Sample, Tissue specimen, Internal medicine, Biopsy, medicine, Circulating DNA, Clinical care, business
Abstract: The standard diagnostic approach to cancer relies on the analysis of a surgical or biopsy tumor sample from a primary or metastatic site obtained at a given time point. However, due to intratumoral heterogeneity and selection of different subpopulations in metastatic lesions, the analysis of a single tissue specimen will provide only a limited characterization of the molecular makeup of the disease. Monitoring of the molecular tumor characteristics by serial analyses of cell-free, circulating nucleic acids promises to capture the dynamic nature and heterogeneity of the disease and support monitoring and treatment decisions. The analysis of circulating cell-free tumor DNA is continuously evolving with improvements in detection limits and reduction of the operating costs and represents a set of research tools that is poised to enter clinical care. Here we will discuss cell-free circulating DNA, potential clinical applications, and current limitations and challenges.
Published: 2019

20. List of Contributors

Author: Eliana Abdelhay, Pavan P. Adiseshaiah, Massimo Aglietta, Maryline Allègra, Paolo A. Ascierto, Nuria Coll Bastus, Ahmed Basudan, A.M. Sofie Berghuis, Guido Biasco, Renata Binato, Ankita Borah, Janet E. Brown, Vera Cappelletti, Sock Hoai Chan, Alice P. Chen, Ru Chen, Maxime Chénard-Poirier, Nicoletta Chicchinelli, Mauro Cives, Pierfranco Conte, Stephany Corrêa, Raffaele Costanzo, Geraldine O’Sullivan Coyne, Massimo Cristofanilli, Maria Grazia Daidone, Franco Dammacco, Gennaro Daniele, Rosalba De Nola, Amélie Dendooven, Serena Di Cosimo, Massimo Di Maio, Maria Vittoria Dieci, Lorenzo D’Ambrosio, Stella D’Oronzo, Tanja Fehm, Francesca Fenizia, Paola Ferrari, Vikas Ghai, Mario Giuliano, Vinod Gopalan, Paolo Grassi, Giovanni Grignani, Valentina Guarneri, Rekha Gyanchandani, Simon Heeke, Paul Hofman, Véronique Hofman, Alessia Iannaccone, Marius Ilié, Farhadul Islam, Michele Iuliani, Richard Kennedy, Serguei Kozlov, D. Sakthi Kumar, Alfred King-Yin Lam, Rita Lampignano, Mattia Lauriola, Adrian V. Lee, Inyoul Lee, Patrizia Leone, Domenica Lovero, Yong-Jie Lu, Umberto Malapelle, Paolo Manca, Francesco Mannavola, Anna Manzo, Nuala McCabe, Svenja Meierjohann, Alessandra Merlini, Vasiliki Michalarea, Agnese Montanino, Alessandro Morabito, Margherita Nannini, Roman Nawroth, Hans Neubauer, Joanne Ngeow, Andrea Nicolini, Nicola Normanno, Raffaele Palmirotta, Giuliano Palumbo, Sheng Pan, Carolina Panis, Francesco Pantano, Eileen Parkes, Luigi Pasini, Anna Passarelli, Francesco Passiglia, Patrick Pauwels, Eleonora Pellè, Hong Peng, Francesco Perrone, Lisa Phuong, Maria Carmela Piccirillo, Richard Piekarz, Albrecht Piiper, Pasquale Pisapia, Nolan Priedigkeit, Michela Pucci, Davide Quaresmini, Richard Quek, Vito Racanelli, Anna Maria Rachiglio, Raffaele Ratta, Giulia Ribelli, Christian Rolfo, Joseph Ryan, Ahmad R. Safa, Roberto Salgado, Claudia Sandomenico, Dario Sangiolo, Daniele Santini, Francesco Schettini, Clorinda Schettino, Bastian Schilling, Jolanda J. Schoon, Alexei Shimanovsky, Erica Silvestris, Franco Silvestris, Sonia Simonetti, Elizabeth C. Smyth, Nagavalli Somasundaram, Kjetil Søreide, Jonathan Strosberg, Magdalena Swierczewska, Hideyuki Takeshima, Giuseppe Tonini, Toshikazu Ushijima, Angelo Vacca, Grazia Vernaci, Elena Verzoni, Eveline E. Vietsch, Bruno Vincenzi, Oliver Waidmann, Kai Wang, Xiaosheng Wang, Jeffery S. Wasser, Anton Wellstein, Steven L. Wood, Lei Xu, and Harumi Yamada
Published: 2019

21. Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients

Author: Bas Groot Koerkamp, Marc G. Besselink, Dana A M Mustafa, Casper H.J. van Eijck, Eveline E. Vietsch, Fleur van der Sijde, Surgery, and Pathology
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, predictive circulating biomarker, FOLFIRINOX, medicine.medical_treatment, pancreatic cancer, chemotherapy response, Review, Disease, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, medicine, Objective response, Chemotherapy, business.industry, Incidence (epidemiology), gemcitabine, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Gemcitabine, Circulating biomarkers, 030104 developmental biology, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract: Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual patients may not benefit from chemotherapy. Biomarkers are needed to predict who will benefit from chemotherapy and to monitor a patient’s response to chemotherapy. This review summarizes current research and future perspectives on circulating biomarkers for systemic chemotherapy response.
Published: 2019

22. Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice

Author: Louis M. Weiner, Bedilu Allo, Michael J. Pishvaian, Sara C. Sprague, Ivana Peran, Shahin Assefnia, Stephen S. Yoo, Eveline E. Vietsch, Michael B. Atkins, Kelly A. Martin, Anton Wellstein, Andrew A. Quong, Aimy Sebastian, Nicholas R. Hum, Gabriela G. Loots, Matthew McCoy, Stephen W. Byers, Sivanesan Dakshanamurthy, and Anastasia Mavropoulos
Subjects: 0301 basic medicine, Drug Resistance, Deoxycytidine, Mice, 0302 clinical medicine, Cancer-Associated Fibroblasts, Pancreatic tumor, Tumor Microenvironment, 2.1 Biological and endogenous factors, Aetiology, Cancer, Mice, Knockout, biology, Chemistry, Gastroenterology, Cadherins, Extracellular Matrix, Gene Expression Regulation, Neoplastic, Pancreatic Ductal, Disease Progression, Immunohistochemistry, Female, 030211 gastroenterology & hepatology, Antibody, Carcinoma, Pancreatic Ductal, medicine.drug, Stromal cell, Knockout, Clinical Sciences, Article, Pancreaticoduodenectomy, Immunomodulation, Paediatrics and Reproductive Medicine, Pancreatic Cancer, 03 medical and health sciences, Rare Diseases, Activated Stroma, Pancreatic cancer, Anti-Tumor Immunity, medicine, Animals, Humans, Pancreas, Inflammation, Neoplastic, Tumor microenvironment, Gastroenterology & Hepatology, Hepatology, Animal, Carcinoma, Neurosciences, medicine.disease, Gemcitabine, Desmoplasia, Metallothionein 3, Pancreatic Neoplasms, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Drug Resistance, Neoplasm, Disease Models, Cancer cell, Cancer research, biology.protein, Neoplasm, Tumor Escape, Digestive Diseases
Abstract: BACKGROUND & AIMS: Pancreatic ductal adenocarcinomas (PDAC) are characterized by fibrosis and an abundance of cancer-associated fibroblasts (CAFs). We investigated strategies to disrupt interactions among CAFs, the immune system, and cancer cells, focusing on adhesion molecule cadherin 11 (CDH11), which has been associated with other fibrotic disorders and is expressed by activated fibroblasts. METHODS: We compared levels of CDH11 mRNA in human pancreatitis and pancreatic cancer tissues and cells, compared with normal pancreas, and measured levels of CDH11 protein in human and mouse pancreatic lesions and normal tissues. We crossed p48-Cre;LSL-Kras(G12D/+);LSL-Trp53(R172H/+) (KPC) mice with CDH11-knockout mice and measured survival times of offspring. Pancreata were collected and analyzed by histology, immunohistochemistry, and (single-cell) RNA sequencing; RNA and proteins were identified by imaging mass cytometry. Some mice were given injections of PD1 antibody or gemcitabine and survival was monitored. Pancreatic cancer cells from KPC mice were subcutaneously injected into Cdh11(+/+) and Cdh11(−/−) mice and tumor growth was monitored. Pancreatic cancer cells (mT3) from KPC mice (C57BL/6), were subcutaneously injected into Cdh11(+/+) (C57BL/6J) mice and mice were given injections of antibody against CDH11, gemcitabine, or small molecule inhibitor of CDH11 (SD133) and tumor growth was monitored. RESULTS: Levels of CDH11 mRNA and protein were significantly higher in CAFs than in pancreatic cancer epithelial cells, human or mouse pancreatic cancer cell lines, or immune cells. KPC/Cdh11(+/−) and KPC/Cdh11(−/−) mice survived significantly longer than KPC/Cdh11(+/+) mice. Markers of stromal activation entirely surrounded pancreatic intraepithelial neoplasias in KPC/Cdh11(+/+) mice and incompletely in KPC/Cdh11(+/−) and KPC/Cdh11(−/−) mice, whose lesions also contained fewer FOXP3(+) cells in the tumor center. Compared with pancreatic tumors in KPC/Cdh11(+/+) mice, tumors of KPC/Cdh11(+/−) mice had increased markers of antigen processing and presentation; more lymphocytes and associated cytokines; decreased extracellular matrix components; and reductions in markers and cytokines associated with immunosuppression. Administration of the PD1 antibody did not prolong survival of KPC mice with 0, 1, or 2 alleles of Cdh11. Gemcitabine extended survival only of KPC/Cdh11(+/−) and KPC/Cdh11(−/−) mice or reduced subcutaneous tumor growth in mT3 engrafted Cdh11(+/+) mice given in combination with the CDH11 antibody. A small molecule inhibitor of CDH11 reduced growth of pre-established mT3 subcutaneous tumors only if T and B cells were present in mice. CONCLUSIONS: Knockout or inhibition of CDH11, which is expressed by CAFs in the pancreatic tumor stroma, reduces growth of pancreatic tumors, increases their response to gemcitabine, and significantly extends survival of mice. CDH11 promotes immunosuppression and extracellular matrix deposition, and might be developed as a therapeutic target for pancreatic cancer.
Published: 2021

23. Circulating TP53 Mutations Are Predictive and Prognostic Biomarkers in Pancreatic Cancer Patients Treated with FOLFIRINOX Chemotherapy

Author: M.G. Besselink, F. van der Sijde, Johanna W. Wilmink, Marjolein Y.V. Homs, Dana A. M. Mustafa, J.W.B. de Groot, Eveline E. Vietsch, C.H.J. van Eijck, Brigitte C M Haberkorn, Leonie J. M. Mekenkamp, and Saskia A C Luelmo
Subjects: Oncology, medicine.medical_specialty, Chemotherapy, Hepatology, business.industry, FOLFIRINOX, medicine.medical_treatment, Gastroenterology, medicine.disease, Tp53 mutation, Internal medicine, Pancreatic cancer, medicine, business
Published: 2021

24. Circulating biomarkers to monitor cancer progression and treatment

Author: Anton Wellstein, Suthee Rapisuwon, and Eveline E. Vietsch
Subjects: 0301 basic medicine, Mini Review, lcsh:Biotechnology, cell-free RNA, Biophysics, circulating mutant DNA, Disease, Biology, Bioinformatics, Biochemistry, cell-free DNA, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, lcsh:TP248.13-248.65, Gene expression, Genetics, medicine, cell-free microRNA, circulating tumor DNA, Messenger RNA, Nucleic acid sequence, RNA, Cancer, medicine.disease, cell-free circulating nucleic acids, Computer Science Applications, 030104 developmental biology, Cell-free fetal DNA, 030220 oncology & carcinogenesis, Nucleic acid, Biotechnology
Abstract: Tumor heterogeneity is a major challenge and the root cause of resistance to treatment. Still, the standard diagnostic approach relies on the analysis of a single tumor sample from a local or metastatic site that is obtained at a given time point. Due to intratumoral heterogeneity and selection of subpopulations in diverse lesions this will provide only a limited characterization of the makeup of the disease. On the other hand, recent developments of nucleic acid sequence analysis allows to use minimally invasive serial blood samples to assess the mutational status and altered gene expression patterns for real time monitoring in individual patients. Here, we focus on cell-free circulating tumor-specific mutant DNA and RNA (including mRNA and non-coding RNA), as well as current limitations and challenges associated with circulating nucleic acids biomarkers.
Published: 2016
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25. Circulating micrornas associated with the systemic immune-inflammation index and prognosis in resectable pancreatic cancer

Author: F. van der Sijde, Eveline E. Vietsch, and C.H.J. van Eijck
Subjects: Oncology, Resectable Pancreatic Cancer, medicine.medical_specialty, Circulating MicroRNA, Hepatology, business.industry, Internal medicine, Gastroenterology, Medicine, business, Immune inflammation
Published: 2020

26. Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

Author: Giuseppe Giaccone, Aamir Javaid, Eveline E. Vietsch, Garrett T. Graham, Anton Wellstein, Justine N. McCutcheon, and John L. Marshall
Subjects: 0301 basic medicine, Cancer Research, Colorectal cancer, Biology, Adenocarcinoma, Bioinformatics, medicine.disease_cause, Somatic evolution in cancer, 03 medical and health sciences, 0302 clinical medicine, Pancreatic cancer, Genetics, medicine, Biomarkers, Tumor, Humans, Molecular Biology, Neoplasm Staging, Mutation, Cancer, High-Throughput Nucleotide Sequencing, DNA, Neoplasm, medicine.disease, Primary tumor, Pancreatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Cancer research, Disease Progression, CA19-9, Neoplasm Recurrence, Local, Cell-Free Nucleic Acids
Abstract: Cancer is a heterogeneous disease harboring diverse subclonal populations that can be discriminated by their DNA mutations. Environmental pressure selects subclones that ultimately drive disease progression and tumor relapse. Circulating cell-free DNA (ccfDNA) can be used to approximate the mutational makeup of cancer lesions and can serve as a marker for monitoring disease progression at the molecular level without the need for invasively acquired samples from primary or metastatic lesions. This potential for molecular analysis makes ccfDNA attractive for the study of clonal evolution and for uncovering emerging therapeutic resistance or sensitivity. We assessed ccfDNA from colon and pancreatic adenocarcinoma patients using next generation sequencing of 56 cancer-associated genes at the time of primary resectable disease and metastatic progression and compared this to the mutational patterns of the primary tumor. 28%–47% of non-synonymous mutations in the primary tumors were also detected in the ccfDNA while 71%–78% mutations found in ccfDNA were not detected in the primary tumors. ccfDNA collected at the time of progression harbored 3–5 new mutations not detected in ccfDNA at the earlier collection time points. We conclude that incorporation of ccfDNA analysis provides crucial insights into the changing molecular makeup of progressive colon and pancreatic cancer.
Published: 2017

27. Reprint of: Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

Author: Giuseppe Giaccone, Aamir Javaid, Anton Wellstein, John L. Marshall, Garrett T. Graham, Justine N. McCutcheon, and Eveline E. Vietsch
Subjects: 0301 basic medicine, Cancer Research, Mutation, Colorectal cancer, Cancer, Biology, medicine.disease, medicine.disease_cause, Somatic evolution in cancer, Primary tumor, Circulating Cell-Free DNA, Article, 03 medical and health sciences, 030104 developmental biology, Pancreatic cancer, Genetics, medicine, Cancer research, Adenocarcinoma, Molecular Biology
Abstract: Cancer is a heterogeneous disease harboring diverse subclonal populations that can be discriminated by their DNA mutations. Environmental pressure selects subclones that ultimately drive disease progression and tumor relapse. Circulating cell-free DNA (ccfDNA) can be used to approximate the mutational makeup of cancer lesions and can serve as a marker for monitoring disease progression at the molecular level without the need for invasively acquired samples from primary or metastatic lesions. This potential for molecular analysis makes ccfDNA attractive for the study of clonal evolution and for uncovering emerging therapeutic resistance or sensitivity. We assessed ccfDNA from colon and pancreatic adenocarcinoma patients using next generation sequencing of 56 cancer-associated genes at the time of primary resectable disease and metastatic progression and compared this to the mutational patterns of the primary tumor. 28%-47% of non-synonymous mutations in the primary tumors were also detected in the ccfDNA whilst 71%-78% mutations found in ccfDNA were not detected in the primary tumors. ccfDNA collected at the time of progression harbored 3-5 new mutations not detected in ccfDNA at the earlier collection time points. We conclude that incorporation of ccfDNA analysis provides crucial insights into the changing molecular makeup of progressive colon and pancreatic cancer.
Published: 2017

28. Dietary downregulation of mutant p53 levels via glucose restriction

Author: Anton Wellstein, Vamsi K. Kolukula, Eveline E. Vietsch, Olga Rodriguez, Jason Catania, Anju Preet, Jill Bargonetti, Sujatra Choudhury, Katherine Reynoso, Chris Albanese, and Maria Laura Avantaggiati
Subjects: Programmed cell death, Mutation, Normal diet, Mutant, Autophagy, Cell Biology, Biology, medicine.disease_cause, Transplantation, Proteasome, Downregulation and upregulation, Cancer research, medicine, Molecular Biology, Developmental Biology
Abstract: The majority of human tumors express mutant forms of p53 at high levels, promoting gain of oncogenic functions and correlating with disease progression, resistance to therapy and unfavorable prognosis. p53 mutant accumulation in tumors is attributed to the ability to evade degradation by the proteasome, the only currently recognized machinery for p53 disruption. We report here that glucose restriction (GR) induces p53 mutant deacetylation, routing it for degradation via autophagy. Depletion of p53 leads, in turn, to robust autophagic activation and to cell death, while expression of degradation-defective mutant p53 blocks autophagy and enables survival to GR. Furthermore, we found that a carbohydrate-free dietetic regimen that lowers the fasting glucose levels blunts p53 mutant expression and oncogenic activity relative to a normal diet in several animal model systems. These findings indicate that the stability of mutant forms of p53 is influenced by the levels of glucose and by dietetic habits. They also unravel the existence of an inhibitory loop between autophagy and mutant p53 that can be exploited therapeutically.
Published: 2012

29. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author: Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal
Subjects: 0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract: O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1
Published: 2016

30. e-IQ and IQ knowledge mining for generalized LDA

Author: Eveline E. Vietsch, Harold H. Szu, Rutger van Bergem, Jeffrey Jenkins, and Charles Sweet
Subjects: Artificial neural network, business.industry, Computer science, Big data, Collaborative learning, computer.software_genre, Machine learning, Data set, Information extraction, Subject-matter expert, Knowledge extraction, Tacit knowledge, Unsupervised learning, Artificial intelligence, business, computer
Abstract: How can the human brain uncover patterns, associations and features in real-time, real-world data? There must be a general strategy used to transform raw signals into useful features, but representing this generalization in the context of our information extraction tool set is lacking. In contrast to Big Data (BD), Large Data Analysis (LDA) has become a reachable multi-disciplinary goal in recent years due in part to high performance computers and algorithm development, as well as the availability of large data sets. However, the experience of Machine Learning (ML) and information communities has not been generalized into an intuitive framework that is useful to researchers across disciplines. The data exploration phase of data mining is a prime example of this unspoken, ad-hoc nature of ML – the Computer Scientist works with a Subject Matter Expert (SME) to understand the data, and then build tools (i.e. classifiers, etc.) which can benefit the SME and the rest of the researchers in that field. We ask, why is there not a tool to represent information in a meaningful way to the researcher asking the question? Meaning is subjective and contextual across disciplines, so to ensure robustness, we draw examples from several disciplines and propose a generalized LDA framework for independent data understanding of heterogeneous sources which contribute to Knowledge Discovery in Databases (KDD). Then, we explore the concept of adaptive Information resolution through a 6W unsupervised learning methodology feedback system. In this paper, we will describe the general process of man-machine interaction in terms of an asymmetric directed graph theory (digging for embedded knowledge), and model the inverse machine-man feedback (digging for tacit knowledge) as an ANN unsupervised learning methodology. Finally, we propose a collective learning framework which utilizes a 6W semantic topology to organize heterogeneous knowledge and diffuse information to entities within a society in a personalized way.
Published: 2015

31. Circulating DNA and Micro-RNA in Patients with Pancreatic Cancer

Author: Anton Wellstein, Eveline E. Vietsch, and Casper H.J. van Eijck
Subjects: Liquid biopsy, business.industry, Mutant, Pancreatic cancer, Treatment response, medicine.disease, Somatic evolution in cancer, Article, 3. Good health, Circulating microRNA, Prognostic markers, chemistry.chemical_compound, Circulating MicroRNA, chemistry, microRNA, Cancer cell, Immunology, Cancer research, Medicine, Circulating DNA, business, Biomarkers, DNA
Abstract: Collecting repeat samples of blood ("liquid biopsies") is a broadly used clinical approach for serial monitoring of disease or response to treatments. In patients with cancer the most distinct molecular feature are somatic mutations acquired by cancer cells present in the diseased tissue. Indeed, mutant DNA derived from dying or lysed cancer cells can be isolated from patient serum samples, subjected to DNA sequencing and to analysis of abundance as a measure of tumor burden. Also, changes in the DNA mutation patterns in serum samples collected over time can indicate altered pathways or clonal evolution of the disease and altered abundance of mutant DNA suggests an altered disease burden. In addition, during the course of treatment, changes in circulating DNA mutation patterns can indicate the emergence of resistant clones and prompt changes in treatment. In contrast to mutant DNA, microRNAs (miR) are transcribed, processed, packaged and released from cells in normal and in diseased tissues as part of the extracellular crosstalk between cells. Interestingly, released miR can function in cell-to-cell communication and as hormone-like signals that operate at a distance through their release into the circulation and subsequent uptake into cells in distant tissues. Circulating miR expression patterns can be established from serial serum samples and monitored for alterations over time. Circulating miR provide a readout of the organism's steady state and serial analyses will indicate changes in the response to therapy or an altered physiologic or disease state. Furthermore, changes in circulating miR patterns can indicate treatment efficacy or resistance as well as adverse effects associated with the respective intervention. Thus, the combined serial analysis of mutant DNA and miR in the circulation has the potential to provide a molecular footprint of pancreatic cancer and can be used to monitor treatment responses or resistance to treatment in real time with a minimally invasive procedure.
Published: 2015

32. Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma

Author: Mandheer Wadhwa, Yuhao Shi, Alias Smith, Swati Gupta, Mark Manzano, Nivedita Nandakumar, Anton Wellstein, Mahandranauth A. Chetram, Jeffrey A. Toretsky, Chunling Yi, Eveline E. Vietsch, Bhaskar Kallakury, Weiying Zhang, Garrett T. Graham, Sean Z. Laughlin, Fen Wang, and Mrinmayi Joshi
Subjects: MAPK/ERK pathway, Stromal cell, endocrine system diseases, Adenocarcinoma, Biology, medicine.disease_cause, Biochemistry, Article, Mice, medicine, Animals, Humans, RNA, Messenger, neoplasms, Molecular Biology, Transcription factor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Tumor microenvironment, Hippo signaling pathway, Pancreatic Ducts, YAP-Signaling Proteins, Cell Biology, Genes, p53, Phosphoproteins, medicine.disease, digestive system diseases, Genes, ras, medicine.anatomical_structure, Mutation, Disease Progression, Cancer research, KRAS, Pancreas, Carcinoma, Pancreatic Ductal, Transcription Factors
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far not been a viable therapeutic target. We found that the abundance of YAP mRNA, which encodes Yes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia. In genetically engineered Kras(G12D) and Kras(G12D):Trp53(R172H) mouse models, pancreas-specific deletion of Yap halted the progression of early neoplastic lesions to PDAC without affecting normal pancreatic development and endocrine function. Although Yap was dispensable for acinar to ductal metaplasia (ADM), an initial step in the progression to PDAC, Yap was critically required for the proliferation of mutant Kras or Kras:Trp53 neoplastic pancreatic ductal cells in culture and for their growth and progression to invasive PDAC in mice. Yap functioned as a critical transcriptional switch downstream of the oncogenic KRAS-mitogen-activated protein kinase (MAPK) pathway, promoting the expression of genes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenic stromal response in the tumor microenvironment, and PDAC progression in Kras and Kras:Trp53 mutant pancreas tissue. Together, our findings identified Yap as a critical oncogenic KRAS effector and a promising therapeutic target for PDAC and possibly other types of KRAS-mutant cancers.
Published: 2014

33. Abstract A73: De-convoluting therapeutic resistance in a pancreatic cancer model: Pharmacogenomic evaluation of intratumoral clonal heterogeneity

Author: Beverly A. Mock, John K. Simmons, Eveline E. Vietsch, Marianne Stenstra, Anton Wellstein, and Ivana Peran
Subjects: Cancer Research, business.industry, Cancer, medicine.disease, medicine.disease_cause, Gemcitabine, Gene expression profiling, Oncology, Pharmacogenomics, Pancreatic cancer, Immunology, medicine, Cancer research, Adenocarcinoma, KRAS, business, Exome sequencing, medicine.drug
Abstract: Background: The duration of therapeutic response in pancreatic adenocarcinoma to both targeted therapies and conventional chemotherapeutics is abysmal, greatly contributing to the 5-year survival rate of this disease remaining in the single digits. Given the high proliferative rate of these tumors, and the frequent occurrence of mutations in genes critical for maintaining genomic integrity, we hypothesized that rapid therapeutic resistance may largely be the consequence of intratumoral heterogeneity present at the onset of therapy. Materials and Methods: To address this question, an integrated genomic and pharmacologic survey was performed on a panel of clonal cell lines generated from a tumor arising in a Kras/Trp53 mutant mouse model (p48-Cre; LSL-KrasG12D; LSL-Trp53R172H). Results: All lines screened maintained tumorigenicity upon allografting, and exhibited metastatic capacity. Whole exome sequencing confirmed that 94% of driver mutations found in the clonal lines were also present in the tumor. Importantly, each clonal line contains unique passenger mutations. Exposure of these lines to conventional chemotherapeutics in vitro (i.e. gemcitabine, doxorubicin, and vincristine) showed high variance in sensitivity, with 10-fold ranges of IC50s among the lines. Screening of the clonal cell lines with a kinase inhibitor library of 200 compounds, showed distinct vulnerabilities to targeted pathways between the lines. Gene expression profiling and pathway analysis highlighted variation in critical cellular pathways between the lines. Conclusions: Our results in this model system implicate ab initio drug resistance in these heterogeneous tumors as a major contributor to the poor therapeutic outcomes in this disease. This applies to conventional chemotherapy as well as targeted inhibitors. Citation Format: Eveline E. Vietsch, John K. Simmons, Ivana Peran, Marianne Stenstra, Beverly A. Mock, Anton Wellstein. De-convoluting therapeutic resistance in a pancreatic cancer model: Pharmacogenomic evaluation of intratumoral clonal heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A73.
Published: 2015

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33 results on '"Eveline E. Vietsch"'

1. B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients

2. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity

3. Cardiomyocyte-Specific Circulating Cell-Free Methylated DNA in Esophageal Cancer Patients Treated with Chemoradiation

4. Serum cytokine levels are associated with tumor progression during FOLFIRINOX chemotherapy and overall survival in pancreatic cancer patients

5. Circulating mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

6. Serum miR-373-3p and miR-194-5p Are Associated with Early Tumor Progression during FOLFIRINOX Treatment in Pancreatic Cancer Patients: A Prospective Multicenter Study

7. Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib

8. Circulating biomarkers to monitor cancer progression and treatment

9. Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

10. Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma

11. Serum miR-338-3p and miR-199b-5p are associated with the absolute neutrophil count in patients with resectable pancreatic cancer

12. Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors

13. Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

14. Circulating Immunological Biomarkers: Prognosis of Pancreatic Cancer Patients Reflected by the Immune System

15. Cardiomyocyte-Specific Circulating Cell-Free Methylated DNA in Esophageal Cancer Patients Treated with Chemoradiation

16. Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis

17. Circulating cytokine levels as biomarkers for response to FOLFIRINOX chemotherapy in pancreatic cancer patients

18. Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

19. Circulating DNA in Cancer Diagnosis and Prognosis

20. List of Contributors

21. Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients

22. Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice

23. Circulating TP53 Mutations Are Predictive and Prognostic Biomarkers in Pancreatic Cancer Patients Treated with FOLFIRINOX Chemotherapy

24. Circulating biomarkers to monitor cancer progression and treatment

25. Circulating micrornas associated with the systemic immune-inflammation index and prognosis in resectable pancreatic cancer

26. Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

27. Reprint of: Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

28. Dietary downregulation of mutant p53 levels via glucose restriction

29. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

30. e-IQ and IQ knowledge mining for generalized LDA

31. Circulating DNA and Micro-RNA in Patients with Pancreatic Cancer

32. Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma

33. Abstract A73: De-convoluting therapeutic resistance in a pancreatic cancer model: Pharmacogenomic evaluation of intratumoral clonal heterogeneity

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33 results on '"Eveline E. Vietsch"'

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