Using BioMart as a framework to manage and query pancreatic cancer data

We describe the Pancreatic Expression Database (PED), the first cancer database originally designed based on the BioMart infrastructure. The PED portal brings together multidimensional pancreatic cancer data from the literature including genomic, proteomic, miRNA and gene expression profiles. Based on the BioMart 0.7 framework, the database is easily integrated with other BioMart-compliant resources, such as Ensembl and Reactome, to give access to a wide range of annotations alongside detailed experimental conditions. This article is intended to give an overview of PED, describe its data content and work through examples of how to successfully mine and integrate pancreatic cancer data sets and other BioMart resources

Pathological and molecular evaluation of pancreatic neoplasms

Pancreatic neoplasms are morphologically and genetically heterogeneous and include a wide variety of tumors ranging from benign to malignant with an extremely poor clinical outcome. Our understanding of these pancreatic neoplasms has improved significantly with recent advances in cancer sequencing. Awareness of molecular pathogenesis brings new opportunities for early detection, improved prognostication, and personalized gene-specific therapies. Here we review the pathological classification of pancreatic neoplasms from the molecular and genetic perspectives

Peroxisomes in intestinal and gallbladder epithelial cells of the stickleback, Gasterosteus aculeatus L. (Teleostei)

The occurrence of microbodies in the epithelial cells of the intestine and gallbladder of the stickleback, Gasterosteus aculeatus L., is described. In the intestine the organelles are predominantly located in the apical and perinuclear zone of the cells and may contain small crystalline cores. In gallbladder epithelial cells the microbodies are distributed randomly. The latter organdies are characterized by the presence of large crystalloids. Cytochemical and biochemical experiments show that catalase and D-amino acid oxidase are main matrix components of the microbodies in both the intestinal and gallbladder epithelia. These organelles therefore are considered peroxisomes. In addition, in intestinal mucosa but not in gallbladder epithelium a low activity of palmitoyl CoA oxidase was detected biochemically. Urate oxidase and L-α hydroxy acid oxidase activities could not be demonstrated.

Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification

Pancreatic cancer is one of the most lethal of all cancers. The median survival is 6 months, and less than 5% of those diagnosed survive 5-years. Recurrent genetic deletions and amplifications in 73 pancreatic adenocarcinomas, the largest sample set analyzed to date for pancreatic cancer, were defined using comparative genomic hybridization The recurrent genetic alterations identified target a number of previously well-characterized genes, as well as regions that contain possible new oncogenes and tumor suppressor genes. We have focused on chromosome 19q13, a region frequently found amplified in pancreatic cancer, and demonstrate how boundaries of common regions of mutation can be mapped, and how a gene, in this case PAK4 amplified on chromosome19q13, can be functionally validated. We show that although the PAK4 gene is not activated by mutation in cell lines with gene amplification, an oncogenic form of the KRAS2 gene is present in these cells, and oncogenic KRAS2 can activate PAK4. In fact in the three samples we identified with PAK4 gene amplification, the KRAS2 gene was activated and genomically amplified. The kinase activity of the PAK4 protein is significantly higher in cells with genomic amplification as compared to cells without amplification. Our study demonstrates the utility of analyzing copy number data in a large set of neoplasms to identify genes involved in cancer. We have generated a useful dataset which will be particularly useful for the pancreatic cancer community as efforts are undertaken to sequence the pancreatic cancer genome

Copy-Number Variants in Patients with a Strong Family History of Pancreatic Cancer

Copy-number variants such as germ-line deletions and amplifications are associated with inherited genetic disorders including familial cancer. The gene or genes responsible for the majority of familial clustering of pancreatic cancer have not been identified. We used representational oligonucleotide microarray analysis (ROMA) to characterize germ-line copy number variants in 60 cancer patients from 57 familial pancreatic cancer kindreds. Fifty-seven of the 60 patients had pancreatic cancer and three had nonpancreatic cancers (breast, ovary, ovary). A familial pancreatic cancer kindred was defined as a kindred in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Copy-number variants identified in 607 individuals without pancreatic cancer were excluded from further analysis. A total of 56 unique genomic regions with copy-number variants not present in controls were identified, including 31 amplifications and 25 deletions. Two deleted regions were observed in two different patients, and one in three patients. The germ-line amplifications had a mean size of 662 Kb, a median size of 379 Kb (range 8.2 Kb to 2.5 Mb) and included 425 known genes. Examples of genes included in the germ-line amplifications include the MAFK, JunD and BIRC6 genes. The germ-line deletions had a mean size of 375Kb, a median size 151 Kb (range 0.4 Kb to 2.3 Mb) and included 81 known genes. In multivariate analysis controlling for region size, deletions were 90% less likely to involve a gene than were duplications (p < 0.01). Examples of genes included in the germ-line deletions include the FHIT, PDZRN3 and ANKRD3 genes. Selected deletions and amplifications were confirmed using real-time PCR, including a germ-line amplification on chromosome 19. These genetic copy-number variants define potential candidate loci for the familial pancreatic cancer gene

Conductance spectra of (Nb, Pb, In)/NbP -- superconductor/Weyl semimetal junctions

The possibility of inducing superconductivity in type-I Weyl semimetal through coupling its surface to a superconductor was investigated. A single crystal of NbP, grown by chemical vapor transport method, was carefully characterized by XRD, EDX, SEM, ARPES techniques and by electron transport measurements. The mobility spectrum of the carriers was determined. For the studies of interface transmission, the (001) surface of the crystal was covered by several hundred nm thick metallic layers of either Pb, or Nb, or In. DC current-voltage characteristics and AC differential conductance through the interfaces as a function of the DC bias were investigated. When the metals become superconducting, all three types of junctions show conductance increase, pointing out the Andreev reflection as a prevalent contribution to the subgap conductance. In the case of Pb-NbP and Nb-NbP junctions, the effect is satisfactorily described by modified Blonder-Tinkham-Klapwijk model. The absolute value of the conductance is much smaller than that for the bulk crystal, indicating that the transmission occurs through only a small part of the contact area. An opposite situation occurs in In-NbP junction, where the conductance at the peak reaches the bulk value indicating that almost whole contact area is transmitting and, additionally, a superconducting proximity phase is formed in the material. We interpret this as a result of indium diffusion into NbP, where the metal atoms penetrate the surface barrier and form very transparent superconductor-Weyl semimetal contact inside. However, further diffusion occurring already at room temperature leads to degradation of the effect, so it is observed only in the pristine structures. Despite of this, our observation directly demonstrates possibility of inducing superconductivity in a type-I Weyl semimetal.Comment: Accepted for Phys. Rev. B. 13 pages, 12 figures. Second version with major revisions. The title was changed. One author R. Jakiela added. New inset to Fig. 8(A). New fits in Fig. 8 (B) and Fig. 10 (B). Added figures 12 (C)-(E). Added Fig. 12 (F) with SIMS data. Rewritten chapters III-C-2 and III-C-3. Reference no. 38 removed, 11 new references: 9, 21, 22, 40-44, 46-49 were adde

Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site

Serous cystic neoplasm of the pancreas: A multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58\u2005years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40\u2005mm (2-200)), 9% had resection beyond 1\u2005year of follow-up (3\u2005years (1-20), size at diagnosis: 25\u2005mm (4-140)) and 39% had no surgery (3.6\u2005years (1-23), 25.5\u2005mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1\u2005year (n=1271), size increased in 37% (growth rate: 4\u2005mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN

Strong interband Faraday rotation in 3D topological insulator Bi2Se3

The Faraday effect is a representative magneto-optical phenomenon, resulting from the transfer of angular momentum between interacting light and matter in which time-reversal symmetry has been broken by an externally applied magnetic field. Here we report on the Faraday rotation induced in the prominent 3D topological insulator Bi2Se3 due to bulk interband excitations. The origin of this non-resonant effect, extraordinarily strong among other non-magnetic materials, is traced back to the specific Dirac-type Hamiltonian for Bi2Se3, which implies that electrons and holes in this material closely resemble relativistic particles with a non-zero rest mass

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis