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Addressing the challenges of pancreatic cancer: future directions for improving outcomes

  • Hidalgo, Manuel
  • Cascinu, Stefano
  • Kleeff, Jörg
  • Labianca, Roberto
  • Löhr, J. Matthias
  • Neoptolemos, John
  • Real, Francisco X.
  • Van Laethem, Jean-Luc
  • Heinemann, Volker
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease., This manuscript and the original meeting that led to its development were supported by an educational grant from Astellas Pharma EMEA. Highfield Communication Consultancy, Oxford, UK (funded by Astellas Pharma EMEA) provided editorial assistance in the preparation of the manuscript.

Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases

  • Yang, Jialiang
  • Huang, Tao
  • Petralia, Francesca
  • Long, Quan
  • Zhang, Bin
  • Argmann, Carmen
  • Zhao, Yong
  • Mobbs, Charles V.
  • Schadt, Eric
  • Zhu, Jun
  • Tu, Zhidong
  • GTEx Consortium
  • Monlong, Jean
  • Sammeth, Michael
  • Mele, Marta
  • Reverter, Ferran
  • Goldmann, Jakob
  • Guigó Serra, Roderic
Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed, and some essential tissues (e.g., heart and lung) show much stronger "co-aging" than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases., JY is supported through Berg postdoc fellowship. ZT receives financial support from Berg Pharma as a consultant. ZT JZ ES receive support from Fondation Leducq Understanding coronary artery disease genes grant. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 & DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822).

Vitamin D and the epithelial to mesenchymal transition

  • Larriba, María Jesús
  • García de Herreros, Antonio
  • Muñoz, Alberto
Several studies support reciprocal regulation between the active vitamin D derivative 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the epithelial to mesenchymal transition (EMT). Thus, 1,25(OH)2D3 inhibits EMT via the induction of a variety of target genes that encode cell adhesion and polarity proteins responsible for the epithelial phenotype and through the repression of key EMT inducers. Both direct and indirect regulatory mechanisms mediate these effects. Conversely, certain master EMT inducers inhibit 1,25(OH)2D3 action by repressing the transcription of VDR gene encoding the high affinity vitamin D receptor that mediates 1,25(OH)2D3 effects. Consequently, the balance between the strength of 1,25(OH)2D3 signaling and the induction of EMT defines the cellular phenotype in each context. Here we review the current understanding of the genes and mechanisms involved in the interplay between 1,25(OH)2D3 and EMT., The work in the authors’ laboratories is supported by Ministerio de Econom´ıa y Competitividad of Spain-Fondo Europeo de Desarrollo Regional (FEDER) to Alberto Munoz (SAF2013- ˜ 43468-R), Instituto de Salud Carlos III-FEDER to Alberto Munoz (RD12/0036/0021) and Antonio García de Herreros (RD12/0036/0005), and Comunidad de Madrid to Alberto Muñoz and Antonio García de Herreros (S2010/BMD-2344 Colomics2).

The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor.

  • Stanley, Nathaniel H., 1983-
  • Pardo, Leonardo
  • De Fabritiis, Gianni
The binding process through the membrane bilayer of lipid-like ligands to a protein target is an important but poorly explored recognition process at the atomic level. In this work we succeeded in resolving the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) using unbiased molecular dynamics simulations with an aggregate sampling of over 800 μs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a "membrane vestibule" at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the "membrane vestibule" is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies., The authors would like to thank the volunteers of GPUGRID.net for donating compute time to this project. LP (SAF2013-48271-C2-2-R) and GDF (BIO2014-53095-P) acknowledge support by the Spanish Ministry of Science and Innovation and FEDER.

Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia.

  • Costas, Javier
  • Carrera, Noa
  • Alonso, Pino
  • Gurriarán, X.
  • Segalàs, Cinto
  • Real, Eva
  • López-Solà, Clara
  • Mas, Sebastian
  • Gassó, Patricia
  • Domenech Salgado, Laura
  • Morell, Marta
  • Quintela Garcia, Ines
  • Lázaro, Luisa
  • Menchón, José M.
  • Estivill, Xavier, 1955-
  • Carracedo, Ángel
Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10(-5)), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10(-6), explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications., The study was supported by Fundación María José Jove, Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia; and by grants from the Instituto de Salud Carlos III FIS PI13/01136 to AC, CP11/00163 to JC, PI13/00918 to JMM, PI14/00413 to PA; the Generalitat de Catalunya AGAUR 2014 SGR-1138; the Spanish MINIECO SAF2013-49108- R Plan Estatal; and the European Commission 7th Framework Program, Project N. 262055 (ESGI) to XE. LD is supported by a Severo Ochoa fellowship of the Spanish MINIECO.

The pivotal roles of TIA proteins in 5' splice-site selection of alu exons and across evolution

  • Gal-Mark, Nurit
  • Schwartz, Schraga
  • Ram, Oren
  • Eyras Jiménez, Eduardo
  • Ast, Gil
More than 5% of alternatively spliced internal exons in the human genome are derived from Alu elements in a process termed exonization. Alus are comprised of two homologous arms separated by an internal polypyrimidine tract (PPT). In most exonizations, splice sites are selected from within the same arm. We hypothesized that the internal PPT may prevent selection of a splice site further downstream. Here, we demonstrate that this PPT enhanced the selection of an upstream 5' splice site (5'ss), even in the presence of a stronger 5'ss downstream. Deletion of this PPT shifted selection to the stronger downstream 5'ss. This enhancing effect depended on the strength of the downstream 5'ss, on the efficiency of base-pairing to U1 snRNA, and on the length of the PPT. This effect of the PPT was mediated by the binding of TIA proteins and was dependent on the distance between the PPT and the upstream 5'ss. A wide-scale evolutionary analysis of introns across 22 eukaryotes revealed an enrichment in PPTs within approximately 20 nt downstream of the 5'ss. For most metazoans, the strength of the 5'ss inversely correlated with the presence of a downstream PPT, indicative of the functional role of the PPT. Finally, we found that the proteins that mediate this effect, TIA and U1C, and in particular their functional domains, are highly conserved across evolution. Overall, these findings expand our understanding of the role of TIA1/TIAR proteins in enhancing recognition of exons, in general, and Alu exons, in particular., GA is supported by a grant from the Israel Science Foundation (1449/04), MOP Germany-Israel, GIF, and DIP. SS is a fellow of the Edmond J. Safra Bioinformatic Program at Tel Aviv University. OR is supported by EURASNET. EE is supported by the Catalan Institute for Research and Advanced Studies (ICREA) and by the BIO2008-01091 grant from the Spanish Ministry of Science.

Exon creation and establishment in human genes

  • Corvelo, André
  • Eyras Jiménez, Eduardo
BACKGROUND: A large proportion of species-specific exons are alternatively spliced. In primates, Alu elements play a crucial role in the process of exon creation but many new exons have appeared through other mechanisms. Despite many recent studies, it is still unclear which are the splicing regulatory requirements for de novo exonization and how splicing regulation changes throughout an exon's lifespan. RESULTS: Using comparative genomics, we have defined sets of exons with different evolutionary ages. Younger exons have weaker splice-sites and lower absolute values for the relative abundance of putative splicing regulators between exonic and adjacent intronic regions, indicating a less consolidated splicing regulation. This relative abundance is shown to increase with exon age, leading to higher exon inclusion. We show that this local difference in the density of regulators might be of biological significance, as it outperforms other measures in real exon versus pseudo-exon classification. We apply this new measure to the specific case of the exonization of anti-sense Alu elements and show that they are characterized by a general lack of exonic splicing silencers. CONCLUSIONS: Our results suggest that specific sequence environments are required for exonization and that these can change with time. We propose a model of exon creation and establishment in human genes, in which splicing decisions depend on the relative local abundance of regulatory motifs. Using this model, we provide further explanation as to why Alu elements serve as a major substrate for exon creation in primates. Finally, we discuss the benefits of integrating such information in gene prediction., The authors would like to thank J Brosius for useful comments on the manuscript, M Plass (funded by the Spanish Health Institute Carlos III) for EST data handling and R Castelo (funded by the Spanish Ministry of Science) for the splice site position weight matrices. AC received support from the Graduate Program in Areas of Basic and Applied Biology (GABBA) and the Portuguese Foundation for Science and Technology. EE is supported by the Catalan Institution of Research and Advanced Studies (ICREA). This work is partly supported by the grant BIO2005-01287 from the Spanish Ministry of Science and by the project EURASNET from the European Commission.

Integrative annotation of 21,037 human genes validated by full-length cDNA clones

  • Imanishi, Tadashi
  • Eyras Jiménez, Eduardo
  • Sugano, Sumio
The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology., This research is financially supported by the Ministry of Economy, Trade, and Industry of Japan (METI), the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), the Japan Biological Informatics Consortium (JBIC), the New Energy and Industrial Technology Development Organization (NEDO), the United States Department of Energy, the National Institutes of Health of the United States, the Bundesministerium für Bildung und Forschung (BMBF) of Germany, the European Union through the EURO-IMAGE Consortium (grant BMH4-CT97-2284 coordinated by Charles Auffray), the 863 and 973 Program of the Ministry of Science and Technology of China, and CNRS of France. The work on Module 3D-keynote is supported by Grants-in-Aid for Scientific Research on Priority Areas (C) ‘‘Genome Information Science’’ to Mitiko Go and Kei Yura, and for Scientific Research (B) to MG, from MEXT. KY is also supported by a Grant-in-Aid for Encouragement of Young Scientists from MEXT. The work on subcellular localization is supported by a Grant-in-Aid for Scientific Research on Priority Areas (C) ‘‘Genome Information Science’’ from MEXT and the National Project on Protein Structural and Functional Analyses from the same Ministry.

Exotic branes and non-perturbative seven branes

  • Eyras Jiménez, Eduardo
  • Lozano, Yolanda
We construct the effective action of certain exotic branes in the Type II theories which are not predicted by their space-time supersymmetry algebras. We analyze in detail the case of the NS-7B brane, S-dual to the D7-brane, and connected by T-duality to other exotic branes in Type IIA: the KK-6A brane and the KK-8A brane (obtained by reduction of the M-theory Kaluza–Klein monopole and M9-brane, respectively). The NS-7B brane carries charge with respect to the S-dual of the RR 8-form, which we identify as a non-local combination of the electric–magnetic duals of the axion and the dilaton. The study of its effective action agrees with previous results in the literature showing that it transforms as an Full-size image (<1 K) triplet together with the D7-brane. We discuss why this brane is not predicted by the Type IIB space-time supersymmetry algebra. In particular we show that the modular transformation relating the D7 and NS-7B brane solutions can be undone by a simple coordinate transformation in the two-dimensional transverse space, equivalent to choosing a different region to parametrize the Full-size image (<1 K) moduli space. We discuss a similar relation between the D6 and KK-6A branes and the D8 and KK-8A branes.

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

  • Castillejo, Adela
  • Guarinos, Carla
  • Martínez Canto, Ana
  • Barbera, Victor Manuel
  • Egoavil, Cecilia
  • Castillejo, Maria Isabel
  • Pérez Carbonell, Lucía
  • Sánchez Heras, Ana Beatriz
  • Segura, Ángel
  • Ochoa, Enrique
  • Lazaro, Rafael
  • Ruiz Ponte, Clara
  • Bujanda, Luis
  • Andreu García, Montserrat
  • Castells, Antoni
  • Carracedo, Ángel
  • Llor, Xavier
  • Clofent, Juan
  • Alenda, Cristina
  • Paya, Artemio
  • Jover, Rodrigo
  • Soto, José Luis
Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS./nMethods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers./nResults: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients./nConclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.

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