Genetic predisposition for Multiple Myeloma. Identification and functional characterization of risk variants

Multiple myeloma (MM) is a blood malignancy originating from plasma cells. First-degree relatives of patients with MM have two- to four-fold higher risk of MM. However, the molecular basis remains largely unknown. This Ph.D. project aims to identify novel DNA sequence variants predisposing to MM through genome-wide association studies (GWAS) and, subsequently, characterize identified variants functionally.Article I describes a systematic study where we screened for causal gene-regulatory variants at 21 MM risk loci. Article II describes a Nordic GWAS identifying the SOHLH2 (13q13.3) as a novel MM risk locus. Article III describes a novel international meta-analysis of GWAS data totalling 10 906 cases and 366 221 controls, identifying twelve new risk variants for MM accounted for by nine loci: 5q35.2 CPEB4, 6p22.2 BTN3A2, 9q21.33 DAPK1, 10q24.33 STN1, 10q25.2 MXI1, 19p13.3 NFIC, 21q11.2, SAMSN1 and a rare variant at 13q13.1 BRCA2. Finally, in Article IV, we explore the possibility of identifying transcription factors that mediate allele-specific gene-regulatory effects through combined use of CRISPR/Cas9 screening and epistasis analysis of gene expression data.The work presented in this thesis provides new insight into the mechanisms underlying genetic predisposition for multiple myeloma

The insertion/deletion polymorphism rs201494641 at <i>ITGA9</i> influences blood CD34+ cell levels by altering ZNF384 binding

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Inhibidores de bomba de protones vs. antagonistas del receptor 2 de histamina en la protección gástrica en el paciente anticoagulado: ¿qué ha definido la evidencia?

Objective: to evaluate the latest evidence on the difference in gastroprotection generated by proton pump inhibitors (PPIs) and histamine receptor 2 antagonists (H2RAs) in anticoagulated patients, as well as the associated risk of gastrointestinal bleeding. Methods: narrative review. A literature search was conducted in the PubMed, ScienceDirect, Web of Science, and MEDLINE databases. Results: Among the described mechanisms explaining bleeding in the gastrointestinal tract are mucosal damage, alterations in local pH, platelet inhibition, coagulation factor alteration, and vascular lesions. Depending on the pharmacological group, anticoagulants can act on different targets in the coagulation pathway, altering the factors involved in this pathway and potentially triggering bleeding. Antisecretory drugs, on the other hand, aim to inhibit or reduce gastric acid secretion through interaction with enzymatic systems, altering the local pH. Thus, these drugs influence the risk of bleeding. However, the latest evidence shows that PPIs reduce the likelihood of gastrointestinal bleeding by up to 33% compared to H2RAs, without impacting other outcomes such as mortality or hospitalization. Conclusion: Although the evidence is scarce and heterogeneous, it was observed that there is greater scientific support and gastroprotective benefit against the frequency of gastrointestinal bleeding with the use of PPIs compared to H2RAs in anticoagulated patients who concurrently use gastric acid suppressants.Objetivo: evaluar la evidencia más reciente sobre la diferencia de la gastroprotección generada por los inhibidores de bomba de protones (IBP) y antagonistas del receptor de histamina 2 (ARH2) en el paciente anticoagulado, así como del riesgo de sangrado gastrointestinal asociado. Métodos: revisión narrativa. Se realizó una búsqueda bibliográfica en las bases de datos PubMed, ScienceDirect, Web of Science, y MEDLINE. Resultados: dentro de los mecanismos descritos que explican un sangrado en el tracto gastrointestinal, se encuentran el daño a mucosa, alteraciones en el pH local, inhibición plaquetaria y alteración de factores de la coagulación, y lesiones vasculares. Dependiendo del grupo farmacológico, los anticoagulantes pueden actúan a nivel de diferentes dianas de la vía de la coagulación, alterando los factores involucrados en esta vía, y pudiendo desencadenar sangrado. Por su parte, los antisecretores gástricos, tienen como objetivo inhibir o reducir la secreción de ácido gástrico por medio de la interacción con sistemas enzimáticos, alterando el pH local. De esta forma, estos fármacos influyen sobre el riesgo de sangrado. No obstante, la evidencia más reciente demuestra que los IBP reducen la probabilidad de sangrado gastrointestinal hasta en un 33%, comparado con los ARH2, sin impactar en otros desenlaces como mortalidad u hospitalización. Conclusión: aunque la evidencia es escasa y heterogénea, se pudo observar mayor respaldo científico y beneficio gastroprotector contra la frecuencia de sangrado gastrointestinal, con el uso de IBP comparado a ARH2, en pacientes anticoagulados que concomitantemente, utilizan antisecretores gástricos

Inhibidores de bomba de protones vs. antagonistas del receptor 2 de histamina en la protección gástrica en el paciente anticoagulado: ¿qué ha definido la evidencia?

Objetivo: evaluar la evidencia más reciente sobre la diferencia de la gastroprotección generada por los inhibidores de bomba de protones (IBP) y antagonistas del receptor de histamina 2 (ARH2) en el paciente anticoagulado, así como del riesgo de sangrado gastrointestinal asociado. Métodos: revisión narrativa. Se realizó una búsqueda bibliográfica en las bases de datos PubMed, ScienceDirect, Web of Science, y MEDLINE. Resultados: dentro de los mecanismos descritos que explican un sangrado en el tracto gastrointestinal, se encuentran el daño a mucosa, alteraciones en el pH local, inhibición plaquetaria y alteración de factores de la coagulación, y lesiones vasculares. Dependiendo del grupo farmacológico, los anticoagulantes pueden actúan a nivel de diferentes dianas de la vía de la coagulación, alterando los factores involucrados en esta vía, y pudiendo desencadenar sangrado. Por su parte, los antisecretores gástricos, tienen como objetivo inhibir o reducir la secreción de ácido gástrico por medio de la interacción con sistemas enzimáticos, alterando el pH local. De esta forma, estos fármacos influyen sobre el riesgo de sangrado. No obstante, la evidencia más reciente demuestra que los IBP reducen la probabilidad de sangrado gastrointestinal hasta en un 33%, comparado con los ARH2, sin impactar en otros desenlaces como mortalidad u hospitalización. Conclusión: aunque la evidencia es escasa y heterogénea, se pudo observar mayor respaldo científico y beneficio gastroprotector contra la frecuencia de sangrado gastrointestinal, con el uso de IBP comparado a ARH2, en pacientes anticoagulados que concomitantemente, utilizan antisecretores gástricos

Computational tools for splicing defect prediction in breast/ovarian cancer genes: how efficient are they at predicting RNA alterations?

In silico tools for splicing defect prediction have a key role to assess the impact of variants of uncertain significance. Our aim was to evaluate the performance of a set of commonly used splicing in silico tools comparing the predictions against RNA in vitro results. This was done for natural splice sites of clinically relevant genes in hereditary breast/ovarian cancer (HBOC) and Lynch syndrome. A study divided into two stages was used to evaluate SSF-like, MaxEntScan, NNSplice, HSF, SPANR, and dbscSNV tools. A discovery dataset of 99 variants with unequivocal results of RNA in vitro studies, located in the 10 exonic and 20 intronic nucleotides adjacent to exon-intron boundaries of BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, ATM, BRIP1, CDH1, PALB2, PTEN, RAD51D, STK11, and TP53, was collected from four Spanish cancer genetic laboratories. The best stand-alone predictors or combinations were validated with a set of 346 variants in the same genes with clear splicing outcomes reported in the literature. Sensitivity, specificity, accuracy, negative predictive value (NPV) and Mathews Coefficient Correlation (MCC) scores were used to measure the performance. The discovery stage showed that HSF and SSF-like were the most accurate for variants at the donor and acceptor region, respectively. The further combination analysis revealed that HSF, HSF+SSF-like or HSF+SSF-like+MES achieved a high performance for predicting the disruption of donor sites, and SSF-like or a sequential combination of MES and SSF-like for predicting disruption of acceptor sites. The performance confirmation of these last results with the validation dataset, indicated that the highest sensitivity, accuracy, and NPV (99.44%, 99.44%, and 96.88, respectively) were attained with HSF+SSF-like or HSF+SSF-like+MES for donor sites and SSF-like (92.63%, 92.65%, and 84.44, respectively) for acceptor sites. We provide recommendations for combining algorithms to conduct in silico splicing analysis that achieved a high performance. The high NPV obtained allows to select the variants in which the study by in vitro RNA analysis is mandatory against those with a negligible probability of being spliceogenic. Our study also shows that the performance of each specific predictor varies depending on whether the natural splicing sites are donors or acceptors

Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb−1 of s√=7TeV proton-proton collisions

Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb−1 of pp collision data at s√=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction