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Hepatotoxicity prediction by systems biology modeling of disturbed metabolic pathways using gene expression data

  • Carbonell, Pablo
  • López, Oriol
  • Amberg, Alexander
  • Pastor Maeso, Manuel
  • Sanz, Ferran
The present study applies a systems biology approach for the in silico predictive modeling of drug toxicity on the basis of high-quality preclinical drug toxicity data with the aim of increasing the mechanistic understanding of toxic effects of compounds at different levels (pathway, cell, tissue, organ). The model development was carried out using 77 compounds for which gene expression data for treated primary human hepatocytes is available in the LINCS database and for which rodent in vivo hepatotoxicity information is available in the eTOX database. The data from LINCS were used to determine the type and number of pathways disturbed by each compound and to estimate the extent of disturbance (network perturbation elasticity), and were used to analyze the correspondence with the in vivo information from eTOX. Predictive models were developed through this integrative analysis, and their specificity and sensitivity were assessed. The quality of the predictions was determined on the basis of the area under the curve (AUC) of plots of true positive vs. false positive rates (ROC curves). The ROC AUC reached values of up to 0.9 (out of 1.0) for some hepatotoxicity endpoints. Moreover, the most frequently disturbed metabolic pathways were determined across the studied toxicants. They included, e.g., mitochondrial beta-oxidation of fatty acids and amino acid metabolism. The process was exemplified by successful predictions on various statins. In conclusion, an entirely new approach linking gene expression alterations to the prediction of complex organ toxicity was developed and evaluated., The research leading to these results has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement nº 115002 (eTOX), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/200-2013) and EFPIA companie's in kind contributions.

Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology

  • Spataro, Nino, 1984-
  • Rodríguez, Juan Antonio
  • Navarro i Cuartiellas, Arcadi, 1969-
  • Bosch Fusté, Elena
Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease., This work was supported by Ministerio de Ciencia e Innovación, Spain (SAF2011-29239 to EB and BFU2012-38236 to AN), by Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866), by the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026) and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo). Funding to pay the Open Access publication charges for this article was provided by the ICREA Award granted to EB by the Institució Catalana de Recerca i Estudis Avançats (Generalitat de Catalunya).

Differential Gene Expression in the Human Brain Is Associated with Conserved, but Not Accelerated, Noncoding Sequences

  • Meyer, Kyle A.
  • Marquès i Bonet, Tomàs, 1975-
  • Sestan, Nenad
Previous studies have found that genes which are differentially expressed within the developing human brain disproportionately neighbor conserved noncoding sequences (CNSs) that have an elevated substitution rate in humans and in other species. One explanation for this general association of differential expression with accelerated CNSs is that genes with pre-existing patterns of differential expression have been preferentially targeted by species-specific regulatory changes. Here we provide support for an alternative explanation: genes that neighbor a greater number of CNSs have a higher probability of differential expression and a higher probability of neighboring a CNS with lineage-specific acceleration. Thus, neighboring an accelerated element from any species signals that a gene likely neighbors many CNSs. We extend the analyses beyond the prenatal time points considered in previous studies to demonstrate that this association persists across developmental and adult periods. Examining differential expression between non-neural tissues suggests that the relationship between the number of CNSs a gene neighbors and its differential expression status may be particularly strong for expression differences among brain regions. In addition, by considering this relationship, we highlight a recently defined set of putative human-specific gain-of-function sequences that, even after adjusting for the number of CNSs neighbored by genes, shows a positive relationship with upregulation in the brain compared with other tissues examined., This work was supported by the National Science Foundation Graduate Research Fellowship Program (DGE-1122492 to K.A.M); by MINECO grants BFU2014-55090-P (FEDER), BFU2015-7116-ERC, and BFU2015-6215-ERC to T.M.B; and by the National Institutes of Health (MH103339, MH110926, and MH106934 to N.S, MH106874 to T.M.B. and N.S.).

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

  • Mateo, Francesca
  • López Bigas, Núria
  • Pujana, Miguel Angel
Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure., This study was supported by the following bodies and grants: the Scientific Foundation ‘Asociación Española Contra el Cáncer’ (AECC, Stable Coordinated Group, Hereditary Cancer); the BBVA Foundation; the Eugenio Rodríguez Pascual Foundation grant 2012; Generalitat de Catalunya AGAUR SGR 2012 grants 283, 290 and 312, and SGR 2014 grants 364, 530, and 535; Spanish Ministry of Health ISCIII FIS grants PI10/00057, PI10/00222, PI10/01422, PI12/01528, PI13/00132, and PI14/00336. ISCIII RTICC grants RD06/0020/1051, RD12/0036/0007, RD12/0036/0008 and RD12/0036/0063; Spanish Ministry of Science and Innovation, ‘Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa’, MINECO grants SAF2010-20203 and SAF2013-46196; and the Telemaraton 2014 ‘Todos Somos Raros, Todos Somos Únicos’ grant P35. EJA was supported by ‘la Caixa’ PhD fellowship program, F Iorio was supported by a fellowship from the EMBL-EBI and the Wellcome Trust Sanger Institute Postdoctoral (ESPOD) program, and NL-B, ME and RRG were supported by ICREA.

Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants

  • Serra Juhé, Clara, 1984-
  • Martos Moreno, Gabriel A.
  • Bou de Pieri, Francesc
  • Flores Peirats, Raquel
  • González Ruiz, Juan Ramón
  • Rodríguez Santiago, Benjamín
  • Argente, Jesús
  • Pérez Jurado, Luis Alberto
Obesity is a multifactorial disorder with high heritability (50–75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity., LAPJ was funded by the Spanish Ministry of Health (FIS-PI1302481, co-funded by FEDER), the Generalitat de Catalunya (2014SRG1468), the Institució Catalana de Recerca i Estudis Avançats (ICREA Academia program), and the Spanish Ministry of Economy and Competiveness “Programa de Excelencia María de Maeztu” (MDM-2014-0370). JA was funded by the Spanish Ministry of Health (FIS-PI13/02195 & PI16/00485, co-funded by FEDER) and the Fundación de Endocrinología y Nutrición. JRG was supported by the Spanish Ministry of Science and Innovation (MTM2011-26515) and Statistical Genetics Network - GENOMET (MTM2010-09526-E). The "Centro de Investigación Biomèdica en Red" for rare diseases (CIBERER), obesity and nutrition (CIBEROBN), and epidemiology and public health (CIBERESP) are initiatives of the Instituto de Salud Carlos III, Spain.

Disfunción diafragmática: una realidad en el paciente ventilado mecánicamente

  • Dot, Irene
  • Pérez-Terán, Purificación
  • Samper, Manuel-Andrés
  • Masclans Enviz, Joan Ramon
La afectación muscular del paciente crítico está presente en la mayoría de pacientes que ingresan en el Servicio de Medicina Intensiva (SMI). La alteración, en particular, del músculo diafragmático, inicialmente englobada en esta categoría, se ha diferenciado en los últimos años y se ha demostrado la existencia de una disfunción muscular propia de los pacientes sometidos a ventilación mecánica. En este subgrupo de pacientes, encontramos una disfunción muscular que aparece de manera precoz después del inicio de la ventilación mecánica y que se relaciona, principalmente, con el uso de modalidades control, la presencia de sepsis y/o de fracaso multiorgánico. Aunque se desconoce la etiología concreta que desencadena el proceso, el músculo presenta procesos de estrés oxidativo y alteración mitocondrial, que provocan un desequilibrio en la síntesis proteica, con el resultado de atrofia y alteración de la contractilidad y, como consecuencia, una menor funcionalidad. No fue, de hecho, hasta 2004 cuando Vassilakopoulos et al describieron el término “Disfunción diafragmática asociada a ventilación mecánica” que junto a la lesión por sobre distensión pulmonar y por barotrauma, representan un reto en el día a día de los pacientes ventilados. La disfunción diafragmática tiene influencia en el pronóstico, retardando la extubación, aumentando la estancia hospitalaria y afectando la calidad de vida de estos pacientes en los años siguientes al alta hospitalaria. La ecografía, como técnica no invasiva y accesible en la mayoría de Unidades, podría ser de utilidad en el diagnóstico precoz para iniciar, de forma avanzada, la rehabilitación e influir positivamente en el pronóstico de estos enfermos., Muscle involvement is found in most critical patients admitted to the intensive care unit (ICU). Diaphragmatic muscle alteration, initially included in this category, has been differentiated in recent years, and a specific type of muscular dysfunction has been shown to occur in patients undergoing mechanical ventilation. We found this muscle dysfunction to appear in this subgroup of patients shortly after the start of mechanical ventilation, observing it to be mainly associated with certain control modes, and also with sepsis and/or multi-organ failure. Although the specific etiology of process is unknown, the muscle presents oxidative stress and mitochondrial changes. These cause changes in protein turnover, resulting in atrophy and impaired contractility, and leading to impaired functionality. The term 'ventilator-induced diaphragm dysfunction' was first coined by Vassilakopoulos et al. in 2004, and this phenomenon, along with injury cause by over-distention of the lung and barotrauma, represents a challenge in the daily life of ventilated patients. Diaphragmatic dysfunction affects prognosis by delaying extubation, prolonging hospital stay, and impairing the quality of life of these patients in the years following hospital discharge. Ultrasound, a non-invasive technique that is readily available in most ICUs, could be used to diagnose this condition promptly, thus preventing delays in starting rehabilitation and positively influencing prognosis in these patients.

Hypofractionated boost after whole breast irradiation in breast carcinoma: chronic toxicity results and cosmesis

  • Sanz Latiesas, Javier, 1967-
  • Rodríguez, Nuria
  • Foro Arnalot, Palmira
  • Dengra, Josefa
  • Reig, Anna
  • Pérez, Paula
  • Membrive, Ismael
  • Ortiz, Ana
  • Codinach, Maria
  • Algara López, Manuel-Ignacio
PURPOSE: To evaluate the impact of hypofractionated boost after hypofractionated whole breast irradiation in breast carcinoma. METHODS AND MATERIALS: Patients after breast conservative surgery were treated all time with hypofractionation of 2.67 Gy/day. Whole breast dose was 40.05 Gy followed in case of risk of local relapse by a boost of 16.02 Gy or 8.01 Gy. Acute and chronic toxicity results were evaluated including cosmetic software-assisted assessment and objective evaluation of fibrosis parameters (elasticity and hydration) by means of a skin tester. RESULTS: A total of 362 patients were evaluated. Acute toxicities comprised grade 1 dermatitis in 48.1 %, grade 2 in 44.5 % and grade 3 in 17 patients 4.7 %, respectively. After a median follow-up of 4.5 years, in 308 cases (86.6 %) there was no chronic skin or subcutaneous changes. In the first consecutive 50 patients, measures with skin tester showed no statistical differences in parameters for skin and subcutaneous fibrosis. Cosmetic results were considered excellent and good in 26 and 62 %, respectively. CONCLUSIONS: Boost to tumour bed with hypofractionated doses is well tolerated and acute and chronic toxicities are mild with good cosmetic results. Objective systems are encouraging methods to assess skin quality and cosmesis.

Sculpting the labyrinth: Morphogenesis of the developing inner ear

  • Alsina i Español, Berta
  • Whitfield, Tanya T.
The vertebrate inner ear is a precision sensory organ, acting as both a microphone to receive sound and an accelerometer to detect gravity and motion. It consists of a series of interlinked, fluid-filled chambers containing patches of sensory epithelia, each with a specialised function. The ear contains many different differentiated cell types with distinct morphologies, from the flask-shaped hair cells found in thickened sensory epithelium, to the thin squamous cells that contribute to non-sensory structures, such as the semicircular canal ducts. Nearly all cell types of the inner ear, including the afferent neurons that innervate it, are derived from the otic placode, a region of cranial ectoderm that develops adjacent to the embryonic hindbrain. As the ear develops, the otic epithelia grow, fold, fuse and rearrange to form the complex three-dimensional shape of the membranous labyrinth. Much of our current understanding of the processes of inner ear morphogenesis comes from genetic and pharmacological manipulations of the developing ear in mouse, chicken and zebrafish embryos. These traditional approaches are now being supplemented with exciting new techniques—including force measurements and light-sheet microscopy—that are helping to elucidate the mechanisms that generate this intricate organ system., Work in the Whitfield lab is funded by the BBSRC (BB/M01021X/1) and work in the Alsina lab is funded by the MINNECO BFU2014-53203.

Using Electronic Health Records to Assess Depression and Cancer Comorbidities

  • Mayer, Miguel Ángel, 1960-
  • Gutiérrez Sacristán, Alba
  • Leis Machin, Angela
  • De La Peña, Santiago
  • Sanz, Ferran
  • Furlong, Laura I., 1971-
Comorbid diseases are an important concern in oncology since they can affect the choice and effectiveness of treatment. What is particularly relevant is the fact that the diagnosis of depression in cancer patients has an important impact on the quality of life of these patients. Although there is no consensus about a specific relationship of depression with certain cancer types, some authors have proposed that depression constitutes a risk factor for cancer. The objective of this study is to identify the presence of comorbidities in a massive EHR system, between depression and the 10 most common cancers in women and men and to determine if there is a preferred temporal ordering in the co-occurrence of these diseases. All the cancers studied showed a significant co-occurrence with depression, more specifically, twice more frequent than what could be expected by chance. A preferred directionality was identified between some of the comorbid diseases, such as breast cancer followed by depression, and depression followed by either stomach cancer, colorectal cancer or lung cancer. Future work will address other potential factors that have an influence on the likelihood of suffering from depression in patients with cancer, such as drug therapies received, exposure to substance of abuse or other comorbidities., We received support from the IMI-JU under grant agreement no.115372 (EMIF), resources of which are composed of financial contribution from the EU-FP7 (FP7/2007-2013) and EFPIA companies in kind contribution, and from the EU H2020 Research & Innovation Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics: Creating medically-driven integrative bioinformatics applications focused on oncology, CNS disorders and their comorbidities).

New Potent Membrane-Targeting Antibacterial Peptides from Viral Capsid Proteins

  • Dias, Susana A.
  • Freire, Joao Miguel
  • Pérez-Peinado, Clara
  • Domingues, Marco M.
  • Gaspar, Diana
  • Vale, Nuno
  • Gomes, Paula
  • Andreu Martínez, David
  • Henriques, Sónia T.
  • Castanho, Miguel A.R.B.
  • Veiga, Ana Salomé
The increasing prevalence of multidrug-resistant bacteria urges the development of new antibacterial agents. With a broad spectrum activity, antimicrobial peptides have been considered potential antibacterial drug leads. Using bioinformatic tools we have previously shown that viral structural proteins are a rich source for new bioactive peptide sequences, namely antimicrobial and cell-penetrating peptides. Here, we test the efficacy and mechanism of action of the most promising peptides among those previously identified against both Gram-positive and Gram-negative bacteria. Two cell-penetrating peptides, vCPP 0769 and vCPP 2319, have high antibacterial activity against Staphylococcus aureus, MRSA, Escherichia coli, and Pseudomonas aeruginosa, being thus multifunctional. The antibacterial mechanism of action of the two most active viral protein-derived peptides, vAMP 059 and vCPP 2319, was studied in detail. Both peptides act on both Gram-positive S. aureus and Gram-negative P. aeruginosa, with bacterial cell death occurring within minutes. Also, these peptides cause bacterial membrane permeabilization and damage of the bacterial envelope of P. aeruginosa cells. Overall, the results show that structural viral proteins are an abundant source for membrane-active peptides sequences with strong antibacterial properties., This work was supported by Fundação para a Ciência e a Tecnologia (FCT-MCTES, Portugal) projects PTDC/QEQ-MED/4412/2014 and UID/QUI/50006/2013, and by Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE): call H2020-MSCA-RISE-2014, Grant agreement 644167, 2015–2019. SD, JF, and DG acknowledge FCT for fellowships PD/BD/114425/2016, SFRH/BD/70423/2010, and SFRH/BPD/109010/2015, respectively, and MD for a grant (PTDC/BBB-BQB/3494/2014). ASV and NV acknowledge FCT for funding within the FCT Investigator Programme, IF/00803/2012 and IF/00092/2014, respectively. CP-P acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through grant AGL2014-52395-C2-2-R and the “María de Maeztu” Programme for Units of Excellence in R&D (MDM-2014-0370). PG acknowledges “Comissão de Coordenação e Desenvolvimento Regional do Norte (CCDR-N)/NORTE2020/Portugal 2020” for funding through project DESignBIOtechHealth (ref. Norte-01-0145-FEDER-000024). SH is the recipient of an Australian Research Council Future Fellowship (FT150100398).

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