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Pellise F.,Hospital Universitario Vall dHebron | Barastegui D.,Hospital Universitario Vall dHebron | Hernandez-Fernandez A.,Hospital Universitario Donostia | Barrera-Ochoa S.,Institute Universitari Quiron Dexeus | And 4 more authors.
Spine Journal | Year: 2015

Background context Short-segment pedicle screw instrumentation constructs for the treatment of thoracolumbar fractures gained popularity in the 1980s. The load-sharing classification (LSC) is a straightforward way to describe the extent of bony comminution, amount of fracture displacement, and amount of correction of kyphotic deformity in a spinal fracture. There are no studies evaluating the relevance of fracture comminution/traumatic kyphosis on the long-term radiologic outcome of burst fractures treated by short-segment instrumentation with screw insertion in the fractured level. Purpose To evaluate the efficacy of the six-screw construct in the treatment of thoracolumbar junction burst fractures and the influence of the LSC score on the 2-year radiologic outcome. Study design Case series of consecutive patients of a single university hospital. Patient sample Consecutive patients from one university hospital with nonosteoporotic thoracolumbar burst fractures. Outcome measures Being a radiology-based study, the outcome measures are radiologic parameters (regional kyphosis [RK], local kyphosis, and thoracolumbar kyphosis [TLK]) that evaluate the degree and loss of correction. Methods Retrospective analysis of all consecutive patients with nonosteoporotic thoracolumbar burst fractures managed with a six-screw construct in a single university hospital, with more than 2 years' postoperative follow-up. Results Eighty-six patients met the inclusion criteria, and 72 (83.7%) with available data were ultimately included in the study. The sample included 53 men and 19 women, with a mean (standard deviation [SD]) age of 35.6 years (14.4 years) at the time of surgery. Mean LSC score was 6.3 (SD 1.6, range 3-9). Forty-four of 62 (70.9) fractures had a score greater than 6. Mean (SD) RK and TLK deteriorated significantly during the first 6 months of follow-up: 2.90° (4.54°) p=.005 and 2.78°(6.45°) p=.069, respectively. Surgical correction correlated significantly (r=0.521, p<.0001) with the time elapsed until surgery. Loss of surgical correction (postoperative to 6-month RK and TLK increase) correlated significantly with the LSC score (r=0.57, p=.004; r=0.51, p=.022, respectively). Further surgery because of correction loss was not required in any case. Conclusions The six-screw construct is effective for treating thoracolumbar junction burst fractures. The medium-to-long-term loss of correction is affected by the amount of bony comminution of the fracture, objectified through the LSC score. © 2015 Elsevier Inc. All rights reserved.


Cardona S.,Vall Dhebron Institute Of Recerca | Eck A.,Vall Dhebron Institute Of Recerca | Cassellas M.,Vall Dhebron Institute Of Recerca | Gallart M.,Vall Dhebron Institute Of Recerca | And 6 more authors.
BMC Microbiology | Year: 2012

Background: The structure and function of human gut microbiota is currently inferred from metagenomic and metatranscriptomic analyses. Recovery of intact DNA and RNA is therefore a critical step in these studies. Here, we evaluated how different storage conditions of fecal samples affect the quality of extracted nucleic acids and the stability of their microbial communities. Results: We assessed the quality of genomic DNA and total RNA by microcapillary electrophoresis and analyzed the bacterial community structure by pyrosequencing the 16S rRNA gene. DNA and RNA started to fragment when samples were kept at room temperature for more than 24h. The use of RNAse inhibitors diminished RNA degradation but this protection was not consistent among individuals. DNA and RNA degradation also occurred when frozen samples were defrosted for a short period (1h) before nucleic acid extraction. The same conditions that affected DNA and RNA integrity also altered the relative abundance of most taxa in the bacterial community analysis. In this case, intra-individual variability of microbial diversity was larger than inter-individual one. Conclusions: Though this preliminary work explored a very limited number of parameters, the results suggest that storage conditions of fecal samples affect the integrity of DNA and RNA and the composition of their microbial community. For optimal preservation, stool samples should be kept at room temperature and brought at the laboratory within 24h after collection or be stored immediately at 20°C in a home freezer and transported afterwards in a freezer pack to ensure that they do not defrost at any time. Mixing the samples with RNAse inhibitors outside the laboratory is not recommended since proper homogenization of the stool is difficult to monitor. © 2012 Cardona et al.; licensee BioMed Central Ltd.


Marques N.,Barcelona Institute for Research in Biomedicine | Sese M.,Barcelona Institute for Research in Biomedicine | Canovas V.,Barcelona Institute for Research in Biomedicine | Valente F.,Barcelona Institute for Research in Biomedicine | And 13 more authors.
Oncogene | Year: 2014

Prostate tumor overexpressed-1 (PTOV1), a modulator of the Mediator transcriptional regulatory complex, is expressed at high levels in prostate cancer and other neoplasias in association with a more aggressive disease. Here we show that PTOV1 interacts directly with receptor of activated protein C kinase 1 (RACK1), a regulator of protein kinase C and Jun signaling and also a component of the 40S ribosome. Consistent with this interaction, PTOV1 was associated with ribosomes and its overexpression promoted global protein synthesis in prostate cancer cells and COS-7 fibroblasts in a mTORC1-dependent manner. Transfection of ectopic PTOV1 enhanced the expression of c-Jun protein without affecting the levels of c-Jun or RACK1 mRNA. Conversely, knockdown of PTOV1 caused significant declines in global protein synthesis and c-Jun protein levels. High levels of PTOV1 stimulated the motility and invasiveness of prostate cancer cells, which required c-Jun, whereas knockdown of PTOV1 strongly inhibited the tumorigenic and metastatic potentials of PC-3 prostate cancer cells. In human prostate cancer samples, the expression of high levels of PTOV1 in primary and metastatic tumors was significantly associated with increased nuclear localization of active c-Jun. These results unveil new functions of PTOV1 in the regulation of protein translation and in the progression of prostate cancer to an invasive and metastatic disease. © 2014 Macmillan Publishers Limited.


PubMed | CSIC - Biological Research Center, Hospital Clinico and Vall Dhebron Institute Of Recerca
Type: | Journal: The Journal of pathology | Year: 2017

The process of liver colonisation in colorectal cancer remains poorly characterised. Here, we addressed the role of microRNA (miRNA) dysregulation in metastasis. We first compared miRNA expression profiles between colorectal cancer cell lines with different metastatic properties and then identified target proteins of the dysregulated miRNAs to establish their functions and prognostic value. We found that 38 miRNAs were differentially expressed between highly metastatic (KM12SM/SW620) and poorly metastatic (KM12C/SW480) cancer cell lines. After initial validation, we determined that three miRNAs (miR-424-3p, -503, and -1292) were overexpressed in metastatic colorectal cancer cell lines and human samples. Stable transduction of non-metastatic cells with each of the three miRNAs promoted metastatic properties in culture and increased liver colonisation in vivo. Moreover, miR-424-3p and miR-1292 were associated with poor prognosis in human patients. A quantitative proteomic analysis of colorectal cancer cells transfected with miR-424-3p, miR-503, or miR-1292 identified alterations in 149, 129, or 121 proteins, respectively, with an extensive overlap of the target proteins of the three miRNAs. Importantly, downregulation of two of these shared target proteins, CKB and UBA2, increased cell adhesion and proliferation in colorectal cancer cells. The capacity of distinct miRNAs to regulate the same mRNAs boosts the capacity of miRNAs to regulate cancer metastasis and underscores the necessity of targeting multiple miRNAs for effective cancer therapy.


Michelena J.,University of Barcelona | Altamirano J.,University of Barcelona | Altamirano J.,Vall Dhebron Institute Of Recerca | Abraldes J.G.,University of Alberta | And 14 more authors.
Hepatology | Year: 2015

Alcoholic hepatitis (AH) frequently progresses to multiple organ failure (MOF) and death. However, the driving factors are largely unknown. At admission, patients with AH often show criteria of systemic inflammatory response syndrome (SIRS) even in the absence of an infection. We hypothesize that the presence of SIRS may predispose to MOF and death. To test this hypothesis, we studied a cohort including 162 patients with biopsy-proven AH. The presence of SIRS and infections was assessed in all patients, and multivariate analyses identified variables independently associated with MOF and 90-day mortality. At admission, 32 (19.8%) patients were diagnosed with a bacterial infection, while 75 (46.3%) fulfilled SIRS criteria; 58 patients (35.8%) developed MOF during hospitalization. Short-term mortality was significantly higher among patients who developed MOF (62.1% versus 3.8%, P<0.001). The presence of SIRS was a major predictor of MOF (odds ratio=2.69, P=0.025) and strongly correlated with mortality. Importantly, the course of patients with SIRS with and without infection was similar in terms of MOF development and short-term mortality. Finally, we sought to identify serum markers that differentiate SIRS with and without infection. We studied serum levels of high-sensitivity C-reactive protein, procalcitonin, and lipopolysaccharide at admission. All of them predicted mortality. Procalcitonin, but not high-sensitivity C-reactive protein, serum levels identified those patients with SIRS and infection. Lipopolysaccharide serum levels predicted MOF and the response to prednisolone. Conclusion: In the presence or absence of infections, SIRS is a major determinant of MOF and mortality in AH, and the mechanisms involved in the development of SIRS should be investigated; procalcitonin serum levels can help to identify patients with infection, and lipopolysaccharide levels may help to predict mortality and the response to steroids. (Hepatology 2015;62:762-772) © 2015 by the American Association for the Study of Liver Diseases.


Gregori J.,Autonomous University of Barcelona | Gregori J.,University of Barcelona | Villarreal L.,Autonomous University of Barcelona | Sanchez A.,University of Barcelona | And 3 more authors.
Journal of Proteomics | Year: 2013

The microarray community has shown that the low reproducibility observed in gene expression-based biomarker discovery studies is partially due to relying solely on p-values to get the lists of differentially expressed genes. Their conclusions recommended complementing the p-value cutoff with the use of effect-size criteria. The aim of this work was to evaluate the influence of such an effect-size filter on spectral counting-based comparative proteomic analysis. The results proved that the filter increased the number of true positives and decreased the number of false positives and the false discovery rate of the dataset. These results were confirmed by simulation experiments where the effect size filter was used to evaluate systematically variable fractions of differentially expressed proteins. Our results suggest that relaxing the p-value cut-off followed by a post-test filter based on effect size and signal level thresholds can increase the reproducibility of statistical results obtained in comparative proteomic analysis. Based on our work, we recommend using a filter consisting of a minimum absolute log2 fold change of 0.8 and a minimum signal of 2-4 SpC on the most abundant condition for the general practice of comparative proteomics. The implementation of feature filtering approaches could improve proteomic biomarker discovery initiatives by increasing the reproducibility of the results obtained among independent laboratories and MS platforms. Biological significance: Quality control analysis of microarray-based gene expression studies pointed out that the low reproducibility observed in the lists of differentially expressed genes could be partially attributed to the fact that these lists are generated relying solely on p-values. Our study has established that the implementation of an effect size post-test filter improves the statistical results of spectral count-based quantitative proteomics. The results proved that the filter increased the number of true positives whereas decreased the false positives and the false discovery rate of the datasets. The results presented here prove that a post-test filter applying a reasonable effect size and signal level thresholds helps to increase the reproducibility of statistical results in comparative proteomic analysis. Furthermore, the implementation of feature filtering approaches could improve proteomic biomarker discovery initiatives by increasing the reproducibility of results obtained among independent laboratories and MS platforms.This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics. © 2013 Elsevier B.V.


Camara Y.,Vall Dhebron Institute Of Recerca | Camara Y.,Center for Biomedical Network Research on Rare Diseases | Gonzalez-Vioque E.,Vall Dhebron Institute Of Recerca | Gonzalez-Vioque E.,Center for Biomedical Network Research on Rare Diseases | And 9 more authors.
Human Molecular Genetics | Year: 2014

Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several deoxyribonucleoside triphosphates (dNTPs), and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of deoxyguanosine kinase-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides (dNs) involved in each biochemical defect (deoxyguanosine or deoxycytidine, dCtd) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of dN catabolism using tetrahydrouridine (THU; inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using an MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of dCtd or THU. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. Wepropose increasing cellular availability of the deficientdNTPprecursor by direct administrationof thedNor inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism. © The Author 2013. Published by Oxford University Press. All rights reserved.


Pampalona J.,Autonomous University of Barcelona | Pampalona J.,Barcelona Institute for Research in Biomedicine | Frias C.,Autonomous University of Barcelona | Frias C.,Vall Dhebron Institute Of Recerca | And 2 more authors.
PLoS Genetics | Year: 2012

Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosome structure and number. Excessively short telomeres, a known source of chromosome instability, are observed in early human-cancer lesions. Besides telomere dysfunction, it has been suggested that a transient phase of polyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomic instability. Given the significance of telomere dysfunction and tetraploidy in the early stages of carcinogenesis, we investigated whether there is a connection between these two important promoters of chromosomal instability. We report that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background, fail to complete the cytoplasmatic cell division due to the persistence of chromatin bridges in the midzone. Flow cytometry together with fluorescence in situ hybridization demonstrated an accumulation of binucleated polyploid cells upon serial passaging cells. Restoration of telomere function through hTERT transduction, which lessens the formation of anaphase bridges by recapping the chromosome ends, rescued the polyploid phenotype. Live-cell imaging revealed that these polyploid cells emerged after abortive cytokinesis due to the persistence of anaphase bridges with large intervening chromatin in the cleavage plane. In agreement with a primary role of anaphase bridge intermediates in the polyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resulted in tetraploid binucleated cells. Taken together, we demonstrate that human epithelial cells exhibiting physiological telomere dysfunction engender tetraploid cells through interference of anaphase bridges with the completion of cytokinesis. These observations shed light on the mechanisms operating during the initial stages of human carcinogenesis, as they provide a link between progressive telomere dysfunction and tetraploidy. © 2012 Pampalona et al.

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