clelia di serio - Academia.edu (original) (raw)

Papers by clelia di serio

In the context of survival analysis, we define a covariate X as protective (detrimental) for the ... more In the context of survival analysis, we define a covariate X as protective (detrimental) for the failure time T if the conditional distribution of [T | X = x] is stochastically increasing (decreasing) as a function of x. In the presence of another covariate Y, there exist situations where [T | X = x, Y = y] is stochastically decreasing

NeuroImage: Clinical, 2020

Background and aims: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), ... more Background and aims: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline. Methods: 50 ALS patients underwent clinical evaluations and 3 T MRI scans at regular intervals for a maximum of 2 years (total MRI scans = 164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features. Results: The rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression. Conclusions: In this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes.

The Journal of General Psychology, 2018

Selecting visual stimuli for inducing specific emotional states is very challenging, since the ch... more Selecting visual stimuli for inducing specific emotional states is very challenging, since the choice relies on specific conceptualization of emotions. In this work, we present a set of 55 stimuli, realized integrating discrete and dimensional theories of emotions, and specifically selected to investigate anger, fear, and disgust reactions in non-clinical and clinical contexts. Our set of stimuli presents several aspects of novelty since (1) a large and heterogeneous sample of subjects from the general population was involved in the labelling task, and (2) bivariate and multivariate statistical techniques were applied to integrate emotion models. The proposed set of stimuli could be useful for researchers and other professionals in the affective sciences to address negative emotion recognition issues within a broader perspective both in general population and in psychiatric samples. The obtained comprehensive characterization of the stimuli allowed us to confirm the sexual dimorphism in emotional processing.

Blood, 2016

Infection-related mortality (IRM) still represents a major determinant of non-relapse mortality (... more Infection-related mortality (IRM) still represents a major determinant of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the curative potential of allo-HSCT, the profound and prolonged status of immune incompetence following transplantation poses patients at risk for lethal opportunistic infections. This is particularly important in transplants from HLA-mismatched donors. Although numerous studies have investigated the role of pre-transplant clinical variables for the prediction of IRM, very few have focused on biological culprits. This study was aimed at the development of a composite clinico-biological prognostic scoring system for the prediction of early and late IRM after allo-HSCT. A total of 492 consecutive adult patients receiving allo-HSCT for hematological disorders were studied from January 2009 to May 2015. Second transplants were excluded, as well as patients for which pre-transplant biological data were missing....

Nature Communications, 2015

The molecular mechanisms that allow HIV to integrate into particular sites of the host genome are... more The molecular mechanisms that allow HIV to integrate into particular sites of the host genome are poorly understood. Here we tested if the nuclear pore complex (NPC) facilitates the targeting of HIV integration by acting on chromatin topology. We show that the integrity of the nuclear side of the NPC, which is mainly composed of Tpr, is not required for HIV nuclear import, but that Nup153 is essential. Depletion of Tpr markedly reduces HIV infectivity, but not the level of integration. HIV integration sites in Tpr-depleted cells are less associated with marks of active genes, consistent with the state of chromatin proximal to the NPC, as analysed by super-resolution microscopy. LEDGF/p75, which promotes viral integration into active genes, stabilizes Tpr at the nuclear periphery and vice versa. Our data support a model in which HIV nuclear import and integration are concerted steps, and where Tpr maintains a chromatin environment favourable for HIV replication.

Lecture Notes in Computer Science, 2014

In many different research area, identification of clusters or regions showing an increment in ev... more In many different research area, identification of clusters or regions showing an increment in event rate over a given study area is an important and interesting problem. Nowadays literature concerning scan statistics is quite broad and methods can be subdivided based on dimensional complexity of the study area, assumption on distribution generating the data under the null hypothesis and shape-dimension of the scanning window. The aim of this study is to adapt and apply this methodology to the genomics field taking into account for some peculiarities of these data and to compare its performance to existing method based on DBSCAN algorithm.

J Comput Sci Syst Biol, 2009

Background Gene therapy is a form of molecular medicine which treats genetic diseases by replacin... more Background Gene therapy is a form of molecular medicine which treats genetic diseases by replacing a defective gene, responsible for the pathology, with a functional one. The basic principle is to introduce a piece of genetic material into cells via a virus which represents the vector for gene therapy. The virus integrates with the cell DNA and thus delivers the genetic material into the cell nucleus. This process is called integration and may alter the host cell's DNA. Recent studies based on cellular and animal models (Bushman:2005) reported empirical evidence of preference for certain retroviral vectors, i.e. those deriving from Moloney Murine Leukemia Virus (MLV), to integrate near the start of transcriptional units, whereas others (like Simian Immunodefi

Understanding genetic information to code and interpret disease phenotypes represents one major g... more Understanding genetic information to code and interpret disease phenotypes represents one major goal in modern biology. The challenge of integrating separate scientific vocabularies and insight is daunting because of the vastness and rapid evolution of the disciplines. New models and tools are needed to allow scientists to bridge knowledges, integrate concepts and information, and enable complex analysis. In this contribution we show two examples of datasets from Gene Therapy and Tubercolosis to highlight how integration between biostatistics and bioinformatics allows to gain information from the extremely large biogical databases produced with the new biotechnologies, such as Next Generation Sequencing (NGS) data.

PLoS ONE, 2014

Cystic fibrosis (CF) airways disease represents an example of polymicrobial infection whereby dif... more Cystic fibrosis (CF) airways disease represents an example of polymicrobial infection whereby different bacterial species can interact and influence each other. In CF patients Staphylococcus aureus is often the initial pathogen colonizing the lungs during childhood, while Pseudomonas aeruginosa is the predominant pathogen isolated in adolescents and adults. During chronic infection, P. aeruginosa undergoes adaptation to cope with antimicrobial therapy, host response and co-infecting pathogens. However, S. aureus and P. aeruginosa often co-exist in the same niche influencing the CF pathogenesis. The goal of this study was to investigate the reciprocal interaction of P. aeruginosa and S. aureus and understand the influence of P. aeruginosa adaptation to the CF lung in order to gain important insight on the interplay occurring between the two main pathogens of CF airways, which is still largely unknown. P. aeruginosa reference strains and eight lineages of clinical strains, including early and late clonal isolates from different patients with CF, were tested for growth inhibition of S. aureus. Next, P. aeruginosa/S. aureus competition was investigated in planktonic co-culture, biofilm, and mouse pneumonia model. P. aeruginosa reference and early strains, isolated at the onset of chronic infection, outcompeted S. aureus in vitro and in vivo models of co-infection. On the contrary, our results indicated a reduced capacity to outcompete S. aureus of P. aeruginosa patho-adaptive strains, isolated after several years of chronic infection and carrying several phenotypic changes temporally associated with CF lung adaptation. Our findings provide relevant information with respect to interspecies interaction and disease progression in CF.

Science, 2013

Next-Generation Gene Therapy Few disciplines in contemporary clinical research have experienced t... more Next-Generation Gene Therapy Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then ...

Proceedings of the National Academy of Sciences, 2007

Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental f... more Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the progression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macaca nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD4+T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramaticall...

PLoS ONE, 2012

Only few small RNAs (sRNAs) have been characterized in Mycobacterium tuberculosis and their role ... more Only few small RNAs (sRNAs) have been characterized in Mycobacterium tuberculosis and their role in regulatory networks is still poorly understood. Here we report a genome-wide characterization of sRNAs in M. tuberculosis integrating experimental and computational analyses. Global RNA-seq analysis of exponentially growing cultures of M. tuberculosis H37Rv had previously identified 1373 sRNA species. In the present report we show that 258 (19%) of these were also identified by microarray expression. This set included 22 intergenic sRNAs, 84 sRNAs mapping within 59/39 UTRs, and 152 antisense sRNAs. Analysis of promoter and terminator consensus sequences identified sigma A promoter consensus sequences for 121 sRNAs (47%), terminator consensus motifs for 22 sRNAs (8.5%), and both motifs for 35 sRNAs (14%). Additionally, 20/23 candidates were visualized by Northern blot analysis and 59 end mapping by primer extension confirmed the RNA-seq data. We also used a computational approach utilizing functional enrichment to identify the pathways targeted by sRNA regulation. We found that antisense sRNAs preferentially regulated transcription of membrane-bound proteins. Genes putatively regulated by novel cis-encoded sRNAs were enriched for two-component systems and for functional pathways involved in hydrogen transport on the membrane.

PLoS ONE, 2013

This work aims at identifying a set of humoral immunologic parameters that improve prediction of ... more This work aims at identifying a set of humoral immunologic parameters that improve prediction of the activation process in HIV patients. Starting from the well-known impact of humoral immunity in HIV infection, there is still a lack of knowledge in defining the role of the modulation of functional activity and titers of serum antibodies from early stage of infection to the development of AIDS. We propose an integrated approach that combines humoral and clinical parameters in defining the host immunity, implementing algorithms associated with virus control. A number of humoral parameters were simultaneously evaluated in a whole range of serum samples from HIV-positive patients. This issue has been afforded accounting for estimation problems typically related to ''feasibility'' studies where small sample size in each group and large number of parameters are jointly estimated. We used nonparametric statistical procedures to identify biomarkers in our study which included 42 subjects stratified on five different stages of HIV infection, i.e., Elite Controllers (EC), Long Term Non Progressors (LTNP), HAART, AIDS and Acute Infection (AI). The main goal of the paper is to illustrate a novel profiling method for helping to design a further confirmatory study. A set of seventeen different HIV-specific blood humoral factors were analyzed in all subjects, i.e. IgG and IgA to gp120IIIB, to gp120Bal, to whole gp41, to P1 and T20 gp41 epitopes of the MPER-HR2 region, to QARILAV gp41 epitope of the HR1 region and to CCR5; neutralization activity against five different virus strains and ADCC were also evaluated. Patients were selected on the basis of CD4 cell counts, HIV/RNA and clinical status. The Classification and Regression Trees (CART) approach has been used to uncover specific patterns of humoral parameters in different stages of HIV disease. Virus neutralization of primary virus strains and antibodies to gp41 were required to classify patients, suggesting that clinical profiles strongly rely on functional activity against HIV.

PLoS Computational Biology, 2008

Retroviral vectors are widely used in gene therapy to introduce therapeutic genes into patients' ... more Retroviral vectors are widely used in gene therapy to introduce therapeutic genes into patients' cells, since, once delivered to the nucleus, the genes of interest are stably inserted (integrated) into the target cell genome. There is now compelling evidence that integration of retroviral vectors follows non-random patterns in mammalian genome, with a preference for active genes and regulatory regions. In particular, Moloney Leukemia Virus (MLV)-derived vectors show a tendency to integrate in the proximity of the transcription start site (TSS) of genes, occasionally resulting in the deregulation of gene expression and, where proto-oncogenes are targeted, in tumor initiation. This has drawn the attention of the scientific community to the molecular determinants of the retroviral integration process as well as to statistical methods to evaluate the genome-wide distribution of integration sites. In recent approaches, the observed distribution of MLV integration distances (IDs) from the TSS of the nearest gene is assumed to be non-random by empirical comparison with a random distribution generated by computational simulation procedures. To provide a statistical procedure to test the randomness of the retroviral insertion pattern, we propose a probability model (Beta distribution) based on IDs between two consecutive genes. We apply the procedure to a set of 595 unique MLV insertion sites retrieved from human hematopoietic stem/progenitor cells. The statistical goodness of fit test shows the suitability of this distribution to the observed data. Our statistical analysis confirms the preference of MLV-based vectors to integrate in promoter-proximal regions.

PLoS Computational Biology, 2011

Integration of retroviral vectors in the human genome follows non random patterns that favor inse... more Integration of retroviral vectors in the human genome follows non random patterns that favor insertional deregulation of gene expression and may cause risks of insertional mutagenesis when used in clinical gene therapy. Understanding how viral vectors integrate into the human genome is a key issue in predicting these risks. We provide a new statistical method to compare retroviral integration patterns. We identified the positions where vectors derived from the Human Immunodeficiency Virus (HIV) and the Moloney Murine Leukemia Virus (MLV) show different integration behaviors in human hematopoietic progenitor cells. Non-parametric density estimation was used to identify candidate comparative hotspots, which were then tested and ranked. We found 100 significative comparative hotspots, distributed throughout the chromosomes. HIV hotspots were wider and contained more genes than MLV ones. A Gene Ontology analysis of HIV targets showed enrichment of genes involved in antigen processing and presentation, reflecting the high HIV integration frequency observed at the MHC locus on chromosome 6. Four histone modifications/variants had a different mean density in comparative hotspots (H2AZ, H3K4me1, H3K4me3, H3K9me1), while gene expression within the comparative hotspots did not differ from background. These findings suggest the existence of epigenetic or nuclear three-dimensional topology contexts guiding retroviral integration to specific chromosome areas.

Nature Biotechnology, 2006

Insertional mutagenesis represents a major hurdle to gene therapy and necessitates sensitive prec... more Insertional mutagenesis represents a major hurdle to gene therapy and necessitates sensitive preclinical genotoxicity assays. Cdkn2a-/mice are susceptible to a broad range of cancer-triggering genetic lesions. We exploited hematopoietic stem cells from these tumor-prone mice to assess the oncogenicity of prototypical retroviral and lentiviral vectors. We transduced hematopoietic stem cells in matched clinically relevant conditions, and compared integration site selection and tumor development in transplanted mice. Retroviral vectors triggered dose-dependent acceleration of tumor onset contingent on long terminal repeat activity. Insertions at oncogenes and cell-cycle genes were enriched in early-onset tumors, indicating cooperation in tumorigenesis. In contrast, tumorigenesis was unaffected by lentiviral vectors and did not enrich for specific integrants, despite the higher integration load and robust expression of lentiviral vectors in all hematopoietic lineages. Our results validate a much-needed platform to assess vector safety and provide direct evidence that prototypical lentiviral vectors have low oncogenic potential, highlighting a major rationale for application to gene therapy.

The Journal of Urology, 2013