34 results on '"Mihaela Ola"'
Search Results
2. From the first touch to biofilm establishment by the human pathogen Candida glabrata: a genome-wide to nanoscale view
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Mafalda Cavalheiro, Diana Pereira, Cécile Formosa-Dague, Carolina Leitão, Pedro Pais, Easter Ndlovu, Romeu Viana, Andreia I. Pimenta, Rui Santos, Azusa Takahashi-Nakaguchi, Michiyo Okamoto, Mihaela Ola, Hiroji Chibana, Arsénio M. Fialho, Geraldine Butler, Etienne Dague, and Miguel C. Teixeira
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Biology (General) ,QH301-705.5 - Abstract
Mafalda Cavalheiro et al. use single-cell force spectroscopy and RNA-seq to examine the adhesion process of Candida glabrata, an opportunistic human fungal pathogen, to various medical surfaces. Their results suggest that the adhesion forces of C. glabrata to medical material are stronger than those presented for epithelial cells, and highlight the underlying molecular pathways related to adhesion and biofilm formation in this species.
- Published
- 2021
- Full Text
- View/download PDF
3. Identification of a novel Candida metapsilosis isolate reveals multiple hybridization events
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Caoimhe E O’Brien, Bing Zhai, Mihaela Ola, Sean A Bergin, Eoin Ó Cinnéide, Ísla O’Connor, Thierry Rolling, Edwin Miranda, N Esther Babady, Tobias M Hohl, and Geraldine Butler
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Genetics ,QH426-470 - Abstract
Abstract Candida metapsilosisCandida parapsilosisC. metapsilosisCandidaC. metapsilosisC. metapsilosisC. metapsilosisC. metapsilosisC. metapsilosis
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- 2021
- Full Text
- View/download PDF
4. Characterization of the Candida glabrata Transcription Factor CgMar1: Role in Azole Susceptibility
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Pedro Pais, Mónica Galocha, Raquel Califórnia, Romeu Viana, Mihaela Ola, Michiyo Okamoto, Hiroji Chibana, Geraldine Butler, and Miguel C. Teixeira
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Candida glabrata ,azole resistance ,transcription regulatory networks ,CgMar1 ,transcriptomics ,CgRsb1 ,Biology (General) ,QH301-705.5 - Abstract
The prevalence of antifungal resistance in Candida glabrata, especially against azole drugs, results in difficult-to-treat and potentially life-threatening infections. Understanding the molecular basis of azole resistance in C. glabrata is crucial to designing more suitable therapeutic strategies. In this study, the role of the transcription factor encoded by ORF CAGL0B03421g, here denominated as CgMar1 (Multiple Azole Resistance 1), in azole susceptibility was explored. Using RNA-sequencing, CgMar1 was found to regulate 337 genes under fluconazole stress, including several related to lipid biosynthesis pathways. In this context, CgMar1 and its target CgRSB1, encoding a predicted sphingoid long-chain base efflux transporter, were found to contribute to plasma membrane sphingolipid incorporation and membrane permeability, decreasing fluconazole accumulation. CgMar1 was found to associate with the promoter of CgRSB1, which contains two instances of the CCCCTCC consensus, found to be required for CgRSB1 activation during fluconazole stress. Altogether, a regulatory pathway modulating azole susceptibility in C. glabrata is proposed, resulting from what appears to be a neofunctionalization of a Hap1-like transcription factor.
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- 2022
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5. Correction for Ma et al., 'Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in Candida albicans'
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Qinxi Ma, Mihaela Ola, Elise Iracane, and Geraldine Butler
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Microbiology ,QR1-502 - Published
- 2019
- Full Text
- View/download PDF
6. Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in Candida albicans
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Qinxi Ma, Mihaela Ola, Elise Iracane, and Geraldine Butler
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Candida albicans ,aneuploidy ,fatty acids ,Microbiology ,QR1-502 - Abstract
ABSTRACT Fatty acids have known antifungal effects and are used in over-the-counter topical treatments. Screening of a collection of gene knockouts in Candida albicans revealed that one strain, carrying a deletion of the transcription factor DAL81, is very susceptible to the medium-chain fatty acid undecanoic acid. However, reintroducing DAL81 does not restore resistance, and editing DAL81 in a different background does not introduce sensitivity. Whole-genome sequencing revealed that the C. albicans dal81Δ/Δ strain has an extra copy of chromosomes 5 and 7. Reversion to resistance to undecanoic acid was induced by growing the sensitive strain in yeast extract-peptone-dextrose with 60 μg/ml undecanoic acid for up to 9 days. Nine isolates that regained some resistance to undecanoic acid lost one copy of chromosome 7. The copy number of chromosome 5 does not appear to affect resistance to fatty acids. Moreover, the sensitivity may be related to having two copies of haplotype B of chromosome 7. In addition, we find that C. albicans strain SN152, used to delete DAL81 and many other genes, has undergone a major loss of heterozygosity event on chromosome 2 and a smaller one on chromosome 3. IMPORTANCE Aneuploidy (changes in chromosome number) and loss of heterozygosity (LOH) occur frequently in the human-pathogenic yeast Candida albicans and are associated with adaptation to stress and to antifungal drugs. Aneuploidy and LOH can also be induced during laboratory manipulations, such as during genetic transformation. We find that C. albicans strain SN152, commonly used to generate gene deletions, has undergone a major LOH event on chromosome 2. One deletion strain generated in this background has acquired extra copies of chromosomes 5 and 7. We find that trisomy (three copies) of chromosome 7 is associated with sensitivity to fatty acids.
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- 2019
- Full Text
- View/download PDF
7. Identification of an Exceptionally Long Intron in the HAC1 Gene of Candida parapsilosis
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Elise Iracane, Paul D. Donovan, Mihaela Ola, Geraldine Butler, and Linda M. Holland
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Candida parapsilosis ,Hac1 ,introns ,unfolded protein response ,Microbiology ,QR1-502 - Abstract
ABSTRACT The unfolded protein response (UPR) in the endoplasmic reticulum (ER) is well conserved in eukaryotes from metazoa to yeast. The transcription factor HAC1 is a major regulator of the UPR in many eukaryotes. Deleting HAC1 in the yeast Candida parapsilosis rendered cells more sensitive to DTT, a known inducer of the UPR. The deletion strain was also sensitive to Congo red, calcofluor white, and the antifungal drug ketoconazole, indicating that HAC1 has a role in cell wall maintenance. Transcriptomic analysis revealed that treatment of the wild type with DTT resulted in the increased expression of 368 genes. Comparison with mutant cells treated with DTT reveals that expression of 137 of these genes requires HAC1. Enriched GO term analysis includes response to ER stress, cell wall biogenesis and glycosylation. Orthologs of many of these are associated with UPR in Saccharomyces cerevisiae and Candida albicans. Unconventional splicing of an intron from HAC1 mRNA is required to produce a functional transcription factor. The spliced intron varies in length from 19 bases in C. albicans to 379 bases in Candida glabrata, but has not been previously identified in Candida parapsilosis and related species. We used RNA-seq data and in silico analysis to identify the HAC1 intron in 12 species in the CTG-Ser1 clade. We show that the intron has undergone major contractions and expansions in this clade, reaching up to 848 bases. Exposure to DTT induced splicing of the long intron in C. parapsilosis HAC1, inducing the UPR. IMPORTANCE The unfolded protein response (UPR) responds to the build-up of misfolded proteins in the endoplasmic reticulum. The UPR has wide-ranging functions from fungal pathogenesis to applications in biotechnology. The UPR is regulated through the splicing of an unconventional intron in the HAC1 gene. This intron has been described in many fungal species and is of variable length. Until now it was believed that some members of the CTG-Ser1 clade such as C. parapsilosis did not contain an intron in HAC1, suggesting that the UPR was regulated in a different manner. Here we demonstrate that HAC1 plays an important role in regulating the UPR in C. parapsilosis. We also identified an unusually long intron (626 bp) in C. parapsilosis HAC1. Further analysis showed that HAC1 orthologs in several species in the CTG-Ser1 clade contain long introns.
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- 2018
- Full Text
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8. Dal81 Regulates Expression of Arginine Metabolism Genes in Candida parapsilosis
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Siobhan A. Turner, Qinxi Ma, Mihaela Ola, Kontxi Martinez de San Vicente, and Geraldine Butler
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Candida ,nitrogen metabolism ,opportunistic fungi ,Microbiology ,QR1-502 - Abstract
ABSTRACT Fungi can use a wide variety of nitrogen sources. In the absence of preferred sources such as ammonium, glutamate, and glutamine, secondary sources, including most other amino acids, are used. Expression of the nitrogen utilization pathways is very strongly controlled at the transcriptional level. Here, we investigated the regulation of nitrogen utilization in the pathogenic yeast Candida parapsilosis. We found that the functions of many regulators are conserved with respect to Saccharomyces cerevisiae and other fungi. For example, the core GATA activators GAT1 and GLN3 have a conserved role in nitrogen catabolite repression (NCR). There is one ortholog of GZF3 and DAL80, which represses expression of genes in preferred nitrogen sources. The regulators PUT3 and UGA3 are required for metabolism of proline and γ-aminobutyric acid (GABA), respectively. However, the role of the Dal81 transcription factor is distinctly different. In S. cerevisiae, Dal81 is a positive regulator of acquisition of nitrogen from GABA, allantoin, urea, and leucine, and it is required for maximal induction of expression of the relevant pathway genes. In C. parapsilosis, induction of GABA genes is independent of Dal81, and deleting DAL81 has no effect on acquisition of nitrogen from GABA or allantoin. Instead, Dal81 represses arginine synthesis during growth under preferred nitrogen conditions. IMPORTANCE Utilization of nitrogen by fungi is controlled by nitrogen catabolite repression (NCR). Expression of many genes is switched off during growth on nonpreferred nitrogen sources. Gene expression is regulated through a combination of activation and repression. Nitrogen regulation has been studied best in the model yeast Saccharomyces cerevisiae. We found that although many nitrogen regulators have a conserved function in Saccharomyces species, some do not. The Dal81 transcriptional regulator has distinctly different functions in S. cerevisiae and C. parapsilosis. In the former, it regulates utilization of nitrogen from GABA and allantoin, whereas in the latter, it regulates expression of arginine synthesis genes. Our findings make an important contribution to our understanding of nitrogen regulation in a human-pathogenic fungus.
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- 2018
- Full Text
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9. High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis
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Tobias M. Hohl, Eric R. Littmann, Charlotte A Veelken, Emily Fontana, Roberta J. Wright, N. Esther Babady, Marcel R.M. van den Brink, Geraldine Butler, Edwin Miranda, Jonathan U. Peled, Sejal Morjaria, Thierry Rolling, Sari Joshowitz, Nicholas L. Tosini, Ying Taur, Luigi A Amoretti, Bing Zhai, and Mihaela Ola
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0301 basic medicine ,Mycobiota ,medicine.medical_treatment ,Chromosomal translocation ,Hematopoietic stem cell transplantation ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Feces ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,medicine ,Humans ,Transplantation, Homologous ,Candidiasis, Invasive ,Gene ,Candida ,Cross Infection ,Bacteria ,Hematopoietic Stem Cell Transplantation ,General Medicine ,medicine.disease ,biology.organism_classification ,Intestines ,Transplantation ,030104 developmental biology ,030220 oncology & carcinogenesis ,Dysbiosis ,Mycobiome - Abstract
The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi1,2. Although the composition of bacterial constituents has been linked to immune homeostasis and infectious susceptibility3-7, the role of non-bacterial constituents and cross-kingdom microbial interactions in these processes is poorly understood2,8. Fungi represent a major cause of infectious morbidity and mortality in immunocompromised individuals, although the relationship of intestinal fungi (that is, the mycobiota) with fungal bloodstream infections remains undefined9. We integrated an optimized bioinformatics pipeline with high-resolution mycobiota sequencing and comparative genomic analyses of fecal and blood specimens from recipients of allogeneic hematopoietic cell transplant. Patients with Candida bloodstream infection experienced a prior marked intestinal expansion of pathogenic Candida species; this expansion consisted of a complex dynamic between multiple species and subspecies with a stochastic translocation pattern into the bloodstream. The intestinal expansion of pathogenic Candida spp. was associated with a substantial loss in bacterial burden and diversity, particularly in the anaerobes. Thus, simultaneous analysis of intestinal fungi and bacteria identifies dysbiosis states across kingdoms that may promote fungal translocation and facilitate invasive disease. These findings support microbiota-driven approaches to identify patients at risk of fungal bloodstream infections for pre-emptive therapeutic intervention.
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- 2020
10. From the first touch to biofilm establishment by the human pathogen Candida glabrata: a genome-wide to nanoscale view
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Hiroji Chibana, Romeu Viana, Easter Ndlovu, Miguel A. C. Teixeira, Geraldine Butler, Mafalda Cavalheiro, Mihaela Ola, Cécile Formosa-Dague, Etienne Dague, Carolina Leitão, Andreia I. Pimenta, Pedro Pais, Michiyo Okamoto, Diana Pereira, Rui Galhano dos Santos, Azusa Takahashi-Nakaguchi, Arsenio M. Fialho, Universidade de Lisboa (ULISBOA), Transfert, Interface, Mélanges (TBI-TIM), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Équipe Ingénierie pour les sciences du vivant (LAAS-ELIA), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, Chiba University, University College Dublin [Dublin] (UCD), Portuguese Foundation for Science and TechnologyEuropean CommissionPTDC/BBB-BIO/4004/2014PTDC/BII-BIO/28216/2017, 'FundacAo para a Ciencia e a Tecnologia' (FCT) (AEM PhD grant), iBB-Institute for Bioengineering and Biosciences from FCT-Portuguese Foundation for Science and TechnologyUID/BIO/04565/2013UIDB/04565/2020, Universidade de Lisboa = University of Lisbon (ULISBOA), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), and Université de Toulouse (UT)
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QH301-705.5 ,[SDV]Life Sciences [q-bio] ,Medicine (miscellaneous) ,Human pathogen ,Candida glabrata ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Article ,Transcriptome ,03 medical and health sciences ,Opportunistic pathogen ,Biology (General) ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Nanoscale biophysics ,030306 microbiology ,Extramural ,Biofilm ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Cell biology ,Biofilms ,Genome, Fungal ,General Agricultural and Biological Sciences ,Infection ,Transcription Factors - Abstract
Candida glabrata is an opportunistic pathogen that adheres to human epithelial mucosa and forms biofilm to cause persistent infections. In this work, Single-cell Force Spectroscopy (SCFS) was used to glimpse at the adhesive properties of C. glabrata as it interacts with clinically relevant surfaces, the first step towards biofilm formation. Following a genetic screening, RNA-sequencing revealed that half of the entire transcriptome of C. glabrata is remodeled upon biofilm formation, around 40% of which under the control of the transcription factors CgEfg1 and CgTec1. Using SCFS, it was possible to observe that CgEfg1, but not CgTec1, is necessary for the initial interaction of C. glabrata cells with both abiotic surfaces and epithelial cells, while both transcription factors orchestrate biofilm maturation. Overall, this study characterizes the network of transcription factors controlling massive transcriptional remodelling occurring from the initial cell-surface interaction to mature biofilm formation., Mafalda Cavalheiro et al. use single-cell force spectroscopy and RNA-seq to examine the adhesion process of Candida glabrata, an opportunistic human fungal pathogen, to various medical surfaces. Their results suggest that the adhesion forces of C. glabrata to medical material are stronger than those presented for epithelial cells, and highlight the underlying molecular pathways related to adhesion and biofilm formation in this species.
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- 2021
11. Identification of a novel Candida metapsilosis isolate reveals multiple hybridization events
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N. Esther Babady, Geraldine Butler, Mihaela Ola, Caoimhe E. O’Brien, Bing Zhai, Sean A. Bergin, Thierry Rolling, Ísla O’Connor, Tobias M. Hohl, Eoin Ó Cinnéide, and Edwin Miranda
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AcademicSubjects/SCI01140 ,Antifungal Agents ,Candida parapsilosis ,AcademicSubjects/SCI00010 ,Introgression ,Virulence ,Locus (genetics) ,QH426-470 ,AcademicSubjects/SCI01180 ,Genome ,Loss of heterozygosity ,genomics ,Genetics ,LOH ,Humans ,hybridization ,Molecular Biology ,Genetics (clinical) ,Illumina dye sequencing ,Candida ,Investigation ,biology ,Haplotype ,Candidiasis ,biology.organism_classification ,AcademicSubjects/SCI00960 ,Hybridization, Genetic ,mating type-like loci - Abstract
Candida metapsilosis is a member of the Candida parapsilosis species complex, a group of opportunistic human pathogens. Of all the members of this complex, C. metapsilosis is the least virulent, and accounts for a small proportion of invasive Candida infections. Previous studies established that all C. metapsilosis isolates are hybrids, originating from a single hybridization event between two lineages, parent A and parent B. Here, we use MinION and Illumina sequencing to characterize a C. metapsilosis isolate that originated from a separate hybridization. One of the parents of the new isolate is very closely related to parent A. However, the other parent (parent C) is not the same as parent B. Unlike C. metapsilosis AB isolates, the C. metapsilosis AC isolate has not undergone introgression at the mating type-like locus. In addition, the A and C haplotypes are not fully collinear. The C. metapsilosis AC isolate has undergone loss of heterozygosity with a preference for haplotype A, indicating that this isolate is in the early stages of genome stabilization.
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- 2021
12. Identification of a novel Candida metapsilosis isolate suggests ongoing hybridization
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Thierry Rolling, Bing Zhai, Eoin Ó Cinnéide, Edwin Miranda, Caoimhe E. O’Brien, Mihaela Ola, N. Esther Babady, Ísla O’Connor, Tobias M. Hohl, and Geraldine Butler
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Genetics ,Loss of heterozygosity ,Species complex ,Haplotype ,Introgression ,Virulence ,Locus (genetics) ,Biology ,Genome ,Illumina dye sequencing - Abstract
Candida metapsilosis is a member of the C. parapsilosis species complex, a group of opportunistic human pathogens. Of all the members of this complex, C. metapsilosis is the least virulent, and accounts for a small proportion of invasive Candida infections. Previous studies established that all C. metapsilosis isolates are hybrids, originating from a single hybridization event between two lineages, parent A and parent B. Here, we use MinION and Illumina sequencing to characterize a C. metapsilosis isolate that originated from a separate hybridization. One of the parents of the new isolate is very closely related to parent A. However, the other parent (parent C) is not the same as parent B. Unlike C. metapsilosis AB isolates, the C. metapsilosis AC isolate has not undergone introgression at the Mating Type-like Locus. In addition, the A and C haplotypes are not fully collinear. The C. metapsilosis AC isolate has undergone Loss of Heterozygosity (LOH) with a preference for haplotype A, indicating that this isolate is in the early stages of genome stabilization.
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- 2021
13. AB069. SOH22ABS209. The epitranscriptomic landscape in estrogen receptor (ER)-positive breast cancer disease progression
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Stephen Keelan, Mihaela Ola, Sara Charmsaz, Sinead Cocchiglia, Karen Crowley, Siobhan Purcell, Fiona Bane, Aisling Hegarty, Ben Doherty, Katherine Sheehan, Lance Hudson, Nicola Cosgrove, Benjamin Roux, Muriel Laine, Geoffrey Greene, Damir Vareslija, Arnold Hill, and Leonie Young
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General Medicine - Published
- 2022
14. Candida glabrata Transcription Factor Rpn4 Mediates Fluconazole Resistance through Regulation of Ergosterol Biosynthesis and Plasma Membrane Permeability
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Mihaela Ola, Mafalda Cavalheiro, Raquel Califórnia, Miguel C. Teixeira, Romeu Viana, Mónica Galocha, Geraldine Butler, Pedro Pais, Hiroji Chibana, and Azusa Takahashi-Nakaguchi
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Antifungal Agents ,Candida glabrata ,Drug resistance ,Permeability ,CgRpn4 ,Fungal Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,regulatory networks ,Mechanisms of Resistance ,Drug Resistance, Fungal ,Gene Expression Regulation, Fungal ,medicine ,Pharmacology (medical) ,Transcription factor ,Fluconazole ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Ergosterol ,biology ,ergosterol ,030306 microbiology ,Cell Membrane ,biology.organism_classification ,RNA-seq-based transcriptomics ,Cell biology ,Infectious Diseases ,chemistry ,Proteasome ,Azole ,Intracellular ,medicine.drug ,azole resistance mechanisms ,Transcription Factors - Abstract
The ability to acquire azole resistance is an emblematic trait of the fungal pathogen Candida glabrata. Understanding the molecular basis of azole resistance in this pathogen is crucial for designing more suitable therapeutic strategies. This study shows that the C. glabrata transcription factor (TF) CgRpn4 is a determinant of azole drug resistance. RNA sequencing during fluconazole exposure revealed that CgRpn4 regulates the expression of 212 genes, activating 80 genes and repressing, likely in an indirect fashion, 132 genes., The ability to acquire azole resistance is an emblematic trait of the fungal pathogen Candida glabrata. Understanding the molecular basis of azole resistance in this pathogen is crucial for designing more suitable therapeutic strategies. This study shows that the C. glabrata transcription factor (TF) CgRpn4 is a determinant of azole drug resistance. RNA sequencing during fluconazole exposure revealed that CgRpn4 regulates the expression of 212 genes, activating 80 genes and repressing, likely in an indirect fashion, 132 genes. Targets comprise several proteasome and ergosterol biosynthesis genes, including ERG1, ERG2, ERG3, and ERG11. The localization of CgRpn4 to the nucleus increases upon fluconazole stress. Consistent with a role in ergosterol and plasma membrane homeostasis, CgRpn4 is required for the maintenance of ergosterol levels upon fluconazole stress, which is associated with a role in the upkeep of cell permeability and decreased intracellular fluconazole accumulation. We provide evidence that CgRpn4 directly regulates ERG11 expression through the TTGCAAA binding motif, reinforcing the relevance of this regulatory network in azole resistance. In summary, CgRpn4 is a new regulator of the ergosterol biosynthesis pathway in C. glabrata, contributing to plasma membrane homeostasis and, thus, decreasing azole drug accumulation.
- Published
- 2020
15. Polymorphic centromere locations in the pathogenic yeast Candida parapsilosis
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Aisling Y. Coughlan, Caoimhe E. O’Brien, Mihaela Ola, Qinxi Ma, Paul D. Donovan, Geraldine Butler, and Kenneth H. Wolfe
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Genetics ,0303 health sciences ,Candida parapsilosis ,Research ,Centromere ,Inverted Repeat Sequences ,Genomics ,Biology ,biology.organism_classification ,DNA sequencing ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,Pathogenic yeast ,Saccharomycetales ,Chromatin Immunoprecipitation Sequencing ,Chromosomes, Fungal ,Clade ,030217 neurology & neurosurgery ,Genetics (clinical) ,030304 developmental biology - Abstract
Centromeres pose an evolutionary paradox: strongly conserved in function, but rapidly changing in sequence and structure. However, in the absence of damage, centromere locations are usually conserved within a species. We report here that isolates of the pathogenic yeast species Candida parapsilosis exhibit within-species polymorphism for the location of centromeres on two of its eight chromosomes. Its old centromeres have an inverted-repeat (IR) structure, whereas its new centromeres have no obvious structural features, but are located within 30 kb of the old site. Centromeres can therefore move naturally from one chromosomal site to another, apparently spontaneously and in the absence of any significant changes in DNA sequence. Our observations are consistent with a model where all centromeres are genetically determined, such as by the presence of short or long IRs, or the ability to form cruciforms. We also find that centromeres have been hotspots for genomic rearrangements in the C. parapsilosis clade.
- Published
- 2020
16. Correction for Ma et al., 'Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in <named-content content-type='genus-species'>Candida albicans</named-content>'
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Geraldine Butler, Elise Iracane, Qinxi Ma, and Mihaela Ola
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Chromosome 7 (human) ,biology ,medicine ,Parental strain ,Candida albicans ,biology.organism_classification ,Trisomy ,medicine.disease ,Molecular Biology ,Molecular biology ,Microbiology ,QR1-502 - Abstract
Volume 4, no. 3, e00402-19, 2019, [https://doi.org/10.1128/mSphere.00402-19][1]. Following the publication of this paper, it came to our attention that we inadvertently failed to refer to some earlier work in the field. We described two loss-of-heterozygosity (LOH) events in the parental strain used
- Published
- 2019
17. Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in Candida albicans
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Mihaela Ola, Elise Iracane, Qinxi Ma, and Geraldine Butler
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Antifungal Agents ,lcsh:QR1-502 ,Aneuploidy ,Loss of Heterozygosity ,Trisomy ,Ecological and Evolutionary Science ,fatty acids ,Microbiology ,lcsh:Microbiology ,Loss of heterozygosity ,03 medical and health sciences ,Candida albicans ,medicine ,aneuploidy ,Author Correction ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,Chromosome 7 (human) ,Genetics ,0303 health sciences ,biology ,030306 microbiology ,Chromosome ,Fatty acid ,Editor's Pick ,medicine.disease ,biology.organism_classification ,QR1-502 ,3. Good health ,chemistry ,Chromosome 3 ,Chromosomes, Fungal ,Genome, Fungal ,Research Article ,Transcription Factors - Abstract
Aneuploidy (changes in chromosome number) and loss of heterozygosity (LOH) occur frequently in the human-pathogenic yeast Candida albicans and are associated with adaptation to stress and to antifungal drugs. Aneuploidy and LOH can also be induced during laboratory manipulations, such as during genetic transformation. We find that C. albicans strain SN152, commonly used to generate gene deletions, has undergone a major LOH event on chromosome 2. One deletion strain generated in this background has acquired extra copies of chromosomes 5 and 7. We find that trisomy (three copies) of chromosome 7 is associated with sensitivity to fatty acids., Fatty acids have known antifungal effects and are used in over-the-counter topical treatments. Screening of a collection of gene knockouts in Candida albicans revealed that one strain, carrying a deletion of the transcription factor DAL81, is very susceptible to the medium-chain fatty acid undecanoic acid. However, reintroducing DAL81 does not restore resistance, and editing DAL81 in a different background does not introduce sensitivity. Whole-genome sequencing revealed that the C. albicans dal81Δ/Δ strain has an extra copy of chromosomes 5 and 7. Reversion to resistance to undecanoic acid was induced by growing the sensitive strain in yeast extract-peptone-dextrose with 60 μg/ml undecanoic acid for up to 9 days. Nine isolates that regained some resistance to undecanoic acid lost one copy of chromosome 7. The copy number of chromosome 5 does not appear to affect resistance to fatty acids. Moreover, the sensitivity may be related to having two copies of haplotype B of chromosome 7. In addition, we find that C. albicans strain SN152, used to delete DAL81 and many other genes, has undergone a major loss of heterozygosity event on chromosome 2 and a smaller one on chromosome 3. IMPORTANCE Aneuploidy (changes in chromosome number) and loss of heterozygosity (LOH) occur frequently in the human-pathogenic yeast Candida albicans and are associated with adaptation to stress and to antifungal drugs. Aneuploidy and LOH can also be induced during laboratory manipulations, such as during genetic transformation. We find that C. albicans strain SN152, commonly used to generate gene deletions, has undergone a major LOH event on chromosome 2. One deletion strain generated in this background has acquired extra copies of chromosomes 5 and 7. We find that trisomy (three copies) of chromosome 7 is associated with sensitivity to fatty acids.
- Published
- 2019
18. Identification of an Exceptionally Long Intron in the HAC1 Gene of Candida parapsilosis
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Geraldine Butler, Linda M. Holland, Elise Iracane, Paul D. Donovan, and Mihaela Ola
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0301 basic medicine ,Candida parapsilosis ,Hac1 ,introns ,030106 microbiology ,Saccharomyces cerevisiae ,lcsh:QR1-502 ,Antifungal drug ,Intron ,unfolded protein response ,Biology ,biology.organism_classification ,Microbiology ,QR1-502 ,lcsh:Microbiology ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,RNA splicing ,Unfolded protein response ,Candida albicans ,Molecular Biology ,Gene - Abstract
The unfolded protein response (UPR) in the endoplasmic reticulum (ER) is well conserved in eukaryotes from metazoa to yeast. The transcription factor HAC1 is a major regulator of the UPR in many eukaryotes. Deleting HAC1 in the yeast Candida parapsilosis rendered cells more sensitive to DTT, a known inducer of the UPR. The deletion strain was also sensitive to Congo red, calcofluor white, and the antifungal drug ketoconazole, indicating that HAC1 has a role in cell wall maintenance. Transcriptomic analysis revealed that treatment of the wild type with DTT resulted in the increased expression of 368 genes. Comparison with mutant cells treated with DTT reveals that expression of 137 of these genes requires HAC1. Enriched GO term analysis includes response to ER stress, cell wall biogenesis and glycosylation. Orthologs of many of these are associated with UPR in Saccharomyces cerevisiae and Candida albicans. Unconventional splicing of an intron from HAC1 mRNA is required to produce a functional transcription factor. The spliced intron varies in length from 19 bases in C. albicans to 379 bases in Candida glabrata, but has not been previously identified in Candida parapsilosis and related species. We used RNA-seq data and in silico analysis to identify the HAC1 intron in 12 species in the CTG-Ser1 clade. We show that the intron has undergone major contractions and expansions in this clade, reaching up to 848 bases. Exposure to DTT induced splicing of the long intron in C. parapsilosis HAC1, inducing the UPR. IMPORTANCE The unfolded protein response (UPR) responds to the build-up of misfolded proteins in the endoplasmic reticulum. The UPR has wide-ranging functions from fungal pathogenesis to applications in biotechnology. The UPR is regulated through the splicing of an unconventional intron in the HAC1 gene. This intron has been described in many fungal species and is of variable length. Until now it was believed that some members of the CTG-Ser1 clade such as C. parapsilosis did not contain an intron in HAC1, suggesting that the UPR was regulated in a different manner. Here we demonstrate that HAC1 plays an important role in regulating the UPR in C. parapsilosis. We also identified an unusually long intron (626 bp) in C. parapsilosis HAC1. Further analysis showed that HAC1 orthologs in several species in the CTG-Ser1 clade contain long introns.
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- 2018
19. Second Primary Lung Cancer after Breast Cancer: Challenges and Approaches
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Elena-Monica BOGHICI, Andreea-Ioana PAROSANU, Ion Cristian IACIU, Mihaela OLARU, Cristina-Florina PIRLOG, Cristina ORLOV-SLAVU, Ana-Maria POPA, and Cornelia NITIPIR
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breast cancer ,lung cancer ,gastric secondary determinations ,ntestinal secondary determinations ,hypersensitivity reaction ,desensitization to atezolizumab ,Medicine ,Medicine (General) ,R5-920 - Abstract
Breast cancer is one of the most common malignancies, with a 10-year survival rate for early non-metastatic stages of over 80%. However, recurrence or relapse may occur decades after completing therapy, and cancer survivors have also a risk of secondary neoplasia especially due to radiation therapy. This case highlights the challenges of an accurate diagnosis and appropriate treatment in patients with second primary cancer and uncommon metastasis.
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- 2023
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20. Candida Intestinal Domination Precedes Fungal Infections Bloodstream in Allogeneic Hematopoietic Cell Transplant Patients
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Mihaela Ola, Eric R. Littmann, Eric G. Pamer, Bing Zhai, Jonathan U. Peled, Marcel R.M. van den Brink, Sari Joshowitz, Ying Taur, Geraldine Butler, Tobias M. Hohl, Sejal Morjaria, and Nicholas L. Tosini
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Transplantation ,Mycobiota ,business.industry ,Hematology ,Neutropenia ,medicine.disease ,Corpus albicans ,Microbiology ,Real-time polymerase chain reaction ,Bacteremia ,medicine ,business ,Feces ,Fungemia - Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are at high risk of developing invasive bloodstream infections during the period of neutropenia prior to engraftment, even with prophylactic administration of antibacterial and antifungal drugs. Previous studies have demonstrated that disruption of the diversity and stability of commensal intestinal bacteria facilitates intestinal domination by pathobionts, a process that is associated with subsequent bacteremia. The relationship and dynamics of intestinal fungal communities (i.e., mycobiota) and the development of fungemia during allo-HCT remains unknown. In this study, we identified 8 allo-HCT patients that developed fungemia and participated in a prospective collection of fecal samples between 2014 and 2017 at MSKCC. All 8 patients developed Candida species fungemia (6 C. parasilopsis, 1 C. albicans, 1 C. lusitaniae). Using quantitative PCR to analyze fungal 18S rDNA, we found a temporal expansion of total intestinal fungi that coincided with the onset of fungemia (Figure A). We then analyzed the composition of the mycobiota by sequencing the internal transcribed spacer 1 (ITS1) region of the fungal rDNA, and found a significant loss of diversity of gut fungal flora (Figure B). Moreover, in seven of the eight cases, we observed intestinal dominance of the specific Candida species that was associated with fungemia, prior to the identification of positive blood cultures. Through whole genome sequencing of the fecal and the bloodstream fungal isolates, we further confirmed that the bloodstream fungal strain was the same clone as the one that had robustly colonized in the gut. Taken together, our results indicate that Candida intestinal domination precedes Candida bloodstream infection. Thus, monitoring the dynamics and composition of the mycobiota may facilitate identification of patients at-risk for this life-threatening complication and enable improved strategies for prophylactic or therapeutic gain.
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- 2019
21. Protective coatings for ceramic artefacts exposed to UV ageing
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Andrei V. Oancea, George Bodi, Adrian Cernescu, Iuliana Spiridon, Alina Nicolescu, Mioara Drobota, Corneliu Cotofana, Bogdan C. Simionescu, and Mihaela Olaru
- Subjects
Materials of engineering and construction. Mechanics of materials ,TA401-492 - Abstract
Abstract The commercial acrylic copolymer Paraloid B72 (PB72) and a synthesized nanostructured material (AMF) bearing silsesquioxane, methacrylate and fluorine units were analyzed to assess their performances as protective coatings for the conservation of Neolithic Cucuteni ceramic pottery when submitted to UV ageing. In the context of comparative evaluation of the protective efficiency, the present paper reports the use of a functional coating that operates via specific photochemical transformations at the coating-air interface as a UV resistant protection coating for cultural heritage artefacts. The main factors that influenced the photo-degradation behavior of the polymeric materials included their structure, the properties at the polymer/air interfaces, and the preferential orientation of functional groups at the surface of the polymeric coatings.
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- 2023
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22. The Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Patients with Metastatic Renal Cell Carcinoma
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Andreea Ioana Parosanu, Cristina Florina Pirlog, Cristina Orlov Slavu, Ioana Miruna Stanciu, Horia-Teodor Cotan, Radu Constantin Vrabie, Ana-Maria Popa, Mihaela Olaru, Cristian Iaciu, Lucian Ioan Bratu, Ionut Florian Baicoianu, Oana Moldoveanu, Catalin Baston, and Cornelia Nițipir
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NLR ,MSKCC ,IMDC ,metastatic ,renal cell carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Metastatic renal cell carcinoma (mRCC) is an aggressive cancer characterised by an increased recurrence rate and an inadequate response to treatment. This study aimed to investigate the importance of the neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker for long-term survival in patients with mRCC. Methods: We retrospectively analysed data from 74 patients with mRCC treated at our medical centre with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We evaluated the predictive value of NLR for overall survival (OS) in these patients. Results: The median OS was 5.1 months in the higher NLR group (≥3) and 13.3 months in the lower NLR group (p < 0.0001). There was no significant difference in the OS between the TKI and ICI therapies in the low NLR group (12.9 vs. 13.6 months, p = 0.411) or in the high NLR group (4.7 vs. 5.5 months, p = 0.32). Both univariate and multivariate analyses revealed that a higher NLR was an independent prognostic factor of long-term survival in patients with mRCC treated with first-line therapy. Conclusions: This retrospective study showed that adding NLR to other Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) variables might improve the prognostic and predictive power of these models.
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- 2023
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23. Nivolumab Hypersensitivity Reactions a Myth or Reality in Solid Tumors—A Systematic Review of the Literature
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Cristina-Florina Pîrlog, Andreea Ioana Paroșanu, Cristina Orlov Slavu, Mihaela Olaru, Ana Maria Popa, Cristian Iaciu, Irina Niță, Pompilia Moțatu, Cotan Horia, Loredana Sabina Cornelia Manolescu, and Cornelia Nițipir
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Nivolumab ,hypersensitivity reaction ,immune-checkpoint inhibitors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immune-checkpoint inhibitors (ICIs) are the most effective treatments nowadays. Nivolumab was the second ICI used for treating solid tumors with amazing results. Patients treated with Nivolumab may react differently to this treatment. Some people tolerate this treatment very well without experiencing any adverse reactions, whilst some may have mild symptoms and a part of them can present severe reactions. In our research, we sought to identify the answers to four questions: 1. what type of cancer has more severe hypersensitivity reactions to Nivolumab, 2. what is the time frame for developing these severe reactions to Nivolumab, 3. whether it is best to continue or stop the treatment after a severe hypersensitivity reaction to Nivolumab and 4. what severe hypersensitivity reactions are the most frequent reported along Nivolumab treatment. This review also highlights another problem with regard to the usage of concomitant and prior medications or other methods of treatment (e.g., radiation therapy), which can also lead to severe reactions. Treatment with Nivolumab is very well tolerated, but patients should also be warned of the possibility of severe hypersensitivity reactions for which they should urgently see a doctor for a personalized evaluation. There are some options for individuals with severe hypersensitivity reactions, for eg. switching the medication or applying a desensitization protocol.
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- 2022
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24. Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance
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N.C. Gomes, Cidália Pina-Vaz, Joana Branco, Geraldine Butler, C. Martins-Cruz, Ana Silva-Dias, Acácio G. Rodrigues, C. Erraught, Raquel M. Silva, E. Fonseca, Lorraine Brennan, Isabel M. Miranda, Mihaela Ola, and Ana Elisa Bauer de Camargo Silva
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0301 basic medicine ,Microbiology (medical) ,Azoles ,Posaconazole ,Antifungal Agents ,Candida parapsilosis ,030106 microbiology ,Mutant ,Mutation, Missense ,Microbial Sensitivity Tests ,Biology ,medicine.disease_cause ,Mass Spectrometry ,Microbiology ,Fungal Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Resistance, Fungal ,Ergosterol ,medicine ,Missense mutation ,Gene ,chemistry.chemical_classification ,Genetics ,Mutation ,Whole Genome Sequencing ,Gene Expression Profiling ,Provitamins ,General Medicine ,biology.organism_classification ,Infectious Diseases ,chemistry ,Azole ,Oxidoreductases ,Gene Deletion ,medicine.drug ,Transcription Factors - Abstract
Objectives Candida parapsilosis is a healthcare-related fungal pathogen particularly common among immunocompromised patients. Our understanding of antifungal resistance mechanisms in C. parapsilosis remains very limited. We previously described an azole-resistant strain of C. parapsilosis (BC014R PSC ), obtained following exposure in vitro to posaconazole. Resistance was associated with overexpression of ergosterol biosynthetic genes ( ERG genes), together with the transcription factors UPC2 ( CPAR2-207280 ) and NDT80 ( CPAR2-213640 ). The aim of this study was to identify the mechanisms underlying posaconazole resistance of the BC014R PSC strain. Methods To identify the causative mutation, we sequenced the genomes of the susceptible (BC014S) and resistant (BC014R PSC ) isolates, using Illumina technology. Ergosterol content was assessed in both strains by mass spectrometry. UPC2 and NDT80 genes were deleted in BC014R PSC strain. Mutants were characterized regarding their azole susceptibility profile and ERG gene expression. Results One homozygous missense mutation (R135I) was found in ERG3 ( CPAR2-105550 ) in the azole-resistant isolate. We show that Erg3 activity is completely impaired, resulting in a build up of sterol intermediates and a failure to generate ergosterol. Deleting UPC2 and NDT80 in BC014R PSC reduces the expression of ERG genes and restores susceptibility to azole drugs. Conclusions A missense mutation in the ERG3 gene results in azole resistance and up-regulation of ERG genes expression. We propose that this mutation prevents the formation of toxic intermediates when cells are treated with azoles. Resistance can be reversed by deleting Upc2 and Ndt80 transcription factors. UPC2 plays a stronger role in C. parapsilosis azole resistance than does NDT80 .
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- 2016
25. Neurological Paraneoplastic Syndromes: the Early Diagnosis of Lung Cancer
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Andreea PAROSANU, Ana-Maria POPA, Cristian IACIU, Mihaela OLARU, Cristina ORLOV-SLAVU, Horia COTAN, Miruna STANCIU, Radu VRABIE, and Cornelia NITIPIR
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neurologic paraneoplastic syndromes ,small cell lung cancer ,cancer management ,Medicine ,Medicine (General) ,R5-920 - Abstract
Paraneoplastic syndromes of the nervous system are rare disorders, strongly linked with lung cancer. This report aims to explore the challenges in the diagnosis and treatment of a patient with early-stage small cell lung cancer and neurological manifestations as initial clinical symptoms.
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- 2022
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26. How opportune is multigene testing in metastatic colorectal cancer? A review
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Cristina Orlov-Slavu, Andreea Parosanu, Mihaela Olaru, Dragos Serban, Ioana Paunica, and Cornelia Nitipir
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multigene assay ,metastatic ,colorectal cancer ,targeted therapy ,Medicine (General) ,R5-920 - Abstract
Personalized treatment in oncology is the most innovative method of care. The best method to establish personalized treatment is by genetic characterization of the malignant cell. Theoretically, the more detailed the characterization, the more effective the choice of treatment becomes. Currently, there are fast and relatively low-cost options that allow such genetic characterization. However, test results sometimes do not detect targetable alterations and, even if they do detect, the use of the treatment-alteration combination does not always generate a satisfactory oncological response. The present paper aims to answer two questions. First, how targetable can the most common gene alterations in colorectal cancer be. Second, whether it makes sense to use broad molecular testing as a standard in all metastatic patients.
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- 2021
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27. Restricted Mean Survival Time—Can It Be a New Tool in Assessing the Survival of Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors?
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Cristina-Florina Pîrlog, Raluca Costache, Andreea Ioana Paroșanu, Cristina Orlov Slavu, Mihaela Olaru, Ana Maria Popa, Cristian Iaciu, Irina Niță, Pompilia Moțatu, Horia Teodor Cotan, Alexandru Vlad Oprița, Daniel Costache, Loredana Sabina Cornelia Manolescu, and Cornelia Nițipir
- Subjects
lung cancer ,immune checkpoint inhibitors ,immune-related adverse events ,restricted mean survival time ,Medicine (General) ,R5-920 - Abstract
Background: Lung cancer (LC) is the first and most lethal cancer in the world; identifying new methods to treat it, such as immune checkpoint inhibitors (ICIs), is needed. ICIs treatment is very effective, but it comes bundled with a series of immune-related adverse events (irAEs). Restricted mean survival time (RMST) is an alternative tool for assessing the patients’ survival when the proportional hazard assumption (PH) fails. Methods: We included in this analytical cross-sectional observational survey patients with metastatic non-small-cell lung cancer (NSCLC), treated for at least 6 months with ICIs in the first- and second-line settings. Using RMST, we estimated the overall survival (OS) of patients by dividing them into two groups. A multivariate Cox regression analysis was performed to determine the impact of the prognostic factors on OS. Results: Seventy-nine patients were included (68.4% men, mean age 63.8), and 34/79 (43%) presented irAEs. The OS RMST of the entire group was 30.91 months, with a survival median of 22 months. Thirty-two out of seventy-nine (40.5%) died before we ended our study. The OS RMST and death percentage favored the patients who presented irAEs (long-rank test, p = 0.036). The OS RMST of patients with irAEs was 35.7 months, with a number of deaths of 12/34 (35.29%), while the OS RMST of the patients without irAEs was 17 months, with a number of deaths of 20/45 (44.44%). The OS RMST by the line of treatment favored the first line of treatment. In this group, the presence of irAEs significantly impacted the survival of these patients (p = 0.0083). Moreover, patients that experienced low-grade irAEs had a better OS RMST. This result has to be cautiously regarded because of the small number of patients stratified according to the grades of irAEs. The prognostic factors for the survival were: the presence of irAEs, Eastern Cooperative Oncology Group (ECOG) performance status and the number of organs affected by metastasis. The risk of dying was 2.13 times higher for patients without irAEs than for the patients who presented irAEs, (CI) 95% of 1.03 to 4.39. Moreover, by increasing the ECOG performance status by one point, the risk of death increased by 2.28 times, with a CI 95% of 1.46 to 3.58, while the involvement of more metastatic organs was associated with a 1.60 times increase in the death risk, with a CI 95% of 1.09 to 2.36. Age and the type of tumor were not predictive for this analysis. Conclusions: The RMST is a new tool that helps researchers to better address the survival in studies with ICIs treatment where the PH fails, and the long-rank test is less efficient due to the existence of the long-term responses and delayed treatment effects. Patients with irAEs have a better prognosis than those without irAEs in the first-line settings. The ECOG performance status and the number of organs affected by metastasis must be considered when selecting patients for ICIs treatment.
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- 2023
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28. Strategy Based on Michael Addition Reaction for the Development of Bioinspired Multilayered and Multiphasic 3D Constructs
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Mihaela Olaru, Natalia Simionescu, Florica Doroftei, and Geta David
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multilayered construct ,aza-Michael addition ,cryogelation ,biocomposite ,tissue engineering ,Organic chemistry ,QD241-441 - Abstract
The high incidence of osteochondral defects has increased the interest in the development of improved repairing alternatives, with tissue engineering being considered a promising approach. The hierarchical, complex structure of osteochondral tissue requires the design of a biomimetic multilayered scaffold. Here, a multilayered and multiphasic 3D macroporous structure was achieved at subzero temperature by the Michael addition reaction of amino functionalities of collagen with acryloyl groups of a bifunctionalized poly(ε-caprolactone). This green approach has been successfully applied to crosslink layers of different composition, both for their efficient sequential formation and connection. Polyethylenimine functionalized nano-hydroxyapatite (nHApLPEI) was added to the bottom layer. The resulting hybrid cryogels were characterized by morphology, equilibrium swelling ratios, compressive strength analysis, and MTS assay. They presented good stability, integrity, and biocompatibility. The results revealed that the properties of the prepared constructs may be tuned by varying the composition, number, and thickness of the layers. The Young modulus values were between 3.5 ± 0.02 and 10.5 ± 0.6 kPa for the component layers, while for the multilayered structures they were more than 7.3 ± 0.2 kPa. The equilibrium swelling ratio varied between 4.6 and 14.2, with a value of ~10.5 for the trilayered structure, correlated with the mean pore sizes (74–230 µm).
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- 2023
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29. Frequency-Tuned Porous Polyethylene Glycol Films Obtained in Atmospheric-Pressure Dielectric Barrier Discharge (DBD) Plasma
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Bogdan-George Rusu, Cristian Ursu, Mihaela Olaru, and Mihail Barboiu
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atmospheric-pressure plasma polymerization ,dielectric barrier discharge ,porous polymer-like films ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
This study focuses on the fabrication of plasma-polymerized polyethylene glycol (pp-PEG) with porous morphology in a pulsed dielectric barrier discharge (DBD) plasma under atmospheric pressure. The signal frequency that modulates the plasma discharge was found to have a major influence on the pp-PEG film morphology. The recorded discharge current–voltage characteristic allowed us to establish a homogeneous regime of the DBD plasma operated in helium gas flow upon the frequency range 2–10 kHz. The as-prepared pp-PEG films were characterized by the Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and liquid-phase chromatography (HPLC) techniques. The performed analysis revealed that as the discharge frequency increases, the morphology of the obtained films becomes porous due to the plasma-induced stronger monomer fragmentation. To gain knowledge about the plasma species and the interaction processes that impact the film morphology, optical emission spectroscopy (OES) and intensified charge-coupled device (ICCD) fast imaging technique were applied. The determined vibrational (Tvib) and rotational (Trot) temperatures exhibit a decrease with the introduction of monomer vapors into the discharge gap. For instance, Trot drops from approximately 475 K to 350 K, and Tvib falls from 2850 K to 2650 K for a monomer vapor injection rate of 16 µL/min. This was attributed to the energy losses of the plasma-generated particles, as the inelastic collisions augment with the injection of a monomer. Concurrently with the change in temperature, the discharge current varies significantly for the investigated frequency range and exhibits a drop at high frequencies. This discharge current drop was explained by an enhancement of the recombination rate of charged particles and seems to confirm the prevalence of a plasma-induced monomer fragmentation process at high frequencies.
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- 2023
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30. News in Cancer-Related Pain Management
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Cornelia NITIPIR, Andreea PAROSANU, Lucian ALECU, Ana Maria POPA, Cristian IACIU, Mihaela OLARU, Adrian TULIN, Iulian SLAVU, Valentin CALU, and Cristina ORLOV-SLAVU
- Subjects
cancer-related pain ,opioids ,alternative treatments ,Medicine ,Medicine (General) ,R5-920 - Abstract
Introduction: Cancer related- pain causes a negative psychosocial and physical impact on patients’ lives. The purpose of this review was to investigate the current strategies for cancer pain treatment. Material and Methods: We conducted a PubMed search of the literature published from 2018 to 2020, and details were extracted from the articles with adequate study quality. Discussion: Of 63 titles, 19 studies were selected and used in review. Conclusions: This review article focuses on the novel treatments available for cancer pain management.
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- 2020
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31. Can non-small cell lung cancer histologic subtypes predict survival? A single institution experience
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Cornelia Nitipir, Cristina Orlov, Ana-Maria Popa, Mihaela Olaru, Iulian Slavu, Iaciu Cristian, Razvan Hainarosie, Anca Pantea Stoian, and Cristian Balalau
- Subjects
adenocarcinoma ,non-small cell lung cancer ,histologic subtypes ,survival ,Medicine (General) ,R5-920 - Abstract
Introduction. The latest histological classification of lung adenocarcinoma includes lepidic, acinar, papillary, micropapillary, and solid as subtypes. Testing these subtypes for their prognostic and predictive value is an ongoing scientific challenge. The present research article aims to describe the influence this classification has on patient survival. Materials and Methods. Thirty-three patients were included in the trial. The most important enrollment criterion was the clear specification of the adenocarcinoma subtype in the pathology report. Patients were stratified into three groups which included the adenocarcinoma pathological subtypes as follows: lepidic (LEP), acinar and papillary (ACN/PAP), and micropapillary/solid (MIP/SOL). The primary endpoint was progression-free survival. Other endpoints included overall survival. Results. The lepidic subtype of ADC had superior PFS and OS, regardless of stage. Papillary and acinar subtype showed an intermediate prognosis, whereas micropapillary and solid subtypes were the most aggressive. Conclusions. The experience of this single center confirmed data in the literature. Further studies are needed to demonstrate all the possible implications of this pathology classification.
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- 2018
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32. Hard Dental Tissues Regeneration—Approaches and Challenges
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Mihaela Olaru, Liliana Sachelarie, and Gabriela Calin
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stem cells ,growth factors ,biomaterials ,hard dental tissues ,scaffold-based and scaffold-free approach ,tooth regeneration ,Technology ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Microscopy ,QH201-278.5 ,Descriptive and experimental mechanics ,QC120-168.85 - Abstract
With the development of the modern concept of tissue engineering approach and the discovery of the potential of stem cells in dentistry, the regeneration of hard dental tissues has become a reality and a priority of modern dentistry. The present review reports the recent advances on stem-cell based regeneration strategies for hard dental tissues and analyze the feasibility of stem cells and of growth factors in scaffolds-based or scaffold-free approaches in inducing the regeneration of either the whole tooth or only of its component structures.
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- 2021
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33. Possible Influence of Weight Gain and Creatinine Levels in Predicting Response to Nivolumab: A Multicenter Analysis
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Cornelia Nitipir, Cristina Orlov-Slavu, Lucian Alecu, Iulian Slavu, Anca Pantea-Stoian, Ionela Daniela Celmare, Mihaela Olaru, Valentin Calu, Andra-Iulia Suceveanu, Laura Mazilu, Andreea-Daniela Gheorghe, Adelina Silviana Gheorghe, Catalina Poiana, Razvan Hainarosie, Sanziana Octavia Ionescu, and Dana Lucia Stanculeanu
- Subjects
prognostic ,body mass index ,sarcopenia ,Microbiology ,QR1-502 - Abstract
Literature suggests that high body mass index can be correlated with better response to immune checkpoint inhibitors. On the other hand, sarcopenia seems to be a negative predictive marker. The present analysis is a retrospective, multicenter trial that included patients with metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma treated with nivolumab between 2018 and 2020. Patients were stratified by creatinine levels both at treatment initiation and at first follow-up (at three months) and by BMI for the same intervals, as recorded in the patients’ charts. Creatinine was considered a surrogate marker for sarcopenia. IBM SPSS version 20 was used for statistical analysis. A total of 57 (n = 57) patients were included in the trial. Overall response rate (ORR) for the entire population was 38.59% (p = 0.02). Patients with BMI lower than 25 had an ORR of 28.5% (p = 0.003), whereas patients with BMI higher than 25 had an ORR of 42.3% (p = 0.002). Patients who gained weight during treatment had a lower probability of having progressive disease (OR = 0.4 [95% CI; 0.4–1.2]), as did patients with creatinine higher than 0.9 (OR = 0.39 [95% CI: 0.13–1.14]). No superiority was found in progression-free survival (PFS) when patients were dichotomized for BMI = 25 or BMI = 18.5. Mean PFS in the BMI under 18.5 group was 10.2 months [95% CI: 5.8–23.1], versus 11.2 for BMI over 18.5 [95% CI: 5.3–25.3], p < 0.03. Mean PFS for the BMI under 25 was 11.2 months [95% CI: 7.2–20.1], vs. 13.3 months [95% CI: 6.4–22] for the BMI over 25, p < 0.001. There were also differences in PFS in the patients with baseline creatinine over 0.9 when compared with under 0.9 values. Mean PFS in the first group was 19.78 months [95% CI: 16.23–22.9] vs. 16.1 [95% CI: 12.2–20.3], p < 0.001. Patients treated with nivolumab who have weight gain during treatment have a better PFS than the ones who do not. Creatinine levels of over 0.9 at treatment initiation also have positive predictive value.
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- 2020
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34. Effect of SO2 Dry Deposition on Porous Dolomitic Limestones
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Florica Doroftei, Bogdana Simionescu, Magdalena Aflori, Mihaela Olaru, and Lacramioara Stratulat
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limestone ,silsesquioxane ,nanocomposite ,Technology ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Microscopy ,QH201-278.5 ,Descriptive and experimental mechanics ,QC120-168.85 - Abstract
The present study is concerned with the assessment of the relative resistance of a monumental dolomitic limestone (Laspra – Spain) used as building material in stone monuments and submitted to artificial ageing by SO2 dry deposition in the presence of humidity. To investigate the protection efficiency of different polymeric coatings, three commercially available siloxane-based oligomers (Lotexan-N, Silres BS 290 and Tegosivin HL 100) and a newly synthesized hybrid nanocomposite with silsesquioxane units (TMSPMA) were used. A comparative assessment of the data obtained in this study underlines that a better limestone protection was obtained when treated with the hybrid nanocomposite with silsesquioxane units.
- Published
- 2010
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