Publications by authors named "Carmen Salguero-Aranda"

10 Publications

  • Page 1 of 1

A Novel Gene Fusion in Solitary Fibrous Tumor: A Case Report.

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Fundacion Jimenez Diaz University Hospital Health Research Institute (IIS/FJD), 28015 Madrid, Spain.

Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion , resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of mapping to 19p13.2 and mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for in solitary fibrous tumor opens intriguing new hypotheses to refine the role of in the sarcomatogenesis of this entity.
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http://dx.doi.org/10.3390/ijms22147514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305824PMC
July 2021

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

Front Cell Dev Biol 2021 3;9:670185. Epub 2021 Jun 3.

Cancer CIBER (CIBERONC), Madrid, Spain.

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
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http://dx.doi.org/10.3389/fcell.2021.670185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209546PMC
June 2021

Molecular Approaches to Diagnosis in Ewing Sarcoma: Targeted RNA Sequencing.

Methods Mol Biol 2021 ;2226:105-116

Department of Pathology, Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Hospital Universitario Virgen del Rocío, Seville, Spain.

Molecular testing of pathognomonic gene fusions is mandatory for small round cell tumor diagnosis, including Ewing sarcoma which is indeed defined by a variety of chimeric genes. Reference laboratories are increasingly implementing NGS-based techniques to overcome several limitations of conventional singleplex determinations. We have been early adopters of a targeted-RNA sequencing method based on Anchored multiplex PCR, which allows assessing several fusion transcripts simultaneously with previous knowledge of only one partner gene. Here we describe in detail our protocol and tips for nucleic acid extraction, library preparation, sequencing, and reporting of gene fusions.
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http://dx.doi.org/10.1007/978-1-0716-1020-6_8DOI Listing
April 2021

Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape.

Cells 2020 03 26;9(4). Epub 2020 Mar 26.

Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, 41013 Seville, Spain.

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma.
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http://dx.doi.org/10.3390/cells9040804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226764PMC
March 2020

STAT6 knockdown using multiple siRNA sequences inhibits proliferation and induces apoptosis of human colorectal and breast cancer cell lines.

PLoS One 2019 10;14(5):e0207558. Epub 2019 May 10.

Celixir, Stratford-upon-Avon, United Kingdom.

The transcription factor STAT6 is strongly expressed in various tumours and is most highly expressed in human malignant lymphomas and pancreatic, colorectal, prostate and breast cancers. STAT6 is associated with cancer cell proliferation, an increased malignancy and poor prognosis. Thus, techniques aimed at reducing or blocking STAT6 expression may be useful in treating STAT6high cancers. Among these cancers, colorectal and breast cancers represent two of the most common worldwide and their incidence is increasing every year. In 2018, colorectal and breast cancers represented 10.2% and 11.6% of all new cases of cancer diagnosed, respectively. In this study, four proprietary STAT6 specific small interfering RNA (siRNA) sequences were tested in vitro using the human colon adenocarcinoma cell line, HT-29, and the breast/duct carcinoma cell line, ZR-75-1. Decreases in STAT6 mRNA and protein levels were analysed to confirm the transfection was successful and STAT6 knockdown effects were measured by analysing cell proliferation and apoptosis. Results showed that 100nM siRNA concentration was the most effective and, although all individual sequences were capable of significantly inhibiting cell proliferation, STAT6 siRNA sequences 1 and 4 had the largest effects. STAT6 silencing also significantly induced apoptotic events. In conclusion, these results demonstrate that STAT6 siRNA sequences are capable of inhibiting proliferation of and inducing apoptosis of HT-29 colorectal cancer cells and ZR-75-1 breast cancer cells, halving the number of cancer cells in a short period of time. These experiments will be repeated in other STAT6high cancers in vitro, and animal studies in immunocompromised mice have been planned using xenografts of STAT6-expressing human colorectal and breast cancer cells. The STAT6 siRNA sequences therefore represent a potential treatment for STAT6high colorectal and breast cancers and a wide variety of other STAT6-expressing cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207558PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510441PMC
January 2020

Differentiation of Mouse Embryonic Stem Cells toward Functional Pancreatic β-Cell Surrogates through Epigenetic Regulation of Pdx1 by Nitric Oxide.

Cell Transplant 2016 10;25(10):1879-1892

Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.

Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that regulates the embryonic development of the pancreas and the differentiation toward β cells. Previously, we have shown that exposure of mouse embryonic stem cells (mESCs) to high concentrations of diethylenetriamine nitric oxide adduct (DETA-NO) triggers differentiation events and promotes the expression of Pdx1. Here we report evidence that Pdx1 expression is associated with release of polycomb repressive complex 2 (PRC2) and P300 from its promoter region. These events are accompanied by epigenetic changes in bivalent markers of histones trimethylated histone H3 lysine 27 (H3K27me3) and H3K4me3, site-specific changes in DNA methylation, and no change in H3 acetylation. On the basis of these findings, we developed a protocol to differentiate mESCs toward insulin-producing cells consisting of sequential exposure to DETA-NO, valproic acid, and P300 inhibitor (C646) to enhance Pdx1 expression and a final maturation step of culture in suspension to form cell aggregates. This small molecule-based protocol succeeds in obtaining cells that express pancreatic β-cell markers such as PDX1, INS1, GCK, and GLUT2 and respond in vitro to high glucose and KCl.
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http://dx.doi.org/10.3727/096368916X691178DOI Listing
October 2016

Nitric Oxide Prevents Mouse Embryonic Stem Cell Differentiation Through Regulation of Gene Expression, Cell Signaling, and Control of Cell Proliferation.

J Cell Biochem 2016 09 8;117(9):2078-88. Epub 2016 Mar 8.

Andalusian Center for Molecular Biology and Regenerative Medicine, University Pablo de Olavide, Seville, Spain.

Nitric oxide (NO) delays mouse embryonic stem cell (mESC) differentiation by regulating genes linked to pluripotency and differentiation. Nevertheless, no profound study has been conducted on cell differentiation regulation by this molecule through signaling on essential biological functions. We sought to demonstrate that NO positively regulates the pluripotency transcriptional core, enforcing changes in the chromatin structure, in addition to regulating cell proliferation, and signaling pathways with key roles in stemness. Culturing mESCs with 2 μM of the NO donor diethylenetriamine/NO (DETA/NO) in the absence of leukemia inhibitory factor (LIF) induced significant changes in the expression of 16 genes of the pluripotency transcriptional core. Furthermore, treatment with DETA/NO resulted in a high occupancy of activating H3K4me3 at the Oct4 and Nanog promoters and repressive H3K9me3 and H3k27me3 at the Brachyury promoter. Additionally, the activation of signaling pathways involved in pluripotency, such as Gsk3-β/β-catenin, was observed, in addition to activation of PI3 K/Akt, which is consistent with the protection of mESCs from cell death. Finally, a decrease in cell proliferation coincides with cell cycle arrest in G2/M. Our results provide novel insights into NO-mediated gene regulation and cell proliferation and suggest that NO is necessary but not sufficient for the maintenance of pluripotency and the prevention of cell differentiation. J. Cell. Biochem. 117: 2078-2088, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25513DOI Listing
September 2016

Role of nitric oxide in the maintenance of pluripotency and regulation of the hypoxia response in stem cells.

World J Stem Cells 2015 Apr;7(3):605-17

Amparo Beltran-Povea, Estefania Caballano-Infantes, Franz Martín, Francisco J Bedoya, Juan R Tejedo, Gladys M Cahuana, Andalusian Center for Molecular Biology and Regenerative Medicine-University Pablo de Olavide, CIBERDEM, RED-TERCEL, 41092 Seville, Spain.

Stem cell pluripotency and differentiation are global processes regulated by several pathways that have been studied intensively over recent years. Nitric oxide (NO) is an important molecule that affects gene expression at the level of transcription and translation and regulates cell survival and proliferation in diverse cell types. In embryonic stem cells NO has a dual role, controlling differentiation and survival, but the molecular mechanisms by which it modulates these functions are not completely defined. NO is a physiological regulator of cell respiration through the inhibition of cytochrome c oxidase. Many researchers have been examining the role that NO plays in other aspects of metabolism such as the cellular bioenergetics state, the hypoxia response and the relationship of these areas to stem cell stemness.
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http://dx.doi.org/10.4252/wjsc.v7.i3.605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404395PMC
April 2015

Regulation of pancreatic β-cell survival by nitric oxide: clinical relevance.

Islets 2012 Mar-Apr;4(2):108-18. Epub 2012 Mar 1.

Andalusian Center for Molecular Biology and Regenerative Medicine, University Pablo de Olavide, CIBERDEM, RED-TERCEL, Seville, Spain.

The reduction of pancreatic β-cell mass is an important factor in the development of type 1 and type 2 diabetes. Understanding the mechanisms that regulate the maintenance of pancreatic β-cell mass as well as β-cell death is necessary for the establishment of therapeutic strategies. In this context, nitric oxide (NO) is a diatomic, gaseous, highly reactive molecule with biological activity that participates in the regulation of pancreatic β-cell mass. Two types of cellular responses can be distinguished depending on the level of NO production. First, pancreatic β-cells exposed to inflammatory cytokines, lipid stress or hyperglycaemia produce high concentrations of NO, mainly due to the activation of inducible NO synthase (iNOS), thus promoting cell death. Meanwhile, under homeostatic conditions, low concentrations of NO, constitutively produced by endothelial NO synthase (eNOS), promote cell survival. Here, we will discuss the current knowledge of the NO-dependent mechanisms activated during cellular responses, emphasizing those related to the regulation of cell survival.
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http://dx.doi.org/10.4161/isl.19822DOI Listing
January 2013
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