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1. A Novel MSH6 Gene Variant in a Lynch Syndrome Patient with Lipomas

Author

Ana Paula Giannoni, Ina Sevic, Fernanda Parenti, and Laura Alaniz

Subjects
MSH6, Lynch syndrome, lipomas, genetic screening, cancer risk, Medicine (General), R5-920
Abstract

Colorectal cancer is one of the most frequently occurring cancers today, with a large percentage of cases having a hereditary basis. Lynch syndrome is the most common cause of hereditary colorectal cancer. The genetic defect characteristics of this syndrome involve mutations in mismatch repair (MMR) genes, which result in microsatellite instability. Early detection of the mutation can help evaluate the cancer risk and, consequently, a proper course of clinical management for the person harboring the mutation. Herein, we describe the first report of a c.1458dup (p.Glu487*) new mutation in a 53-year-old colorectal cancer patient with diagnosed Lynch syndrome. Additionally, the existence of lipomas in this patient and his family could be related to this syndrome. Further investigation may provide a possible visual clue that can indicate a need for genetic screening.

Published
2023
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2. CD105 expression in cancer-associated fibroblasts: a biomarker for bone metastasis in early invasive ductal breast cancer patients

Author

María Belén Giorello, Leandro Marcelo Martinez, Francisco Raúl Borzone, María del Rosario Padin, María Florencia Mora, Ina Sevic, Laura Alaniz, María de Luján Calcagno, Hernán García-Rivello, Alejandra Wernicke, Vivian Labovsky, and Norma Alejandra Chasseing

Subjects
cancer-associated fibroblasts, CD105, breast cancer, prognosis factor, bone metastasis, Biology (General), QH301-705.5
Abstract

Introduction: Bone metastasis is one of the causes that mainly decrease survival in patients with advanced breast cancer. Therefore, it is essential to find prognostic markers for the occurrence of this type of metastasis during the early stage of the disease. Currently, cancer-associated fibroblasts, which represent 80% of the fibroblasts present in the tumor microenvironment, are an interesting target for studying new biomarkers and developing alternative therapies. This study evaluated the prognostic significance of the CD105 expression in cancer-associated fibroblasts in early breast cancer patients.Methods: Immunohistochemistry was used to assess CD105 expression in invasive ductal breast carcinomas (n = 342), analyzing its association with clinical and pathological characteristics.Results: High CD105 expression in cancer-associated fibroblasts was associated with an increased risk of metastatic occurrence (p = 0.0003), particularly bone metastasis (p = 0.0005). Furthermore, high CD105 expression was associated with shorter metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0002, 0.0006, and 0.0002, respectively). CD105 expression also constituted an independent prognostic factor for metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0003, 0.0006, and 0.0001, respectively).Discussion: The high CD105 expression in cancer-associated fibroblasts is an independent prognostic marker for bone metastasis in early breast cancer patients. Therefore, the evaluation of CD105(+) CAFs could be crucial to stratify BCPs based on their individual risk profile for the development of BM, enhancing treatment strategies and outcomes.

Published
2023
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3. Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

Author

Daiana L. Vitale, Antonella Icardi, Paolo Rosales, Fiorella M. Spinelli, Ina Sevic, and Laura D. Alaniz

Subjects
4-methylumbelliferone, hyaluronan, extracellular matrix, cancer, antitumoral action, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

In antineoplastic therapy, one of the challenges is to adjust the treatment to the needs of each patient and reduce the toxicity caused by conventional antitumor strategies. It has been demonstrated that natural products with antitumoral properties are less toxic than chemotherapy and radiotherapy. Also, using already developed drugs allows developing substantially less costly methods for the discovery of new treatments than traditional drug development. Candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4-MU), an orally available dietetic product, derivative of coumarin and mainly found in the plant family Umbelliferae or Apiaceae. 4-MU specifically inhibits the synthesis of glycosaminoglycan hyaluronan (HA), which is its main mechanism of action. This agent reduces the availability of HA substrates and inhibits the activity of different HA synthases. However, an effect independent of HA synthesis has also been observed. 4-MU acts as an inhibitor of tumor growth in different types of cancer. Particularly, 4-MU acts on the proliferation, migration and invasion abilities of tumor cells and inhibits the progression of cancer stem cells and the development of drug resistance. In addition, the effect of 4-MU impacts not only on tumor cells, but also on other components of the tumor microenvironment. Specifically, 4-MU can potentially act on immune, fibroblast and endothelial cells, and pro-tumor processes such as angiogenesis. Most of these effects are consistent with the altered functions of HA during tumor progression and can be interrupted by the action of 4-MU. While the potential advantage of 4-MU as an adjunct in cancer therapy could improve therapeutic efficacy and reduce toxicities of other antitumoral agents, the greatest challenge is the lack of scientific evidence to support its approval. Therefore, crucial human clinical studies have yet to be done to respond to this need. Here, we discuss and review the possible applications of 4-MU as an adjunct in conventional antineoplastic therapies, to achieve greater therapeutic success. We also describe the main proposed mechanisms of action that promote an increase in the efficacy of conventional antineoplastic strategies in different types of cancer and prospects that promote 4-MU repositioning and application in cancer therapy.

Published
2021
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4. Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells

Author

Daiana L. Vitale, Ilaria Caon, Arianna Parnigoni, Ina Sevic, Fiorella M. Spinelli, Antonella Icardi, Alberto Passi, Davide Vigetti, and Laura Alaniz

Subjects
UDP-glucose dehydrogenase, hyaluronan, epirubicin, drug resistance, extracellular matrix, breast cancer, Microbiology, QR1-502
Abstract

UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan–Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2--patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.

Published
2021
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5. Hyaluronan Metabolism is Associated with DNA Repair Genes in Breast and Colorectal Cancer. Screening of Potential Progression Markers Using qPCR

Author

Ina Sevic, Fiorella Mercedes Spinelli, Daiana Lujan Vitale, Antonella Icardi, Lucia Romano, Alejandra Brandone, Paula Giannoni, Carolina Cristina, Marcela Fabiana Bolontrade, and Laura Alaniz

Subjects
tumor microenvironment, hyaluronan, hyaluronan metabolism, breast cancer, colorectal cancer, qPCR, Biology (General), QH301-705.5
Abstract

In this work, we compared mRNA levels of Hyaluronan (HA) metabolism members and BRCA genes, known to be involved in the tumoral process, between tumor and non-tumor adjacent tissue and its correlation with previously proposed biomarkers (ER, PR, HER2 and KI67) in order to assess their value as a progression biomarkers. We show alteration in HA metabolism in colorectal but not breast cancer. However, we found a decrease in Hyaluronidase 1 HYAL1 levels in the breast but not colorectal cancer. We also show lower HA levels in tumor compared with normal tissue that could indicate a possible influence of tumor on its surrounding “normal” tissue. In both breast and colorectal cancer, CD44 and BRCA2 showed a strong positive correlation. Besides, our results show first indicators that qPCR of the analyzed genes could be used as an easy and low cost procedure for the evaluation of molecular markers we propose here.

Published
2020
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6. HBV subgenotypes F1b and F4 replication induces an incomplete autophagic process in hepatocytes: Role of BCP and preCore mutations.

Author

María Mercedes Elizalde, Paula Soledad Pérez, Ina Sevic, Daniel Grasso, Alejandro Ropolo, Luciana Barbini, Rodolfo Héctor Campos, María Inés Vaccaro, and Diego Martín Flichman

Subjects
Medicine, Science
Abstract

Hepatitis B virus (HBV) genotypes and mutants have been associated with differences in clinical and virological characteristics. Autophagy is a cellular process that degrades long-lived proteins and damaged organelles. Viruses have evolved mechanisms to alter this process to survive in host cells. In this work, we studied the modulation of autophagy by the replication of HBV subgenotypes F1b and F4, and the naturally occurring mutants BCP and preCore. HBV subgenotypes F1b and F4 replication induced accumulation of autophagosomes in hepatoma cells. However, no autophagic protein degradation was observed, indicating a blockage of autophagic flux at later stages. This inhibition of autophagy flux might be due to an impairment of lysosomal acidification in hepatoma cells. Moreover, HBV-mediated autophagy modulation was independent of the viral subgenotypes and enhanced in viruses with BCP and preCore naturally occurring mutations. These results contribute to understand the mechanisms by which different HBV variants contribute to the pathogenesis of HBV infections. In addition, this study is the first to describe the role that two highly prevalent naturally occurring mutations exert on the modulation of HBV-induced autophagy.

Published
2018
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7. HBV DNA genome co-transfection procedure for the evaluation of relative fitness.

Author

Ina Sevic, Maria Mora Gonzalez Lopez Ledesma, Diego Martin Flichman, and Rodolfo Hector Campos

Subjects
Medicine, Science
Abstract

Hepatitis B virus (HBV) has a high mutation rate and exists as a mixture of genetically different but closely related variants. We present a HBV DNA co-transfection fitness assay and use it to evaluate the relative fitness of different HBV variants in two scenarios: seroconversion process and occupation of an ecological niche. In the seroconversion experiment, subgenotype D1 (sgtD1) deletion (1763-1770) had significantly lower fitness comparing with both sgtD1 wild type and sgtD1mut G1896A, while, in the case of occupation of ecological niche experiment, the results showed the same relative fitness between all of the genotype combinations, except F1b-F4. In this case sgtF1b clearly overgrow sgtF4, which is in accordance with the observation that F1b is the most prevalent in the new infections in Argentina. In summary, we present a method aimed to evaluate HBV viral fitness which improve the analysis of the relative frequency of viral variants during the HBV infection process.

Published
2017
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8. Analysis of the Molecular Evolution of Hepatitis B Virus Genotypes in Symptomatic Acute Infections in Argentina.

Author

María Belén Rodrigo, Laura Noelia Mojsiejczuk, Carolina Torres, Ina Sevic, María Mora González López Ledesma, Paula Soledad Perez, María Belén Bouzas, Omar Galdame, Sebastián Marciano, Hugo Fainboim, Diego Martín Flichman, and Rodolfo Héctor Campos

Subjects
Medicine, Science
Abstract

Hepatitis B virus (HBV) is a globally distributed human pathogen that leads to both self-limited and chronic infections. At least eight genotypes (A-H) with distinct geographical allocations and phylodynamic behaviors have been described. They differ substantially in many virological and probably some clinical parameters. The aim of this study was to analyze full-length HBV genome sequences from individuals with symptomatic acute HBV infections using phylogenetic and coalescent methods. The phylogenetic analysis resulted in the following subgenotype distribution: F1b (52.7%), A2 (18.2%), F4 (18.2%) and A1, B2, D3 and F2a 1.8% each. These results contrast with those previously reported from chronic infections, where subgenotypes F1b, F4, A2 and genotype D were evenly distributed. This differential distribution might be related to recent internal migrations and/or intrinsic biological features of each viral genotype that could impact on the probability of transmission. The coalescence analysis showed that after a diversification process started in the 80s, the current sequences of subgenotype F1b were grouped in at least four highly supported lineages, whereas subgenotype F4 revealed a more limited diversification pattern with most lineages without offspring in the present. In addition, the genetic characterization of the studied sequences showed that only two of them presented mutations of clinical relevance at S codifyng region and none at the polymerase catalytic domains. Finally, since the acute infections could be an expression of the genotypes currently being transmitted to new hosts, the predominance of subgenotype F1b might have epidemiological, as well as, clinical relevance due to its potential adverse disease outcome among the chronic cases.

Published
2016
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9. Hepatitis B virus genotype distribution and genotype-specific BCP/preCore substitutions in acute and chronic infections in Argentina.

Author

María Mora González López Ledesma, Laura Noelia Mojsiejczuk, Belén Rodrigo, Ina Sevic, Lilia Mammana, Omar Galdame, Adrian Gadano, Hugo Fainboim, Rodolfo Campos, and Diego Flichman

Subjects
Medicine, Science
Abstract

In order to assess Hepatitis B Virus genotype (g) and subgenotype (sg) implications in the course of infection, 234 HBsAg positive patients in different infection stages were characterized (66 acute infections, 63 HBeAg positive chronic infections and 105 anti-HBe positive chronic infections).Overall, sgA2 (17.9%), gD (20.9%), sgF1b (34.2%) and sgF4 (19.7%) were the most prevalent. Subgenotype F1b was overrepresented in acute and chronic HBeAg infections (56.1%), whereas gD was the most frequent (40.0%) in anti-HBe positive chronic infections. Among chronic infections, HBeAg positivity rates were 50.0, 12.5, 62.8 and 35.3% for sgA2, gD, sgF1b and sgF4, respectively (p

Published
2015
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11. The effects of sulfated hyaluronan in breast, lung and colorectal carcinoma and monocytes/macrophages cells: Its role in angiogenesis and tumor progression

Author

Fiorella M. Spinelli, Paolo Rosales, Stefano Pluda, Daiana L. Vitale, Antonella Icardi, Cristian Guarise, Andrea Reszegi, Ilona Kovalszky, Mariana García, Ina Sevic, Devis Galesso, and Laura Alaniz

Subjects
Lung Neoplasms, Neovascularization, Pathologic, Sulfates, Macrophages, Clinical Biochemistry, Interleukin-8, Biocompatible Materials, Cell Biology, Biochemistry, Monocytes, Hyaluronan Receptors, Genetics, Tumor Microenvironment, Humans, Hyaluronic Acid, Colorectal Neoplasms, Molecular Biology, Lung
Abstract

Hyaluronan (HA) is a component of the extracellular matrix (ECM) it is the main non-sulfated glycosaminoglycan able to modulate cell behavior in the healthy and tumor context. Sulfated hyaluronan (sHA) is a biomaterial derived from chemical modifications of HA, since this molecule is not naturally sulfated. The HA sulfation modifies several properties of the native molecule, acquiring antitumor properties in different cancers. In this study, we evaluated the action of sHA of ~30-60 kDa with different degrees of sulfation (0.7 sHA1 and 2.5 sHA3) on tumor cells of a breast, lung, and colorectal cancer model and its action on other cells of the tumor microenvironment, such as endothelial and monocytes/macrophage cells. Our data showed that in breast and lung tumor cells, sHA3 is able to modulate cell viability, cytotoxicity, and proliferation, but no effects were observed on colorectal cancer cells. In 3D cultures of breast and lung cancer cells, sHA3 diminished the size of the tumorsphere and modulated total HA levels. In these tumor models, treatment of monocytes/macrophages with sHA3 showed a downregulation of the expression of angiogenic factors. We also observed a decrease in endothelial cell migration and modulation of the hyaluronan-binding protein TSG-6. In the breast in vivo xenograft model, monocytes/macrophages preincubated with sHA1 or sHA3 decreased tumor vasculature, TSG-6 and HA levels. Besides, in silico analysis showed an association of TSG-6, HAS2, and IL-8 with biological processes implicated in the progression of the tumor. Taken together, our data indicate that sHA in a breast and lung tumor context is able to induce an antiangiogenic action on tumor cells as well as in monocytes/macrophages (Mo/MØ) by modulation of endothelial migration, angiogenic factors, and vessel formation.

Published
2022

12. Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells

Author

Davide Vigetti, Arianna Parnigoni, Ina Sevic, Alberto Passi, Antonella Icardi, Laura Alaniz, Ilaria Caon, Daiana Lujan Vitale, and Fiorella Mercedes Spinelli

Subjects
0301 basic medicine, medicine.medical_treatment, extracellular matrix, lcsh:QR1-502, Apoptosis, Triple Negative Breast Neoplasms, Uridine Diphosphate Glucose Dehydrogenase, Biochemistry, Article, lcsh:Microbiology, UDP-glucose dehydrogenase, breast cancer, drug resistance, epirubicin, hyaluronan, Flow cytometry, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Western blot, Cell Line, Tumor, Biomarkers, Tumor, Medicine, Humans, Hyaluronic Acid, skin and connective tissue diseases, Molecular Biology, Gene knockdown, Chemotherapy, Antibiotics, Antineoplastic, medicine.diagnostic_test, business.industry, medicine.disease, Prognosis, carbohydrates (lipids), 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Female, business, Epirubicin, medicine.drug
Abstract

UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan–Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2--patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.

Published
2021

13. The Hyaluronic Acid–CD44 Interaction in the Physio- and Pathological Stem Cell Niche

Author

Ina Sevic, Daiana Lujan Vitale, Laura Alaniz, Luciana M. Gutierrez, Fiorella Mercedes Spinelli, Marcela F. Bolontrade, and Matías Valenzuela Alvarez

Subjects
Extracellular matrix, Haematopoiesis, chemistry.chemical_compound, Stromal cell, biology, Chemistry, Cancer stem cell, CD44, Hyaluronic acid, Niche, biology.protein, Stem cell, Cell biology
Abstract

The CD44 protein is a single-chain transmembrane glycoprotein able to bind several ligands. Hyaluronic acid is its main ligand and this interaction is the most extensively studied. Hyaluronic acid, as a component of the extracellular matrix, through CD44 is able to modulate several mechanisms that control stem cell behavior, such as migration and anchorage, efflux of toxic compounds, growth in hypoxic conditions and quiescence, besides their self-renewal and differentiation potential. In this chapter we describe the hyaluronic acid–CD44 interaction as part of the communication between the extracellular matrix and different cells that belong to the stem niche, focusing on the hematopoietic and adipose niche. Finally, we discuss the role of these interactions in the transformation of the normal stem niche to a tumorigenic niche that allows the development of cancer stem cells.

Published
2021
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14. Knockdown Of Udp-Glucose Dehydrogenase Facilitates Epirubicin-Resistance In MDA-MB-231 Breast Cancer Cells By Regulation Of Hyaluronan Synthesis

Author

Daiana L. Vitale, Ilaria Caon, Arianna Parnigoni, Ina Sevic, Fiorella M. Spinelli, Antonella Icardi, Alberto Passi, Davide Vigetti, and Laura Daniela Alaniz

Abstract

Background: The catalytic action of the UDP-glucose transferase dehydrogenase (UGDH) enzyme produces UDP-glucuronic acid (UDP-GlcUA). The main detoxifying pathway of Epirubicin (EPI) is via glucuronidation by the specific transferase UGT2B7 (UDP-Glucuronosyltransferase-2B7), adding UDP-GlcUA to generates 4´-O-b-D-glucuronyl-4´-epi-doxorubicin. UDP-GlcUA is also a precursor of several glycosaminoglycans (GAGs) like hyaluronan (HA). Therefore, the EPI detoxifying pathway might be associated with GAGs metabolism, related to drug deactivation and tumor resistance. This work aimed to evaluate the effect of knockdown on the UGDH gene on EPI response and HA metabolism in the aggressive breast cancer cells MDA-MB 231. Methods: MDA-MB-231 cells were transfected in vitro with UGDH-specific siRNA for UGDH knockdown and treated with EPI. Viability, apoptosis, and cytotoxicity effects were evaluated. EPI intracellular accumulation was analyzed by flow cytometry. Differences in extracellular matrix (ECM) were analyzed through a particle exclusion assay and the composition of HA using hyaluronidase. The soluble HA secreted was detected by an ELISA like assay. Besides, gene expression of HA synthase and hyaluronidase (HYAL) enzymes were analyzed by RT-qPCR. To analyze the effect of UGDH knockdown and EPI treatment on autophagy, we evaluated the expression of the autophagosome marker, LC3-II by RT-qPCR and western blot, and its subcellular localization by confocal microscopy. Results: EPI accumulation increased during UGDH knockdown, but it was observed a decrease in cell death. HA synthesis and HA coated around the cells increased. In turn, it was found up-regulation of the expression of HYALs. Within the mechanisms activated by tumor cells to avoid EPI activity, an increase in autophagy was detected. Conclusions: for the first time we show that an increase in the expression, deposition and catabolism of HA positively contributed to the development of a resistant phenotype in breast cancer cells by a mechanism associated to sugar metabolism, specifically of UDP-GlcUA .

Published
2020
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15. Analysis of fitness differences of hepatitis B virus genotypes D and F using a cotransfection assay

Author

María Mora González López Ledesma, Rodolfo Hector Campos, Ina Sevic, María Mercedes Elizalde, and Diego Martin Flichman

Subjects
Hepatitis B virus, HBsAg, FITNESS, Genotype, HEPATITIS B VIRUS, Mutant, Biology, Transfection, Virus Replication, medicine.disease_cause, GENOTYPE D, Ciencias Biológicas, 03 medical and health sciences, Virology, Extracellular, medicine, Humans, Hepatitis B e Antigens, GENOTYPE F, 030304 developmental biology, 0303 health sciences, Hepatitis B Surface Antigens, Coinfection, 030306 microbiology, virus diseases, General Medicine, Hepatitis B, digestive system diseases, MUTANTS, HBeAg, Virología, CIENCIAS NATURALES Y EXACTAS, Intracellular
Abstract

Hepatitis B virus (HBV) circulates as a collection of genetically related variants that evolve throughout the chronic infection. Those viral variants that have the greatest ftness are fxed. We recently showed diferent ftness for HBV variants involved in two epidemiological situations. To understand these ftness diferences better, we determined the levels of extracellular HBV DNA, the synthesis of HBV DNA intermediates, and the expression of HBeAg and HBsAg in transfection and cotransfection assays. Our results show that for the subgenotype (sgt) D1, which has an 8-nucleotide deletion (sgtD1del) and exhibits lower ftness, the levels of extracellular DNA and intracellular replicative intermediates were much lower than with sgtD1wt or sgtD1mut (G1896A), which had higher ftness. In addition, in the cotransfection assay, sgtD1del inhibited sgtD1mut but not sgtD1wt replication. We also found that sgtF1b, which exhibits higher ftness, produces signifcantly higher levels of both extracellular DNA and intracellular replicative intermediates than does the lower-ftness sgtF4. These results demonstrate a relationship between ftness and the replicative ability of the HBV genome in the transfection assay. In addition, the data obtained by cotransfecting cells with sgtD1del and sgtD1mut provide new information about the impact of simultaneous replication of two viral variants in the same cell system on HBV replication. Fil: Sevic, Ina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Inmunología; Argentina Fil: Elizalde, Maria Mercedes. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: González López Ledesma, María Mora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Inmunología; Argentina Fil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Inmunología; Argentina Fil: Campos, Rodolfo Hector. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Published
2018
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16. Human hepatocytes apoptosis induced by replication of hepatitis B virus subgenotypes F1b and F4: Role of basal core promoter and preCore mutations

Author

Ina Sevic, María Mercedes Elizalde, Luciana Fernanda Barbini, Rodolfo Hector Campos, María Mora González López Ledesma, and Diego Martin Flichman

Subjects
PRECORE MUTATION, 0301 basic medicine, Hepatitis B virus, Programmed cell death, CIENCIAS MÉDICAS Y DE LA SALUD, HEPATITIS B VIRUS, PATHOGENESIS, Mutant, Apoptosis, Context (language use), Biology, Virus Replication, medicine.disease_cause, Virus, Cell Line, 03 medical and health sciences, 0302 clinical medicine, SUBGENOTYPE F1B, Virology, medicine, Humans, Promoter Regions, Genetic, BASAL CORE PROMOTER MUTATIONS, virus diseases, Bioquímica y Biología Molecular, Hepatitis B Core Antigens, Molecular biology, digestive system diseases, APOPTOSIS, Medicina Básica, 030104 developmental biology, HBeAg, Viral replication, Mutation, SUBGENOTYPE F4, Hepatocytes, 030211 gastroenterology & hepatology
Abstract

In the context of pathogenesis of HBV infection, HBV genotypes and mutants have been shown to affect the natural course of chronic infection and treatment outcomes. In this work, we studied the induction of apoptosis by the replication of HBV subgenotypes F1b and F4, and the naturally occurring mutants BCP and preCore. Both subgenotypes F1b and F4 HBV genome transfections induced cell death by apoptosis in human hepatocytes. The BCPdm (A1762T/G1764A) and preCore (G1896A) mutants induced higher levels of apoptosis than the wt virus. This increase in apoptosis was not associated with the enhanced viral replication of the variants. HBV-mediated apoptosis was independent of viral subgenotypes, and associated with the modulation of members of the regulatory Bcl-2 family proteins expression in the mitochondrial apoptotic pathway. Finally, the apoptosis induction increase observed for the preCore mutants suggests that HBeAg might have an anti-apoptotic effect in human hepatocytes. Fil: Elizalde, Maria Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina Fil: Sevic, Ina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: González López Ledesma, María Mora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina Fil: Campos, Rodolfo Hector. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina Fil: Barbini, Luciana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Flichman, Diego Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Published
2018
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17. Hyaluronan in the Tumor Microenvironment

Author

Daiana Lujan Vitale, Laura Alaniz, Fiorella Mercedes Spinelli, and Ina Sevic

Subjects
Tumor microenvironment, biology, Chemistry, DNA damage, CD44, Cell biology, carbohydrates (lipids), Glycosaminoglycan, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer stem cell, biology.protein, Extracellular, 030212 general & internal medicine
Abstract

The extracellular matrix is part of the microenvironment and its functions are associated with the physical and chemical properties of the tissue. Among the extracellular components, the glycosaminoglycan hyaluronan is a key component, defining both the physical and biochemical characteristics of the healthy matrices. The hyaluronan metabolism is strictly regulated in physiological conditions, but in the tumoral tissues, its expression, size and binding proteins interaction are dysregulated. Hyaluronan from the tumor microenvironment promotes tumor cell proliferation, invasion, immune evasion, stemness alterations as well as drug resistance. This chapter describes data regarding novel concepts of hyaluronan functions in the tumor. Additionally, we discuss potential clinical applications of targeting HA metabolism in cancer therapy.

Published
2020
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18. The Role of the Tumor Microenvironment in the Development and Progression of Hepatocellular Carcinoma

Author

Andrea Reszegi, Ina Sevic, Laura Alaniz, Fiorella Mercedes Spinelli, Ilona Kovalszky, Mariana Garcia, and María José Cantero

Subjects
Tumor microenvironment, Stromal cell, Mesenchymal stem cell, Hepatocellular Carcinoma, Bioquímica y Biología Molecular, medicine.disease, purl.org/becyt/ford/1 [https], Ciencias Biológicas, Extracellular matrix, chemistry.chemical_compound, Immune system, chemistry, Hepatocellular carcinoma, Hyaluronic acid, medicine, Hepatic stellate cell, Cancer research, purl.org/becyt/ford/1.6 [https], Hyaluronan, CIENCIAS NATURALES Y EXACTAS
Abstract

There is a growing evidence that supports the role of the tumor microenvironment (TME) in the development and progression of cancer. TME is composed of cellular components, bioactive substances (e.g. growth factors) and extracellular matrix (ECM) comprising of proteins such as collagens, proteoglycans and the linear glycosaminoglycan hyaluronan, which is a key component of ECM. Hepatocellular carcinoma (HCC), generally arises from fibrotic or cirrhotic liver, characterized by excessive expression and alteration of ECM components which facilitates tumor development. On the other hand, non-tumoral cells, as such as the mesenchymal stem/stromal cells (MSCs) are typically recruited to the injured or hypoxic area within the tumor. Besides the secretion of immunoregulatory, growth factors and cytokines, MSCs and hepatic stellate cells (HSCs) can also synthesize hyaluronan, amongst other components, that affects several tumor processes. The TME also contains different types of immune cells. A key component in tumorigenesis in HCC are the macrophages, as tumor-associated macrophages (TAM). This chapter will describe specific data regarding the interaction of MSCs-hyaluronan-TAMs and tumor cells and how this interaction potentially contributes to the development and progression of HCC. Fil: Sevic, Ina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Spinelli, Fiorella Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Cantero, María José. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Reszegi, Andrea. Semmelweis University; Hungría Fil: Kovalszky, Ilona. Semmelweis University; Hungría Fil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina

Published
2019
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19. Hyaluronan preconditioning of monocytes/macrophages affects their angiogenic behavior and regulation of TSG-6 expression in a tumor type-specific manner

Author

Virginia Saturno, Antonella Icardi, Alejandra Brandone, Fiorella Mercedes Spinelli, Alberto Passi, Laura Alaniz, Ilaria Caon, Mariana Garcia, Paula Giannoni, Daiana Lujan Vitale, and Ina Sevic

Subjects
0301 basic medicine, Vascular Endothelial Growth Factor A, CIENCIAS MÉDICAS Y DE LA SALUD, Angiogenesis, HYALURONAN, Ciencias de la Salud, Breast Neoplasms, Biology, Monocyte-Macrophage Precursor Cells, BREAST CARCINOMA, Biochemistry, ANGIOGENESIS, 03 medical and health sciences, Mice, purl.org/becyt/ford/3.3 [https], 0302 clinical medicine, Cell Line, Tumor, Monocytes macrophages, Animals, Humans, Tumor type, Hyaluronic Acid, TSG-6, Molecular Biology, Neovascularization, Pathologic, Carcinoma, Interleukin-8, MONOCYTES/MACROPHAGES, Cell Biology, 3. Good health, Otras Ciencias de la Salud, 030104 developmental biology, 030220 oncology & carcinogenesis, Culture Media, Conditioned, Cancer research, Matrix Metalloproteinase 2, Female, Fibroblast Growth Factor 2, purl.org/becyt/ford/3 [https], COLORECTAL CARCINOMA, Breast carcinoma, Colorectal Neoplasms, Cell Adhesion Molecules
Abstract

Hyaluronan is a glycosaminoglycan normally present in the extracellular matrix in most tissues. Hyaluronan is a crucial player in many processes associated with cancer, such as angiogenesis, invasion and metastasis. However, little has been reported regarding the action of hyaluronan on monocytes/macrophages in tumor angiogenesis and its consequences on tumor development. In the present study, we investigated the effects of hyaluronan of different sizes on human monocytes/macrophages angiogenic behavior in colorectal and breast carcinoma. In vitro, treatment of monocytes/macrophages with lysates and conditioned media from a breast, but not from colorectal, carcinoma cell line plus high molecular weight hyaluronan induced: i) an increased expression of angiogenic factors VEGF, IL‐8, FGF‐2 and MMP‐2, ii) increased endothelial cell migration and iii) a differential expression of hyaluronan‐binding protein TSG‐6. Similar results were observed in monocytes/macrophages derived from breast cancer patients treated with tumor lysates. Besides, macrophages primed with high molecular weight hyaluronan and inoculated in human breast cancer xenograft tumor increased blood vessel formation and diminished TSG‐6 levels. In contrast, the effects triggered by high molecular weight hyaluronan on monocytes/macrophages in breast cancer context were not observed in the context of colorectal carcinoma. Taken together, these results indicate that the effect of high molecular weight hyaluronan as an inductor of the angiogenic behavior of macrophages in breast tumor context is in part consequence of the presence of TSG‐6. Fil: Spinelli, Fiorella Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Vitale, Daiana Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Icardi, Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Caon, Ilaria. Università degli Studi dell’Insubria; Italia Fil: Brandone, Alejandra. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Doctor Abraham Felix Piñeyro.; Argentina Fil: Giannoni, Ana Paula. No especifíca; Fil: Saturno, Maria Virginia. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Passi, Alberto. Università degli Studi dell’Insubria; Italia Fil: García, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Sevic, Ina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina

Published
2019
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20. Molecular epidemiology of hepatitis B virus in Misiones, Argentina

Author

Domingo Javier Liotta, Rodolfo Hector Campos, Laura Noelia Mojsiejczuk, Ina Sevic, Ines Badano, Richard Malan, Diego Martin Flichman, and Carolina Torres

Subjects
0301 basic medicine, Microbiology (medical), Hepatitis B virus, Genotype, 030106 microbiology, Argentina, Biology, medicine.disease_cause, Microbiology, Coalescent theory, 03 medical and health sciences, Phylogenetics, Genetics, medicine, Humans, Promoter Regions, Genetic, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Phylogeny, Molecular Epidemiology, Molecular epidemiology, Phylogenetic tree, Genetic Variation, Bayes Theorem, Hepatitis B, medicine.disease, Virology, 030104 developmental biology, Infectious Diseases, Genetic distance, Mutation
Abstract

Hepatitis B virus (HBV) infection is a major public health problem worldwide. The aims of this study were to describe the molecular epidemiology of HBV in the Province of Misiones, Argentina and estimate the phylodynamic of the main groups in a Bayesian coalescent framework. To this end, partial or complete genome sequences were obtained from 52 blood donor candidates. The phylogenetic analysis based on partial sequences of S/P region showed a predominance of genotype D (65.4%), followed by genotype F (30.8%) and genotype A as a minority (3.8%). At subgenotype level, the circulation of subgenotypes D3 (42.3%), D2 (13.5%), F1b (11.5%) and F4 (9.6%) was mainly identified. The Bayesian coalescent analysis of 29 complete genome sequences for the main groups revealed that the subgenotypes D2 and D3 had several introductions to the region, with ancestors dating back from 1921 to 1969 and diversification events until the late '70s. The genotype F in Misiones has a more recent history; subgenotype F4 isolates were intermixed with sequences from Argentina and neighboring countries and only one significant cluster dated back in 1994 was observed. Subgenotype F1b isolates exhibited low genetic distance and formed a closely related monophyletic cluster, suggesting a very recent introduction. In conclusion, the phylogenetic and coalescent analyses showed that the European genotype D has a higher circulation, a longer history of diversification and may be responsible for the largest proportion of chronic HBV infections in the Province of Misiones. Genotype F, especially subgenotype F1b, had a more recent introduction and its diversification in the last 20years might be related to its involvement in new transmission events.

Published
2015

21. Hepatitis B virus genotype distribution and genotype-specific BCP/preCore substitutions in acute and chronic infections in Argentina

Author

Laura Noelia Mojsiejczuk, Rodolfo Hector Campos, Diego Martin Flichman, Lilia Mammana, Adrián Gadano, Omar Galdame, María Mora González López Ledesma, Ina Sevic, Hugo Fainboim, and Belén Rodrigo

Subjects
Hepatitis B virus genotype, Hepatitis B virus, Genotype, Molecular Sequence Data, Argentina, lcsh:Medicine, Biology, medicine.disease_cause, Amino acid analysis, Species Specificity, Computer software, Prevalence, medicine, Humans, Base sequence, Promoter Regions, Genetic, lcsh:Science, Analysis of Variance, Multidisciplinary, Base Sequence, lcsh:R, virus diseases, Sequence Analysis, DNA, Hepatitis B, medicine.disease, Virology, Molecular biology, Cross-Sectional Studies, Mutation, lcsh:Q, Research Article
Abstract

Aim In order to assess Hepatitis B Virus genotype (g) and subgenotype (sg) implications in the course of infection, 234 HBsAg positive patients in different infection stages were characterized (66 acute infections, 63 HBeAg positive chronic infections and 105 anti-HBe positive chronic infections). Results Overall, sgA2 (17.9%), gD (20.9%), sgF1b (34.2%) and sgF4 (19.7%) were the most prevalent. Subgenotype F1b was overrepresented in acute and chronic HBeAg infections (56.1%), whereas gD was the most frequent (40.0%) in anti-HBe positive chronic infections. Among chronic infections, HBeAg positivity rates were 50.0, 12.5, 62.8 and 35.3% for sgA2, gD, sgF1b and sgF4, respectively (p

Published
2015

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