Publications by authors named "Laura Sánchez"

196 Publications

Triazole-Based Half-Sandwich Ruthenium(II) Compounds: From Antiproliferative Potential to Toxicity Evaluation.

Inorg Chem 2021 Jun 11;60(11):8011-8026. Epub 2021 May 11.

Instituto de Tecnologia Química e Biológica António Xavier, ITQB NOVA, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal.

A new series of half-sandwich ruthenium(II) compounds [(η-arene)Ru(L)Cl][CFSO] bearing 1,2,3-triazole ligands (arene = -cymene, L = (); arene = -cymene, L = (); arene = benzene, L = (); arene = benzene, (); = 2-[1-(-tolyl)-1-1,2,3-triazol-4-yl]pyridine and = 1,1'-di--tolyl-1,1'-4,4'-bi(1,2,3-triazole) have been synthesized and fully characterized by H and C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of , , and have been determined by single-crystal X-ray diffraction. The cytotoxic activity of - was evaluated using the MTS assay against human tumor cells, namely ovarian carcinoma (A2780), colorectal carcinoma (HCT116), and colorectal carcinoma resistant to doxorubicin (HCT116dox), and against normal primary fibroblasts. Whereas compounds and showed no cytotoxic activity toward tumor cell lines, compounds and were active in A2780, while showing no antiproliferative effect in human normal dermal fibroblasts at the IC concentrations of the A2780 cell line. Exposure of ovarian carcinoma cells to IC concentrations of compound or led to an accumulation of reactive oxygen species and an increase of apoptotic and autophagic cells. While compound displayed low levels of angiogenesis induction, compound showed an ability to induce cell cycle delay and to interfere with cell migration. When the toxicity studies using zebrafish and chicken embryos are considered, compounds and , which were not lethal, are promising candidates as anticancer agents against ovarian cancer due to their good cytotoxic activity in tumor cells and their low toxicity both and .
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http://dx.doi.org/10.1021/acs.inorgchem.1c00527DOI Listing
June 2021

Development and characterization of two equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19.

Sci Rep 2021 05 10;11(1):9825. Epub 2021 May 10.

Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, San José, Costa Rica.

In the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited high in vitro neutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.
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http://dx.doi.org/10.1038/s41598-021-89242-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110969PMC
May 2021

Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model.

Sci Rep 2021 May 10;11(1):9873. Epub 2021 May 10.

Nano-Oncology and Translational Therapeutics Unit, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital of Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain.

Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells' proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.
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http://dx.doi.org/10.1038/s41598-021-87968-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110995PMC
May 2021

A Family of Nonribosomal Peptides Modulate Collective Behavior in Pseudovibrio Bacteria Isolated from Marine Sponges*.

Angew Chem Int Ed Engl 2021 May 7. Epub 2021 May 7.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.

Although swarming motility and biofilms are opposed collective behaviors, both contribute to bacterial survival and host colonization. Pseudovibrio bacteria have attracted attention because they are part of the microbiome of healthy marine sponges. Two-thirds of Pseudovibrio genomes contain a member of a nonribosomal peptide synthetase-polyketide synthase gene cluster family, which is also found sporadically in Pseudomonas pathogens of insects and plants. After developing reverse genetics for Pseudovibrio, we isolated heptapeptides with an ureido linkage and related nonadepsipeptides we termed pseudovibriamides A and B, respectively. A combination of genetics and imaging mass spectrometry experiments showed heptapetides were excreted, promoting motility and reducing biofilm formation. In contrast to lipopeptides widely known to affect motility/biofilms, pseudovibriamides are not surfactants. Our results expand current knowledge on metabolites mediating bacterial collective behavior.
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http://dx.doi.org/10.1002/anie.202017320DOI Listing
May 2021

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion.

Cancers (Basel) 2021 Apr 16;13(8). Epub 2021 Apr 16.

Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.
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http://dx.doi.org/10.3390/cancers13081925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073317PMC
April 2021

Zebrafish Models of Autosomal Recessive Ataxias.

Cells 2021 Apr 8;10(4). Epub 2021 Apr 8.

Department of Zoology, Genetics and Physical Anthropology, Faculty of Veterinary Science, Universidade de Santiago de Compostela, 27002 Lugo, Spain.

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.
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http://dx.doi.org/10.3390/cells10040836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068028PMC
April 2021

Comparative anatomo-radiological study of intrahepatic venous vascularization in the Spain.

Ann Anat 2021 Sep 22;237:151740. Epub 2021 Apr 22.

Institute of Clinical and Functional Anatomy, Medical University of Innsbruck (MUI), Innsbruck, Austria. Electronic address:

Background: Anatomic variations in the hepatic venous system are the least understood aspect of hepatic anatomy. The variations are diverse, and data are lacking with respect to the population of Spain and methods of detection. The objective was to examine morphological patterns of variations in hepatic venous vascularization using cadaveric dissections vs. radiological imaging, and to analyze the findings with respect to Spain and to published studies.

Methods: Thirty-one livers were anatomically dissected and analyzed for their hepatic venous anatomy and then compared to the venous anatomy of livers examined in 216 CT scans from 119 men and 97 women, ranging between 27 and 89 years of age. Statistical analysis was done using the Chi squared and Fisher homogeneity tests.

Results: The hepatic portal vein showed morphological variations in cadavers vs. CT of 67.3% vs. 67.6% (p-I), 29% vs. 12.2% (p-II), 0% vs. 14.6% (p-III), 0% vs. 14.6% (p-IV), 3.2% vs. 0.5% (p-V) and 6.5% vs. 1.9% (p-VI), respectively in cadavers vs. CT. Hepatic vein pattern variation were found in 64.5% vs. 50.7% (h-I), 32.2% vs. 31.5% (h-II), 0% vs. 2.3% (h-III), 0% vs. 4.7% (h-IV), respectively in dissections vs. CT). In Accessory Hepatic Veins the frequency in pattern variation was 64.5% vs. 18.8% (a-2.1), 29.0% vs. 8.0% (a-2.2), 58.1% vs. 11.3% (a-2.3), 9.7% vs. 0.9% (a-2.4), 67.7% vs. 16.9% (a-2.5), 9.7% vs. 4.2% (a-2.6) and 0% vs. 0.5% (a-2.7), respectively, in cadavers vs. CT. CT showed in 27.2% no accessory hepatic veins. Sex was not a factor influencing patterns of variation.

Conclusion: Anatomical variants of the hepatic portal vein, the hepatic vein and accessory hepatic veins are very diverse and show greater variability in the specimens compared to those detected with radiological images, finding a wider spectrum of variations as it allows the clinician to have a more precise definition of the vasculature. A higher precision in the definition of anatomical variations is warranted for surgical planning in liver resection and transplantation.
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http://dx.doi.org/10.1016/j.aanat.2021.151740DOI Listing
September 2021

A comprehensive structural, lectin and immunohistochemical characterization of the zebrafish olfactory system.

Sci Rep 2021 Apr 23;11(1):8865. Epub 2021 Apr 23.

Department of Zoology, Genetics and Physical Anthropology, Faculty of Veterinary, University of Santiago de Compostela, Lugo, Spain.

Fish chemosensory olfactory receptors allow them to detect a wide range of water-soluble chemicals, that mediate fundamental behaviours. Zebrafish possess a well-developed sense of smell which governs reproduction, appetite, and fear responses. The spatial organization of functional properties within the olfactory epithelium and bulb are comparable to those of mammals, making this species suitable for studies of olfactory differentiation and regeneration and neuronal representation of olfactory information. The advent of genomic techniques has been decisive for the discovery of specific olfactory cell types and the identification of cell populations expressing vomeronasal receptors. These advances have marched ahead of morphological and neurochemical studies. This study aims to fill the existing gap in specific histological, lectin-histochemical and immunohistochemical studies on the olfactory rosette and the olfactory bulb of the zebrafish. Tissue dissection and microdissection techniques were employed, followed by histological staining techniques, lectin-histochemical labelling (UEA, LEA, BSI-B) and immunohistochemistry using antibodies against G proteins subunits αo and αi2, growth-associated protein-43, calbindin, calretinin, glial-fibrillary-acidic-protein and luteinizing-hormone-releasing-hormone. The results obtained enrich the available information on the neurochemical patterns of the zebrafish olfactory system, pointing to a greater complexity than the one currently considered, especially when taking into account the peculiarities of the nonsensory epithelium.
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http://dx.doi.org/10.1038/s41598-021-88317-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065131PMC
April 2021

Atypical presentation of immunoglobulin G4-related disease as subglottic stenosis: a case-based review.

Rheumatol Int 2021 Jun 8;41(6):1161-1167. Epub 2021 Apr 8.

Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, Avda. Valdecilla s/n, 39008, Santander, Spain.

Background: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory pathology that has been reported to affect principally the retroperitoneum, hepatobiliary system, salivary glands, orbital structures or lymph nodes. However, IgG4-RD with laryngeal involvement is a very rare entity. Our aims were to describe a case of subglottic stenosis as first and only manifestation of IgG4-RD and review the literature. A patient with IgG4-RD affecting the larynx that presented as subglottic stenosis is described. A MEDLINE database search of IgG4-RD cases with laryngopharyngeal manifestations was also conducted. A 30-year-old Caucasian woman was referred to a tertiary care hospital for dyspnea on exertion, which had been increasing for the last 4 months. Medical and surgical procedures revealed a subglottic stenosis, with a histological finding of IgG4 positive plasma cell infiltration. There was no evidence of other organ involvement. She was successfully treated with oral glucocorticoids and rituximab infusions. Glucocorticoids were rapidly tapered and the rituximab regimen was optimized, with no evidence of relapses. In the literature review, we found a total of 12 reported cases with laryngopharyngeal involvement, two of them with subglottic stenosis. IgG4-RD of the larynx is rare but should be considered after excluding more common disorders.
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http://dx.doi.org/10.1007/s00296-021-04816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079302PMC
June 2021

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments.

Cancers (Basel) 2021 Mar 3;13(5). Epub 2021 Mar 3.

Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain.

Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood-brain-barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBM.
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http://dx.doi.org/10.3390/cancers13051087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961726PMC
March 2021

VATS Lobectomy Morbidity and Mortality is Lower in Patients with the Same ppoDLCO: Analysis of the Database of the Spanish Video-Assisted Thoracic Surgery Group.

Arch Bronconeumol (Engl Ed) 2021 Feb 13. Epub 2021 Feb 13.

Servicio de Cirugía Torácica, Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza, España; Servicio de Cirugía Torácica, Hospital Clínico Universitario Lozano Blesa, IIS Aragón, Zaragoza, España.

Introduction: Measuring predicted post-operative diffusion capacity of the lung for carbon monoxide (ppoDLCO) is essential to determine patient operability and to stratify the risk of patients who are candidates for major lung cancer surgery. Studies that established surgical risk variables were based on open surgery series. The aim of our study was to analyze morbidity and mortality as a function of ppoDLCO and to compare its behavior in open and video-assisted thoracic surgery (VATS).

Methods: We compared 90-day mortality and morbidity in patients undergoing open surgery versus VATS as a function of decline in ppoDLCO. Propensity score matching (using age, ASA, arterial vascular disease, BMI, sexo, stage, ppoDLCO, and ppoFEV) was applied to create comparable open surgery and VATS groups.

Results: Of 2,530 patients with lung cancer and ppoDLCO values, a sample of 1,624 (812 per group) was obtained after score matching. The relative risk of mortality associated with thoracotomy in patients with ppoDLCO<60 is 2.66 (P<.02) compared to VATS. The risk of thoracotomy in terms of overall and cardiac and respiratory morbidity is higher than that of VATS for almost all ppoDLCO values.

Conclusions: Major resection by VATS shows lower morbidity and mortality in patients with the same ppoDLCO. A steady rise in the risk of mortality begins to occur at higher ppoDLCO values in thoracotomy (∼60) than in VATS (∼45).
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http://dx.doi.org/10.1016/j.arbres.2021.01.030DOI Listing
February 2021

A Small Molecule Coordinates Symbiotic Behaviors in a Host Organ.

mBio 2021 03 9;12(2). Epub 2021 Mar 9.

Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA

The lifelong relationship between the Hawaiian bobtail squid and its microbial symbiont represents a simplified model system for studying microbiome establishment and maintenance. The bacteria colonize a dedicated symbiotic light organ in the squid, from which bacterial luminescence camouflages the host in a process termed counterillumination. The squid host hatches without its symbionts, which must be acquired from the ocean amidst a diversity of nonbeneficial bacteria, such that precise molecular communication is required for initiation of the specific relationship. Therefore it is likely there are specialized metabolites used in the light organ microenvironment to modulate these processes. To identify small molecules that may influence the establishment of this symbiosis, we used imaging mass spectrometry to analyze metabolite production in with altered biofilm production, which correlates directly to colonization capability in its host. "Biofilm-up" and "biofilm-down" mutants were compared to a wild-type strain, and ions that were more abundantly produced by the biofilm-up mutant were detected. Using a combination of structural elucidation and synthetic chemistry, one such signal was determined to be a diketopiperazine, cyclo(d-histidyl-l-proline). This diketopiperazine modulated luminescence in and, using imaging mass spectrometry, was directly detected in the light organ of the colonized host. This work highlights the continued need for untargeted discovery efforts in host-microbe interactions and showcases the benefits of the squid- system for identification and characterization of small molecules that modulate microbiome behaviors. The complexity of animal microbiomes presents challenges to defining signaling molecules within the microbial consortium and between the microbes and the host. By focusing on the binary symbiosis between and , we have combined genetic analysis with direct imaging to define and study small molecules in the intact symbiosis. We have detected and characterized a diketopiperazine produced by strong biofilm-forming strains that was detectable in the host symbiotic organ, and which influences bacterial luminescence. Biofilm formation and luminescence are critical for initiation and maintenance of the association, respectively, suggesting that the compound may link early and later development stages, providing further evidence that multiple small molecules are important in establishing these beneficial relationships.
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http://dx.doi.org/10.1128/mBio.03637-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092321PMC
March 2021

Zebrafish Models of Autosomal Dominant Ataxias.

Cells 2021 Feb 17;10(2). Epub 2021 Feb 17.

Department of Zoology, Genetics and Physical Anthropology, Faculty of Veterinary Science, Universidade of Santiago de Compostela, 27002 Lugo, Spain.

Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal disorders due to its conserved vertebrate genetics that easily support genetic edition and their optic transparency that allows observing the intact CNS and its connections. In addition, its small size and external fertilization help to develop high throughput assays of candidate drugs. Here, we discuss the contributions of zebrafish models to the study of dominant ataxias defining phenotypes, genetic function, behavior and possible treatments. In addition, we review the zebrafish models created for X-linked repeat expansion diseases X-fragile/fragile-X tremor ataxia. Most of the models reviewed here presented neuronal damage and locomotor deficits. However, there is a generalized lack of zebrafish adult heterozygous models and there are no knock-in zebrafish models available for these diseases. The models created for dominant ataxias helped to elucidate gene function and mechanisms that cause neuronal damage. In the future, the application of new genetic edition techniques would help to develop more accurate zebrafish models of dominant ataxias.
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http://dx.doi.org/10.3390/cells10020421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922657PMC
February 2021

Loss of Active Neurogenesis in the Adult Shark Retina.

Front Cell Dev Biol 2021 11;9:628721. Epub 2021 Feb 11.

Departamento de Bioloxía Funcional, Facultade de Bioloxía, CIBUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.

Neurogenesis is the process by which progenitor cells generate new neurons. As development progresses neurogenesis becomes restricted to discrete neurogenic niches, where it persists during postnatal life. The retina of teleost fishes is thought to proliferate and produce new cells throughout life. Whether this capacity may be an ancestral characteristic of gnathostome vertebrates is completely unknown. Cartilaginous fishes occupy a key phylogenetic position to infer ancestral states fixed prior to the gnathostome radiation. Previous work from our group revealed that the juvenile retina of the catshark , a cartilaginous fish, shows active proliferation and neurogenesis. Here, we compared the morphology and proliferative status of the retina in catshark juveniles and adults. Histological and immunohistochemical analyses revealed an important reduction in the size of the peripheral retina (where progenitor cells are mainly located), a decrease in the thickness of the inner nuclear layer (INL), an increase in the thickness of the inner plexiform layer and a decrease in the cell density in the INL and in the ganglion cell layer in adults. Contrary to what has been reported in teleost fish, mitotic activity in the catshark retina was virtually absent after sexual maturation. Based on these results, we carried out RNA-Sequencing (RNA-Seq) analyses comparing the retinal transcriptome of juveniles and adults, which revealed a statistically significant decrease in the expression of many genes involved in cell proliferation and neurogenesis in adult catsharks. Our RNA-Seq data provides an excellent resource to identify new signaling pathways controlling neurogenesis in the vertebrate retina.
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http://dx.doi.org/10.3389/fcell.2021.628721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905061PMC
February 2021

Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, 50009 Zaragoza, Spain.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133 CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential.
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http://dx.doi.org/10.3390/cancers13040698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914708PMC
February 2021

Morphological Abnormalities and Gene Expression Changes Caused by High Incubation Temperatures in Zebrafish Xenografts with Human Cancer Cells.

Genes (Basel) 2021 Jan 19;12(1). Epub 2021 Jan 19.

Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain.

Published studies show that most of the human cancer xenograft studies in zebrafish embryos have used incubation temperatures in the range of 32-34 °C for 3-6 days post-injection, trying to find a compromise temperature between the zebrafish embryos (28 °C) and the human injected cells (37 °C). While this experimental setup is widely used, a question remains: is possible to overcome the drawbacks caused by a suboptimal temperature for the injected cells? To clarify the effect of temperature and injected cells on the host, in this study, we analyzed the development and health of the last in response to different temperatures in the presence or absence of injected human cancer cells. Comparing different incubation temperatures (28, 34 and 36 °C), we determined morphological abnormalities and developmental effects in injected and non-injected embryos at different time points. Besides this, the expression of selected genes was determined by qPCR to determine temperature affected metabolic processes in the embryos. The results indicate that an incubation temperature of 36 °C during a period of 48 h is suitable for xenotransplantation without morphological or metabolic changes that could be affecting the host or the injected cells, allowing them to proliferate near their optimal temperature.
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http://dx.doi.org/10.3390/genes12010113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832305PMC
January 2021

Randomised trial of dobutamine versus placebo for low superior vena cava flow in preterm infants: Long-term neurodevelopmental outcome.

J Paediatr Child Health 2021 06 19;57(6):872-876. Epub 2021 Jan 19.

Department of Neonatology, Hospital Universitario La Paz, Madrid, Spain.

Aim: Although circulatory impairment during the transitional circulation associates morbidity and mortality, its treatment remains controversial. In a pilot trial on circulatory impairment defined as low superior vena cava (SVC) flow, dobutamine (Db) versus placebo (PL) showed a trend towards improved short-term outcomes. The purpose of this study was to report on the long-term outcome of the infants who were observed for SVC flow patterns.

Methods: Among the 126 infants <31 weeks of gestation prospectively scanned from birth, 28 presented low SVC flow within the first 24 h after birth and received Db (n = 16) or PL (n = 12). Follow-up of survivors included motor assessment and Bayley Scales II or III at 2 years, and the Reynolds Intellectual Assessment Scale at 6 years. Neurodevelopmental impairment (NDI) was defined as: cerebral palsy (Gross Motor Function Classification System ≥ level 2), or a cognitive function score < -2 standard deviations; or moderate or severe hearing or visual impairment. Db group, PL group and normal-flow group were compared.

Results: Eighteen infants died (Db: 5; PL: 2; normal flow group: 11, P = 0.1). Follow-up in survivors was accomplished in 80% and 55% of the cohort at 2 years and 6 years, respectively. No significant difference in the combined outcome (mortality or NDI) was found between the groups (42% Db, 36% PL, 30% normal flow group).

Conclusions: This exploratory analysis did not show any differences in the long-term outcome of infants according to SVC flow patterns or its treatment early after birth.
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http://dx.doi.org/10.1111/jpc.15344DOI Listing
June 2021

Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish.

Genes (Basel) 2020 11 20;11(11). Epub 2020 Nov 20.

Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain.

Autism Spectrum Disorders (ASD) affect around 1.5% of the global population, which manifest alterations in communication and socialization, as well as repetitive behaviors or restricted interests. ASD is a complex disorder with known environmental and genetic contributors; however, ASD etiology is far from being clear. In the past decades, many efforts have been put into developing new models to study ASD, both in vitro and in vivo. These models have a lot of potential to help to validate some of the previously associated risk factors to the development of the disorder, and to test new potential therapies that help to alleviate ASD symptoms. The present review is focused on the recent advances towards the generation of models for the study of ASD, which would be a useful tool to decipher the bases of the disorder, as well as to conduct drug screenings that hopefully lead to the identification of useful compounds to help patients deal with the symptoms of ASD.
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http://dx.doi.org/10.3390/genes11111376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699923PMC
November 2020

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition.

Nat Commun 2020 11 11;11(1):5712. Epub 2020 Nov 11.

GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada, Av. de la Ilustración, 114, 18016, Granada, Spain.

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.
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http://dx.doi.org/10.1038/s41467-020-19430-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658363PMC
November 2020

Bacterial-fungal interactions revealed by genome-wide analysis of bacterial mutant fitness.

Nat Microbiol 2021 01 2;6(1):87-102. Epub 2020 Nov 2.

Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.

Microbial interactions are expected to be major determinants of microbiome structure and function. Although fungi are found in diverse microbiomes, their interactions with bacteria remain largely uncharacterized. In this work, we characterize interactions in 16 different bacterial-fungal pairs, examining the impacts of 8 different fungi isolated from cheese rind microbiomes on 2 bacteria (Escherichia coli and a cheese-isolated Pseudomonas psychrophila). Using random barcode transposon-site sequencing with an analysis pipeline that allows statistical comparisons between different conditions, we observed that fungal partners caused widespread changes in the fitness of bacterial mutants compared to growth alone. We found that all fungal species modulated the availability of iron and biotin to bacterial species, which suggests that these may be conserved drivers of bacterial-fungal interactions. Species-specific interactions were also uncovered, a subset of which suggested fungal antibiotic production. Changes in both conserved and species-specific interactions resulted from the deletion of a global regulator of fungal specialized metabolite production. This work highlights the potential for broad impacts of fungi on bacterial species within microbiomes.
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http://dx.doi.org/10.1038/s41564-020-00800-zDOI Listing
January 2021

Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells.

Nat Commun 2020 10 16;11(1):5265. Epub 2020 Oct 16.

Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, Madrid, Spain.

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7-9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.
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http://dx.doi.org/10.1038/s41467-020-18954-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567808PMC
October 2020

Developmentally-programmed cellular senescence is conserved and widespread in zebrafish.

Aging (Albany NY) 2020 Sep 29;12(18):17895-17901. Epub 2020 Sep 29.

Laboratory of Stem Cells in Cancer and Aging, Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.

Cellular senescence is considered a stress response imposing a stable cell cycle arrest to restrict the growth of damaged cells. More recently however, cellular senescence was identified during mouse embryo development at particular structures during specific periods of time. This programmed cell senescence has been proposed to serve developmental and morphogenetic functions and to potentially represent an evolutionary origin of senescence. Cellular senescence has also been described to take place during bird (chick and quail) and amphibian (xenopus and axoltl) development. Fish however, have been described to show a very narrow and restricted pattern of developmental cell senescence. Here we carried out a detailed characterization of senescence during zebrafish development and found it to be conserved and widespread. Apart from yolk and cloaca, previously described structures, we also identified senescence in the developing central nervous system, intestine, liver, pronephric ducts, and crystalline. Interestingly, senescence at these developing structures disappeared upon treatment with senolytic compound ABT-263, supporting their senescent identity and opening the possibility of studying the contribution of this process to development. In summary, our findings extend the description of developmentally-programmed cell senescence to lower vertebrates contributing to the notion of the relevance of this process for embryo development.
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http://dx.doi.org/10.18632/aging.103968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585104PMC
September 2020

The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells.

Blood 2021 Feb;137(6):775-787

Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.

Hematopoietic and nervous systems are linked via innervation of bone marrow (BM) niche cells. Hematopoietic stem/progenitor cells (HSPCs) express neurotransmitter receptors, such as the γ-aminobutyric acid (GABA) type B receptor subunit 1 (GABBR1), suggesting that HSPCs could be directly regulated by neurotransmitters like GABA that directly bind to GABBR1. We performed imaging mass spectrometry and found that the endogenous GABA molecule is regionally localized and concentrated near the endosteum of the BM niche. To better understand the role of GABBR1 in regulating HSPCs, we generated a constitutive Gabbr1-knockout mouse model. Analysis revealed that HSPC numbers were significantly reduced in the BM compared with wild-type littermates. Moreover, Gabbr1-null hematopoietic stem cells had diminished capacity to reconstitute irradiated recipients in a competitive transplantation model. Gabbr1-null HSPCs were less proliferative under steady-state conditions and upon stress. Colony-forming unit assays demonstrated that almost all Gabbr1-null HSPCs were in a slow or noncycling state. In vitro differentiation of Gabbr1-null HSPCs in cocultures produced fewer overall cell numbers with significant defects in differentiation and expansion of the B-cell lineage. To determine whether a GABBR1 agonist could stimulate human umbilical cord blood (UCB) HSPCs, we performed brief ex vivo treatment prior to transplant into immunodeficient mice, with significant increases in long-term engraftment of HSPCs compared with GABBR1 antagonist or vehicle treatments. Our results indicate a direct role for GABBR1 in HSPC proliferation, and identify a potential target to improve HSPC engraftment in clinical transplantation.
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http://dx.doi.org/10.1182/blood.2019004415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885825PMC
February 2021

Modeling Cancer Using Zebrafish Xenografts: Drawbacks for Mimicking the Human Microenvironment.

Cells 2020 08 27;9(9). Epub 2020 Aug 27.

Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain.

The first steps towards establishing xenografts in zebrafish embryos were performed by Lee et al., 2005 and Haldi et al., 2006, paving the way for studying human cancers using this animal species. Since then, the xenograft technique has been improved in different ways, ranging from optimizing the best temperature for xenografted embryo incubation, testing different sites for injection of human tumor cells, and even developing tools to study how the host interacts with the injected cells. Nonetheless, a standard protocol for performing xenografts has not been adopted across laboratories, and further research on the temperature, microenvironment of the tumor or the cell-host interactions inside of the embryo during xenografting is still needed. As a consequence, current non-uniform conditions could be affecting experimental results in terms of cell proliferation, invasion, or metastasis; or even overestimating the effects of some chemotherapeutic drugs on xenografted cells. In this review, we highlight and raise awareness regarding the different aspects of xenografting that need to be improved in order to mimic, in a more efficient way, the human tumor microenvironment, resulting in more robust and accurate in vivo results.
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http://dx.doi.org/10.3390/cells9091978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564051PMC
August 2020

Effect of a High-Intensity Tandem Bicycle Exercise Program on Clinical Severity, Functional Magnetic Resonance Imaging, and Plasma Biomarkers in Parkinson's Disease.

Front Neurol 2020 24;11:656. Epub 2020 Jul 24.

School of Medicine, Universidad de los Andes, Bogota, Colombia.

The optimal modality, intensity, duration, frequency, and dose-response of exercise as a therapy for Parkinson's Disease (PD) are insufficiently understood. To assess the impact of a high-intensity tandem bicycle program on clinical severity, biomarkers, and functional MRI (fMRI) in PD. A single-center, parallel-group clinical trial was conducted. Thirteen PD patients aged 65 or younger were divided in two groups: a control group and an intervention group that incorporated a cycling program at 80% of each individual's maximum heart rate (HR) (≥80 rpm), three times a week, for 16 weeks. Both groups continued their conventional medications for PD. At baseline and at the end of follow-up, we determined in all participants the Unified Parkinson's Disease Rating Scale, anthropometry, VOmax, PD biomarkers, and fMRI. VOmax improved in the intervention group (IG) (+5.7 ml/kg/min), while it slightly deteriorated in the control group (CG) (-1.6 ml/kg/min) ( = 0.041). Mean Unified Parkinson's Disease Rating Scale (UPDRS) went down by 5.7 points in the IG and showed a small 0.9-point increase in the CG ( = 0.11). fMRI showed activation of the right fusiform gyrus during the motor task and functional connectivity between the cingulum and areas of the frontal cortex, and between the cerebellar vermis and the thalamus and posterior temporal gyrus. Plasma brain-derived neurotrophic factor (BDNF) levels increased more than 10-fold in the IG and decreased in the CG ( = 0.028). Larger increases in plasma BDNF correlated with greater decreases in UPDRS ( = -0.58, = 0.04). Our findings suggest that high-intensity tandem bicycle improves motor function and biochemical and functional neuroimaging variables in PD patients. ISRCTN 13047118, Registered on February 8, 2018.
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http://dx.doi.org/10.3389/fneur.2020.00656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393207PMC
July 2020

C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease.

Acta Neuropathol Commun 2020 07 16;8(1):110. Epub 2020 Jul 16.

GENYO. Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain.

A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.
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http://dx.doi.org/10.1186/s40478-020-00982-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364817PMC
July 2020