Publications by authors named "Maria Castro"

589 Publications

Driver glare exposure with different vehicle frontlighting systems.

J Safety Res 2021 Feb 8;76:228-237. Epub 2021 Jan 8.

Departamento de Ingeniería del Transporte, Territorio y Urbanismo, Universidad Politécnica de Madrid, Spain. Electronic address:

Introduction: Highway safety performance at night has received less attention in research than daytime, despite the higher accident rates occurring under night-time conditions. This study presents a procedure to assess the potential hazard for drivers created by headlight glare and its interaction with the geometric design of highways.

Method: The proposed procedure consists of a line-of-sight analysis performed by a geoprocessing model in geographic information systems to determine whether the rays of light that connect headlights and oncoming drivers are obstructed by either the roadway or its roadsides. Then, the procedure checks whether the non-obstructed rays of light are enclosed by a given headlight beam. Different hypotheses were set concerning the headlight beam features, including the horizontal spread angle and whether the headlights are fixed or swiveling. A highway section was selected to test and validate the procedure proposed. A 3D recreation of the highway and its environment derived from a LiDAR point cloud was used for this purpose.

Results: The findings disclose how glare is produced on tangents, horizontal curves, transitions between them and sequences of curves. The effect of visual obstructions conveniently placed is also discussed.

Conclusions: A greater glare incidence is produced as the horizontal headlights spread angle increases. Swiveling headlights increase glare on highways left curves and reduce it on right curves. Practical Applications: The procedure and conclusions of this study can contribute to develop more effective glare avoidance technologies as well as identify and assess glare-prone sections. The glare evaluation assists in evaluating glare countermeasures such as deciding whether to place a vegetation barrier and where.
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http://dx.doi.org/10.1016/j.jsr.2020.12.018DOI Listing
February 2021

Inhibitory Mechanism of the Isoflavone Derivative Genistein in the Human Ca3.3 Channel.

ACS Chem Neurosci 2021 Feb 28;12(4):651-659. Epub 2021 Jan 28.

School of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico.

Regulation of cellular excitability and oscillatory behavior of resting membrane potential in nerve cells are largely mediated by the low-voltage activated T-type calcium channels. This calcium channel family is constituted by three isoforms, namely, Ca3.1, Ca3.2, and Ca3.3, that are largely distributed in the nervous system and other parts of the body. Dysfunction of T-type calcium channels is associated with a wide range of pathophysiologies including epilepsy, neuropathic pain, cardiac problems, and major depressive disorders. Due to their pharmacological relevance, finding molecular agents able to modulate the channel's function may provide therapeutic means to ameliorate their related disorders. Here we used electrophysiological experiments to show that genistein, a canonical tyrosine kinase inhibitor, reduces the activity of the human Ca3.3 channel in a concentration-dependent manner. The inhibitory effect of genistein is independent of tyrosine kinase modulation and does not affect the voltage-dependent gating of the channel. Subsequently, we used computational methods to identify plausible molecular poses for the interaction of genistein and the Ca3.3 channel. Starting from different molecular poses, we carried out all-atom molecular dynamics (MD) simulations to identify the interacting determinants for the Ca3.3/genistein complex formation. Our extensive (microsecond-length) simulations suggest specific binding interactions that seem to stabilize the protein/inhibitor complex. Furthermore, our results from the unbiased MD simulations are in good agreement with the recently solved cryoelectron microscopy structure of the Ca3.1/Z944 complex in terms of both the location of the ligand binding site and the role of several equivalent amino acid residues. Proposed interacting complex loci were subsequently tested and corroborated by electrophysiological experiments using another naturally occurring isoflavone derivative, daidzein. Thus, by using a combination of and techniques, we have identified interacting determinants relevant to the Ca3.3/genistein complex formation and propose that genistein directly blocks the function of the human Ca3.3 channel as a result of such interaction. Specifically, we proposed that a combination of polar interactions involving the three hydroxyl groups of genistein and an aromatic interaction with the fused rings are the main binding interactions in the complex formation. Our results pave the way for the rational development of improved and novel low-voltage activated T-type calcium channel inhibitors.
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http://dx.doi.org/10.1021/acschemneuro.0c00684DOI Listing
February 2021

Big Five Personality Traits, Coping Strategies and Compulsive Buying in Spanish University Students.

Int J Environ Res Public Health 2021 Jan 19;18(2). Epub 2021 Jan 19.

Department of Clinical Psychology and Psychobiology, Faculty of Psychology, C/Xosé María Suárez Núñez, s/n, Campus Vida, 15782 Santiago de Compostela, Spain.

Personality traits and coping strategies have historically been two key elements in the field of health psychology. It is, therefore, striking that there is no study in the field of compulsive buying that integrates the most generic, decontextualized and stable aspects (traits) with those having a more marked processual and dynamic nature, which are closer to goal-based views of human nature (coping strategies). Another weakness of the compulsive buying field is that, despite the confirmed growing increase in compulsive buying in the younger age groups, most studies have been conducted with adult samples. Hence, this study seeks to clarify the role of the Big Five domains and different coping strategies in university students' compulsive buying. The sample consisted of 1093 participants who were classified as either compulsive buyers or non-compulsive buyers. Both groups were compared regarding sociodemographic variables (gender, age), the Big Five personality traits, and coping strategies through chi-square tests or Student's -tests. Besides, a multivariate logistic regression analysis was conducted to determine which of these determinants might play a part in the construction of a risk profile for compulsive buying. The results showed that other than gender (specifically being female), Neuroticism and the use of such coping strategies as problem avoidance and wishful thinking are risk factors that increase the propensity for compulsive buying. The use of active coping strategies such as problem solving, cognitive restructuring and social support, as well as the Conscientiousness dimension are protection factors that decrease the likelihood of becoming a compulsive buyer. Finally, and on the basis of the findings obtained, possible guidelines are given, which, hopefully, may effectively contribute to the prevention of and/or intervention in compulsive buying among young adults.
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http://dx.doi.org/10.3390/ijerph18020821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833433PMC
January 2021

Immune-stimulatory (TK/Flt3L) gene therapy opens the door to a promising new treatment strategy against brainstem gliomas.

Oncotarget 2020 Dec 15;11(50):4607-4612. Epub 2020 Dec 15.

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Diffuse intrinsic pontine glioma (DIPG) is a rare brainstem tumor which carries a dismal prognosis. To date. there are no effective treatments for DIPG. Transcriptomic studies have shown that DIPGs have a distinct profile compared to hemispheric high-grade pediatric gliomas. These specific genomic features coupled with the younger median age group suggest that DIPG is of developmental origin. There is a major unmet need for novel effective therapeutic approaches for DIPG. Clinical and preclinical studies have expanded our understanding of the molecular pathways in this deadly disease. We have developed a genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, activin A receptor type I (ACVR1)-G328V (mACVR1) using the sleeping beauty transposon system. DIPG neurospheres isolated from the genetically engineered mouse model were implanted into the pons of immune-competent mice to assess the therapeutic efficacy and toxicity of immunostimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). Immunostimulatory adenoviral-mediated delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and improved median survival by stimulating the host antitumor immune response. Therapeutic efficacy of the immunostimulatory gene therapy strategy will be tested in the clinical arena in a Phase I clinical trial. We also discuss immunotherapeutic interventions currently being implemented in DIPG patients and discuss the profound therapeutic implications of immunotherapy for this patient populations.
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http://dx.doi.org/10.18632/oncotarget.27834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747859PMC
December 2020

BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance.

Cancers (Basel) 2020 Dec 30;13(1). Epub 2020 Dec 30.

Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, C1405BCK Buenos Aires, Argentina.

The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and MCL1. The role of BCL2L10, another member of this group, has been poorly studied in cancer and never has been in melanoma. We describe here that BCL2L10 is abundantly and frequently expressed both in melanoma cell lines and tumor samples. We established that BCL2L10 expression is driven by STAT3-mediated transcription, and by using reporter assays, site-directed mutagenesis, and ChIP analysis, we identified the functional STAT3 responsive elements in the BCL2L10 promoter. BCL2L10 is a pro-survival factor in melanoma since its expression reduced the cytotoxic effects of cisplatin, dacarbazine, and ABT-737 (a BCL2, Bcl-xL, and Bcl-w inhibitor). Meanwhile, both genetic and pharmacological inhibition of BCL2L10 sensitized melanoma cells to cisplatin and ABT-737. Finally, BCL2L10 inhibited the cell death upon combination treatments of PLX-4032, a BRAF inhibitor, with ABT-737 or cisplatin. In summary, we determined that BCL2L10 is expressed in melanoma and contributes to cell survival. Hence, targeting BCL2L10 may enhance the clinical efficacy of other therapies for malignant melanoma.
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http://dx.doi.org/10.3390/cancers13010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795116PMC
December 2020

Blocking NHE1 stimulates glioma tumor immunity by restoring OXPHOS function of myeloid cells.

Theranostics 2021 1;11(3):1295-1309. Epub 2021 Jan 1.

Department of Neurology and Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh, Pittsburgh, PA 15213.

Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is one of the contributing factors for failed immunotherapies. Therefore, there is an urgent need to better understand TME and to identify novel modulators of TME for more effective GBM therapies. We hypothesized that H extrusion protein Na/H exchanger 1 (NHE1) plays a role in dysregulation of glucose metabolism and immunosuppression of GBM. We investigated the efficacy of blockade of NHE1 activity in combination with temozolomide (TMZ) therapy in increasing anti-tumor immunity. Mouse syngeneic intracranial glioma model was used to test four treatment regimens: DMSO (Vehicle-control), TMZ, NHE1 specific inhibitor HOE642, or TMZ+HOE642 (T+H) combination. H/Fluorine magnetic resonance imaging (MRI) with cell tracking agent Vsense was performed to monitor the infiltration of glioma-associated microglia/myeloid cells (GAMs). Glucose metabolism and transcriptome profiles were analyzed by Seahorse analyzer and bulk RNA-sequencing. The impact of selective deletion in GAMs on sensitivity to anti-PD-1 therapy was evaluated in transgenic knockout () mice. Among the tested treatment regimens, the T+H combination therapy significantly stimulated the infiltration of GAMs and T-cells; up-regulated Th1 activation, and mitochondrial oxidative phosphorylation (OXPHOS) pathway genes, increased glucose uptake and mitochondrial mass, and decreased aerobic glycolysis in GAMs. Selective deletion of in Cx3cr1 mice increased anti-tumor immunity and sensitivity to TMZ plus anti-PD-1 combinatorial therapy. NHE1 plays a role in developing glioma immunosuppressive TME in part by dysregulating glucose metabolism of GAMs and emerges as a therapeutic target for improving glioma immunity.
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http://dx.doi.org/10.7150/thno.50150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738877PMC
January 2021

Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA.

Int J Mol Sci 2020 Dec 28;22(1). Epub 2020 Dec 28.

Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, Neonatology Service, Department of Paediatrics, Hospital Clínico Universitario de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), CIBERER, MetabERN, 15706 Santiago de Compostela, Spain.

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the -acetylgalactosamine-6-sulfatase () gene. Skeletal dysplasia and the related clinical features of MPS IVA are caused by disruption of the cartilage and its extracellular matrix, leading to a growth imbalance. Enzyme replacement therapy (ERT) with recombinant human GALNS has yielded positive results in activity of daily living and endurance tests. However, no data have demonstrated improvements in bone lesions and bone grow thin MPS IVA after ERT, and there is no correlation between therapeutic efficacy and urine levels of keratan sulfate, which accumulates in MPS IVA patients. Using qualitative and quantitative proteomics approaches, we analyzed leukocyte samples from healthy controls ( = 6) and from untreated ( = 5) and ERT-treated ( = 8, sampled before and after treatment) MPS IVA patients to identify potential biomarkers of disease. Out of 690 proteins identified in leukocytes, we selected a group of proteins that were dysregulated in MPS IVA patients with ERT. From these, we identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: lactotransferrin, coronin 1A, neutral alpha-glucosidase AB, and vitronectin. Further studies of cartilage and bone alterations in MPS IVA will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.
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http://dx.doi.org/10.3390/ijms22010226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795692PMC
December 2020

Genetically Engineered Mouse Model of Brainstem High-Grade Glioma.

STAR Protoc 2020 Dec 25;1(3):100165. Epub 2020 Nov 25.

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Brainstem gliomas are aggressive tumors that are more prevalent in pediatric patients. The location of these tumors makes them inoperable, and currently there is no effective treatment. Recent genomic data revealed the unique biology of these tumors. The following protocol provides a method to incorporate these specific genetic lesions in a mouse glioma model. Using this model, the effects of these mutations in tumor progression and response to treatments can be studied within a relevant context. For complete details on the use and execution of this protocol, please refer to Mendez et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757359PMC
December 2020

Anti-cancer mechanisms of linalool and 1,8-cineole in non-small cell lung cancer A549 cells.

Heliyon 2020 Dec 15;6(12):e05639. Epub 2020 Dec 15.

Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata La Plata, Argentina.

Linalool and 1,8-cineole are plant-derived isoprenoids with anticancer activities in lung cancer cells, nevertheless, the cellular and molecular mechanisms of action remain poorly understood. The purpose of this study was to determine the anticancer mechanisms of action of linalool and 1,8-cineole in lung adenocarcinoma A549 cells. Linalool (0-2.0 mM) and 1,8-cineole (0-8.0 mM) inhibited cell proliferation by inducing G0/G1 and/or G2/M cell cycle arrest without affecting cell viability of normal lung WI-38 cells. None of the two monoterpenes were able to induce apoptosis, as observed by the lack of caspase-3 and caspase-9 activation, PARP cleavage, and DNA fragmentation. Linalool, but not 1,8-cineole, increased reactive oxygen species production and mitochondrial membrane potential depolarization. Reactive oxygen species were involved in cell growth inhibition and mitochondrial depolarization induced by linalool since the antioxidant N-acetyl-L-cysteine prevented both effects. Besides, linalool (2.0 mM) and 1,8-cineole (8.0 mM) inhibited A549 cell migration. The combination of each monoterpene with simvastatin increased the G0/G1 cell cycle arrest and sensitized cells to apoptosis compared with simvastatin alone. Our results showed that both monoterpenes might be promising anticancer agents with antiproliferative, anti-metastatic, and sensitizer properties for lung cancer therapy.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749389PMC
December 2020

Type 1 Diabetes Mellitus in Pediatric Patients and Its Impact on Relationships in the Family Environment.

Diabetes Metab Syndr Obes 2020 15;13:4973-4980. Epub 2020 Dec 15.

Faculty of Nursing, Universidad de Valladolid, Valladolid, Spain.

Purpose: The aim of this study is to assess the impact of type 1 diabetes mellitus on family environment relationships, as well as the management and approach to this disease.

Patients And Methods: One hundred one children, 52.47% male and 47.52% female, with an average age of 8.55 ± 4.01 years, diagnosis of type 1 diabetes mellitus. Quantitative cross-sectional descriptive study was conducted using the validated questionnaires "Modified Diabetes Quality of Life" and "Questionnaire for the assessment of psychological impact in parents/guardians of diabetic children".

Results: Most of the children (70.3% versus 29.7%) identified diabetes as unpleasant or not fun. The ≤5-year-olds expressed that they felt concerned about the consequences of being diabetic (8.1% by age group), as opposed to the 10-year-olds who did not feel concerned (85.1% by age group), P <0.001. The family environment was affected in 98.1% (n=99) of the cases.

Conclusion: Self-care of type 1 diabetes mellitus in pediatric patients is a complex process that impacts the family environment and their relationship with their peers, especially for children under the age of 5. Fear, concern and insecurity were prevalent feelings in children suffering type 1 diabetes mellitus.
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http://dx.doi.org/10.2147/DMSO.S281949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751600PMC
December 2020

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities.

Int J Mol Sci 2020 Dec 17;21(24). Epub 2020 Dec 17.

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.
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http://dx.doi.org/10.3390/ijms21249654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766684PMC
December 2020

Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice.

J Clin Invest 2021 Feb;131(4)

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma-bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in WT-IDH gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint blockade and observed complete tumor regression in 60% of mIDH1 glioma-bearing mice. This combination strategy reduced T cell exhaustion and favored the generation of memory CD8+ T cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data support the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.
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http://dx.doi.org/10.1172/JCI139542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880418PMC
February 2021

Development and feasibility of 4 checklists for the evaluation of comorbidity in patients with rheumatoid arthritis, axial spondyloarthritis and psoriatic arthritis: GECOAI Project.

Reumatol Clin 2020 Dec 5. Epub 2020 Dec 5.

Servicio de Reumatología, Hospital Monte Naranco, Oviedo, España.

Objective: To develop and assess the feasibility in daily practice of four comorbidity checklists, for common use in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA).

Methods: A multidisciplinary panel of experts on comorbidity was established. Data from the GECOAR, GECOAX and GECOAP projects were analysed and a narrative literature review in Medline on RA, axSpA and PsA comorbidity was performed in order to select the most relevant and common comorbidities across the three diseases. With these results and those obtained from a focus group of patients, in a nominal group meeting, the experts generated preliminary checklists. These were afterwards modified by an external evaluation by two associations, a patients' association and an association of health professionals related to rheumatology. As a result, the final checklists were generated. A cross-sectional study was conducted to test the feasibility of three of the checklists in daily practice, in which eight health professionals evaluated the checklists in five patients with RA, five with axSpA and five with SpA.

Results: Four comorbidity checklists were designed, three for health professionals (one to assess current comorbidity, one on prevention/health promotion and one with the referral criteria to other health professionals), and another for patients. The feasibility study showed them to be simple, clear, and useful for use in routine clinical practice.

Conclusions: The use of specific and common checklists for patients with RA, axSpA and PsA is feasible and might contribute favorably to their prognosis as well as in daily practice.
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http://dx.doi.org/10.1016/j.reuma.2020.09.003DOI Listing
December 2020

Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy.

Nat Commun 2020 11 10;11(1):5687. Epub 2020 Nov 10.

Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.

Glioblastoma (GBM), the most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in part, due to the absence of effective drug delivery strategies. Intravenous injection is the least invasive drug delivery route to the brain, but has been severely limited by the blood-brain barrier (BBB). Inspired by the capacity of natural proteins and viral particulates to cross the BBB, we engineered a synthetic protein nanoparticle (SPNP) based on polymerized human serum albumin (HSA) equipped with the cell-penetrating peptide iRGD. SPNPs containing siRNA against Signal Transducer and Activation of Transcription 3 factor (STAT3i) result in in vitro and in vivo downregulation of STAT3, a central hub associated with GBM progression. When combined with the standard of care, ionized radiation, STAT3i SPNPs result in tumor regression and long-term survival in 87.5% of GBM-bearing mice and prime the immune system to develop anti-GBM immunological memory.
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http://dx.doi.org/10.1038/s41467-020-19225-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655867PMC
November 2020

Mosaic genome evolution and phylogenetics of Chrysodeixis includens nucleopolyhedrovirus (ChinNPV) and virulence of seven new isolates from the Brazilian states of Minas Gerais and Mato Grosso.

Arch Virol 2021 Jan 27;166(1):125-138. Epub 2020 Oct 27.

Embrapa Recursos Genéticos e Biotecnologia, Parque Estação Biológica, Brasília, DF, Brazil.

In a comparative analysis of genome sequences from isolates of the baculovirus Chrysodeixis includens nucleopolyhedrovirus (ChinNPV) from Brazil and Guatemala, we identified a subset of isolates possessing chimeric genomes. We identified six distinct phylogenetically incongruous regions (PIRs) dispersed in the genomes, of between 279 and 3345 bp in length. The individual PIRs possessed high sequence similarity among the affected ChinNPV isolates but varied in coverage in some instances. The donor for four of the PIRs implicated in horizontal gene transfer (HGT) was identified as Trichoplusia ni single nucleopolyhedrovirus (TnSNPV), an alphabaculovirus closely related to ChinNPV, or another unknown but closely related virus. BLAST searches of the other two PIRs returned only ChinNPV sequences, but HGT from an unknown donor baculovirus cannot be excluded. Although Chrysodeixis includens and Trichoplusia ni are frequently co-collected from soybean fields in Brazil, pathogenicity data suggest that natural coinfection of C. includens larvae with ChinNPV and TnSNPV is probably uncommon. Additionally, since the chimeric ChinNPV genomes with tracts of TnSNPV sequence were restricted to a single monophyletic lineage of closely related isolates, a model of progressive restoration of the native DNA sequence by recombination with ChinNPV possessing a fully or partially non-chimeric genome is reasonable. However, multiple independent HGT from TnSNPV to ChinNPV during the evolution of these isolates cannot be excluded. Mortality data suggest that the ChinNPV isolates with chimeric genomes are not significantly different in pathogenicity towards C. includens when compared to most other ChinNPV isolates. Exclusion of the PIRs prior to phylogenetic analysis had a large impact on the topology of part of the maximum-likelihood tree, revealing a homogenous clade of three isolates (IB, IC and ID) from Paraná state in Brazil collected in 2006, together with an isolate from Guatemala collected in 1972 (IA), comprising the lineage uniquely affected by HGT from TnSNPV. The other 10 Brazilian ChinNPV isolates from Paraná, Mato Grosso, and Minas Gerais states showed higher variability, where only three isolates from Paraná state formed a monophyletic group correlating with geographical origin.
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http://dx.doi.org/10.1007/s00705-020-04858-2DOI Listing
January 2021

Reference values of mandibular condyles metabolic activity: A study using Tc-MDP single-photon emission computed tomography.

Orthod Craniofac Res 2020 Oct 22. Epub 2020 Oct 22.

Centro Médico Imbanaco, Cali, Colombia.

Objective: To assess the condylar bone metabolic activity in patients with temporomandibular joint health by measuring Tc-MDP uptake using a single-photon emission computed tomography (SPECT) to establish reference values of the uptake difference between condyles and the ratio with respect to the clivus.

Setting And Sample Population: Eighty consecutive patients of both sexes who were admitted to a Nuclear Medicine Centre between 2017 and 2019 were included in the study.

Method: This was an observational cross-sectional study in patients with SPECT indications to evaluate pathologies other than those of the temporomandibular joint. The values of the total and normalized counts in a fixed region of interest of five trans-axial slides were obtained to assess the percentage difference between the sides and the uptake ratio. The reference values are expressed as median and 5th and 95th percentiles.

Results: The sample included 53 women (66.25%) and 27 men (33.75%) aged 15-55 years. The percentage of uptake difference between condyles was 5.04% (0.46-14.78) for men and 5.17% (0.27-13.21) for women (difference not significant, P = .9). The uptake difference was below 10% in 85% of the subjects (n = 68). The ratio values for total counts in women (0.87, 0.46-1.33) were significantly different (P = .0030) from those in men (1.08, 0.61-2.09). No significant correlation with age was found.

Conclusions: These new reference ranges are applicable to the diagnosis of unilateral and bilateral condylar hyperplasia.
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http://dx.doi.org/10.1111/ocr.12434DOI Listing
October 2020

Synthesis, Crystal Structure, and Computational Methods of Vanadium and Copper Compounds as Potential Drugs for Cancer Treatment.

Molecules 2020 Oct 14;25(20). Epub 2020 Oct 14.

Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, 18 sur y Av. San Claudio, Col. San Manuel, Puebla C. P. 72570, Mexico.

Transition metal-based compounds have shown promising uses as therapeutic agents. Among their unique characteristics, these compounds are suitable for interaction with specific biological targets, making them important potential drugs to treat various diseases. Copper compounds, of which Casiopeinas are an excellent example, have shown promising results as alternatives to current cancer therapies, in part because of their intercalative properties with DNA. Vanadium compounds have been extensively studied for their pharmacological properties and application, mostly in diabetes, although recently, there is a growing interest in testing their activity as anti-cancer agents. In the present work, two compounds, [Cu(Metf)(bipy)Cl]Cl·2HO and [Cu(Impy)(Gly)(HO)]VO, were obtained and characterized by visible and FTIR spectroscopies, single-crystal X-ray diffraction, and theoretical methods. The structural and electronic properties of the compounds were calculated through the density functional theory (DFT) using the Austin-Frisch-Petersson functional with dispersion APFD, and the 6-311 + G(2d,p) basis set. Non-covalent interactions were analyzed using Hirshfeld surface analysis (HSA) and atom in molecules analysis (AIM). Additionally, docking analysis to test DNA/RNA interactions with the Casiopeina-like complexes were carried out. The compounds provide metals that can interact with critical biological targets. In addition, they show interesting non-covalent interactions that are responsible for their supramolecular arrangements.
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http://dx.doi.org/10.3390/molecules25204679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587343PMC
October 2020

Effects of Nutritional Interventions in the Control of Musculoskeletal Pain: An Integrative Review.

Nutrients 2020 Oct 9;12(10). Epub 2020 Oct 9.

Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Goiás, Goiânia 74605-050, Goiás, Brazil.

Food consumption has significant positive effects on an individual's health status, including the reduction of symptoms associated with musculoskeletal pain. However, specific food groups indicated for the treatment of pain are not yet determined. Hence, this review aimed to analyze the effects of nutritional interventions with specific diets, oils and/or fatty acids, and foodstuffs in natura in the reduction of musculoskeletal pain. An integrative review was conducted in the following databases: Embase, PubMed, LILACS, and Google Scholar. Clinical trials written in English, Spanish, and Portuguese and published between 2000 and March 2020 were included in this review. Seventeen studies were included. Among these, a reduction of musculoskeletal pain with different types of nutritional interventions, such as vegan and Mediterranean diets and the consumption of blueberry, strawberry, passion fruit peel extract, argan oil, fish oil (omega-3), olive oil, and undenatured type II collagen and vitamin D gel capsules, was observed in 14 studies. Eight studies evaluated the profiles of several inflammatory markers, and of these, decreased interleukin (IL)-6, IL-1β, and tumor necrosis factor-α levels were observed in two studies. This review suggests that different nutritional interventions with specific diets, oils and/or fatty acids, and foodstuffs in natura reduce musculoskeletal pain, specifically in adults with osteoarthritis. Besides pain improvement, nutritional interventions, including the consumption of strawberry and vitamin D gel capsules, decrease the levels of several inflammatory markers.
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http://dx.doi.org/10.3390/nu12103075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601187PMC
October 2020

An Optimized Protocol for In Vivo Analysis of Tumor Cell Division in a Sleeping Beauty-Mediated Mouse Glioma Model.

STAR Protoc 2020 Sep 6;1(2). Epub 2020 Jun 6.

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Malignant gliomas are the most common and aggressive primary brain tumor in adults, and high mitotic rates are associated with their malignancy. Gliomas were modeled in mice using the Sleeping Beauty system to encode genetic lesions recapitulating the human disease. The presented workflow allows the study of the proliferation of glioma cells , enabling the identification of different phases of the cell cycle, with the advantage that 5-ethynyl-2'-deoxyuridine staining does not involve denaturation steps and samples do not require histological processing. For complete details on the use and execution of this protocol, please refer to Núñez et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2020.100044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518519PMC
September 2020

A New Antagonist of Glutamate-Activated Chloride Channels With Anthelmintic Activity.

Front Neurosci 2020 19;14:879. Epub 2020 Aug 19.

Departamento de Biología, Bioquímica y Farmacia, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina.

Nematode parasitosis causes significant mortality and morbidity in humans and considerable losses in livestock and domestic animals. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds for which the free-living nematode has emerged as a valuable platform. We have previously synthetized a small library of oxygenated tricyclic compounds and determined that dibenzo[]oxepin-11(6H)-one (doxepinone) inhibits motility. Because doxepinone shows potential anthelmintic activity, we explored its behavioral effects and deciphered its target site and mechanism of action on Doxepinone reduces swimming rate, induces paralysis, and decreases the rate of pharyngeal pumping required for feeding, indicating a marked anthelmintic activity. To identify the main drug targets, we performed an screening of selected strains carrying mutations in Cys-loop receptors involved in worm locomotion for determining resistance to doxepinone effects. A mutant strain that lacks subunit genes of the invertebrate glutamate-gated chloride channels (GluCl), which are targets of the widely used antiparasitic ivermectin (IVM), is resistant to doxepinone effects. To unravel the molecular mechanism, we measured whole-cell currents from GluClα1/β receptors expressed in mammalian cells. Glutamate elicits macroscopic currents whereas no responses are elicited by doxepinone, indicating that it is not an agonist of GluCls. Preincubation of the cell with doxepinone produces a statistically significant decrease of the decay time constant and net charge of glutamate-elicited currents, indicating that it inhibits GluCls, which contrasts to IVM molecular actions. Thus, we identify doxepinone as an attractive scaffold with promising anthelmintic activity and propose the inhibition of GluCls as a potential anthelmintic mechanism of action.
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http://dx.doi.org/10.3389/fnins.2020.00879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466757PMC
August 2020

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor.

Molecules 2020 Sep 17;25(18). Epub 2020 Sep 17.

Department of Medicine and General Cytometry Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain.

Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.
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http://dx.doi.org/10.3390/molecules25184258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571232PMC
September 2020

Cu-based chimeric T1 copper sites allow for independent modulation of reorganization energy and reduction potential.

Chem Sci 2020 Jun 1;11(24):6193-6201. Epub 2020 Jun 1.

Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE, CONICET-UBA) , Argentina . Email:

Attaining rational modulation of thermodynamic and kinetic redox parameters of metalloproteins is a key milestone towards the (re)design of proteins with new or improved redox functions. Here we report that implantation of ligand loops from natural T1 proteins into the scaffold of a Cu protein leads to a series of distorted T1-like sites that allow for independent modulation of reduction potentials (°') and electron transfer reorganization energies (). On the one hand °' values could be fine-tuned over 120 mV without affecting . On the other, values could be modulated by more than a factor of two while affecting °' only by a few millivolts. These results are in sharp contrast to previous studies that used T1 cupredoxin folds, thus highlighting the importance of the protein scaffold in determining such parameters.
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http://dx.doi.org/10.1039/d0sc01620aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480511PMC
June 2020

Thermoregulatory capacity of hair ewes of different genotypes associated with coat colors raised in a hot environment.

J Appl Anim Welf Sci 2020 Sep 20:1-11. Epub 2020 Sep 20.

Center of Agricultural and Biological Sciences, State University of Acaraú Valley , Sobral, Brazil.

The relationship between hair color characteristics and thermoregulatory responses in ewes raised in hot environment were evaluated. 15 hair ewes of different genotypes associated with coat colors (light brown, dark brown and black) with body weight of 41.2 ± 8.1 kg were evaluated during three consecutive days. Rectal temperature (R, °C) and coat surface temperature (C, °C) of seven anatomical points (front, back, croup, loin, side, thigh, and belly) were measured during the morning and afternoon periods. Thermoregulatory responses were recorded along with meteorological variables. Heat tolerance index (H) and thermal gradient (T, °C) were estimated for each genotype. R and C were influenced by periods of the day ( < 0.05), being higher in the afternoon, but T did not differ ( > 0.05) between periods. H, C, and T were equal ( > 0.05) among the three genotypes. Only R was higher in animals with dark brown coats compared to light brown, but equal to the black coat. It was observed that animals with black or dark brown hairs have a strong association between the C under study, and yet these had an inverse behavior with the R. Animals with a darker coat tend to trigger heat dissipation in various anatomical regions of the body, presenting dynamics in thermoregulatory responses in relation to those with lighter coats. ewes have heat dissipation mechanisms as a function of different genotypes associated with coat colors, but have the same thermoregulatory aspects to maintain homeostasis, demonstrating an excellent adaptive mechanism in a hot environment.
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http://dx.doi.org/10.1080/10888705.2020.1819808DOI Listing
September 2020

COMDORA-SBN recommendations for patients with rare kidney diseases in relation to the Covid-19 pandemic.

J Bras Nefrol 2020 Aug;42(2 suppl 1):36-40

Universidade de São Paulo, Instituto da Criança, São Paulo, SP, Brazil.

During the Covid-19 pandemic, the issue is how to maintain adequate care for people with other diseases. In this document, the SBN Rare Diseases Committee (COMDORA) gives some guidelines on the care of patients with rare kidney diseases. These patients should follow the recommendations for the general population, bearing in mind that, as they have chronic kidney disease, they are included in the risk group for more serious outcomes if they develop Covid-19. Non-essential decision-making procedures should be postponed. In stable cases under appropriate treatment, we must choose to contact our patients remotely, using teleconsultations and home exam collections (if possible). In the presence of a symptom or sign of decompensation of the underlying disease, or infection with Sars-cov-2, advise the patient to seek medical assistance. The patient should not be waiting to get worse. Changes to the prescription should only be made on a scientific basis. Dosage suspension or change is not recommended, even in cases in which the patient needs to go to a center to receive his medication; in this case, the infusion center must follow the recommendations of the Ministry of Health. If the patient develops Covid-19 and uses any drugs, check the need for dose adjustment of the routine medications. Avoid the use of antimetabolics and anti-CD20 in patients with Covid-19, as they reduce viral clearance and predispose to bacterial infections. Contact between the patient and the medical team is essential; changes are recommended only with specialized medical guidance.
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http://dx.doi.org/10.1590/2175-8239-JBN-2020-S109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479978PMC
August 2020

Quantifying the Brain Metastatic Tumor Micro-Environment using an Organ-On-A Chip 3D Model, Machine Learning, and Confocal Tomography.

J Vis Exp 2020 08 16(162). Epub 2020 Aug 16.

Department of Internal Medicine, University of Michigan Ann Arbor; Rogel Cancer Center, University of Michigan Ann Arbor;

Brain metastases are the most lethal cancer lesions; 10-30% of all cancers metastasize to the brain, with a median survival of only ~5-20 months, depending on the cancer type. To reduce the brain metastatic tumor burden, gaps in basic and translational knowledge need to be addressed. Major challenges include a paucity of reproducible preclinical models and associated tools. Three-dimensional models of brain metastasis can yield the relevant molecular and phenotypic data used to address these needs when combined with dedicated analysis tools. Moreover, compared to murine models, organ-on-a-chip models of patient tumor cells traversing the blood brain barrier into the brain microenvironment generate results rapidly and are more interpretable with quantitative methods, thus amenable to high throughput testing. Here we describe and demonstrate the use of a novel 3D microfluidic blood brain niche (µmBBN) platform where multiple elements of the niche can be cultured for an extended period (several days), fluorescently imaged by confocal microscopy, and the images reconstructed using an innovative confocal tomography technique; all aimed to understand the development of micro-metastasis and changes to the tumor micro-environment (TME) in a repeatable and quantitative manner. We demonstrate how to fabricate, seed, image, and analyze the cancer cells and TME cellular and humoral components, using this platform. Moreover, we show how artificial intelligence (AI) is used to identify the intrinsic phenotypic differences of cancer cells that are capable of transit through a model µmBBN and to assign them an objective index of brain metastatic potential. The data sets generated by this method can be used to answer basic and translational questions about metastasis, the efficacy of therapeutic strategies, and the role of the TME in both.
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http://dx.doi.org/10.3791/61654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831113PMC
August 2020

Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy.

iScience 2020 Aug 13;23(9):101453. Epub 2020 Aug 13.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA. Electronic address:

Glioblastoma (GBM) metabolism has traditionally been characterized by a primary dependence on aerobic glycolysis, prompting the use of the ketogenic diet (KD) as a potential therapy. In this study we evaluated the effectiveness of the KD in GBM and assessed the role of fatty acid oxidation (FAO) in promoting GBM propagation. In vitro assays revealed FA utilization throughout the GBM metabolome and growth inhibition in nearly every cell line in a broad spectrum of patient-derived glioma cells treated with FAO inhibitors. In vivo assessments revealed that knockdown of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme for FAO, reduced the rate of tumor growth and increased survival. However, the unrestricted ketogenic diet did not reduce tumor growth and for some models significantly reduced survival. Altogether, these data highlight important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.
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http://dx.doi.org/10.1016/j.isci.2020.101453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471621PMC
August 2020

Triple Negative Breast Cancer and Breast Epithelial Cells Differentially Reprogram Glucose and Lipid Metabolism upon Treatment with Triterpenic Acids.

Biomolecules 2020 08 8;10(8). Epub 2020 Aug 8.

Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal.

Plant-derived pentacyclic triterpenic acids (TAs) have gained increasing attention due to their multiple biological activities. Betulinic acid (BA) and ursolic acid (UA) modulate diverse pathways in carcinogenesis, offering increased changes of success in refractory cancers, such as triple negative breast cancer (TNBC). The present work aimed to assess the metabolic effects of BA and UA in MDA-MB-231 breast cancer cells (TNBC model), as well as in MCF-10A non-cancer breast epithelial cells, with a view to unveiling the involvement of metabolic reprogramming in cellular responses to these TAs. Cell viability and cell cycle analyses were followed by assessment of changes in the cells exo- and endometabolome through H NMR analysis of cell culture medium supernatants, aqueous and organic cell extracts. In MDA-MB-231 cells, BA was suggested to induce a transient upregulation of glucose consumption and glycolytic conversion, tricarboxylic acid (TCA) cycle intensification, and hydrolysis of neutral lipids, while UA effects were much less pronounced. In MCF-10A cells, boosting of glucose metabolism by the two TAs was accompanied by diversion of glycolytic intermediates to the hexosamine biosynthetic pathway (HBP) and the synthesis of neutral lipids, possibly stored in detoxifying lipid droplets. Additionally, breast epithelial cells intensified pyruvate consumption and TCA cycle activity, possibly to compensate for oxidative impairment of pyruvate glycolytic production. This study provided novel insights into the metabolic effects of BA and UA in cancer and non-cancer breast cells, thus improving current understanding of the action of these compounds at the molecular level.
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http://dx.doi.org/10.3390/biom10081163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464159PMC
August 2020

Preventive effectiveness of varicella vaccine in healthy unexposed patients.

Medwave 2020 Jul 30;20(6):e7983. Epub 2020 Jul 30.

Proyecto Epistemonikos, Santiago, Chile; Departamento de Medicina Familiar del Niño, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. Email: Address: Centro Evidencia UC, Pontificia Universidad Católica de Chile, Diagonal Paraguay 476, Santiago, Chile.

Introduction: Chickenpox is an infectious disease caused by varicella-zoster virus. Varicella vaccine is conventionally used for its prevention, and its administration seeks to reduce the onset of the disease and complications associated. However, there is still controversy about its effectiveness.

Methods: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

Results And Conclusions: We identified two systematic reviews including 16 studies overall, of which three were randomized trials. We concluded that the varicella vaccine decreases the risk of contracting the disease in the long term and probably reduces the risk of developing the disease in the short term in healthy unexposed patients. Nevertheless, the vaccination increases the occurrence of local reactions 48 hours after its administration and probably increases the presence of fever and chickenpox-like rash.
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http://dx.doi.org/10.5867/medwave.2020.06.7982DOI Listing
July 2020