Publications by authors named "M Carmen del Río"

940 Publications

Placental growth factor testing in the management of late preterm pre-eclampsia without severe features: A multi-center, randomized, controlled trial.

Am J Obstet Gynecol 2021 Apr 3. Epub 2021 Apr 3.

BCNatal. Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia, Obstetrícia i Neonatologia Fetal i+D Fetal Medicine Research Center, Barcelona, Spain.. Electronic address:

Background: In women with late preterm pre-eclampsia the optimal time of delivery is controversial, because of the fine balance between maternal benefits from early delivery and the risks for prematurity. It remains challenging to define prognostic markers to identify women at the highest risk of complication, in which a selective planned delivery may reduce maternal and perinatal adverse outcomes.

Objective: This trial aimed to determine whether using an algorithm based on maternal levels of placental growth factor (PlGF) in women with late preterm pre-eclampsia to decide the best time of delivery reduced the progression to pre-eclampsia with severe features without increasing the adverse perinatal outcomes.

Study Design: This parallel-group, open-label, multicenter, randomized controlled trial was conducted in seven maternity units across Spain. We compared selective planned delivery based on maternal levels of PlGF at admission (revealed group) and expectant management under usual care (concealed group) with individual randomization in singleton pregnancies with late preterm pre-eclampsia from 34 to 36 weeks gestation. The co-primary maternal outcome was the progression to pre-eclampsia with severe features. The co-primary neonatal outcome was morbidity up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were conducted by intention-to-treat.

Results: Between January 1, 2016, and December 31, 2019, 178 women were recruited. Of those women, 88 women were assigned to the revealed group and 90 were assigned to the concealed group. The data analysis was performed before the completion of the required sample size. The proportion of women with progression to pre-eclampsia with severe features was significantly lower in the revealed group than in the concealed group (adjusted relative risk [RR], 0.5; 95% confidence interval [CI], 0.33-0.76; p=0.001). The proportion of infants with neonatal morbidity was not significantly different between groups (adjusted RR, 0.77; 95% CI, 0.39-1.53; p=0.45).

Conclusions: There is evidence to suggest that the use of an algorithm based on PlGF levels in women with late preterm pre-eclampsia results in a lower rate of progression to pre-eclampsia with severe features and reduces maternal complications, without worsening the neonatal outcomes. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on the timing of delivery.
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http://dx.doi.org/10.1016/j.ajog.2021.03.044DOI Listing
April 2021

Electro-clinical features in epileptic children with chromosome 15q duplication syndrome.

Clin Neurophysiol 2021 Mar 10;132(5):1126-1137. Epub 2021 Mar 10.

Department of Clinical Neurophysiology, Necker-Enfants-Malades Hospital, Assistance Publique -Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France.

Objective: We aimed to describe epilepsy and EEG patterns related to vigilance states and age, in chromosome15-long-arm-duplication-syndrome (dup15q) children with epilepsy, in both duplication types: interstitial (intdup15) and isodicentric (idic15).

Methods: Clinical data and 70 EEGs of 12 patients (5 intdup15, 7 idic15), followed from 4.5 m.o to 17y4m (median follow-up 8y3m), were retrospectively reviewed. EEGs were analyzed visually and using power spectrum analysis.

Results: Seventy video-EEGs were analyzed (1-16 per patient, median 6), follow-up lasting up to 8y10m (median 4y2m): 25 EEGs in intdup15 (8 m.o to 12y.o, median 4y6m) and 45 EEGs in idic15 (7 m.o to 12 y.o, median 15 m). Epilepsy: 6 West syndrome (WS) (2intdup15, 4idic15); 4 Lennox-Gastaut syndromes (LGS) (1 intdup15, 3 idic15), 2 evolving from WS; focal epilepsy (3 intdup15). In idic15, WS displayed additional myoclonic seizures (3), atypical (4) or no hypsarrhythmia (2) and posterior predominant spike and polyspike bursts (4). Beta-band rapid-rhythms (RR): present in 11 patients, power decreased during non-REM-sleep, localization shifted from diffuse to anterior, peak frequency increased with age.

Conclusion: WS with peculiar electro-clinical features and LGS, along with beta-band RR decreasing in non-REM-sleep and shifting from diffuse to anterior localization with age are recognizable features pointing towards dup15q diagnosis in children with autism spectrum disorder and developmental delay.

Significance: This study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children, including some recent extensions regarding sleep features; and illustrates how the temporo-spatial organization of beta oscillations can be of significant help in directing towards dup15q diagnosis hypothesis.
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http://dx.doi.org/10.1016/j.clinph.2021.02.010DOI Listing
March 2021

Immunotherapeutic effect of adenovirus encoding antimicrobial peptides in experimental pulmonary tuberculosis.

J Leukoc Biol 2021 Mar 8. Epub 2021 Mar 8.

Experimental Pathology Section, Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

As components of the innate immune response, antimicrobial peptides (AMPs) efficiently contribute to infection control and maintenance of a latent state in pulmonary tuberculosis (TB). As a therapeutic strategy, the administration of recombinant AMPs could be limited by enzymatic degradation and high production costs. Likewise, strategies based on the induction of AMPs have generated controversial results. In this study, 2 recombinant type-5 adenoviruses (Ad) expressing the human β-defensin 3 (HβD3) or cathelicidin (LL37) were assessed in a murine pulmonary TB model. Mice infected with either a high dose of a drug-sensitive (H37Rv) or a multidrug-resistant (MDR) strain of Mycobacterium tuberculosis (Mtb) were treated with a single administration of AdHβD3, AdLL37, AdGFP (control vector expressing a green fluorescent protein), or saline solution (SS). Lungs were obtained to determine the bacterial burden, histologic damage, and cytokine expression at different time points. Mice treated with AdHβD3 or AdLL37 showed significantly lower bacterial load and pneumonia, and higher proinflammatory cytokine expression than the control groups AdGFP and SS. A synergistic therapeutic effect could be observed when first- or second-line antibiotics (ABs) were administered with adenoviral therapy in animals infected with H37Rv or MDR strains, respectively. Adenovirus-delivered AMP's administration constitutes a promising adjuvant therapy for current anti-TB drugs by enhancing a protective immune response and potentially reducing current AB regimes' duration.
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http://dx.doi.org/10.1002/JLB.4MA0920-627RDOI Listing
March 2021

Correction of recessive dystrophic epidermolysis bullosa by homology-directed repair-mediated genome editing.

Mol Ther 2021 Feb 18. Epub 2021 Feb 18.

Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain; Fundación Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain; Epithelial Biomedicine Division, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain. Electronic address:

Genome-editing technologies that enable the introduction of precise changes in DNA sequences have the potential to lead to a new class of treatments for genetic diseases. Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by extreme skin fragility. The recessive dystrophic subtype of EB (RDEB), which has one of the most severe phenotypes, is caused by mutations in COL7A1. In this study, we report a gene-editing approach for ex vivo homology-directed repair (HDR)-based gene correction that uses the CRISPR-Cas9 system delivered as a ribonucleoprotein (RNP) complex in combination with donor DNA templates delivered by adeno-associated viral vectors (AAVs). We demonstrate sufficient mutation correction frequencies to achieve therapeutic benefit in primary RDEB keratinocytes containing different COL7A1 mutations as well as efficient HDR-mediated COL7A1 modification in healthy cord blood-derived CD34 cells and mesenchymal stem cells (MSCs). These results are a proof of concept for HDR-mediated gene correction in different cell types with therapeutic potential for RDEB.
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http://dx.doi.org/10.1016/j.ymthe.2021.02.019DOI Listing
February 2021

Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.

Genes (Basel) 2020 Dec 31;12(1). Epub 2020 Dec 31.

Department of Bioengineering, Carlos III University, Av. de la Universidad, 30, Leganés, 28911 Madrid, Spain.

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.
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http://dx.doi.org/10.3390/genes12010047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824036PMC
December 2020

Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report.

Front Med (Lausanne) 2020 26;7:576558. Epub 2020 Nov 26.

Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 10 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6-9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.
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http://dx.doi.org/10.3389/fmed.2020.576558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726418PMC
November 2020

COVID-19 in Children With Kidney Disease: A Report of 2 Cases.

Kidney Med 2021 Jan-Feb;3(1):120-123. Epub 2020 Nov 21.

Pediatric Nephrology Division at the Children's Hospital at Montefiore, Bronx, NY.

The presentation of novel coronavirus disease 2019 (COVID-19) in children with kidney disease is largely unknown. We report on 2 children with kidney disease not receiving long-term immunosuppression who were hospitalized due to COVID-19. The first case is an infant with end-stage kidney disease secondary to bilateral cystic dysplastic kidneys and posterior urethral valves receiving peritoneal dialysis, with a history of prematurity previously requiring mechanical ventilation in the neonatal intensive care unit, who presented with fever, hypertension, and emesis. He had no respiratory symptoms and recovered with supportive care. His hypertension was managed well with amlodipine. The second case is a child with steroid-sensitive nephrotic syndrome who presented with a relapse of nephrotic syndrome with concurrent peritonitis and sepsis caused by . He was treated with antibiotics and prophylactic anticoagulation therspy. Steroid therapy was initiated after 48 hours of antibiotic therapy. Neither child required mechanical ventilation or developed COVID-19-related multisystem inflammatory syndrome.
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http://dx.doi.org/10.1016/j.xkme.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679656PMC
November 2020

Combined adipose mesenchymal stromal cell advanced therapy resolved a recalcitrant leg ulcer in an 85-year-old patient.

Regen Med 2020 09 27;15(9):2053-2065. Epub 2020 Nov 27.

Department of Bioengineering, Carlos III University (UC3M). Avda. Universidad, 30. 28911. Leganés, Madrid, Spain.

Venous leg ulcers (VLU) represent an uphill economic, health and social burden, aggravated in the elderly. Best-practice care interventions are often insufficient and alternative therapies need to be explored. Herein, we have treated for the first time a chronic VLU in an elderly patient by combining cell therapy and tissue engineering in the context of a compassionate use. The administration of allogeneic adipose-derived mesenchymal stromal cells (MSCs) embedded in a plasma-based bioengineered dermis covering the ulcer bed and also injected into the ulcer margins led to the complete closure of a 10-year recalcitrant VLU in an 85-year-old patient. Regenerative properties of MSCs might be boosted by the use of bioengineered matrices for their delivery.
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http://dx.doi.org/10.2217/rme-2020-0139DOI Listing
September 2020

Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

J Med Genet 2020 Nov 16. Epub 2020 Nov 16.

Necker Hospital, APHP, Reference Center for Mitochondrial Diseases, Genetics Department, Institut Imagine, University of Paris, Paris, France

Background: Biallelic variants in cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs.

Objective And Methods: To document neuroimaging data in six patients with PNPT1 highlighting novel findings.

Results: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection.

Conclusion: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.
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http://dx.doi.org/10.1136/jmedgenet-2020-107367DOI Listing
November 2020

Effect of intravenous lidocaine on ischemia-reperfusion injury in DIEP microsurgical breast reconstruction. A prospective double-blind randomized controlled clinical trial.

J Plast Reconstr Aesthet Surg 2021 Apr 24;74(4):809-818. Epub 2020 Oct 24.

Department of Oncology, Autonomous University of Madrid, University Hospital Puerta de Hierro Majadahonda, Madrid, Spain.

Background: Ischemia-reperfusion injury in free flaps is associated with tissue damage and is one of the main factors causing flap failure in reconstructive microsurgery. The aim of this study is to assess whether any ischemia-reperfusion injury takes place during a microsurgical flap reconstruction as seen through the levels of malondialdehyde (MDA) and superoxide dismutase, biomarkers of oxidative stress, and to analyze the effect of lidocaine in this process.

Methods: Twenty-four patients operated for immediate breast reconstruction using the Deep Inferior Epigastric Perforator free flap technique were divided into two groups: one group was treated with a lidocaine intravenous perfusion and the other group with a saline perfusion. MDA and superoxide dismutase (SOD) levels were measured at several points before, during, and after surgery.

Results: There was an increase in MDA levels in both groups, but the lidocaine group experienced a decrease during reperfusion. On the other hand, we observed a rise in SOD levels in both groups, but a decrease during reperfusion in the placebo group. However, these differences between groups were not statistically significant.

Conclusions: The decreased SOD activity and increased MDA content in our research prove a redox imbalance and high reactive oxygen species levels in flaps, indicating that tissues experience ischemia-reperfusion injury during microsurgical reconstruction. Lidocaine may have a protective effect in free flap surgery, but our results were not statistically significant, so further studies will be required.
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http://dx.doi.org/10.1016/j.bjps.2020.10.018DOI Listing
April 2021

Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival.

Eur J Hum Genet 2021 Mar 9;29(3):533-538. Epub 2020 Nov 9.

Laboratory for Genetics of Mitochondrial Disorders, UMR U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.

Mitochondrial translation is essential for the biogenesis of the mitochondrial oxidative phosphorylation system (OXPHOS) that synthesizes the bulk of ATP for the cell. Hypomorphic and loss-of-function variants in either mitochondrial DNA or in nuclear genes that encode mitochondrial translation factors can result in impaired OXPHOS biogenesis and mitochondrial diseases with variable clinical presentations. Compound heterozygous or homozygous missense and frameshift variants in the FARS2 gene, that encodes the mitochondrial phenylalanyl-tRNA synthetase, are commonly linked to either early-onset epileptic mitochondrial encephalopathy or spastic paraplegia. Here, we expand the genetic spectrum of FARS2-linked disease with three patients carrying novel compound heterozygous variants in the FARS2 gene and presenting with spastic tetraparesis, axial hypotonia and myoclonic epilepsy in two cases.
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http://dx.doi.org/10.1038/s41431-020-00757-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940479PMC
March 2021

Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease.

Brain Sci 2020 Oct 22;10(11). Epub 2020 Oct 22.

CHU de Limoges, Service de Biochimie et Génétique Moléculaire, F-87000 Limoges, France.

Cerebral folate deficiency (CFD) is a neurological disorder characterized by low levels of 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF). The prevalence of this autosomal recessive disorder is estimated to be <1/1,000,000. Fifteen different pathogenic variants in the folate receptor 1 gene () encoding the receptor of folate α (FRα) have already been described. We present a new pathogenic variation in the in a childhood-stage patient. We aim to establish the core structure of the FRα protein mandatory for its activity. A three-year-old child was admitted at hospital for a first febrile convulsions episode. Recurrent seizures without fever also occurred a few months later, associated with motor and cognitive impairment. Various antiepileptic drugs failed to control seizures. Magnetic resonance imaging (MRI) showed central hypomyelination and biological analysis revealed markedly low levels of 5-MTHF in CSF. Next generation sequencing (NGS) confirmed a CFD with a homozygous variation (c.197 G > A, p.Cys66Tyr). This variation induces an altered folate receptor α protein and underlines the role of a disulfide bond: Cys66-Cys109, essential to transport 5-MTHF into the central nervous system. Fortunately, this severe form of CFD had remarkably responded to high doses of oral folinic acid combined with intravenous administrations.
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http://dx.doi.org/10.3390/brainsci10110762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690394PMC
October 2020

Urethane-Acrylate/Aramid Nanocomposites Based on Graphenic Materials. A Comparative Study of Their Mechanical Properties.

Polymers (Basel) 2020 Oct 16;12(10). Epub 2020 Oct 16.

Departamento de Ingeniería Química y Ambiental, Universidad Politécnica de Cartagena, Paseo Alfonso XIII, 30203 Cartagena, Spain.

Urethane-acrylate thermoset resins (UATR) are a new type of polymeric matrix that have recently made a strong breakthrough in the composites sector. This is because of their properties, which make them an advantageous alternative to epoxy resins, especially if they are reinforced with high-performance fibers such as aramids. Graphene-based nanocomposites are one of the most dynamic research fields in nanotechnology, because graphenic materials greatly improve the properties of traditional composites. This work represents a comparative study of the effect of adding three types of graphenic materials on the mechanical properties of UATR/aramid composites. Several UATR polymeric matrices were doped at 2% / with graphene nanoplatelets (GNPs), reduced graphene oxide (rGO) and pristine few-layer graphene (FLG), and reinforced with Twaron CT709 para-aramid fibers. The obtained laminates showed low density (1.38 g·cm), a high volumetric fiber-resin ratio (80:20), homogeneous dispersion of the nanoreinforcement, high reproducibility, and easy scalability. The tensile, flexural and impact strength properties of the undoped composite and the graphene-doped nanocomposites were determined. FLG-doped nanocomposites showed the highest increase in all the mentioned mechanical properties and attained a very significant relative improvement over the undoped laminate (up to 134.4% in a).
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http://dx.doi.org/10.3390/polym12102388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603057PMC
October 2020

Revision of the Pantomorus albosignatus species group (Coleoptera: Curculionidae: Entiminae) from Mexico and Central America.

Zootaxa 2020 Jul 24;4819(3):zootaxa.4819.3.7. Epub 2020 Jul 24.

División Entomología, Museo de La Plata, FCNyM, Universidad Nacional de La Plata, CONICET, Paseo del Bosque s/n, 1900 La Plata, ARGENTINA..

Pantomorus albosignatus Boheman, 1840 (Entiminae: Naupactini), type species of the genus Pantomorus Schoenherr, 1840, is broadly distributed in Mexico, from Oaxaca and Veracruz to Chihuahua and Coahuila, and is probably related to P. parvulus Sharp 1891 (México: Oaxaca and Veracruz), P. andersoni sp. nov. (México: Guerrero), and P. crinitus (Boheman, 1840) (southern Mexico, El Salvador and Guatemala). The four species are small (5-8 mm), apterous, usually show a characteristic maculation and erect setae on the elytra, short antennae, vestigial to absent humeri, and well-developed, squamose corbels of the metatibiae, and are here referred to as the Pantomorus albosignatus species group. Our study was based on the examination of type material and about 500 specimens from different collections, and provides a dichotomous key, descriptions or redescriptions of the species, habitus photographs, line drawings of female and male genitalia, a map of distribution, new locality records and new plant associations. We propose that Pantomorus nobilis (Boheman 1840) is a new junior subjective synonym of P. crinitus (Boheman, 1840), and we designate lectotypes for the species Pantomorus albosignatus Boheman, P. parvulus Sharp, P. crinitus (Boheman), P. nobilis (Boheman) and P. affinis Sharp, 1891 (the latter is also a junior synonym of P. crinitus). Pantomorus albosignatus usually inhabits Acacia grasslands and cactus deserts of the Mexican Plateau, at higher elevations than remaining species; P. parvulus occurs in cloud forests and tropical deciduous forests of southern Mexico; P. crinitus in open oak pine forests, cloud forests and tropical deciduous forests of southern Mexico, Guatemala and El Salvador; and P. andersoni is endemic to the state of Guerrero, in Acacia-cactus woodlands.
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http://dx.doi.org/10.11646/zootaxa.4819.3.7DOI Listing
July 2020

Features of the Energy Spectrum of Cosmic Rays above 2.5×10^{18}  eV Using the Pierre Auger Observatory.

Authors:
A Aab P Abreu M Aglietta J M Albury I Allekotte A Almela J Alvarez Castillo J Alvarez-Muñiz R Alves Batista G A Anastasi L Anchordoqui B Andrada S Andringa C Aramo P R Araújo Ferreira H Asorey P Assis G Avila A M Badescu A Bakalova A Balaceanu F Barbato R J Barreira Luz K H Becker J A Bellido C Berat M E Bertaina X Bertou P L Biermann T Bister J Biteau A Blanco J Blazek C Bleve M Boháčová D Boncioli C Bonifazi L Bonneau Arbeletche N Borodai A M Botti J Brack T Bretz F L Briechle P Buchholz A Bueno S Buitink M Buscemi K S Caballero-Mora L Caccianiga L Calcagni A Cancio F Canfora I Caracas J M Carceller R Caruso A Castellina F Catalani G Cataldi L Cazon M Cerda J A Chinellato K Choi J Chudoba L Chytka R W Clay A C Cobos Cerutti R Colalillo A Coleman M R Coluccia R Conceição A Condorelli G Consolati F Contreras F Convenga C E Covault S Dasso K Daumiller B R Dawson J A Day R M de Almeida J de Jesús S J de Jong G De Mauro J R T de Mello Neto I De Mitri J de Oliveira D de Oliveira Franco V de Souza E De Vito J Debatin M Del Río O Deligny H Dembinski N Dhital C Di Giulio A Di Matteo M L Díaz Castro C Dobrigkeit J C D'Olivo Q Dorosti R C Dos Anjos M T Dova J Ebr R Engel I Epicoco M Erdmann C O Escobar A Etchegoyen H Falcke J Farmer G Farrar A C Fauth N Fazzini F Feldbusch F Fenu B Fick J M Figueira A Filipčič T Fodran M M Freire T Fujii A Fuster C Galea C Galelli B García A L Garcia Vegas H Gemmeke F Gesualdi A Gherghel-Lascu P L Ghia U Giaccari M Giammarchi M Giller J Glombitza F Gobbi F Gollan G Golup M Gómez Berisso P F Gómez Vitale J P Gongora N González I Goos D Góra A Gorgi M Gottowik T D Grubb F Guarino G P Guedes E Guido S Hahn R Halliday M R Hampel P Hansen D Harari V M Harvey A Haungs T Hebbeker D Heck G C Hill C Hojvat J R Hörandel P Horvath M Hrabovský T Huege J Hulsman A Insolia P G Isar J A Johnsen J Jurysek A Kääpä K H Kampert B Keilhauer J Kemp H O Klages M Kleifges J Kleinfeller M Köpke G Kukec Mezek B L Lago D LaHurd R G Lang M A Leigui de Oliveira V Lenok A Letessier-Selvon I Lhenry-Yvon D Lo Presti L Lopes R López R Lorek Q Luce A Lucero A Machado Payeras M Malacari G Mancarella D Mandat B C Manning J Manshanden P Mantsch S Marafico A G Mariazzi I C Mariş G Marsella D Martello H Martinez O Martínez Bravo M Mastrodicasa H J Mathes J Matthews G Matthiae E Mayotte P O Mazur G Medina-Tanco D Melo A Menshikov K-D Merenda S Michal M I Micheletti L Miramonti D Mockler S Mollerach F Montanet C Morello M Mostafá A L Müller M A Muller K Mulrey R Mussa M Muzio W M Namasaka L Nellen P H Nguyen M Niculescu-Oglinzanu M Niechciol D Nitz D Nosek V Novotny L Nožka A Nucita L A Núñez M Palatka J Pallotta M P Panetta P Papenbreer G Parente A Parra M Pech F Pedreira J Pȩkala R Pelayo J Peña-Rodriguez J Perez Armand M Perlin L Perrone C Peters S Petrera T Pierog M Pimenta V Pirronello M Platino B Pont M Pothast P Privitera M Prouza A Puyleart S Querchfeld J Rautenberg D Ravignani M Reininghaus J Ridky F Riehn M Risse P Ristori V Rizi W Rodrigues de Carvalho G Rodriguez Fernandez J Rodriguez Rojo M J Roncoroni M Roth E Roulet A C Rovero P Ruehl S J Saffi A Saftoiu F Salamida H Salazar G Salina J D Sanabria Gomez F Sánchez E M Santos E Santos F Sarazin R Sarmento C Sarmiento-Cano R Sato P Savina C Schäfer V Scherini H Schieler M Schimassek M Schimp F Schlüter D Schmidt O Scholten P Schovánek F G Schröder S Schröder A Schulz S J Sciutto M Scornavacche R C Shellard G Sigl G Silli O Sima R Šmída P Sommers J F Soriano J Souchard R Squartini M Stadelmaier D Stanca S Stanič J Stasielak P Stassi A Streich M Suárez-Durán T Sudholz T Suomijärvi A D Supanitsky J Šupík Z Szadkowski A Taboada A Tapia C Timmermans O Tkachenko P Tobiska C J Todero Peixoto B Tomé G Torralba Elipe A Travaini P Travnicek C Trimarelli M Trini M Tueros R Ulrich M Unger M Urban L Vaclavek M Vacula J F Valdés Galicia I Valiño L Valore A van Vliet E Varela B Vargas Cárdenas A Vásquez-Ramírez D Veberič C Ventura I D Vergara Quispe V Verzi J Vicha L Villaseñor J Vink S Vorobiov H Wahlberg A A Watson M Weber A Weindl L Wiencke H Wilczyński T Winchen M Wirtz D Wittkowski B Wundheiler A Yushkov O Zapparrata E Zas D Zavrtanik M Zavrtanik L Zehrer A Zepeda M Ziolkowski F Zuccarello

Phys Rev Lett 2020 Sep;125(12):121106

Università di Catania, Dipartimento di Fisica e Astronomia, Catania, Italy.

We report a measurement of the energy spectrum of cosmic rays above 2.5×10^{18}  eV based on 215 030 events. New results are presented: at about 1.3×10^{19}  eV, the spectral index changes from 2.51±0.03(stat)±0.05(syst) to 3.05±0.05(stat)±0.10(syst), evolving to 5.1±0.3(stat)±0.1(syst) beyond 5×10^{19}  eV, while no significant dependence of spectral features on the declination is seen in the accessible range. These features of the spectrum can be reproduced in models with energy-dependent mass composition. The energy density in cosmic rays above 5×10^{18}  eV is [5.66±0.03(stat)±1.40(syst)]×10^{53}  erg Mpc^{-3}.
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http://dx.doi.org/10.1103/PhysRevLett.125.121106DOI Listing
September 2020

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Epilepsia 2020 11 21;61(11):2461-2473. Epub 2020 Sep 21.

Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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http://dx.doi.org/10.1111/epi.16679DOI Listing
November 2020

Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa.

Cells 2020 09 16;9(9). Epub 2020 Sep 16.

Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, U-707 CIBERER, 28040 Madrid, Spain.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.
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http://dx.doi.org/10.3390/cells9092108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565802PMC
September 2020

Gastronomy and Tourism: Socioeconomic and Territorial Implications in Santiago de Compostela-Galiza (NW Spain).

Int J Environ Res Public Health 2020 08 25;17(17). Epub 2020 Aug 25.

School of Education, International University of La Rioja, 26006 Logroño, Spain.

It is a worldwide well-known fact that gastronomic tourism does not always contribute to the cultural, social, economic, and territorial development of the host community. Therefore, its study requires a multidisciplinary and holistic approach to explore and interpret this phenomenon. From this perspective, the paper analyses the consumption of food products by tourists in Santiago de Compostela in Spain (2013-2014). Personal interviews (2081) with visitors and food industry establishment representatives were done. Compared with the normal food consumption of the Galician population, the food production capacity established by the corresponding Santiago foodshed calculation, and with the gastronomy official advertising (tourism web pages analysed by multimodal analysis), the gastronomic tourist experience is standardized and poor, limited to practically two products: rice with lobster, and octopus. This standardization supposes a high reduction in the diversity of the product that can be offered and produced in terms of proximity, and its territorial differentiation, comparing to the usual consumption of the Galician population, to the potential agricultural production by associated foodshed, and to the gastronomic advertising through official web pages. Thus, in this case, gastronomic tourism is not contributing to the social, economic, and territorial development of the host community or, ultimately, to the sustainability of tourism.
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http://dx.doi.org/10.3390/ijerph17176173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504474PMC
August 2020

Transradial Secondary Approach During Transfemoral TAVI: Usefulness of Placing a Wire Before Femoral Puncture for Management and Treatment of Vascular Complications.

Cardiovasc Revasc Med 2021 Feb 3;23:94-99. Epub 2020 Aug 3.

Clinical Cardiology, HM Hospitales-Centro Integral de enfermedades Cardiovasculares HM-CIEC, Madrid, Spain.

Vascular complications during transcatheter aortic valve implantation (TAVI) are relatively common, and some of them related to the transfemoral secondary access. The use of the transradial access (TRA) as an alternative vascular approach for transfemoral TAVI could reduce these complications, however, the treatment of potential vascular peripheral issues from this access has been scarcely described. The advance of a wire from the TRA to the primary transfemoral access at the beginning of the procedure could help the management of eventual vascular complications. A new TRA technique during transfemoral TAVI procedures is described, reporting the results in the first forty-two patients in one center.
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http://dx.doi.org/10.1016/j.carrev.2020.07.024DOI Listing
February 2021

PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review.

Eur J Med Genet 2020 Nov 8;63(11):104033. Epub 2020 Aug 8.

Centre de Référence des Surdités Génétiques, Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP.Centre, Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, AP-HP.Centre, Paris, France; Laboratoire d'Embryologie et de Génétique des Malformations Congénitales, INSERM UMR 1163, Institut Imagine, Université Paris Descartes, Paris, France. Electronic address:

We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this rare condition, both in females and in males. Moreover, our observation of a new family in which hemizygous males display hearing loss without any neurological or ophthalmological symptoms prompts us to suggest analysing PRPS1 in cases of isolated hearing loss. Eventually, PRPS1 variants should be considered as a differential diagnosis of mitochondrial disorders.
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http://dx.doi.org/10.1016/j.ejmg.2020.104033DOI Listing
November 2020

Efficient CRISPR-Cas9-Mediated Gene Ablation in Human Keratinocytes to Recapitulate Genodermatoses: Modeling of Netherton Syndrome.

Mol Ther Methods Clin Dev 2020 Sep 11;18:280-290. Epub 2020 Jun 11.

Epithelial Biomedicine Division, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain.

Current efforts to find specific genodermatoses treatments and define precise pathogenesis mechanisms require appropriate surrogate models with human cells. Although transgenic and gene knockout mouse models for several of these disorders exist, they often fail to faithfully replicate the clinical and histopathological features of the human skin condition. We have established a highly efficient method for precise deletion of critical gene sequences in primary human keratinocytes, based on CRISPR-Cas9-mediated gene editing. Using this methodology, in the present study we generated a model of Netherton syndrome by disruption of . Gene-edited cells showed absence of LEKTI expression and were able to recapitulate a hyperkeratotic phenotype with most of the molecular hallmarks of Netherton syndrome, after grafting to immunodeficient mice and in organotypic cultures. To validate the model as a platform for therapeutic intervention, we tested an gene therapy approach using a lentiviral vector expressing . Re-expression of in an immortalized clone of -knockout keratinocytes was capable of reverting from Netherton syndrome to a normal skin phenotype and . Our results demonstrate the feasibility of modeling genodermatoses, such as Netherton syndrome, by efficiently disrupting the causative gene to better understand its pathogenesis and to develop novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.omtm.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329935PMC
September 2020

Persistent hypogammaglobulinemia in pediatric solid organ transplant recipients.

Clin Transplant 2020 10 17;34(10):e14021. Epub 2020 Aug 17.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

Introduction: Hypogammaglobulinemia has not been well studied in pediatric solid organ transplant (SOT) recipients. We evaluated plasma immunoglobulin (Ig) and lymphocyte phenotypes among 31 pediatric heart and kidney recipients for two years post-transplant and from 10 non-transplanted children.

Methods: Plasma IgM, IgG, and IgA were quantified by immunoturbidimetric assays, IgG subclasses were quantified by bead-based multiplex immunoassay, and lymphocyte phenotypes were assessed by flow cytometry.

Results: Median age at transplant for SOT recipients was similar to that of the control cohort (15 vs. 12.5 years, respectively; P = .61). Mean plasma IgG and IgM levels for SOT recipients fell significantly below the control cohort means by 1 month post-transplant (P < .001 for both) and remained lower than control levels at 12-18 months post-transplant. Heart recipients had lower frequencies of a CD4 naïve T lymphocytes relative to kidney recipients.

Conclusions: Hypogammaglobulinemia was prevalent and persistent among pediatric SOT recipients and may be secondary to immunosuppressive medications, as well as loss of thymus tissue and CD45RA   CD4 T cells in heart recipients. Limitations of our study include but are not limited to small sample size from a single center, lack of samples for all participants at every time point, and lack of peripheral blood mononuclear cell samples for the non-transplanted cohort.
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http://dx.doi.org/10.1111/ctr.14021DOI Listing
October 2020

AICA-ribosiduria due to ATIC deficiency: Delineation of the phenotype with three novel cases, and long-term update on the first case.

J Inherit Metab Dis 2020 11 9;43(6):1254-1264. Epub 2020 Jul 9.

Service de Génétique, CHU-Hôpital Nord, Saint-Etienne, France.

5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH (ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA-riboside in urine. AICA-ribosiduria had been reported in only one individual, 15 years ago. In this article, we report three novel cases of AICA-ribosiduria from two independent families, with two novel pathogenic variants in ATIC. We also provide a clinical update on the first patient. Based on the phenotypic features shared by these four patients, we define AICA-ribosiduria as the syndromic association of severe-to-profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features were observed in all four cases, especially neonatal/infancy coarse facies with upturned nose. Early-onset epilepsy is frequent and can be pharmacoresistant. Less frequently observed features are aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis. Alteration of the transformylase activity of ATIC might result in a more severe impairment than the alteration of the cyclohydrolase activity. Data from literature points toward a cytotoxic mechanism of the accumulated AICA-riboside.
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http://dx.doi.org/10.1002/jimd.12274DOI Listing
November 2020

The importance of immunity in the development of reliable animal models for psoriasis and atopic dermatitis.

Immunol Cell Biol 2020 09 15;98(8):626-638. Epub 2020 Jul 15.

Department of Bioengineering, Universidad Carlos III de Madrid, Leganés, 28911, Spain.

Psoriasis (PS) and atopic dermatitis (AD) are common inflammatory skin diseases characterized by an imbalance in specific T-cell subsets, resulting in a specific cytokine profile in patients. Obtaining models closely resembling both pathologies along with a relevant clinical impact is crucial for the development of new therapies because of the high prevalence of these diseases. Single-gene mouse models developed until now do not fully reflect the complexity of these disorders, in part not only because of inherent differences between mice and humans but also because of the multifactorial nature of these pathologies. The skin-humanized mouse model developed by our group, based on a tissue engineering approach, has been used to test therapeutic strategies, although this methodology is still technically challenging and not widely available. The skin-humanized mouse models for PS and AD reproduce human skin phenotypes, providing valuable tools for drug development and testing in the preclinical setting. The tissue engineering approach allows the development of personalized medicine, covering the broad genotypic spectrum of these pathologies. This review highlights the main differences between available murine models focusing on the tissue-specific immunity of PS and AD. We discuss their contribution to unravel the complex pathophysiology of these diseases and to translate this knowledge into more accurate therapies.
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http://dx.doi.org/10.1111/imcb.12365DOI Listing
September 2020

The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens.

Int J Mol Sci 2020 May 9;21(9). Epub 2020 May 9.

Transplantation Immunobiology, School of Biology and Biotechnology, Institute of Molecular Biology, Genomics and Proteomics, University of Leon, 24071 Leon, Spain.

Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.
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http://dx.doi.org/10.3390/ijms21093347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247540PMC
May 2020

Humanization of Tumor Stroma by Tissue Engineering as a Tool to Improve Squamous Cell Carcinoma Xenograft.

Int J Mol Sci 2020 Mar 12;21(6). Epub 2020 Mar 12.

Department of Bioengineering, Universidad Carlos III de Madrid, 28911 Leganés, Spain.

The role of stroma is fundamental in the development and behavior of epithelial tumors. In this regard, limited growth of squamous cell carcinomas (SCC) or cell-lines derived from them has been achieved in immunodeficient mice. Moreover, lack of faithful recapitulation of the original human neoplasia complexity is often observed in xenografted tumors. Here, we used tissue engineering techniques to recreate a humanized tumor stroma for SCCs grafted in host mice, by combining CAF (cancer associated fibroblasts)-like cells with a biocompatible scaffold. The stroma was either co-injected with epithelial cell lines derived from aggressive SCC or implanted 15 days before the injection of the tumoral cells, to allow its vascularization and maturation. None of the mice injected with the cell lines without stroma were able to develop a SCC. In contrast, tumors were able to grow when SCC cells were injected into previously established humanized stroma. Histologically, all of the regenerated tumors were moderately differentiated SCC with a well-developed stroma, resembling that found in the original human neoplasm. Persistence of human stromal cells was also confirmed by immunohistochemistry. In summary, we provide a proof of concept that humanized tumor stroma, generated by tissue engineering, can facilitate the development of epithelial tumors in immunodeficient mice.
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http://dx.doi.org/10.3390/ijms21061951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139348PMC
March 2020

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):338-355. Epub 2020 Feb 27.

Wessex Clinical Genetics, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 5YA, UK; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK. Electronic address:

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058823PMC
March 2020

Expanding the phenotype of mitochondrial disease: Novel pathogenic variant in ISCA1 leading to instability of the iron-sulfur cluster in the protein.

Mitochondrion 2020 05 21;52:75-82. Epub 2020 Feb 21.

Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France.

We report a patient carrying a novel pathogenic variant p.(Tyr101Cys) in ISCA1 leading to MMDS type 5. He initially presented a psychomotor regression with loss of gait and language skills and a tetrapyramidal spastic syndrome. Biochemical analysis of patient fibroblasts revealed impaired lipoic acid synthesis and decreased activities of complex I and II of respiratory chain. While ISCA1 is involved in the mitochondrial machinery for iron-sulfur cluster biogenesis, these dysfunctions are secondary to impaired maturation of mitochondrial proteins containing the [4Fe-4S] clusters. Expression and purification of the human ISCA1 showed a decreased stability of the [2Fe-2S] cluster in the mutated protein.
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http://dx.doi.org/10.1016/j.mito.2020.02.008DOI Listing
May 2020

Critical role of PD-L1 expression on non-tumor cells rather than on tumor cells for effective anti-PD-L1 immunotherapy in a transplantable mouse hematopoietic tumor model.

Cancer Immunol Immunother 2020 Jun 22;69(6):1001-1014. Epub 2020 Feb 22.

Transplantation Immunobiology Section, Institute of Molecular Biology, Proteomics and Genomics, University of Leon, Campus de Vegazana s/n, 24071, León, Spain.

The expression of PD-L1 on tumor cells or within the tumor microenvironment has been associated with good prognosis and sustained clinical responses in immunotherapeutic regimens based on PD-L1/PD-1/CD80 immune checkpoint blockade. To look into the current controversy in cancer immunotherapy of the relative importance of PD-L1 expression on tumor cells versus non-tumor cells of the tumor microenvironment, a hematological mouse tumor model was chosen. By combining a genetic CRISPR/Cas9 and immunotherapeutic approach and using a syngeneic hematopoietic transplantable tumor model (E.G7-cOVA tumor cells), we demonstrated that dual blockade of PD-L1 interaction with PD-1 and CD80 enhanced anti-tumor immune responses that either delayed tumor growth or led to its complete eradication. PD-L1 expression on non-tumor cells of the tumor microenvironment was required for the promotion of tumor immune escape and its blockade elicited potent anti-tumor responses to PD-L1 WT and to PD-L1-deficient tumor cells. PD-L1 tumors implanted in PD-L1-deficient mice exhibited delayed tumor growth independently of PD-L1 blockade. These findings emphasize that PD-L1 expression on non-tumor cells plays a major role in this tumor model. These observations should turn our attention to the tumor microenvironment in hematological malignancies because of its unappreciated contribution to create a conditioned niche for the tumor to grow and evade the anti-tumor immune response.
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http://dx.doi.org/10.1007/s00262-020-02520-zDOI Listing
June 2020

Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20.

Eur J Hum Genet 2020 08 18;28(8):1044-1055. Epub 2020 Feb 18.

Centre de Génétique et Centre de référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France.

Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
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http://dx.doi.org/10.1038/s41431-020-0582-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382504PMC
August 2020