RESUMEN
Therapeutic irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, hence causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. Such mechanisms include the selective elimination of particularly radiosensitive cell types and consequent loss of specific cellular functions, the local release of cytokines and danger signals by dying radiosensitive cells, and altered cytokine secretion by surviving radioresistant cells. Altogether, these processes create chemotactic and immunomodulatory cues for incoming and resident immune cells. Here we discuss how cytoprotective and cytotoxic signaling modules activated by radiation in specific cell populations reshape the immunological tumor microenvironment.
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Muerte Celular/efectos de la radiación , Transducción de Señal/inmunología , Transducción de Señal/efectos de la radiación , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación , Animales , HumanosRESUMEN
Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.
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Trampas Extracelulares/metabolismo , Neoplasias Experimentales/terapia , Receptores de Quimiocina/agonistas , Receptores de Interleucina-8A/agonistas , Receptores de Interleucina-8B/agonistas , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica/inmunología , Células HT29 , Humanos , Microscopía Intravital/métodos , Células Asesinas Naturales/inmunología , Ligandos , Ratones , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Receptores de Quimiocina/inmunología , Receptores de Quimiocina/metabolismo , Receptores de Interleucina-8A/inmunología , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/inmunología , Receptores de Interleucina-8B/metabolismo , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Antigen cross-priming of CD8+ T cells is a critical process necessary for the effective expansion and activation of CD8+ T cells endowed with the ability to recognize and destroy tumor cells. The cross-presentation of tumor antigens to cross-prime CD8+ T cells is mainly mediated, if not only, by a subset of professional antigen-presenting cells termed type-1 conventional dendritic cells (cDC1). The demise of malignant cells can be immunogenic if it occurs in the context of premortem stress. These ways of dying are termed immunogenic cell death (ICD) and are associated with biochemical features favoring cDC1 for the efficient cross-priming of tumor antigens. Immunosurveillance and the success of immunotherapies heavily rely on the ability of cytotoxic immune cells, primarily CD8+ T cells and NK cells, to detect and eliminate tumor cells through mechanisms collectively known as cytotoxicity. Recent studies have revealed the significance of NK- and CTL-mediated cytotoxicity as a prominent form of immunogenic cell death, resulting in mechanisms that promote and sustain antigen-specific immune responses. This review focuses on the mechanisms underlying the cross-presentation of antigens released during tumor cell killing by cytotoxic immune cells, with an emphasis on the role of cDC1 cells. Indeed, cDC1s are instrumental in the effectiveness of most immunotherapies, underscoring the significance of tumor antigen cross-priming in contexts of immunogenic cell death. The notion of the potent immunogenicity of cell death resulting from NK or cytotoxic T lymphocyte (CTL)-mediated cytotoxicity has far-reaching implications for cancer immunotherapy.
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Linfocitos T CD8-positivos , Reactividad Cruzada , Humanos , Presentación de Antígeno , Muerte Celular Inmunogénica , Antígenos de Neoplasias , Células DendríticasRESUMEN
The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."
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Encefalopatías , Moléculas de Adhesión Celular , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Animales , Ratones , Alelos , Encefalopatías/genética , Moléculas de Adhesión Celular/genética , Células Endoteliales/metabolismo , Hemorragias Intracraneales/genética , Malformaciones del Sistema Nervioso/genética , Trastornos del Neurodesarrollo/genética , Uniones Estrechas/genética , HumanosRESUMEN
C-REPEAT BINDING FACTORS (CBFs) are highly conserved plant transcription factors that promote cold tolerance. In Arabidopsis (Arabidopsis thaliana), three CBFs (CBF1 to CBF3) play a critical role in cold acclimation, and the expression of their corresponding genes is rapidly and transiently induced during this adaptive response. Cold induction of CBFs has been extensively studied and shown to be tightly controlled, yet the molecular mechanisms that restrict the expression of each CBF after their induction during cold acclimation are poorly understood. Here, we present genetic and molecular evidence that the decline in the induction of CBF3 during cold acclimation is epigenetically regulated through the Polycomb Repressive Complex (PRC) 2. We show that this complex promotes the deposition of the repressive mark H3K27me3 at the coding region of CBF3, silencing its expression. Our results indicate that the cold-inducible long noncoding RNA SVALKA is essential for this regulation by recruiting PRC2 to CBF3. These findings unveil a SVALKA-PRC2 regulatory module that ensures the precise timing of CBF3 induction during cold acclimation and the correct development of this adaptive response.
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Aclimatación , Proteínas de Arabidopsis , Arabidopsis , Frío , Regulación de la Expresión Génica de las Plantas , Complejo Represivo Polycomb 2 , Arabidopsis/genética , Arabidopsis/fisiología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Aclimatación/genética , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Histonas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1-3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2-/-Il2rg-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.
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Anticuerpos Monoclonales/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Inmunoterapia/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores del Factor de Necrosis Tumoral/farmacología , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/inmunología , Colitis/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Sulfato de Dextran/farmacología , Femenino , Enfermedad Injerto contra Huésped , Hepatitis/tratamiento farmacológico , Humanos , Ipilimumab/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Discovery of deafness genes and elucidating their functions have substantially contributed to our understanding of hearing physiology and its pathologies. Here we report on DNA variants in MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness. Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities. MINAR2 is a recently annotated gene with limited functional understanding. We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL). The c.393G > T variant is shown to disrupt a splice donor site. We show that Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis. Mice with loss of function of the Minar2 protein (Minar2tm1b/tm1b) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age. We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL. Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies.
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Pérdida Auditiva Sensorineural , Receptor Notch2 , Receptores de Superficie Celular , Animales , Pérdida Auditiva Sensorineural/genética , Humanos , Mutación con Pérdida de Función , Ratones , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores de Superficie Celular/genética , Estereocilios/metabolismoRESUMEN
Motor improvements, such as faster movement times or increased velocity, have been associated with reward magnitude in deterministic contexts. Yet whether individual inferences on reward probability influence motor vigor dynamically remains undetermined. We investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial. We conducted three studies that coupled a reversal learning paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. In Study 1, we tested healthy younger [HYA; 37 (24 females)] and older adults [HOA; 37 (17 females)], and medicated Parkinson's disease (PD) patients [20 (7 females)]. We showed that stronger predictions about the tendency of the action-reward contingency led to faster performance tempo, commensurate with movement time, on a trial-by-trial basis without robustly modulating reaction time (RT). Using Bayesian linear mixed models, we demonstrated a similar invigoration effect on performance tempo in HYA, HOA, and PD, despite HOA and PD being slower than HYA. In Study 2 [HYA, 39 (29 females)], we additionally showed that retrospective subjective inference about credit assignment did not contribute to differences in motor vigor effects. Last, Study 3 [HYA, 33 (27 females)] revealed that explicit beliefs about the reward tendency (confidence ratings) modulated performance tempo trial-by-trial. Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster tempo. We also provide robust evidence for a preserved sensitivity of motor vigor to inferences about the action-reward mapping in aging and medicated PD.SIGNIFICANCE STATEMENT Navigating a world rich in uncertainty relies on updating beliefs about the probability that our actions lead to reward. Here, we investigated how inferring the action-reward contingencies in a volatile environment modulated motor vigor trial-by-trial in healthy younger and older adults, and in Parkinson's disease (PD) patients on medication. We found an association between trial-by-trial predictions about the tendency of the action-reward contingency and performance tempo, with stronger expectations speeding the movement. We additionally provided evidence for a similar sensitivity of performance tempo to the strength of these predictions in all groups. Thus, dynamic beliefs about the changing relationship between actions and their outcome enhanced motor vigor. This positive bias was not compromised by age or Parkinson's disease.
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Envejecimiento Saludable , Enfermedad de Parkinson , Femenino , Humanos , Anciano , Enfermedad de Parkinson/complicaciones , Motivación , Teorema de Bayes , Estudios Retrospectivos , Recompensa , ProbabilidadRESUMEN
Homeostasis constitutes a key concept in physiology and refers to self-regulating processes that maintain internal stability when adjusting to changing external conditions. It diminishes internal entropy constituting a driving force behind evolution. Natural selection might act on homeostatic regulatory mechanisms and control mechanisms including homeodynamics, allostasis, hormesis and homeorhesis, where different stable stationary states are reached. Regeneration is under homeostatic control through hormesis. Damage to tissues initiates a response to restore the impaired equilibrium caused by mild stress using cell proliferation, cell differentiation and cell death to recover structure and function. Repair is a homeorhetic change leading to a new stable stationary state with decreased functionality and fibrotic scarring without reconstruction of the 3-D pattern. Mechanisms determining entrance of the tissue or organ to regeneration or repair include the balance between innate and adaptive immune cells in relation to cell plasticity and stromal stem cell responses, and redox balance. The regenerative and reparative capacities vary in different species, distinct tissues and organs, and at different stages of development including ageing. Many cell signals and pathways play crucial roles determining regeneration or repair by regulating protein synthesis, cellular growth, inflammation, proliferation, autophagy, lysosomal function, metabolism and metalloproteinase cell signalling. Attempts to favour the entrance of damaged tissues to regeneration in those with low proliferative rates have been made; however, there are evolutionary constraint mechanisms leading to poor proliferation of stem cells in unfavourable environments or tumour development. More research is required to better understand the regulatory processes of these mechanisms.
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Evolución Biológica , Homeostasis , Regeneración , Homeostasis/fisiología , Animales , Humanos , Regeneración/fisiologíaRESUMEN
Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.
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Conexina 30 , Pérdida Auditiva , Animales , Ratones , Conexina 26/genética , Conexina 30/genética , Modelos Animales de Enfermedad , Pérdida Auditiva/genética , Mutación , FenotipoRESUMEN
BACKGROUND: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. METHODS: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. RESULTS: Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. CONCLUSIONS: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. TRIAL REGISTRATION: EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912.
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Neoplasias Colorrectales , Neoplasias Pulmonares , Radiocirugia , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Colorrectales/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Radiocirugia/efectos adversos , Adulto Joven , Adulto , Anciano , Anciano de 80 o más Años , FemeninoRESUMEN
The pathophysiology and genetic risk for sickle cell disease (SCD)-related chronic kidney disease (CKD) are not well understood. In 70 adults with SCD-related CKD and without APOL1 inherited in a high-risk pattern, 24 (34%) had pathogenic variants in candidate genes using KidneySeq™. A moderate impact INF2 variant was observed in 20 (29%) patients and those with 3 versus 0-2 pathogenic or moderate impact glomerular genetic variants had higher albuminuria and lower estimated glomerular filtration rate (adjusted p ≤ 0.015). Using a panel of preselected genes implicated in kidney health, we observed several variants in people with sickle cell nephropathy.
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Anemia de Células Falciformes , Insuficiencia Renal Crónica , Humanos , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/complicaciones , Masculino , Femenino , Adulto , Persona de Mediana Edad , Prevalencia , Insuficiencia Renal Crónica/genética , Variación Genética , Tasa de Filtración Glomerular , Apolipoproteína L1/genética , Predisposición Genética a la EnfermedadRESUMEN
Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel.
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Biomarcadores , Inmunodeficiencia Variable Común , Humanos , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Modelos Logísticos , Adulto Joven , Adolescente , Anciano , Cadenas kappa de Inmunoglobulina/sangre , Cadenas kappa de Inmunoglobulina/genética , Sensibilidad y Especificidad , Linfocitos B/inmunología , Cadenas lambda de Inmunoglobulina , Células B de Memoria/inmunologíaRESUMEN
BACKGROUND: The periderm is basic for land plants due to its protective role during radial growth, which is achieved by the polymers deposited in the cell walls. In most trees, like holm oak, the first periderm is frequently replaced by subsequent internal periderms yielding a heterogeneous outer bark made of a mixture of periderms and phloem tissues, known as rhytidome. Exceptionally, cork oak forms a persistent or long-lived periderm which results in a homogeneous outer bark of thick phellem cell layers known as cork. Cork oak and holm oak distribution ranges overlap to a great extent, and they often share stands, where they can hybridize and produce offspring showing a rhytidome-type bark. RESULTS: Here we use the outer bark of cork oak, holm oak, and their natural hybrids to analyse the chemical composition, the anatomy and the transcriptome, and further understand the mechanisms underlying periderm development. We also include a unique natural hybrid individual corresponding to a backcross with cork oak that, interestingly, shows a cork-type bark. The inclusion of hybrid samples showing rhytidome-type and cork-type barks is valuable to approach cork and rhytidome development, allowing an accurate identification of candidate genes and processes. The present study underscores that abiotic stress and cell death are enhanced in rhytidome-type barks whereas lipid metabolism and cell cycle are enriched in cork-type barks. Development-related DEGs showing the highest expression, highlight cell division, cell expansion, and cell differentiation as key processes leading to cork or rhytidome-type barks. CONCLUSION: Transcriptome results, in agreement with anatomical and chemical analyses, show that rhytidome and cork-type barks are active in periderm development, and suberin and lignin deposition. Development and cell wall-related DEGs suggest that cell division and expansion are upregulated in cork-type barks whereas cell differentiation is enhanced in rhytidome-type barks.
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Corteza de la Planta , Quercus , Quercus/genética , Quercus/crecimiento & desarrollo , Corteza de la Planta/genética , Corteza de la Planta/química , Corteza de la Planta/metabolismo , Transcriptoma , Hibridación Genética , Pared Celular/metabolismo , Regulación de la Expresión Génica de las Plantas , LípidosRESUMEN
OBJECTIVES: While an increase in the levels of MDR in Salmonella enterica sevorar Choleraesuis has been reported in Europe, little is known about the situation in Spain. Therefore, we first aimed to assess the phenotypic resistance profile and to determine the presence of genetic determinants of resistance of S. Choleraesuis isolates collected in animal and human. Our second objective was to identify and characterize clusters of highly related isolates. METHODS: We analysed 50 human and 45 animal isolates retrieved from 2006 to 2021 using the disc diffusion method and performed WGS followed by analyses of genetic determinants and phylogenetic analysis. RESULTS: All isolates were of ST145 and corresponded to the variant Kunzendorf. Swine isolates harboured a significantly higher number of antimicrobial resistance genes than human isolates, and often carried plasmid replicons of the IncHI2/IncHI2A type (42% of all animal isolates). In addition, we identified several MDR S. Choleraesuis strains circulating in humans and swine between 2006 and 2021. The phylogenetic analyses identified four clades associated with specific patterns of resistance genes and plasmid replicons. The clades also included isolates that differed in terms of year and region of isolation as well as host of origin. CONCLUSIONS: This One Health approach highlights that reducing human MDR S. Choleraesuis infections may require the adoption of strategies that not only seek to prevent cases in humans but also to characterize and reduce the infection burden in swine.
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Antiinfecciosos , Salmonelosis Animal , Salmonella enterica , Salmonella , Humanos , Porcinos , Animales , Antibacterianos/farmacología , España/epidemiología , Serogrupo , Filogenia , Salmonelosis Animal/epidemiología , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana Múltiple/genéticaRESUMEN
AIMS: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. METHODS AND RESULTS: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs. CONCLUSION: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs.
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Neoplasias Renales , Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Teratoma , Tumor de Wilms , Masculino , Femenino , Humanos , Variaciones en el Número de Copia de ADN , Tumor de Wilms/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Teratoma/genética , Teratoma/patología , Neoplasias Renales/genética , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
OBJECTIVES: Attenuation of otoacoustic emissions over time has been reported for many patients with hearing impairment harboring mutations in the OTOF gene. In this study, the time course of changes of distortion product otoacoustic emissions (DPOAEs) has been analyzed in a cohort of patients in the light of tympanometry results. DESIGN: The changes of DPOAEs in 16 patients with OTOF -related hearing impairment were retrospectively analyzed. RESULTS: All but one subject showed DPOAEs bilaterally at the time of diagnosis. Three patients diagnosed as adults still had DPOAEs at ages of 27, 31, and 47 years, respectively. Follow-up was available for 7 children diagnosed at the age of 1 to 3 years, who still showed preservation of DPOAEs at ages of 5 to 16 years. The responses were absent or attenuated in amplitude at some follow-up appointments in association with type B or C tympanograms. CONCLUSIONS: DPOAEs are preserved much longer than expected in a cohort of patients with OTOF -related hearing impairment. The previously reported loss of DPOAEs may have been caused in some children by increased middle ear impedance due to otitis media.
Asunto(s)
Pérdida Auditiva , Adulto , Niño , Humanos , Lactante , Preescolar , Estudios Retrospectivos , Pérdida Auditiva/diagnóstico , Emisiones Otoacústicas Espontáneas/fisiología , Pruebas de Impedancia Acústica , Oído Medio , Audiometría de Tonos Puros , Umbral Auditivo/fisiología , Proteínas de la MembranaRESUMEN
PURPOSE: The diagnosis of a disease such as breast cancer (BC) can be experienced as a sudden, unexpected, and life-threatening event accompanied by considerable uncertainty. This experience can precipitate the development of post-traumatic symptoms and depression. Conversely, certain individuals exhibit the capacity to reframe this traumatic event and transform it into an opportunity for personal growth. Existing research shows that individuals with high trait emotional intelligence (trait EI) tend to experience fewer post-traumatic stress symptoms (PTS), and greater post-traumatic growth (PTG). The aim of this study was to investigate the interrelationship among these variables and specifically examine whether PTS and PTG play a mediating role between trait EI, depression, and life satisfaction. METHODS: Questionnaires were administered to 338 women with BC to assess trait EI, PTS, PTG, depression, and life satisfaction. RESULTS: Results highlighted that trait EI was negatively related to PTS and depression and positively related to PTG and life satisfaction. In addition, both PTS and PTG showed a mediating role in the relationship between trait EI, depression, and life satisfaction. This study highlights the close link between depressive symptoms and post-traumatic cognitions in women with BC. CONCLUSION: Current findings highlight links between trait EI, PTS, PTG, depressive symptoms, and life satisfaction. Clinicians could use these findings when developing interventions aimed at alleviating PTS, such as low mood and worry, and facilitating PTG. This study demonstrated that trait EI can reduce PTS and increase PTG, therefore it is important to include programs aimed at fostering trait EI.
Asunto(s)
Neoplasias de la Mama , Depresión , Inteligencia Emocional , Satisfacción Personal , Trastornos por Estrés Postraumático , Humanos , Femenino , Neoplasias de la Mama/psicología , Persona de Mediana Edad , Depresión/psicología , Adulto , Encuestas y Cuestionarios , Trastornos por Estrés Postraumático/psicología , Crecimiento Psicológico Postraumático , Anciano , Adaptación PsicológicaRESUMEN
PURPOSE: Recent studies have highlighted the potential role of a short lingual frenulum as a risk factor for pediatric obstructive sleep apnea syndrome. A shortened frenulum may contribute to abnormal orofacial development, leading to increased upper airway resistance and susceptibility to upper airway collapsibility during sleep. Recognizing early indicators, such as a short lingual frenulum, is crucial for prompt intervention. This systematic review aims to evaluate the association between a short lingual frenulum and the risk of obstructive sleep apnea syndrome in children. METHODS: This systematic review adheres to PRISMA criteria for a quantitative analysis. A comprehensive search was conducted on five databases until January 2024 to identify relevant studies. The selected articles underwent rigorous analysis, considering study design, sample characteristics, lingual frenulum characterization, sleep assessment methods, and key findings. RESULTS: A total of 239 references were initially identified. Finally, six studies were included in the qualitative synthesis, with four studies eligible for the quantitative synthesis. The Newcastle-Ottawa scale was employed to assess study quality. Meta-analysis, supported by a moderate evidence profile according to the GRADE scale, revealed statistically significant differences, with odds ratios of 3.051 (confidence interval: 1.939 to 4.801) for a short frenulum and 12.304 (confidence interval: 6.141 to 24.653) for a high-arched palate. CONCLUSION: This systematic review and meta-analysis provide evidence supporting the association between ankyloglossia and obstructive sleep apnea in children. Nevertheless, it is crucial to consider additional factors such as tongue mobility and the presence of a high-arched palate in further evaluations.