RESUMEN
Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3' partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3' partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.
Asunto(s)
Neoplasias de los Tejidos Conjuntivo y Blando , Proteínas de Fusión Oncogénica , Proteína EWS de Unión a ARN , Neoplasias de los Tejidos Blandos , Humanos , Proteínas de Unión a Calmodulina/genética , Condrosarcoma/genética , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Proteínas de Unión al ARN/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genéticaRESUMEN
Tumor growth depends on the vascular system, either through the expansion of blood vessels or novel adaptation by tumor cells. One of these novel pathways is vasculogenic mimicry (VM), which is defined as a tumor-provided vascular system apart from endothelial cell-lined vessels, and its origin is partly unknown. It involves highly aggressive tumor cells expressing endothelial cell markers that line the tumor irrigation. VM has been correlated with high tumor grade, cancer cell invasion, cancer cell metastasis, and reduced survival of cancer patients. In this review, we summarize the most relevant studies in the field of angiogenesis and cover the various aspects and functionality of aberrant angiogenesis by tumor cells. We also discuss the intracellular signaling mechanisms involved in the abnormal presence of VE-cadherin (CDH5) and its role in VM formation. Finally, we present the implications for the paradigm of tumor angiogenesis and how targeted therapy and individualized studies can be applied in scientific analysis and clinical settings.
Asunto(s)
Antígenos CD , Neoplasias , Humanos , Línea Celular Tumoral , Antígenos CD/metabolismo , Cadherinas/metabolismo , Neovascularización Patológica/metabolismoRESUMEN
Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.
Asunto(s)
Neoplasias Óseas , Endoglina/metabolismo , Sarcoma de Ewing , Neoplasias Óseas/genética , Endoglina/genética , Humanos , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Proteómica , Receptores de Factores de Crecimiento , Sarcoma de Ewing/patología , Transducción de SeñalRESUMEN
YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Sarcoma de Ewing/genética , Transactivadores/metabolismo , Adulto , Anciano , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Vía de Señalización Hippo , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZRESUMEN
Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2-STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2-STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8-STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity.
Asunto(s)
Fusión Génica , Factores de Transcripción NFI/genética , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción STAT6/genética , Tumores Fibrosos Solitarios/genética , Tumores Fibrosos Solitarios/patología , Anciano , Femenino , Humanos , PronósticoRESUMEN
BACKGROUND: small intestinal bacterial overgrowth (SIBO) is a heterogeneous condition with nonspecific symptoms. This study aimed to report its management by pediatric gastroenterologists in Spain. METHODS: a descriptive study was performed by means of a survey sent to 184 active members of the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP). RESULTS: one hundred and forty-eight responses (80.4 %) were received. Forty-four patients had no predisposing condition, 31.1 % used antibiotics followed by probiotics, 33.1 % antibiotherapy concomitant with probiotics, 24.3 % only antibiotics and 10.8 % only probiotics. The diagnosis was established via clinical parameters in 73.8 % of participants and the therapeutic response was checked only by clinical data in 90 %. CONCLUSIONS: there is high variability in the management of SIBO among pediatric population in Spain.
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Infecciones Bacterianas , Gastroenterólogos , Gastroenterología , Probióticos , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/epidemiología , Niño , Humanos , España/epidemiologíaRESUMEN
BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here. METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15. FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]). INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour. FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
Asunto(s)
Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tumores Fibrosos Solitarios/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios Prospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tumores Fibrosos Solitarios/patología , Tasa de SupervivenciaRESUMEN
This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR-rearranged sarcomas, CIC-fused sarcomas) and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high-throughput techniques could be applied to sarcoma diagnosis in the short term. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Sarcoma de Ewing , Sarcoma de Células Pequeñas , Sarcoma/genética , Biomarcadores de Tumor/genética , Humanos , Reino UnidoRESUMEN
BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here. METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15. FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]). INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials. FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Tumores Fibrosos Solitarios/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Femenino , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias de los Tejidos Blandos/patología , Tumores Fibrosos Solitarios/patología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Análisis de SupervivenciaRESUMEN
Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR-200 family regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo.
Asunto(s)
Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/fisiología , MicroARNs/genética , Factores de Transcripción/fisiología , Animales , Metilación de ADN , Perros , Epigénesis Genética , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby , MicroARNs/metabolismo , Fenotipo , Regiones Promotoras Genéticas , Factores de Transcripción de la Familia Snail , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer.
Asunto(s)
Carcinoma/patología , Neoplasias Endometriales/patología , Transición Epitelial-Mesenquimal/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Western Blotting , Carcinoma/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Neoplasias Endometriales/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Xenoinjertos , Vía de Señalización Hippo , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Espectrometría de Masas , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismo , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZRESUMEN
Although it is becoming clear that certain miRNAs fulfil a fundamental role in the regulation of the epithelial-to-mesenchymal transition (EMT), a comprehensive study of the miRNAs associated with this process has yet to be performed. Here, we profiled the signature of miRNA expression in an in vitro model of EMT, ectopically expressing in MDCK cells one of seven EMT transcription factors (SNAI1, SNAI2, ZEB1, ZEB2, TWIST1, TWIST2 or E47) or the EMT inducer LOXL2. In this way, we identified a core subset of deregulated miRNAs that were further validated in vivo, studying endometrial carcinosarcoma (ECS), a tumour entity that represents an extreme example of phenotypic plasticity. Moreover, epigenetic silencing through DNA methylation of miRNA genes of the miR-200 family and miR-205 that are down-regulated during EMT was evident in both the in vitro (MDCK transfectants) and in vivo (ECS) models of EMT. The strong correlation between expression and DNA methylation suggests a major role for this epigenetic mark in the regulation of the miR-141-200c locus.
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Carcinosarcoma/genética , Neoplasias Endometriales/genética , Transición Epitelial-Mesenquimal/genética , MicroARNs/genética , Transcriptoma/genética , Animales , Western Blotting , Línea Celular Tumoral , Metilación de ADN/genética , Perros , Femenino , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa , TransfecciónRESUMEN
INTRODUCTION: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community. MATERIAL: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25⯵mol/L. RESULTS: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500â¯g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life. CONCLUSIONS: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas , Glutaril-CoA Deshidrogenasa , Tamizaje Neonatal , Humanos , Tamizaje Neonatal/métodos , Recién Nacido , Estudios Retrospectivos , Glutaril-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Masculino , Femenino , Encefalopatías Metabólicas/diagnóstico , Espectrometría de Masas en Tándem , Glutaratos/sangre , Edad Gestacional , Carnitina/análogos & derivadosRESUMEN
Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (â¼33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.
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Biomarcadores de Tumor/análisis , Cadherinas/análisis , Carcinoma/química , Diferenciación Celular , Neoplasias Endometriales/química , Proteínas de Homeodominio/análisis , MicroARNs/análisis , Factores de Transcripción/análisis , Antígenos CD , Biomarcadores de Tumor/genética , Cadherinas/genética , Carcinoma/genética , Carcinoma/patología , Metilación de ADN , Reparación de la Incompatibilidad de ADN , Regulación hacia Abajo , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Clasificación del Tumor , Valor Predictivo de las Pruebas , Pronóstico , Regiones Promotoras Genéticas , España , Proteína p53 Supresora de Tumor/análisis , Estados Unidos , Regulación hacia Arriba , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
OBJECTIVE: The aim of the present study was to explore the relation between lung function and serum retinol (SR) in cystic fibrosis (CF) patients. METHODS: This was a cross-sectional study conducted in a group of 98 young patients with CF (6.8-22.3 years), after the exclusion of those with pulmonary exacerbation, vitamin A deficiency, or other risks, from an initial group of 124 cases. RESULTS: Data of forced expiratory volume in 1 second (FEV1) were widely scattered (87.7% ± 16.9%). These were similar in the 78 pancreatic insufficient and 11 pancreatic sufficient patients. SR (56.6 ± 18.4 µg/dL) was >2.5th percentile of healthy people in the whole group, although 31 patients were situated above the 97.5th percentile (higher value: 110 µg/dL). The FEV1 was noticeably higher in these than in those within the normal range (93.6 ± 14.0 vs 85.0 ± 17.6 µg/dL; P < 0.05). The z score of SR correlated positively with FEV1 (r = 0.364; P = 0.000), after adjusting data for sex, age, body mass index, and pancreatic function. The odds ratio for a FEV1 >80% is 3.78 in patients with SR above the 97.5th percentile, versus only 0.26 in those within the normal range. There were no cases with retinol toxicity. CONCLUSIONS: FEV1 of young patients with CF correlates positively with SR, regardless of age, pancreatic function, or nutritional condition. Those with a moderately high retinol (up to 110 µg/dL) maintain the best respiratory function (FEV1 ≥80% in >90% of them) without any signs of toxicity.
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Fibrosis Quística/sangre , Fibrosis Quística/fisiopatología , Pulmón/fisiopatología , Regulación hacia Arriba , Vitamina A/sangre , Adolescente , Adulto , Antioxidantes/efectos adversos , Antioxidantes/análisis , Antioxidantes/uso terapéutico , Índice de Masa Corporal , Niño , Estudios de Cohortes , Estudios Transversales , Fibrosis Quística/dietoterapia , Suplementos Dietéticos/efectos adversos , Insuficiencia Pancreática Exocrina/etiología , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Oportunidad Relativa , Estrés Oxidativo , Estudios Prospectivos , Delgadez/etiología , Vitamina A/efectos adversos , Vitamina A/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: In pediatric clinical practice, it is common to be asked about the presence of black stains on teeth in children and teenagers. According to controversial etiology, it is known to be related to a low rate of caries. The aim of this study was to determine the prevalence of black stain and associated risk factors in Spanish preschool children. METHODS: A total of 3272 children aged 6 years old (3058 non-emigrant and 214 immigrant children) living in Oviedo (Spain), were enrolled in the present study. RESULTS: The prevalence of black stain was 3.1% in the whole group. The index of primary decayed, missing, and filled teeth (dmft index) associated with black stain was 0.35 ± 1.123. A statistical association between black stain and the consumption of iron supplements was noted. CONCLUSIONS: The regular consumption of foods rich in iron and the use of iron supplements during pregnancy and early childhood, could favor the development of chromogenic microbiota. The prevalence of black stain did not differ significantly between non-emigrant and immigrant children in Spain.
Asunto(s)
Emigrantes e Inmigrantes/estadística & datos numéricos , Decoloración de Dientes/epidemiología , Niño , Índice CPO , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Compuestos de Hierro/administración & dosificación , Compuestos de Hierro/efectos adversos , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Factores de Riesgo , España , Decoloración de Dientes/diagnóstico , Decoloración de Dientes/etiologíaRESUMEN
Introduction: The COVID-19 pandemic forced a change in the working dynamics of all healthcare professionals, leading to the sudden introduction of telemedicine. Although until that moment telemedicine applications had been described in the paediatric age, their use was anecdotal. Objective: To analyse the experience of Spanish paediatricians after the forced digitization of consultations due to the pandemic. Methods: A cross-sectional survey-type study was designed to obtain information from Spanish paediatricians about the changes that took place in the usual clinical practice. Results: 306 health professionals participated in the study Most of them agreed on the use of the internet and social networks during the pandemic, referring to mail or WhatsApp® as usual channels of communication with their patients' families. There was a great agreement among paediatricians that the evaluation of newborns after hospital discharge and establishing methodologies that allow childhood vaccination and the identification of subsidiary patients for face-to-face evaluation were necessary although the limitations of the lockdown. The idea that telephone and digital consultations have optimized the consultation time and that they will probably continue after the end of the pandemic was generally accepted. No changes in adherence to breastfeeding or the start of complementary feeding were referred to, but an increase in the duration of breastfeeding and the appearance of frequent hoaxes in social networks concerning infant feeding were found. Conclusions: It is necessary to analyse the impact of telemedicine in paediatric consultations during the pandemic to evaluate its effectiveness and quality to maintain it in routine paediatric practice.
RESUMEN
One of the most common food allergies in children is cow's milk allergy (CMA). In breast-fed infants with CMA, the mother is encouraged to avoid dairy products. If this is not possible, or in formula fed infants, use of hypoallergenic replacement formulas such as extensively hydrolyzed formulas (EHF) is recommended. However, in â¼5% of patients EHFs are not tolerated and/or allergy symptoms can persist. When EHFs are ineffective and in severe forms of CMA, amino acid-based formulas (AAF) should be considered. Six pediatric gastroenterologists with extensive experience in food allergy management reviewed scientific publications and international clinical practice guidelines to provide practical recommendations on AAF. The guidelines reviewed had discrepancies and ambiguities around the specific indications for using formulas as a milk substitute. The panel recommends AAFs as the first therapeutic option in anaphylaxis due to CMA, in acute and chronic severe food protein-induced enterocolitis syndrome, in CMA associated with multiple food allergy, and in cases of eosinophilic esophagitis not responding to an extended exclusion diet or not eating solids. The main benefit of AAF is its absence of residual allergenicity, making it a safe treatment option in severe CMA patients who do not tolerate or respond to an EHF.
RESUMEN
Management of cow's milk protein allergy (CMPA) can vary depending on the experience and area of expertise of the clinician responsible for the patient's follow-up, which may or may not align with the recently published literature. To analyze the perspectives of Spanish pediatricians on this topic, a survey was conducted. The survey aimed to determine the current opinions and attitudes of 222 primary care and hospital pediatricians toward CMPA prevention and nutritional management. Participating pediatricians completed the questionnaire, providing insights into their daily clinical practices, including access to testing, attitudes with respect to various aspects of CMPA diagnosis, prevention, oral food challenges, and treatment. The findings revealed that pediatricians generally agree on the use of extensively hydrolyzed formulas (eHFs) to prevent CMPA in high-risk atopic children, despite limited evidence supporting the widespread use of this practice. However, consensus was lacking regarding the utility of formulas with prebiotics and probiotics for expediting tolerance development. In most cases, pediatricians preferred eHFs for the nutritional management of CMPA, followed by hydrolyzed rice formulas (HRFs), with amino-acid-based formulas (AAFs) being the third option. Certain issues remained controversial among pediatricians, such as prevention methods, symptom assessment, and the role of probiotics. These variations in management approaches reflect the influence of clinician experience and area of expertise, underscoring the need for standardized guidelines in this field.