RESUMEN
BACKGROUND: Although the implication of receptor of advanced glycation endproducts (RAGE) has been reported in coronary artery disease, its roles in coronary artery ectasia (CAE) have remained undetermined. Furthermore, the effect of RAGE polymorfisms were not well-defined in scope of soluble RAGE (sRAGE) levels. Thus, we aimed to investigate the influence of the functional polymorphisms of RAGE -374T > A (rs1800624) and G82S (rs2070600) in CAE development. METHODS: This prospective observational study was conducted in 2 groups selected of 2452 patients who underwent elective coronary angiography (CAG) for evaluation after positive noninvasive heart tests. Group-I included 98 patients with non-obstructive coronary artery disease and CAE, and Group-II (control) included 100 patients with normal coronary arteries. SNPs were genotyped by real-time PCR using Taqman® genotyping assay. Serum sRAGE and soluble lectin-like oxidized receptor-1 (sOLR1) were assayed by ELISA and serum lipids were measured enzymatically. RESULTS: The frequencies of the RAGE -374A allele and -374AA genotype were significantly higher in CAE patients compared to controls (p < 0.001). sRAGE levels were not different between study groups, while sOLR1 levels were elevated in CAE (p = 0.004). In controls without systemic disease, -374A allele was associated with low sRAGE levels (p < 0.05), but this association was not significant in controls with HT. Similarly, sRAGE levels of CAE patients with both HT and T2DM were higher than those no systemic disease (p = 0.02). The -374A allele was also associated with younger patient age and higher platelet count in the CAE group in both total and subgroup analyses. In the correlation analyses, the -374A allele was also negatively correlated with age and positively correlated with Plt in all of these CAE groups. In the total CAE group, sRAGE levels also showed a positive correlation with age and a negative correlation with HDL-cholesterol levels. On the other hand, a negative correlation was observed between sRAGE and Plt in the total, hypertensive and no systemic disease control subgroups. Multivariate logistic regression analysis confirmed that the -374A allele (p < 0.001), hyperlipidemia (p < 0.05), and high sOLR1 level (p < 0.05) are risk factors for CAE. ROC curve analysis shows that RAGE -374A allele has AUC of 0.713 (sensitivity: 83.7 %, specificity: 59.0 %), which is higher than HLD (sensitivity: 59.2 %, specificity: 69.0 %), HT (sensitivity: 62.4 %, specificity: 61.1 %) and high sOLR1 level (≥0.67 ng/ml)) (sensitivity: 59.8 %, specificity: 58.5 %). CONCLUSION: Beside the demonstration of the relationship between -374A allele and increased risk of CAE for the first time, our results indicate that antihypertensive and antidiabetic treatment in CAE patients causes an increase in sRAGE levels. The lack of an association between the expected -374A allele and low sRAGE levels in total CAE group was attributed to the high proportion of hypertensive patients and hence to antihypertensive treatment. Moreover, the RAGE -374A allele is associated with younger age at CAE and higher Plt, suggesting that -374A may also be associated with platelet activation, which plays a role in the pathogenesis of CAE. However, our data need to be confirmed in a large study for definitive conclusions.
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Enfermedad de la Arteria Coronaria , Polimorfismo de Nucleótido Simple , Receptor para Productos Finales de Glicación Avanzada , Humanos , Femenino , Masculino , Persona de Mediana Edad , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/sangre , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/sangre , Estudios Prospectivos , Anciano , Dilatación Patológica/genética , Predisposición Genética a la Enfermedad , Receptores Depuradores de Clase E/genética , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Estudios de Casos y Controles , Alelos , Angiografía Coronaria , Frecuencia de los Genes , Genotipo , Proteínas Relacionadas con Receptor de LDL , Proteínas de Transporte de MembranaRESUMEN
PURPOSE: Dural ectasia (DE) may significantly impact Marfan syndrome (MFS) patients' quality of life due to chronic lower back pain, postural headache and urinary disorders. We aimed to evaluate the association of quantitative measurements of DE, and their evolution over time, with demographic, clinical and genetic characteristics in a cohort of MFS patients. METHODS: We retrospectively included 88 consecutive patients (39% females, mean age 37.1 ± 14.2 years) with genetically confirmed MFS who underwent at least one MRI or CT examination of the lumbosacral spine. Vertebral scalloping (VS) and dural sac ratio (DSR) were calculated from L3 to S3. Likely pathogenic or pathogenic FBN1 variants were categorized as either protein-truncating or in-frame. The latter were further classified according to their impact on the cysteine content of fibrillin-1. RESULTS: Higher values of the systemic score (revised Ghent criteria) were associated with greater DSR at lumbar (p < 0.001) and sacral (p = 0.021) levels. Patients with protein-truncating variants exhibited a greater annual increase in lumbar (p = 0.039) and sacral (p = 0.048) DSR. Mutations affecting fibrillin-1 cysteine content were linked to higher VS (p = 0.009) and DSR (p = 0.038) at S1, along with a faster increase in VS (p = 0.032) and DSR (p = 0.001) in the lumbar region. CONCLUSION: Our study shed further light on the relationship between genotype, dural pathology, and the overall clinical spectrum of MFS. The identification of protein-truncating variants and those impacting cysteine content may therefore suggest closer patient monitoring, in order to address potential complications associated with DE.
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Duramadre , Fibrilina-1 , Síndrome de Marfan , Humanos , Síndrome de Marfan/genética , Síndrome de Marfan/diagnóstico por imagen , Femenino , Masculino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Duramadre/diagnóstico por imagen , Duramadre/patología , Dilatación Patológica/genética , Dilatación Patológica/diagnóstico por imagen , Fibrilina-1/genética , Adulto Joven , AdipoquinasRESUMEN
Background: Coronary artery ectasia (CAE), known for localized or diffuse excessive dilatation of the coronary artery, has an unknown etiology, but it has been reported that the underlying cause may be atherosclerosis and genetic changes that may affect the arterial lumen. MicroRNAs have been shown to have an effect in aneurysm diseases and are known to contribute to vascular development and atherosclerosis. The purpose of this study was to investigate whether they are also associated with CAE. Methods: This cross-sectional study consisted of 25 patients with CAE and 25 subjects with normal coronary arteries. Blood was collected and miRNA expression was detected using the Rotor-GeneQ real-time polymerase chain reaction cycler (Qiagen) to investigate expression levels of miR-24-1-5p, miR-34a-5p, miR-126-5p, miR-143-5p, and miR-145-5p. Results: Demographic variables of CAE (mean age 59.5 ± 1.7; 12 women) and controls (mean age 57.2 ± 2.1; 16 women) were similar. miR-126-5p (p = 0.014) and miR-145-5p (p = 0.003) levels were found to be <2-fold upregulated in CAE compared to controls; miR-143-5p also showed upregulation, but it was not significant (p = 0.078). Conversely, miR-24-1-5p (p = 0.032) levels were downregulated in CAE compared to controls. miR-34a-5p was also downregulated, but this was not considered significant (p = 0.185). Conclusions: According to our study findings, miR-126-5p, miR-145-5p, and miR-24-1-5p may be associated with CAE. These microRNAs could be of diagnostic and therapeutic significance for further studies of CAE involving abnormal angiogenesis and vascular disorders and potentially serve as useful biomarkers.
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Aneurisma , Aterosclerosis , MicroARNs , Humanos , Femenino , Persona de Mediana Edad , Dilatación Patológica/genética , MicroARNs/genética , Vasos Coronarios , Estudios Transversales , Aterosclerosis/genéticaRESUMEN
AIMS: Visceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti-inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro-inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1-SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1-SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD). METHODS: Rats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1-SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT-PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology. RESULTS: In neonatal-CRD-induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL-6 levels elevated in PVN. However, infusion of Epac agonist 8-pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV-SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL-6 neutralizing antibody also alleviated the visceral hypersensitivity. In naïve rats, Epac antagonist ESI-09 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL-6 into PVN simulated the visceral hypersensitivity. CONCLUSIONS: Inactivation of Epac1-SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.
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Factores de Intercambio de Guanina Nucleótido , Hiperalgesia , Enfermedades Intestinales , Proteína 3 Supresora de la Señalización de Citocinas , Dolor Visceral , Animales , Enfermedades del Colon/genética , Enfermedades del Colon/metabolismo , Enfermedades del Colon/patología , Hormona Liberadora de Corticotropina/metabolismo , Dilatación Patológica/complicaciones , Dilatación Patológica/genética , Dilatación Patológica/metabolismo , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Hiperalgesia/etiología , Hiperalgesia/genética , Hiperalgesia/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Recién Nacido , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/metabolismo , Interleucina-6/metabolismo , Enfermedades Intestinales/complicaciones , Enfermedades Intestinales/genética , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/metabolismo , Neuronas/metabolismo , Dolor , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Sprague-Dawley , Enfermedades del Recto/genética , Enfermedades del Recto/metabolismo , Enfermedades del Recto/patología , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Dolor Visceral/etiología , Dolor Visceral/genética , Dolor Visceral/metabolismoRESUMEN
BACKGROUND: Due to permanent aortic dilation, thoracic aortic aneurysm (TAA) is a life-threatening disease. Once ruptured, TAA has a high lethality and disability rate. Although studies have focused on transcriptomic alterations in TAA, more detailed analysis is still lacking, especially the different aortic intima-media and adventitia roles. This study aimed to identify the different co-expression patterns between the aortic intima-media and the adventitia underlying the aortic dilation. METHODS: We analyzed the gene expression profiles obtained from Gene Expression Omnibus (GEO, GSE26155) database. With a false discovery rate (FDR) < 0.05 and |log2FC| ≥ 1, 56 and 33 differential genes in the intima-media and adventitia, respectively, between the non-dilated and dilated status. Gene ontology (GO) and gene set enrichment analysis revealed that degranulation and activation of neutrophils play an essential role in the intima-media of dilated aortas. Through weighted gene co-expression network analysis (WGCNA), we identified essential co-expressed modules and hub genes to explore the biological functions of the dysregulated genes. RESULTS: Functional pathway analysis suggested that lipid metabolism, C-C motif chemokine pathways were significantly enriched in the adventitia, whereas ribosome proteins and related mRNA translation pathways were closely related to intima and media. Furthermore, the ssGSEA analysis indicated that macrophages, helper T cells, and neutrophils were higher in the intima-media of the dilated thoracic aorta. Finally, we validated the critical findings of the study with the murine model of TAA. CONCLUSION: This study identified and verified hub genes and pathways in aortic intima-media and adventitia prominently associated with aortic dilation, providing practical understanding in the perspective of searching for new molecular targets.
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Adventicia/metabolismo , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Transcriptoma , Túnica Íntima/metabolismo , Animales , Quimiocinas/metabolismo , Dilatación Patológica/genética , Dilatación Patológica/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Inflamación , Metabolismo de los Lípidos , ARN Mensajero/metabolismo , Proteínas Ribosómicas/metabolismoAsunto(s)
Anomalías Congénitas/diagnóstico por imagen , Pelvis Renal/diagnóstico por imagen , Pelvis Renal/patología , Diagnóstico Diferencial , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/genética , Femenino , Pruebas Genéticas , Humanos , Hidronefrosis/diagnóstico por imagen , Hidronefrosis/etiología , Embarazo , Pronóstico , Ultrasonografía PrenatalRESUMEN
No disponible
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Humanos , Lactante , Factor Nuclear 1-beta del Hepatocito , Dilatación Patológica/diagnóstico , Dilatación Patológica/genética , QuistesAsunto(s)
Aorta/patología , Enfermedad de la Válvula Aórtica/diagnóstico por imagen , Síndrome de Loeys-Dietz/diagnóstico por imagen , Ultrasonografía Prenatal , Aorta/diagnóstico por imagen , Aorta/embriología , Enfermedad de la Válvula Aórtica/congénito , Enfermedad de la Válvula Aórtica/embriología , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/embriología , Dilatación Patológica/genética , Femenino , Humanos , Nacimiento Vivo , Síndrome de Loeys-Dietz/embriología , Síndrome de Loeys-Dietz/genética , Ilustración Médica , Embarazo , Adulto JovenRESUMEN
Background Homoarginine ( hA rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hA rg can inhibit tissue-nonspecific alkaline phosphatase ( TNAP ), an enzyme that promotes vascular calcification. We hypothesized that hA rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low-density lipoprotein receptor mutation (wicked high cholesterol [ WHC ] allele). WHC and WHC -endothelial TNAP mice received placebo or hA rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC -endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P<0.0001), increased coronary calcium and lipids ( P<0.01), increased left ventricular end-diastolic diameter ( P<0.0001), reduced ejection fraction ( P<0.05), and increased myocardial fibrosis ( P<0.0001) compared with WHC mice. Contrary to our hypothesis, hA rg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC -endothelial TNAP mice; however, compared with the placebo, hA rg prevented left ventricular dilatation ( P<0.01), preserved ejection fraction ( P<0.05), and reduced myocardial fibrosis ( P<0.001). Conclusions The beneficial effect of hA rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.
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Fosfatasa Alcalina/efectos de los fármacos , Enfermedad de la Arteria Coronaria/fisiopatología , Endotelio/efectos de los fármacos , Corazón/efectos de los fármacos , Homoarginina/farmacología , Calcificación Vascular/patología , Función Ventricular Izquierda/efectos de los fármacos , Fosfatasa Alcalina/genética , Animales , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Dieta Aterogénica , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/genética , Dilatación Patológica/fisiopatología , Modelos Animales de Enfermedad , Ecocardiografía , Endotelio/metabolismo , Fibrosis , Hipercolesterolemia/genética , Masculino , Ratones , Ratones Transgénicos , Mutación , Miocardio/patología , Receptores de LDL/genética , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/genética , Tasa de Supervivencia , Sístole , Calcificación Vascular/genética , Función Ventricular Izquierda/genéticaRESUMEN
Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles in inflammation and endothelial cell function including cytokines and growth factors, cell surface receptors and the Activator Protein 1 (AP-1) transcription factor family (FOS, FOSB and JUN) which was chosen for further study. AP-1 was differentially expressed within paired BAV aneurysmal samples (nâ¯=â¯8) but not Marfan patients (nâ¯=â¯5). FOS protein was significantly enriched in BAV aortas compared to normal aortas but unexpectedly, ERK1/2 activity, an upstream regulator of FOS was reduced. ERK1/2 activity was restored when BAV smooth muscle cells were cultured in vitro. An mRNA-miRNA network within paired patient samples identified AP-1 as a central hub of miRNA regulation. FOS knockdown in BAV SMCs increased expression of miR-27a, a stretch responsive miRNA. AP-1 and miR-27a were also dysregulated in a mouse model of aortic constriction. In summary, this study identified a central role for AP-1 signaling in BAV aortic dilatation by using paired mRNA-miRNA patient sample. Upstream analysis of AP-1 regulation showed that the ERK1/2 signaling pathway is dysregulated and thus represents a novel chain of mediators of aortic dilatation in BAV which should be considered in future studies.
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Aneurisma de la Aorta/patología , Enfermedades de la Aorta/patología , Válvula Aórtica/anomalías , Biomarcadores/metabolismo , Dilatación Patológica/patología , Enfermedades de las Válvulas Cardíacas/patología , Animales , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Válvula Aórtica/fisiopatología , Enfermedad de la Válvula Aórtica Bicúspide , Dilatación Patológica/genética , Dilatación Patológica/metabolismo , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/metabolismo , Enfermedades de las Válvulas Cardíacas/fisiopatología , Humanos , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Transducción de SeñalRESUMEN
Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1C642* homozygotes. Interestingly, aged female Pkhd1C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.
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Quistes/diagnóstico por imagen , Enfermedades Renales/diagnóstico por imagen , Túbulos Renales Proximales/diagnóstico por imagen , Hepatopatías/diagnóstico por imagen , Riñón Esponjoso Medular/diagnóstico por imagen , Receptores de Superficie Celular/metabolismo , Animales , Quistes/genética , Quistes/metabolismo , Diagnóstico Diferencial , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/genética , Dilatación Patológica/metabolismo , Modelos Animales de Enfermedad , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Túbulos Renales Proximales/metabolismo , Hepatopatías/genética , Hepatopatías/metabolismo , Imagen por Resonancia Magnética , Riñón Esponjoso Medular/genética , Riñón Esponjoso Medular/metabolismo , Ratones , Ratones Noqueados , Receptores de Superficie Celular/genéticaRESUMEN
BACKGROUND: Breast cancer (BRCA) mutations account for the highest proportion of hereditary causes of pancreatic ductal adenocarcinoma (PDAC). Screening is currently recommended only for patients with one first-degree relative or two family members with PDAC. We hypothesized that screening all BRCA1/2 patients would identify a higher rate of pancreatic abnormalities. METHODS: All BRCA1/2 patients at a single academic center were retrospectively reviewed (2005-2015). Pancreatic abnormalities were defined on cross-sectional imaging as pancreatic neoplasm (cystic/solid) or main-duct dilation. RESULTS: Two hundred and four patients were identified with BRCA mutations. Forty-seven (40%) had abdominal imaging (20 computerized tomography and 27 magnetic resonance imaging). Twenty-one percent had pancreatic abnormalities (PDAC [n = 2] and intraductal papillary mucinous neoplasm [IPMN; n = 8]). The prevalence of pancreatic abnormalities and IPMN was higher in BRCA2 patients than in the general population (21% vs 8% and 17% vs 1%; P = 0.0007 and P < 0.0001, respectively), with no influence of family history. Similarly, BRCA1 patients had an increased prevalence of IPMN (8.3% vs 1%; P < 0.0001). CONCLUSIONS: In this series, 4% and 17% of BRCA2 patients developed PDAC and IPMN, respectively. Eight percent of BRCA1 patients developed IPMN. Under current recommended screening, 60% of BRCA1/2 patients had incompletely pancreatic assessment. With no influence of family history, this study suggests all BRCA1/2 patients should undergo a high-risk screening protocol that will identify a higher rate of precancerous pancreatic neoplasms amenable to curative resection.
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Adenocarcinoma/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Dilatación Patológica/genética , Mutación , Conductos Pancreáticos/diagnóstico por imagen , Neoplasias Pancreáticas/genética , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma Mucinoso/diagnóstico por imagen , Adenocarcinoma Mucinoso/genética , Carcinoma Papilar/diagnóstico por imagen , Carcinoma Papilar/genética , Dilatación Patológica/diagnóstico por imagen , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico por imagen , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
The uppermost aspect of the hair follicle, known as the infundibulum or hair canal, provides a passageway for hair shaft egress and sebum secretion. Recent studies have indicated that the infundibulum and sebaceous ducts are lined by molecularly distinct differentiated cells expressing markers including Keratin 79 and Gata6. Here, we ablated Gata6 from the skin and observed dilation of both the hair canal and sebaceous ducts, independent of gender and hair cycle stage. Constitutive loss of Gata6 yielded only a mild delay in depilation-induced entry into anagen, while unperturbed mutant mice possessed overtly normal skin and hair. Furthermore, we noted that Keratin 79 and Gata6 expression and localization did not depend upon each other. Our findings implicate Gata6 in maintaining the upper hair follicle and suggest that regulation of this transcription factor may be compromised in pathologies such as acne or infundibular cystic diseases that are characterized by abnormal expansion of this follicular domain.
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Factor de Transcripción GATA6/genética , Folículo Piloso/patología , Glándulas Sebáceas/patología , Animales , Núcleo Celular/metabolismo , Dilatación Patológica/genética , Femenino , Factor de Transcripción GATA6/metabolismo , Folículo Piloso/crecimiento & desarrollo , Folículo Piloso/metabolismo , Queratinas/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Regeneración/genética , Glándulas Sebáceas/metabolismoRESUMEN
BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. CASE PRESENTATION: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. CONCLUSIONS: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.
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Albinismo Oculocutáneo/genética , Dilatación Patológica/genética , Síndrome de Loeys-Dietz/genética , Herencia Materna , Mosaicismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Adulto , Albinismo Oculocutáneo/diagnóstico por imagen , Albinismo Oculocutáneo/patología , Aorta/diagnóstico por imagen , Aorta/metabolismo , Aorta/patología , Niño , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/patología , Femenino , Expresión Génica , Mutación de Línea Germinal , Humanos , Síndrome de Loeys-Dietz/diagnóstico por imagen , Síndrome de Loeys-Dietz/patología , Angiografía por Resonancia Magnética , Masculino , Mutación Missense , Miocardio/metabolismo , Miocardio/patología , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Neoplasias Colorrectales/tratamiento farmacológico , Hígado/efectos de los fármacos , Hígado/patología , Oxaliplatino/efectos adversos , Transcriptoma , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Capilares/efectos de los fármacos , Capilares/metabolismo , Capilares/patología , Neoplasias Colorrectales/patología , Dilatación Patológica/inducido químicamente , Dilatación Patológica/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Hígado/irrigación sanguínea , Hígado/metabolismo , Neoplasias Hepáticas/secundario , Macaca fascicularis , Masculino , Persona de Mediana Edad , Neovascularización Patológica/inducido químicamente , Neovascularización Patológica/genética , Oxaliplatino/administración & dosificación , Transcriptoma/efectos de los fármacosRESUMEN
OBJECTIVE: The objective of this study was to assess whether functional genetic polymorphisms of matrix metalloproteinases (MMPs) 1, 3, 9, and 12 are associated with arterial enlargements or aneurysms of the thoracic aorta or popliteal arteries in patients with abdominal aortic aneurysm (AAA). METHODS: The associations between MMP1 (-1607 G in/del, rs1799750), MMP3 (-1171 A in/del rs35068180), MMP9 (13-26 CA repeats around -90, rs2234681, rs917576, rs917577), and MMP12 (G/T missense variation, rs652438) polymorphisms and enlargements or aneurysms of the thoracic aorta and popliteal arteries were tested in 169 consecutive AAA patients. RESULTS: Thoracic aorta enlargement or aneurysm (TE/A; maximum diameter, >35 mm) was detected in 34 patients (20.1% prevalence). MMP9 rs2234681 microsatellite was the only genetic determinant of TE/A in AAA patients (P = .003), followed by hypercholesterolemia and antiplatelet use. Carriers of both alleles with ≥22 CA repeats had a 5.9 (95% confidence interval, 1.9-18.6; P < .0001) increased odds of TE/A, and a score considering all three variables showed 98% negative predictive value and 30% positive predictive value for thoracic aortic aneurysm detection. Eighty-two popliteal artery enlargements or aneurysms (diameter >10 mm) occurred in 55 patients (33.1% prevalence). Carriers of MMP12 rs652438 C allele showed an 18% (P = .006) increased diameter in popliteal arteries and a 2.8 (95% confidence interval, 1.3-6; P = .008) increased odds of popliteal artery enlargement or aneurysm compared with TT genotype. CONCLUSIONS: Among patients with AAA, carriers of homozygous ≥22 CA repeats in MMP9 rs12234681 and of C allele in MMP12 rs652438 have a substantial risk of carrying thoracic and popliteal enlargements, respectively.
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Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Torácica/genética , ADN/genética , Predisposición Genética a la Enfermedad , Metaloproteinasas de la Matriz/genética , Polimorfismo Genético , Arteria Poplítea , Anciano , Anciano de 80 o más Años , Alelos , Aneurisma de la Aorta Abdominal/diagnóstico , Aneurisma de la Aorta Abdominal/enzimología , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/enzimología , Angiografía por Tomografía Computarizada , Dilatación Patológica/diagnóstico , Dilatación Patológica/enzimología , Dilatación Patológica/genética , Femenino , Variación Genética , Genotipo , Humanos , Masculino , Metaloproteinasas de la Matriz/metabolismo , Factores de RiesgoAsunto(s)
Córnea/anomalías , Enfermedades de la Córnea/genética , Enfermedades Hereditarias del Ojo/genética , Homocigoto , Proteoglicanos/genética , Niño , Preescolar , Consanguinidad , Enfermedades de la Córnea/diagnóstico , Topografía de la Córnea , Dilatación Patológica/genética , Enfermedades Hereditarias del Ojo/diagnóstico , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Agudeza Visual/fisiologíaRESUMEN
BACKGROUND: Congenital biliary dilatation (CBD) is a congenital malformation involving both dilatation of the extrahepatic bile duct and pancreaticobiliary maljunction. Persistent reflux of pancreatic juice injures the biliary tract mucosa, resulting in chronic inflammation and higher rates of carcinogenesis in the biliary tract, including the gallbladder. Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal instability due to telomere dysfunction plays an important role in the carcinogenesis of many organs. This study was performed to determine whether excessive shortening of telomeres occurs in the gallbladder mucosa of patients with CBD. METHODS: Resected gallbladders were obtained from 17 patients with CBD, ten patients with cholecystolithiasis without pancreatic juice reflux, and 17 patients with normal gallbladders (controls) (median age of each group of patients: 37, 50, and 53 years, respectively). The telomere lengths of the gallbladder epithelium were measured by quantitative fluorescence in situ hybridization using tissue sections, and the normalized telomere-to-centromere ratio (NTCR) was calculated. RESULTS: The NTCRs in the CBD, cholecystolithiasis, and control groups were 1.24 [interquartile range (IQR) 1.125-1.52], 1.96 (IQR 1.56-2.295), and 1.77 (IQR 1.48-2.53), respectively. The NTCR in the CBD group was significantly smaller than that in the cholecystolithiasis and control groups (p = 0.003 and 0.004, respectively), even in young patients. CONCLUSIONS: Our findings indicate that telomere shortening in the gallbladder mucosa plays an important role in the process of carcinogenesis in patients with CBD. These results support the recommendation of established guidelines for prophylactic surgery in patients with CBD because CBD is a premalignant condition with excessive telomere shortening.
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Conductos Biliares Extrahepáticos/anomalías , Vesícula Biliar/patología , Conductos Pancreáticos/anomalías , Acortamiento del Telómero , Adulto , Conductos Biliares Extrahepáticos/diagnóstico por imagen , Neoplasias del Sistema Biliar/diagnóstico por imagen , Neoplasias del Sistema Biliar/genética , Colangiopancreatografia Retrógrada Endoscópica , Pancreatocolangiografía por Resonancia Magnética , Conducto Colédoco/anomalías , Conducto Colédoco/diagnóstico por imagen , Dilatación Patológica/congénito , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/genética , Epitelio/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Conductos Pancreáticos/diagnóstico por imagen , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/genética , Tomografía Computarizada por Rayos XRESUMEN
Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the in vivo expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the Srf gene was conditionally inactivated with NPHS2-Cre exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the Srf-null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.